OXFORD MEDICAL PUBLICATIONS

Paediatric
Rheumatology
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Oxford Specialist
Handbooks in
Paediatrics
Paediatric
Rheumatology
Edited by

Helen Foster
MBBS(Hons), MD, Cert Med Ed, DCH, FRCP, FRCPCH
Professor Paediatric Rheumatology
Newcastle University
Honorary Consultant in Paediatric Rheumatology,
Great North Children's Hospital, Newcastle Hospitals
NHS Foundation Trust,
Newcastle upon Tyne, UK

Paul A. Brogan
BSC(Hon), MBChB(Hon), MSC, PhD, MRCPCH, FRCPCH
Senior Lecturer in Paediatric Vasculitis and Honorary
Consultant in Paediatric Rheumatology
UCL Institute of Child Health, and Great Ormond
St Hospital for Children NHS Trust
London, UK

1
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 v

Preface

The purpose of this book

This handbook aims to help you understand and manage virtually any
paediatric rheumatology condition that may present to you in clinical
practice; it is pocket-sized with a system of bullet points to allow easy
reference to up-to-date evidence-based (where possible) and consensus-
derived opinion. This first edition of the handbook is written amidst a
revolution in clinical genetics and novel therapeutics in the field of mul-
tisystemic inflammatory disease, and captures state-of-the-art clinical
care and best current practice in this context. Essential further reading,
including website links, direct you to sources where more information
can be obtained. The handbook is divided into sections to cover essential
elements of the clinical assessment, the approach to investigations and
management, along with important key facts of knowledge and practical
advice. It includes advice on the care of acute emergencies, chronic disor-
ders, and the spectrum of common conditions seen by all paediatricians
to those seen rarely and usually cared for in specialized paediatric rheu-
matology centres, in collaboration with local units. Many of the chapters
will be applicable to the day-to-day care of patients on a general paediatric
ward or in the outpatient clinic. Acute emergencies that can occur in multi-
system disease and issues arising from the use of potent immunosuppressive
treatments are dealt with in detail.
This handbook will provide guidance for trainees, the general paediatrician,
and the multidisciplinary team specialists (doctors, nurses, physiotherapists,
occupational therapists, podiatrists, and psychologists) who care for chil-
dren with rheumatological conditions. We bring together for the first time
practical guidance for the use of outcome measures, clinical scores of
disease activity, and drug prescribing relevant to paediatric rheumatology.
‘State-of-the-art treatment’ of paediatric rheumatology conditions includes
an ever increasing number of biologic and novel therapies—we provide
practical guidance for the use of such treatments with guidelines, algo-
rithms, and emphasis of the role of the multidisciplinary team to deliver
optimal clinical care.
We are very proud of our extensive authorship, including doctors and
allied health professionals, many of whom are international leaders in
their field. We have successfully engaged with the breadth of the British
Society for Paediatric and Adolescent Rheumatology (BSPAR) community,
with representation from the majority of centres across the UK and have
contributions from all current UK trainees in paediatric rheumatology
working in partnership with consultant supervisors. We also have input
from parents of children with rheumatic disease to emphasize their role
in working together with healthcare professionals—much of what we
do in clinical practice lacks a robust evidence base and we emphasize the
importance of input from consumers on how to involve and fully engage
children and their families with clinical decision-making and research
opportunities to facilitate growth of evidence to inform best practice.
vi PREFACE

This book is a measure of the growing collaboration of paediatric rheuma-

tology both within the UK and with our colleagues further afield to develop
and share knowledge, promote highest quality clinical care, education,
and training to facilitate access to optimal care for all children with rheu-
matic disease.
All profits from the sales of the handbook will be donated to BSPAR.
Helen Foster
Paul A. Brogan
 vii

Foreword 1

UK’s Paediatric Rheumatology Clinical Studies Group

The importance of supporting the very best clinical research to improve
the care of children with rheumatic and musculoskeletal health has been
exemplified by the establishment by the National Institute of Health
Research (NIHR) Medicines for Children Research Network (MCRN)1
and Arthritis Research UK of the MCRN/Arthritis Research UK Paediatric
Rheumatology Clinical Studies Group (CSG).2 This partnership of exper-
tise has supported a major opportunity and development in recent years
of taking forward a comprehensive and long lasting, national clinical
research programme for Paediatric Rheumatology.
Following a detailed, widespread consultation and consensus process,
involving all relevant stakeholders including consumers (see Foreword 2
for comment on consumer input), the CSG’s primary task was to define
the key strategic priorities in paediatric rheumatology with respect to:
‘What are the key clinical research priorities that will change clinical practice
in paediatric rheumatology?’
To achieve this, the CSG:
• Looks to address the gaps in the evidence base in the management
of children and young people with rheumatic or musculoskeletal
conditions.
• Works with all interested parties towards developing a comprehensive
portfolio of key research clinical trials and related studies covering the
entire spectrum of major disease areas in paediatric rheumatology in
the UK.
• Has a strong multidisciplinary membership including: 4 consumer
representatives, clinicians, clinical academics, basic scientists, allied
health professionals, and a pharmacist expert in paediatric formulations.
The CSG’s ‘goal’ is that:
• ‘All children and young people in the UK with a rheumatological
condition may be given the opportunity to be enrolled in a clinical trial
or well-conducted clinical study from point of diagnosis onwards, and
in so doing improve the care and outcome of them and patients with
similar conditions in the future;
• That all children have the option of contributing towards a related, fully
informed and consented Biobank (e.g. DNA and serum) for subsequent
investigation into the cause of their condition.’
To facilitate this process, the CSG has developed (to date) 9 ‘topic specific
groups’ (TSGs) to foster collaboration and support multidisciplinary efforts
to address the key priority areas within paediatric rheumatology, as well as
organizing ad hoc meetings to focus on specific projects.
• Each TSG has members of the CSG as ‘link-persons’ to support
communication and integration of the activities of the TSGs within the
wider CSG research agenda and support structures.
viii FOREWORD 1

• The 9 TSGs are: Auto-inflammatory diseases; Bone Health; Juvenile

Dermatomyositis; Juvenile Idiopathic Arthritis and associated Uveitis;
Juvenile-onset Systemic Lupus Erythematosus; Childhood Scleroderma;
Non-inflammatory, musculoskeletal disorders; Childhood Vasculitides.
In addition, the CSG supports investigators in the following way:
• Welcoming and publicizing expressions of interest in working towards
these priority studies, calling for submission of protocols and proposals
to address these priorities.
• Working with stakeholders and funding bodies and to identify
barriers to research participation and identifying strategies to facilitate
engagement and collaboration in clinical research.
• Supporting protocols where relevant can also include pilot and
feasibility studies to provide proof of concept for definitive studies in
terms of recruitment, data acquisition.
• Encouraging consideration of research ‘add-ons’ to bring value-added
benefit to the children participating in these studies, e.g. pharmacogenetic
and qualitative studies.
• Being advisory to investigators, the MCRN on studies submitted for
NIHR Portfolio adoption, including commercial trials, and to the
Arthritis Research UK and assist with their development.
• Working in close collaboration with other MCRN and Arthritis
Research UK CSGs, as well as other topic specific research networks in
all areas of mutual interest.
References
1 M http://www.mcrn.org.uk.
2 M http://www.arthritisresearchuk.org/research/clinical_study_groups/csg_-_mcrn_paediatric_
rheumato.aspx.
 ix

Foreword 2

Parent and young person involvement in research—a

‘consumer’s’ perspective
The social and psychological aspects of living with any chronic condition
can create a different type of expertise to that of clinicians and researchers.
Consumer involvement is concerned with creating a forum where the
experience, knowledge, and expertise of both healthcare professionals
and the public can come together in an equal partnership to benefit
healthcare research. High-quality research, optimal accrual to research
projects, and improved patient outcomes are dependent on listening to
the voices of children and young people, their families and carers, and
taking account of their experiences, priorities, and perspectives. Engaged
effectively, consumers can contribute to all aspects of clinical research and
clinical service development and including:
• Identifying and prioritizing research ideas that are relevant to clinical
practice.
• Commissioning research to highlight topic areas of concern to patients.
• Designing research studies and associated documentation to enhance
the feasibility of the project by identifying potential barriers to study
participation.
• The management of studies (e.g. as members of steering group).
• Analysis or interpretation of research results to address key issues
relevant to patients.
• Dissemination of research results throughout the lay community.
Key principles for the productive involvement of patients, parents, young
people and families, (referred to as patient and public involvement or PPI),
in partnership for research and clinical service development are discussed
in detail. In summary these are:
• All members of the clinical research group should understand the
benefits of PPI perspective.
• Participation of new PPI members will be facilitated if they are formally
introduced and effort is made to find out about their background/
experiences.
• In advance of meetings, it is important to consider the PPI angle on all
agenda items and identify those which may be of particular interest to
PPI members so they may prepare for discussions.
• Include introductions at the start of a meeting and clarify the meeting
purpose, use plain English, and minimize jargon.
• During the meetings, encourage questions and invite the PPI members
to comment on all issues.
• Consumers’ contributions are often based on their own experiences of
an illness, and wherever possible they should be representative of the
broader community.
• After a meeting it is important to minute contributions made by PPI
members with a follow-up process for feedback.
x FOREWORD 2

Further reading
TwoCan Associates for the UKCRC and NCRI. Patient and public involvement in research
groups – Guidance for Chairs. TwoCan Associates, 2010. M http://www.twocanassociates.
co.uk/pubs.php.
 xi

Foreword 3

I am delighted as the current Convenor of The British Society for

Paediatric and Adolescent Rheumatology (BSPAR) to provide a Foreword
for this Oxford Handbook of Paediatric Rheumatology.
BSPAR has evolved over several decades from the multidisciplinary British
Paediatric Rheumatology Group to achieve its new charitable status, and
is determined and committed to encourage and support clinical care,
research, education, and training in paediatric rheumatology in the UK.
It was in order to help deliver these goals that in 2010 BSPAR achieved
charitable status and I am truly proud of the commitment made by all the
contributing authors of this book to donate any fees due and profits made
to BSPAR.
This handbook has been produced by a dedicated editorial team and with
contributions from a large and truly multidisciplinary authorship. This
highlights the fundamental principle that underpins the ethos of BSPAR—
namely the sense of teamwork that helps individual teams deliver day-to-day
healthcare to children and young people with rheumatologic disorders
and also drives us towards our goal of high-quality research continually
improving the delivery of clinical care.
Throughout our activities it is our patients and their families who directly
benefit from the improved training and dissemination of information that
BSPAR provides to the medical and allied health carers with whom they
come into direct contact. Through education and training, all healthcare
professionals improve the service which they provide to their patients,
and I am sure that this handbook will prove invaluable to many working
in this field.
Dr Gavin Cleary
Convenor
xii

Foreword 4

Paediatric rheumatology training in the UK

In the UK, training in paediatric rheumatology follows completion of
general paediatric training and is overseen by the Royal College of
Paediatrics and Child Health (RCPCH) with a Competency Based
Framework and a process of assessment. Training in paediatric rheuma-
tology is through the national training programme for the training of spe-
cialists in paediatrics (called the ‘Grid’) with competitive entry organized
by RCPCH. This programme of training is a minimum of 2 years, recom-
mended to be in more than one accredited centre, and trainees complete
a programme of formative and summative assessments which are com-
petency-based. Ultimately trainees acquire a Certificate of Completion
of Training to be eligible to be appointed to Consultant posts working
in the National Health Service. Training for general paediatricians with
an interest in rheumatology is also encouraged and such trainees do not
need to be appointed to the Grid but are recommended to have 1 year’s
training in a recognized paediatric rheumatology centre. The Competency
Frameworks for Speciality Paediatrics form the basis of the curriculum
for training and there is a Framework for the Specialist in Paediatric
Rheumatology and also for the general paediatrician with an interest in
rheumatology. Further details are given on the format of training and the
Competency Frameworks are given on the British Society of Paediatric
and Adolescent Rheumatology website (M http://www.bspar.org.uk/
pages/trainees_area_members.asp) and the RCPCH website (M http://
www.rcpch.ac.uk/Training/Competency-Framework).
Increasingly throughout the UK and elsewhere, there are networks of
clinical services working together to deliver paediatric rheumatology care,
often across large geographical areas and encompassing various models of
care with specialist expertise linking with other, and often smaller units.
The role of adult rheumatologists is still very important as part of these
clinical networks, although in many areas the focus of the adult rheuma-
tology team is increasingly towards transitional care. There is a great need
to raise awareness of paediatric rheumatology and the importance of early
and prompt access to appropriate specialist care. There is a shortage of
specialist paediatric rheumatology multidisciplinary teams in the UK and
further afield. The role of shared care between specialist services with
local general paediatric and adult rheumatology teams is increasingly
important so that high-quality clinical care can be delivered and equi-
tably. Such clinical networks require personnel with training and support,
highlighting the need for training, training positions, and a mechanism for
support and teaching resources. This content of this handbook is largely
based on the content of the Competency Frameworks for Paediatric
Rheumatology and aims to address learning needs of paediatric rheuma-
tology trainees, general paediatricians with an interest in rheumatology,
as well as other healthcare professionals working within the specialty and
clinical networks. To date there are no competency frameworks or curricula
 FOREWORD 4 xiii
for allied health professionals working in paediatric rheumatology but
through involvement of nurses and therapists as contributors to the hand-
book, we aim to have addressed some of the learning needs.
Helen Foster
Chair of RCPCH Specialist Advisory Committee for Rheumatology
This page intentionally left blank
 xv

Contents

Detailed contents xvii

Symbols and abbreviations xxiii
Contributors xxix

1 Clinical skills and assessment 1

2 Common and important clinical problems 53
3 Juvenile idiopathic arthritis 129
4 Systemic diseases 167
5 Bone diseases, skeletal dysplasias, disorders
of collagen 329
6 Infection and immunization 355
7 The multidisciplinary approach to management 377
8 Specialized therapeutic approaches 389
9 British Society of Paediatric and Adolescent
Rheumatology clinical guidelines and protocols 409
10 Rashes in paediatric rheumatology 447

Index 457
This page intentionally left blank
 xvii

Detailed contents

Symbols and abbreviations xxiii

Contributors xxix

1 Clinical skills and assessment 1

Epidemiology of paediatric musculoskeletal conditions 2
History taking, physical examination, and approaches to
investigation 4
Normal variants of lower limb development 9
The gait cycle and abnormal gait patterns 11
Normal gait and musculoskeletal development 15
pGALS: paediatric gait, arms, legs, spine
musculoskeletal screening examination 18
pREMS: paediatric regional examination of the
musculoskeletal system 23
Musculoskeletal ultrasound in juvenile idiopathic arthritis 28
Autoantibodies 32
Thermography in rheumatic disease 35
Nailfold capillaroscopy in rheumatic disease 37
Outcome measures in paediatric rheumatology 41
The Child Health Assessment Questionnaire (CHAQ) 45

2 Common and important clinical problems 53

Musculoskeletal presentations and non-accidental injury 54
Malignancy and musculoskeletal presentations 56
Bone tumours 60
Bone and joint infections 64
Infections in the immunocompromised 70
Fractures in children and adolescents 76
The limping child 80
Pain syndromes and the assessment of pain 87
Growing pains 92
Pyrexia of unknown origin 94
Back pain in children and adolescents 100
Scoliosis 103
xviii DETAILED CONTENTS

Hip pain and hip problems in children and adolescents 106

Knee pain in children and adolescents 117
Foot and ankle problems 121
Joint hypermobility 124

3 Juvenile idiopathic arthritis 129

Genetics and JIA: HLA and non-HLA/MHC associations with
subtypes of JIA 130
Immunology and aetiology of JIA 137
Classification of JIA 139
JIA subtypes and their clinical presentations 141
Prognostic indicators in JIA 146
Uveitis screening in JIA: the approach to screening and guidelines 148
Surgery in the young adult with JIA: practical issues 152
Treatment approaches in JIA 155
Treatment pathways in JIA 159
Disease activity scores in rheumatoid arthritis and JIA 165

4 Systemic diseases 167

Vasculitis
The classification of paediatric vasculitis 168
The epidemiology of paediatric vasculitis 171
The investigation of primary systemic vasculitis 172
The standard treatment of childhood vasculitis 174
Henoch–Schönlein purpura 179
Kawasaki disease 183
The anti-neutrophil cytoplasmic antibody (ANCA)-associated
vasculitides 188
Polyarteritis nodosa (PAN) 192
Cutaneous polyarteritis nodosa (cPAN) 198
Takayasu arteritis 199
Behçet’s disease 205
Central nervous system vasculitis in children 209
Other vasculitides 214
Vasculitis mimics: non-inflammatory vasculopathies 217
Juvenile systemic lupus erythematosus
JSLE: epidemiology and aetiology 223
JSLE: clinical features and diagnostic criteria 226
 DETAILED CONTENTS xix
Assessment of the child with JSLE and monitoring
of disease activity 229
JSLE: approach to management 232
JSLE: renal involvement 236
Neonatal lupus syndrome 240
B-cell-targeted therapies for systemic lupus erythematosus 241
British Isles Lupus Assessment Group (BILAG) 2004 Index 248
SLEDAI 2000 Disease Activity Index 256
SLICC/ACR Damage Index (paediatric) 258
Connective tissue diseases
Scleroderma 260
Juvenile dermatomyositis 266
Overlap syndromes 275
Antiphospholipid syndrome (APS) 279
Paediatric uveitis 283
Autoinflammatory diseases and immunodeficiency
Periodic fever syndromes/autoinflammatory disease 288
Chronic recurrent multifocal osteomyelitis 297
Sarcoidosis 300
Macrophage activation syndrome 305
Primary immunodeficiency and rheumatological disease 309
Other systemic diseases
Mucopolysaccharidoses (MPS) and mucolipidoses (ML) 312
Chromosomal abnormalities and associated
musculoskeletal morbidity 318
Arthritis and other musculoskeletal features associated
with cystic fibrosis 323
Inflammatory bowel disease and musculoskeletal features 326

5 Bone diseases, skeletal dysplasias, disorders of collagen 329

Metabolic bone diseases 330
Skeletal dysplasias 333
The osteochondroses 343
Heritable disorders of connective tissue 346

6 Infection and immunization 355

Tuberculosis and mycobacterial disease 356
Rheumatic fever 363
xx DETAILED CONTENTS

Lyme disease 368

Varicella zoster infections 371
Immunization schedules and the immunocompromised 374

7 The multidisciplinary approach to management 377

The multidisciplinary team 378
The role of the clinical nurse specialist 380
The role of the physiotherapist 382
The role of the occupational therapist 384
The role of the podiatrist 385
Transitional care 387

8 Specialized therapeutic approaches 389

Corticosteroid intra-articular injections 390
Biologic therapies for paediatric rheumatological diseases 393
Approvals for use of biologic therapies 399
Medicines for children and paediatric rheumatology 401
Haematopoietic stem cell transplantation 405

9 British Society of Paediatric and Adolescent

Rheumatology clinical guidelines and protocols 409
BSPAR standards of care for children and young people with JIA 410
BSPAR drug information leaflets for parents and families 412
BSPAR guidelines for treatments used in paediatric
rheumatology 415
Non-steroidal anti-inflammatory drugs (NSAIDs) 416
Disease-modifying anti-rheumatic drugs (DMARDs) 418
Azathioprine 423
Ciclosporin 425
Intravenous cyclophosphamide 427
Pamidronate 431
Epoprostenol/iloprost 433
Etanercept (Enbrel®) 434
Other anti-TNF-A: adalimumab (Humira®) and
infliximab (Remicade®) 436
Anti-IL-1 treatments: anakinra (Kineret®), rilonacept
(Regeneron®), and canakinumab (Ilaris®) 437
Abatacept (Orencia®) 439
 DETAILED CONTENTS xxi
®
Anti-IL-6 treatment: tocilizumab (Ro-Actemra ) 440
Anti-B-cell therapies: rituximab (Mabthera®) 441
Systemic corticosteroids (oral, intramuscular, and intravenous) 443
Intra-articular corticosteroid use in JIA 445

10 Rashes in paediatric rheumatology 447

Systemic JIA 448
Palmar psoriasis in a patient with psoriatic JIA 448
Nail pits and psoriasis in a patient with psoriatic JIA 449
Psoriatic JIA (elbows) 449
Psoriatic JIA (hands) 450
HSP with bilateral ankle swelling 450
Juvenile dermatomyositis with periorbital oedema 451
Severe juvenile dermatomyositis with anterior chest wall
vasculitis—‘shawl sign’ 451
Extensor surface vasculitis in juvenile dermatomyositis 452
Subtle Gottron’s papules in a patient with severe
juvenile dermatomyositis 452
Periungual erythema in undifferentiated connective
tissue disease 453
Systemic vasculitis with pyrexia, livido reticularis, vasculitic rash with
skin necrosis 453
Maculo-papular rash of Epstein–Barr virus associated with
haemophagocytic lymphohistiocytosis (HLH) 454
Erythema nodosum 454
Generalized peeling in Kawasaki disease 455
Purpura in Wegener’s granulomatosis 455
SLE associated with congenital C1q deficiency 456

Index 457
This page intentionally left blank
 xxiii

Symbols and abbreviations

b cross-reference
i increase/d
d decrease/d
4 male
5 female
7 approximately
± plus/minus
2D two-dimensional
3D three-dimensional
AAV ANCA-associated vasculitides
ACE angiotensin-converting enzyme
ACL anticardiolipin
ACR American College of Rheumatology
ALL acute lymphoblastic leukaemia
ALP alkaline phosphatase
ALPS autoimmune lymphoproliferative syndrome
ANA antinuclear antibody
ANCA anti-neutrophil cytoplasmic antibody
anti-CCP anti-cyclic citrullinated protein
AP anteroposterior
aPL antiphospholipid [antibody]
APS antiphospholipid syndrome
APTT activated partial thromboplastin time
ARF acute rheumatic fever
ASIC anterior superior iliac crest
ASOT anti-streptolysin O titre
AZA azathioprine
BD Behçet’s disease
BJHS benign joint hypermobility syndrome
BNFC British National Formulary for Children
BP blood pressure
BPRG British Paediatric Rheumatology Group
BSA body surface area
BSPAR British Society of Paediatric and Adolescent
Rheumatology
CAA coronary artery abnormality
xxiv SYMBOLS AND ABBREVIATIONS

cANCA cytoplasmic anti-neutrophil cytoplasmic antibody

CAPS catastrophic antiphospholid syndrome or cryopyrin
associated periodic syndrome
CAU chronic anterior uveitis
CCP cyclic citrullinated protein
CD Crohn’s disease
CF cystic fibrosis
CHAQ Child Health Assessment Questionnaire
CINCA chronic infantile neurologic cutaneous and articular
syndrome
CNS central nervous system or clinical nurse specialist
cPACNS primary angiitis of the central nervous system in children
cPAN cutaneous polyarteritis nodosa
CRMO chronic recurrent multifocal osteomyelitis
CRP C-reactive protein
CRPS complex regional pain syndrome
CSF cerebrospinal fluid
CSS Churg–Strauss syndrome
CT computed tomography
CTA computed tomography angiography
CTD connective tissue disease
CXR chest x-ray
CYC cyclophosphamide
DAS Disease Activity Score
DD Degos disease
DDH developmental dysplasia of the hip
DIRA deficiency of IL-1 receptor antagonist
DMARD disease-modifying antirheumatic drug
DXA dual-emission X-ray absorptiometry
ECG electrocardiogram
EEG electroencephalogram
EMG electromyography
ENA extractable nuclear antigen
EOS early-onset sarcoidosis
ERA enthesitis-related arthritis
ERT enzyme replacement therapy
ESR erythrocyte sedimentation rate
EULAR European League Against Rheumatism
FBC full blood count
FCAS familial cold autoinflammatory syndrome
FII factitious or induced illness
 SYMBOLS AND ABBREVIATIONS xxv
FMD fibromuscular dysplasia
FMF familial Mediterranean fever
G6PD glucose-6-phosphate dehydrogenase
GAG glycosaminoglycan
GBM glomerular basement membrane
GFR glomerular filtration rate
GI gastrointestinal
GN glomerulonephritis
GP General practitioner
GvHD graft-versus-host disease
GWAS genome-wide association study
HA healthy adults
HC healthy children
HIV human immunodeficiency virus
HLA human leucocyte association
HLH haemophagocytic lymphohistiocytosis
HSCT haematopoietic stem cell transplantation
HSN Henoch–Schönlein nephritis
HSP Henoch–Schönlein purpura
HUVS hypocomplementaemic urticarial vasculitic syndrome
IA intra-articular
IAC intra-articular corticosteroid
IBD inflammatory bowel disease
IC indeterminate colitis
Ig immunoglobulin
ILAR International League of Associations for Rheumatology
IM intramuscular
INR international normalized ratio
IV intravenous
IVIG intravenous immunoglobulin
IVMP intravenous methylprednisolone
JDM juvenile dermatomyositis
JIA juvenile idiopathic arthritis
JSLE juvenile-onset systemic lupus erythematosus
jSSc juvenile systemic sclerosis
KD Kawasaki disease
kg kilogramme/s
L litre/s
LDH lactate dehydrogenase
LFT liver function test
xxvi SYMBOLS AND ABBREVIATIONS

LMWH low-molecular-weight heparin

LN lupus nephritis
LS localized scleroderma
LTBI latent tuberculosis infection
LV livedoid vasculopathy
MAS macrophage activation syndrome
MC&S microscopy, culture and sensitivity
MCPJ metacarpophalangeal joint
MCTD mixed connective tissue disease
MDT multidisciplinary team
MED multiple epiphyseal dysplasia
mg milligramme/s
MHC major histocompatibility complex
min minute/s
MKD mevalonate kinase deficiency
ML mucolipidoses
mL millilitre/s
mm millimetre/s
MMF mycophenolate mofetil
MPO myeloperoxidase
MPS mucopolysaccharidoses
MRA magnetic resonance angiography
MRI magnetic resonance imaging
MSK musculoskeletal
MSUS musculoskeletal ultrasound
MTPJ metatarsophalangeal joint
MTX methotrexate
MWS Muckle–Wells syndrome
NAI non-accidental injury
NBO non-bacterial osteitis
NFC nailfold capillary
NICE National Institute for Health and Clinical Excellence
NOMID neonatal onset multisystem inflammatory disease
NTI narrow therapeutic index
OCD osteochondritis dissecans
OI osteogenesis imperfecta
OT occupational therapist
PA posterior–anterior
PACNS primary angiitis of the central nervous system
PAH pulmonary arterial hypertension
 SYMBOLS AND ABBREVIATIONS xxvii
PAN polyarteritis nodosa
pANCA perinuclear anti-neutrophil cytoplasmic antibody
PAPA pyogenic sterile arthritis, pyoderma gangrenosum, and
acne [syndrome]
PCR polymerase chain reaction
PET positron emission tomography
pGALS paediatric gait, arms, legs, spine musculoskeletal screening
examination
PIPJ proximal interphalangeal joint
PK pharmacokinetic
PO per os (orally)
PR3 proteinase 3
pREMS paediatric regional examination of the musculoskeletal
system
PRT paediatric rheumatology team
PTH parathyroid hormone
PUO pyrexia of unknown origin
PVL Panton–Valentine leukocidin
PXE pseudoxanthoma elasticum
QoL quality of life
RA rheumatoid arthritis
RCT randomized control trial
RD Raynaud’s disease
RF rheumatoid factor
RICE Rest, ice, compress, elevate
RP Raynaud’s phenomenon
sec second/s
SAPHO synovitis acne pustulosis hyperostosis osteitis [syndrome]
SEDC spondyloepiphyseal dysplasia congenita
SIADH syndrome of inappropriate anti-diuretic hormone
secretion
sJIA systemic juvenile idiopathic arthritis
SLE systemic lupus erythematosus
SmPC summary of product characteristics
SNP single nucleotide polymorphism
SSc systemic sclerosis
SSZ sulphasalazine
TA triamcinolone acetonide
TB tuberculosis
TGFB transforming growth factor-beta
TH triamcinolone hexacetonide
xxviii SYMBOLS AND ABBREVIATIONS

TMJ temporomandibular joint

TNF tumour necrosis factor
TPMT thiopurine methyltransferase
TRAPS TNF receptor-associated period syndrome
TRM transplant-related mortality
TST tuberculin skin test
U&E urea and electrolyte
UC ulcerative colitis
UK United Kingdom
US ultrasound
VAS visual analogue score
VZIG varicella-zoster immunoglobulin
VZV varicella zoster virus
WCC white cell count
yr year/s
 xxix

Contributors

Dr Mario Abinun clinical presentations; Treatment

Consultant Paediatric approaches in JIA
Immunologist Chapter 7: The multidisciplinary
Great North Children’s Hospital, team
Newcastle upon Tyne NHS Chapter 9: Disease-modifying anti-
Hospitals Foundation Trust, rheumatic drugs (DMARDs):
Newcastle upon Tyne, UK Hydroxychloroquine
Chapter 2: Infections in the Dr Kate Armon
immunocompromised
Chapter 4: Autoinflammatory Consultant Paediatric
diseases and immunodeficiency: Rheumatologist and Honorary
Primary immunodeficiency and Senior Lecturer at the University
rheumatological disease of East Anglia
Chapter 6: Immunization schedules Jenny Lind Children’s Hospital,
and the Immunocompromised Norfolk and Norwich University
Chapter 8: Haematopoietic stem Hospital, UK
cell transplantation Chapter 2: Joint hypermobility

Mr Alwyn Abraham Dr Eileen Baildam

Consultant, Trauma Orthopaedics Consultant Paediatric
and Paediatric Orthopaedics Rheumatologist and Honorary
Leicester Royal Infirmary, UK Senior Lecturer
Chapter 1: Normal variants of lower Alder Hey Children’s Foundation
limb development; Normal gait NHS Trust, Liverpool, UK
and musculoskeletal development; Chapter 4: Connective tissue
The gait cycle and abnormal gait diseases: Scleroderma
patterns Dr Kathy Bailey
Chapter 2: Fractures in children and Consultant Paediatric
adolescents Rheumatologist
Dr Beverley Almeida George Eliot Hospital,
Specialist Registrar, Paediatric Nuneaton, UK
Rheumatology Chapter 4: Autoinflammatory
Great Ormond Street Hospital for diseases and immunodeficiency:
Children NHS Foundation Trust, Inflammatory bowel disease and
London, UK musculoskeletal features
Chapter 1: Thermography in Ms Catrin Barker
rheumatic disease; Nailfold Acting Deputy Chief Pharmacist
capillaroscopy in rheumatic disease Pharmacy Department, Alder Hey
Dr Tania Amin Children’s NHS Foundation Trust,
Specialist Registrar, Paediatrics Liverpool, UK
Royal Hospital for Sick Children, Chapter 8: Medicines for children
Edinburgh, UK and paediatric rheumatology
Chapter 3: JIA subtypes and their
xxx CONTRIBUTORS

Mr Tom Beckingsale UCL Institute of Child Health and

Specialist Registrar, Trauma and Great Ormond St Hospital for
Orthopaedics Children NHS Foundation Trust,
Newcastle upon Tyne NHS London, UK
Hospitals Foundation Trust, Preface: The purpose of this book
Newcastle upon Tyne, UK Chapter 4: Vasculitis: The
Chapter 2: Bone tumours classification of paediatric vasculitis;
The epidemiology of paediatric
Prof Michael Beresford vasculitis; The investigation of
Professor, Child Health, and primary systemic vasculitis; The
Honorary Consultant standard treatment of childhood
Paediatric Rheumatology vasculitis; Henoch-Schönlein
Department of Women’s and purpura; Kawasaki disease;
Children’s Health, Institute of The anti-neutrophil cytoplasmic
Translational Medicine, University antibody (ANCA)-associated
of Liverpool; and Alder Hey Vasculitides; Polyarteritis nodosa
Children’s NHS Foundation Trust, (PAN); Cutaneous polyarteritis
Liverpool, UK nodosa (cPAN); Takayasu arteritis;
Foreword 1: UK’s Paediatric Behçet’s Disease; Central nervous
Rheumatology Clinical Studies Group system vasculitis in children; Other
Chapter 4: Juvenile systemic lupus vasculitides; Vasculitis mimics:
erythematosus: JSLE: non-inflammatory vasculopathies
epidemiology and aetiology; JSLE: Chapter 4: Juvenile systemic
clinical features and diagnostic lupus erythematosus: JSLE: renal
criteria; Assessment of the child involvement; B-cell-targeted
with JSLE and monitoring of therapies for systemic lupus
disease activity; JSLE: approach erythematosus
to management; Neonatal lupus Chapter 4: Connective tissue
syndrome; British Isles Lupus diseases: Antiphospholipid
Assessment Group (BILAG) 2004 syndrome (APS)
Index; SLEDAI 2000 Disease Activity Chapter 4: Autoinflammatory
Index; SLICC/ACR Damage Index diseases and immunodeficiency:
(paediatric) Sarcoidosis
Chapter 9: Intravenous
Prof Nick Bishop cyclophosphamide
Professor of Paediatrics and
Honorary Consultant Dr Richard Brough
Sheffield Children’s Hospital, UK Consultant Paediatrician
Chapter 5: Metabolic bone diseases Shrewsbury and Telford
NHS Trust, Royal Shrewsbury
Dr Emily Boulter Hospital, UK
Specialist Trainee Paediatrics Chapter 2: Foot and ankle
Great Ormond Street Hospital, problems
London, UK
Chapter 4: Vasculitis: Behçet’s Dr Jenny Campbell
Disease Specialist Registrar, Clinical
Genetics
Dr Paul A. Brogan Northern Genetics Service,
Senior Lecturer, Paediatric Institute of Genetic Medicine,
Vasculitis and Honorary International Centre for Life,
Consultant in Newcastle upon Tyne, UK
Paediatric Rheumatology Chapter 5: Skeletal dysplasias
 CONTRIBUTORS xxxi
Dr Amparo Cavalle Bristol Royal Hospital for
Specialist Registrar Children, Bristol and Royal
Department of Paediatric National Hospital for Rheumatic
Rheumatology, Birmingham Diseases, UK
Children’s Hospital, UK Chapter 2: Pain syndromes and the
Chapter 7: Transitional care assessment of pain
Chapter 9: Disease-modifying
Dr Tariq Chaudry anti-rheumatic drugs (DMARDs):
Clinical Fellow, Paediatric Sulphasalazine; Azathioprine
Rheumatology
Great Ormond Street Hospital for Dr Hannah Connell
Children NHS Foundation Trust, Consultant Clinical Psychologist
London, UK Bristol Royal Hospital for
Chapter 1: Autoantibodies Children, Bristol and Royal
National Hospital for Rheumatic
Dr Alice Chieng Diseases, Bristol, UK
Consultant, Paediatric Chapter 2: Pain syndromes and the
Rheumatology assessment of pain
Royal Manchester Children’s
Hospital, UK Dr Mary Cruikshank
Chapter 4: Other systemic diseases: Specialist Registrar, Paediatric
Mucopolysaccharidoses (MPS) and Rheumatology
mucolipidoses (ML) Royal Hospital for Sick Children,
Glasgow, UK
Dr Julia Clark Chapter 3: Classification of JIA;
Consultant, Paediatric Immunology Prognostic indicators in JIA
and Infectious Diseases, Chapter 4: Other systemic diseases:
Honorary Senior Clinical Chromosomal abnormalities
Lecturer and associated musculoskeletal
Great North Children’s Hospital, morbidity
Newcastle upon Tyne NHS Chapter 9: Intra-articular
Hospitals Foundation Trust, corticosteroid use in JIA
Newcastle upon Tyne, UK
Chapter 6: Tuberculosis and Dr Joyce Davidson
mycobacterial infections Consultant Paediatric
Rheumatologist
Dr Gavin Cleary Royal Hospital for Sick Children,
Consultant Paediatric Glasgow, UK
Rheumatologist Chapter 3: JIA subtypes and their
Department of Rheumatology, clinical presentations;
Alder Hey Children’s NHS Prognostic indicators in JIA
Foundation Trust, Liverpool, UK Chapter 9: Intra-articular
Foreword 3 corticosteroid use in JIA
Chapter 4: Autoinflammatory
diseases and immunodeficiency: Dr Karen Davies
Chronic recurrent multifocal Consultant Paediatrician and
osteomyelitis Paediatric Rheumatologist
Chapter 10 and Colour plate section New Cross Hospital,
Wolverhampton, UK
Dr Jacqui Clinch Chapter 9: BSPAR standards of
Consultant, Paediatric care for children and young people
Rheumatology and Childhood Pain with JIA
xxxii CONTRIBUTORS

Dr Penny Davis NHS Foundation Trust and UCL

Consultant Paediatric Institute of Child Health,
Rheumatologist London, UK
Department of Rheumatology, Chapter 4: Vasculitis: The standard
Birmingham Children’s treatment of childhood
Hospital, UK vasculitis; Kawasaki disease; The
Chapter 2: Hip pain and hip anti-neutrophil cytoplasmic antibody
problems in children and (ANCA)-associated Vasculitides;
adolescents Central nervous system vasculitis
in children; Other vasculitides;
Prof Michael Dillon Vasculitis mimics: non-inflammatory
Emeritus Professor vasculopathies
Department of Nephrology, Great Chapter 4: Connective Tissue
Ormond Street Hospital for Diseases: Antiphospholipid
Children NHS Foundation Trust Syndrome (APS)
and UCL Institute of Child Health,
London, UK Ms Jill Ferrari
Chapter 4: Vasculitis: Polyarteritis Senior Lecturer
nodosa (PAN); Cutaneous Department of Health and
polyarteritis nodosa (cPAN) Bioscience, University of East
London, and Great Ormond
Ms Sharon Douglas Street Hospital for Children,
Consumer volunteer on the London, UK NHS Foundation Trust
MCRN/ARUK Paediatric Chapter 7: The role of the podiatrist
Rheumatology Clinical Study
Group, Consumer representative, Dr Daniel Fishman
Longniddry, Scotland, UK Consultant Rheumatologist
Foreword 2: Parent and young Luton and Dunstable NHS
person involvement in research—a Foundation Trust, UK
‘consumer’s’ perspective Chapter 3: Disease activity scores in
rheumatoid arthritis and JIA
Ms Deborah Eastwood
Consultant Orthopaedic Surgeon Prof Helen Foster
Great Ormond Street Hospital for Professor Paediatric
Children NHS Foundation Trust, Rheumatology, Newcastle
London, UK University and Honorary
Chapter 5: The osteochondroses Consultant
Great North Children’s Hospital,
Mr Clive Edelsten Newcastle upon Tyne NHS
Consultant, Paediatric Hospitals Foundation Trust,
Ophthalmology Newcastle upon Tyne, UK
Medical Ophthalmology Preface: The purpose of this book
Department, Great Ormond Foreword 4: Paediatric rheumatology
Street Hospital for Children NHS training in the UK
Foundation Trust, London, UK Chapter 1: History taking, physical
Chapter 4: Connective tissue examination, and approaches to
diseases: Paediatric uveitis investigation; Normal variants
Dr Despina Eleftheriou of lower limb development;
Normal gait and musculoskeletal
Clinical Research Fellow and development; The gait cycle and
Honorary Consultant abnormal gait patterns; pGALS:
Great Ormond Street Hospital
 CONTRIBUTORS xxxiii
paediatric gait, arms, legs, Mr Craig Gerrand
spine musculoskeletal screening Consultant Orthopaedic Surgeon
examination; pREMS: paediatric Newcastle upon Tyne NHS
regional examination of the Hospitals Foundation Trust,
musculoskeletal system Newcastle Upon Tyne, UK
Chapter 2: The limping child; Chapter 1: Bone tumours
Growing pains
Dr Sophie Hambleton
Dr Mark Friswell Clinical Senior Lecturer and
Consultant Paediatric Honorary Consultant
Rheumatologist Newcastle University and the
Great North Children’s Hospital, Great North Children’s Hospital,
Newcastle upon Tyne NHS Newcastle upon Tyne NHS
Hospitals Foundation Trust, Hospitals Foundation Trust,
Newcastle upon Tyne, UK Newcastle upon Tyne, UK
Chapter 3: Treatment Chapter 6: Varicella zoster infections
pathways in JIA
Chapter 9: BSPAR guidelines for Ms Liz Hardy
treatments used in paediatric Specialist Physiotherapist,
rheumatology; Disease-modifying Paediatric Rheumatology
anti-rheumatic drugs (DMARDs): Great North Children’s Hospital,
Mycophenolate mofetil (MMF); Newcastle upon Tyne NHS
Intravenous cyclophosphamide; Hospitals Foundation Trust,
Pamidronate; Epoprostenol/iloprost, Newcastle upon Tyne, UK
Etanercept (Enbrel®); Other Chapter 1: Normal variants of lower
anti-TNF-α: adalimumab limb development
(Humira®) and infliximab Chapter 2: Knee pain in children
(Remicade®); Anti-IL-1 treatments: and adolescents
anakinra (Kineret®), rilonacept
(Regeneron®), and canakinumab Dr Kirsty Haslam
(Ilaris®), Abatacept (Orencia®); Consultant Paediatrician with
Systemic corticosteroids (oral, special interest in Rheumatology
intramuscular, and intravenous) Bradford Teaching Hospitals
NHS Foundation Trust,
Dr Paul Galea Bradford, UK
Honorary Clinical Senior Lecturer Chapter 2: Back pain in children
University of Glasgow and adolescents; Scoliosis
Royal Hospital for Sick Children,
Glasgow, UK Dr Nathan Hasson
Chapter 3: Classification of JIA Consultant, Paediatric
Rheumatology
Dr Janet Gardner-Medwin The Portland Hospital, London, UK
Senior Lecturer, Paediatric Chapter 5: Heritable disorders of
Rheumatology connective tissue
University of Glasgow, UK
Chapter 3: Uveitis screening in JIA: Dr Dan Hawley
the approach to screening Consultant Paediatric
and guidelines Rheumatologist
Chapter 4: Other systemic diseases: Department of Paediatric
Chromosomal abnormalities and Rheumatology, Sheffield Children’s
associated musculoskeletal NHS Foundation Trust,
morbidity Sheffield, UK
xxxiv CONTRIBUTORS

Chapter 4: Connective tissue Dr Sharmila Jandial

diseases: Scleroderma Consultant Paediatric
Chapter 9: Disease-modifying Rheumatologist
anti-rheumatic drugs (DMARDs) Great North Children’s Hospital,
Dr Anne Hinks Newcastle NHS Hospitals
Foundation Trust, Newcastle upon
Lecturer Tyne, UK
Arthritis Research UK Chapter 1: History taking, physical
Epidemiology Unit, University examination, and approaches to
of Manchester, Manchester investigation; pGALS: paediatric gait,
Academic Health Science Centre, arms, legs, spine musculoskeletal
Manchester, UK screening examination
Chapter 3: Genetics and JIA: HLA
and non-HLA/MHC associations Dr Akhila Kavirayani
with subtypes of JIA Specialist Registrar, Paediatric
Dr Richard Hull Rheumatology
Bristol Royal Hospital for
Consultant Adult and Paediatric Children, Bristol, UK
Rheumatologist Chapter 2: Hip pain and hip problems
Queen Alexandra Hospital, in children and adolescents
Portsmouth, UK Chapter 9: Disease-modifying
Chapter 3: Surgery in the young anti-rheumatic drugs (DMARDs):
adult with JIA: practical issues Sulphasalazine
Dr Kimme Hyrich Dr Alison Kelly
Senior Lecturer, Rheumatic Specialist Registrar, Paediatric
Disease Epidemiology Rheumatology
Arthritis Research UK Bristol Royal Hospital for Children,
Epidemiology Unit, University of University Hospitals Bristol NHS
Manchester, UK Foundation Trust, Bristol, UK
Chapter 1: Epidemiology of Chapter 4: Connective tissue
musculoskeletal conditions diseases: Paediatric uveitis
Mr Talal Ibrahim Chapter 4: Autoinflammatory
Clinical Fellow, Paediatric diseases and immunodeficiency:
Orthopaedic Surgery Macrophage activation syndrome
Hospital for Sick Children, Ms Jane Kelly
Toronto, Canada Clinical Nurse Specialist, Paediatric
Chapter 1: Normal gait and Rheumatology
musculoskeletal development; Alder Hey Children’s Foundation
The gait cycle and abnormal gait Trust, Liverpool, UK
patterns Chapter 8: Biologic therapies for
Chapter 2: Fractures in children and paediatric rheumatological diseases
adolescents
Mr Chris Kershaw
Ms Gill Jackson
Consultant Orthopaedic Surgeon
Clinical Nurse Specialist, Paediatric Leicester Royal Infirmary,
Rheumatology Leicester, UK
Leeds Teaching Hospitals NHS Chapter 1: The gait cycle and
Trust, The General Infirmary, abnormal gait patterns
Leeds, UK
Chapter 7: The role of the clinical Dr Khulood Khawaja
nurse specialist Consultant Paediatrician,
 CONTRIBUTORS xxxv
Paediatric Rheumatologist Dr Clodagh Lowry
Bradford Teaching Hospitals NHS Consultant Paediatric
Foundation Trust, Bradford, UK Rheumatologist
Chapter 4: Autoinflammatory The Children’s University Hospital,
diseases and immunodeficiency: Dublin, Ireland
Arthritis and other musculoskeletal Chapter 4: Connective tissue
features associated with cystic diseases: Juvenile
fibrosis dermatomyositis
Dr Orla Killeen Ms Sue Maillard
Consultant Paediatric Physiotherapist
Rheumatologist Great Ormond Street Hospital for
Our Lady’s Children’s Children NHS Foundation Trust,
Hospital Crumlin, Dublin, London, UK
Ireland Chapter 4: Connective tissue
Chapter 2: Malignancy and diseases: Juvenile dermatomyositis
musculoskeletal presentations Chapter 7: The role of the
Dr Sophia King physiotherapist
Specialist Registrar, Paediatrics Dr Despoina Maritsi
Yorkhill Hospital, Glasgow, UK Clinical Fellow in Paediatric
Chapter 9: Non-steroidal Rheumatology
anti-inflammatory drugs Great Ormond Street Hospital for
(NSAIDs); Methylprednisolone Children NHS Foundation Trust,
Dr Helen Lachmann London, UK
Chapter 4: Vasculitis: Takayasu
Consultant Physician arteritis
UK National Amyloidosis
Centre, University College Dr Stephen Marks
London Medical School, Consultant Paediatric Nephrologist
London, UK Department of Paediatric
Chapter 4: Autoinflammatory Nephrology, Great Ormond
diseases and immunodeficiency: Street Hospital for Children
Periodic fever syndromes/ NHS Foundation Trust,
autoinflammatory disease London, UK
Chapter 4: Vasculitis: Henoch–
Dr Alice Leahy
Schönlein purpura
Consultant Paediatric Chapter 4: Juvenile systemic
Rheumatologist lupus erythematosus: JSLE: renal
Southampton General Hospital, involvement
Southampton, UK
Chapter 6: Lyme disease Dr Kate Martin
Consultant Paediatrician
Dr Valentina Leone Cheltenham General Hospital,
Specialist Registrar, Paediatric Cheltenham, UK
Rheumatology Chapter 2: Musculoskeletal
Great North Children’s Hospital, presentations and non-accidental
Newcastle upon Tyne NHS injury
Hospitals Foundation Trust,
Newcastle upon Tyne, UK Dr Neil Martin
Chapter 6: Tuberculosis and Specialist Registrar, Paediatric
mycobacterial disease Rheumatology
xxxvi CONTRIBUTORS

Great Ormond Street Hospital for Dr Sabrina McHale

Children NHS Foundation Trust, Specialist Registrar
London, UK Rheumatology Department, Our
Chapter 4: Autoinflammatory Lady’s Hospital for Sick Children,
diseases and immunodeficiency: Dublin, Ireland
Sarcoidosis Chapter 1: Epidemiology of
Chapter 5: Heritable disorders of paediatric musculoskeletal
connective tissue conditions
Chapter 9: Methylprednisolone
Dr Anne-Marie McMahon
Dr Joanne May Consultant, Paediatric
Specialist Registrar, Paediatric Rheumatology
Rheumatology Sheffield Children’s Hospital,
Bristol Children’s Hospital, Sheffield, UK
Bristol, UK Chapter 2: Bone and joint infections
Chapter 2: Pain syndromes and the
assessment of pain Ms Carolyn McTimoney
Chapter 9: Azathioprine Paediatric Rheumatology
Occupational Therapist
Dr Liza McCann Great North Children’s Hospital,
Consultant Paediatric Newcastle upon Tyne NHS
Rheumatologist Hospitals Foundation Trust,
Alder Hey Children’s NHS Newcastle upon Tyne, UK
Foundation Trust, Liverpool, UK Chapter 7: The role of the
Chapter 8: Biologic therapies for occupational therapist
paediatric rheumatological diseases
Chapter 9: Anti-B-cell therapies: Dr Andrea Myers
rituximab (Mabthera®) Consultant Rheumatologist,
Honorary Senior Lecturer
Dr Janet McDonagh Northumbria Healthcare NHS
Clinical Senior Lecturer and Trust, Tyne and Wear, UK
Honorary Consultant Chapter 2: Knee pain in children
Birmingham Children’s Hospital and adolescents
NHS Foundation Trust and
University of Birmingham, Dr Kiran Nistala
Birmingham, UK Arthritis Research UK Career
Chapter 7: Transitional care Progression Fellow, Honorary
Paediatric Rheumatology
Dr Flora McErlane Consultant
Specialist Registrar, Paediatric Rheumatology Unit, UCL Institute
Rheumatology of Child Health, London, UK
Alder Hey Children’s Hospital Chapter 3: Immunology and
NHS Trust, Liverpool, UK aetiology of JIA
Chapter 3: Disease activity scores in
rheumatoid arthritis and JIA Dr Susan O’Connell
Chapter 4: Autoinflammatory Consultant Physician
diseases and immunodeficiency: Lyme Borreliosis Unit, Health
Chronic recurrent multifocal Protection Agency laboratory,
osteomyelitis Southampton, UK
Chapter 9: Anti-B-cell therapies: Chapter 6: Lyme disease
rituximab (Mabthera®)
 CONTRIBUTORS xxxvii
Dr Clare Pain Rheumatologist
Specialist Registrar, Paediatric Great Ormond Street Hospital for
Rheumatology Children NHS Foundation Trust,
Alder Hey Children’s NHS London, UK
Foundation Trust, Liverpool, UK Chapter 4: Connective tissue
Chapter 4: Juvenile systemic lupus diseases: Juvenile dermatomyositis
erythematosus: JSLE: epidemiology Dr Athimalaipet Ramanan
and aetiology; JSLE: clinical features
and diagnostic criteria; Assessment Consultant, Paediatric
of the child with JSLE and monitoring Rheumatology
of disease activity; JSLE: approach Bristol Royal Hospital for Children
to management; Neonatal lupus and Royal National Hospital
syndrome; British Isles Lupus for Rheumatic Diseases, Bristol,
Assessment Group (BILAG) 2004 and Honorary Reader, Bristol
Index; SLEDAI 2000 Disease Activity University, Bristol, UK
Index; SLICC/ACR Damage Index Chapter 4: Connective tissue
(paediatric) diseases: Paediatric uveitis
Chapter 8: Biologic therapies for Chapter 4: Autoinflammatory
paediatric rheumatological diseases diseases and immunodeficiency:
Macrophage activation syndrome
Dr Anand Patel Chapter 9: Ciclosporin
Specialist Registrar
Dermatology Department, Dr Tim Rapley
Nottingham University Social Scientist
Hospitals NHS Trust, Institute of Health and Society,
Nottingham, UK Newcastle University, Newcastle
Chapter 6: Rheumatic fever upon Tyne, UK
Chapter 1: pREMS: paediatric
Dr Sanjay Patel regional examination of the
Consultant Paediatrician musculoskeletal system
Department of Paediatric
Infectious Diseases, St Mary’s Dr Phil Riley
Hospital, London, UK Consultant Paediatric
Chapter 2: Infections in the Rheumatologist
immunocompromised Royal Manchester Children’s
Chapter 4: Autoinflammatory Hospital, Manchester, UK
diseases and immunodeficiency: Chapter 4: Other systemic diseases:
Primary immunodeficiency and Mucopolysaccharidoses (MPS) and
rheumatological disease mucolipidoses (ML)
Chapter 8: Haematopoietic stem
cell transplantation Dr Madeleine Rooney
Senior Lecturer and Consultant in
Dr James Peters Paediatric Rheumatology
Specialist Registrar Centre for Infection and Immunity,
Department of Rheumatology, Queen’s University Belfast, Ireland
University College Hospital Chapter 1: Musculoskeletal
London, UK ultrasound and inflammatory arthritis
Chapter 4: Connective tissue Chapter 5: Metabolic bone diseases
diseases: Overlap syndromes
Dr Clive Ryder
Dr Clarissa Pilkington Consultant Paediatric
Consultant Paediatric Rheumatologist
xxxviii CONTRIBUTORS

Birmingham Children’s Hospital, Prof Taunton Southwood

Birmingham, UK Professor and Honorary
Chapter 8: Corticosteroid Consultant Paediatric
intra-articular injections Rheumatologist
Dr Rangaraj Satyapal School of Infection and Immunity,
College of Medical and Dental
Consultant Paediatric and Sciences, University of
Adolescent Rheumatologist Birmingham, UK
Nottingham Children’s Hospital; Chapter 1: Capillaroscopy in
Queen’s Medical Centre Campus, rheumatic disease
Nottingham University Hospitals
NHS Trust, Nottingham, UK Ms Liz Stretton
Chapter 6: Rheumatic fever Clinical Nurse Specialist, Paediatric
Chapter 9: Methotrexate Rheumatology
Dr Debajit Sen Nottingham Children’s Hospital;
Queen’s Medical Centre Campus,
Consultant, Paediatric and Nottingham University Hospitals
Adolescent Rheumatology NHS Trust, Nottingham, UK
University College London Chapter 8: Approvals for use of
Hospital, and Great Ormond biologic therapies
Street Hospital for Children NHS
Foundation Trust, London, UK Ms Helen Strike
Chapter 4: Connective tissue Clinical Nurse Specialist, Paediatric
diseases: Overlap syndromes Rheumatology
Dr Ethan Sen Paediatric and Adolescent
Rheumatology, Bristol Royal
Specialist Registrar, Paediatric Hospital for Children, Bristol, UK
Rheumatology Chapter 9: BSPAR drug information
Bristol Royal Hospital for leaflets for parents and families
Children, Bristol, UK
Chapter 9: Ciclosporin Dr Alexandra Tabor
Dr Utpal Shah Consultant Paediatrician
University Hospital of North
Formulation Research Fellow Staffordshire, Stoke-on-Trent,
Cheshire, Merseyside and North Staffordshire, UK
Wales Local Research Network; Chapter 1: Autoantibodies and
Medicines for Children Research rheumatic disease
Network; Alder Hey Children’s Chapter 4: Vasculitis: The
NHS Foundation Trust, classification of paediatric vasculitis;
Liverpool, UK The epidemiology of paediatric
Chapter 8: Medicines for children vasculitis
and paediatric rheumatology
Prof Wendy Thomson
Dr Eve Smith
Professor of Genetic Epidemiology
Specialist Trainee Paediatrics Arthritis Research UK
Great North Children’s Hospital, Epidemiology Unit, School
Newcastle upon Tyne NHS of Translational Medicine,
Hospitals Foundation Trust, Manchester Academy of Health
Newcastle upon Tyne, UK Sciences, The University of
Chapter 2: The limping child Manchester, UK
 CONTRIBUTORS xxxix
Chapter 3: Genetics and JIA: HLA Birmingham, UK
and non-HLA/MHC associations Chapter 9: BSPAR drug information
with subtypes of JIA leaflets for parents and families
Dr Helen Venning Dr Nick Wilkinson
Consultant Paediatric and Consultant Paediatric
Adolescent Rheumatologist Rheumatologist
Nottingham Children’s Hospital; Nuffield Orthopaedic Centre NHS
Queen’s Medical Centre Campus, Trust, Oxford, UK
Nottingham University Hospitals Chapter 1: Outcome measures
NHS Trust, Nottingham, UK in paediatric rheumatology; The
Chapter 8: Approvals for use of Childhood Health Assessment Score
biologic therapies
Prof Patricia Woo
Ms Katherine Venter Emeritus Professor
Lecturer in Sociology University College London, UK
University of Leicester, UK Chapter 4: Autoinflammatory
Foreword 2: Parent and young diseases and immunodeficiency:
person involvement in research—a Periodic fever syndromes/
‘consumer’s’ perspective autoinflammatory disease
Dr Joanna Walsh Dr Mark Wood
Consultant Paediatric Consultant Paediatric and
Rheumatologist Adolescent Rheumatologist
Royal Hospital for Sick Children, Leeds General Infirmary,
Edinburgh, UK Leeds, UK
Chapter 3: Treatment approaches Chapter 2: Pyrexia of unknown
in JIA origin
Chapter 7: The multidisciplinary team
Chapter 9: Hydroxychloroquine Dr Joanna Worsfold
Consumer volunteer on the
Dr Kishore Warrier MCRN/ARUK Paediatric
Specialist Trainee in Paediatrics Rheumatology Clinical Study
Great North Children’s Hospital, Group
Newcastle upon Tyne NHS Foreword 2: Parent and young
Hospitals Foundation Trust, person involvement in research—a
Newcastle upon Tyne, UK ‘consumer’s’ perspective
Chapter 6: Immunization schedules
and the immunocompromised Prof Edmond Wraith
Consultant Paediatrician and
Prof Lucy Wedderburn Honorary Professor
Professor of Paediatric St Mary’s Hospital, Manchester,
Rheumatology UK
Rheumatology Unit, UCL Institute Chapter 4: Other systemic diseases
of Child Health, London, UK Mucopolysaccharidoses (MPS) and
Chapter 3: Immunology and mucolipidoses (ML)
aetiology of JIA
Dr Michael Wright
Ms Pamela Whitworth Consultant Clinical Genetics
Clinical Nurse Specialist Northern Genetics Service,
Birmingham Children’s Hospital, Newcastle upon Tyne Hospitals
xl CONTRIBUTORS

NHS Foundation Trust, Newcastle Newcastle upon Tyne NHS

upon Tyne, UK Hospitals Foundation Trust,
Chapter 5: Skeletal dysplasias Newcastle upon Tyne, UK
Chapter 7: The role of the clinical
Dr Sue Wyatt nurse specialist
Consultant Paediatric
Rheumatologist Ms Karen Wynne
Leeds General Infirmary, Clinical Nurse Specialist, Paediatric
Leeds, UK Rheumatology
Chapter 2: Back pain in children Great Ormond Street Hospital for
and adolescents; Scoliosis Children NHS Foundation Trust,
London, UK
Ms Ruth Wyllie Chapter 4: Vasculitis: The
Clinical Nurse Specialist, Paediatric investigation of primary systemic
Rheumatology vasculitis
Great North Children’s Hospital,
 Chapter 1 1

Clinical skills and

assessment

Epidemiology of paediatric musculoskeletal conditions 2

History taking, physical examination, and approaches to
investigation 4
Normal variants of lower limb development 9
The gait cycle and abnormal gait patterns 11
Normal gait and musculoskeletal development 15
pGALS: paediatric gait, arms, legs, spine musculoskeletal
screening examination 18
pREMS: paediatric regional examination of the
musculoskeletal system 23
Musculoskeletal ultrasound in juvenile idiopathic arthritis 28
Autoantibodies 32
Thermography in rheumatic disease 35
Nailfold capillaroscopy in rheumatic disease 37
Outcome measures in paediatric rheumatology 41
The Child Health Assessment Questionnaire (CHAQ) 45
2 CHAPTER 1 Clinical skills and assessment

Epidemiology of paediatric
musculoskeletal conditions
Inflammatory musculoskeletal conditions
• Juvenile idiopathic arthritis (JIA), the most common chronic rheumatic
disease of childhood, is a clinically heterogeneous group of disorders
characterized by chronic inflammatory arthritis. JIA is considered to
be an autoimmune disease, which is thought to result of an immune
reaction caused or triggered by environmental factors such as
infectious agents in a genetically susceptible host, although the exact
aetiology has yet to be determined.
• Determining the incidence and prevalence, both within the UK and
internationally, has been challenged by changing classification criteria
(American College of Rheumatology [ACR] versus European League
Against Rheumatism [EULAR] versus League of Associations for
Rheumatology [ILAR]) as well as differences in case ascertainment.
• The earliest epidemiological studies of JIA performed in populations
from Western Europe and North America showed an incidence
varying between 1.3 per 100,000 person-years in France and 22.6 per
100,000 person-years in Norway. The prevalence of JIA was reported
as between 7 and 148 per 100,000 person-years, in France and Norway
respectively. However, comparison of these studies is difficult, because
different diagnostic criteria, e.g. EULAR vs. ACR, and different study
designs were used.
• More recent population-based studies data have shown a higher
prevalence of JIA, between 167 and 400 per 100,000 person-years;
this difference is likely due to undiagnosed cases being identified
in ‘healthy’ children when they underwent examination by trained
paediatric rheumatologists. A recent population-based multicentre
study performed in southeastern Norway found the annual incidence
of childhood arthritis was 71 per 100,000 children; however this study
included transient arthritis, postinfectious arthritis, and infectious
arthritis as well as JIA.
• A diagnostic register was established in the UK in 1989 with the
objectives of describing the demography and diagnostic classification
of children referred to paediatric rheumatology clinics and also to
estimate the incidence of juvenile arthritis in the UK. The annual
incidence rate for juvenile arthritis from 2 centres in 1996 was
10 per 100,000, and for all rheumatic disorders was 32–42 per
100,000 children under age 16.
• Ethnicity has also been found to play a role. Children of European
ancestry have been found to be at the highest risk of developing all
types of JIA compared to other ethnic groups, except rheumatoid
factor (RF)+ve polyarticular JIA. Also, native North American children
are at a higher risk than children of European descent of developing
a polyarticular course of disease, such as extended oligoarticular JIA,
RF−ve polyarticular JIA, and RF+ve polyarticular JIA.
 EPIDEMIOLOGY OF PAEDIATRIC MUSCULOSKELETAL CONDITIONS 3

Juvenile-onset systemic lupus erythematosus

• Childhood-onset juvenile systemic lupus erythematosus (SLE) was
found to account for <1% of patients in paediatric rheumatology clinics
in a UK Registry, compared to 1.5–3% in Canada and 4.5% in the USA.
In a Canadian study from a national Registry, the mean annual incidence
of SLE was estimated at 0.36 per 100,000 children.
Juvenile dermatomyositis
• The incidence of juvenile dermatomyositis in the UK and Ireland is
reported at a rate of 0.19 per 100,000 children. This compares with
rates of 0.25–0.41 per 100,000 for children in a US registry.
Juvenile scleroderma
• Scleroderma in childhood remains very rare. A recent UK study has
estimated the annual incidence to be 3.4 per million children for
localized scleroderma; and 0.27 per million for systemic disease.
Non-inflammatory musculoskeletal conditions
Hypermobility
• The prevalence of hypermobility in children as a phenomenon, as
opposed to benign joint hypermobility syndrome (BJHS), has been
measured in a number of studies previously and, depending on the age
or ethnicity of the study population or the inclusion criteria, has been
reported to be between 2.3% and 30%.
• However, the presence of hypermobility in children does not equate
to having BJHS. The latter is defined as the presence of a degree of
joint hypermobility measured by a prearranged and validated scoring
system, associated with musculoskeletal symptoms and signs, and other
connective tissue problems likely to be attributable to it.
• There is wide divergence in the joint laxity observed amongst
different ethnic groups. The Europeans are most stiff; the Bantu
tribes of intermediate joint laxity; and those originally from the Indian
subcontinent of most marked joint laxity.
• Considerable overlap between benign hypermobility and mild variants
of Ehlers–Danlos syndrome, Marfan syndrome, and osteogenesis
imperfect has been reported.
Complex regional pain syndrome
• The incidence of complex regional pain syndrome (CRPS) in children
is unknown. In a population study in the USA, the overall risk of CRPS
was 5.46 per 100,000 person years. However, this mainly reflected
adult CRPS, as the median age at diagnosis was 46yr.
• In large paediatric series CRPS is more common in girls (70%), and the
mean age at diagnosis is 13yr of age (range 5–17yr).
Further reading
Bowyer S, Roettcher P, and the members of the Pediatric Rheumatology Database Research
Group. Pediatric rheumatology clinic populations in the United States: results of a 3 year
survey. J Rheumatol 1996; 23:1968–74.
Malleson PN, Fung MY, Rosenberg AM. The incidence of pediatric rheumatic diseases: results from
the Canadian Pediatric Rheumatology Association Disease Registry. J Rheumatol 1996; 23:1981–7.
Symmons DP, Jones M, Osborne J, et al. Pediatric rheumatology in the United Kingdom: data from the
British Pediatric Rheumatology Group National Diagnostic Register. J Rheumatol 1996; 23:1975–80.
4 CHAPTER 1 Clinical skills and assessment

History taking, physical examination,

and approaches to investigation
• The differential diagnosis of musculoskeletal pain in children is broad
(Box 1.1). Taking a history and performing a physical examination
(general and musculoskeletal) are integral to making an accurate
diagnosis.
• In history taking it is worth asking open questions (Table 1.1), probing
for features that may suggest mechanical or inflammatory pathology
(Table 1.2), seeking any suggestion of systemic disease and ‘red flags’
(Box 1.2) to warrant urgent concern or clues in the history to suggest
inflammatory musculoskeletal disease (Box 1.3).
• Appropriate clinical assessment requires knowledge of normal
development, normal variants (see b Normal variants of lower limb
development, p 9), normal and abnormal gait patterns (see b The
gait cycle and abnormal gait patterns, p 11), clinical presentations at
different ages (e.g. the hip, see b Hip pain and hip problems in children
and adolescents, p 106), and an approach to initial investigations.
Further details are given in chapters relating to individual diseases.
Key points to note in the clinical assessment:
• A common pitfall in making a diagnosis is to inappropriately attribute
a child’s problem to trauma (which is a common event in the life of all
ambulant children).
• The history (often given by the parent or carer), may be based on
observations and interpretation of events made by others (such as
teachers or friends), and may be rather vague and ill-defined with
non-specific complaints such as ‘my child is limping’ or ‘my child is not
walking quite right’.
• Consider the age and development of the child and modify the
questioning and consultation style accordingly.
• The young child may deny having pain when asked directly, and this
should not be taken to mean that the child does not have any pain.
• Physical examination needs to be comprehensive:
• Assessment of pain is important (see b Pain syndromes and the
assessment of pain, p 87) and can result in physical examination
being challenging for everyone present.
• A musculoskeletal screening examination (e.g. pGALS—see b
pGALS, p 18) will identify areas of significant joint abnormality
which may not be apparent from the history alone. Some aspects
of pGALS, such as gait observation may be modified or need to be
postponed in the acutely unwell child.
• A more detailed regional musculoskeletal examination (see b
pREMS, p 23) is an adjunct to the screening examination and the
possibility of referred pain needs to be considered.
• Indolent presentations of chronic musculoskeletal disease can
impact on growth (either localized or generalized). It is important to
assess height and weight, review growth charts in the Parent Held
Record where available, and look for evidence of disproportionate
growth (e.g. asymmetrical leg length) or muscle wasting.
 HISTORY TAKING, PHYSICAL EXAMINATION 5

• Additional clinical skills are required pending the clinical scenario

and include capillaroscopy (see b Nailfold capillaroscopy in
rheumatic disease, p 37) and muscle testing (see b Juvenile
dermatomyositis, p 266).
• Musculoskeletal ultrasound is increasingly being used as an adjunct
to clinical examination (see b Musculoskeletal ultrasound in
juvenile idiopathic arthritis, p 28).

Box 1.1 The differential diagnosis of musculoskeletal pain

in children and adolescents
Life-threatening conditions
• Malignancy (leukaemia, lymphoma, bone tumour)
• Sepsis (septic arthritis, osteomyelitis)
• Non-accidental injury (NAI).
Joint pain with minimal or no swelling
• Hypermobility syndromes
• Orthopaedic syndromes (e.g. Osgood–Schlatter disease, Perthes
disease)
• Idiopathic pain syndromes (reflex sympathetic dystrophy,
fibromyalgia)
• Metabolic (e.g. hypothyroidism, lysosomal storage diseases)
• Tumour (benign and malignant).
Joint pain with swelling
• Trauma (haemarthrosis)
• Infection
• Septic arthritis and osteomyelitis (viral, bacterial, mycobacterial):
• Reactive arthritis (post-enteric, sexually acquired)
• Infection related (rheumatic fever, post-vaccination)
• JIA
• Arthritis related to inflammatory bowel disease
• Connective tissue diseases (SLE, scleroderma, dermatomyositis,
vasculitis)
• Metabolic (e.g. osteomalacia/rickets, cystic fibrosis)
• Haematological (e.g. haemophilia, haemoglobinopathy)
• Tumour (benign and malignant)
• Chromosomal (e.g. Down’s related arthritis)
• Auto-inflammatory syndromes (e.g. periodic syndromes, chronic
recurrent multifocal osteomyelitis)
• Sarcoidosis
• Developmental/congenital (e.g. achondroplasia).
6 CHAPTER 1 Clinical skills and assessment

Table 1.1 Key questions to ask when taking a musculoskeletal history

Questions to Points to Comments
parent/carer check for
(and the
child as
appropriate)
What have you Behaviour, mood, Limping, whether intermittent or
or anyone else joint swelling, persistent, always warrants further
noticed? limping, bruising assessment. Deterioration in school
performance (e.g. sport, handwriting) is
always significant. Joint swelling is always
significant but can be subtle and easily
overlooked by the parent (and even
healthcare professionals!), especially if
the changes are symmetrical
Rather than describing stiffness, the
parents may notice the child is reluctant
to weight-bear or limps in the mornings
or ‘gels’ after periods of immobility
(e.g. after long car rides or sitting in a
classroom)
What is the Irritability, grumpy, Young children in pain may not verbalize
child like in ‘clingy’, reluctant pain but may present with behavioural
him/herself? to play, systemic changes or avoidance of activities
features (e.g. fever, previously enjoyed
anorexia,
Systemic features including ‘red flags’ to
weight loss)
suggest malignancy or infection
Where is the Take a pain history Asymmetrical persistent site of pain is
pain? (Ask the and focus on locality, invariably a cause for concern. Referred
child to point) exacerbating/ pain from the hip may present with non-
and what is it relieving factors, specific pain in the thigh or knee
like? timescale pattern
How is he/she Diurnal variation Pain on waking or daytime symptoms
in the mornings and daytime suggestive of stiffness or gelling (after
and during the symptoms periods of inactivity), are indicative of
day? (e.g. limping, difficulty inflammatory joint (or muscle) disease
walking, dressing,
toileting, stairs?)
What is he/she Motor milestones Regression of achieved motor
like with walking and suggestion of milestones, functional impairment or
and running? delay or regression avoidance of activity (including play,
Has there been of achieved sport, or writing), are more suggestive
any change in milestone, including of acquired joint or muscle disease (and
his/her speech and language. especially inflammatory causes). An
activities? Avoidance of assessment of global neurodevelopment
activities that is indicated with delay or regression
previously enjoyed in speech, language, or motor skills.
(e.g. sport, play) are ‘Clumsiness’ is a non-specific term but
noteworthy may mask significant musculoskeletal or
neurological disease
 HISTORY TAKING, PHYSICAL EXAMINATION 7

Table 1.1 (Contd.)

Questions to Points to Comments
parent/carer check for
(and the
child as
appropriate)
How is School attendance Behavioural problems in the young
he/she at (any suggestion of child may manifest as non-specific pains
school/ school avoidance, (headaches, tummy aches, or leg pains).
nursery? bullying) Sensitive questioning may reveal stressful
events at home or school
Does he/she Pattern of night Night waking is a common feature of
wake at night waking growing pains (and usually intermittent,
with pain? and often predictable). Conversely
persistent night waking, especially if
there are other concerns (such as
unilaterality, limping, unusual location,
or systemic features) are of concern
and invariably necessitate further
investigation
Can you Relationship to Growing pains tend to be worse later
predict when physical activity in the day, evenings and often after
the pains may (including during busy days
occur? or after sporting
activities)
What do Response to Lack of response to simple analgesia is
you do when analgesics, a concern. Vicious circle of reinforced
he/she is anti-inflammatory behaviour can occur
in pain? medication,
massages, and
reaction of parent
What is Sleep disturbance, A family history of muscle disease,
your main cosmesis, anxiety arthritis or autoimmune disease may
concern? about serious indicate a predisposition to muscle or
disease (arthritis, joint disease. Observed ‘abnormalities’
cancer, family (such as flat feet, curly toes) may be part
history), pain of normal development. The parent or
control. carer will undoubtedly have anxieties
and concerns about the child, often fear
severe illness and both child and parent
have an expectation of investigations
(i.e. blood tests!)
8 CHAPTER 1 Clinical skills and assessment

Table 1.2 Distinguishing mechanical from inflammatory

musculoskeletal presentations
Mechanical Inflammatory
Pain Worse on weight Often eased by movement and may be
bearing and after seemingly absent in young children and
activity such as manifest as behavioural change or avoidance
walking of activity
Joint Usually mild and Tends to be persistent
swelling maybe transient
Morning Usually absent Often marked
stiffness or
gelling after
rest
Instability May be present Usually absent
(giving way)
Locking May be present Usually absent
Loss of full May be present Often present
movement

Box 1.2 RED FLAGS (to raise concern about infection or

malignancy or non-accidental malignancy)
• Fever, systemic upset
• Bone/joint pain with fever
• Weight loss, sweats, persistent night waking
• Incongruence between history and clinical presentation pattern of
physical findings.

Box 1.3 Important points when considering inflammatory

joint or muscle disease
• The lack of reported pain does not exclude arthritis.
• There is need to probe for symptoms such as:
• Gelling (e.g. stiffness after long car rides).
• Altered function (e.g. play, handwriting skills, writing, regression of
milestones).
• Deterioration in behaviour (irritability, poor sleeping).
• There is need to examine all joints as often joint involvement may be
‘asymptomatic’ or illocalized.
• There is need to assess muscle strength (e.g. proximal muscle
weakness).
 NORMAL VARIANTS OF LOWER LIMB DEVELOPMENT 9

Normal variants of lower limb

development
Table 1.3 Normal variants of lower limb development
Indications for concern and Comments
referral to physiotherapy (see b Foot and ankle
or paediatric orthopaedics problems, p 121, b The role
unless specified of the podiatrist, p 385, and
b Joint hypermobility, p 124)
Tip-toe • Toe walking is persistent • Can associate with clubfoot
walking or asymmetrical or neurological disease
• Associated developmental (e.g. muscular dystrophy,
Common
delay cerebral palsy, poliomyelitis).
in healthy
• Child unable to squat or Careful neuromuscular/
young
stand with their heels on assessment required.
children
the floor (tightness of calf Check for gastrocnemius
muscles) contracture and shoes for
• Child >3yr old, and unable sole wear. Physiotherapy
to stand from floor sitting may help mild cases but
without using hands surgery may be required
Flat feet • Signs of pressure on the • Persistence often familial,
foot, e.g. blistering more common in
Common
• The longitudinal arch hypermobility
and normal
does not form normally • Insoles may help but
for babies
when the child stands on shouldn’t be worn all the
and toddlers,
tip toe time—walking in bare in
resolves with
• The foot is stiff (i.e. the feet helps promote foot
development
normal arch does not development
of longitudinal
form when the child stands • A non-flexible flat foot
arch usually
on tip toe or the big toe is may indicate tarsal coalition
by 4–6yr
passively extended) (often teens)
of age
• In newborn exclude vertical
talus
Pes cavus • Often associated with • Careful neuromuscular/
toe clawing, calluses, heel musculoskeletal assessment
Not common—
varus, and pain with difficult required. Neurological
the opposite
to fit footwear conditions to consider
of flat feet
• May be physiological include—spina bifida, spinal
and is when
(familial—so check parents’ dysraphism, poliomyelitis,
the arch is
feet!), residual from clubfoot Charcot–Marie–Tooth,
extremely
abnormality, or associated Friedrich’s ataxia
pronounced
with neurological • Insoles may help and surgery
abnormalities. Paediatric may be required
neurology/orthopaedics
referral usually needed
Curly toes • Surgery rarely needed • Check shoes are well fitting
Most resolve
by 4yr
(continued )
10 CHAPTER 1 Clinical skills and assessment

Table 1.3 (Contd.)

Indications for concern and Comments
referral to physiotherapy (see b Foot and ankle
or paediatric orthopaedics problems, p 121, b The role
unless specified of the podiatrist, p 385, and
b Joint hypermobility, p 124)
Knock knees • Associated with pain or • A gap of 6–7cm between the
asymmetrical ankles is normal (between
Usually resolve
• Extreme (>6cm 2–4yr)
by the age
intermalleolar distance • Late feature of arthritis of
of 6yr
at ankles) or persistent knee (e.g. JIA)
(>6yr)
Bow legs • Associated with pain or • Conditions to exclude
asymmetrical or the child is include rickets, skeletal
Common and
short in stature or has other dysplasias, syndromes
normally seen
medical problems associated with dwarfism
in children
• Extreme (>6cm (e.g. achondroplasia),
until the age
intercondylar distance Blount’s disease
of 2yr
at knees) or persistent • Late feature of arthritis of
(>6yr) knee (e.g. JIA)
Out-toeing • Recent onset in a
Feet point teenager—check hips for
outwards and a slipped upper femoral
usually resolves epiphysis.
by 4yr
JIA, juvenile idiopathic arthritis.

Further reading
Staheli, L.T. Fundamentals of Pediatric Orthopedics—Foot and lower limb. Philadelphia,
PA: Lippincott-Raven, 2008.
 THE GAIT CYCLE AND ABNORMAL GAIT PATTERNS 11

The gait cycle and abnormal gait

patterns
A child with an abnormal gait is a common presentation and can be due
to many different causes (Tables 1.4 and 1.5). Clearly there is considerable
overlap with neurological problems and careful clinical assessment, rec-
ognition of different gait patterns, and knowledge of potential differential
diagnoses is very helpful (Table 1.6).
General effects of neuromuscular disease on joint action
• Muscle weakness reduces stability.
• Muscle weakness and spasticity reduces range of motion.
• Muscle weakness and spasticity reduces efficiency.
• Muscle weakness and spasticity encourages compensatory movements.
• Longstanding weakness and spasticity may cause joint contracture.
• Longstanding contracture and compensatory movements may cause
bone deformities (lever arm dysfunction).
Indications for neuromuscular assessment
• To study abnormal inefficient gait or gait that is deteriorating.
• To identify specific targets for surgical correction, e.g. osteotomies,
muscle lengthening.
• Allows detailed assessment of gait by multidisciplinary team.
• Assess outcomes of intervention, i.e. orthoses, physiotherapy, or
surgery.
Limitations of gait analysis
• Expense, training, and operator experience dependent.
• Variation between observers, of assessments and recommendations.

Table 1.4 The normal gait cycle and abnormal patterns observed in
neuromuscular disease
Gait cycle Normal Abnormal Examples of
phase characteristics characteristics abnormality in
in neuromuscular musculoskeletal
disease disease

• Dorsiflexed • Lack of • Tip-toe walking

ankle for weight dorsiflexion range with short
acceptance due to weakness, gastrocnemius
• Heel strike contracture or muscles or
(for shock calf muscle painful hindfoot
Loading absorption) spasticity (e.g. Sever’s
response • High stepping gait disease)
(no heel strike),
e.g. poliomyelitis
and other paralytic
disorders

(continued )
12 CHAPTER 1 Clinical skills and assessment

Table 1.4 (Contd.)

Gait cycle Normal Abnormal Examples of
phase characteristics characteristics abnormality in
in neuromuscular musculoskeletal
disease disease

• Stable ankle • Peroneal weakness • Painful ankle

• Dorsiflexors may reduce (e.g. JIA)
contract, plantar ankle stability,
flexors relax e.g. common
• Knee extends peroneal nerve
• Hip extends palsy
Mid stance • Hamstring
contracture or
spasticity may
reduce knee
extension
• Full hip • Pelvic lurch due to • Leg-length
extension abductor weakness discrepancy
• Full knee affects hip stability (longer leg scuffs
extension (Trendelenburg the ground or
• Allows gait) circumducts)
contralateral • Psoas spasticity
Terminal limb clearance and contracture
stance prevents hip
extension,
e.g. spastic diplegia
• Ankle plantar • Weak calf • Restricted ankle
flexion muscle generates (e.g. JIA)
• Power generation less power,
for propulsion e.g. poliomyelitis

Pre/early swing
• Hip max flexion • Poor clearance • Loss of full
• Knee max flexion due to tibialis extension due
• Ankle dorsiflexion anterior and to inflammatory
for clearance peronei weakness joint (knee)
e.g. Charcot– or muscle
Marie–Tooth (quadriceps)
and other disease
peripheral
Mid swing neuropathies
• Knee extends • Lack of full • Pain inhibition
(allows adequate extension due to of hip abductors
step length) quads weakness, in Legg–Calve–
• Ankle dorsiflexes e.g. spastic diplegia Perthes disease
for heel • Lack of dorsiflexion
strike (foot range due to
Terminal pre-positioning) weakness, contrac-
stance ture or calf muscle
spasticity e.g. spastic
hemiplegia
 THE GAIT CYCLE AND ABNORMAL GAIT PATTERNS 13

Table 1.5 Neuromuscular assessment

Component Risk factors Examples
History Prenatal infection or bleeding Varicella zoster, abruption
Postnatal special care Postnatal respiratory distress
Family history of Charcot–Marie–Tooth disease
neuromuscular disorder
Deteriorating mobility Deteriorating gait, fatigue
Milestones not achieved Poor head control, not sitting
unsupported by age 12 months
Examination Muscle weakness
i muscle tone Spasticity
Joint contracture Tip toeing, hamstring tightness
Bone deformity Femoral neck anteversion,
cavovarus or plano valgus feet
Gait analysis Abnormal gait High stepping or crouch gait
Slow motion playback Lack of heel strike
(calf muscle spasticity)
Force plate studies Loss of knee extension
(hamstring spasticity)
Joint motion sensors Loss of hip extension
Electromyography Abnormal muscle contraction
14 CHAPTER 1 Clinical skills and assessment

Table 1.6 Abnormal gait patterns seen in musculoskeletal disease

Description Potential causes
Antalgic gait Due to pain on the affected • Multiple causes and sites,
side, where the stance phase including trauma, sepsis,
(the length of time spent JIA, Legge–Calve–Perthes
bearing weight) on the disease
affected side is shorter.
May present with limp or
non-weight-bearing
Trendelenburg Results from hip abductor • Hip joint disease (e.g. Legge–
gait muscle weakness and whilst Calve–Perthes disease, slipped
weight-bearing on ipsilateral capital femoral epiphysis,
side, the pelvis drops on developmental dysplasia of the
contralateral side, rather hip, JIA involving the hip).
than rising as is normal. • Muscle disease (juvenile
With bilateral hip disease—a Dermatomyositis or inherited
waddling ‘rolling sailor’ gait myopathies)
with hips, knees and feet • Neurological conditions (spina
externally rotated. This gait bifida, cerebral palsy, and
is also observed secondary spinal cord injury)
to painful hip conditions due
to pain inhibition of normal
muscle activity
Circumduction A circular movement of • A lack of full knee extension
gait (‘peg leg’) the leg with excessive hip (JIA, trauma)—in JIA may be
abduction as the leg swings due to leg-length discrepancy
forward • Unilateral spasticity as in
hemiplegic cerebral palsy
Waddling gait A wide-based gait suggests • Inflammatory myopathies
proximal muscle weakness
Spastic gait Refers to stiff walking with • Upper motor neuron
foot-dragging and the foot neurologic disease
inverted (e.g. diplegic or quadriplegic
cerebral palsy, stroke)
Ataxic gait Due to instability with an • Neurological disease
alternating narrow to wide (e.g. ataxic cerebral palsy
base of gait affecting the cerebellum,
cerebellar ataxia and
Friedreich’s ataxia)
Toe-walking Absent heel contact • Habitual toe walking (common
gait (‘equinus’) and associated with normal
foot examination and normal
walking on request)
• Persistent toe walking
(spastic upper motor
neuron neurologic disease
(e.g. diplegic cerebral palsy),
JIA, and mild lysosomal
storage disorders
 NORMAL GAIT AND MUSCULOSKELETAL DEVELOPMENT 15

Normal gait and musculoskeletal

development
• It is important to be aware of normal motor milestones (Table 1.7) and
normal variants in gait and leg alignment (see b Normal variants of
lower limb development, p 9).
• Patterns of abnormal gait are important to recognize and are based on
understanding of the gait cycle (see b The gait cycle and abnormal gait
patterns, p 11).
• There is considerable variation in the way normal gait patterns
develop—such variation may be familial (e.g. ‘bottom-shufflers’ often
walk later) and subject to racial variation (e.g. African black children
tend to walk sooner and Asian children later than average).
• The normal toddler has a broad-base gait for support, and appears to
be high stepped and flat footed with arms outstretched for balance.
• The legs are externally rotated with a degree of bowing. Heel strike
develops around 15–18 months with reciprocal arm swing.
• Running and change of direction occur after the age of 2yr, although
this is often accompanied by frequent falls until the child acquires
balance and coordination.
• In the school-age child, the step length increases and step frequency
slows. Adult gait and posture occur around the age of 8yr.
The approach to investigation
• The approach to investigation is based on the differential diagnosis
derived from the clinical setting; details of investigations required and
their interpretation are given in this handbook for the various diseases.
• With regard to suspected inflammatory joint disease, it must be
remembered that JIA is a diagnosis of exclusion, there is no diagnostic
test and pending the clinical scenario the child may undergo multiple
tests to confirm the diagnosis (Table 1.8).
• It is important that the child is referred for a paediatric rheumatology
assessment as soon as the diagnosis is suspected and certainly before
invasive tests such as arthroscopy or procedures requiring general
anaesthetic (e.g. magnetic resonance imaging [MRI] in the young child)
are contemplated.
• Delay in making a diagnosis of JIA is well reported and often
exacerbated through waiting for procedures that may be unnecessary.
16 CHAPTER 1 Clinical skills and assessment

Table 1.7 Normal musculoskeletal development

Sits without support 6–8 months
Creep on hands and knees 9–11 months
Cruise/or bottom shuffle 11–12 months
Walk independently 12–14 months
Climb up stairs on hands and knees ~15 months
Run stiffly ~16 months
Walk down steps (non-reciprocal) 20–24 months
Walk up steps, alternate feet 3yr
Hop on one foot, broad jump 4yr
Skipping 5yr
Balance on one foot for 20sec 6–7yr
Adult gait and posture 8yr
 NORMAL GAIT AND MUSCULOSKELETAL DEVELOPMENT 17

Table 1.8 Investigations in the child with suspected JIA—cautionary

notes
FBC and May be normal in JIA, especially oligo-articular subtype
blood film
Anaemia of chronic disease may be present in polyarticular JIA
and systemic onset JIA
Raised white cell count and raised platelets a feature of systemic
onset JIA
A blood film is helpful to exclude leukaemia but suspicion of this
requires a bone marrow examination
Acute phase May be raised, and often very high in systemic JIA
reactants
ESR, CRP
Ferritin May be raised and often extremely high in systemic JIA or
macrophage activation syndrome
Antinuclear May be absent in 50% of JIA and may be found in viral illnesses,
factor non-rheumatic disease, and many healthy children as well as
connective tissue disease (such as SLE)
In the presence of JIA, ANA indicates high risk of chronic
anterior uveitis, which affects 30% of children with JIA and is
potentially blinding if undetected and untreated
Rheumatoid Rarely found in children with JIA (<10% of cases) but associates
factor with poor prognosis
Slit lamp All children with suspected JIA require prompt referral
examination to ophthalmology for eye screening for uveitis which is
invariably asymptomatic in the early stages and if undetected and
untreated, can lead to blindness
Synovial fluid Not required to make a diagnosis of JIA but is mandatory to
examination exclude sepsis in the child with a single hot swollen joint (and
any suspicion of tuberculosis).
Arthroscopy Not required to make a diagnosis of JIA. Seldom indicated
and synovial and not recommended before child has been assessed by a
biopsy paediatric rheumatologist.
Radiographs May be normal in early JIA—loss of joint space and joint damage
occur in severe or untreated disease. Useful to exclude other
pathology (and tumour).
Ultrasound Ultrasonography is sensitive to early changes, is well tolerated by
young children, and is increasingly more available
MRI MRI is sensitive to early changes of inflammatory arthritis but
may not be available and in young children invariably requires
sedation. Referral to paediatric rheumatology should not be
delayed whilst awaiting MRI scanning. Gadolinium contrast
should be remembered—often not given to children who
have MRI prior to paediatric rheumatology assessment,
resulting in need for repeat scans.
ANA, antinuclear antibody; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; FBC,
full blood count; MRI, magnetic resonance imaging.
18 CHAPTER 1 Clinical skills and assessment

pGALS: paediatric gait, arms, legs, spine

musculoskeletal screening examination
• The pGALS screening assessment (Box 1.4) is a simple evidence-
based approach to musculoskeletal assessment based on the adult
GALS (gait, arms, legs, spine) screen and has been shown to have high
sensitivity to detect significant joint abnormalities.
• Key to distinguishing normal from abnormal is a knowledge of ranges of
movement in different age groups and ethnicity, looking for asymmetry,
and careful examination for subtle changes.
• pGALS is primarily aimed at the school-aged child, but younger
children will often comply with pGALS, especially if they copy the
examiner and see this as a game.
• pGALS incorporates a series of simple manoeuvres, takes an average
of 2min to perform and simple practical tips facilitate the examination
(Box 1.5 and Tables 1.9 and 1.10).
• The pGALS screen includes 3 questions relating to pain and
function although a negative response does not exclude significant
musculoskeletal disease and at a minimum the screening examination
should be done in all clinical scenarios where musculoskeletal disease is
a concern (Box 1.6).
• It is essential to perform all parts of the pGALS screen as joint
involvement may be apparently ‘asymptomatic’, symptoms may not be
localized, and it is important to check for verbal and non-verbal clues
of joint discomfort such as facial expression or withdrawal of limb.
• The information needs to be interpreted in the context of the physical
examination elsewhere (e.g. chest, abdomen, neurological examinations
in the case of the limping child) or in the presence of any ‘red flags’ in
the unwell child.
• Documentation of findings in the case notes is simple, using a grid
(Fig. 1.1).
 pGALS 19

Box 1.4 The pGALS musculoskeletal screening

examination
Screening questions
• ‘Do you (or does your child) have any pain or stiffness in your joints,
muscles, or your back?’
• ‘Do you have any difficulty getting yourself dressed without any help?’
• ‘Do you have any difficulty going up and down stairs?’
Gait
• Observe the child walking.
• ‘Walk on your tip-toes/walk on your heels.’
Arms (see Table 1.9)
• ‘Put your hands out in front of you.’
• ‘Turn your hands over and make a fist.’
• ‘Pinch your index finger and thumb together.’
• ‘Touch the tips of your fingers with your thumb.’
• Squeeze the metacarpophalangeal joints.
• ‘Put your hands together/put your hands back to back.’
• ‘Reach up and touch the sky.’
• ‘Look at the ceiling.’ (assesses neck)
• ‘Put your hands behind your neck.’
Legs (see Table 1.10)
• Feel for effusion at the knee.
• ‘Bend and then straighten your knee’ (active movement of knees and
examiner feels for crepitus).
• Passive flexion (90°) with internal rotation of hip.
Spine (see Table 1.10)
• ‘Open your mouth and put 3 of your [child’s own] fingers in your mouth.’
• Lateral flexion of cervical spine—‘Try and touch your shoulder with
your ear.’
• ‘Look at the ceiling.’
• Observe the spine from behind.
• ‘Can you bend and touch your toes?’ Observe curve of the spine
from side and behind.

Box 1.5 Practical tips: while performing the pGALS

screening examination
• Get the child to copy you doing the manoeuvres.
• Look for verbal and non-verbal clues of discomfort (e.g. facial
expression, withdrawal).
• Do the full screen as extent of joint involvement may not be obvious
from the history.
• Look for asymmetry (e.g. muscle bulk, joint swelling, range of joint
movement).
• Consider clinical patterns (e.g. non-benign hypermobility and
Marfanoid habitus or skin elasticity, and association of leg-length
discrepancy and scoliosis).
20 CHAPTER 1 Clinical skills and assessment

Box 1.6 Practical tips: when to perform pGALS in the

assessment
• Child with muscle, joint, or bone pain.
• Unwell child with pyrexia.
• Child with limp.
• Delay or regression of motor milestones.
• The ‘clumsy’ child in the absence of neurological disease.
• Child with chronic disease and known association with
musculoskeletal presentations.

Documentation of the pGALS screen

Documentation of the pGALS screening assessment is important and a simple pro forma is proposed with
the following example–a child with a swollen left knee with limited flexion of the knee and antalgic gait.

pGALS screening questions

Any pain? Left knee
Problems with dressing? No difficulty
Problems with walking? Some difficulty on walking
Appearance Movement
Gait
Arms
Legs
Spine

Fig. 1.1 Documentation of the pGALS screen findings. Reproduced with permis-
sion by Arthritis Research UK (see Free educational resources.)

Further reading and resources

Foster HE, Kay LJ, Friswell M, Coady D, Myers A. Musculoskeletal screening examination (pGALS)
for school-age children based on the adult GALS screen. Arthritis Care Res 2006; 55(5):709–16.
Free educational resources (DVD and handouts) to demonstrate pGALS and the manouvres
are available: http://www.arthritisresearchuk.org/files/6535_05032010155008.pdf.
http://www.arthritisresearchuk.org/arthritis_information/information_for_medical_
profes/medical_student_handbook.aspx.
 pGALS 21

Table 1.9
Figure Screening manoeuvres What is being assessed?
‘Touch the tips of your • Manual dexterity
fingers’ • Coordination of small
joints of fingers and
thumbs

Squeeze the • Metacarpophalangeal

metacarpophalangeal joints
joints for tenderness

‘Put your hands together • Extension of small joints

palm to palm’ and ‘put of fingers
your hands together • Wrist extension
back to back’ • Elbow flexion

‘Reach up,“touch the • Elbow extension

sky”’ and ‘Look at the • Wrist extension
ceiling’ • Shoulder abduction
• Neck extension

‘Put your hands behind • Shoulder abduction

your neck’ • External rotation of
shoulders
• Elbow flexion

Table adapted and used with permission by Arthritis Research UK (see Free educational
resources).
22 CHAPTER 1 Clinical skills and assessment

Table 1.10
Figure Screening manoeuvres What is being assessed?
‘Try and touch your • Cervical spine lateral
shoulder with your ear’ flexion

‘Open wide and put • Temporomandibular

three (child’s own) joints (and check
fingers in your mouth’ for deviation of jaw
movement)

Fell for effusion at the • Knee effusion (small

knee (patella tap, or effusion may be missed
crossfluctuation) by patella tap alone)

Active movement of • Knee flexion

knees (flexion and • Knee extension
extension) and feel
for crepitus

Passive movement • Hip flexion and internal

of hip (knee flexed to rotation
90°, and internal
rotation of hip)

‘Bend forwards and • Forward flexion of

touch your toes’ thoraco-lumbar spine
(and check for scoliosis)

Table adapted and used with permission by Arthritis Research UK (see Free educational
resources).
 pREMS 23

pREMS: paediatric regional examination

of the musculoskeletal system
• Following the musculoskeletal screening examination (pGALS), the
observer is directed to a more detailed examination of the relevant
area, based on the ‘look, feel, move,’ principle described in the adult
regional examination of the musculoskeletal system (called REMS), with
active movements performed first and then passively by the examiner.
• A paediatric version of REMS (called pREMS) has been developed from
observation of clinicians in clinical practice and is the first consensus-
based regional musculoskeletal examination for school-aged children.
• pREMS is similar to adult REMS using the same general principles
(Box 1.7) although it differs by anatomical region reflecting different
pathologies from those observed in adults (Box 1.8).

Box 1.7 General principles

Introduction
• Introduce yourself to child and parent/carer.
• Explain what you want to examine, gain verbal consent to examine.
• Be aware of normal variants in leg alignment, joint range, gait,
developmental milestones.
Look for:
• Swellings, rashes (e.g. psoriasis/vasculitis), muscle wasting, scars,
leg-length discrepancy.
• Deformity/dysmorphism/‘disproportions’/discomfort, i.e. non-verbal
signals.
Feel for:
• Temperature, swelling, tenderness (along bones and joint line).
Movement
• Full range of movement—active and passive (note any asymmetry).
• Restriction—mild, moderate, or severe.
Function and measure
• Functional assessment of joint/anatomical region to include power of
muscles and stability.
• Measurement of height/leg length.
24 CHAPTER 1 Clinical skills and assessment

Box 1.8 Examination schedules by anatomical region

The options refer to additional manoeuvres suggested pending common
clinical scenarios. Details on the examination techniques used are available
(see b ‘Further reading’, p 27).
Examination of the hand and wrist
• Inspect hands (palms and backs) for muscle wasting, skin, and nail
changes.
• Feel for radial pulse, tendon thickening, and bulk of thenar and
hypothenar eminences.
• Feel for skin temperature.
• Squeeze metacarpophalangeal joints (MCPJs).
• Bimanually palpate swollen or painful joints, including wrists.
• Look and feel along ulnar border.
• Assess full finger extension and full finger tuck.
• Assess wrist flexion and extension, abduction and adduction—active
and passive.
• Assess function: grip and pinch, picking up small object, writing/
drawing.
• Options—assess for hypermobility syndromes, muscle power,
capillaroscopy, peripheral neuropathy.
Examination of the elbow
• Look for carrying angle, scars, swellings or rashes, deformity.
• Feel for skin temperature.
• Palpate over head of radius, joint line, medial and lateral epicondyles.
• Assess full flexion and extension, pronation and supination—actively
and passively.
• Assess function—e.g. hand to nose or mouth, hands behind head.
• Options—assess for hypermobility syndromes, muscle power,
instability tests, enthuses.
Examination of the shoulder
With the patient standing or sitting:
• Inspect shoulders, clavicles, and sternoclavicular joints from the front,
side, and behind, and assess shoulder height.
• Inspect skin in axillae and palpate for lymphadenopathy.
• Assess skin temperature.
• Palpate bony landmarks and surrounding muscles.
• Assess movement and function: hands behind head, hands behind
back.
• Assess (actively and passively) external rotation, flexion, extension,
and abduction.
• Observe scapular movement.
• Options—assess for hypermobility syndromes, muscle power,
instability.
Examination of the hip
With the patient supine lying on couch:
• Look for flexion deformity and leg-length discrepancy.
• Check for scars, rashes.
 pREMS 25

Box 1.8 (Contd.)

• Feel the greater trochanter for tenderness.
• Assess full hip flexion, internal and external rotation, abduction and
adduction.
• Perform Thomas’ test.
• Hip abduction (lying on side).
Patient lying prone on couch:
• Sacroiliac joint palpation.
• Hip internal (and external) rotation.
With the patient standing:
• Assess posture and leg alignment.
• Look for gluteal muscle bulk.
• Perform the Trendelenburg test.
• Assess function (gait with turning and running, ancillary movements).
• Options—assess for hypermobility, muscle power, enthesitis,
thigh–foot angle (child with in-toeing).
Examination of the knee
With the patient standing:
• Look for varus/valgus deformity, hyperextension and popliteal
swellings.
• Inspect skin for pattern of bruising and rashes.
• Assess gait (see Examination of the hip, this Box).
With the patient lying on couch:
• Look from the end of the couch for varus/valgus deformity, muscle
wasting, scars, and swellings.
• Look from the side for fixed flexion deformity.
• Check for passive hyperextension and leg-length discrepancy.
• Feel skin temperature.
• With the knee slightly flexed palpate the joint line and the borders of
the patella.
• Feel the popliteal fossa.
• Perform a patellar tap and cross fluctuation (bulge sign).
• Assess full flexion and extension (actively and passively).
• Option: assess stability of knee ligaments—medial and lateral
collateral—and perform anterior draw test.
• Option: tests for anterior knee pain/patellar maltracking/
apprehension/patella glide.
• Option—assess for hypermobility, enthesitis, hamstring tightness,
iliotibial band tightness/thigh–foot angle.
Examination of the foot and ankle
With the patient lying supine on couch:
• Look at dorsal and plantar surfaces of the foot.
• Feel the skin temperature.
• Palpate for peripheral pulses.
• Squeeze the MTPJs.
• Palpate the midfoot, ankle joint line, and subtalar joint.
(continued )
26 CHAPTER 1 Clinical skills and assessment

Box 1.8 (Contd.)

• Assess movement (actively and passively) at the subtalar joint
(inversion and eversion), the big toe (dorsi- and plantar flexion), the
ankle joint (dorsi- and plantar flexion), and mid-tarsal joints (passive
rotation).
• Look at the patient’s footwear.
• Option: assess for hypermobility, thigh–foot angle, enthesitis, muscle
power, capillaroscopy.
With the patient standing:
• Look at the forefoot, midfoot (foot arch), and the hindfoot.
• Assess gait cycle (heel strike, stance, toe off), running and turning,
ancillary movement.
• Assess muscle bulk (calves).
Examination of the spine
With the patient standing:
• Inspect from the side and from behind.
• Inspect skin and natal cleft.
• Inspect limb/trunk proportions.
• Inspect facial and jaw profile.
• Palpate the spinal processes and paraspinal muscles and
temporomandibular joints (TMJs).
• Assess movement: lumbar flexion and extension and lateral flexion;
cervical flexion, extension, rotation and lateral flexion, thoracic
rotation.
• Assess TMJ opening.
• Options: Schober’s test, ‘stork test’.*
With the patient sitting on couch (standing in younger child):
• Assess thoracic rotation.
With the patient lying on couch:
• Perform straight leg raising and dorsi-flexion of the big toe.
• Assess limb reflexes.
• Options: assess for leg-length discrepancy, hypermobility, sacroiliac
joint irritation on palpation.
‘Stork test’—standing on one leg and extension of spine causes pain (suggestive of
spondylolysis)—see b Back pain in children and adolescents, p 100.
 pREMS 27

Further reading
Coady, D, Walker D, Kay L. Regional Examination of the Musculoskeletal System (REMS): a core
set of clinical skills for medical students. Rheumatology 2004. 43(5):633–9.
Foster HE, Kay L, May CR, et al. pREMS—a consensus approach to pediatric regional
musculoskeletal examination. Arthritis Care Res 2011. 63(11):1503–10.
Clinical skills in the evaluation of arthritis Szer IS. Malleson PN. Arthritis in Children and
Adolescents—Eds Szer, Kimura, Malleson and Southwood. Oxford University Press 2006; 3–18.
Houghton KM. Review for the generalist: evaluation of anterior knee. Pediatr Rheumatol 2007; 5:8.
M http://www.ped-rheum.com/content/pdf/1546-0096-5-8.pdf.
Houghton KM. Review for the generalist: evaluation of pediatric foot and ankle pain. Pediatr
Rheumatol 2008; 6:6. M http://www.ped-rheum.com/content/pdf/1546-0096-6-6.pdf.
Houghton KM. Review for the generalist: evaluation of pediatric hip pain. Pediatr Rheumatol 2009;
7:10. M http://www.ped-rheum.com/content/pdf/1546-0096-7-10.pdf.
Houghton KM. Review for the generalist: evaluation of low back pain in children and adolescents.
Pediatr Rheumatol 2010; 8:28. M http://www.ped-rheum.com/content/pdf/1546-0096-8-28.pdf.
Staheli, L.T. Fundamentals of Pediatric Orthopedics—Foot and lower limb. Philadelphia,
PA: Lippincott-Raven, 2008.
28 CHAPTER 1 Clinical skills and assessment

Musculoskeletal ultrasound in juvenile

idiopathic arthritis
Musculoskeletal ultrasound (MSUS) is becoming increasingly used at
the bedside by clinicians (Table 1.11). MSUS is valuable in guiding intra-
articular steroid injections and detecting subclinical disease. MSUS helps
to identify the structures involved in a clinically swollen joint allowing the
operator to distinguish between joint and or tendon or tendon sheath
involvement. Key points to note making MSUS very practical for use in
children:
• MSUS provides images in real time and allows the operator to examine
the joint during motion.
• It provides both anatomical and pathological information.
• It is cheap and quick to perform.
• It is well tolerated by children.
• It is an important adjunct to clinical examination.
• It frequently avoids the need for examinations such as MRI which
require sedation for the younger child, are costly and not always readily
available.

Table 1.11 Musculoskeletal ultrasound in paediatric rheumatology

MSUS is valuable for MSUS is not MSUS is less
the identification of: useful for: useful for:

• Joint effusions • Bone pathology • Deep structures

• Synovial hypertrophy
• Synovitis
• Enthesitis
• Tendonitis
• Tenosynovitis
• Bursa and bursitis

Getting started
• Current ultrasound (US) machines are very user friendly, with
images that are easily recognizable with some practice. However, it is
strongly advised to begin with a basic MSUS course (see b Further
reading, p 31), often available within adult rheumatology and refresh
musculoskeletal anatomical knowledge to enable interpretation of the
images.
• Once the basic technique is mastered then it is important to practise
and become familiar with the US machine as each tends to have its
own unique features.
• Briefly, the probe transmits and receives the US signal. Low frequency
probes (5–10Hz) are useful for large or deep joints such as the hip
and knee, however resolution is lower. High frequency probes >15Hz
have limited penetration and are thus only useful in small joints and
superficial structures. However, they have excellent resolution. The
latter is thus invaluable in paediatric examination of children’s joints.
 MUSCULOSKELETAL ULTRASOUND IN JIA 29

• Scans are usually performed along the longitudinal and transverse axis
of structures to give a ‘3D’ (three-dimensional) image of the joint and
soft tissues.
• Grey scale refers to the processed images received by the probe. Here
hypoechoic (black) structures such as cartilage and joint fluid can be
identified. Hyperechoic (white) structures such as the interface with
bone and intermediate (grey) structures such as muscle, tendon, and
synovial tissue can be seen.
• Power Doppler signal represents blood flow. With the right settings
synovial blood flow representing synovitis can be identified. However,
power Doppler signal is prone to artefact so it is important that the
user is aware of these to avoid erroneous diagnoses.
• The knee joint is a good starting point. It is a commonly involved joint
and the images easy to interpret with a little practice.
• Fig. 1.2 represents a longitudinal scan of the knees of a child aged 8yr,
normal and abnormal. Note the appearance of the partially ossified
patella with the large cartilage halo, the growth plates, the longitudinal
striations of the quadriceps tendon, and the potential space of the
suprapatellar pouch.
Hypoechoic fluid
in suprapatellar
Quadriceps Patella with pouch
cartilage halo Synovial
tendon
hypertrophy

Potential space
suprapatellar pouch

Normal knee Joint effusion

Growth plate
distal femur
Fig. 1.2 MSUS appearance of knee arthritis compared to normal.

• Fig. 1.3 demonstrates positive power Doppler signal in the tendon

sheath of the tibialis posterior tendon.
• Even deeply seated joints such as the hip are easily viewed in
children—MSUS can distinguish between a limited range of movement
in a hip due to damage and that due to active inflammation which can
be difficult to do clinically.
30 CHAPTER 1 Clinical skills and assessment

Tibialis posterior tendon Hypoechoic fluid

Medial malleolus Positive power doppler

signal indicating synovitis
Fig. 1.3 Doppler signal indicating active synovitis in the tibialis posterior tendon at
the ankle joint.

Acetabulum Iliofemoral ligament

Iliofemoral ligament

Femoral head Normal joint Femoral head

Growth plate space and growth Widened joint space
plate with convex contour

Fig. 1.4 Effusion at the hip joint compared to a normal hip.

 MUSCULOSKELETAL ULTRASOUND IN JIA 31

• Fig. 1.4 demonstrates an effusion in a hip joint compared to the

normal contra-lateral normal hip. Note the convex appearance of the
Iliofemoral ligament and the i joint space.
Pitfalls of MSUS in children
• Cartilage appears hypoechoic, similar to joint fluid. Thus pathology can
be over diagnosed; the non-compressibility of cartilage compared to
fluid is an important difference to help discriminate.
• The hypoechoic appearance of growth plates can mimic fractures and
erosions; knowing anatomy relative to age and always viewing in
2 planes is essential.
• Nutrient arteries, especially around growth plates, can mimic synovitis;
knowing the normal appearance of epiphysis and comparing the
contralateral side can be very helpful.
• MSUS findings are user dependent; standardizing procedures and
comparing findings between observers is therefore important. More
work is needed in this area of research.
• There is currently limited published information on the appearance of
joints in healthy children; normative data and images are being collated
in research studies.
Further reading
British Society for Rheumatology ultrasound courses: M http://www.rheumatology.org.uk/education.
EULAR musculoskeletal imaging and courses: M http://www.eular.org.
Mc Nally EG. Practical Musculoskeletal Ultrasound. Philadelphia, PA: Elsevier, 2005.
Wakefield RJ, D’Agostino MA. Essential Applications of Musculoskeletal Ultrasound in Rheumatology.
Philadelphia, PA: Saunders, 2010.
32 CHAPTER 1 Clinical skills and assessment

Autoantibodies
Antibodies are immunoglobulins produced in response to an antigen and
form an important part of the adaptive immune system and our humoral
response to infection. Autoantibodies are formed in response to self-
antigens. The presence of autoantibodies does not imply or inevitably
result in autoimmune diseases, although in some autoimmune diseases the
associated antibodies are directly involved in the pathogenesis e.g. anti-
glomerular basement membrane (GBM) disease; myasthenia gravis; and
anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides.
This chapter describes some of the important and/or frequently observed
autoantibodies in paediatric rheumatology.
Anti-neutrophil cytoplasmic antibodies
(see b The ANCA-associated vasculitide, p 188)
• Antibodies against lysosomal enzymes in neutrophils and (to a lesser
extent) monocytes.
• The main enzymes targeted are myeloperoxidase (MPO) and
proteinase 3 (PR3), however other antigens may also be targeted.
• There are 2 main patterns of staining detectable by indirect
immunofluorescence: perinuclear (pANCA) and cytoplasmic (cANCA).
• About 90% of cANCA is directed against PR3 (PR3-ANCA) and 70% of
pANCA is against MPO (MPO-ANCA).
• PR3-ANCA is commonly seen in Wegener’s granulomatosis; although
it can be detected in some cases of microscopic polyangiitis.
• MPO-ANCA is typically associated with:
• Microscopic polyangiitis.
• Churg–Strauss syndrome (occasional).
• Idiopathic renal limited pauci-immune glomerulonephritis.
• ANCAs are not 100% specific for the ANCA-associated vasculitides:
they can also be positive in chronic infections or malignancy including
tuberculosis, HIV, and Hodgkin’s lymphoma. Atypical ANCA (BPI-
ANCA) are sometimes observed in cystic fibrosis, and are not
necessarily associated with vasculitis in that scenario.
• Atypical pANCA are detected in some forms of inflammatory bowel
disease and may be associated with sclerosing cholangitis, and can also
be drug induced.
Antinuclear antibodies (ANAs)
• ANAs are directed against the cell’s nuclear contents. Titres vary
between laboratories but are usually reported to be ‘positive’ at
1:40–1:80. In clinical practice titres may be significant at 1:320 or higher.
• A positive ANA titre alone is not diagnostic of a specific condition, nor
is ANA necessarily a useful screening test for autoimmune disease.
A positive ANA can be found in up to 15% of normal children.
• A positive ANA can be associated with a variety of conditions
including:
• SLE
• Drug-induced lupus
• Undifferentiated connective tissue disease
• Sjögren’s syndrome
 AUTOANTIBODIES 33

• Juvenile dermatomyositis
• Scleroderma and systemic sclerosis
• Morphoea
• JIA, particularly those who have (or may develop) uveitis.
• Positive ANA is rare in systemic juvenile idiopathic arthritis (sJIA).
• ANA can also occur in immunoglobulin A (IgA) deficiency, viral
infections, neoplasias and may also be drug-induced.
Anti ds-DNA antibodies
• These autoantibodies are highly specific for SLE and are seen in
the majority of children with lupus nephritis. Titres can be useful in
monitoring disease activity however they do not always correlate with
disease activity in all patients.
Rheumatoid factor and anti-cyclic citrullinated
protein (anti-CCP) antibodies
• Classic RF is IgM directed against IgG. RFs of other immunoglobulin
isotypes have been reported but their significance is uncertain.
• <10% of children with JIA are RF+ve. Those who are positive, are
usually older girls with a polyarticular disease course.
• RF can also be positive in SLE and in a minority of patients with
systemic sclerosis.
• RF may also be elevated as an acute phase reactant, for example in
bacterial endocarditis, and so a positive result should be confirmed by
repeating.
• Anti-CCP antibodies are also found in children with RF+ve
polyarthritis.
• Anti-CCP antibodies are less prevalent in JIA than adult RA but
are detectable in a significant proportion of RF+ve patients with
polyarticular-onset JIA.
• There may be a significant relation between anti-CCP positivity and
erosive joint disease in polyarticular RF+ve JIA.
Antiphospholipid antibodies (see b Antiphospholipid syndrome
(APS), p 279)
• These are a heterogeneous group of antibodies which bind to
phospholipids in the cell membrane and include IgG and IgM
anticardiolipin (ACL) Ab, and beta 2-glycoprotein 1 antibodies. The
lupus anticoagulant (LAC) is typically measured using the dilute Russell
viper venom assay (see b Antiphospholipid syndrome (APS), p 279).
• May be positive in p antiphospholipid syndrome, SLE, some
vasculitides, viral infections (often associated with transient ACL
positivity), drug induced, and up to 8% of the normal population.
• Not all ACL are pathogenic, nor is the mechanism of ACL
pathogenicity fully understood. This is an area of ongoing research.
Anti-C1q antibodies
• Cause low C1q and are seen in almost all patients with
hypocomplementaemic urticarial vasculitic syndrome (HUVS), but also
in a variety of other autoimmune conditions such as SLE.
34 CHAPTER 1 Clinical skills and assessment

Extractable nuclear antigens (ENAs)

• A number of ENAs have been identified. In fact not all ENAs are truly
nuclear, some can be directed against cytoplasmic components.
The following may be present in paediatric rheumatology patients
(Table 1.12).

Table 1.12 Common ENAs in paediatric rheumatology

Antibody Common disease association
Anti-RNP mixed connective tissue disease (MCTD), SLE, scleroderma
Anti-histone Drug-induced lupus
Anti-Smith SLE—possible association with central nervous system
(CNS) disease when present along with anti U1 RNP
SS-A/anti-Ro SLE, Sjögren’s syndrome
SSB/anti-La Anti-Ro and anti-La are associated with recurrent
spontaneous abortions, heart block in neonatal lupus and
may be detectable in ANA−ve lupus.
Anti-SCL-70 Diffuse systemic sclerosis.
Anti-centromere Systemic sclerosis and related disorders; may be associated
with an i risk of developing calcinosis and telangiectasia.
May be a risk factor for developing pulmonary hypertension,
gastrointestinal involvement, and Raynaud’s phenomenon.
Anti-LKM Some forms of autoimmune hepatitis
Smooth muscle Post-viral infection; some forms of autoimmune hepatitis
antibodies

Other autoantibodies
• There are many other organ-specific and non-organ-specific
autoantibodies associated with paediatric autoimmune disease beyond
the scope of this chapter.
• These include antibodies against components of the nephron and
lung (notably anti-GBM antibodies); renal tubules; striated muscle;
endocrine and reproductive organs; components of the brain
(associated with the emerging and increasingly described autoimmune
encephalopathies); peripheral nervous system (including myasthenia
gravis); the gastrointestinal tract; skin; and many others.
• Not all of these fulfil Koch’s postulates as the defined cause of the
disease, although some are directly involved in the pathogenesis of the
associated disease.
 THERMOGRAPHY IN RHEUMATIC DISEASE 35

Thermography in rheumatic disease

Introduction
Thermography is a non-invasive technique able to detect infrared radia-
tion and provide an image of the temperature distribution across the body
surface. The skin temperature is influenced by the skin vasculature or by
the conduction of heat generated in structures deeper to the skin surface
and this can be detected by thermography.
Indications
• Assessment of inflamed joints.
• Response to cold challenge of the hands in Raynaud’s phenomenon.
• Detection of disease activity and monitoring of treatment in
scleroderma.
Preparation
• The environmental temperature should be 22–24°C.
• Patients should remove their clothing from the area to be examined for
at least 15min prior to examination to balance the body temperature
with the environment.
• The infrared camera should be allowed to acclimatize with the room
temperature and be calibrated.
Techniques
• The infrared camera should be focused and the distance from the
camera to patient should be recorded.
• A thermograph (static, single image) of the relevant lesion is taken.
• For comparison, images of the matching opposite site or surrounding
skin are also taken.
Images and interpretation
• Images are analysed for skin asymmetries with corresponding opposite
sites or surrounding skin. Lesions are considered active (or positive)
on thermography and appear red when the affected area is more
than 0.5°C warmer than the matching opposite limb or body site.
Alternatively this can be 0.5°C warmer than the surrounding skin if
bilateral sites are involved.
• In Fig. 1.5 the lesion on the right leg as indicated by the 3 arrowheads
was clinically causing limb-length discrepancy. The corresponding
thermal image prior to treatment shows i temperature on the affected
area representing an active lesion.
• Thermography can also be used after the onset of treatment, in which
you would expect to see cooling of the initial ‘hot’, active lesion.
Limitations
• Changes in heat conduction through the skin from deep tissues in
lesions associated with extensive subcutaneous atrophy can lead to
‘false-positive’ thermograms so older scleroderma lesions can often
appear ‘active’ despite their clinical inactivity.
• Thermography is only a substitute measure of blood flow, laser
Doppler techniques provides a direct measure of blood flow.
36 CHAPTER 1 Clinical skills and assessment

(a)

(b) 36.0 °C

34

32

30
30.0 °C
Fig. 1.5 (a) Clinical and (b) thermographic images of a patient with linear
morphoea.
 NAILFOLD CAPILLAROSCOPY IN RHEUMATIC DISEASE 37

Nailfold capillaroscopy in rheumatic

disease
Introduction
• Nailfold capillaroscopy is a useful, non-invasive investigation.
• Morphological changes of the finger nailfold capillaries (NFCs)
can be directly visualized with magnification and appear to reflect
microvascular abnormalities in many rheumatological conditions.
• Nailfold capillaroscopy can be employed when clinical features suggest an
underlying connective tissue disease (CTD) or vasculopathy (Table 1.13).

Table 1.13 When to consider nailfold capillaroscopy

Underlying cause Clinical features
Non-specific/ Fever, anorexia, nausea, lethargy, easy fatiguability,
constitutional non-specific pain, weakness
Raynaud’s Primary Raynaud’s disease: if RP occur in the absence
phenomenon (RP) of a definable underlying disease
Secondary Raynaud’s syndrome: if RP is associated
with a connective tissue disease/vasculopathy
Juvenile Muscle weakness, heliotrope rash, Gottron’s papules
dermatomyositis (JDM)
Progressive systemic Raynaud’s syndrome, peripheral skin tightening and
sclerosis/scleroderma ulceration, respiratory symptoms, abdominal pain,
malabsorption
Other vasculopathy/ (Although many do not appear to have prominent
vasculitis nailfold capillaroscopy abnormalities)
SLE and Fever, malaise, joint pain, myalgia, fatigue, malar rash
undifferentiated CTD

Preparation
• The environmental temperature should be 20–24°C.
• Both hands must be uncovered at least 30min before the examination
to balance the body temperature with the environment.
• Place a drop of water, immersion oil or aqua gel over the edge of the
nailfold and look through this to reduce the reflections of the keratin
layer.
Techniques
• Hand-held ophthalmoscope:
• Set the magnification (dioptres) to at least +20 or preferably +40.
• Use the ‘non-ophthalmoscope’ hand to hold the patient’s fingertip
and bring the ophthalmoscope to within about 0.5cm of the nailfold
with the drop of fluid (typically KY-jelly) on it.
• Small adjustments in the distance between the ophthalmoscope
head and the nailfold will bring the capillaries into sharp focus.
38 CHAPTER 1 Clinical skills and assessment

• Hand-held dermatoscope:
• Easier to use than a hand-held ophthalmoscope and can be attached
to a digital camera, but does not give as much magnification (x10)
• 2 types: either an oil immersion (technique as for ophthalmoscope)
or cross-polarized dermatoscope which can be placed directly on
the nailfold.
• Direct capillaroscopy using a dissecting stereomicroscope (such as an
Olympus SZ-40).
Images and interpretation
6 parameters aid more precise definition:
• Capillary density, capillary width, capillary tortuosity, visible avascular
areas, capillary disarrangement, number of abnormal vessels (Fig. 1.6a–e).
Healthy children (HC) have a lower density of capillaries than healthy
adults (HA) (Fig. 1.7). JDM and scleroderma (grouped as CTD) demon-
strate significantly reduced capillary density compared with HC and other
childhood rheumatological diseases (JIA, SLE, primary Raynaud’s disease,
(RD) and vasculitis).
Limitations
• If the patient has ‘vertical capillary loops,’ as marked abnormalities can
only be visualized if present in the horizontal plane.
• Fingernail/cuticle biters may traumatize the nailfold and disrupt the
capillary appearance.
• It is unclear whether nailfold capillaroscopy is useful for disease
monitoring. Some patients with a previous CTD may continue to have
abnormal NFCs for years after disease remission.
 NAILFOLD CAPILLAROSCOPY IN RHEUMATIC DISEASE 39

(a)

(b)

(c)

Fig. 1.6 (a) Nailfold capillaries. Normal pattern of NFCs (original magnification
×66). Regular pattern of thin ‘hairpin’ loops. There is an uncommon normal
anatomical variation where the capillaries loop more vertically up towards the
surface of the skin, so the horizontal ‘hairpin’ appearance may not always be seen.
(b) Naked eye view. Note the tiny red dots on the nailfolds.
(c) Hand-held ophthalmoscope at +40 dioptres. Note irregular size and pattern of
capillaries.
40 CHAPTER 1 Clinical skills and assessment

(d)

(e)

Fig. 1.6 (continued ) (d) Abnormal NFCs (original magnification x66). Dilated
capillaries with reduced number in the field of view.
(e) Abnormal NFCs (original magnification x66). Abnormal ‘bushy’ shapes and bare
areas suggesting capillary drop out.

14 P<0.01 P<0.001
12
10
Cap/mm

8
6
4
2
0
HA HC JIA SLE CTD RS Vasc
Fig. 1.7 Differences in nailfold capillary density in childhood rheumatic diseases.
Reproduced from Dolezalova P, Young SP, Bacon PA, et al. Nailfold capillary
microscopy in healthy children and in childhood rheumatic diseases: a prospective
single blind observational study. Ann Rheum Dis 2003; 62:444–9.
 OUTCOME MEASURES IN PAEDIATRIC RHEUMATOLOGY 41

Outcome measures in paediatric

rheumatology
When it is not possible to cure a disease, it is important to determine how
far treatment and disease compromise the child’s quality of life (QoL).
Measures of disease activity and pain guide immediate intervention, but
broader holistic assessments of mental, physical, family, and social func-
tioning, life satisfaction, and well-being are outcomes ultimately valued by
the patient and family. Since there is a degree of subjectivity, each measure
has to be reliable (repeatable on more than one occasion), valid (asks the
right questions), and responsive (sensitive to true changes in patient’s con-
dition to guide effective care). A summary of the outcome measure often
used in paediatric rheumatology is given in Table 1.14.
The American College Rheumatology (ACR) Core Outcome Variables are
the standard composite measure for disease activity in juvenile arthritis,
used successfully in most drug trials of JIA since defined in 1997. The 6
variables are:
• Active 71-joint count
• Restricted 71-joint count
• CHAQ
• Patient global and physician global assessments (10cm visual analogue
scales: 0cm = well; 10cm = unwell)
• ESR.
Improvement is defined as 30% improvement from baseline in 3 of 6 vari-
ables (so called ACR30) with no more than one of the remaining variables
deteriorating by more than 30%. ACR50 and ACR70 represent greater
levels of improvement and the criteria can be used to define flares of
arthritis (worsening in 2 variables by 40%). The most responsive measure
is the physician global assessment of disease activity, and active joint count.
Least responsive is the CHAQ and ESR/CRP. The JADAS, a modification
of the variables, provides a numeric score.

Table 1.14 Outcome measures in paediatric rheumatology

Outcome Components/scope Comments
measure
Disease activity
ACR core Standard assessment in JIA assessing
outcome 6 variables (see b Outcome measures
variables in paediatric rheumatology, p 41)
Juvenile Composite score of physician VAS, Scored out of 57.
Arthritis Disease parent/patient VAS, active 27-joint Other JADAS
Activity Score count and normalized ESR versions available
(JADAS-27)
(see b Disease
activity scores in
rheumatoid arthritis
and JIA, p 165)

(continued )
42 CHAPTER 1 Clinical skills and assessment

Table 1.14 (Contd.)

Outcome Components/scope Comments
measure
Childhood 14-item quantitative assessment Scored out of 53.
myositis of muscle strength and endurance. Requires trained
assessment Used in JDM along with global personnel. Manual
scale (CMAS) assessments of activity and myometry testing may
CHAQ be an alternative
(see b Juvenile
dermatomyositis, p 266)
British Isles Scoring based on the physicians BILAG has been
Lupus intention to treat and used in adapted for paediatric
Assessment association with biological data use. An alternative is to
Group index and global assessments use SLEDAI
(BILAG)
(see b British Isles
Lupus Assessment
Group (BILAG) 2004
Index, p 248 and
Table 4.11)
Paediatric Scoring based on the physicians Adapted from the adult
vasculitis intention to treat BVAS (Birmingham
activity score Vasculitis Activity
(PVAS) Score) tool and validity
is being assessed
Damage measures
Juvenile Assesses articular (36 joints) and
arthritis damage extra-articular (5 organs including
index (JADI) eyes) damage
Systemic Lupus See lupus section
International (b SLICC/ACR Damage Index
Collaborative (paediatric), p 258)
Clinics (SLICC)
Paediatric Cumulative index of items Adapted from VDI
vasculitis damage persisting for 3 months and validity is being
index (pVDI) or more assessed
Physical function
Childhood Standard tool. Takes 10min Translated in to many
health to complete 8 domains, languages. Forms for
assessment focusing on disability and child (8–19yr) & parent
questionnaire discomfort. Easy to score (patient 2–19yr).
(CHAQ) and interpret Insensitive to short term
(see b The Child Health changes in children.
Assessment Questionnaire
(CHAQ), p 45)
Juvenile arthritis Comprehensive assessment Requires standardized
functional of function in children >7yr equipment and trained
assessment using 10 timed tasks health professionals.
scale (JAFAS) Responsiveness not known
 OUTCOME MEASURES IN PAEDIATRIC RHEUMATOLOGY 43

Table 1.14 (Contd.)

Outcome Components/scope Comments
measure
Juvenile arthritis 23-item evaluation of both
functional child (>7yr) and parent reports
assessment
report (JAFAR)
Juvenile arthritis Short 15-item questionnaire Responsive and
functionality of function in lower limbs, discriminative
scale (JAFS) hand/wrist and upper segment
Functional Health status (eating, play
status measure behaviour, sleep, and emotional
FSII (R) health) of children 0–16yr
Child activity Assesses impairment due to
limitations recurrent pain in school age
interview children and adolescents
(CALI)
Health status and quality of life
Child health Domains in health perception, Adapted from the SF-36.
questionnaire function, behaviour, mental Sensitive to clinical
(CHQ) health, impact on parents, family change in children with
cohesion, limitations in family JIA
activity, activities with friends,
change in health, bodily pain,
school, work, self-esteem
Paediatric A quick (23-item) measure Versions for both parents
Quality of for healthy and sick children and children.
Life Inventory aged 2–18yr assessing physical, A PedsQL rheumatology
(PedsQoL) emotional, social and school module takes 10–15min
functioning
Juvenile Disease specific measure Successful in adolescents
arthritis quality of physical and psychosocial
of life function
questionnaire
(JAQQ)
EQ5D Generic health utility index Valid for JIA
(EuroQoL) extensively used in adult studies
VAS, visual analogue score.
44 CHAPTER 1 Clinical skills and assessment

Interpretation of outcome measures needs to consider a child’s changing

cognitive skills, needs, and expectations and a parent’s physical and emo-
tional well-being, relationships, and adjustment. Parents are used as proxy
respondents and the level of parent/child agreement varies for disability,
pain and QoL with good correlation for CHAQ. Adolescents are less
positive than parents about health and well-being. Parent and physician
reports tend to agree in 70% of cases with over-rating by parents in 20%
(typically due to pain intensity) and over-rating by physician in 12% (typi-
cally rated to CRP and a number of active joints). Other problems include
ceiling and floor effect, e.g. a patient may continue to improve or deterio-
rate but the test does not capture this change.
Further reading
Moorthy LN, Peterson MG, Harrison MJ, et al. Physical function assessment tools in pediatric
rheumatology. Pediatr Rheumatol Online J 2008; 6:9.
Ruperto N, Ravelli A, Falcini F, et al. Performance of the preliminary definition of improvement
in juvenile chronic arthritis patients treated with methotrexate. Italian Pediatric Rheumatology
Study Group. Ann Rheum Dis 1998; 57:38–41.
 THE CHILD HEALTH ASSESSMENT QUESTIONNAIRE (CHAQ) 45

The Child Health Assessment

Questionnaire (CHAQ)*
*
Adapted from Singh G, Athreya B, Fries J, et al. Measurement of health status in children with
juvenile rheumatoid arthritis. 1994. Arthritis Rheum 37:1761–9.

CHAQ scoring (see Table 1.15)

1. Each of the 8 sections or scored for the highest value tick in its own
section
• 0 for ‘without any difficulty’ or ‘not applicable’
• 1 for ‘with some difficulty’
• 2 for ‘with much difficulty’
• 3 for ‘unable to do’
2. Then look at the section that refers to help required by aids or devices
or another person
• If any of these are ticked look at the section that the comment
refers to.
• If that section is scored a 0 or 1 than increase it to a 2.
• If that section scored 2 leave it as a 2.
• If that section scored 3 leave it as a 3.
3. Add the eight totals and divide that total by 8 (see Table 1.16) to
derive the CHAQ score (0–3)
4. In addition, pain and general evaluation are scored on a 10cm visual
analogue score were 0 signifies no pain and normal functioning, and 10
signifies severe pain and severe limitation of functioning.
 46
Table 1.15 Childhood Health Assessment Questionnaire

CHAPTER 1
PATIENT HOSP NO: DATE:
NAME:

Clinical skills and assessment

In this section we are interested in learning how your child's pain affects his/her ability to function in daily life. Please feel free to add any comments on the back
of this page. In the following questions, please tick the one response which best describes your child's usual activities OVER THE PAST WEEK. If most children
at your child's age are not expected to do a certain activity, please mark it as "Not Applicable". For example, if your child has difficulty in doing a certain activity
or is unable to do it because he/she is too young but not because he/she is RESTRICTED BY PAIN or ILLNESS, please mark it as "NOT Applicable".
Without ANY With SOME With MUCH UNABLE Not
Difficulty Difficulty Difficulty To do Applicable
DRESSING & PERSONAL CARE
Is your child able to:
- Dress, including tying shoelaces and doing buttons? ο ο ο ο ο
- Shampoo his/her hair? ο ο ο ο ο
- Remove socks? ο ο ο ο ο
- Cut fingernails? ο ο ο ο ο
GETTING UP
Is your child able to:
- Stand up from a low chair or floor? ο ο ο ο ο
- Get in and out of bed or stand up in a cot? ο ο ο ο ο
 Without ANY With SOME With MUCH UNABLE Not
Difficulty Difficulty Difficulty To do Applicable
EATING

THE CHILD HEALTH ASSESSMENT QUESTIONNAIRE (CHAQ)

Is your child able to:
- Cut his/her own meat? ο ο ο ο ο
- Lift up a cup or glass to mouth? ο ο ο ο ο
- Open a new cereal box? ο ο ο ο ο
WALKING
Is your child able to:
- Walk outside on flat ground? ο ο ο ο ο
- Climb up five steps? ο ο ο ο ο
* Please tick any AIDS or DEVICES that your child usually uses for any of the above activities:
- Walking stick ο - Devices used for dressing (button hook, zip pull, ο
long-handled shoe horn, etc.)
- Walking frame ο - Built up pencil or special utensils ο
- Crutches ο - Special or built up chair ο
- Wheelchair ο - Other (Specify:_____________________________) ο

* Please tick any categories for which your child usually needs help from another person BECAUSE OF PAIN or ILLNESS:
- Dressing and personal care ο - Eating ο
- Getting up ο - Walking ο

47
 48
CHAPTER 1
HYGIENE
Is your child able to:
- Wash and dry entire body? ο ο ο ο ο
- Take a bath (get in and out of bath)? ο ο ο ο ο

Clinical skills and assessment

- Get on and off the toilet or potty? ο ο ο ο ο
- Brush teeth? ο ο ο ο ο
- Comb/brush hair? ο ο ο ο ο
REACH
Is your child able to:
- Reach and get down a heavy object such as a large ο ο ο ο ο
game or books from just above his/her head?
- Bend down to pick up clothing or a piece of paper ο ο ο ο ο
from the floor?
- Pull on a jumper over his/her head? ο ο ο ο ο
- Turn neck to look back over shoulder? ο ο ο ο ο
GRIP
Is your child able to:
- Write or scribble with pen or pencil? ο ο ο ο ο
- Open car doors? ο ο ο ο ο
- Open jars which have been previously opened? ο ο ο ο ο
- Turn taps on and off? ο ο ο ο ο
- Push open a door when he/she has to turn a door knob? ο ο ο ο ο
 Without ANY With SOME With MUCH UNABLE Not Applicable
Difficulty Difficulty Difficulty To do

THE CHILD HEALTH ASSESSMENT QUESTIONNAIRE (CHAQ)

ACTIVITIES
Is your child able to:
- Run errands and shop? ο ο ο ο ο
- Get in and out of a car or toy car or school bus? ο ο ο ο ο
- Ride bike or tricycle? ο ο ο ο ο
- Do household chores (e.g. wash dishes, take out ο ο ο ο ο
rubbish, hoovering, gardening, make bed, clean room)?
- Run and play? ο ο ο ο ο
* Please tick any AIDS or DEVICES that your child usually uses for any of the above activities:
- Raised toilet seat ο - Bathrail ο

- Bath seat ο - Long-handled appliances for reach ο

- Jar opener (for jars previously opened) ο - Long-handled appliances in bathroom ο

* Please tick any categories for which your child usually needs help from another person BECAUSE OF PAIN:
- Hygiene ο - Gripping and opening things ο

- Reach ο - Errands and chores ο

49
 50
CHAPTER 1
PAIN
- How much pain do you think your child has had IN THE PAST WEEK?
- Place a mark on the line below, to indicate the severity of the pain

Clinical skills and assessment

No pain 0 ________________________________________________________ 100 Very severe pain

GENERAL EVALUATION: Considering all the ways that your child’s pain or illness affects him/her, rate how he/she is doing by placing a single mark
on the line below (* Core assessment*)

Very well 0 ________________________________________________________ 100 Very poor

Person/s completing questionnaire:- SCORE:

Mother …
Father …
Child … Other … Date of completion: ______________
Table 1.16 Converting the CHAQ responses into a final score
Eighths CHAQ score Eighths CHAQ score Eighths CHAQ score

THE CHILD HEALTH ASSESSMENT QUESTIONNAIRE (CHAQ)

1 0.125 9 1.125 17 2.125
2 0.25 10 1.25 18 2.25
3 0.375 11 1.375 19 2.375
4 0.5 12 1.5 20 2.5
5 0.625 13 1.625 21 2.625
6 0.75 14 1.75 22 2.75
7 0.875 15 1.875 23 2.875
8 1 16 2 24 3

51
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 Chapter 2 53

Common and important

clinical problems

Musculoskeletal presentations and non-accidental injury 54

Malignancy and musculoskeletal presentations 56
Bone tumours 60
Bone and joint infections 64
Infections in the immunocompromised 70
Fractures in children and adolescents 76
The limping child 80
Pain syndromes and the assessment of pain 87
Growing pains 92
Pyrexia of unknown origin 94
Back pain in children and adolescents 100
Scoliosis 103
Hip pain and hip problems in children and adolescents 106
Knee pain in children and adolescents 117
Foot and ankle problems 121
Joint hypermobility 124
54 CHAPTER 2 Common clinical problems

Musculoskeletal presentations and

non-accidental injury
Child maltreatment is common, serious, and can be fatal. The true incidence
of child abuse is difficult to ascertain (and it is probably under-diagnosed
and under-reported) but a national survey amongst 18–24yr-olds con-
ducted in the UK reports a prevalence of 7% describing ‘serious physical
abuse’ in their childhood years. Early detection and intervention may help
to prevent further abuse and limit resulting damage to the child. It is there-
fore important that all medical staff who have contact with children are
aware of the possibility of non-accidental injury (NAI) and consider this
where there are features of concern and that professionals are familiar
with the procedures to be followed if abuse or neglect is suspected.
Possible musculoskeletal presentations of NAI include:
• A child with a limp or loss of function of a limb, which may result
from a fracture or soft tissue injury with no history of trauma or an
inadequate history.
• Joint swelling which may be due to haemarthrosis resulting from
trauma (although JIA is a much more common cause of joint swelling in
childhood).
• Direct impact injury to fingers may cause fusiform swelling which may
mimic symmetrical small-joint arthritis.
• Cold injury may produce redness and swelling of hands and feet.
• A history of inconsistent or unexplained symptoms or clinical findings
may be indicative of factitious or induced illness (FII).
Conversely, NAI may occasionally be suspected in cases
where the underlying cause is a rheumatological disease:
• Vasculitis or panniculitis presenting with bruising, purpura, or soft tissue
swelling in the absence of a history of trauma.
• Henoch–Schönlein purpura should be identifiable by its characteristic
evolution from urticarial lesions to purpura and by the associated
abdominal pain and arthritis. The typical distribution is a symmetrical
rash on the buttocks and lower limbs but the rash may occur
elsewhere.
• Chilblains have been misdiagnosed as NAI.
• Infantile cortical hyperostosis or Caffey’s disease may present with
multiple areas of soft tissue swelling, bone lesions, and irritability in
a young infant and has been mistaken for NAI.
• Degos disease is a rare occlusive vasculopathy that can present
with subdural effusions and an ulcerative skin rash which may mimic
cigarette burns.
• Remember children with rheumatological disease may also be
subjected to abuse and considering safeguarding issues is an important
role of the paediatric rheumatology MDT (see b The multidisciplinary
team, p 378).
 MUSCULOSKELETAL PRESENTATIONS AND NAI 55

Features in the presentation suggestive or supportive of

a diagnosis of NAI
• Usually, one single feature is not diagnostic of abuse, but it is the
overall pattern of presentation that is suspicious.
• Vague, unwitnessed, inconsistent, discrepant history.
• Inappropriate carer response, e.g. delayed presentation.
• Previous or ongoing social concerns.
• Repeated presentations to A&E departments with episodes of poorly
explained trauma.
• Features which may indicate neglect such as:
• Inappropriate or dirty clothing
• Failure to thrive,
• Developmental impairment
• Behavioural difficulties.
• Bruises in children should be assessed in the context of the child’s
medical and social history, developmental stage, and explanation given.
Maltreatment may be suggested by bruises:
• In children who are not independently mobile
• Away from bony prominences
• To particular sites, e.g. face, back
• That are multiple and in clusters (e.g. fingertip bruises)
• With imprint of implement.
• Fractures: no fracture in isolation is pathognomonic of child abuse.
Features of concern include:
• Fractures inconsistent with the developmental stage of the child or
where there is an inadequate explanation as to cause.
• Multiple fractures of different ages.
Principles of management of suspected NAI
• The child’s welfare is paramount. In particular, the child’s best interests
over-ride other considerations such as confidentiality and the carer’s
interests.
• Discuss concerns with senior colleagues or the lead or designated
professional for child protection.
• Record history and observations carefully.
• If you have concerns that a child may be being abused or neglected
you have a responsibility to refer to children’s social care so that
a multi-agency assessment can take place.
Further reading
Cawson P, Wattam C, Brooker S, et al. Child maltreatment in the United Kingdom: A study of the
prevalence of abuse and neglect. London: NSPCC, 2000. M http://www.nspcc.org.uk/inform/
research/findings/childmaltreatmentintheunitedkingdom_wda48252.html.
HM Government Department for children, schools and families. Working together to safeguard
children: A guide to inter-agency working to safeguard and promote the welfare of children. London:
DfE, 2010.
Welsh Child Protection Systematic Review Group. Core-info: Bruises on Children. Available at:
M http://www.core-info.cf.ac.uk.
Welsh Child Protection Systematic Review Group. Core-info: Fractures in Children. Available at:
M http://www.core-info.cf.ac.uk.
56 CHAPTER 2 Common clinical problems

Malignancy and musculoskeletal

presentations
• In childhood malignancies, it is estimated that up to 2/3 of children have
musculoskeletal manifestations at initial presentation.
• Bone pain, myalgia, and articular symptoms such as arthritis and
arthralgia are all well described.
• Malignancy can occasionally present with arthritis, mimicking JIA and
should be excluded in all children with musculoskeletal complaints to
avoid diagnostic delay.
• An incorrect diagnosis of JIA and resulting pre-treatment with
corticosteroids or cytotoxic agents such as methotrexate (MTX) may
cause difficulty with bone marrow interpretation and may even lead to
a poor response to chemotherapeutic agents.
• It is reported that neoplasia accounts for 1% of referrals to paediatric
rheumatology services. The majority of these malignancies are
accounted for by leukaemias and lymphomas, but occasionally such
musculoskeletal findings may occur as a result of solid tumours.
Leukaemia
• Leukaemia is by far the commonest form of cancer in children,
accounting for 30% of all childhood malignancies, with acute
lymphoblastic leukaemia (ALL) representing the majority.
• Arthritis is noted in >25% at presentation. Large joints are more
frequently involved than small joints and an oligoarticular course more
commonly reported than a polyarticular course.
• Distinguishing ALL from JIA can be difficult. Clinical and laboratory
features that may help discriminate ALL from JIA are outlined in
Box 2.1.
• Children with ALL and joint or bone disease often report intense
continuous pain that is often out of context with clinical findings.
• Affected children typically have exquisite tenderness across the
metaphysis of the surrounding bones of the swollen joints.
• Progressive anaemia is the most common haematological change, with
changes in platelet count and white cell counts (WCCS) less frequently
seen.
• It is imperative to be aware that a normal/low WCC and normal blood
film can be seen, especially in the early stages of ALL, and may remain
normal for weeks and months after onset of joint symptoms.
• The pathognomonic leukaemic cells or blast cells are typically absent at
the onset of the disease.
• Systemic features such as daily fever and hepatosplenomegaly can
occur with all types of neoplasia and can mimic childhood rheumatic
diseases such as systemic onset JIA and connective tissue disorders.
 MALIGNANCY AND MUSCULOSKELETAL PRESENTATIONS 57

Box 2.1 Red flags! Features suggestive of malignancy

rather than JIA
• Severe metaphyseal tenderness or other non-articular bone pain.
• Intense continuous pain and immobility.
• Nocturnal pain (especially if unilateral).
• Back pain.
• Absence of early morning stiffness.
• Low/normal WCC; low/normal platelet count; dropping Hb; normal
serum ferritin with systemic features (rash, fever).
• Arthritis with raised LDH levels.*
• Abnormal blood film (not always present).
• Radiological findings of metaphyseal radiolucent bands, periosteal
reaction, sclerotic and osteolytic lesions.
Presence of abnormal blood count and nocturnal pain has a sensitivity
and specificity 85% for ALL.
*
Raised LDH alone has a low sensitivity in distinguishing JIA from ALL.

Investigations
• Routine blood tests including: FBC and blood film, routine clinical
chemistry (U&Es, LFTs, bone biochemistry), ESR, CRP.
• Serum LDH, uric acid.
• Plain film X-rays (Fig. 2.1).
• Bone marrow aspirate and trephine.
Management
• With the initiation of appropriate treatment for ALL, the associated
arthritis will usually quickly resolve.
• The use of analgesia in the form of NSAIDs and supportive measures
from physiotherapy and occupational therapy is beneficial particularly
in the acute state of the illness, and can be particularly useful
symptomatically whilst investigations are completed and definitive
treatment started.
Lymphoma
• Musculoskeletal symptoms in association with lymphoma are less
commonly seen than with ALL.
• Bone pain is the commonest feature described and a true arthritis is
rarely seen.
• Non-Hodgkin and Hodgkin lymphomas can cause bone pain as a result
of direct invasion of the cortex or marrow by the tumour leading to
bone infarction.
• Other causes of bone pain result from hypertrophic osteoarthropathy
that stimulates an acute and painful periostitis.
• Lymphomas need in particular to be excluded in those with suspected
systemic onset JIA, as many overlapping clinical features exist such as
arthralgia, fever, malaise, splenomegaly, and lymphadenopathy.
• The lymphadenopathy in lymphomas is often described as matted and
may be more rubbery than that of systemic onset JIA, although these
are not reliable distinguishing features.
• Abdominal/thoracic imaging (US/CT scan).
58 CHAPTER 2 Common clinical problems

• Lymph node biopsy: lymph node removal by excision is preferred over

needle biopsy, and should be performed in all patients where possible.
Neuroblastoma
• The commonest solid tumour in toddlers and also the commonest
tumours to occur outside the CNS in children are neuroblastomas.
• As 75% of children have metastatic disease including bone involvement
at diagnosis, musculoskeletal symptoms (in particular bone pain) are
frequently reported.
• Back pain in any young child or toddler is a cause for alarm and urinary
catecholamines and catecholamine metabolites (VMA and HVA) are
warranted in addition to imaging such as MRI.
• Lytic lesions may be visible on plain film x-ray as well as the other red
flags outlined in Box 2.1.
Osteoid osteoma
See b Bone tumours, p 60.
Osteosarcoma
See b Bone tumours, p 60.
Further reading
Barbosa CM, Hilario MO, Terreri MT, et al. Musculoskeletal manifestations at the onset of acute
leukaemias in childhood. J Pediatr (Rio J) 2002; 78:481–4.
Cabral DA, Tucker LB. Malignancies in children who initially present with rheumatic complaints.
J Pediatr 1999; 134:53–7.
Robazzi TC, Mendonca N, Silva LR, et al. Osteoarticular manifestations as initial presentation
of acute leukemias in children and adolescents in Bahia, Brazil. J Pediatr Hematol Oncol 2007;
29:622–62.
 MALIGNANCY AND MUSCULOSKELETAL PRESENTATIONS 59

(a)

(b) (c)

Fig. 2.1 X-ray images of ALL. The bones are osteopenic. There is periosteal reaction
along both distal radius and ulna (a). There is patchy metaphyseal sclerosis and
lucency of both wrists (a), also at both ankle joints (b, c). Faint periosteal reaction is
visible along the lateral distal tibia (c).
60 CHAPTER 2 Common clinical problems

Bone tumours
Presentation
Bone tumours (benign or malignant) can present with unexplained pain and
swelling. Malignant bone tumours are rare but life threatening and early
detection is important. The following clinical features may be present:
• Pain—worse at night.
• Swelling—initially soft-tissue oedema; later bony enlargement and soft
tissue extension.
• Cachexia and weight-loss.
• Coincidental injury. Not causative but may bring attention to swelling.
• Pathological fracture through the lesion (5–10%).
• Rarely, symptoms of metastases to lung. Shortness of breath, chest
pain, haemoptysis.
Principles of investigation and management
• Patients with suspicious lesions should be referred urgently to a
specialist bone tumour MDT for biopsy (which requires careful
planning) and further treatment. Referral should not wait for further
imaging investigations.
• Blood tests may show raised inflammatory markers (but not always),
serum alkaline phosphatase or lactate dehydrogenase (LDH).
• Imaging:
• Plain x-ray is mandatory and detects most p bone tumours.
• MRI—delineates local extent of tumour, size of associated soft
tissue mass, involvement of critical anatomical structures, skip
lesions in malignant tumours, and allows biopsy planning.
• CT and whole body isotope bone scan aid staging for malignant
p bone and soft tissue tumour. Metastases occur most frequently in
the lungs or lymph nodes.
• US—helpful screening investigation for soft tissue masses, can
confirm a diagnosis of benign lipoma or vascular malformation, and
may also show intralesional calcification, e.g. in synovial sarcomas.
• Biopsies provide a histological diagnosis and tumour grading; they
should be performed by the surgical team who will perform the
definitive resection.
• Staging systems depend on the diagnosis, histological grade of
the tumour, size of the tumour, and the presence or absence of
metastases. Staging determines future management.
Malignant bone tumours (Fig. 2.2)
Most common malignant bone tumours are osteosarcoma (55%) and Ewing’s
sarcoma (35%). Chondrosarcoma is extremely rare in children (<5%).
 Suspected malignant
Ewing’s sarcoma (35%) tumour of bone Osteosarcoma (55%)

X-ray X-ray
• Lytic, moth-eaten, permeative History, examination, & X-ray • ‘Sunburst’ periosteal bone
appearance formation
• ‘Onion Peel’ laminated new bone • Osteoid matrix permeating into
formation Refer to MDT soft tissues
• Pathological fracture 5–10% • Pathological fracture 5–10%
Children especially adolescents Adolescents during growth spurt
White 6:1 black MRI Male 1.6:1 Female
• Shows local extent 9 skip
Diaphyses of long bones lesions Metaphyses of long bones
• Femur (25%) • Distal femur (40%)
• T1 images–hypointense
• Tibia (10%) • Proximal tibia (20%)
• Humerus (10%) • T2 images–hyperintense • Proximal humerus (10%)
Fever, dHb, iWBC, iESR • ‘Skip lesions’ Intramedullary (95%)
• Must be distinguished from • Within same bone • High grade (90%)
osteomyelitis • Across adjacent joint • Low grade (10%)
• Plan biopsy Surface (≅5%)
• High grade (10%)
• Low grade (90%)
Malignant small-cell tumour Soft-tissue/intracortical (rare)
Biopsy to confirm diagnosis
Reciprocal translocation between
chromosomes 11 & 22, bands q24 and q12
CT chest Malignant osteoid formation
• t(11;22)(q24;q12)
• Staging investigation
• Both tumours metastasise to
lung
• Vincristine
• Doxorubicin • Platinum (cisplatin)
• Cyclofosfamide Neo-adjuvant chemotherapy • Anthracycline (doxorubicin)
• Ifosfamide • High-dose methotrexate
• Etoposide

BONE TUMOURS
Local treatment*

Adjuvant chemotherapy
Post-operative radiotherapy (Agents determined in line with tumour
response to neo-adjuvant treatment)

Fig. 2.2 Treatment algorithm for suspected malignant tumour of bone. *Surgery as mainstay of local treatment and the aim being complete removal of the
tumour with a surrounding cuff of normal tissue. Limb-salvage surgery rather than amputation is performed in 90% of cases. Major long-bone defects are most
often reconstructed with massive endoprostheses, and these can extend to accommodate for growth in children. Radiotherapy can be used as an adjunct to
surgery in Ewing’s sarcoma, or as the sole local treatment if surgical resection is not feasible.

61
62 CHAPTER 2 Common clinical problems

Benign bone tumours (Fig. 2.3)

Benign bone tumours are more common than malignant lesions. However,
urgent investigation and referral to an MDT must be initiated for any
suspicious lesion.

Benign tumours of
bone

Benign osseous Benign fibrous Benign cartilaginous

tumours tumours tumours

Osteoid osteoma Osteochondroma

Fibrous dysplasia
• Small (<1 cm), • Juxta-articular
solitary • Solitary, often pain/mass
• Aspirin sensitive asymptomatic, • Solitary cartilage-
night pain incidental finding capped, sub-periosteal
• Diaphyses of LL long • Femur 35%, tibia 20% bony projection
bones • Pathological fracture • X-ray: contiguous
• X-ray: well-defined, with adjacent cortical
• X-ray: lucent nidus
‘ground glass’ matrix bone
• Rx: radiofrequency • Rx: observation or
ablation • Rx: excision
curettage & grafting. • Polyostotic in MHE
Osteoblastoma • Polyostotic in
• Malignant
• Pain, swelling, McCune-Albright
transformation to
scoliosis syndrome
chondrosarcoma
• 40% in spine • (≅2–4% in MHE)
• X-ray: lucency with Non-ossifying fibroma
central density. • Solitary,
asymptomatic, Enchondroma
• Rx: en bloc resection/
curettage incidental finding • Asymptomatic, 50%
• Pathological fracture in hands
• Long bone metaphyses • Low potential for
• Femur 40%, tibia 35% malignant
Tumour-like transformation.
• X-ray: eccentric,
condition of bone Difficult distinction
demarcated lucency,
sclerotic margins from low-grade
• Rx: observation as chondrosarcoma
often regress, • X-ray: demarcated
Unicameral bone cyst lucency with stippled
particularly after
• Solitary, metaphyseal fracture healing calcification
lesion • Rx: curettage and
• Proximal humerus grafting
50%, proximal femur 27%. • Multiple lesions in
• Pathological fracture Ollier’s disease
• LL: lower limb
• X-ray: lytic, soap-
• Rx: treatment Chondroblastoma
bubble appearance.
‘Fallen Leaf’ sign • MHE: multiple • Juxta-articular pain/mass
hereditary exostoses
• Rx: observation or • Epiphyses of long bones
curettage & grafting. • X-ray: epiphyseal
Often partly resolve lucency with mottled
after fracture & calcification
usually disappear by
adulthood • Rx: curettage and grafting

Fig. 2.3 Treatment algorithm for benign tumours of bone.

Soft-tissue sarcomas (Fig. 2.4)

• Although most soft tissue masses are benign, the following are ‘red
flags’ suggestive of malignancy:
• Lump increasing in size, lump deep to fascia, lump >5cm diameter.
• Pain, often worse at night.
• Lump recurring after previous excision.
• Paediatric soft tissue sarcomas are usually classified as
rhabdomyosarcomas or non-rhabdomyosarcomas.
• Non-rhabdomyosarcomas are a rare but heterogenous group of
tumours in children. Chemotherapy is usually given for malignant
tumours.
 Rhabdomyosarcoma Suspected soft tissue sarcoma Non-rhabdomyosarcoma

Children: 87% <15 years old Adolescents and young adults

4% of childhood cancers
Malignant tumour of skeletal muscle
Subtypes: History, examination, & X-ray* Malignant tumours of mesenchymal origin
• Embryonal 55% Most common subtypes:
• Alveolar 20% • Dermatofibrosarcoma
• Undifferentiated 20% Refer to MDT protuberans
Head and neck 28% • Malignant fibrous hystiocytoma
Extremities 24% • Synovial sarcoma
Genito-urinary tract 18% MRI • Malignant peripheral nerve
• Shows local extent ± satellite sheath tumour
lesions • Fibrosarcoma
• T1 images—hypointense
• T2 images—hyperintense
Small round ‘blue-cells’
• Plan biopsy
• Alveolar: translocation Heterogenous group of tumours
t(2;13)(q35;14)
• Embryonal: loss of Biopsy to confirm diagnosis
heterozygosity at chromosome
11p15.5
CT chest/abdo/pelvis
• Staging investigation
• Pulmonary or lymphatic
involvement
Tumours generally less chemosensitive
Multi-agent therapy Neo-adjuvant chemotherapy
than rhabdomyosarcomas.

BONE TUMOURS
Surgery**

Radiotherapy

Fig. 2.4 Treatment algorithm for suspected soft tissue sarcoma. *X-rays are mandatory to rule out soft tissue extension of bony tumours and may also show
intralesional calcification, e.g. in synovial sarcomas. **The aim of surgery must be complete removal of the tumour with a surrounding cuff of normal tissue. In
extremity tumours, limb-salvage surgery is usual but complete removal must not be jeopardized to achieve this.

63
64 CHAPTER 2 Common clinical problems

Bone and joint infections

Septic arthritis and osteomyelitis
• Incidence—2–10 per 100,000 in the general childhood population.

Bacterial infection of the bone or joint should be suspected in infants or

children with acute onset of:
• Fever
• Unexplained limp (see b The limping child, p 80) and/or abnormal
posture/gait and/or reluctance to use the limb, inability to weight
bear, and complete or partial limitation of movement on examination.
• Musculoskeletal pain ± presence of local bone or joint tenderness,
bone or joint swelling, erythema (‘hot, swollen, joint’), or pain on
passive motion of the joint.

• Septic arthritis and osteomyelitis may occur separately or together,

may affect 1 or many joints, and the clinical presentation depends on
the organism and host immunity. Infants may not appear unwell, and
may not always have a high fever. Careful comprehensive examination
must be undertaken by a clinician experienced in the assessment of
joints.
• Prognosis: usually good unless the diagnosis is delayed.
Septic arthritis
• Septic arthritis is an infectious arthritis of a synovial joint, and is a
medical emergency.
• The frequency is highest in young children; 50% of all cases present in
first 2 years of life with a greater tendency in boys (2:1). Most common
joints (75%) affected in lower limb (knee >hip >ankle). Approximately
25% infections affecting the upper limbs.
• Bacteria may reach the joint:
• Through haematogenous spread (most common route for bacterial
joint infection).
• By direct penetration (e.g. through the skin).
• Or by local spread from an adjacent infected site.
• Neonates and infants are at high risk of septic arthritis developing from
osteomyelitis, as infection can spread easily from the metaphysis via the
patent transepiphyseal vessels.

Most common pathogens for both septic arthritis and

osteomyelitis
• <12 months old: Staphylococcus aureus, Group B Streptococcus,
Gram-negative bacilli.
• 1–5 years: Staphylococcus aureus, Group A Streptococcus, Streptococcus
pneumoniae, Haemophilus influenzae, Enterobacter (osteomyelitis).
• 5–12yr: Staphylococcus aureus, Group A Streptococcus.
• 12–18yr: Staphylococcus aureus, Neisseria gonorrhoea.
 BONE AND JOINT INFECTIONS 65

Osteomyelitis
• Osteomyelitis is infection of bone.
• The frequency of osteomyelitis is greatest in infants. 1/3 of all cases
occur in the first 2 years of life. Half of all cases occur by 5 years of age.
Boys >girls (2:1)
• Often preceded by history of trauma in the affected extremity.
• Infection is usually seen in the metaphyseal region of bones.
• Most infections are spread via the haematogenous route from a p site
of entry (e.g. respiratory, ear, nose, or throat, skin). Infection may also
occur by direct inoculation (open fractures, penetrating wounds) or
local extension from adjacent sites.
• In the neonate or infant transepiphyseal vessels are patent and
infection may spread to the adjacent joint causing a septic arthritis.
• Organisms are not always isolated. The yield for bacterial growth from
synovial fluid and bone aspirate is usually poor.

Types of osteomyelitis
• Acute.
• Subacute (2–3 weeks’ duration).
• Chronic: may develop sequestrum and involucrum.
• Bone abscesses may develop with surrounding thick fibrous tissue and
sclerotic bone (Brodie’s abscess).
• Chronic recurrent multifocal osteomyelitis (CRMO, see b Chronic
recurrent multifocal osteomyelitis, p 297).

General principles of management for bone and joint

infections
• Prompt diagnosis, adequate and urgent washout, and drainage of joint
is required followed by immediate institution of appropriate antibiotics
are important to optimize outcome.
• Assessment and management should involve on-call teams for
paediatrics, orthopaedics, and microbiology and be guided by local
policy for clinical service and antibiotic use. Consideration of antibiotics
to cover MRSA or Panton–Valentine leukocidin (PVL) producing
Staphylococcus aureus may be warranted in certain clinical situations.
• Early referral to orthopaedic team for consideration of irrigation and
debridement of the affected joint, and drainage of any associated
osteomyelitis. Joint washout and drainage generally always requires a
general anaesthetic. Orthopaedic opinion should be sought early to
clarify if an aspiration of bone or bone biopsy should be taken, before
instituting IV antibiotics.
• Empirical IV antibiotics (penicillin and cephalosporin) while awaiting
cultures. General current practice is IV antibiotics for up to 3 weeks
(until inflammatory markers normalize), followed by oral antibiotics for
a total of 4–6 weeks. There is no evidence comparing long versus short
courses of antibiotics.
• Appropriate analgesia and anti-inflammatory medication is required.
The affected joint should be rested until there is clinical improvement
and pain has settled.
66 CHAPTER 2 Common clinical problems

• Early physiotherapy assessment is important to guide mobilization as

appropriate.
• Investigations:
• Joint aspiration with Gram-stain microscopy and culture of synovial
fluid. (Consider mycobacterial infection; see b Tuberculosis and
mycobacterial disease, p 356.)
• Inoculating blood culture bottles directly with synovial fluid
improves yield and may be helpful for isolating certain bacteria.
• PCR (polymerase chain reaction) on synovial fluid or of synovial
tissue may be useful if other cultures have been negative.
• Blood cultures (ideally, 3 sets over 3 days, always worthwhile;
repeat blood cultures if reinserting a cannula in a child).
• FBC, ESR, CRP can be helpful in the assessment; for bacterial
infections, expect WCC to be raised with neutrophilia, and
moderately raised CRP. CRP is a better predictor than ESR for
acute infection. If high at beginning as a baseline marker, they may
be helpful with assessment of progress (resolution towards normal
indicating improvement); however, blood tests are not diagnostic of
septic arthritis, they can only guide management with assessment of
the clinical situation.
• Imaging:
• X-ray—may be normal initially; may show fluid or soft tissue
swelling; or widened joint space. Bony changes may not be evident
for 14–21 days.
• USS joint—may show effusion and can guide joint aspiration.
• MRI—useful if diagnosis unclear or osteomyelitis suspected. Sensitive
to early changes and very useful in suspected vertebral osteomyelitis.
• Radionuclide bone scan (showing i uptake) can be useful if MRI
unavailable.
Pointers towards septic arthritis
Kocher proposed clinical prediction scores based on 4 independent
factors to differentiate septic arthritis from transient synovitis (Box 2.2).

Box 2.2 Four factors used to predict septic arthritis*

• Fever >38.5*C.
• Non-weight-bearing or pain with passive motion of the joint.
• ESR: >40mm/h.
• WCC: >12 × 109.
Probability of septic arthritis with the number of predictors present:
Number of factors Probability
0 <0.2%
1 3.0%
2 40.0%
3 93.1%
4 99.6%
*Kocher MS, Zurakowski D, Kasser JR Differentiating between septic arthritis and transient
synovitis of the hip in children: an evidence-based clinical prediction algorithm. Bone Joint Surg
Am 1999; 81(12):1662–70.
 BONE AND JOINT INFECTIONS 67

Reactive arthritis
• Definition—reactive arthritis is an aseptic acute inflammatory arthritis
occurring with, or following, an intercurrent infection, without
evidence of the causative organism in the joint. Should be suspected
where >1 joint affected and clinical presentation includes potential
source of extra-articular infection.
• The infectious agent responsible for triggering the arthritis is generally
outside the joint. For agents commonly associated with reactive
arthritis, see Table 2.1.
• Reactive arthritis can occur at any age. Reactive arthritis typically
follows 7–10 days after an episode of gastroenteritis (young children),
typically involves lower limb large joints (knee >ankle >hip) and there
is an association of this type of arthritis with HLA B-27 positivity. Acute
phase reactants are usually raised (often very high), blood cultures and
autoantibodies are negative and the diagnosis may rest on serology or
urethral or stool cultures.
• In adolescents, it is important to differentiate reactive arthritis
(following an episode of sexually-acquired urethritis from gonococcal
arthritis or Chlamydia infection. Reiter’s disease/syndrome is former
terminology used to describe the triad of urethritis, conjunctivitis, and
arthritis. Patients may have multiple infections (Chlamydia, Gonococcus,
and HIV).
• Investigations in suspected reactive arthritis:
• Acute phase reactants
• Cultures:
— Blood
— Stool (Shigella, Salmonella, Yersinia, Campylobacter)
— Urethral (Gonococcus [Gram negative], Chlamydia)
— Synovial fluid (Gram stain and culture)
— Throat swab (Streptococcus)
• Serology:
— Salmonella, Yersinia, Campylobacter
— ASOT and anti-DNAseB (streptococcal infection) seeTables 2.1
and 2.9.
• HLA B27.
• Management involves establishing a diagnosis and excluding infection,
symptoms control with NSAIDS, analgesia, and early physiotherapy
involvement. Intra-articular steroid injection will be helpful with
persistent arthritis (and once septic arthritis excluded).
Gonococcal arthritis
• Gonococcal arthritis may present as a septic arthritis associated
with fever, rigors, skin lesions (macular rash, pustules, or blisters),
tenosynovitis, and polyarthritis.
• The knee is the most commonly affected joint, but any joint may be
involved.
• If suspected, Gram stain, and culture of synovial fluid, blood cultures,
and any exudative lesions will be useful. The possibility of sexual abuse
should be considered in a child with gonococcal arthritis.
68 CHAPTER 2 Common clinical problems

Table 2.1 Pathogens associated with arthritis

Type Organism Organism associated with
condition
Septic Osteomyelitis Reactive
arthritis arthritis
Bacteria Staphylococcus aureus √ √
Streptococcus spp √ √ √
Group A √ √
(Group B Strep in neonate) √ √ √
Streptococcus pneumoniae √ √ √
Salmonella √
Shigella √
Campylobacter √
Neisseria meningitidis, √ √ √
N. gonorrhoeae
Brucella melitensis, canis √ √
Chlamydia √
Mycoplasma pneumoniae √ √
(ureaplasma)
Mycobacteria Mycobacterium √ √
tuberculosis
(see b Tuberculosis and
mycobacterial disease,
p 356)
Atypical M. avium complex √
mycobacteria*
M. malmoense √
(see b Tuberculosis and
mycobacterial disease,
p 356)
Spirochaete Borrelia burgdorferi (see √ √
b Lyme disease p 368)
Viruses Parvovirus B19 √
Rubella √
Protozoa Toxoplasma* √
Giardiasis √
Helminths Toxocara √ √
Dracunculus √
Schistosoma √ √
Fungi* Histoplasma √ √
Cryptococcus √
*
In the immunosuppressed patient (see b Tuberculosis and mycobacterial disease, p 356).
 BONE AND JOINT INFECTIONS 69

Further reading
Frank G, Mahoney HM, Eppes SC. Musculoskeletal infections in children. Pediatr Clin North Am
2005; 52(4):1083–6, ix.
Mathews CJ, Kingsley G, Field M, et al. Management of septic arthritis: a systematic review.
Ann Rheum Dis 2007; 66(4):440–5.
70 CHAPTER 2 Common clinical problems

Infections in the immunocompromised

Background
• Chronic inflammatory diseases are managed with a combination of
immunosuppressive and anti-inflammatory agents, including steroids
and disease modifying anti-rheumatic drugs (DMARDs) and recent
novel biological agents have had significant impact on symptom relief
and quality of life.
• However, in order to reduce inflammation, they inhibit innate and
adaptive immune pathways, making patients increasingly susceptible to
both serious and opportunistic infections.
• Although the benefits usually outweigh the risks, infectious
complications need to be minimized by careful assessment prior to
their commencement and close monitoring whilst on them.
• Serious infection: requiring treatment with IV antibiotics, needing
hospitalization, or causing death.
• Opportunistic infection: causing infection only in the
immunocompromised host or causing mild disease in normal hosts
but disseminated, severe infection in the immunocompromised host.

At-risk populations
A lack of high-quality epidemiological data limits our current knowledge
about the relative risks (RR) of serious and opportunistic infections in
children receiving immunosuppressive and anti-inflammatory regimens. In
addition, it is difficult to determine the relative contributions of the under-
lying disease itself, comorbidities, and immunosuppressive treatment. The
following statements are consensus derived:
Corticosteroids
• Immunosuppressive if >2mg/kg given for over 1 week or 1mg/kg for
over 4 weeks.
• Mechanism of action by inhibition of inflammatory transcription factors
(NFκB), resulting in downregulation of proinflammatory cytokines and
genes encoding T-cell growth factors.
• Cause broad cellular immunodeficiency, resulting in susceptibility to
viral, bacterial, and fungal infections.
• Infection risk i with higher doses and longer duration of treatment.
• It is important to use the lowest dose for shortest duration.
DMARDs
• May be associated with significant risk of infection, particularly if
neutropenia occurs.
• Numerous case reports of opportunistic infections:
• PCP, reactivation of viruses (EBV, CMV, HSV, VZV).
• In descending order, the risk of infection is greatest with
cyclophosphamide >corticosteroids >azathioprine >MTX
>cyclosporine/mycophenolate mofetil (MMF).
• The infection risk i when DMARDs are used in combination and/or
neutropenia occurs.
 INFECTIONS IN THE IMMUNOCOMPROMISED 71

Novel biological agents

• Various agents, including TNF-A inhibitors, IL-1 and IL-6 antagonists,
T-cell co-stimulation modulators (CTLA-4 fusion proteins), and anti-
CD20 agents are increasingly used (see b Biologic therapies for
paediatric rheumatological diseases, p 393), with well-defined mode of
action of these agents allows potential infectious complications to be
anticipated (Table 2.2).
• The RR of infection associated with these agents is unknown in
children although adult epidemiological data suggest higher rates
of infection with novel biological agents compared to DMARDs.
In descending order the risk is greatest with TNF-A inhibitors >
IL-1R/IL-6R antagonists/anti-CD20 agents > T cell co-stimulation
modulators.
• The risk highest in the 1st year of treatment and markedly i when
used in combination and/or with conventional immunosuppressive
therapy.
• Infections include TB reactivation/infection (see b Tuberculosis
and mycobacterial disease, p 356), fungal infections, severe pyogenic
bacterial infections, PCP, virus reactivation.
Strategies for managing severe and opportunistic
infections (Fig. 2.5)
• Fever—may arise from infection or be caused by the underlying
inflammatory pathology itself.
• Clinical presentation of infection may be altered by underlying disease/
immunomodulatory therapy.
• Opportunistic infections—hard to recognize by virtue of their rare
presentation but can cause significant morbidity and mortality.
Screening
• Prior to starting immunosuppressive therapy, patients should be
screened for latent infections, especially TB.
• Thorough history to evaluate TB risk, varicella immunity, immunization
status, and future travel plans; clinical examination to exclude active
infections, including dental status and investigations including TB
screening as per local guidelines, VZV serology, and FBC to exclude
neutropenia or lymphopenia.
Vaccination
• Ideally vaccinate prior to commencing immunosuppressive therapy.
• Vaccinate if varicella antibody status negative.
• Consider vaccinating 1st-degree family members (history and/or
serologically negative).
• Ensure vaccination with Prevenar-13 as per the recommended
childhood schedule.
• Immunocompromised children should also receive a single dose of
Pneumovax (23-valent polysaccharide vaccine) when aged >2yr.
• Influenza vaccination recommended annually in the autumn.
• Avoid live vaccines; rest of childhood immunization schedule should be
followed.
• Live vaccines can be given once off steroid treatment for >3 months
or other immunosuppression for >6 months.
72 CHAPTER 2 Common clinical problems

• Give zoster immunoglobulin (ZIG) if significant exposure to

chickenpox in non-immune patients, up to 7 days post-exposure.
Immunoglobulin if significant contact with measles, irrespective of
antibody status.
Prophylactic antimicrobials
• Treat active or latent TB prior to starting immunosuppressive therapy.
• Prophylaxis should be considered if the patient is neutropenic,
lymphopenic, or living in an ‘endemic’ area (e.g. Histoplasma). Seek
specialist paediatric infectious diseases advice.
Education
• Avoid foods associated with Listeria and Salmonella infection
(unpasteurized milk, soft cheeses and undercooked eggs and meat).
Avoid visits to zoo/animal farms.
• Ensure that parents recognize the early signs of infection and
understand that urgent medical assessment is required (see b Biologic
therapies for paediatric rheumatological diseases, p 393 and b The
role of the clinical nurse specialist, p 380).

Screening for
latent/chronic
infections

PREVENTION IS
Education BETTER THAN Vaccination
CURE!

Prophylactic
antimicrobials
Fig. 2.5 Prevention of infection.
Table 2.2 The infectious complications and organisms associated with novel biological agents
Drug TNF-A inhibitors IL-1 antagonists Anti-CD20 agents T cell costimulation IL-6
modulators antagonists
Most Etanercept Anakinra Rituximab Abatacept Tocilizumab
commonly Infliximab Rilonacept
used Adalimumab Canakinumab
Infectious Pneumonia URTI Pneumonia URTI inc. sinusitis URTI
complications UTI Pneumonia UTI Pneumonia Gastroenteritis
URTI incl. sinusitis Cellulitis URTI Septicaemia

INFECTIONS IN THE IMMUNOCOMPROMISED

Skin + soft tissue infections Shingles Skin+soft tissue inf.
Musculoskeletal infections
Organisms M. tuberculosis Bacteria Bacteria including Staphylococcus VZV EBV
NTM ?VZV and Pseudomonas HSV PCP
Salmonella spp. Enterovirus Aspergillus
Listeria Hepatitis B Candida
Nocardia Hepatitis C
Candida JC virus (risk of progressive multifocal
Aspergillus leukoencephalopathy)
Histoplasma VZV
Coccidioides
Blastomyces
Cryptococcus
Hepatitis B
VZV
CMV
Toxoplasma
TNF, tumour necrosis factor; UTI, urinary tract infection; URTI, upper respiratory tract infection; NTM, non-tuberculous mycobacteria; VZV, varicella zoster virus; CMV,
cytomegalovirus; EBV, Epstein–Barr virus; PCP, Pneumocystis jiroveci pneumonia.

73
74 CHAPTER 2 Common clinical problems

The approach to the immunocompromised child presenting

with fever
• Fever may be the only sign of serious infection, especially in the child
with neutropenia.
• Beware: TNF-A and IL-1/IL-6 inhibitors may ‘mask’ fever and an
inflammatory response (i.e. CRP may be normal or only mildly
elevated).
• Serious bacterial infections, invasive fungal infections, and disseminated
viral infections must be distinguished from self-limiting viral infections.
• Empirical treatment is often initiated until this distinction is made.
• The profile of infection (organism, severity) varies with the
immunosuppressive therapy being used (especially for combinations).
• The highest risk is in haematopoietic stem cell transplantation.
• The algorithm in Fig. 2.6 provides an approach for managing the
immunocompromised child presenting with fever.
Important notes
Children with persistent musculoskeletal pain should have the following
work-up considered:
• Complete/FBC with differential.
• Acute phase reactants (ESR, CRP).
• Routine serum chemistries (including creatinine, liver, and muscle
enzymes).
• Urinalysis.
• Imaging studies (plain x-rays of involved area, other studies as indicated
in the algorithm(s)).
• Testing for mycobacterial infection.
Caveats
• Minor trauma and infections are common in children and may not
necessarily be related to the diagnosis.
• Remember infection, malignancy and non-accidental injury (child abuse)
at each stage.
Further reading
RCPCH. Immunisation against infectious disease—’The Green Book’, 2006; Best Practice
Guidelines, Immunisation of the Immunocompromised Child. London: RCPCH, 2002.
Available at: M http://www.RCPCH.ac.uk/guidelines.
 HISTORY Focal symptoms? Period of immunosuppression and drug/dose used? Immunisation status? TB contact? Oral/cutaneous fungal infections?
Oral/cutaneous fungal infections? Prolonged, severe neutropenia (neut <0.5)? Contact history? Recent foreign travel?

EXAMINATION Signs of septic shock requiring immediate intervention?

Full systemic examination to look for focus of infection.

LIKELY PATHOLOGY SEPTICAEMIA URTI LRTI CNS INFECTION SKIN INFECTION

CAUSATIVE Bacteria: Otitis media Viral: Bacteria: Viral:

ORGANISMS Strep. pyrogenes Gram +ve and −ve bacteria RSV, CMV, parainfluenza 1–4 Incl. pneumococcus, HiB. VZV, HSV, HHV6, adenovirus, measles
Strep. pneumoniae Sinusitis influenza A/B, HMPV, adenovirus, VZV If abscess, consider anaerobes Bacteria:
N. meningitidis Anaerobes, Pneumococcus, Bacterial: and Gram −ve’s Staph. aureus and Strep. pyrogenes
Staph. aureus Haemophilus, Gram’s −ve’s Pneumococcus, H. influenzae, Moraxella Viral: Consider non-infective pathologies
Gram −ve bacteria Fungi Pseudomonas, Mycoplasma CMV, adeno, HHV6, HSV, JC virus such as Stevens–Johnson syndrome,
Fungal: Fungal: Fungal: vasculitis or disease relapse
Candidiasis, others PCP, Aspergillus, Zygomycetes Cryptococcal, Aspergillus

INFECTIONS IN THE IMMUNOCOMPROMISED

Viral: Candida, Zygomycetes
VZV, enterovirus, HSV, adenovirus Toxoplasmosis

INITIAL INVESTIGATIONS Blood cultures FBC CRP Biochemical profile including U&E
Chest X-ray Culture of urine, sputum, nasopharyngeal aspirate, throat swab, stool etc. as clinically indicated

SPECIFIC Meningococcal + pneumococcal PCR CT chest if fungal infection suspected CSF (MC+S, prot/gluc, viral PCRs, Skin/vesicle scrapings for
INVESTIGATIONS Urinary pneumococcal Ag NPA/sputum for respiratory virus (IF/PCR) cryptococcal Ag) bacterial C+S, viral PCR/IF
Blood for fungal culture and consider fungal
antigen tests (mannan, galactomannan, 1,3-B-D-
glucan—repeated sampling required) CT/MRI brain with contrast Consider skin biopsy
CT sinuses if fungal infection
suspected Bronchoalveolar lavage Consider biopsy if CNS lesion

Consider lung biopsy if suspected fungal lesion

EMPIRICAL TREATMENT
Use broad-spectrum antibiotics Cover Gram +ve and Gram Consider empirical PCP treatment with co- Broad-spectrum antiobiotics, often
to cover Gram +ve and −ve’s −ve’s with broad spectrum trimoxazole and steroids with a 3rd generation cephalosporin +-
as per local guidelines. If antibiotics such as amoxicillin If viral aetiology confirmed, consider specific metronidazole
central venous line in situ, and ciprofloxacin anti-viral agent +- IVIg
consider antibiotics to cover If fungal infection suspected, consider
Staph. epidermidis Amphotericin B or voriconazole if Aspergillus Amphotericin B or voriconazole.
suspected.
If persisting fever after 48–72 h,
consider changing antibiotics
and adding empirical anti-fungal
therapy
If neutropenic, consider G-CSF
Consider disseminated viral
infection including enterovirus,
adenovirus and VZV.

DEFINITIVE THERAPY Consult with Infectious Diseases colleagues

Fig. 2.6 The approach to the immunocompromised child presenting with fever.

75
76 CHAPTER 2 Common clinical problems

Fractures in children and adolescents

See Tables 2.3–2.5.
Excluding fractures as a cause of pain
• Check for a history of injury, e.g. witnessed fall, pain immediately after
fall.
• Be alert for potential of NAI (see b Musculoskeletal presentations
and non-accidental injury, p 54)
• Be alert for fragility fractures (see b Metabolic bone diseases,
p 330)
• In school age children and older, accurate palpation to determine site
of pain, e.g. periarticular versus shaft of long bones, supracondylar
humerus versus epicondyles, distal radius versus scaphoid.
• Imaging appropriately—focal x-rays are better than whole, long-bone
x-rays. US scan and bone scan are not useful for detection of acute
fractures. In young children with unossified epiphyses, an arthrogram
under general anaesthesia is useful to exclude displaced intra-articular
fractures.
• Interpret radiographs appropriately for the age—fractures can be
confused with physes (growth plates), e.g. is the physis at the site of
tenderness? Compare with normal age specific radiographs and x-ray
contralateral limb for comparison.
• Growth arrest and subsequent deformity are most common following
direct physeal trauma.
• The rate of complications is dependent on the type of fracture, the
actual physis involved and the age of the patient (Fig. 2.7).
• Salter-Harris type IV and V fractures are more likely to cause bone
bridge formation than types I–III (Fig. 2.8).
• The distal femur and proximal tibia are the most susceptible physeal
plates to develop bone bridges following trauma.
• Peripheral growth arrest usually causes angular deformity and the
management depends on the extent of the bone bridge. Whereas,
central growth arrests usually cause leg-length discrepancy and 50% of
the physeal plate may be resected and still allow continued longitudinal
growth.
 FRACTURES IN CHILDREN AND ADOLESCENTS 77

Table 2.3 Fractures in children: epidemiology

Age Incidence Common Common fractures
groups number per mechanisms (prevalence %)*
(yr) 1000 children
per year
0–1 3.6 Non accidental Clavicle 22.2
injury (NAI)
(infants and Distal humerus 22.2
pre -walkers) Fall below
bed height Distal radius 11.1
Radius & ulna shaft 11.1
Tibia 8.9
2–4 12.9 Fall below Distal humerus 22.0
bed height
(pre-school) Distal radius 21.3
NAI
Falls down stairs Clavicle 15.0
Radius & ulna shaft 9.5
Finger phalanges 7.1
5–11 23.2 Fall below bed height Distal radius 40.3
(school Sports Finger phalanges 14.4
children)
blunt trauma
Distal humerus 7.5
Falls down stairs
Radius & ulna shaft 5.9
Trauma (road traffic
accident [RTA]) Metacarpus 5.3
12–16 26.6 Sports Distal radius 28.0
(adolescents)
Fights Finger phalanges 20.3
Blunt trauma
Metacarpus 14.3
RTA
Clavicle 7.0
Fall below
bed height Metatarsus 5.3
*
Rennie L, Court-Brown CM, Mok JY, et al. The epidemiology of fractures in children. Injury
2007; 38(8):913–22.
78 CHAPTER 2 Common clinical problems

Diaphysis—cortical bone (shaft)

Metaphysis—site of osteogenesis

Physis—cellular growth plate

Epiphysis—articular segment

Fig. 2.7 Sites of fracture.

Fig. 2.8 Salter and Harris classification of fractures.

 FRACTURES IN CHILDREN AND ADOLESCENTS 79

Table 2.4 Fractures in children: management

Principles Objectives Options (depends on fracture site,
of fracture rehabilitation requirements and
management surgeon’s preference)
Reduction Restores alignment Closed reduction: general anaesthetic
and function or local anaesthetic manipulation
Reduces pain Open reduction: especially for
intra-articular fractures.
Immobilization Maintains alignment Non operative: casts/splints
(after reduction)
Operative: percutaneous wires,
Reduces pain plate & screws, intramedullary
fixation, external fixation
Rehabilitation Restores strength, Mobilization
range of motion and
Gradual return to activity
function
Physiotherapy

Table 2.5 Fractures in children and adults: comparison of

complications
Differences Adult Child
Angular Due to Due to malunion or eccentric physeal injury
deformity malunion at <50%. Depends on age of child and site of
fracture fracture.
Shortening Due to bone Due to bone loss or central physeal injury >50%.
loss Depends on age of child and site of fracture
Healing time Longer Shorter due to cellular periosteum
Fragility Due to Osteogenesis imperfecta or rickets—check
fractures osteoporosis for short stature, family history, serum calcium
and PTH
80 CHAPTER 2 Common clinical problems

The limping child

• Limping is a symptom and not a diagnosis. Acute limping invariably
results from pain and the antalgic (painful) gait refers to the child
minimizing weight bearing on the sore limb, with a shortened stance
phase and increasing the swing phase of the gait cycle (see b The
gait cycle and abnormal gait patterns, p 11). When assessing gait in the
young child, especially the preschool age, it is important to be aware
of the normal process of gait development, normal variants, and
age-related gait changes (see b Chapter 1).
• Epidemiological studies are sparse—in one study children with an acute
limp accounted for <2% of all paediatric emergency department
attendances, although may well be more common in the primary care
setting.
• The age of the child is most helpful in establishing a differential diagnosis
(Table 2.6). Trauma is the commonest cause of limping and in the case
of atraumatic limp, many will resolve spontaneously. However common
pitfalls in the assessment of limp are important to note (Box 2.3).
• Most cases of limp are acquired abnormality of gait. However, in the child
who has ‘always had a limp’ from initial weight bearing it is important
to consider a ‘missed’ diagnosis of developmental dysplasia of the hip
(DDH) or neurological conditions such as cerebral palsy. Furthermore,
limping typically affects one leg but in some instances bilateral
involvement can occur (e.g. Perthes’ disease, DDH, slipped capital
femoral epiphysis) and makes clinical assessment particularly difficult.
See b Hip pain and hip problems in children and adolescents, p 106.
• It is important to assess limping children very carefully for ‘red flags’
suggestive of potentially life-threatening causes (including sepsis,
malignancy, and NAI)—all of which must not be missed (Table 2.7).
• The discrimination between septic arthritis and reactive arthritis
(transient synovitis) at the hip is a common clinical scenario. Kocher’s
clinical prediction rules (see Box 2.4) can be helpful but should not
replace experienced clinical judgement (see also b Chapter 6 and
b Hip pain and hip problems in children and adolescents, p 106).
• It is also worth remembering that children with established conditions
such as JIA or cerebral palsy, can develop acute limp from causes such
as slipped upper femoral epiphysis (SUFE) or Perthes’ disease. Septic
arthritis can occur although is a rare complication post intra-articular
steroid injection in JIA management, but must be considered in the era
of increasingly immunosuppressive treatments (see b Infections in the
immunocompromised, p 70).
• It is important that children presenting with a limp are followed-up
with clear instructions (e.g. parent information leaflet) on when to
re-seek medical attention. Children with persistent or intermittent limp
warrant further assessment to establish the diagnosis.
• Suggested approaches to the limping child (according to presence or
absence of fever) are given (Figs. 2.9 and 2.10).
 THE LIMPING CHILD 81

Indications for urgent assessment of limp

• The very young (under 3 years of age).
• The ill and febrile.
• The non-weight bearing.
• Children with painful restricted hip movements.
• The child who is immunosuppressed.

Table 2.6 Causes of limp by age

0–3 years 4–10 years 11–16 years
Most • Trauma (including • Trauma • Trauma
common toddler’s fracture) • Transient synovitis • Osgood–Schlatter
• Perthes’ disease disease
Conditions • Osteomyelitis • Osteomyelitis • Osteomyelitis
requiring • Septic arthritis • Septic arthritis • Septic arthritis
urgent • NAI • NAI • Slipped upper
intervention • Malignancy (e.g. • Malignant disease femoral epiphysis
neuroblastoma) (e.g. acute • Malignancy
• Testicular torsion lymphocytic (e.g. bone tumours)
• Inguinal hernia leukaemia) • Testicular torsion
• Testicular torsion Appendicitis
Appendicitis • Inguinal hernia
• Inguinal hernia
Other • Developmental • JIA • JIA
important dysplasia of the hip
conditions • JIA
to consider
• Metabolic (e.g. rickets)
• Haematological disease (e.g. sickle cell anaemia)
• Reactive arthritis
• Lyme arthritis
82 CHAPTER 2 Common clinical problems

Box 2.3 Common pitfalls observed in the assessment of

the limping child
• Ascribing limp to trauma and overlooking features that suggest other
causes.
• Referred pain (e.g. from the abdomen [and testes in boys], back, or
chest and hip pathology manifesting as knee pain).
• Think beyond the hip (!) and examine the child comprehensively.
• Classical clinical features of sepsis may be masked in the
immunosuppressed child.
• Mycobacterial infection can be easily missed.
• Synovial fluid may be sterile in partially treated septic arthritis.
• Labelling children with daytime symptoms as having ‘growing pains’.
• Medically unexplained limp or physical symptoms warrant specific
management and referral (i.e. discharge without a diagnosis and
follow-up plan is not advised).
• The blood film may be normal in children with malignancy.
• Radiographs are often normal in children with early sepsis or arthritis.
• Acute phase reactants may be normal in children with arthritis.
• RF is usually negative in children with arthritis.
• ANA and RF may be false positives in children without inflammatory
joint or muscle disease.
Table 2.7 The limping child and features that suggest severe life-threatening conditions
Malignancy Non-accidental injury Sepsis

• Night pain • Delay in seeking medical attention • Complete non-weight bearing

• Pain severe and non-remitting • Changeable history inconsistent with pattern • Pseudo-paralysis of limb
• Bone pain of injury • Any attempt to passively move the limb
• Pallor • Explanation of injury incongruent is resisted and causes extreme distress
• Bruising with developmental stage of child • Pain severe and non-remitting
• Lymphadenopathy • Repeated presentations • Limb held in a position which
• Hepatosplenomegaly • Un-witnessed injury accommodates i joint volume due
• Anaemia, thrombocytopenia • Patterns of injury suggestive of NAI to effusion
• Systemic symptoms (lethargy, weight (e.g. bruising over soft tissue areas, multiple • Night pain and waking
loss, night sweats, fever) bruises, bruises that carry • Fever
• Complete non-weight bearing the imprint of an implement) • Immunocompromised child—due to
• Back pain in the unwell child • Distinctive burns, e.g. round p disease or medications
• Weight loss cigarette burn, forced immersion burn • Back pain in the unwell child
• Complete non-weight bearing with
occult fracture
• Type of fracture, e.g. metaphyseal
• Multiple injuries

THE LIMPING CHILD

• Unkempt appearance and poor hygiene

83
84 CHAPTER 2 Common clinical problems

Box 2.4 Kocher’s clinical prediction rule for septic

arthritis at the hip in the presence of confirmed hip
effusion on US
Factors
• Fever >38*C.
• Unable to weight bear.
• ESR >40mm/h or CRP >20mg/L.
• Serum WCC >12 x 106/L.
Probability of septic arthritis
• 0 factors present: <0.2%.
• 2 factors present: 40%.
• 3 factors present: 93%.
• 4 factors present: >99%.

Further reading
Fischer SU, Beattie TF. The limping child: epidemiology, assessment and outcome. J Bone Joint Surg
1999; 81B:1029–34.
Kocher MS, Mandiga R, Zurakowski D, et al. Validation of a clinical prediction rule for the
differentiation between septic arthritis and transient synovitis of the hip in children. J Bone Joint
Surgery of Am 2004; 86A(8):1629–35.
 THE LIMPING CHILD 85

A child with fever and limping

Number of involved joints

1 joint None >1 joint: likely an inflammatory

disorder, but need to go through
algorithm

Strongly consider Appears ill, refuses to bear weight or has bony

arthrocentesis: No point tenderness?
purulent joint fluid, If none of the above but fever & pain continue:
positive Gram stain and/or Go to “Diagnosis still unknown” below
culture?
Yes

Possible osteomyelitis, discitis or malignancy?

Yes

Yes, could be osteomyelitis No Yes, could be malignancy

Discuss further imaging studies MALIGNANCY

INFECTION
with radiologist Bone marrow
Treat for septic arthritis
Treat according to diagnosis aspiration/biopsy
or aspirate bone and treat
for osteomyelitis or other diagnostic testing
as appropriate

DIAGNOSIS STILL UNKNOWN: consider

syndromes associated with infection. If not
consistent, go to next step

Child continues to have musculoskeletal pain and fever

Check or repeat CBC, ESR, CRP, chemistry panel, urinalysis
Blood, urine cultures (Obtain ferritin and D-dimer if systemic JIA strongly suspected)

Negative cultures and Negative cultures but elevated Positive culture(s)

normal acute phase acute phase reactants
reactants

CONSIDER LOOK FOR ADDITIONAL CLUES CONSIDER EXTRA-

PSYCHOGENIC CAUSES (Look for symptom and fever patterns, rash, ARTICULAR INFECTION
‘IDIOPATHIC’ other organ system involvement) Remember such as endocarditis, pyomyositis,
Factitious fever and/or other Kawasaki disease, Autoinflammatory perinephric, psoas, renal or other
psychogenic illness; disorders (periodic fever syndromes) (e.g. intra-abdominal abscess)
continue to monitor and consider If diagnosis still unknown & symptoms still
other conditions if symptoms present, continue algorithm
continue

Complete FUO Work-up:

Repeat blood and urine cultures;
Chest X-ray, CT abdomen/pelvis, gallium or bone scan
Consider bone marrow aspiration (for morphology and cultures)
If indicated, lymph node biopsy and/or GI work-up for IBD

FUO work-up is negative and diagnosis is still unknown

Patient has arthritis, typical systemic rash, and Patient has arthritis but does not have typical
quotidian fever pattern systemic rash and quotidian fever pattern

Consider SYSTEMIC Consider OTHER CHRONIC RHEUMATIC OR

JIA* and referral to a INFLAMMATORY CONDITIONS (i.e,. lupus, dermatomyositis,
pediatric rheumatologist IBD, vasculitis, sarcoidosis, etc.) and referral to a pediatric
rheumatologist

Fig. 2.9 Treatment algorithm for a child with fever and limping. Reproduced
with permission from Oxford University Press (and adapted from the original
version with permission from the author). Y Kimura. Common presenting problems.
In Szer IS, Kimura Y, Malleson PN, et al. (eds) Arthritis in Children and Adolescents.
Oxford: Oxford University Press, 2006.
86 CHAPTER 2 Common clinical problems

Afebrile child with limp

Does the child appear ill, Y Consider bacterial infection or malignancy

or refuse to weight bear? Go to Fig. 2.8

Y Consider traumatic injury (remember NAI) and

Has there been a history of significant
trauma or evidence of trauma on exam?** referral to an orthopaedic specialist

Y Consider reactive arthritis and other infection related

Was there an antecedent infection in
the month before pain began?** arthritis (remember acute rheumatic fever), and
sexually acquired infection in older patient
Y
Is pain limited to the hip or anterior Consider isolated hip diseases (e.g. Perthes, transient
thigh/knee? synovitis, slipped upper femoral epiphysis depending
on the age of child)
Y
Is there weakness, loss of sensation or other Consider inflammatory myositis if proximal weakness,
neurological symptom? neurological problem, or neurogenic pain
Discuss appropriate imaging studies with radiologist
& neurologist
Y
Is there a rash? Consider dermatologic manifestations of rheumatic
diseases (e.g. vasculitis)

Y Consider causes of chronic arthritis (JIA and other

Is there joint swelling, tenderness, loss of inflammatory/rheumatic conditions such as lupus,
motion or pain on motion associated with dermatomyositis, vasculitis, inflammatory bowel
morning stiffness? disease, related arthritis)

Is there short or tall stature, excessive Y Consider inherited conditions (e.g. skeletal dysplasias,
hypermobility, dysmorphic features, or connective tissue diseases such as Marfan’s or Ehlers–
family history of similar symptoms? Danlos)

Are there symptoms compatible with a Y Consider MSK symptoms associated with rickets,
metabolic or endocrine disorder? storage diseases or endocrinopathies

Y
Is the pain mainly related to or worsened
with physical activity? Consider mechanical joint/bone problems

Y
Is the pain only in the evening or night and Consider growing pains
not associated with any MSK dysfunction?

Consider idiopathic pain

syndromes/complex Consider somatization Consider fabricated or induced cause
regional pain

Fig. 2.10 Treatment algorithm for an afebrile child with a limp. Reproduced with
permission from Oxford University Press (and adapted from the original version
with permission from the author). Y Kimura. Common presenting problems.
In Szer IS, Kimura Y, Malleson PN, et al. (eds) Arthritis in Children and Adolescents.
Oxford: Oxford University Press, 2006.
 PAIN SYNDROMES AND THE ASSESSMENT OF PAIN 87

Pain syndromes and the assessment

of pain
The chronic experience of pain often has a large and wholly negative
impact on the physical and psychological well-being of a young person
and their family. Both the child and family may be distressed, fearful, and
hoping for cure. There may be feelings of being doubted and past experi-
ences of failed and pain-exacerbating interventions.
The pain assessment (Table 2.8) should aim to:
• Exclude serious possible causes of pain (identification of ‘red flags’—see
b Chapter 1, p 8).
• Identify key problems (the physical, social, and psychological impact of
pain).
• Identify a treatment plan (acknowledging aetiological factors,
environmental stressors and factors that convey resilience), and
• Commence the therapeutic process, building trust and understanding.

Table 2.8 History: important areas to cover in the assessment of pain

Onset of pain When/where/how pain started
Important factors in the history, e.g. preceding infection,
trauma, operation, or persisting disease
Characteristics Nature/site/severity/variation
of the pain
Getting better/worse
Aggravators/ameliorators
Specific symptoms, e.g. paraesthesia, allodynia (extreme
hypersensitivity), skin changes, nocturnal pain
Other symptoms Systemic/abdominal/genito-urinary/neurological symptoms,
e.g. fever, rash, weight loss, appetite change, fatigue, change
in mood
Effect of pain Sleep disturbance, daytime naps, concentration/
on daily living memory/mood
Activity: on bad/good days, school attendance, fitness,
hobbies
Affects on independence and family dynamics
Past and family Past illness/operations; family history of illness or pain,
history of illness e.g. history of painful conditions/fatigue/anxiety/sleep
disturbance
Family, emotional, Family environment/occupations/changes since onset of
and social pain, e.g. any stressors in school, family or peer groups
circumstances
88 CHAPTER 2 Common clinical problems

Examination
Full examination at the beginning may prevent repetition and unneces-
sary investigations later. Any concerns regarding the diagnosis should be
followed-up at this point, avoiding delays that can lead to a worsening of
fear, pain symptoms, and associated disability.
Assessing the impact of pain
The history will outline the impact that the pain is having on the individual
and their family (e.g. affect on sleep, mood, appetite and fitness, disruption
to schooling, social isolation, loss of independence, and widespread family
disruption, including financial hardship).
Assessment tools
• Visual analogue scale (VAS)—a simple tool for measurement of pain
severity as perceived by the child or carer; useful for assessing pain
intensity experienced; patients mark their level of pain on a continuous
scale from 0 to 10.
• Faces pain scale—pictures of faces depicting expressions showing
various levels of a pain response; often used in younger children.
• Bath Adolescent Pain Questionnaire & Bath Adolescent Pain Questionnaire
for Parent—2 multidisciplinary tools developed specifically for use in
measuring the impact of pain on adolescents with chronic pain and
their parents.
Clinical features associated with chronic pain conditions
Pain may start in a localized area with an associated avoidance of movement,
and may lead to radiation to other areas of the body, i pain intensity,
muscle spasms, abnormal posture, reduced fitness, and pain-associated
anxiety. Affects on other body systems include:
• Hypersensitivity or allodynia—unbearable pain on minimal contact;
heightened fear of being touched.
• Thermodysregulation—cool and mottled or red and hot skin,
especially limbs; abnormal perception of temperature.
• Autonomic dysfunction—sympathetic nervous system stimulation by
continuous pain and anxiety signals.
• Musculoskeletal disequilibrium—changes to gait and resting postures of
the trunk and limbs; muscle and tendon tightening; altered mechanical
load associated with adaptive, protective positioning.
Recognized pain conditions
The most common chronic pain conditions reviewed in paediatric rheu-
matology settings are:
• Diffuse idiopathic musculoskeletal pain (juvenile fibromyalgia): generalized
pain, often with gradual onset and may follow a period of illness or
hypermobility. Fatigue, poor sleep, and low mood are often prominent.
• Chronic pain related to hypermobility: ligamentous laxity of joints
presenting in association with diffuse pain conditions such as lower-
limb. With arthralgia, anterior knee pain, and back pain; not all
hypermobile individuals will be symptomatic.
• Complex regional pain syndrome (CRPS): see b Complex regional
pain syndrome, p 89.
 PAIN SYNDROMES AND THE ASSESSMENT OF PAIN 89

• Chronic back pain (see b Back pain in children and adolescents,

p 100): low back pain common in adolescence; may be associated with
posture, load bearing, and sedentary activity.
• Persistent joint pain following previous or controlled inflammation:
the degree of disabling pain does not always mirror inflammatory joint
activity; environmental and cognitive behavioural factors influence the
experience of pain.
Principles of management
• The focus is on symptom management and psychosocial rehabilitation
rather than cure.
• Education—to support the rationale for rehabilitation: understand how
the body works to maintain pain that is no longer useful, challenge
misconceptions of pain always signifying pathology and reduce pain-
associated fear.
• Pharmacotherapy—simple analgesics can be tried; gabapentin and
pregabalin may be helpful in neuropathic pain, as well as amitriptyline;
medication should be used alongside multidisciplinary therapy. Medicine
review is often an essential task in this population. Polypharmacy, risk
of dosing and combination errors, and confusion over the utility of
previously and currently prescribed medication is common. Drug
withdrawal, detoxification, and replacement should be carefully managed.
• Physical therapy—early intensive physiotherapy is the treatment of
choice to accelerate mobilization; psychological support is important.
• Psychological therapy—should ideally be delivered by a paediatric
psychologist who may use therapies such as cognitive-behavioural
therapy, acceptance and mindfulness to help the young person and
family move forward with rehabilitation and support engagement with
normal life activities.
Complex regional pain syndrome (CRPS)
CRPS type I (CRPS I) is a potentially incapacitating syndrome which can
occur after a minor injury or operation to a limb. CRPS I has an impact on
all tissues and can impair all functions of that extremity, possibly resulting
in severe impairment and therapy-resistant pain. In children it is seen more
commonly in adolescent girls and not infrequently in young people who
are premorbidly very physically active and able. Much academic attention
in this condition is targeting the neurophysiological changes that are now
evident and the mechanisms of central sensitization.
Clinical features
In children the lower limb is more commonly involved than the upper
limb. The pain is usually out of proportion to the inciting event and
accompanied by allodynia.
The International Association for the Study of Pain (IASP) has diagnostic
criteria for adults with CRPS but not children. Although these diagnostic
criteria hold true for children and adolescents, it is widely believed that the
dystrophic changes and long-term disability are less common when com-
pared with adults. Occasionally >1 limb may be affected at presentation.
It is not unusual for a hand or other leg to develop CRPS months after a
leg has been affected.
90 CHAPTER 2 Common clinical problems

Features commonly seen in CRPS

• Unexplained diffuse pain (although occasionally very localized).
• Difference in skin colour in relation to the healthy symmetrical limb.
• Oedema (may be transient).
• Difference in skin temperature in relation to the healthy symmetrical
limb.
• Limited range of movement and impaired function.
• Worsening of symptoms during exercise.

Rehabilitation
• Key to rehabilitation is reversing the unusual positioning of the limb
and returning children to a more active lifestyle while the pain, altered
proprioception, and thermodysregulation are still present. Many young
people find gentle physical therapy intolerable and continue to hold
the affected limb in a fixed position and this further i pain-associated
disability with heightening anxiety and low mood.
• Medical therapies are limited but, in addition to regular analgesics,
gabapentin and pregabalin may help neuropathic pain. Amitriptyline
may have a specific role to help the burning sensation. The true efficacy
of these treatments in CRPS is unknown; the consensus is that they are
to be used only as an adjunct with ongoing physical and psychological
therapy. Other interventions (e.g. pain-relieving blocks/topical patches)
are still used albeit with little evidence for their effect.
• Early recognition of CRPS is key. At this stage multidisciplinary input
including pain education, targeted physical rehabilitation, psychological
support, and analgesia should be instigated. In the majority the
condition becomes less bothersome with children returning to normal
activities, often leading to complete cessation of symptoms. A few
continue to have long-term problems with escalating pain associated
disability.
The role of the psychologist in the multidisciplinary team
• Persistent pain brings distress, disability, adult attention, and
widespread family disruption. Young people with chronic pain report
sleep disturbance, disordered mood, appetite disruption, low feelings,
social isolation and unwelcome dependency on parents. When
maintained, these factors perpetuate pain and disability.
• Routines of normal schooling can become unmanageable and further
strained by interpersonal problems in explaining confusing problems.
School absence commonly occurs, further removing the child from
their normal social environment. This contributes to the impact on
their developmental trajectory, especially around adolescence: usually
a time of change, experimentation, social maturation, and development
of independence.
• Parental stress is also significant—parents experience distress and
conflict in parenting their child. They report struggling to cure and
comfort their child, recognizing that the desire to protect may be
counterproductive.
 PAIN SYNDROMES AND THE ASSESSMENT OF PAIN 91

Delivering psychological support

It is important that psychological support is integrated in the overall
management of patients with chronic pain as early as possible. Once the
diagnosis is made the emphasis can move from investigation and cure to
symptom management, functional improvement, and psychosocial reha-
bilitation. This should be delivered by all members of the MDT with a
consistent approach.
Components of psychological intervention
• Pain education, pacing, and activity management.
• Communication and managing social interactions.
• Peer relationships and friendships, family support and parenting.
• Goals and ambitions, integration with school and learning.
Key principles
• Disengagement from the pursuit of pain relief and engagement with
normal life activities.
• Focus on goals that are important to the individual child.
• Exercise and physical therapy is key to the rehabilitation of young
people with persistent pain and psychological support is crucial to
provide motivation, reduce fear of damage, and support engagement
despite persistent pain.
• Involvement of the parents in the rehabilitation process.
Specific psychological therapies
Cognitive behavioural therapy, mindfulness, acceptance, motivational
counselling.
Further reading
Clinch J, Eccleston C. Chronic musculoskeletal pain in children: assessment and management.
Rheumatology 2009; 48:466–74.
Eccleston C, Jordan A, McCracken LM, et al. The Bath Adolescent Pain Questionnaire (BAPQ):
development and preliminary psychometric evaluation of an instrument to assess the impact of
chronic pain on adolescents. Pain 2005; 118:263–70.
92 CHAPTER 2 Common clinical problems

Growing pains
Overview
• A ‘lay term’ encompassing non-specific musculoskeletal pains
commonly experienced by many healthy young children (with equal
gender ratio), characterized by poorly localized aches and pains in the
calves, shins, feet, and ankles, usually relieved with massage or simple
analgesics, and often predictable to occur later in the day, evenings, and
after periods of activity.
• The cause is unknown but there is no clear association with growth
(thus the term is a misnomer). Children with growing pains often
have features of hypermobility although not all hypermobile children
have pain; the causal association of hypermobility with pain in children
remains controversial. There is often a family history of growing pains.
• There is no specific test to positively confirm the diagnosis and clinical
assessment is integral to excluding potential causes of MSK pains
(see b Chapter 1).
• The ‘rules’ (red flags) of growing pains (Table 2.9) are important—
where the clinical pattern ‘does not fit’ these rules, further
investigation is required.
• The history should focus on the pattern, predictability, and site of
pain—it is important to probe for indicators of concern (Table 2.9).
• Physical examination requires a comprehensive MSK examination
(see b Chapter 1) and general examination.
• Nocturnal pain is common in growing pains—concern is warranted
if night waking is becoming more frequent, unremitting, or localized
to one site. Response to NSAIDS is common but (benign) bone
tumours need to be considered (see b Bone tumours, p 60).
Management
• Investigation is not needed unless concern has been raised (Box 2.5).
Investigations are summarized in Box 2.6.
• Reassurance and explanation is paramount:
• Growing pains are likely to improve as the child gets older.
• Advice on footwear (supportive and well fitting); trainers with
arch supports are ideal (note shoelaces are best tied and ‘Velcro’
fastened firmly). Specialist orthotics rarely needed.
• Given the predictability of pains and to prevent night waking,
analgesics before physical activities or at bedtime may be helpful.
• It is important to address parental concerns and give clear instructions
when to seek medical attention again (e.g. limping, joint swelling,
asymmetrical involvement 1 leg being affected or pains elsewhere
(e.g. fingers), or daytime symptoms, systemically unwell avoidance of
previously enjoyed activities).
• A parent information leaflet is available: M http://www.
arthritisresearchuk.org/files/6541_20022010162934.pdf.
 GROWING PAINS 93

Box 2.5 The ‘rules’ of growing pains

‘Rules’ of growing pains
• Pains never present at the start of the day after waking.
• Child doesn’t limp.
• Physical activities not limited by symptoms.
• Pains symmetrical in lower limbs and not limited to joints.
• Physical examination normal (joint hypermobility may or may not be
detected).
• Systemically well and major motor milestones normal.
• Age range 3–12yr.
Indications for concern
• Systemic upset (red flags to suggest sepsis or malignancy).
• Abnormal growth (height and weight).
• Abnormal developmental milestones:
• Delay (especially major motor skills) suggestive of neurological
disease or metabolic bone disease or
• Regression of achieved motor milestones (consider inflammatory
joint or muscle disease).
• Impaired functional ability (ask about play, sport, schoolwork,
‘clumsiness’).
• Limping (intermittent or persistent).
• Morning symptoms (other than tiredness after disturbed sleep) or
mood changes may suggest inflammatory arthritis.
• Widespread pain (such as upper limbs and back).
• School absenteeism.

Box 2.6 Investigations that may be indicated

• FBC (and film), acute phase reactants (ESR, CRP).
• Biochemistry (bone biochemistry and vitamin D) to exclude
metabolic bone disease including osteomalacia (see b Metabolic
bone diseases, p 330).
• Thyroid function, muscle enzymes to exclude inflammatory muscle
disease (see b Juvenile dermatomyositis, p 266).
• X-ray of legs (hips with frog views) to exclude hip pathology,
e.g. Perthes disease (seeTable 2.13).
• Radioisotope bone scan to exclude local hot spots (e.g. osteoid
osteoma, occult fracture)—see b Bone tumours, p 60.

Further reading
Foster HE, Boyd D, Jandial S. Growing Pains. A Practical Guide for Primary Care. ARC, 2008.
Available at: M http://www.arthritisresearchuk.org/files/6541_20022010162934.pdf.
94 CHAPTER 2 Common clinical problems

Pyrexia of unknown origin

Definition
Several definitions have been proposed: essentially this is a term for per-
sistent or recurrent pyrexia that persists for longer than you would expect
from a self-limiting viral illness (e.g. 5 days) and has evaded diagnosis from
reasonable 1st-line history, examination, and investigation.
One useful working definition of pyrexia of unknown origin (PUO) is:
pyrexia >38.0ºC on several occasions, >3 weeks’ duration of illness, and
failure to reach diagnosis despite 1 week of inpatient investigations.
Key points
• Always consider incomplete Kawasaki disease, especially if faced with
an irritable young child with fever ± any other suggestive history, signs,
or suggestive blood results (see b Kawasaki disease, p 183). Missing
out on early treatment of this can i risk of significant coronary artery
aneurysms.
• In the immunosuppressed child (e.g. neonate, neutropenic, HIV+ve,
on immunosuppressive treatment, or p immunodeficiency), different
causes (especially infections, e.g. fungal, cryptosporidium) are more
likely and treatment against relevant possible infection should be given
alongside investigation.
• Antibiotics have often been tried and no benefit seen, especially in
young children.
• 1st-line investigation usually includes:
• Blood cultures when pyrexial.
• Urine microscopy and culture.
• Chest x-ray (CXR).
• Cerebrospinal fluid (CSF) microscopy, culture, and PCR analysis for
herpes simplex virus (HSV).
Assessment
The approach includes investing time in carefully reviewing the history
including:
• Detailed review of all systems including rashes, weight loss, bowel
symptoms, joint symptoms, mouth ulcers.
• Foreign travel, history of tick bites.
• Health of family members recently and family history of unexplained
fever.
• Pets and their health.
• Drug and medication history.
• Hobbies (e.g. camping/trekking), swimming in lakes or rivers, and
especially recently.
• Sexual history when relevant.
Detailed examination of all systems and repeated examination including:
• Examining skin for rashes, especially when pyrexial.
• Lymphadenopathy.
• Mouth for ulcers.
• Auscultation of heart sounds.
 PYREXIA OF UNKNOWN ORIGIN 95

• Assessment of hands for features of endocarditis and nailfold

capillaries.
• Abdomen and testes for any tenderness/swelling.
• Joints for any evidence of arthritis.
• Routine fundoscopy and consider requesting slit lamp examination by
ophthalmologist to look for uveitis/other intraocular pathology.
• Eyes, lips, palms, soles, perineum (peeling is often overlooked at this
site), neck and trunk for features of Kawasaki disease: remember that
clinical signs can present sequentially, may be subtle and can only last a
few days.
Investigation and management
• Further investigations follow-up on clues found from the history,
examination and initial test results. Table 2.9 includes the more
common causes (focus being for a patient in the UK) and clues that
should guide investigations, although this is not an exhaustive list.
• Foreign travel will raise the chances of different infections linked to the
area visited.
• There are a few paediatric cohort studies published describing the
ultimate diagnoses, but all are very dependent on local population and
pathway of referral to the cohort.
• Management depends on the proven or strongly suspected diagnosis.
Consider consulting other specialties
• Infectious diseases
• Haematology/oncology
• Gastroenterology
• Endocrinology
• Interventional radiology
• Surgery.
Prognosis
• 5–15% remain undiagnosed even after extensive evaluation.
• No evidence to support prolonged hospitalization if patient stable and
whose work-up is unrevealing.
• Further outpatient care:
96 CHAPTER 2 Common clinical problems

Table 2.9 Causes and relevant investigations for PUO

Diagnosis Suggestive features Useful investigations
a) Localized bacterial infections
Abscess, Localizing symptoms Imaging e.g. USS, CT, MRI,
e.g. abdominal, white cell scan
pelvic
Endocarditis New murmur, haematuria, Repeated blood cultures,
splinter haemorrhages, transthoracic echocardiogram;
Janeway lesions, consider oesophageal
Roth’s spots echocardiogram (seek expert
advice)
Septic arthritis Localizing symptoms Imaging e.g. US, MRI, joint
and signs aspiration
Osteomyelitis Localizing symptoms Plain x-ray (although
insensitive), bone scan, MRI
Sinusitis/ Localized pain/tenderness CT with contrast
mastoiditis
b) Other infections
EBV, CMV Lymphadenopathy IgM against EBV/CMV, PCR
of blood
Cat scratch Lymphadenopathy. Serology (Bartonella). Lymph
disease Contact with cats node biopsy
Tuberculosis Family contact history, CXR, Mantoux, Quantiferon
travel, night sweats TB test, specific culture,
16s ribosomal PCR of lesional
tissue or fluid
HIV Recurrent infections, Blood HIV PCR
maternal ill-health,
sexually active or other
risk factors
HHV6 Rash, febrile convulsion, PCR of blood and CSF
aseptic meningitis
Brucellosis Farming community, Serology (Brucella). Specific
hepatosplenomegaly culture of urine + blood
Campylobacter, Diarrhoea Stool microscopy and culture.
Salmonella,
Shigella, or
Yersinia
Hepatitis Jaundice, abdominal pain, Serology for HAV, HBV, HCV
diarrhoea
 PYREXIA OF UNKNOWN ORIGIN 97

Table 2.9 (Contd.)

Diagnosis Suggestive features Useful investigations
Leptospirosis Farming/river contact, Serology (Leptospira)
headache, myalgia then
headache
Malaria Travel to endemic area in Repeated blood films
preceding months
Lyme disease Rash, tick bite, aseptic Serology (Borrelia)
meningitis
c) Post-infectious
Acute Recent pharyngitis, carditis, Throat swab, ASOT/
rheumatic Ducket Jones criteria anti-DNAase B, ECG,
fever echocardiogram
Post Recent pharyngitis, fleeting Throat swab, ASOT/
streptococcal arthritis anti-DNAase B
reactive
arthritis
Other reactive Arthritis, urethritis, HLA B27 status, stool culture,
arthritis conjunctivitis, recent urethral swab including
infection Chlamydia culture/PCR and
gonorrhoea microscopy/
culture
d) Malignancy
Leukaemia Anaemia, cytopenia, Blood film, bone marrow
night pain aspirate
Lymphoma Lymphadenopathy, weight LDH, lymph node biopsy
loss, night sweats
Neuroblastoma Mass, anaemia Urine VMA and HVA:
creatinine ratio, abdominal US
Wilm’s tumour Abdominal pain and mass, Abdominal/renal US
haematuria
e) Autoimmune/auto-inflammatory
Systemic Typical rash with daily Ferritin
juvenile pyrexia, arthritis (may be
idiopathic later), lymphadenopathy,
arthritis mild splenomegaly
Kawasaki Irritable (with sterile CSF), Echocardiogram. NB a normal
disease eye and mouth changes, result does not exclude
rash, lymphadenopathy, Kawasaki disease.
peeling skin

(continued )
98 CHAPTER 2 Common clinical problems

Table 2.9 (Contd.)

Diagnosis Suggestive features Useful investigations
Systemic Rash, low mood and ANA screen (and if positive:
lupus lethargy, ENA Abs and dsDNA
erythematosus antibodies), ACL and lupus
Lymphopenia, cytopenia,
anticoagulant, C3 and C4, renal
proteinuria
biopsy if significant nephritis
Juvenile Typical rashes, proximal CK, LDH, MRI thigh
dermatomyositis weakness muscles—see b Juvenile
dermatomyositis, p 266
Periodic fever Chronic episodic fever, well Acute phase response when
syndromes in between, oral ulceration well and soon after onset, gene
(see b p 288) and lymphadenopathy, mutation analysis
otherwise thriving
CINCA Neonatal onset, irritable, Gene mutation analysis. See b
rash, arthritis Cryopyrin associated periodic
syndrome (CAPS), p 294
Sarcoidosis Arthritis, rash, uveitis, Serum ACE, CXR, consider
chest disease (hilar lesional tissue biopsy.
lymphadenopathy ± See b Sarcoidosis, p 300
interstitial lung disease)
Vasculitis Rash, renal concerns, Skin biopsy, selective
arthritis, testicular/abdominal visceral digital subtraction
pain, many other potential arteriography, ANCA
multisystemic features
Inflammatory Diarrhoea and/or nausea, Upper and lower GI
bowel disease weight loss endoscopy, MRI bowel,
labelled white cell scan
Thyrotoxicosis Weight loss, tremor, Thyroid function tests
sweating, tachycardia (including T3 if strongly
suspect, as well as TSH and
T4), thyroid autoantibodies
f) Miscellaneous
Factitious Not recorded in hospital Careful observation in hospital
by others
Drug-induced fever Suggestive history Stop suspected drug(s)
Kikuchi disease Lymphadenopathy progressing Lymph node biopsy
to necrotizing lymphadenitis
(especially cervical), leukopenia,
Asian origin especially;
observed particularly in SLE
Castleman’s ‘Giant lymph node HHV8 serology and/or PCR,
disease hypertrophy’, unifocal or lymph node excision biopsy.
multicentric FDG PET-CT scan, serum
cytokine analysis (esp. IL-6)
if available
 PYREXIA OF UNKNOWN ORIGIN 99

• Close follow-up procedures and systematic re-evaluation to ensure

that no deterioration occurs, and to guide further outpatient
investigation.
Further reading
Cogulu O, Koturoglu G, Kurugol Z, et al. Evaluation of 80 children with prolonged fever. Pediatr
Int 2003; 45:564–9.
Joshi N, Rajeshwari K, Dubey AP, et al. Clinical spectrum of fever of unknown origin among Indian
children. Ann Trop Paediatr 2008; 28:261–6.
Pasic S, Minic A, Djuric P, et al. Fever of unknown origin in 185 paediatric patients: a single-centre
experience. Acta Paediatr 2006; 95:463–6.
100 CHAPTER 2 Common clinical problems

Back pain in children and adolescents

Recent epidemiological studies report back pain in children to be more
common than previously thought, with a higher prevalence (15.7–28.8%)
of non-specific lower back pain as the child matures. A detailed history
and examination identifying red flag symptoms (Table 2.10) and signs
(Table 2.11) should point towards appropriate investigation and diagnosis
of pathological causes.

Table 2.10 ‘Red flag’ symptoms in back pain

Examination Red flag symptoms
Age of child <4yr
Chronicity >4 weeks, persistent and worsening
Site Cervical spine
Exacerbating factors Hyperextension
Diurnal variation Worse at night, early morning stiffness
Systemic features Pyrexia, weight loss, malaise
Neurological symptoms Altered bladder and bowel function, headaches
Past medical or Systemic disease, e.g. JIA, sickle cell, TB, (see b
family history Tuberculosis and mycobacterial disease, p 356),
neurofibromatosis
Drug history Pain unresponsive to analgesia,* chronic steroid use
Social activities History of trauma or foreign travel, interference with
function. Lifestyle and psychological factors should also
be enquired about (e.g. bullying at school)
*
Benign osteoid osteoma pain often responds well to NSAID therapy.

Table 2.11 ‘Red flag’ signs in back pain

Examination Red flag signs
Cardiovascular Tachycardia
Respiratory Reduced air entry, mediastinal shift
Gastrointestinal Abdominal mass
Neurological Altered power, tone, reflexes, sensation
Musculoskeletal Altered normal spine curvature or gait. Scoliosis (especially
if painful). Vertebral/intervertebral tenderness
Systemic Pyrexia, lymphadenopathy
Dermatological Rash, bruising, café au lait patches, infected skin, midline
skin lesions
 BACK PAIN IN CHILDREN AND ADOLESCENTS 101

Back examination
(See b pREMS, p 23.)
• Look: observe posture and gait (evidence of kyphosis, loss of lumbar
lordosis, scoliosis (and if present assess whether fixed or postural),
pelvic tilt, shoulder asymmetry, leg-length discrepancy.
• Feel: palpate spine for point tenderness, muscle spasm. Palpate
sacroiliac joints.
• Move: range of spinal movement (forward/lateral flexion, extension,
rotation), and hyperextension on one leg (‘stork test’: for lumbar
spondylosis—standing on one leg and bringing back into lumbar
extension elicits pain ipsilateral to the pars interarticularis lesion).
• Also examine hips, test straight leg raise with dorsiflexion of foot
and assess hamstring length.
• Measure/other: leg-length discrepancy, neurological assessment.
Investigation
If no red flags, imaging unlikely to be helpful. If investigation clinically indi-
cated, do not be reassured by a normal x-ray. MRI, CT, or bone scan may
be needed.
Muscular pain
Common. Causes include poor posture, hypermobility, leg-length discrep-
ancy, idiopathic scoliosis, asymmetrical load bearing (e.g. schoolbag on
one shoulder). No need for imaging (refer scoliosis to scoliosis service).
Treatment—advice, analgesia, physiotherapy.
Spondylosis
A bony defect in the pars articularis, analogous to a stress fracture.
• The commonest identifiable cause of low back pain in young athletes,
and commonest in sports involving repetitive hyperextension and
rotational spinal loading, e.g. gymnastics, weight lifting, cricket. Pain may
radiate to buttocks. Usual sites L5 (85–95%), or L4.
• If bilateral may progress to spondylolisthesis; the forward slip of one
vertebra on the vertebra below—usually L5/S1. May compress nerve roots.
• One-legged hyperextension test (stork test—see b Chapter 1, p 26)
may be positive. A lumbosacral step may be palpated.
• The defect may be seen on PA/lateral x-ray. If x-rays normal but clinical
suspicion high, arrange localized MRI or CT (discuss with radiology).
• Management includes review by orthopaedic surgeon—rest, analgesia,
physiotherapy. Indications for bracing and/or surgery include a slip of
>50% vertebral body width, progressive changes, neurological deficit
present.
Scheuermann’s disease (juvenile kyphosis)
Often a coincidental finding on x-ray and considered a normal variant of
unknown aetiology. May be associated with mild/moderate pain, onset
around puberty.
• Kyphotic deformity of thoracic or thoracolumbar spine which does not
disappear on lying supine or with hyperextension. Fixed kyphosis is 40°
or more.
• X-ray criterion—>5° anterior wedging of at least 3 adjacent vertebral
bodies. In addition there may be irregularity and flattening of vertebral
102 CHAPTER 2 Common clinical problems

end plates, narrowed disc spaces, Schmorl’s nodes (extrusion of disc

substance through the vertebral end plate).
• If pain is severe, consider whether other pathology is present.
• Management—analgesia. Symptoms usually resolve with skeletal
maturity.
Disc degeneration
This is present in a significant number (16–26%) of 10–19yr-olds.
May be asymptomatic but pain more likely if disc prolapse is present.
• May present with sciatica and/or have positive straight leg raise.
• MRI if suspect disc herniation.
• Management: rest, analgesia, NSAIDs, physiotherapy. Conservative
management is less successful than in adults and surgery may be
required (e.g. severe pain, progressive neurology).
Tumours
• Consider if painful scoliosis, persistent or night pain, progressive pain/
disability.
• X-ray then MRI, CT or bone scan (discuss with radiology), ± bloods:
FBC, CRP, LDH, urine: catecholamines, and abdominal US.
Osteoporosis
See b Metabolic bone diseases, p 330.
Idiopathic pain syndrome (see b Pain syndromes and the
assessment of pain, p 87), and infective causes (see b p 64) are
discussed elsewhere.
It is also important to remember the possibility of referred pain (e.g. from
abdomen, chest, or renal causes).
Further reading
Houghton KM. Review for the generalist: evaluation of low back pain in children and adolescents.
Pediatric Rheumatology 2010; 8:28 (open access): M http://www.ped-rheum.com/content/
pdf/1546-0096-8-28.pdf.
 SCOLIOSIS 103

Scoliosis
Scoliosis is a three-dimensional deformity in which the spine deviates from
the midline in the coronal plane by >10° and the affected vertebrae rotate
maximally at the apex of the curve. The curve may be single or double
(Fig. 2.11).
Causes
• Non-structural: postural/compensatory
• Transient: sciatic/hysterical/inflammatory/infection
• Structural:
• Idiopathic (most common)
• Congenital, e.g. hemivertebrae
• Neuromuscular, e.g. muscular dystrophies, cerebral palsy
• Neurofibromatosis-related
• Connective tissue-related
• Trauma
• Tumour (intra- or extraspinal).

Idiopathic scoliosis
• 80% are idiopathic and classified according to age of onset:
• Infantile <3yr
• Juvenile 3–10yr (or onset puberty)
• Adolescent >10yr (or after puberty).
• More common in adolescents than juveniles, more common in females:
• Thoracic curves are usually to the right.
Symptoms
Idiopathic scoliosis is not associated with significant pain and may present
with asymmetry of shoulders, trunk skin creases, or skirt hem, or be
noticed by others. Often found incidentally. School screening programmes
are not deemed cost-effective. A painful scoliosis or with neurological
involvement suggest an underlying serious cause (‘red flag’ for urgent
referral).
Examination (see b pREMS, p 23)
• ‘Look’—observe standing posture. Is the head in the midline, is there
shoulder asymmetry, are the iliac crests level?
• Observe in forward flexion from behind and from the side—is there
a single or double curve, is the curve to right or left, is a rib hump
visible, are there skin changes (e.g. cafe au lait spots suggestive of
neurofibromatosis)?
• ‘Feel’—is there spinal tenderness?
• ‘Move’—does the curve correct on lateral flexion, sitting, or is it fixed?
• ‘Measure/other’—is there leg-length discrepancy? Is there neurological
deficit?
Red flags (for urgent referral)
Pain, neurological signs (root or cord compression).
104 CHAPTER 2 Common clinical problems

Fig. 2.11 X-ray of patient with idiopathic scoliosis. A right thoracic and left lumbar
curve is seen.

Management
• If red flags, refer urgently to scoliosis service.
• If idiopathic scoliosis likely, refer to local scoliosis service for further
assessment.
• Treatment options depend on severity and include physiotherapy,
bracing, and surgical interventions.
Investigations
• Anteroposterior (AP) and lateral x-rays should be taken standing in a
standardized way.
• The Cobb angle is determined by identifying the vertebrae at the upper
and lower end of the curve, with greatest tilt to concavity of curve and
drawing a line along the upper and lower end plates accordingly.
• The Cobb angle is the angle between these two lines (Fig. 2.12). Note:
the Cobb angle correlates poorly with overall cosmetic appearance
 SCOLIOSIS 105

which may be affected by number, size, and location of curves,

associated chest wall deformity, muscle bulk, and fat distribution.
• MRI and isotope bone scan are required with a painful scoliosis—bone
scan may detect osteoid osteomas which can be missed on MRI.
• MRI required with presence of red flags. It is reported that left-hand
thoracic curves have a high incidence of neural axis abnormalities
(e.g. Arnold Chiari malformation). Albeit a contentious observation,
MRI is advised with left-hand thoracic curves.
• Pulmonary function tests are necessary in significant thoracic scoliosis;
impact on cardiovascular function is low unless the curve is large with
Cobb angle >100°.

45°

Fig. 2.12 Cobb angle.

Prognosis
Worse prognosis and greater likelihood of progression:
• Large curves, thoracic and double p curves.
• Earlier onset pre-skeletal maturation as scoliosis progresses through
pubertal growth phases.
• In adolescent idiopathic scoliosis, the Riser grade (degree of fusion of
the iliac apophysis reflecting skeletal age) can be used with the Cobb
angle to give an estimate of the chance of progression in a population.
• Riser stage 0–1: curves 20–29° have >65% risk of progression.
• Riser grade 2–4: curves 20–29° have >20% risk of progression.
106 CHAPTER 2 Common clinical problems

Hip pain and hip problems in children

and adolescents
• Hip problems in children and adolescents can present with pain,
limp (see b p 80), deformity, inability to bear weight or as part
of a systemic illness. Early diagnosis and appropriate treatment is
paramount to avoid permanent damage.
• Children are optimally managed by an experienced MDT including
orthopaedics, rheumatology, and infectious diseases as indicated,
especially before invasive procedures are contemplated. Alleviation of
pain should be given due importance from the start and throughout the
investigation phase.
• The clinical assessment is integral to making a diagnosis and the
differential diagnosis is broad but may be differentiated by age (see
Tables 2.12–2.14 with more detail given in relevant chapters). Red flags
(see b p 8, p 64, p 66) for septic arthritis, osteomyelitis, malignancy
and NAI are vital to consider and exclude. Investigations should be
tailored to the most likely differential diagnoses based on the clinical
assessment.
• Key features in the clinical assessment include:
• History: onset and symptom duration, characteristics of pain,
morning stiffness, functional impairment, presence of other joints
affected, fever and associated systemic symptoms, coexistent
medical conditions, and identification of precipitating factors
including trauma. Note that trauma is common in the young child and
a common error to explain musculoskeletal presentations which can be
due to other causes.
• Hip problems can present with subtle or vague symptoms, e.g.
irritability, crying during nappy-change, or as delay in, or regression,
of motor milestones in children. Hip pain can be localized to the
groin or referred to the thigh or knee. Pain felt at the pelvic brim
should not be confused with hip pain.
• Physical examination:
• Presence of fever and systemic features of any concurrent illness.
Examine all joints (the pGALS screen is useful—see b pGALS,
p 18), assess gait and check for limb shortening. Pain on passive
movements, specifically internal rotation, suggest hip pathology—
note that the position that allows for maximal intracapsular volume
and resultant comfort in the presence of an effusion, is that of
external rotation, flexion, and abduction.
• Pathology elsewhere (e.g. abdomen, spine, sacroiliac joint, nerves)
can mimic hip problems and requires diligent exclusion.
• Other differential diagnoses across all age groups:
• JIA from late infancy: monoarthritis of hip is uncommon, but does
occur.
• Infection-related arthritis: reactive arthritis (Yersinia, Salmonella,
Shigella, Campylobacter, and Chlamydia in adolescents); post-
streptococcal arthritis; TB arthritis, gonococcal arthritis in
adolescents—see b p 64. Rarer bacteria: Mycoplasma, Borrelia
burgdorferi (Lyme disease), Brucella.
 HIP PAIN AND HIP PROBLEMS IN CHILDREN AND ADOLESCENTS 107

• Congenital causes—epiphyseal dysplasia (see b p 333), metabolic

storage disorders (e.g. Gaucher’s (see b p 312).
• Malignancy—p bone tumours, benign and malignant (see b p 60)—
referred pain from the spine or abdomen or pelvis (including
retrocaecal appendicitis) may present with hip pain.
• Osteoarthritis—p (rare in the absence of predisposing conditions
such as skeletal dysplasia (see b p 333) and s to pre-existing hip
disease.
• Chronic idiopathic pain syndromes (see b p 87) needs careful
exclusion of organic pathology.
Further reading
Fabry G. Clinical practice: the hip from birth to adolescence. Eur J Pediatr 2010; 169(2):143–8.
Houghton KM. Review for the generalist: evaluation of pediatric hip pain. Pediatr Rheumatol
Online J 2009; 7:10.
 108
Table 2.12 Differential diagnosis of hip pathology by age: age group: 0–4 years

CHAPTER 2
Developmental Transient synovitis Septic arthritis/ Malignancy (see b p 56) Trauma
dysplasia of hip osteomyelitis
(see b p 64)

Common clinical problems

Demographics 5>4 4>5 Slightly more common Generally more common Commonest cause in
in boys in boys general—beware not all
1–5 per 1000 1–2 per 1000
causes of hip pain are
5–10 per 100000
(True dislocation) trauma related!
Patho- Disruption of normal Idiopathic self-limiting Haematogenous spread Bone marrow infiltration- Green-stick fractures
relation between synovial inflammation most often, direct extension leukaemia, metastatic common in toddlers
physiology
femoral head & less common. Staph. aureus tumours (neuroblastoma),
Consider NAI
acetabulum most common pathogen
p bone tumours and soft
overall. Consider Group B
tissue tumours (such as
Strep. & Gram–ve bacilli in
rhabdomyosarcoma)
neonates. Others: TB, rarer
are rare
bacteria
Predisposing Family history Viral or bacterial Immunosuppression Congenital: Bone mineralization
factors & illness Down’s, Bloom’s, disorders (see b p 330)
Breech Trauma
associations Fanconi’s syndromes
Minor trauma Social history in NAI
Oligohydramnios Sickle-cell disease
Neuromuscular Interventional procedures
disease in neonates especially
preterms
Clinical Hip click/clunk Pain +, limp ± Fever, pain++, inability Severe/nocturnal pain, Pain, inability to weight

HIP PAIN AND HIP PROBLEMS IN CHILDREN AND ADOLESCENTS

features to bear weight, restriction inability to weight-bear, bear, local tenderness,
Can present later in Most common cause
of joint movement, other bony tenderness ±, local bruising ±
infancy, asymmetry of hip pain in children
systemic signs
of skin creases excluding trauma Systemic—fever, anaemia,
weight loss
Shortening of limb
Diagnosis Clinical (neonatal Blood tests can be USS useful to show Radiology for site & History for mechanism
screening)—Ortolani abnormal effusion, MRI for extent—MRI/CT, bone scan of injury
& Barlow test, MSUS osteomyelitis/abscess may show ‘hotspots’
Radiology might show Imaging—x-ray usually
(check abbreviation)
effusion (MSUS and Inflammatory markers are FBC/bone marrow to suffices
4–6 months of age
MRI) often high. Joint exclude leukaemia
MRI for detailed
X-ray—for late aspiration—gold standard
Urinary catecholamines- evaluation & to exclude
presentation
A high index of suspicion screening for neuroblastoma other causes
MRI—for is required for diagnosis
Bone biopsy—definitive
complications (Kochers prediction rule;
histological diagnosis
see b p 66)
Treatment Abduction brace Symptomatic Arthroscopic/open Modality dependent on Orthopaedic management
drainage ± joint lavage pathology: chemotherapy,
Closed reduction NSAIDs Pain relief
radiotherapy, surgical
Antibiotics—in general, IV
Open surgical resection Management of NAI
followed by oral, although
reduction
duration is not clearly
Acetabuloplasty defined

(continued )

109
 110
Table 2.12 (Contd.)

CHAPTER 2
Developmental Transient synovitis Septic arthritis/ Malignancy (see b p 56) Trauma
dysplasia of hip osteomyelitis
(see b p 64)

Common clinical problems

Course & Good outcome if Usually resolves Increase in intra-articular Prognosis dependent Excellent prognosis with
complications early identification within 2 weeks pressure l compromised on staging early treatment
& treatment blood supply & avascular
Recurrence risk of Poor prognosis in advanced Prognosis for NAI is
necrosis
Persistent dysplasia 15 %, usually within malignant disease dependent on coexistent
6 months—unclear Joint destruction can occur injuries and chronic
Avascular necrosis
if associated without prompt or impact
(s to treatment)
with subsequent adequate treatment
development of
Perthes’ disease
Table 2.13 Differential diagnosis of hip pathology by age: age group: 4–8 years

HIP PAIN AND HIP PROBLEMS IN CHILDREN AND ADOLESCENTS

Perthes’ disease Septic arthritis and Tumours/malignancy Transient
(Legg–Calve–Perthes) osteomyelitis synovitis
Demographics 4>5 See Table 2.12 and b Bone See Table 2.12 and b Bone tumours, Less
5–15 per 100,000 and joint infections, p 64 p 60 common as
age advances
Patho- Idiopathic avascular necrosis of femoral epiphysis Septic arthritis diminishes Frequency of bone tumours after 4–6yr
physiology in frequency after 2yr of increases with age
age—however should be
Predisposing Epiphyseal dysplasia excluded Benign bone tumours:
factors & • Osteochondroma—most common
Hypothyroidism • Osteioid osteoma—pain dramatically
associations
Delayed bone age responsive to NSAIDs
Caucasians
Coagulation abnormalities
Clinical Pain ±, limp worsening with exercise
features Bilateral in 10–15% Malignant bone tumours:
• Osteosarcoma most common—
Diagnosis Clinical: restriction of internal rotation and abduction association with previous irradiation
X-ray, MRI, bone scintigraphy • Ewing’s sarcoma 2nd most common—
commoner in white boys, diaphyseal
Treatment NSAIDs in contrast to most p bone tumours
Restriction of activity/immobilization which are metaphyseal
Surgery: osteotomy, augmentation plasty
Course & Treatment does not halt natural course
complications Bad prognosis if older age at onset & greater extent
of femoral head involvement
Deformity of femoral head in severe cases
Long term—early osteoarthritis

111
 112
CHAPTER 2
Common clinical problems
Table 2.14 Differential diagnosis of hip pathology by age group: 8–16 years
Slipped capital Trauma Tumours/malignancy Infection Avascular necrosis
femoral epiphysis or
(SCFE) osteonecrosis
Demographics 4>5 4>5 Refer to Tables 2.12 and 2.13 Refer to Tables 2.12 4=5
and 2.13
1–3 per 100,000 Benign tumours can arise from
bone, cartilage, fibrous tissue or Amongst other
soft tissues pathogens, also
consider Gonococcus
Benign tumours such as osteoid
and Chlamydia
osteoma, and malignant tumours
in sexually active
such as osteosarcoma and Ewing’s
adolescents
sarcoma are more common in this
age group Gonococcal arthritis
can lead to early joint
As in all age groups, it is important
destruction if not
to consider malignancy not
identified in time
arising primarily from the bone,
e.g. leukaemia
Patho- Posterior & inferior Sports-related injuries: Circulatory

HIP PAIN AND HIP PROBLEMS IN CHILDREN AND ADOLESCENTS

physiology displacement of Ligamentous injuries compromise-
epiphysis (s to can be p or s to
Avulsion injuries—due to
displacement of causes listed below
inherent weakness across
proximal femoral
open epiphysis Bilateral occurrence
metaphysis)
in 50%, if not
Apophyseal injuries &
Classification: associated with
apophysitis—chronic
• Acute/chronic/ trauma
overuse & repetitive
acute-on-chronic
muscle contractions
• Stable/unstable
• Radiographic Stress fractures—chronic
• Preslip, Grade I, II, III repetitive microtrauma
Transient demineralization
of hip
Post-traumatic
chondrolysis of hip

(continued )

113
 114
CHAPTER 2
Common clinical problems
Table 2.14 (Contd.)
Slipped capital Trauma Tumours/ malignancy Infection Avascular necrosis
femoral epiphysis or
(SCFE) osteonecrosis
Predisposing Overweight or obese High-impact sports Drugs—steroids,
factors & (but can also occur in LMW heparin
Chronic or repeated
associations thin patients)
microtrauma/sustained Haemoglobinopathies
Hypothyroidism overuse
Coagulopathies
Growth hormone Inherent bone
Skeletal dysplasias
deficiency mineralization problems
Infections—HIV,
Exposure to radiation
Meningococcus
Afro-Caribbeans
Inflammatory bowel
disease, trauma,
malignancy, vasculitis/
JIA, orthopaedic
(previous DH, SCFE,
Perthe’s)
Clinical Pain +, limp +, Pain, restriction of Insidious onset of

HIP PAIN AND HIP PROBLEMS IN CHILDREN AND ADOLESCENTS

features movement, pain which typically
Inability to walk in
occurs with standing
unstable variety localized swelling/bruising ±,
or walking
Presentation with presence of hernia in
d abduction
knee pain or limp ‘sportsman’s hernia’ (a type
and rotation on
alone leads to delayed of imminent direct hernia
examination
diagnosis that can cause chronic groin
pain in athletes) Limp is a late finding
Bilateral in 20–40%
Sudden pain following
intense physical activity
typical of acute chondrolysis
Diagnosis X-ray: Typical history Low index of
• AP—‘Klein’s line’ suspicion if associated
X-ray
(a line drawn along risk factors
the superior femoral MRI
MRI—most sensitive
neck should normally
Hip arthroscopy for isolated for early diagnosis
intersect a portion
labral tears, loose bodies
of the femoral head)
• Frog lateral view
MRI—useful in ‘pre-slip’
stage
(continued )

115
 116
Table 2.14 (Contd.)

CHAPTER 2
Slipped capital Trauma Tumours/ malignancy Infection Avascular necrosis
femoral epiphysis or
(SCFE) osteonecrosis

Common clinical problems

Treatment Surgical: early in situ Orthopaedic management Medical: pain relief,
stabilization by screw bisphosphonates
Pain relief
fixation
Surgical: core
Unstable SCFE is an decompression and
orthopaedic emergency bone grafting
Course & Bad prognosis if i Consider pain syndromes Femoral head
complications severity of slippage and if not getting better with collapse can occur if
delay in diagnosis conventional treatment diagnosis is delayed,
after excluding important in which case total
Complications:
differentials hip replacement
• Avascular necrosis
might be needed
• Acute chondrolysis
Fractures can occur
Long-term—early
as a complication of
osteoarthritis
surgery
 KNEE PAIN IN CHILDREN AND ADOLESCENTS 117

Knee pain in children and adolescents

Pain in and around the knee joint is very common and often recovers
spontaneously. More persistent knee pain may indicate a specific condi-
tion as described in the ‘Causes’ section.
Causes (Table 2.15)
Mechanical
• Anterior knee pain/patellofemoral pain:
• Pain at the front of the knee, made worse by inactivity, stair
climbing, or any activity involving bending the knee. Often
aggravated by sport. Common at time of growth spurts.
• Genu valgum, hypermobility, femoral torsion, and pronated feet
contribute to anterior knee pain.
• Management:
— Optimizing strength of pelvifemoral musculature.*
— Optimizing balance between quadriceps and hamstrings.
— Optimizing strength between individual components of quadriceps
muscle bellies.
— Improving proprioception.
— Note: non-participation in PE/sport does not influence rate of recovery
so participation is strongly encouraged where possible.
• Chondromalacia patellae:
• This term is a misnomer and source of confusion. The presence of
‘soft cartilage’ is not correlated with patellar pain.
• If anterior knee pain then see earlier in this list.
• Patella dislocation:
• The patella commonly tilts and glides toward the lateral aspect of
the knee—the patella may slip and stay there—‘dislocation’—
although slips which sublux and return to the anatomically correct
position are more common.
• Several anatomical conditions can precipitate recurrent
dislocation—flat patella, patella alta, shallow femoral trochlea,
femoral torsion, loose medial structures, general joint laxity.
• Management: optimizing strength of pelvifemoral musculature,
reduction of patella, and knee immobilized. For recurrent
dislocation—arthroscopic lateral release of lateral retinaculum or
stabilization of the patella.
• Osgood–Schlatter’s disease:
• Caused by repetitive microtrauma to the tibial tubercle apophysis,
usually in jumping sports (overuse traction apophysitis).
• Symptoms—often low-grade ache and inflammation around tibial
tuberosity, associated with activity. Pain relieved by rest.
• Signs—pain reproduced by resisted extension from 90° of flexion.
• Imaging –x-ray usually normal. US/MRI may show fragmented
apophysis.
• Management—ice for pain, activity modification, i.e. encourage
swimming and cycling and avoid jumping. Symptoms are self-limiting.
118 CHAPTER 2 Common clinical problems

• Sinding–Larsen and Johansson syndrome:

• Caused by repetitive microtrauma at the insertion of patellar
tendon onto lower patella pole (overuse traction apophysitis).
Often seen in conjunction with over pronated feet.
• Symptoms—pain and tenderness precipitated by overstraining or
trauma.
• Signs—slightly swollen, warm tender bump. Pain worse on resisted
extension.
• Imaging—US/MRI may show fragmented lower pole of patella.
Helpful to monitor disease course.
• Management—initially ice, stretching, and strengthening exercises.
Avoid running, jumping, squatting activities. Usually resolves in
3–6 months.
• Plica syndrome:
• Result of remnant fetal tissue in the knee. When knee flexed plica is
exposed to injury and becomes inflamed.
• Can be confused with meniscal tears or patellar tendonitis.
• Imaging—MRI often not helpful. Often seen on arthroscopic
examination.
• Management—NSAIDs, intra-articular cortisone, activity
modification.
• Osteochondritis dissecans:
• Focal area of detached or semi-detached subchondral bone with
hyaline articular cartilage on top. Common cause of loose body
within the knee. 4:5=3:1.
• History of trauma in approx 40%.
• Symptoms—initially pain, then locking and weakness.
• Signs—may be normal.
• Imaging—x-ray, MRI, or arthroscopy can be used to confirm
diagnosis.
• Management—referral to Orthopaedics. Fix bone fragments in
place or remove if loose.
• Loose body:
• Can be fibrinous (i.e. inflammation), cartilaginous (i.e. meniscal
tear), or osteocartilaginous (i.e. osteochrondritis dissecans).
• Presents with knee, pain, intermittent locking, the joint may ‘give
way’ and signs of tenderness, soft tissue swelling, joint effusion may
be present and extension may be limited.
• Imaging—x-ray may demonstrate larger lesions. US/MRI and
arthroscopy can confirm diagnosis.
• Management—for small lesions NSAIDs may be helpful but in
general loose bodies need to be removed by arthroscopy.
• Haemarthrosis:
• In ~80% cases, this follows a twisting injury to the knee, i.e. anterior
cruciate ligament rupture with pain and swelling (ofen large)
<15 to 30min of injury with large tense knee effusion, often
hamstring spasm and severe limitation of movement.
• Imaging—x-ray, MRI, or arthroscopy to confirm underlying injury.
• Management—aspiration to confirm. Referral to Orthopaedics.
 KNEE PAIN IN CHILDREN AND ADOLESCENTS 119

• Fat pad impingement syndrome:

• Traumatic and inflammatory changes in the infrapatellar fat pad.
• Symptoms—pain, swelling, restricted movement, and symptoms
may be chronic and infrapatellar. Pain is present when the flexed
knee is extended suddenly.
• Imaging—MRI, acute findings of i fluid and chronic findings similar
to scarring after arthroscopy. Arthroscopy doesn’t visualize the fat
pad well.
• Management—NSAIDs if inflammation persistent, quadriceps
strengthening or taping may be helpful.
• Iliotibial band* or tensor fascia lata (TFL) problems can present with
knee pain or pain may be higher up thigh.
Inflammatory
• Septic arthritis or osteomyelits (see b p 64)
• Juvenile idiopathic arthritis (see b p 28 and p 129)
• Reactive arthritis (see b p 67)
• The presence of red flag symptoms (fever, chills, weight loss) indicate
urgent referral.
Tumours
• Benign—osteochondromas can occur in femur or tibia resulting in knee
pain. Often not painful and don’t require surgery.
• Malignant—osteosarcoma (commonly around the knee) and Ewing’s
Sarcoma (involves long bones of leg or pelvis). Need urgent referral to
paediatric orthopaedics/local bone tumour service (see b p 60).
*
Optimizing hip abductors strength helps to support the knee whilst a tight iliotibial band can pull
the patella laterally exacerbating maltracking along the femoral groove.

Further reading
Arthritis Research UK. Topical Review –– Anterior knee pain. Available at: M http://www.
arthritisresearchuk.org/files/6524_05032010143501.pdf.
120 CHAPTER 2 Common clinical problems

Table 2.15 Summary of causes of mechanical knee pain

Symptoms Signs Management Orthopaedic
referral
Patellofemoral Pain Genu valgum Physiotherapy No
pain
Worse with Hypermobility Activity
activity modification
Tibial torsion
Pronated
forefeet
Patella Pain Dislocated Reduction Yes if
dislocation patella of patella recurrent
dislocation
Mobilization
Osgood– Pain on Pain on Ice No
Schlatter activity resisted
Activity
extension
modification
Sinding– Pain lower Tender Ice No
Larsen– pole patella lower pole
Physiotherapy
Johannson patella
Activity
Worse on
modification
extension
Plica Pain on May be NSAID, IA No
syndrome flexion tenderness steroids,
activity
modification
Osteochrondritis Pain, May be Analgesics Yes
Locking normal
Weakness
Loose body Pain, Locking May be NSAIDs Yes—
normal arthroscopic
Giving way
removal of
Tenderness,
Swelling loose body
effusion,
d extension
Haemarthrosis Pain Large, tense Aspiration to Yes
effusion confirm
Swelling
(soon after Hamstring
injury) spasm
Fat pad Pain, swelling Pain when NSAIDS, No
impingement knee flexed Physiotherapy
d movement
suddenly
 FOOT AND ANKLE PROBLEMS 121

Foot and ankle problems

Flexible flat feet
• Clinical—considered ‘normal’ in many children (see b Normal
variants and chapters on podiatry, p 9):
• By 8yr, few children have flat feet.
• Absence of arch when standing flat, but arches apparent when stand
on tip-toe or big toes passively dorsiflexed.
• More common in hypermobile children—typically symptomless
(present with parental anxiety).
• Management—reassurance and footwear advice, most do not benefit
from insoles/physiotherapy input.

Red flag
Failure of arch to return on tip-toe standing implies rigid flat feet:
consider tarsal coalition or arthritis at sub-talar joint (see b p 385).

Tarsal coalition
• Definition:
• Failure of segmentation of tarsal bones, typically calcaneonavicular
or talocalcaneal joints.
• May be cartilaginous/fibrous (and therefore missed on x-ray).
• Clinical:
• Painful feet, non-flexible flat feet (50% bilateral).
• Typically presents in adolescents (4>5).
• Management—orthotics, NSAIDs, in extreme cases, surgery is
required.
Pes cavus
• Clinical:
• A normal variant (see b p 9).
• ‘High arches’ and may associate with persistent tip-toe gait.
• May be asymptomatic or present with pain (2° to metatarsal
compression) or clumsy walking.
• Consider neurological/neuromuscular abnormalities, e.g. spina
bifida, Charcot–Marie–Tooth, Friedreich’s ataxia, or metabolic
storage diseases (see b p 312).
• Management:
• Typically no treatment is needed.
• May require insoles/orthoses and refer for surgery if pain is severe.
Metatarsus adductus
• Clinical:
• A normal variant (see b p 9).
• Causes in-toeing (medial deviation of foot); can be familial or
positional.
• Management—tends to correct with wearing shoes, rarely needs
treatment (such as serial casting, splints).
122 CHAPTER 2 Common clinical problems

Rocker bottom feet

(= congential convex pes valgus = congenital vertical talus)
• Clinical:
• Usually detected in newborn, talus dislocated, pointing downwards.
• Associated with neurological problems but often idiopathic.
• Management—casting is little use if foot not flexible and surgery may
be required.
Congenital talipes equinovarus
(=clubfoot)
• Clinical:
• Usually detected in newborn, foot held pointing down (equino) and
folded in (varus).
• Structural abnormality (as opposed to positional talipes which
resolved with physio).
• Management:
• Casting (Ponseti method) is current treatment of choice.
• May need surgery.
Intoeing
• Clinical:
• Normal variant (see b p 9 Normal variants).
• Usually a result of a rotational deformity of long bones rather than
an abnormality in the foot (most often due to femoral anteversion
(90%) or tibial torsion):
— Assess patella position with child standing feet pointing
forwards—if patella pointing straight, then rotational deformity
is distal, if pointing medially, rotational deformity is proximal).
— Assess thigh–foot angle (see b Clinical skills, p 1).
Achilles tendonitis
• Clinical:
• Typically an overuse injury in sporty children.
• Rare in those <14yr, pain with activity, especially jumping.
• Management:
• Rest, ice, compress, elevate (RICE).
• Modify activity/stretching exercises/physiotherapy/orthoses (gel
heel cup).
• NSAIDs.
• Never inject steroids (this weakens the tendon, risking rupture).
Sever’s disease (similar to apophysitis at other sites)
• Definition—apophysitis of os calcis at insertion of Achilles tendon.
• Clinical:
• Typically occurs before skeleton matures, as a result of either rapid
growth or excessive activity.
• Usually children 7–14yr old and present with pain increasing with
activity.
• Management: similar to Achilles tendonitis.
 FOOT AND ANKLE PROBLEMS 123

Plantar fasciitis
• Clinical:
• Inflammation of plantar fascia, usually from repeat microtrauma.
• Heel pain, worse with i activity (or impact to ground).
• Differential diagnosis: includes JIA (enthesitis-related arthritis)
see b JIA, p 129.
• Management—similar to Achilles tendonitis.
Osteochondroses (also see b Osteochondroses, p 343)
• Occur in growing skeleton, with disruption of blood supply due to
recurrent insult.
• Kohlers’s disease:
• Osteochondrosis of navicular bone.
• Typically 5–9yr-olds with midfoot pain, swelling, (can be bilateral).
• X-ray: i sclerosis of navicular bone.
• Management—as for Achilles tendonitis.
• Freiberg’s disease:
• Osteonecrosis of 2nd or 3rd metatarsal head.
• Typically adolescent girls, increasing forefoot pain and focal
tenderness over head of affected head.
• Management—RICE, modify activity/footwear, surgery in extremes.
Arthritis
• Can affect any joint in ankle/foot especially if swollen or restricted in
range of movement.
• Need to consider septic/reactive/JIA (see b p 64):
• Septic—febrile, unwell child, extreme reluctance to move joint,
raised acute inflammatory markers (esp. CRP), other markers of
sepsis—see b Infection, p 355.
• Reactive—recent history URTI or GI upset (and sexually acquired
infection in the adolescent)—see b Infection, p 64.
• JIA: see b Chapter 3, p 129.
124 CHAPTER 2 Common clinical problems

Joint hypermobility
Background
• The normal range of motion of joints is variable, with children
possessing an inherently greater range than adults, and 4>5.
• The prevalence of hypermobility in children has been variously
reported between 2.3% and 39% dependent on the age, ethnicity, and
defining criteria used.
• The majority of these children are asymptomatic, and many use their
hypermobility to advantage, e.g. ballet dancers who are hypermobile
appear to be at less risk of injury, and musicians benefit from a wide
hand span.
• Conversely, some children and young people suffer symptoms,
presumed to be s to their hypermobility, and in this case the condition
is called ‘benign joint hypermobility syndrome’ (BJHS).
• Various symptoms have been attributed to the BJHS including delayed
motor milestones, constipation, urinary tract infection and dysfunction,
impaired proprioception (i falls and developmental co-ordination
disorder), and musculoskeletal pain although the relationship with
these symptoms is controversial.
• Symptoms do not appear to be directly correlated with the number of
joints involved.
Definition
• There are no validated scoring systems for hypermobility in children.
• The Beighton score and modified Brighton score are recognized in
adults.
• However, 26.5% of healthy Dutch children (n=773) aged 4–9yr scored
4, and 5.3% aged 10–12yr. Thus Beighton scoring defines a quarter
of all children <10yr of age as hypermobile. This scoring system is
therefore not sufficient alone, to define those children with BJHS.
• There have been attempts at refining these scores (Bulbena score) but
there is no scoring system validated for children.
• Pragmatic definition of BJHS—a child or young person with
musculoskeletal pain and signs of hypermobility, with no other cause
found for their symptoms.
9-point Beighton scoring system for joint hypermobility
(4 points defines hypermobility)
Scoring 1 point each side
• Passive dorsiflexion of the 5th MCP joint to 90°.
• Apposition of thumb to volar forearm.
• Hyperextension of the elbow >10°.
• Hyperextension of the knee >10°.
Scoring 1 point
• Touch palms to floor with knees straight.
 JOINT HYPERMOBILITY 125

10-point Bulbena scoring system (3 in males and 4 in

females defines hypermobility)
(% denotes incidence in 114 subjects with BJHS.)
Upper arm
• Passive apposition of thumb to flexor aspect of forearm at
<21mm (92%).
• Palm of hand resting on table, passive dorsiflexion of the 5th finger
90° (93%).
• Hyperextension of the elbow 10° (75%).
• Excess shoulder lateral rotation: upper arm touching body, elbow
flexed at 90, forearm externally rotates by >85° (84%).
Lower extremity, supine position
• Passive hip abduction >85 (78%).
• Patellar hypermobility—holding proximal tibia, excess passive lateral
movement of the patella (89%).
• Excess range of passive dorsiflexion of the ankle and eversion of the
foot (94%).
• Dorsal flexion of the 1st MTPJ 90° (61%).
Lower extremity prone position
• Knee flexion allows heel to contact buttock.
• Ecchymoses after minimal trauma (63%).
Epidemiology
• There is a greater range of joint mobility in Asians than sub-Saharan
Africans, who are more mobile than Caucasians. Girls affected more
commonly than boys.
• A significant proportion of new referrals to paediatric rheumatology
clinics have musculoskeletal pain and hypermobility.
Pathophysiology
Unknown. Genes encoding collagens and collagen-modifying enzymes are
considered to be good candidates. Adult studies suggest abnormality in
collagen bundle structure on skin biopsy.
Clinical presentation
Symptoms
• The child has joint pain during or after activity. Typically they complain
of pain in lower limbs after walking just short distances and this is
commonly manifested when walking to and from school.
• Pain occurring in the evening after an active day, again typically in the
lower limbs (see b Anterior knee pain, p 117).
• Occasional joint swelling, lasting a few days only.
• Handwriting difficulties.
• Joint dislocation/subluxation—less common.
• ‘Clicking’ and ‘cracking’ of joints.
• Frequent ‘sprained ankles’.
• Back pain, anterior knee pain, and TMJ dysfunction may be associated.
126 CHAPTER 2 Common clinical problems

Family history
Frequently 1st-degree relatives are also described as having lax joints or
being ‘double jointed’.
Past history
• There is some evidence that BJHS is linked with delayed motor
development and the mean age of first walking may be later
(15 months).
• Described as clumsy, poor coordination and some have a diagnosis of
developmental coordination disorder.
• Constipation, urinary tract infections/dysfunction.
• Non-specific abdominal pain, headaches and generalized pain
sometimes associated.
Examination
• Height and weight show normal growth.
• Normal examination of cardiovascular, respiratory, and abdominal
systems. Neurological examination reveals normal muscle bulk,
strength, and reflexes.
• Musculoskeletal examination shows i range of joint movement.
Pes planus with calcaneo valgus, i.e. a mobile flat foot (arch forms
when child stands on tip-toe) and valgus heel position are common.
Paradoxically tight hamstrings are often found (see b Anterior knee
pain, p 117).
• Normal skin elasticity, absence of scarring, dentition, and palate.
Bruising may be more common.
Differential diagnoses
BJHS is primarily a clinical diagnosis dependent on typical clinical history
and physical signs. The following differentials should be considered and
ruled out clinically or by investigation:
• Known heritable connective tissue disorder (see b Heritable
connective tissue disorders, p 346), e.g.:
• Ehlers–Danlos syndrome (other than type III—the hypermobility
type)—look for skin hyperextensibility, bruising, tissue paper
scarring.
• Marfan syndrome—mafanoid habitus, cardiovascular or ocular
involvement.
• Osteogenesis imperfecta—blue sclerae, short stature, multiple
fractures and hearing loss.
• Juvenile idiopathic arthritis (see b JIA, p 129).
• Pain syndromes: diffuse idiopathic pain syndrome; localized idiopathic
pain syndrome; fibromyalgia (see b Pain syndromes, p 87).
• Malignancy: leukaemia; Ewing’s sarcoma; osteosarcoma.
• Congenital disorders associated with hypermobility: Down syndrome;
Williams’ syndrome, Stickler’s syndrome; autistic spectrum disorders;
metabolic disorders such as homocystinuria.
Management
• In the majority of mild cases, all that is required is a diagnosis with
explanation of the condition, reassurance that serious pathology has been
excluded and written information (see b Patient information, p 127)
 JOINT HYPERMOBILITY 127

• The child and family need to know that there are no long-term
consequences (the link with later osteoarthritis unproven).
• Escalation of analgesia is common, but universally unhelpful and should
be avoided.
• Supportive footwear is often beneficial (e.g. trainers—fastened
properly!). The evidence for orthotics is poor.
• More severe cases may benefit from physiotherapy, targeted or
generalized and occupational therapy may help with handwriting and
manual dexterity.
• If there are particular problems with generalized pain resulting in
fatigue, reduced activities, and school absence, cognitive behavioural
therapy with graded physical exercise and goal setting may benefit the
child/young person.
Idiopathic nocturnal leg pain
Common, benign condition, otherwise known as ‘growing pains’ charac-
terized by intermittent lower limb pain with symptom-free intervals of
days, weeks or months. There is a reported association with hypermo-
bility. See b Growing pains, p 92.
Patient information
• The Hypermobility Syndrome Association website for kids and teens:
M http://teens.hypermobility.org/index.php.
• Arthritis Research UK patient information leaflet: M http://www.
arthritisresearchuk.org/arthritis_information/arthritis_types__symptoms/
joint_hypermobility.aspx http://www.arthritisresearchuk.org/files/
6019_HYPER_05-3_01032010140241.pdf.
Further reading
Kemp S, Roberts I, Gamble C, et al. A randomised comparative trial of generalised vs targeted
physiotherapy in the management of childhood hypermobility. Rheumatology 2010; 49:315–25.
This page intentionally left blank
 Chapter 3 129

Juvenile idiopathic
arthritis

Genetics and JIA: HLA and non-HLA/MHC associations

with subtypes of JIA 130
Immunology and aetiology of JIA 137
Classification of JIA 139
JIA subtypes and their clinical presentations 141
Prognostic indicators in JIA 146
Uveitis screening in JIA: the approach to screening and
guidelines 148
Surgery in the young adult with JIA: practical issues 152
Treatment approaches in JIA 155
Treatment pathways in JIA 159
Disease activity scores in rheumatoid arthritis and JIA 165
130 CHAPTER 3 Juvenile idiopathic arthritis

Genetics and JIA: HLA and non-HLA/MHC

associations with subtypes of JIA
Association studies in JIA
The association study is the standard methodology used in the search for
genetic risk factors for JIA. There are a number of issues regarding study
design that the clinician must be aware of, to understand and put into
context the genetic findings to date for JIA (Fig. 3.1).
Genetic risk factors identified to date for JIA
Human leucocyte association (HLA)
• The major histocompatibility complex (MHC) is the most consistently
associated locus in JIA.
• Multiple HLA class I and class II associations exist with JIA, with each
ILAR subtype having a specific pattern of HLA associations, although
it should be noted that there are also overlapping associations,
particularly between oligoarthritis and RF−ve polyarthritis.
Non-HLA/MHC loci
• The candidate gene approach has been the main strategy used in the
search for JIA susceptibility loci to date.
• Some association studies performed in the past for JIA have suffered
from inadequate sample sizes.
• There are now 10 regions of the genome that show association with
JIA in more than one dataset, these are highlighted in Table 3.1.
• There has been only one genome wide association study (GWAS)
for JIA published to date. This GWAS identified the HLA region as
being associated with JIA and association of the VTCN1 (B7-Homolog 4
[B7-H4]) gene with JIA was identified and subsequently validated in an
independent dataset.
• Larger well-powered GWAS will be required to detect additional
loci with modest effect sizes. The International Childhood Arthritis
Genetics (INCHARGE) consortium has now been established and this
will enable the collection of large sample sizes for all JIA ILAR subtypes,
which will be used for GWAS and validation.
Subgroup-specific associations
There is an issue with association analysis by JIA subtype in that, for many
JIA case cohorts, it results in small sample sizes that often are not suffi-
ciently powered to detect the modest effects conferred by these complex
disease genes. A few potential subtype specific effects are emerging:
• A number of SNPs in the IL1 ligand cluster and IL1 receptor cluster
show replicated association with sJIA.
• A SNP in the IL6 promoter shows association with sJIA.
• A SNP in the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene,
formerly known as ARTS1, which shows robust association with AS
has been shown to be associated with the enthesitis-related arthritis
subtype of JIA.
• A SNP in the IL23 receptor gene shows association with the psoriatic
arthritis subtype of JIA.
 GENETICS AND JIA 131

Association studies
• Case–control study design
• Marker of choice: single nucleotide polymorphism (SNP).
• Statistical analysis to investigate differences in allele or genotype frequencies between cases and controls.

Candidate gene study Genome-wide association study (GWAS)

Select genes:
• Known to be important in disease pathogenesis. • Scans the whole genome.
• Associated with other clinically similar diseases. • No a priori hypothesis.
• Important in related traits in animal models. • Genotyped on pre-designed microarrays.
• In which rare mutations lead to clinically similar • Uses information from linkage disequilibrium between
monogenic diseases. SNPs, to cover all variation across the genome.

Genotyping method Genotyping method

Robust technologies include: • Microarray technologies including Affymetrix Inc. and
• Sequenom Illumina Inc.
• TaqMan. • Very high-throughput and much cheaper.
Outdated and less accurate method: • Enables the genotyping of a large number of SNPs in
• Restriction fragment length polymorphism (RFLP). a large sample size.

Data quality
Vitally important when assessing a genetic association study:
• That the study has checked for systematic error and dealt with the problem of missing data.
• The study should set stringent quality control levels for SNP and sample genotyping success rate.
• Checking for Hardy–Weinburg equilibrium in cases and controls can highlight genotyping errors.

Sample size and power

• The key issue for understanding the limitations of many papers reporting genetic associations for complex
genetic diseases is that the susceptibility loci confer small effect sizes (odds ratios).
• Many early studies underpowered to detect these modest effect sizes.
• Studies should perform a power calculation to determine what effect size their sample size is powered to detect.

Ethnicity
• The case and control cohorts should be matched for ethnicity to avoid population stratification.
• Can be a cause of false positive associations
• There have been methods developed to both detect and correct for population stratification.

Corrections for multiple testing

Another major reason for false positive findings:
• Performing analysis on a large number of SNPs, by chance a small proportion will be significant.
• Should adopt statistical significance threshold appropriate for the number of tests performed.
• One approach is the Bonferroni correction, however this assumes all tests are independent and may be an
over-correction and lead to false negatives.
• In a GWAS because of the large number of SNPs tested, a genome-wide significance threshold has been
proposed which is 5 x10−8 (equivalent to a p-value of 0.05 after correction of 1 million independent tests).
• Other methods (such as permutation) to correct for multiple testing, but the best approach to confirm findings
is to replicate the association in an independent cohort, often called validation.

Validation
• This involves genotyping the putative SNP in a broadly similar (same population and similar ascertainment),
independent cohort.
• Preferably using a different genotyping method to reveal spurious association due to technical issues.
• The validation cohort must be powered to detect the original association otherwise may get a false negative.
• For validation the same allele as identified in the original study should confer the same risk or protective effect.

Meta-analysis
• Meta-analysis from comparable GWAS studies or candidate gene studies can increase power and allow the
identification of additional susceptibility loci.

Fig. 3.1 Association studies.

132 CHAPTER 3 Juvenile idiopathic arthritis

What happens once a genetic effect has been identified?

Resequencing/fine-mapping
• This is the stage that many of the studies are currently at, and the next
step is a challenging one.
• In most cases it is unlikely that the candidate gene study or GWAS will
identify the actual causal variant, but they detect single nucleotide
polymorphisms (SNPs) which happen to be correlated with the causal
variant.
• In most situations it will be important to screen the whole region
for all genetic variation, by resequencing and then fine-mapping the
association by genotyping them in cases and controls.
Functional analysis
• Once all the statistical analysis has been performed and the most likely
causal variants have been identified then the functional role of the
implicated variants will be investigated.
• This will highlight the molecular and pathological mechanisms that are
involved in the development of the disease.
What can these genetic findings tell the clinician about JIA?
• It will inform us of the important pathways involved in JIA disease
pathogenesis. We are already seeing strong evidence to suggest a
vital role for the IL-2 pathway in JIA and other autoimmune diseases.
Once we know more about the biology of JIA, we may identify novel
therapeutic targets.
• Eventually it may help us predict disease risk. We are not at this stage
yet as it is important to remember that for many of the loci identified to
date the actual causative genetic variant has not yet been clearly defined.
• Genetic susceptibility factors may be important in determining not only
susceptibility to JIA but also to a child’s disease outcome. Prospective,
long-term outcome studies, such as the CAPS (Childhood Arthritis
Prospective Study), will be vital in exploring this hypothesis.
Conclusions
We have made some progress in the search for genetic risk factors for
JIA, but the next few years look set to bring huge advances in the genetic
knowledge for JIA, with the publication of well-powered GWAS in JIA as
a whole and by subtype.
 GENETICS AND JIA 133

Table 3.1 Non-MHC loci associated with JIA and validated in

independent cohorts
Gene SNP Study Subtypes tested Association
population
PTPN22 rs2476601 UK All Y
rs2476601 Norway All Y
rs2476601 Finland O and RF-P N not in total dataset
rs2476601 US O, EO, and RF-P Y
IL2RA rs2104286 UK All Y
rs2104286 US O, EO, and RF-P Y
rs2104286 US All N
IL2 rs6822844 Dutch O, EO, RF-P, and Y
SO
rs6822844 UK All Y
rs17388568 US O, EO, and RF-P Y
STAT4 rs7574865 UK All Y
rs7574865 US All Y
rs7574865 US O, EO, and RF-P Y
TRAF1/C5 rs10818488 Dutch O, EO, RF-P, N not in total
RF+P and SO dataset. Association
in the O subset
rs3761847 US All Y
rs2900180 UK All Y
rs3761847 US All N
rs3761847 US O, EO, and RF-P N
rs2900180
TNFAIP3 rs6920220 UK All Y
rs13207033*
rs6920220 US All Y
rs10499194
rs6920220 US O, EO, and RF-P N
rs13207033
rs10499194
O=Oligoarticular; EO= Extended oligoarticular; RF-P=Rheumatoid factor polyarticular;
RF+P=Rheumatiod factor positive polyarticular; SO=Systemic onset
(continued )
134 CHAPTER 3 Juvenile idiopathic arthritis

Table 3.1 (Contd.)

Gene SNP Study Subtypes tested Association
population
CCR5 CCR5Z32 US O, EO, RF-P, Y
RF+P and SO
CCR5Z32 Norway All N
CCR5Z32 UK All Y
C12orf30/ rs17696736 US All Y
SH2B3
rs653178 UK All Y
/ATXN2
rs17696736 US O, EO, and RF-P Y
SLC11A1 D2S1471 Latvia O, EO, RF-P and Y
(NRAMP1) RF+P
D2S1471 Finland O, EO, RF-P Y
and RF+P
PTPN2 rs7234029 US O, EO, and RF-P Y
rs7234029 UK All Y
O=Oligoarticular; EO= Extended oligoarticular; RF-P=Rheumatoid factor polyarticular;
RF+P=Rheumatiod factor positive polyarticular; SO=Systemic onset

Definitions often used in Clinical Genetics

Allele
Alternative form of a genetic locus; a single allele for each locus is inherited
from each parent.
Association study
Investigation of correlation between a genetic variant and disease/trait.
Bonferroni correction
The simplest correction of individual p-values for multiple testing, the
formula is pcorrected = 1 − (1 − puncorrected)n.
Candidate gene
A gene for which there is evidence for a possible role in the disease or
trait that is under investigation.
Case–control design
An association study design which compares group of individuals (cases)
that are selected for the phenotype of interest with a group not ascertained
for the phenotype (controls).
Causal variant
The actual disease causing variant. This may be a non-synonymous coding
SNP which has a significant effect on the protein, or it can affect expression
of the gene, causing upregulation or downregulation of the protein.
 GENETICS AND JIA 135

Genome wide association study (GWAS)

Association study performed for a dense array of SNPs, which capture
a substantial proportion of common variation in the genome, genotyped
in disease cases and ethnically matched controls.
Genotype
The combination of each allele inherited from each parent forms a
person’s genotype for a SNP.
Haplotype
A combination of alleles at a region (locus) on a chromosome that are
transmitted together.
Hardy–Weinberg equilibrium (HWE)
A theoretical relationship between genotype and allele frequencies, for
a SNP, that is found in a stable population. In the context of genetic
association studies, deviations from HWE can be used to highlight geno-
typing errors.
Linkage analysis
Mapping of genes, by typing genetic variants, in families to identify
regions that are associated with a disease or trait within a pedigree more
often than expected by chance.
Linkage disequilibrium
Combinations of alleles or genetic markers which occur together more
or less frequently in a population than would be expected from a random
formation of haplotypes from alleles based on their frequencies.
Meta-analysis
A method of combining results across genetic studies. It can involve the
combination of p-values or, more commonly, effect sizes. It can lead to
increased statistical power, give more precise estimates of effect size,
and also allows assessment of consistency and heterogeneity of associa-
tion across different study populations.
Minor allele frequency (MAF)
The frequency of a SNP's less frequent allele in a given population.
Odds ratio (OR)
A measurement of association that is commonly used in case–control
studies. It is defined as the odds of exposure to the susceptible genetic
variant in cases compared with the odds of exposure in controls. If the
odds ratio is >1, then the genetic variant is associated with disease.
Population stratification
This is caused by systematic differences in allele frequencies between
subpopulations in a population possibly due to different ancestry; if
these subgroups also have a difference in prevalence of the disease or
trait studied that it can lead to false positive associations.
136 CHAPTER 3 Juvenile idiopathic arthritis

Power calculation
Assessment of how many samples must be collected and analysed in
order to achieve sufficient power to detect the hypothesized effect.
After conducting a study, power analysis can also shed light on negative
results by indicating whether the study was underpowered, or what the
smallest detectable effect size would be given the actual sample size.
Single nucleotide polymorphism (SNP)
DNA sequence variations that occur when a single nucleotide (A, T, C,
or G) in the genome sequence is altered.

Further reading
Angeles-Han S, Prahalad S. The genetics of juvenile idiopathic arthritis: what is new in 2010?
Curr Rheumatol Rep 2010;12(2):87–93.
 IMMUNOLOGY AND AETIOLOGY OF JIA 137

Immunology and aetiology of JIA

Pathogenesis
• JIA is an autoimmune disorder; the immune system fails to distinguish
between self and non-self and attacks synovium (membrane lining of
the joint), leading to arthritis. The synovium becomes thickened, highly
vascular, and infiltrated with T cells, macrophages, dendritic cells,
B cells, and NK cells, and secretes an exudate (synovial fluid).
• Persistence of inflammation: cells are recruited into the joint by
attaching to upregulated adhesion molecules on inflamed endothelium
(inner layer of blood vessels). Resident fibroblasts (synoviocytes),
and recruited immune cells, secrete high levels of chemokines, which
attract further inflammatory cells, angiogenic factors (e.g. VEGF) lead
to highly vascular proliferation of synovium.
• T cells are i in synovium and synovial fluid and secrete several potent
cytokines (see Table 3.2), leading to cartilage and bony damage. T cells
secreting IL-17 (Th17 cells) are heavily implicated in chronic uveitis,
extended oligoarthritis, psoriatic- and enthesitis-related arthritis.
Remission in JIA is linked with high levels of synovial regulatory T cells
(specialized T cells which counter inflammation).
• B cells are d in synovial fluid, but circulating B cells secrete cytokines
and activate T cells. Specialized B cells, plasma cells, secrete auto-
antibodies (RF, anti-cyclic citrullinated protein [CCP], and ANA)
associated with specific disease subtypes but are not thought to be
directly pathogenic.
• sJIA shares features with other auto-inflammatory disorders (see b
p 288); high levels of IL-1B and IL-6 cause systemic features and
growth retardation. Macrophage activation syndrome (MAS, see
b p 305) in sJIA is associated with a defect in NK cell function which
prevents NK cells from killing activated lymphocytes and macrophages
(see also b Genetics and JIA, p 130).
Genetics
• JIA is linked with several genetic polymorphisms (variations in the
genetic code), but each only contributes a small risk of developing the
disease.
• Genes linked with JIA include:
• HLA system of immune recognition, expressed on almost all cells:
HLA-B27 is strongly associated with enthesitis related arthritis
(ERA), A*02 with oligoarthritis and DRB1*11, DQB1 with RF –ve
polyarthritis, DR4 with RF+ve polyarthritis (as in adult RA).
• Cytokine/chemokine-related genes: IL-10 with oligoarthritis,
IL-6 with sJIA, and IL-23 receptor with psoriatic arthritis and the
chemokine CCL5 and its receptor CCR5, and TNFA across all JIA
subtypes.
• Immune associated genes: PTPN22, TRAF1, STAT4, CD25
are important in the control of T cell activation, mutations
of MUNC13-4, and perforin in sJIA may be important in the
development of MAS.
138 CHAPTER 3 Juvenile idiopathic arthritis

Environment
• Infection: there is no clear infectious trigger for JIA. DNA from several
bacteria and viruses including parvovirus B19 have been detected in JIA
serum and joints but are of uncertain significance.
• Family conditions: high parental income and being an only child are
associated with JIA which relates to the hygiene hypothesis: lack of
early childhood infection increases the risks of autoimmunity. Fetal
exposure to smoking may increase the risk of JIA in girls.

Table 3.2 Summary of cytokines and inflammatory mediators

important in JIA
Cytokine/mediator Cell Pathology

TNFA Monocytes, T, Activates monocytes and neutrophils

B cells, PMN, mast Damages cartilage
cells, fibroblasts i endothelial cell adhesion molecules
Inhibits regulatory T cells
IL-1B Monocytes, B cells, Activates osteoclasts (bone damage)
fibroblasts Fibroblast cytokine, chemokine release
i endothelial cell adhesion molecules
IL-17 T cells (Th17), Chemokine release (recruit PMN)
mast cells Cartilage damage
Activates osteoclasts
Synergizes with TNFA and IL-1B
IL-6 Monocytes, B cell activation
fibroblasts, B cells Inhibits regulatory T cells
Growth retardation
Acute phase response and anaemia
IFNG T cells (Th1, Activates monocytes
CD8, NK cells) i endothelial cell adhesion molecules
May assist recruitment of Th17 cells
MRP8/14 Monocytes, PMN Activates monocytes,
(inflammatory Promotes pathological CD8+ T cells
mediator important Secretion of IL-1B
in sJIA)
i endothelial cell adhesion molecules
 CLASSIFICATION OF JIA 139

Classification of JIA
• The Classification Taskforce of the Pediatric Standing Committee of
the ILAR proposed consensus criteria for the classification of childhood
arthritis under the umbrella term Juvenile Idiopathic Arthritis (JIA).
• The aim of this classification system was to attempt to address the
differences in nomenclature and criteria between Europe and North
America, enabling research on cause, epidemiology, therapeutic trials
and outcome studies. A comparison of 3 criteria sets is given in
Table 3.3.
• Many paediatric rheumatologists have embraced the ILAR classification.
There are 7 different subtypes based on features present in the first
6 months of the illness as noted in Table 3.4. It was last updated in 2001.
• It is acknowledged that there are restrictions intrinsic to any
classification system based on clinical criteria and there remains
the need for further validation, modification, and consensus as new
information on pathogenesis and genetics becomes available.

Table 3.3 Comparison of classification systems

ILAR EULAR ACR
Name Juvenile idiopathic Juvenile chronic Juvenile rheumatoid
arthritis arthritis arthritis
Age of onset <16yr <16yr <16yr
Duration 6 weeks 3 months 6 weeks
Subtypes of 1. Systemic 1. Systemic 1. Systemic
arthritis 2. Oligoarticular: 2. Pauciarticular 2. Pauciarticular
• Persistent 3. Polyarticular 3. Polyarticular
• Extended (excludes RF+ve 4. (excludes spondy-
3. Poly; RF–ve disease: known as loarthopathies and
4. Poly; RF+ve juvenile rheumatoid psoriatic arthritis)
5. Enthesitis related arthritis)
6. Psoriatic
7. Other

Further reading
Petty RE, Southwood TR, Baum J, et al. Revision of the proposed classification criteria for juvenile
idiopathic arthritis: Durban. J Rheumatol 1998; 25:1991–4.
Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology
classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004;
31:390–2.
 140
Table 3.4 Summary of ILAR classification of JIA

CHAPTER 3
Subtype Systemic onset Oligoarthritis Polyarthritis Polyarthritis Psoriatic Enthesitis related Other
RF –ve RF +ve arthritis arthritis
Arthritis In 1 or more joints In 1–4 joints during In 5 or more In 5 or more Arthritis and Arthritis and enthesitis or Undifferentiated

Juvenile idiopathic arthritis

with or preceded by first 6 months of joints during joints during psoriasis, or arthritis with at least 2 of with no category
daily (quotidian) fever disease the first the first arthritis and at the following or 2 or more
for at least 3 days, 6 months of 6 months least 2 of • Presence or history of categories
Subcategories:
accompanied by t1 of: disease of disease • Dactylitis sacroiliac joint tenderness
• Persistent—affecting
• Evanescent • Nail pitting and/or inflammatory
no more than 4 RF test RF test
erythematous rash or lumbosacral pain
joints throughout negative positive
• Generalized onycholysis • Presence of HLA B27
course
lymphadenopathy • Psoriasis in antigen
• Extended—affecting
• Hepatomegaly 1st-degree • Onset in 4 >6yr
a total of >4 joints
and/or splenomegaly relative • Acute anterior uveitis
after the first
• Serositis • Ankylosing spondylitis,
6 months of disease
enthesitis-related arthritis
• Sacroiliitis with inflam-
matory bowel disease
• Reiter syndrome
• Acute uveitis in 1st-degree
relative
Exclusions A,B,C,D A,B,C,D,E A,B,C,D,E A,B,C,E B,C,D,E A,D,E
A: psoriasis or history of psoriasis in patient or 1st-degree relative, B: arthritis in HLAB27-positive male after 6th birthday, C: ankylosing spondylitis, enthesitis-related arthritis,
sacroiliitis with inflammatory bowel disease, Reiter syndrome or acute uveitis, or history of 1 of these in 1st-degree relative. D: presence of IgM RF on at least 2 occasions at least
3 months apart, E: the presence of systemic JIA.
 JIA SUBTYPES AND THEIR CLINICAL PRESENTATIONS 141

JIA subtypes and their clinical

presentations
• JIA is the commonest form of chronic inflammatory joint disease in
children and adolescents and is defined as persistent joint swelling (of
>6 weeks’ duration) presenting before 16yr of age in the absence of
infection or any defined cause.
• 95% of children with JIA have a disease that is clinically and
immunogenetically distinct from RA in adults.
• Newly presenting JIA is one of the commonest physically disabling
conditions of childhood, with a prevalence of approximately 1 in
1000 children, (i.e. the same as diabetes or epilepsy) and amounting
to over 12,000 affected children in the UK.
• JIA is a heterogeneous group of conditions and clinical presentations
vary with both the disease subtype (Table 3.5).There are at least 7
different subtypes of JIA, the classification is essentially clinical and
based on the number of joints affected in the first 6 months, the
presence or absence of RF, HLA B27 tissue type, systemic features
(such as fever or rash), and other extra-articular features (such as
psoriasis or enthesitis).
• JIA is essentially clinical and one of exclusion with a wide differential
diagnosis (see b Clinical skills p 1):
• Classically a joint affected by arthritis is swollen and painful with
some restriction of movement. In the younger child, however, a
history of pain is often absent. Parents may describe a child who
refuses to stand or has a limp first thing in the morning but runs
about normally later in the day. In the youngest children, JIA may
present as delay in walking. Examination may be limited by lack of
cooperation and findings may be subtle. Fortunately in the young
child, joint involvement is usually asymmetrical and subtle loss of
range of movement may be detected in comparison with the
normal side.
• Infection and malignancy are not uncommon and require careful
consideration.
• Consider septic arthritis in an unwell child with a single hot, swollen,
painful joint (see b p 64).
• Consider malignancy in child with severe joint pain, especially at
night (see b p 56).
• Consider haematological malignancy in a child presenting with
suspected systemic onset JIA but with low white count and/or
platelets and/or low ferritin (see b p 56).
• Acute rheumatic fever and Lyme disease are both increasingly seen
in the UK and should be remembered in the differential diagnosis
(see b p 363 and p 368 respectively).
 142
CHAPTER 3
Table 3.5 Clinical features of JIA subtypes

Juvenile idiopathic arthritis

Population Specific features of Characteristic clinical Helpful investigations Clinical course
affected history findings
Systemic 5=4 Fever pattern: 2 weeks Arthritis: may not be present Full blood count and blood Variable:
onset of fever with daily for several weeks/months film—typical features: • Monocyclic
Peak at 4–7yr
(quotidian) spikes for at • Low haemoglobin • Intermittent/recurrent
Extra-articular:
~10% JIA least 3 days; temperature • Raised platelets • Persistent (50%)
Systemically unwell: (but may
falls to baseline or below • Leucocytosis and neutrophilia systemic and
look surprisingly well between
in between. Fever spikes • Serum ferritin elevated (if very polyarticular phases
fever spikes)
tend to be in the evenings marked, consider macrophage
but can occur at other Rash: salmon pink, intermittent, activation syndrome—see b
times macular rash (occasionally p 305)
urticarial), rarely on the face, • High ESR, high CRP
Rash: intermittent; most
most evident during fever • Low albumin
noticed when febrile or in
spikes. Koebner phenomenon • Raised ALT/AST (transaminases)
bath/shower
may be observed and abnormal clotting may
Other systemic indicated MAS*
Other lymphadenopathy,
features: general malaise; • Extensive investigations to rule
hepatosplenomegaly,
anorexia out infection and malignancy
pericardial rub, other evidence
frequently necessary
serositis
• Bone marrow and urine
catecholamines to exclude
malignancy
Oligo- 5>>4 Swollen joint/s Arthritis • ANA: positive in 50–70% Persistent:
articular • 1–4 joints. Knee most • Normal inflammatory • 1–4 joints throughout
Peak 2–4yr Limp or abnormal gait
onset common but also markers do not exclude JIA course of disease
~50% JIA ankles/wrists • Eye screening for uveitis • Up to 50% remission
• Up to 50% present with • Imaging (x-ray/MRI):to
Extended: evolves to
single joint exclude other pathology
polyarticular course

JIA SUBTYPES AND THEIR CLINICAL PRESENTATIONS

• With late presentation • Exclude TB in mono-articular
disease (>4 joints) after
may have limb length presentation
6 months
discrepancy or contracture
Extra-articular: risk
of uveitis
Polyarticular 5>>4 Joint swelling, pain and Arthritis: symmetrical joint RF+ve (antibodies to anti-CCP Clinically equivalent to
onset loss of function, frequently involvement; small and large used as alternative in some adult RA
Usually
RF+ve affecting small joints of the joints centres)
10yr+
hands
~5% JIA Extra-articular: ESR/CRP raised May be aggressive with
• If acute often associated early erosive changes.
malaise, weight loss
• Occasionally rheumatoid
nodules
• Uveitis very rare

(continued )

143
 144
CHAPTER 3
Table 3.5 (Contd.)
Population Specific features of Characteristic clinical Helpful investigations Clinical course

Juvenile idiopathic arthritis

affected history findings
Polyarticular 5>4 Varies from: Arthritis RF−ve Variable
onset • 5 or more joints
Peaks at Acute: history of joint ANA+ve or −ve
RF–ve • Large and small joints
2–4yr and pain, swelling and
• Usually symmetrical Normal inflammatory markers
7–12yr systemic upset
involvement do not exclude JIA
to • Risk of uveitis
Low grade: an insidious Extra-articular
onset, often presenting • Poor growth if late
late with stiffness and/or presentation
joint deformity • May have uveitis: i risk if
ANA is positive
Psoriatic 5>4 Psoriasis in child or Arthritis Variable
1st-degree relative • Large or small joints; any
Peak 9–11yr Oligo- or polyarticular
number
course
• Dactylitis (diffuse swelling
of a finger or toe; joint and
surrounding tissues)
Extra-articular
• Psoriasis 9 nail pitting/dystrophy
• Uveitis not uncommon
Enthesitis 4>5 Joint swelling and Arthritis: HLA B27 positive (30–50% Variable
related or stiffness, usually • Lower limb, large joint depending on ethnic background)
>6yr May evolve insidiously
lower limbs involvement
Imaging to exclude alternative through teenage years to
• Hips common
pathology, e.g. SUFE include spinal involvement
• Sacroiliitis in minority (but
(highest in those who are
may not be clinically evident MRI to determine sacroiliac
HLA B27+ve)

JIA SUBTYPES AND THEIR CLINICAL PRESENTATIONS

until late adolescence/early joint involvement
adulthood)
Extra-articular: enthesitis
(inflammation of insertion
of tendons into bone)
characteristic
Other Variable Joint pain and swelling
confirming inflammatory
arthritis but excluded from
other category by classification

145
146 CHAPTER 3 Juvenile idiopathic arthritis

Prognostic indicators in JIA

It remains difficult to predict the prognosis for a child with JIA. Expert
clinical consensus supports the view that current management of JIA, with
its emphasis on rapid and effective disease control early in the disease
course, is improving outcome; disability should now be preventable in the
majority.
An ideal outcome for a child or young person with JIA is one where there
is lifelong disease remission with no long-term functional or psychological
effects. Suboptimal outcomes may result from:
• Poorly controlled joint disease with resultant joint damage.
• Visual loss from JIA-associated uveitis.
• Psychosocial morbidity.
The existing literature on the long-term outcomes generally shows
poor functional outcome for many young people with JIA. However,
these studies reflect historical treatment regimens rather than current
best practice. Evidence predicting outcomes from current therapeutic
approaches is limited to anecdote and awaits validation from ongoing
long-term outcome studies, e.g. the Childhood Arthritis Prospective Study
(CAPS, UK) and Research in Arthritis in Canadian Children Emphasizing
Outcomes Study (ReACCH-Out, Canada).
In predicting the prognosis for a child with JIA, 2 main factors require to
be taken into consideration:
• Heterogeneity in the disease and its response to treatment.
• Variability in access to optimal clinical care.
Disease heterogeneity
Indicators of poor outcome related to the disease itself are summarized in
Table 3.6 and can be divided into:
• Risk factors for continuing active disease.
• Risk factors for long-term damage.
Access to care
For any child with JIA, regardless of the disease subtype and features, there
is increasing consensus that access to appropriate care is an important
determinant of outcome. The British Society of Paediatric and Adolescent
Rheumatology (BSPAR) Standards of Care for children and young people
with JIA (see b BSPAR, p 409) emphasize the importance of:
• Prompt diagnosis and referral to specialist care*
• Early aggressive treatment to control inflammation
• Support from a paediatric rheumatology MDT.
Success in achieving a good outcome mandates that the management
must remain patient-centred, maximizing both physical and psychosocial
well being. Optimal disease control may require challenging drug regimens
and the support of a MDT is essential.

* Defined as: all children in whom JIA is suspected should be seen by a specialist paediatric
rheumatology MDT within 10 weeks from onset of symptoms and 4 weeks from date of referral
in order to facilitate early diagnosis, eye screening, and commence appropriate treatment.
 PROGNOSTIC INDICATORS IN JIA 147

Adverse prognostic factors for any child with JIA therefore

include:
• Delay in diagnosis.
• Delay in referral to specialist team.
• Late disease control.
• Continued disease activity.
Paediatric rheumatology is a rapidly changing specialty. In the near future
improvements in our ability to predict prognosis for a child with JIA will
undoubtedly result from further advances in our understanding of:
• Genetic and molecular mechanisms involved in the immunological and
inflammatory processes.
• Genetic predictors of response to drugs.
• Detection of subclinical disease with imaging.
• Availability of new targeted therapeutic approaches.

Table 3.6 JIA subtypes and risk factors for poor disease outcomes
Risk factors for:
Continuing active Long-term damage
disease
Subtype Psoriatic Polyarticular onset: both onset and disease
of JIA course (e.g. extended oligoarticular disease)
sJIA: ongoing active systemic features
at 6 months defined as fever, need for
corticosteroids, and thrombocytosis
Sex 4 in sJIA
Age Young age in
oligoarticular and
RF−ve polyarticular
Blood RF+ve RF+ve
markers ANA+ve (i risk of Normal inflammatory markers with late
uveitis) diagnosis
Persistently raised
platelet count in sJIA
Clinical Subcutaneous nodules Symmetrical joint disease
features Hip involvement
Rapid & early involvement of small joints of
hand and feet
Early radiographic changes
Presentation with uveitis as 1st symptom; or
visual loss at 1st eye screen

Further reading
CAPS: M http://www.medicine.manchester.ac.uk/musculoskeletal/research/arc/
clinicalepidemiology/outcomestudies/caps.
ReACCH-Out: M http://www.icaare.ca/index.php?option=com_content&task=view&id=28&Item
id=46.
148 CHAPTER 3 Juvenile idiopathic arthritis

Uveitis screening in JIA: the approach

to screening and guidelines
Rationale for screening
• JIA is associated with a significant risk of developing asymptomatic
chronic anterior uveitis (CAU).
• JIA CAU is the leading cause of visual loss from childhood uveitis, and is
associated with a high level of eye complications.
• Early regular eye-screening is a key component in the care of JIA
patients because it aims to reduce the incidence of visual impairment
by early detection and intervention.
Justification for a screening programme
• Provision of expensive screening is justified because it fulfils many, but
not all, of the criteria for an effective screening programme, principally:
• Slit lamp examination is a safe, effective screening test identifying
CAU earlier in the disease course than children can themselves
identify the subtle eye symptoms.
• The incidence of CAU is high, affecting 10% of all JIA patients;
the highest-risk subgroup of JIA, extended oligoarthritis, has an
incidence of 35–57%.
• 40% of CAU is present at the first eye screen.
• The duration of persistent inflammation in the eye is a key poor
prognostic factor which can be reduced by screening.
• The outcome of JIA CAU remains poor despite screening, indicated by
the following:
• Bilateral disease in 67–85%; significant eye complications in >40% of
cases—cataract, glaucoma, macular oedema, hypotony.
• Early treatment is a key aim to improve outcomes. There is increasingly
effective treatment for CAU available.
Population requiring screening
• Screening should equally be offered to children with JIA (all subgroups),
whether they have few or many affected joints, and despite some
variation in risk.
• Evidence of significant risk to warrant screening exists for persistent
and extended oligoarthritis, RF−ve polyarthritis, psoriatic arthritis,
and also undifferentiated arthritis
• Performing the first screen as early as possible is a key aim and in
reality eye screening is often performed before the diagnosis of JIA
is absolutely clear (e.g. in cases which are ultimately are diagnosed as
reactive arthritis). Screening should be performed before the subgroup
of JIA is confirmed as the classification evolves over time.
• Uveitis is more common in the following:
• Girls, younger age patients.
• JIA patients who are ANA+ve (albeit of patients with uveitis, 50%
are ANA−ve)—therefore children with JIA and who are ANA−ve
also need eye screening).
• Severe uveitis is associated with younger age and male sex.
 UVEITIS SCREENING IN JIA 149

• Enthesitis-related arthritis (ERA) is usually associated with acute

anterior uveitis (and often patients carry HLA B27) which presents
promptly with a painful red eye. However, reports of asymptomatic
CAU in ERA, leads to its inclusion in some screening programmes.
Exclusions to screening
Two subgroups of JIA are not associated with a high level of CAU, and are
not offered screening in all programmes. A single eye screen at presenta-
tion of JIA is recommended, particularly where the diagnosis is unclear.
• RF+ve polyarticular JIA (RF+JIA) is not associated with CAU, and as
disease onset is usually in later adolescence may not be considered for
screening in some programmes.
• A small number of case reports exist of CAU in sJIA. Other conditions
that could mimic sJIA, such as CINCA (amongst many others), do
develop CAU, which raises a question about the diagnosis in these
older case reports. As a rule of thumb developing CAU in sJIA should lead
to the question: ‘Is this really sJIA?’.
Structure of the screening programme
The core principles of the screening programmes are listed in Table 3.7.
Variations in screening programmes between countries often relate to
the lack of a clear evidence base to address these statements. Important
points to consider are the following:
• Those providing eye screening should be appropriately trained, skilled
at examining young children, and should audit the robustness of their
screening programme.
• Most uveitis develops early in the disease course:
• The first eye screen is critical, and should be made immediately
after the diagnosis of JIA, or before certain diagnosis if JIA is likely.
• Screening in the first and early years should be adhered to robustly.
• Robust mechanisms to identify non-adherence to the screening
programme are important.
• Immediate access to advice and assessment should be offered should
eye symptoms develop between screening visits or after discharge
from the screening programme.
• A revised screening schedule should be offered if the risk of uveitis
increases, such as discontinuation of maintenance drugs (e.g. patients on
biologics who stop taking methotrexate—anecdotally there are reports of de
novo uveitis or flares occurring with etanercept use—see b p 434).
• Children with JIA who are too young or otherwise unable (e.g. learning
difficulties) to recognize subtle changes in their vision associated with
the development of CAU must be offered eye screening.
• Rapid access to an examination under anaesthetic (EUA) should be
available for all children unable to comply with screening examinations.
The children least likely to comply are at the highest risk for
undetected disease, i.e. the youngest or those with learning disability.
• Once considered high enough risk to merit inclusion in the screening
programme, the screening interval offered should not be related to the risk
of developing uveitis, but to the natural history of uveitis should it develop.
• The screening intervals should be short enough so that should uveitis
develop, no irreversible damage occurs between screening visits.
150 CHAPTER 3 Juvenile idiopathic arthritis

• There is a poor evidence base for determining the screening interval.

• Eye screening continues until the child is old enough to detect the
symptoms of uveitis and is usually 12yr of age as a minimum.
• Whilst the risk of developing uveitis falls with time from the date
of last active arthritis, date of diagnosis, and with increasing age,
children discharged from screening are still at risk of uveitis, and
are discharged because they are considered old enough to identify
subtle changes in their vision. In children with learning difficulties
screening may be required for longer until the risk is low.
Details of the screening assessment
• Screening involves slit lamp examination of anterior, intermediate, and
posterior chambers of the eye:
• A slit lamp examination by a skilled operator is required, i.e.
ophthalmologist (or optometrist) skilled and experienced at
examining children’s eyes.
• Examination by ophthalmoscope alone is not able to detect the
presence of uveitis.
• Anterior uveitis is by far the commonest presentation, but the other
chambers are also affected.
• Macular involvement, whilst rare, is associated with a poor prognosis
and is particularly important to detect.
• Some screening programmes also check visual acuity, and proceed to
intraocular pressure measurements as indicated.

Table 3.7 Comparison of screening programmes between different

countries
Core principle Current UK Current USA German variation
guidance* guidance on USA guidance
Rapid first eye Within 6 weeks Within 1 month None given
screen of referral to eye of diagnosis
clinic of arthritis
Minimizing delay Seen within 10 weeks Not discussed
of symptom of onset of symptoms
onset of JIA to and 4 weeks of the
diagnosis of JIA referral
Screening 2-monthly for the 3–12-monthly 3–12-monthly
intervals first 6 months, then depending on depending on risk
3–4-monthly risk category. category. Recognizes
No discussion psoriatic as important
of psoriatic risk factor in addition
arthritis at all to oligoarthritis and
RF−ve JIA
Access to ‘Urgent’ if deemed Not discussed
examination high risk—no
under anaesthetic timescale given
as appropriate
Access if Within 1 week Urgent access, Not discussed
symptomatic no time interval
given
 UVEITIS SCREENING IN JIA 151

Table 3.7 (Contd.)

Core principle Current UK Current USA German variation
guidance* guidance on USA guidance
Altered screening Return to 1st- year Complex algorithm dependent on age,
with altered risk screening intervals ANA status, and disease duration
on discontinuation of
methotrexate
Adherence to Priority to rebook Not discussed
screening (no time given)
Ages included, Complex detail, Continue with Continue with
and duration of summarized as 12-monthly 12-monthly
screening until 12th birthday screening screening throughout
throughout adolescence
adolescence
Exclusions from RF+ve JIA and sJIA Uses 1986 None, RF positive JIA,
screening offered baseline classification, ERA and sJIA offered
screen only and screens 12-monthly screening
only sJIA,
oligoarthritis,
and polyarthritis
Note: current screening programmes are not fully evidence-based because of lack of adequate
study in large enough numbers of patients. There is little or no evidence to support different
screening regimens between subgroups of JIA, nor to determine the best screening interval.
This lack of evidence leads to some debate about the validity of the use of the term screening,
suggest surveillance as a better term, and also discussion about the validity of guidelines which
are not fully evidence-based. Nonetheless screening is performed in many countries with
consensus that it is effective and worthwhile.
* Current UK guidance is based on the following:
• The Royal College of Ophthalmologists 2006 guidelines for screening for uveitis in juvenile
idiopathic arthritis. Produced jointly by BSPAR and the RCPOphth (2006) available at
M http://www.rcophth.ac.uk/docs/publications.
• BSPAR Standards of Care 2010. BSPAR Standards of Care for JIA. M http://www.bspar.org.
uk/downloads/clinical_guidelines/Standards_of_Care.pdf.

Further reading
Cassidy J, Kivlin L, Lindsley C, et al. Ophthalmological examination in children with juvenile
rheumatoid arthritis Pediatrics 2006: 117:1843–5.
Heiligenhaus A, Niewerth M, Ganser G, et al., and the German Uveitis in Childhood Study Group.
Prevalence and complications of uveitis in juvenile idiopathic arthritis in a population-based
nation-wide study in Germany: suggested modification of the current screening guidelines
Rheumatology 2007; 46:1015–19.
152 CHAPTER 3 Juvenile idiopathic arthritis

Surgery in the young adult with JIA:

practical issues
Introduction
• Surgery has an important but diminishing part in the overall management
of JIA.
• The literature reports that young adults in their 20s have limited
physical function and continued disease activity although these studies
are retrospective and predate the effects of newer treatments such as
biologic drugs in combination with methotrexate. Better treatment has
also meant that growth has been completed with epiphyseal closure
and bone density has reached the adult peak.
• Since the advent of these drugs, many centres have noted the
reduction in need for certain types of surgery such as synovectomy and
soft tissue release (tenotomies and capsulotomies) and delay in others
such as joint replacement.
• Surgery for joint failure in most centres has been delayed into young
adulthood rather than in adolescence when maturation is incomplete.
• There is currently a cohort of young adult patients who have received
biologic drugs in their later years after a period of sustained disease
activity and who present new problems for those providing services for
people with arthritis.
• It is important that the surgeon has skill in this age group and JIA.
• Combined management with a rheumatologist and surgeon is
important but may have to be in a dedicated setting.
Orthopaedic surgery in the young adult
• There is now experience in young people in arthroplasty of the
hip, knee, ankle, shoulder, elbow, and wrist. Cervical surgery and
arthrodesis of various joints may be considered.
• The highest requirement for surgery is in polyarticular course JIA,
especially if RF+ve and systemic onset disease, as well as RF−ve
disease and extended oligoarticular arthritis, particularly if disease
has been active for many years.
• The best results are obtained in controlled disease with joints in
a good position. If >1 joint needs surgery, the proximal one should
be first and lower limbs should precede upper limbs.
• Intra-articular steroid may reduce activity and fixed flexion deformity
although should not be used within 3 months of surgery. Soft
tissue release to obtain a good position is equally rarely necessary.
Hydrotherapy may be needed to maintain muscle strength.
• There is still a place for synovectomy if disease remains
uncontrolled despite drug treatment.
• Many orthopaedic surgeons are reluctant to operate on young people.
Hip and knee arthroplasty are now the commonest operations with
achievement of good 10-yr survival in specialist centres. The key
symptoms requiring surgery are:
• Pain despite control of the other joints with active therapy.
• Reducing exercise tolerance (walking distance in the legs or pain on
movement in the arms.
 SURGERY IN THE YOUNG ADULT WITH JIA 153

• Night pain or pain at rest.

• Increasing disability and instability (locking or giving way of lower
limb joints).
• The threshold should be considerably above the level of immobility
where the person has to regularly use a wheel chair.
Precautions with surgery in adults with JIA
• Cervical spine: x-rays should be performed prior to surgery; any doubt
should be followed with MRI. Poster anterior and lateral views in
flexion and extension views should be obtained to assess for:
• Atlanto-axial subluxation (can be at any level).
• Cervical spondylolisthesis (slip of one vertebra on another).
• Cervical fusion with limited range of movement or movement at
one level.
• Temporomandibular joint disease: micrognathia and abnormal/
restricted jaw opening may cause intubation difficulty.
• Occasionally there may have been previous intubation difficulty due
to a small larynx or cricoarytenoid arthritis.
• Medications:
• Methotrexate should not be stopped prior to surgery. Infection
rates after replacement surgery are less if the drug is continued. It is
better to be immunosuppressed and have controlled disease then have
no immunosuppression and uncontrolled disease.
• Biologics—the current advice is to stop anti TNF therapy in the peri-
operative period—the half-life of etanercept is 100h, adalimumab
15–19 days, and infliximab 8–9.5 days.
• A practical rule is to omit the biologic drug for 14 days before and
14 days after surgery for etanercept and adalimumab, and
4 weeks for infliximab (if surgery is timed correctly within the
8-week interval between infusions no dosage will be missed).
• There is a balance between successful wound healing and reduction
of infection by stopping anti-TNF therapy versus perioperative risk
of disease flare.
• There is some evidence that anti-TNF therapy has a higher
incidence of infection and deep vein thrombosis in patients with RA
undergoing surgery but the numbers studied were small.
• Other considerations:
• Small stature—patients should be assessed against standard growth
charts and consideration given to a need for greater anaesthetic
care for small airways. Special surgical prostheses may be required
(small standard prosthesis or a custom-made prosthesis).
• Osteoporosis—bone densitometry is recommended prior to
surgery with higher risk in those patients with long disease duration
or previous high steroid requirement.
• Down’s syndrome—higher risk of atlanto-axial subluxation and also
an i sensitivity to marrow suppression from immunosuppressant
and other drugs.
• Corticosteroid usage—steroid dosage may need to be adjusted
over the perioperative period depending on the length and dosage
of steroid use in the preceding months and years.
154 CHAPTER 3 Juvenile idiopathic arthritis

• Preoperative assessment—blood counts and routine chemistry

should be performed prior to surgery particularly if the patient
is on disease-modifying therapy. In particular, patients with
systemic disease may need cardiac assessment with ECG and
echocardiogram. Thrombosis risk should be assessed.
• Amyloidosis—it is important not to dehydrate young people with
amyloid undergoing surgery. An IV line will be needed prior to
surgery to maintain hydration.
Perioperative care
• Anaesthetists should be experienced in treating young people with JIA.
They should be aware of potential intubation difficulties and the need
for nasal intubation using a fibreoptic laryngoscope.
• Pressure-reducing measures may be required to avoid skin ischaemia in
vulnerable patients.
• Early mobilization is important and hydrotherapy should be considered.
• Preoperative physiotherapy assessments should alert the need for
temporary or permanent aids and adaptations.
• Written antibiotic advice needs to be given for future surgical and
dental procedures.
Advice concerning pregnancy
• Young women who have had arthroplasty are often unaware of issues
related to pregnancy. All young people should be under consultant
care. The physician and obstetrician will need to assess:
• Pelvic size.
• Stability of prosthesis.
• Neck issues as outlined on b p 153.
• Drug therapy in pregnancy and risk of postpartum disease flares.
• Physical issues around breastfeeding and child care.
• Timing of reintroduction of drug therapy in relation to delivery and
breastfeeding.
• Even if the mother has not had an arthroplasty, long labours should
be avoided and the mother should be aware of the potential need for
assisted delivery and Caesarean section.
Further reading
Ding T, Ledingham J, Luqmani R, et al. BSR and BHPR rheumatoid arthritis guidelines on the safety
on anti-TNF therapies. London: BSR, 2010. Available at: M http://www.rheumatology.org.uk/
includes/documents/cm_docs/2010/d/draft_anti_tnf_safety_guideline_april_2010.pdf.
Hall MA Surgical interventions. In Szer IS, Kimura Y, Malleson PN, et al. (eds) Arthritis in Children
and Adults. Oxford: Oxford University Press, 2006; 403–14.
 TREATMENT APPROACHES IN JIA 155

Treatment approaches in JIA

• JIA is a complex and chronic condition and is therefore optimally
managed by an experienced MDT as part of a managed clinical network
as outlined in the BSPAR Standards of Care (see b p 409).
• The MDT is integral to the management with the patient and family
at the centre (Fig. 3.2), with input from specialist consultant, specialist
nurse, paediatric physiotherapist, and paediatric occupational therapist
(with interests in musculoskeletal conditions if possible).
• Access to ophthalmology for monitoring and treatment of JIA-associated
eye disease is vital, with other services such as orthopaedic surgeons,
radiology, social work and psychology services able to be accessed
readily as required; these disciplines all have to interlink efficiently to
achieve the best possible outcome. See b p 377 and related chapters
for more information on MDT members and their specific roles.
• The general treatment approach is to achieve early diagnosis and rapid
control of the inflammatory process, whilst minimizing adverse effects of
treatment and supporting general physical and mental health (Fig. 3.3).
• Early and adequate treatment aims to prevent long-term joint damage
and the need for joint replacement therapy.
• Each member of the team contributes to the holistic management of
the patient and family, with medical treatment forming only one strand
of the overall picture.
• Education and information form one of the most important features
of management throughout the duration of disease and should be
undertaken by all members of the team, although the nurse specialist
often takes an ongoing role in this area.
• Physiotherapy and occupational therapy have important roles in
maintaining maximum function—the aim of treatment is as near to
functional normality as possible. It is important to maintain muscle
strength despite inflammatory processes within joints and these
disciplines aim to achieve this by teaching specific exercises, pain
management, and joint protection techniques as necessary.
• A healthy balanced diet with particular emphasis on calcium and
vitamin D intake for bone health are recommended in JIA but there is
no evidence for dietary modification affecting the inflammatory process
in this disease.
Specific medical management in subtypes of JIA
• Table 3.8 illustrates some of the similarities and differences in the
specific management of the different subtypes but should only be
regarded as a guide to management.
• There is a lack of good evidence for many aspects of JIA management,
therefore variability in practice between specialists exists.
• Particular management controversies remain around joint injection;
dose, timing, number, and duration of treatment whilst in remission; and
the use of specific disease-modifying drugs in particular disease types.
• In future, the possibility of genetic and phenotypic subtyping may
determine prognosis and more predictable response to particular drugs.
156 CHAPTER 3 Juvenile idiopathic arthritis

Sp
con eciali
GP sul st
tan
ts
Consultant
Social work

School
Patient Physio
Family
and OT

Nurse
specialist

Psychology

Fig. 3.2 Patient-centred MDT management of JIA.

Symptomatic
Rx

Steroids
treatment of eye disease
Functional improvement

Psychological support
pain management
self-management

Monitoring and
Education and

DMARDS

Biologics

Experimental
Rx (eg BMT)

Surgical Rx

Fig. 3.3 General treatment approach in JIA.

Rx=Treatment; DMARDS=Disease Modifying Anti-Rheumatic Drugs; BMT=Bone
marrow transplant.
Table 3.8 Specific management of subtypes of JIA
Systemic onset Oligoarthritis Polyarthritis Established polyarthritis/ Enthesitis related arthritis
JIA oligoarthritis
Psoriatic arthritis

Early/mild Medium-dose Intra-articular MTX NSAID

disease corticosteroids steroids
Steroids IVMP/ high-dose
NSAIDs (intra-articular or corticosteroids followed by
systemic) 2–4 weeks of low dose
Established/ Pulsed IV methyl See next column MTX (ensure maximum Disease >2–4 months’ duration
severe prednisolone (IVMP)*. dose, SC route)
Sulphasalazine (may work
disease Methotrexate (MTX) (usually
May need to add etanercept. better than other DMARDS)
given by subcutaneous (SC)

TREATMENT APPROACHES IN JIA

route) ± corticosteroids + joint MTX/anti-TNF
injections
Consider ciclosporin, and
biologics (e.g. anakinra or
tecilizumab) pending local and
national guidelines/availability
Remission Wean prednisolone slowly Ongoing monitoring Wean off Continue treatment for Continue sulfasalazine
Steroid first several months 6 months–1yr
Reduce other treatment with
extreme caution—high risk DMARD continues Wean and discontinue
of relapse longer then steroids first
consider reduction
Wait 1 year before weaning
or discontinuation
off DMARDs—off MTX last
(continued )

157
 158
Table 3.8 (Contd.)

CHAPTER 3
Systemic onset Oligoarthritis Polyarthritis Established polyarthritis/ Enthesitis related arthritis
JIA oligoarthritis
Psoriatic arthritis

Juvenile idiopathic arthritis

Relapse Repeat high-dose If previous IACS Reintroduce all Reintroduce all drugs that Generally episodic course
corticosteroids effect >4 months drugs on which induced remission
Short courses of NSAID and
repeat injection remission was
Consider other biologic Often requires step up sulphasalazine sufficient to
achieved.
agents If lasted <4 months in treatment to reinduce obtain remission in recurrences
add NSAID, repeat remission
IAC consider
DMARD
Persistent IL-6 and IL-1ra directed IAC targeted Consider alternate biologic
disease treatments joints agents
Tocilizumab (anti-IL-6) and In severe cases consider
canakinumab (anti-IL-1B) bone marrow transplant
(see b p 405)
* If macrophage activation syndrome develops (see b p 305).
MTX, methotrexate; IAC, intra-articular corticosteroid; DMARD, disease-modifying anti-rheumatic drug; NSAID, non-steroidal anti-inflammatory drug.
 TREATMENT PATHWAYS IN JIA 159

Treatment pathways in JIA

Note these are suggested treatment pathways and where possible based
on current national (BSPAR) guidance for biologics and methotrexate use
(see b other chapters for details, p 415). These treatment pathways have
not been validated in clinical practice but illustrate the different manage-
ment approaches for the spectrum of JIA subtypes (Figs. 3.4–3.8).
Please note that reference to referral for consideration of autologous
stem cell transplantation is after failure to response to at least 2 different
biologic agents—this differs from the BSPAR (2006) guidance from autolo-
gous stem cell transplantation (see b AHSCT, p 405) with the i experi-
ence and range of biologic agents now available.
160 CHAPTER 3 Juvenile idiopathic arthritis

Consider need for varicella

vaccination (see b p 371
Varicella prevention)

Age <8 yr and/or small–

Age >8yr and <4 large
medium-sized joints
joints involved
involved

Inject all affect joints with Inject all affected joints

triamcinolone with triamcinolone
hexacetonide using hexacetonide under
Entonox® as analgesia general anaesthesia

Assess response
after 3 months

Active synovitis in Active synovitis in

new joints and total same or new joints No evidence of
cumulative count but cumulative total active synovitis
now >4 still <5

Start extended Re-inject joints with Re-assess 3–6-

oligoarticular JIA triamcinolone hexacetonide monthly, Re-start
pathway and re-assess in 3 months. If pathway if disease
>2 injections within 6–12 relapses
months consider starting
extended oligoarticular JIA
pathway

Fig. 3.4 Suggested treatment pathway for oligoarticular JIA.

 TREATMENT PATHWAYS IN JIA 161

All patients should receive either intra-articular steroids to all affected joints or
systemic (preferably IV) corticosteroids at diagnosis and then start methotrexate
(MTX) 10–15 mg/m2 given once a week. Assess response after 3 months. If ≥3 swollen
joints and oral MTX being used—switch to SC MTX 15 mg/m2
Assess response in 3 months

*Co- ≥3 swollen joints/not tolerating therapy?

administration of
biologics is not
currently Does patient have currently, or recently, active uveitis?
recommended. It
is therefore
recommended If no active/recent uveitis start s/c If active/recent uveitis start
that after stopping etanercept 0.4 mg/kg twice a SC adalimumab 24 mg/m2 every
any biologic week 14 days
therapy the Assess response after 3 months Assess response after 3 months
equivalent of 2
doses of the drug
stopped should be
missed before ≥3 swollen joints/not tolerating therapy?
starting the new
treatment
If on etanercept can be switched, If on adalimumab,
after washout, to adalimumab and active or
Assess response after 3 months recent uveitis
<3 tender or swollen
joints and tolerating
therapy?
≥3 swollen joints/not tolerating therapy?

Inject active joints Stop anti-TNF. After washout* start IV abatacept 10 mg/kg
with triamcinolone every 28 days
hexacetonide. Assess response after 3 months
Continue current
therapy. Re-assess at
least 3-monthly ≥3 swollen joints or not tolerating therapy?

Stop abatacept. After washout* start IV tocilizumab

8–12 mg/kg given every 2–4 weeks
Assess response after 3 months
Refer for consideration of
autologous/allogeneic
bone-marrow transplant
≥3 swollen joints or not tolerating therapy?

Fig. 3.5 Suggested treatment pathways in children with extended oligoarticular JIA,
polyarticular (RF−ve) JIA, psoriatic JIA, and enthesitis-related arthritis, affecting a
cumulative total of >4 non-axial joints.
162 CHAPTER 3 Juvenile idiopathic arthritis

All patients should receive either intra-articular steroids to all affected joints or
systemic (preferably IV) corticosteroids at diagnosis and then start methotrexate (MTX)
10–15 mg/m2 given once a week. Assess response after 3 months. If ≥3 swollen joints
and oral MTX being used—switch to SC MTX 15 mg/m2
Assess response in 3 months

≥3 swollen joints/not tolerating therapy?

Start anti-TNF therapy. If MTX tolerated then add anti-TNF to MTX,

if not tolerated substitute anti-TNF for MTX. Either use:
• SC etanercept 0.4 mg/kg/dose twice a week (any age) or
• SC adalimumab 24 mg/m2 every 2 weeks (age 12 or over)
Assess response after 3 months

≥3 swollen joints or not tolerating therapy?

<3 tender or
swollen
joints and
tolerating Stop anti-TNF therapy. After washout give 2 doses IV rituximab
therapy? 750 mg/m2 2 weeks apart. Assess response after 6 months

≥3 swollen joints or not tolerating therapy?

Rituximab can be repeated if If no response to

initial good clinical response rituximab despite
(see main text) adequate B-cell depletion:

Assess response ?3 swollen joints or

Inject active joints not tolerating
after 6 months therapy?
with triamcinolone
hexacetonide.
Continue current
therapy. Re-assess Start IV abatacept 10 mg/kg every 28 days. Assess
at least 3-monthly response after 3–6 months

≥3 swollen joints or not tolerating therapy?

Refer for
consideration of
autologous/allogeneic
bone-marrow Stop abatacept. Start IV tocilizumab 8–12 mg/kg
transplant, if given every 2–4 weeks.
refractory disease Assess response after 3–6 months.

Fig. 3.6 Suggested treatment pathways in children with polyarticular (RF+ve) JIA.
 TREATMENT PATHWAYS IN JIA 163

All patients should receive IV corticosteroids at diagnosis and then start MTX 10–
15 mg/m2 given once a week, preferably by SC injection
Assess response after 3 months
If active disease despite oral MTX then switch to 15 mg/m2 SC MTX
Assess response after 3 months

*Systemic ≥3 swollen joints and/or active systemic features*

symptoms include: despite SC MTX 15 mg/m2 or not tolerating therapy?
Spiking fever
Rash
Serositis Start SC etanercept 0.4 mg/kg twice a week
Hepatomegaly If MTX tolerated add etanercept to MTX, if not tolerated
Splenomegaly substitute etanercept for MTX.
Lymphadenopathy If no response within 6 weeks dose of etanercept can be
increased from 0.4 mg/kg to maximum 0.8 mg/kg/dose
Assess response after total 3 months

Systemic features* still Systemic features*

present along with ≥3 absent but ≥3 swollen
swollen joints joints

<3 tender or Stop etanercept. Stop etanercept. Start IV

swollen joints, no Start SC anakinra 60 mg/m2 tocilizumab 8–12 mg/kg given
systemic features given daily. Assess every 2–4 weeks. Assess
and tolerating response after 3 months response after 3 months
therapy?

Active systemic features*, ≥3 swollen joints, or not tolerating

therapy: after washout switch from anakinra to tocilizumab
(or vice-versa). Assess response after 3 months

Inject active
joints with Active systemic features, ≥3 swollen joints, or not
triamcinolone tolerating therapy: stop anakinra or tocilizumab and after
hexacetonide. washout start IV abatacept 10 mg/kg every 28 days
Continue current Assess response after 3 months
therapy

Refer for consideration of Active systemic features*, 3 or more swollen

autologous/allogeneic bone- joints or not tolerating therapy?
marrow transplant

Fig. 3.7 Suggested treatment pathway in children with systemic-onset JIA.

164 CHAPTER 3 Juvenile idiopathic arthritis

All patients should receive either intra-articular steroids to all affected joints,
or systemic (preferably IV) corticosteroids at diagnosis and then start MTX 10–
15 mg/m2 given once a week
Assess response after 3 months

If clinically active disease, consider If oral MTX being used then switch to SC
confirming with US/MRI. MTX. Re-assess in 3 months

Start anti-TNF therapy.

1. MTX tolerated: add anti-TNF to MTX
>3 tender or
2. MTX not tolerated: substitute anti-TNF for MTX
swollen joints or
entheses or Either use:
• Etanercept 0.4 mg/kg SC twice a week (any age)
intolerant of
or
therapy? • Adalimumab 24 mg/m2 SC every 14 days (>12 year)

<3 tender or swollen Assess response after >3 tender or swollen

joints or entheses 3 months. If active disease joints or entheses or
and tolerating clinically then consider intolerant of therapy?
therapy? confirming with US/MRI

Assess response after

Switch from etanercept to
3 months. If clinically
adalimumab or vice versa.
active disease, consider
Alternatively consider
confirming with US/MRI.
infliximab 6 mg/kg 4-weekly

Inject active joints >3 tender or swollen joints Stop anti-TNF.

with triamcinolone or entheses or intolerant Start abatacept 10 mg/kg
hexacetonide. of therapy? IV every 28 days.
Continue current
therapy.
Re-assess at least
3-monthly Assess response after >3 tender or swollen joints
3–6 months. If clinically or entheses or intolerant
active disease consider of therapy?
confirming with US/MRI

Stop abatacept.
Start IV tocilizumab 8 mg/kg
given every 4 weeks.

Fig. 3.8 Suggested treatment pathways in children with enthesitis-related arthritis

affecting the entheses, sacro-iliac, or other axial joints.
 DISEASE ACTIVITY SCORES IN RHEUMATOID ARTHRITIS AND JIA 165

Disease activity scores in rheumatoid

arthritis and JIA
Composite indices of disease activity are more precise tools than their
individual components with higher sensitivity to change; the Disease
Activity Score (DAS) was developed in an attempt to improve upon
the arbitrary classification of adult RA into high or low disease activity.
The DAS28 is commonly used in adult practice and involves scoring of
28 joints (PIPs, MCPs, wrists, elbows, shoulders, and knees) for swelling
and tenderness, in combination with ESR and general health assessment
(visual analogue scale, VAS).
Key points of the DAS 28 are:
• The score is derived from:
DAS28 = 0.56 x square root (tender count 28) + 0.28 x square root
(swollen count 28) + 0.70 x log(to base 10)(ESR) + 0.014 x VAS
• Many desktop and Internet-based calculators available.
• The DAS28 score (0 to 10) indicates current disease activity; >5.1
defines ‘high’ disease activity; <3.2 defines ‘low’ disease activity.
• Remission is defined as DAS28 score <2.6 (comparable to the ACR
remission criteria)—EULAR response criteria are based on change
in DAS28 score.
• Frequent assessment by DAS is now considered best practice in
optimizing RA control for the best long-term outcome, particularly
when using ‘tight’ control and combination therapies. Health
professionals are trained to rapidly and consistently score the DAS28
using standard examination with low inter-and intra-observer variation.
• Serial measurements of the DAS28 are strong predictors of physical
disability, radiological progression, and are a sensitive discriminator
between patients (high/low disease activity) and treatments (active/
placebo-treated patient groups).
• The clinical utility of the DAS28 led to its central position in determining
the suitability of adult RA patients for receiving anti-TNF therapy
• A score >5.1 on 2 occasions, 1 month part, is considered to be the
minimal disease activity to receive anti-TNF therapy.
• To continue therapy >3 months, the score must have fallen by >1.2
or be <3.2.
Disease Activity Score in JIA (see b Outcome measures, p 41)
There is no currently accepted paediatric analogue of the DAS28 for
assessing disease activity in JIA. The proposed Juvenile Arthritis Disease
Activity Score (JADAS) includes the following:
• Physicians’ global assessment of disease activity (VAS).
• Parents’ global assessments of disease activity (VAS).
• Active joint count assessed by 1 of a) JADAS-10 (any involved joint
to a maximum of 10); or b) JADAS-27 (27 joints); or c) JADAS-71 (all
71 joints).
• ESR normalized to a 1–10 scale.
166 CHAPTER 3 Juvenile idiopathic arthritis

Evidence to date reports that JADAS is a valid instrument for the assessment
of disease activity in JIA and it can predict disease outcome (radiographic
progression at 3yr). Potential confounders exist, e.g. ESR may be normal in
children with active oligoarticular JIA, it may not be sensitive to change with
low joint counts and there is to date no evidence of utility in the various
subsets of JIA.
Further reading
Consolaro A, Ruperto N, Bazso A, et al. Development and validation of a composite disease activity
score for juvenile idiopathic arthritis. Arthritis and Rheum 2009; 61(5):658–66.
DAS website: M http://www.das-score.nl.
Neogi T, Felson DT. Composite versus individual measures of disease activity in rheumatoid arthritis.
J Rheumatol 2008; 35(2):185–7.
Rheumatology Research website: M http://www.reuma-nijmegen.nl/.
 Chapter 4 167

Systemic diseases

Vasculitis British Isles Lupus

The classification of Assessment Group
paediatric vasculitis 168 (BILAG) 2004 Index 248
The epidemiology of SLEDAI 2000 Disease
paediatric vasculitis 171 Activity Index 256
The investigation of SLICC/ACR Damage Index
primary systemic (paediatric) 258
vasculitis 172 Connective tissue
The standard treatment of diseases
childhood vasculitis 174
Henoch–Schönlein Scleroderma 260
purpura 179 Juvenile dermatomyositis 266
Kawasaki disease 183 Overlap syndromes 275
The anti-neutrophil Antiphospholipid
cytoplasmic antibody syndrome (APS) 279
(ANCA)-associated Paediatric uveitis 283
vasculitides 188 Autoinflammatory
Polyarteritis nodosa diseases and
(PAN) 192 immunodeficiency
Cutaneous polyarteritis Periodic fever syndromes/
nodosa (cPAN) 198 autoinflammatory
Takayasu arteritis 199 disease 288
Behçet’s disease 205 Chronic recurrent multifocal
Central nervous system osteomyelitis 297
vasculitis in children 209 Sarcoidosis 300
Other vasculitides 214 Macrophage activation
Vasculitis mimics: syndrome 305
non-inflammatory Primary immunodeficiency
vasculopathies 217 and rheumatological
Juvenile systemic lupus disease 309
erythematosus Other Systemic diseases
JSLE: epidemiology and Mucopolysaccharidoses
aetiology 223 (MPS) and mucolipidoses
JSLE: clinical features and (ML) 312
diagnostic criteria 226 Chromosomal abnormalities
Assessment of the child with and associated
JSLE and monitoring of musculoskeletal
disease activity 229 morbidity 318
JSLE: approach to Arthritis and other
management 232 musculoskeletal features
JSLE: renal involvement 236 associated with cystic
Neonatal lupus syndrome 240 fibrosis 323
B-cell-targeted therapies Inflammatory bowel disease
for systemic lupus and musculoskeletal
erythematosus 241 features 326
168 CHAPTER 4 Systemic diseases

The classification of paediatric

vasculitis
Background to classification criteria
• Classification criteria are often described for diseases where the
pathogenesis and/or molecular mechanisms are poorly understood.
• They are used to facilitate clinical trials and improve epidemiological
descriptions by providing a set of agreed criteria that can be used by
investigators anywhere in the world.
• Classification criteria for vasculitis are designed to differentiate one
form of vasculitis from another once the diagnosis of vasculitis has been
secured. They are not the same as diagnostic criteria (such as those
described for Kawasaki disease), but are often misused as such.
• Thus, classification criteria aim to:
• Identify a set of clinical findings (criteria) that recognize a high
proportion of patients with the particular disease (sensitivity), and
• Exclude a high proportion of patients with other diseases
(specificity).
• Classification criteria typically include manifestations that are
characteristics of the disease in question that occur with less frequency
or are absent in other conditions.
• Symptoms or findings that might be typical or common but may also be
present in other diseases tend to be excluded.
• An important limitation to these criteria is that they are not based on
a robust understanding of the pathogenesis and as such are relatively
crude tools that are likely to be modified as scientific understanding of
these diseases progresses.
Paediatric vasculitis classification 2010
• New paediatric classification criteria are described, and validated on
>1300 cases worldwide (Table 4.1).
• These criteria do not include Kawasaki disease (see b Kawasaki
disease, p 183); nor do they include definitions for microscopic
polyangiitis (too few cases included in dataset).
• For Takayasu arteritis, care must be taken to exclude fibromuscular
dysplasia (or other cause of non-inflammatory large- and medium-
vessel arteriopathy) since undoubtedly there could be scope for
overlap in the clinical presentation between these 2 entities, although
the pathogenesis and treatment for these are clearly distinct.
General scheme for the classification of paediatric
vasculitides
• This is based on the size of the vessel predominantly involved in the
vasculitic syndrome and is summarized as follows.
• It should be noted, however, that most vasculitides exhibit a significant
degree of ‘polyangiitis overlap’: e.g. Wegener’s granulomatosis can
affect the aorta and its major branches, and small vessel vasculitis can
occur in polyarteritis nodosa.
 THE CLASSIFICATION OF PAEDIATRIC VASCULITIS 169

1. Predominantly large-vessel vasculitis

• Takayasu arteritis.
2. Predominantly medium-sized vessel vasculitis
• Childhood polyarteritis nodosa
• Cutaneous polyarteritis
• Kawasaki disease.
3. Predominantly small-vessel vasculitis
• Granulomatous:
• Wegener’s granulomatosis
• Churg–Strauss syndrome
• Non-granulomatous:
• Microscopic polyangiitis
• Henoch–Schönlein purpura
• Isolated cutaneous leucocytoclastic vasculitis
• Hypocomplementemic urticarial vasculitis.
4. Other vasculitides
• Behçet’s disease
• Vasculitis s to infection (including hepatitis B-associated PAN),
malignancies and drugs, including hypersensitivity vasculitis
• Vasculitis associated with other connective tissue diseases
• Isolated vasculitis of the CNS (childhood p angiitis of the central
nervous system: cPACNS)
• Cogan’s syndrome
• Unclassified.
170 CHAPTER 4 Systemic diseases

Table 4.1 Classification criteria for specific vasculitic syndromes1

Vasculitis Classification criteria Sensitivity2 Specificity*
HSP Purpura, predominantly lower limb or 100% 87%
diffuse* (mandatory) plus 1 out of 4 of:
• Abdo pain
• IgA on biopsy
• Haematuria/proteinuria
• Arthritis/arthralgia
*
If diffuse (i.e. atypical distribution) then
IgA deposition on biopsy required
WG At least 3 out of 6 of the following 93% 99%
criteria:
• Histopathology
• Upper airway involvement
• Laryngo-tracheobronchial stenoses
• Pulmonary involvement
• ANCA positivity
• Renal involvement
PAN Histopathology or angiographic 89% 99%
abnormalities (mandatory) plus 1 out
of 5 of the following criteria:
• Skin involvement
• Myalgia/muscle tenderness
• Hypertension
• Peripheral neuropathy
• Renal involvement
TA Angiographic abnormalities of the aorta or 100% 99%
its main branches (also pulmonary arteries)
showing aneurysm/dilatation (mandatory
criterion), plus 1 out of 5 of the following
criteria:
• Pulse deficit or claudication,
• 4 limb BP discrepancy
• Bruits
• Hypertension
• Acute phase response
1
Adapted from Ozen S, Pistorio A, Iusan SM, et al. Paediatric Rheumatology International
Trials Organisation (PRINTO). EULAR/PRINTO/PRES criteria for Henoch–Schönlein purpura,
childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu
arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis 2010; 69:798–806.
2
Based on 1347 children with miscellaneous vasculitides. Ruperto N, Ozen S, Pistorio A, et al.;
for the Paediatric Rheumatology International Trials Organisation (PRINTO). EULAR/PRINTO/
PRES criteria for Henoch–Schönlein purpura, childhood polyarteritis nodosa, childhood
Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part I: Overall
methodology and clinical characterisation. Ann Rheum Dis 2010; 69:790–7.
 THE EPIDEMIOLOGY OF PAEDIATRIC VASCULITIS 171

The epidemiology of paediatric

vasculitis
• Childhood vasculitis is rare and the incidence and prevalence are not
accurately described.
• Henoch–Schönlein purpura (HSP) and Kawasaki disease (KD) are the
2 commonest childhood vasculitides and as such those with the most
epidemiological information.
• There is undoubtedly some ethnic variation for these diseases (see
individual section).
• In paediatric populations other systemic vasculitides including
polyarteritis nodosa (PAN), Wegener’s granulomatosis (and other
ANCA-associated vasculitides), Behçet’s disease, and Takayasu arteritis
are rare and epidemiology difficult to assess.
• Some ethnic variation has been noted: Takayasu’s being more
common in Asians than North Americans and Europeans.
Henoch–Schönlein purpura
The estimated annual incidence in the West Midlands, UK has been
reported as 20.4 per 100,000 and was highest in the 4–7yr age group. This
is comparable to reported figures from the Czech Republic of 10.2 per
100,000 and Taiwan of 12.9 per 100,000.
Kawasaki disease
• KD has the highest incidence and prevalence in Asian populations,
particularly Japan.
• Nationwide surveys conducted in Japan show the incidence of KD in
children aged 0–4yr continues to rise with the average annual incidence
in 2007 being 184.6 per 100,000.
• This compares to an estimated annual incidence rate of 5.5–8.1 per
100,000 (0–5yr) in the UK and an estimated annual incidence rate
of 1.6 per 100,000 (0–5yr) in the Czech Republic.
• There are limitations to these studies as they were all done by survey
or questionnaire reporting.
Further reading
Dolezalova P, Telekesova P, Nemcova D, et al. Incidence of vasculitis in children in the Czech
Republic: 2-year prospective epidemiology survey. J Rheumatol 2004; 31:2295–9.
Gardner-Medwin JMM, Dolezalova P, Cummins C, et al. Incidence of Henoch-Scholein purpura,
Kawasaki disease, and rare vasculitides in children of different ethnic origins. Lancet 2002;
360:1197–202.
Yang YH, Hung CF, Hsu CR, et al. A nationwide survey on epidemiological characteristics of
childhood Henoch-Scholein purpura in Tiawan. Rheumatology 2005; 44:618–22.
172 CHAPTER 4 Systemic diseases

The investigation of primary systemic

vasculitis
Background
Clinical features that suggest a vasculitic syndrome:
• Pyrexia of unknown origin
• Palpable purpura, urticaria, dermal necrosis
• Mononeuritis multiplex
• Unexplained arthritis, myositis, serositis
• Unexplained pulmonary, cardiovascular, or renal disease
• Plus 1 or more of:
• Leucocytosis, eosinophilia
• Hypocomplementaemia, cryoglobulinaemia
• Circulating immune complexes
• Raised ESR or CRP, thrombocytosis.
Level 1 investigations—to be performed in all
• Haematology and acute phase reactants:
• FBC, ESR, CRP, clotting, prothrombotic screen (if patchy ischaemia
of digits or skin), blood film
• Basic biochemistry:
• Renal and liver function, CPK, thyroid function, LDH, amylase/lipase,
urine dip and UA:UC (spot urine albumin:creatinine ratio)
• Infectious disease screen:
• Blood cultures
• Urine MC&S
• ASOT and anti-DNase b
• Mycoplasma pneumoniae serology
• Immunological tests:
• ANA, dsDNA Abs, ENAs, ANCA, RF,
• Anti-GBM antibodies
• TTG antibodies (coeliac disease screen)
• Immunoglobulins: IgG, IgA, IgM, and IgE
• Anticardiolipin antibodies, lupus anticoagulant
• C3/C4, MBL (memose binding lectin, if available), CH100 or
alternative functional complement assay if available
• VZV antibody status (prior to starting immunosuppressive therapy)
• Serum ACE
• Radiological: CXR, abdominal and renal USS
• Other: ECG, echocardiography, digital clinical photography of lesions.
Level 2 investigations—to be considered on an individual
basis
• Infection screen:
• Mantoux 1:1000, and/or quantiferon
• PCR for CMV, EBV, enterovirus, adenovirus, VZV, HBV, HCV
• Serology for HIV, Rickettsiae, Borrelia burgdorferi
• Viral serology for: hepatitis B & C, parvovirus B19.
 THE INVESTIGATION OF PRIMARY SYSTEMIC VASCULITIS 173

• Imaging:
• Radiograph of bones and joints.
• Selective contrast visceral angiography.
• DMSA scan.
• MRI/MRA of brain (for suspected cerebral vasculitis).
• CT abdomen, thorax, brain, sinus X ray (for Wegener’s).
• Labelled white cell scan (for extent and location of inflammation).
• Cerebral contrast angiography (for suspected cerebral vasculitis).
• PET-CT: for differential of malignancy or Castleman’s disease.
• DEXA scan.
• V/Q scan.
• USS Doppler of peripheral arteries.
• Thermography and nail fold capillaroscopy.
• Tissue biopsy: skin, nasal or sinus, kidney, sural nerve, lung, liver, gut,
temporal artery, brain, other.
• Bone marrow analysis and/or lymph node excision biopsy (for suspected
malignancy).
• Biochemistry, immunology and immunogenetics:
• Serum amyloid A.
• Formal GFR.
• Organ specific autoantibodies.
• IgD.
• B2 Glycoprotein 1 antibodies.
• Urinary catecholamines (consider plasma catecholamines as well),
and urine VMA, HVA (for phaeochromocytoma, or neuroblastoma).
• Cryoglobulins (if there is a history of cold sensitivity/vasculitis mainly
present in exposed areas of the body).
• Basic lymphocyte panel and CD19 count if monitoring post rituximab.
• Mitochondrial DNA mutations.
• DNA analysis for periodic fever syndromes that can mimic vasculitis:
MEFV (familial Mediterranean fever, TNFRSF1A (TNFA receptor
associated periodic fever syndrome, TRAPS), MVK (hyper IgD
syndrome, HIDS), NLRP3 (cryopyrin associated periodic syndrome,
CAPS), and NOD2 (Crohn’s/Blau’s/juvenile sarcoid mutations).
• Nitroblue tertrazolium test if granulomatous inflammation found
on biopsy.
• Nerve conduction studies (PAN, WG, Behçet’s [before starting
thalidomide]).
• Ophthalmology screen.
• Ambulatory 24h BP/4-limb BP.
174 CHAPTER 4 Systemic diseases

The standard treatment of childhood

vasculitis
Guidelines for the use and monitoring of cytotoxic drugs in non-malignant
disease are shown in Table 4.2. Standard vasculitis therapy (excluding
crescentic glomerulonephritis) is described in Fig. 4.1. Prior to using this
approach, remember there should be:
• A well-established diagnosis.
• Severe, potentially life-threatening disease.
• Inadequate response to less toxic therapy—milder cases of vasculitis
(e.g. isolated cutaneous forms) may respond to less toxic agents such
as colchicine. Therapy should always be tailored for each individual.
• No known infection or neoplasm.
• No pregnancy or possibility thereof.
• Informed consent obtained and documented in notes.
Other points of note
• Although the use of oral cyclophosphamide is highlighted in Table
4.3, increasingly IV cyclophosphamide is favoured over the oral route
in children and adults because of reduced side effects and lower
cumulative dose, but comparable efficacy as suggested by a number of
studies in adults with ANCA vasculitis (e.g. the ‘CYCLOPS’ trial).
• IV cyclophosphamide has the added advantage of ensuring adherence
to therapy, of particular relevance in adolescents with vasculitis.
Use of biologic therapy in systemic vasculitis of the young
• Whilst the therapeutic approach and drugs used as suggested in
Figs. 4.1 and 4.2 undoubtedly have improved survival and long-term
outlook for children with severe vasculitis, concerns relating to
toxicity particularly with cyclophosphamide, and relapses despite this
conventional therapeutic approach have led to the increasing use of
biologic therapy such as rituximab, anti-TNF alpha, or other biologic
therapy.
• Evidence to support the use of rituximab as a p induction agent in
place of cyclophosphamide for the treatment of ANCA-associated
vasculitis is now available for adults with this group of diseases
(RITUXIVAS, and RAVE trials).
• Evidence to support this approach in children remains anecdotal,
but undoubtedly rituximab is being increasingly used for children
with ANCA vasculitis that is not adequately controlled using the
conventional cyclophosphamide followed by azathioprine therapeutic
regimen outlined in Fig. 4.1.
• Evidence for the use of anti-TNFA or other biologic agents such as
anakinra remains anecdotal for children and adults with vasculitis.
• Whilst there is not enough evidence to recommend specific biologic
therapy for specific vasculitic syndromes, a general approach favoured
by the author is given in Table 4.3
Table 4.2 Doses, side effects, and clinical monitoring of commonly used immunosuppressant and cytotoxic immunosuppressant drugs used for the
treatment of vasculitis
Cyclophosphamide Azathioprine Mycophenolate mofetil Ciclosporin Methotrexate
(CYC) (MMF)
Dose 2–3mg/kg once a day PO 2–3 0.5–2.5mg/kg once a day PO (600 mg/m2 twice a day) 3–5mg/kg/day PO in 2 10–15mg/m2/week PO or SC
months; 0.5–1.0g/m2 IV monthly for 1yr or more divided doses (single dose)
with mesna to prevent cystitis (see
b p 427 Chapter 9 for mesna dose
and IV CYC administration protocol)
Side Leucopenia; haemorrhagic cystitis; GI toxicity; hepatotoxicity; Bone marrow suppression; Renal impairment, Bone marrow suppression and
effects reversible alopecia; infertility; rash; leucopenia; teratogenicity; severe diarrhoea; hypertension, interstitial pneumonitis
leukaemia, lymphoma, transitional no increase in malignancy in pulmonary fibrosis hepatotoxicity, tremor, (d risk with folic acid), reversible
cell carcinoma of bladder adults with RA; no conclusive gingival hyperplasia, elevation of transaminases,
data for cancer risk in children hypertrichosis, lymphoma hepatic fibrosis
Cumulative Not described for malignancy; Not described Not described Not described Not described
toxic dose 500mg/kg for azoospermia
Clinical Weekly FBC for duration of therapy Weekly FBC for 1 month, Fortnightly FBC for 2 months, Weekly measurement Baseline CXR, FBC, and LFTs,
monitoring (usually 2–3 months); baseline and then 3-monthly then monthly for 2/12. of BP; baseline then then FBC and LFTs fortnightly until
monthly renal and liver function 3-monthly when stable. monthly renal and dose stable, then monthly to every
Temporarily discontinue and/or
Baseline monthly renal and liver function; maintain 6 weeks (after 6 months). Reduce
Temporarily discontinue and/or reduce dose if neutropenia <1.5
liver function until stable 12h trough level at or discontinue if hepatic enzymes
reduce dose if neutropenia <1.5 × × 109/L, platelets <150 × 109/L,
50–100ng/mL. >3× upper limit of normal,
109/L, platelets <150 × 109/L, and check TPMT enzyme- Discontinue temporarily
6–12-monthly GFR. neutropenia <1.5× 109/L, new or
or haematuria patients deficient in TPMT and/or reduce dose if
Consider renal biopsy worsening cough, severe nausea,
require reduced doses (or neutropenia <1.5 × 109/L,
Day 10 FBC if IV. Reduce dose every 2 years vomiting, or diarrhoea, platelets
may not tolerate) azathioprine platelets <150 × 109/L, or
if renal or hepatic failure e.g. to <150 × 109/L or falling rapidly
because of i marrow toxicity significant GI side effects
250–300mg/m2.
176 CHAPTER 4 Systemic diseases

Induction therapy Consider

• Prednisolone 30–60 mg/m2 once a • Single dose of IV CYC
day (1–2 mg/kg) for 4 weeks, 750–1000 mg/m2 if previously
weaning over next 6–8 weeks given oral CYC for induction
(depending on response to Rx) to of remission
0.3–0.7 mg/kg on alternate days; • Methylprednisolone
or IV methylprednisolone 30 mg/kg 30 mg/kg (max. 1 g) IV x3
(max. 1g) for 3 consecutive days Failed • 5- or 10-day course of daily
followed by oral prednisolone as induction 2-volume plasma exchange
above with 4.5% HAS
• CYC 2–3 mg/kg PO once a day for • 2nd course of oral CYC
2–3/12 or 500–1000 mg/m2 IV 2 mg/kg once a day for
(max. 1.2 g) once a month for 2 weeks
6 months (reduce dose if renal or
• IVIG 2 g/kg
hepatic failure). Aspirin 1–2 mg/kg
once a day (or dipyridamole • Biologic agent:
2.5 mg/kg BD if aspirin • Anti-TNF therapy
contraindicated) • Rituximab

Post induction (maintenance) phase:

18 months to 3 yr for PAN; may
Major relapse
require prolonged Rx in some
whilst on
vasculitic syndromes
maintenance
• Azathioprine 2–3 mg/kg PO once therapy
a day (start 3–5 days after stopping
PO CYC; 10 days after IV CYC):
consider measuring TPMT first
• Prednisolone 0.2–0.5 mg/kg Notes:
alternate days (daily if ongoing 1. 2nd-line maintenance agents
disease activity) 1. MMF
• Aspirin 1–2 mg/kg once a day or 2. Ciclosporin
dipyridamole 2.5 mg/kg twice a 3. MTX
day 4. Colchicine
2. Consider sperm
• Consider ranitidine or proton cryopreservation for all
pump inhibitor post-pubertal males receiving
CYC
3. For monitoring of
complications of therapy
• Minor relapse: i oral refer to Table 4.2
prednisolone 4. Beware neutropenia as
• Recurrent minor relapses or prednisolone dose is weaned
‘grumbling vasculitis’: consider during maintenance phase of
IV pulsed methylprednisolone therapy
and/or switch to 2nd-line 5. Miscellaneous vasculitides
maintenance therapy such as Behçet’s may require
colchicine and/or thalidomide
6. Treatment with biological
agents in select individuals
who fail to respond to
Stopping treatment standard induction therapy
• Usually withdrawn slowly over (see separate guidelines).
6 months if no relapse for 7. Epoprostenol (prostacyclin)
12 months 1–20 ng/kg/min IV for
incipient gangrene
• Recommend stopping azathioprine
8. Other agents with as yet
first over 3 months, followed by unproven efficacy in
gradual taper of prednisolone over childhood vasculitis:
next 3 months leflunamide; DSG

Fig. 4.1 Standard vasculitis therapy (excluding crescentic glomerulonephritis).

 THE STANDARD TREATMENT OF CHILDHOOD VASCULITIS 177

Crescentic GN on
renal biopsy

Pauci-immune on Granular deposits on

Linear IgG staining on immunofluorescence immunofluorescence—
immunofluorescence —consider indicative of immune
microscopic complex disease
polyangiitis or ‘renal-
limited vasculitis’—
Anti GBM + may be ANCA + Electron microscopy

• Plasma exchange for Treatment as per Treat specific disorders (refer

10–14 days (2 volume, vasculitis algorithm to relevant protocols):
4.5% HAS)—or until above, but consider • HSP
anti GBM Ab disappears using plasma • IgA nephropathy
• Pulsed IV methyl exchange as 1st-line • Post streptococcal
prednisolone 30 mg/kg induction therapy • SLE
(max. 1 g) x3, then oral in conjunction • Membranoproliferative GN
prednisolone 2 mg/kg with steroid • Membranous GN
once a day (weaned over and CYC
2 months then stop)
• CYC 2 mg/kg PO once a
day for 2 months, or IV at
500 mg/m2 monthly
(reduced dose because of
renal failure), possibly
increasing by 250 mg/m2 per
month (response dependent)
to maximum of 1000 mg/m2
(max. 1.2 g) for 6 months
Consideration of biologic
therapy:
• Rituximab
Failed • Anti-TNF therapy
Consider prolonging therapy if
remission Refer to specific protocols
Anti GBM still detectable

Fig. 4.2 Guidelines for treatment of crescentic glomerulonephritis (note early

diagnosis and starting therapy is of major importance).
178 CHAPTER 4 Systemic diseases

Table 4.3 Recommendations for indication and choice of biologic

therapy for primary systemic vasculitis of the young based on published
experience1
Vasculitis Indication for biologic agent Proposed first choice
type of biologic agent
ANCA- Critical organ or life-threatening disease Rituximab or other B cell
associated which has failed to respond to standard depleting monoclonal
vasculitis vasculitis therapy or concerns regarding antibody
cumulative CYC dose.
Polyarteritis Failed therapy with standard agents or Rituximab or anti-TNFA*†
nodosa concern regarding cumulative CYC dose
Behçet’s Recalcitrant and severe disease; Anti-TNFA (infliximab,
disease alternative to thalidomide adalimumab or etanercept)
CYC, cyclophosphamide; *Authors have more experience with infliximab than etanercept
for PAN, although etanercept has been used in individual cases of childhood PAN; †no firm
recommendation is made regarding first choice of biologic for PAN.
1
Adapted from Eleftheriou D, Melo M, Marks SD, et al. Biologic therapy in primary systemic
vasculitis of the young. Rheumatology 2009; 48:978–86.

Further reading
Eleftheriou D, Melo M, Marks SD, et al. Biologic therapy in primary systemic vasculitis of the
young. Rheumatology 2009; 48:978–86.
 HENOCH–SCHÖNLEIN PURPURA 179

Henoch–Schönlein purpura
Introduction
• Henoch-Schönlein purpura (HSP), the commonest systemic vasculitis
in childhood is predominantly a small-vessel, non-granulomatous
leucocytoclastic vasculitis of unknown aetiology.
• Reported by Heberden (1801), Willan (1808), Schönlein (1832), and
Henoch (1874).
• Also called anaphylactoid purpura (1948).
• Classification criteria are palpable purpura in a predominantly lower
limb distribution with at least 1 of 4 of:
• Diffuse abdominal pain.
• Any biopsy showing IgA deposition (mandatory criterion if rash is
atypical).
• Arthritis and/or arthralgia.
• Haematuria and/or proteinuria.
• Variable and often relapsing course without specific laboratory findings
with 1/3 of children having symptoms up to a fortnight, another 1/3 up
to 1 month and recurrence of symptoms within 4 months of resolution
in 1/3.
• Henoch–Schönlein nephritis (HSN) accounts for 1.6–3% of all
childhood cases of end-stage renal failure (ESRF) in the UK.
Epidemiology
• Commoner in Caucasian and Asian populations and boys:
• 4:5 ratio of 1.5–2:1.
• 50% present before the age of 5yr, 75% present before the age
of 10yr.
• Incidence of 10–20.4 (mean of 13.5) per 100,000 children.
• 22.1 per 100,000 children under 14yr of age.
• 70.3 per 100,000 children aged 4–7yr.
• Almost 20× rarer in adults.
• 0.8 cases per 100,000 adults.
• More severe in adults.
• Seasonal variation (commoner in winter) with infectious triggers.
• Associations with bacteria (e.g. Group A beta-haemolytic
streptococci) and viruses (hepatitis, CMV, HSV, human parvovirus
B19, coxsackie, and adenovirus), and some cases after vaccination
described.
Immunopathology
• Type III hypersensitivity reaction with immune complex.
• IgA deposition: galactose deficient IgA may contribute to this.
• Alternate pathway complement activation.
• Associated C2 deficiency.
• Vasculitis of small blood vessels with diffuse angiitis.
• Perivascular exudate of leucocytes.
• Polygenic inheritance with renal involvement associated with HLA-B35,
IL-1B (–511) T allele, and IL-8 allele A.
180 CHAPTER 4 Systemic diseases

Systemic involvement
Dermatological
• All patients have purpura but skin involvement may not be present at
time of initial presentation.
• Generally symmetrical purpura involving lower limbs and buttocks but
can spread to upper limbs (rarely abdomen, chest or face).
• Urticaria and angio-oedema can occur.
Gastrointestinal
• Commonly occurs (68% of patients).
• Abdominal pain precedes rash by 1–14 days in 43% of patients.
• Presents with intermittent colicky abdominal pain, vomiting with
or without haematemesis or melaena (faecal occult blood may be
positive) as a result of haemorrhage into gut wall.
• Involvement may result in intussusception, appendicitis, cholecystitis,
pancreatitis, GI haemorrhage, ulceration, infarction, or perforation.
Rheumatological
60% of patients will have joint involvement with arthritis and/or arthralgia
usually affecting the knees and ankles resulting in pain, swelling and d range
of movement.
Renal
• 25–60% of patients will have renal involvement with HSN:
• 76% will develop within 4 weeks of disease onset.
• 97% will develop within 3 months of disease onset.
• Most cases are usually asymptomatic which necessitates screening up
to 6 months after last recrudescence of rash or HSP symptoms with
<10% having significant involvement requiring referral for consideration
of renal biopsy (Fig. 4.3).
• Microscopic haematuria without proteinuria is benign.
• 82% have normal renal function after 23yr.
• Good prognosis with isolated haematuria and mild proteinuria with
mild histological changes as less than 5% will develop chronic kidney
disease (CKD) within 10–25yr.
• Improved renal prognosis in children <7yr.
• Severe disease indicated by increasing proteinuria, development of
nephrotic syndrome and/or renal failure.
• 20% of patients with acute mixed nephritic and nephrotic syndrome
progress to ESRF.
• 44–50% develop hypertension or CKD.
• Histological pattern is identical to IgA nephropathy and includes
focal segmental proliferative glomerulonephritis and rapidly
progressive crescentic glomerulonephritis (Table 4.4).
Other
Patients may present with orchitis, severe pulmonary haemorrhage, and/or
cerebral vasculitis (which may respond to immunosuppression combined
with plasmapheresis).
 HENOCH–SCHÖNLEIN PURPURA 181

Treatment
• Symptomatic treatment with rest and analgesia.
• No role of antibiotics unless suspected or proven infection.
• Prophylactic corticosteroid therapy at commencement of HSP does
not prevent renal or GI involvement.
• However, corticosteroids do seem to be effective in treating these
complications and severe facial and/or scrotal haemorrhagic oedema.
• Patients with severe renal involvement may require other
immunosuppressive agents, antiproteinuric and antihypertensive agents.

Table 4.4 ISKDC classification of Henoch–Schönlein nephritis

ISKDC grade Pathoanatomical findings
I Minimal alterations
II Mesangial proliferation
III A Focal proliferation or sclerosis with <50% crescents
III B Diffuse proliferation or sclerosis with <50% crescents
IV A Focal proliferation or sclerosis with 50–75% crescents
IV B Diffuse proliferation or sclerosis with 50–75% crescents
VA Focal proliferation or sclerosis with >75% crescents
VB Diffuse proliferation or sclerosis with >75% crescents
VI Membranoproliferative glomerulonephritis
ISKDC=International Study of Kidney Diseases in Children.
 182
W1–W4: weekly GP* review

CHAPTER 4
General paediatrician Discuss with nephrologist if:
(BP, EMU dipstick) Baseline: • Hypertension
Hypertension/macroscopic • Wt, Ht, BP, urine dipstick • Abnormal renal function
haematuria/proteinuria • EMU UP:UC • Macroscopic haematuria—5 days
• U&E, creat, albumin • Nephrotic syndrome:
• FBC, clotting UP:UC>250 mg/mmol plasma albumin<25 g/l oedema
W5–W12: fortnightly

Systemic diseases
GP* review (BP, EMU dipstick) • ASOT antiDNAse B Consider • Acute nephritic syndrome:
• C3, C4 AIP, ANCA, lgs Haematuria/proteinuria/oedema, hypertension/oliguria
Hypertension/macroscopic • Thereafter (pending results), Or if persisting abnormalities with:
haematuria/proteinuria weekly:
• Persistent proteinuria:
• EMU UP:UC • UP:UC>250 mg/mmol for 4 weeks
6–12: month GP* review • BP and weight monitoring
(BP, EMU dipstick) • UP:UC>100 mg/mmol for 3 months
• Clinical assessment • UP:UC>50 mg/mmol for 6 months

No renal
Hypertension/macroscopic
involvement
Microscopic haematuria haematuria/proteinuria
Indications for consideration of renal biopsy:
Hypertension/macroscopic 1. Acute nephritic syndrome/ARF
Discharge 2. Nephrotic syndrome/nephrotic range proteinuria (UP:UC>250 mg/mmol)
haematuria/proteinuria
for 4–6 weeks
Annual GP review (BP, EMU dipstick)

* Review in primary care/with local paediatrician according to local arrangements NB children with recurrent episodes should monitored as for the first episode

Fig. 4.3 Clinical pathway for investigation and referral for renal biopsy in HSN: Reproduced with permission from Tizard EJ, Hamilton-Ayres MJJ.
Henoch–Schönlein purpura. Arch Dis Child Educ Pract Ed 2008; 93:1–8.AIP, auto-immune profile; ANCA, anti-neutrophil cytoplasmic Abs; ARF, acute renal
failure; ASOT, anti-streptolysin O titre; BP, blood pressure; C3,C4, complement C3 and C4; EMU, early morning urine; GP, general practitioner; Ht, height;
U&E, urea and electrolytes; Wt, weight; UP:UC, urine protein:creatinine ratio.
 KAWASAKI DISEASE 183

Kawasaki disease
Kawasaki disease (KD) is a self-limiting vasculitic syndrome that predomi-
nantly affects medium- and small-sized arteries. It is the 2nd commonest
vasculitic illness of childhood (the commonest being HSP) and it is the
leading cause of childhood acquired heart disease in developed countries.
Pathogenesis and epidemiology
• Pronounced seasonality and clustering of KD cases have led to the hunt
for infectious agents as a cause. However, so far no single agent has
been identified.
• The aetiology of KD remains unknown but it is currently felt that
one or more widely distributed infectious agents evoke an abnormal
immunological response in genetically susceptible individuals, leading to
the characteristic clinical presentation of the disease.
• KD has a world-wide distribution with a 4 preponderance, an ethnic
bias towards Asian and in particular Japanese or Chinese children, some
seasonality, and occasional epidemics.
• The incidence of KD is rising world-wide, including the UK. The current
reported incidence in the UK is 8.1/100,000 children aged <5yr. This
may reflect a truly rising incidence or i clinician awareness.
Clinical features
The principal clinical features of KD are:
• Fever persisting for 5 days or more.
• Peripheral extremity changes (reddening of the palms and soles,
indurative oedema, and subsequent desquamation).
• A polymorphous exanthema.
• Bilateral conjunctival injection/congestion.
• Lips and oral cavity changes (reddening/cracking of lips, strawberry
tongue, oral and pharyngeal injection), and
• Acute non-purulent cervical lymphadenopathy.

• For the diagnosis of KD to be established 5 of the 6 clinical features

should be present.
• Patients with <5 or 6 principal features can be diagnosed with KD when
coronary aneurysm or dilatation is recognized by two-dimensional (2D)
echocardiography or coronary angiography.
• The cardiovascular features are the most important manifestations of the
condition with widespread vasculitis affecting predominantly medium-
size muscular arteries, especially the coronary arteries. Coronary artery
involvement occurs in 15–25% of untreated cases with additional cardiac
features in a significant proportion of these including pericardial effusion,
electrocardiographic abnormalities, pericarditis, myocarditis, valvular
incompetence, cardiac failure, and myocardial infarction.
• Of note, irritability is an important sign, which is virtually universally
present although not included in the diagnostic criteria.
• Another clinical sign that may be relatively specific to KD is the
development of erythema and induration at sites of BCG inoculations.
The mechanism of this sign is thought to be cross reactivity of T cells
184 CHAPTER 4 Systemic diseases

in KD patients between specific epitopes of mycobacterial and human

heat shock proteins.
• An important point worthy of emphasis is that the principal symptoms
and signs may present sequentially such that the full set of criteria may
not be present at any one time. Awareness of other non-principal signs
(such as BCG scar reactivation) may improve the diagnostic pick-up
rate of KD.
• Other clinical features include: arthritis, aseptic meningitis, pneumonitis,
uveitis, gastroenteritis, meatitis and dysuria, and otitis.
• Relatively uncommon abnormalities include hydrops of the gallbladder,
GI ischaemia, jaundice, petechial rash, febrile convulsions, and
encephalopathy or ataxia, macrophage activation syndrome, and
syndrome of inappropriate anti-diuretic hormone secretion (SIADH).
Differential diagnosis
Conditions that can cause similar symptoms to KD and must be considered
in the differential diagnosis include:
• Scarlet fever
• Rheumatic fever
• Streptococcal or staphylococcal toxic shock syndrome
• Staphylococcal scalded skin syndrome
• Systemic JIA
• Infantile PAN
• SLE
• Adenovirus, enterovirus. Epstein–Barr virus, CMV, parvovirus, influenza
virus infection
• Mycoplasma pneumoniae infection
• Measles
• Leptospirosis
• Rickettsiae infection
• Adverse drug reaction
• Mercury toxicity (acrodynia)
• Lymphoma—particularly for IVIg resistant cases.
Investigations
In cases of suspected KD the following investigations should be considered:
• FBC and blood film.
• ESR.
• CRP.
• Blood cultures.
• ASOT and anti-DNase B.
• Nose and throat swab, and stool sample for culture (superantigen
toxin typing if Staphylococcus aureus and/or beta-haemolytic
streptococci detected).
• Renal and liver function tests.
• Coagulation screen.
• Autoantibody profile (ANA, ENA, RF, ANCA).
• Serology (IgG and IgM) for Mycoplasma pneumoniae, enterovirus,
adenovirus, measles, parvovirus, Epstein–Barr virus, cytomegalovirus.
• Urine MC&S.
 KAWASAKI DISEASE 185

• Dip test of urine for blood and protein.

• Consider serology for rickettsiae and leptospirosis if history suggestive.
• Consider CXR.
• ECG.
• 2D echocardiography to identify coronary artery involvement acutely
and monitoring changes long term.
• Coronary arteriography has an important role for delineating detailed
anatomical injury, particularly for children with giant coronary artery
aneurysms (>8mm), where stenoses adjacent to the inlet/outlet of the
aneurysms are a concern. Note that the procedure may need to be
delayed until at least 6 months after disease onset since there could
be a risk of myocardial infarction if performed in children with ongoing
severe coronary artery inflammation.
Treatment (Fig. 4.4)
The treatment of KD comprises of:
• IVIg at a dose of 2g/kg as a single infusion over 12h (consider splitting
the dose over 2–4 days in infants with cardiac failure).
• IVIg should be started early preferably within the first 10 days of the
illness. However, clinicians should not hesitate to give IVIg to patients
who present after 10 days if there are signs of persisting inflammation.
• Aspirin 30–50mg/kg/day in 4 divided doses.
• The dose of aspirin can be reduced to 2–5mg/kg/day when the
fever settles (disease defervescence). Aspirin at antiplatelet doses is
continued for a minimum of 6 weeks.
• If the symptoms persist within 48h or there is disease recrudescence
within 2 weeks a 2nd dose of IVIg at 2g/kg over 12h should be
considered.
• However, IVIg resistance occurs up to 20% of cases.
• When a patient fails to respond to a 2nd dose of IVIg, consider IV
pulsed methylprednisolone at 15–30mg/kg daily for 3 days to be
followed by oral prednisolone 2mg/kg/day once a day weaning over
6 weeks. Some clinicians are increasingly using corticosteroids after
disease recrudescence following one dose of IVIg based on the results
of a recent study. This remains an area of controversy, but seems
rational since this is associated in most cases with rapid resolution of
inflammation.
• In refractory cases infliximab, a human chimeric anti-TNFA monoclonal
antibody, given IV at a single dose of 6mg/kg has been reported to be
effective, and is increasingly used for IVIg resistant cases. Considering
that rapid and effective interruption of inflammation is a p target of
KD therapy, TNFA blockade may be a logical step following one failed
dose of IVIg, particularly in very active disease with evidence of early
coronary artery dilatation.
• Echocardiography should be repeated at 2 weeks and 6 weeks from
initiation of treatment (refer to paediatric cardiology).
• If the repeat echocardiogram shows no coronary artery abnormalities
(CAAs) at 6 weeks, aspirin can be discontinued and lifelong follow-up
at least every 2yr should be considered.
186 CHAPTER 4 Systemic diseases

• In cases of CAA <8mm with no stenoses present, aspirin should be

continued until aneurysms resolve.
• If CAA >8mm and/or stenoses is present, aspirin at a dose
of 2–5mg/kg/day should be continued lifelong. The combination
of aspirin and warfarin therapy in these patients with giant aneurysms
has been shown to d the risk of myocardial infarction.
• In patients who develop CAA, echocardiography and ECG should be
repeated at 6-monthly intervals and an exercise stress test considered.
• Other specific interventions such as PET scanning, addition of calcium
channel blocker therapy, and coronary angioplasty should be organized
at the discretion of the paediatric cardiologist.
Outcome
• Treatment with IVIg and aspirin reduces CAA from 25% for untreated
cases to 4–9%.
• IVIg resistance occurs in approximately 20%, and is associated with a
higher risk of CAA.
• The overall outlook of children with KD is good, with the acute
mortality rate due to myocardial infarction having been reduced
to <1% by i alertness of the clinicians to the diagnosis and prompt
treatment.
• Nonetheless the disease may contribute to the burden of adult
cardiovascular disease and cause premature atherosclerosis, an area of
active ongoing research.
 Establish diagnosis of Kawasaki diseasea

• IVIG 2g/kg as a single infusion over 12 h (consider Seek expert advice to

splitting the dose over 2–4 days in infants with consider:
cardiac failure)
• Aspirin 30–50 mg/kg /day in 4 divided doses • 2nd dose of IVIG at 2 g/kg over 12 h
• Perform echocardiography, and ECG • Pulsed IV methyl prednisolone
• Aspirin 2–5 mg/kg/day when fever settled (disease at 15–30 mg/kg daily for 3 days to
defervescence) continuing for a minimum of 6 weeks No disease defervescence be followed by oral prednisolone
within 48 h, or disease 2 mg/kg/day once a day weaning over
recrudescence within 2 6 weeks—seek expert advice
weeks • Infliximab (6 mg/kg) for refractory
Disease defervescence cases-seek expert advice

• bRepeat echocardiography at 2 weeks and 6 weeks

No coronary artery CAA <8 mm, no stenoses cCAA >8 mm, and/or stenoses
abnormalities (CAAs)
• Continue aspirin until aneurysms resolve • Lifelong aspirin 2–5 mg/kg/day
• Stop aspirin at 6 weeks • Warfarin (with initial full heparinization
Notes:
• Consider lifelong follow- • Repeat echocardiography & ECG at aTreatment can be commenced before full
6-monthly intervals to prevent paradoxical thrombosis)

KAWASAKI DISEASE
up at least every 2 years • Consider coronary angiography 5 days of fever if sepsis excluded; treatment
• Discontinue aspirin if aneurysms resolve
• Consider exercise stress test if multiple (after at least 6 months from disease should also be given if the presentation is
aneurysms onset) and exercise stress testing >10 days from fever onset
• Repeat echocardiography & ECG at bRefer to paediatric cardiologist
• Specific advice re: minimizing atheroma cOther specific interventions such as PET
risk factors, and consider lifelong follow-up 6-monthly intervals
• Specific advice re: minimizing atheroma scanning, addition of calcium channel
risk factors blocker therapy, and coronary angioplasty at
• Lifelong follow-up discretion of paediatric cardiologist.

Fig. 4.4 Guideline for the management of Kawasaki disease.

187
188 CHAPTER 4 Systemic diseases

The anti-neutrophil cytoplasmic

antibody (ANCA)-associated vasculitides
Background
• The ANCA-associated vasculitides (AAV) are:
• Wegener’s granulomatosis (WG)
• Microscopic polyangiitis (MPA)
• Churg–Strauss syndrome (CSS) and
• Renal limited vasculitis (previously referred to as idiopathic
crescentic glomerulonephritis).
• Although rare, the AAV do occur in childhood.
Definitions of AAV
Definitions for each of the AAV describing the salient major clinical
and laboratory features are given here. These are not the same as clas-
sification criteria, which (for WG) are provided in a separate section on
classification.
• WG: granulomatous inflammation involving the respiratory tract and
necrotizing vasculitis affecting small- to medium-size vessels
• MPA: necrotizing vasculitis, with few or no immune deposits, affecting
small vessels; necrotizing arteritis involving small- and medium-
sized arteries may be present; pulmonary capillaritis often occurs.
Clinically, it often presents with rapidly progressive pauci-immune
glomerulonephritis, in association with perinuclear ANCA (pANCA,
MPO-ANCA) positivity.
• CSS: an eosinophil-rich and granulomatous inflammation involving the
respiratory tract and necrotizing vasculitis affecting small- to medium-
sized vessels; there is an association with asthma and eosinophilia.
• Renal limited: rapidly progressive glomerulonephritis, often with ANCA
positivity (usually MPO-ANCA) but without other organ involvement.
Pathogenesis
• It is not known why patients develop ANCA in the first instance.
• When ANCA are present, the most accepted current model
of pathogenesis proposes that ANCA activate cytokine-primed
neutrophils, leading to bystander damage of endothelial cells and an
escalation of inflammation with recruitment of mononuclear cells.
• However, other concomitant exogenous factors and genetic
susceptibility appear to be necessary for disease expression.
Clinical features of WG
From a clinical perspective WG may be broadly considered as having 2 forms:
• Predominantly granulomatous form with mainly localized disease, and
• Florid, acute small vessel vasculitic form characterized by severe
pulmonary haemorrhage and/or rapidly progressive vasculitis or other
severe vasculitic manifestation.
These 2 broad presentations may coexist or present sequentially in
individual patients.
 ANCA-ASSOCIATED VASCULITIDES 189

Organ specific involvement includes:

• Upper respiratory tract:
• Epistaxis.
• Otalgia, and hearing loss (conductive and/or sensorineural); chronic
otitis media; mastoiditis.
• Nasal septal involvement with cartilaginous collapse results in the
characteristic saddle nose deformity (Fig. 4.5).
• Chronic sinusitis.
• Glottic and subglottic polyps and/or large- and medium-sized airway
stenosis.
• Lower respiratory tract manifestations include (singly or in
combination):
• Granulomatous pulmonary nodules with or without central
cavitation.
• Pulmonary haemorrhage with respiratory distress, frank
haemoptysis, and/or evanescent pulmonary shadows (CXR).
• Interstitial pneumonitis.
• Renal involvement: typically a focal segmental necrotizing
glomerulonephritis, with pauci-immune crescentic glomerular changes.
The clinical manifestations associated with this lesion are:
• Hypertension.
• Significant proteinuria.
• Nephritic and nephrotic syndrome.
• Other protean manifestations of renal failure.
• Ophthalmological disease: retinal vasculitis, conjunctivitis, episcleritis,
uveitis, optic neuritis. Unilateral or bilateral proptosis may be caused by
granulomatous inflammation affecting the orbit (pseudotumour) (Fig. 4.5).
• Malaise, fever, weight loss or growth failure, arthralgia, and arthritis.
• Other manifestations include: peripheral gangrene with tissue loss, and
vasculitis of the skin, gut (including appendicitis), heart, central nervous
system and/or peripheral nerves (mononeuritis multiplex), salivary
glands, gonads, and breast.
Investigations (also see b Vasculitis investigation, p 172)
• WG is commonly associated with a cytoplasmic staining pattern of
ANCA by IIF, and ELISA reveals specificity against PR3 (PR3-ANCA).
• MPA and renal limited AAV are typically associated with pANCA by IIF
and with MPO-ANCA specificity on ELISA.
• ANCA-negative forms of WG, MPA, renal limited vasculitis, and CSS
are well described in children.
• While the diagnostic value of ANCA is without question important,
the value of ANCA for the longitudinal monitoring of disease activity is
probably unreliable in many patients with WG.
• Tissue diagnosis, in particular renal biopsy but also biopsy of skin,
nasal septum, or other tissue, can be important diagnostically
for diagnosing all of the AAV and can help stage the disease for
therapeutic decision-making.
190 CHAPTER 4 Systemic diseases

• Other commonly observed non-specific findings include:

• Mild normochromic normocytic anaemia together with a
leucocytosis and thrombocytosis.
• Elevated ESR and CRP.
• Raised immunoglobulins (polyclonal IgG).
• Laboratory manifestations relating to renal involvement include:
• Dipstick haematuria and proteinuria positive.
• Raised urinary spot protein creatinine ratio.
• Raised serum creatinine and other associated laboratory features of
renal failure.
• Chest radiography may be abnormal but high resolution CT chest has
better sensitivity for demonstrating pulmonary infiltrates or discrete
nodular and/or cavitating lesions
• Plain x-ray or CT sinuses for sinusitis

(a) (b)

Fig. 4.5 Right orbital and characteristic saddle nose deformity in Wegener’s granu-
lomatosis.
 ANCA-ASSOCIATED VASCULITIDES 191

Treatment of AAV
(See b BSPAR guidelines for treatments used in paediatric rheumatology,
p 415.)
When considering therapy, it is useful to remember that most evidence
for treatment is derived from adult trials. It is also useful to consider the
different phases of the therapeutic journey for AAV:
• The pre-diagnostic phase: occasionally lasting years. Significant organ
damage can accrue in this phase, or even death.
• Induction of remission phase: typically 3–6 months.
• Maintenance of remission phase: usually 18–24 months.
• Therapy withdrawal phase: not all patients achieve this.
The following general points are worthy of note:
• The key to successful treatment is early diagnosis to limit organ damage.
• Treatment for paediatric AAV is broadly similar to the approach used
in adults and involves corticosteroids, cyclophosphamide, and in some
individuals plasma exchange (particularly for pulmonary capillaritis
and/or rapidly progressive glomerulonephritis—’pulmonary-renal
syndrome’) to induce remission; followed by low-dose corticosteroids
and azathioprine to maintain remission.
• Antiplatelet doses of aspirin can also be considered empirically on the
basis of the i risk of thrombosis associated with the disease process.
• MTX in combination with corticosteroids may have a role for inducing
remission in patients with limited WG.
• Co-trimoxazole is commonly added to therapeutic programmes for
the treatment of WG, particularly in those with upper respiratory tract
involvement, serving both as prophylaxis against opportunistic infection
and as a possible disease-modifying agent.
• Newer immunosuppressive agents and immunomodulatory strategies
such as MMF and rituximab (see the ‘RAVE’ and ‘RITUXIVAS’ trials in
adults), have been reported to be effective at inducing or maintaining
remission in adults with AAV and are increasingly used in children for
recalcitrant disease.
• Anti-TNF therapy is less effective for the treatment of AAV, although has
been used anecdotally in this context with some success in select patients.
Outcome of AAV
• The AAV still carry considerable disease-related morbidity and mortality,
particularly due to progressive renal failure or aggressive respiratory
involvement, and therapy-related complications, such as sepsis.
• The mortality for WG from one recent paediatric series was 12% over
a 17yr period of study inclusion. The largest paediatric series of patients
with WG reported 40% of cases with chronic renal impairment at
33 months of follow-up despite therapy.
• Mortality in paediatric patients with MPA during follow-up has been
reported to be 0–14%.
• For CSS in children, the most recent series quotes a related mortality
of 18%
Further reading
Brogan P, Eleftheriou D, Dillon M. Small vessel vasculitis. Pediatr Nephrol 2010; 25:1025–35.
192 CHAPTER 4 Systemic diseases

Polyarteritis nodosa (PAN)

Background
• PAN is a necrotizing vasculitis associated with aneurysmal nodules
along the walls of medium-sized muscular arteries.
• Despite some overlap with smaller-vessel disease, PAN appears to be
a distinct entity and, in adults in Europe and the USA, has an estimated
annual incidence of 2.0–9.0/million.
• Although comparatively rare in childhood, it is the most common form
of systemic vasculitis after HSP and KD.
• Peak age of onset in childhood is 7–11yr, often with a 4 preponderance.
• Classification criteria for PAN are not diagnostic criteria, and meeting
classification criteria is not equivalent to making a diagnosis in an individual
patient—see rest of section and b Vasculitis classification, p 168.
Aetiology
• Unknown: possible interaction between infection and aberrant host
response.
• There may be genetic factors that make individuals vulnerable to PAN
and other vasculitides, but these are not yet defined.
• There are reports of PAN occurring in siblings that add weight to
this hypothesis, but there are no detailed genetic studies.
• There is a well-recognized association of PAN and familial
Mediterranean fever in parts of the world where this is common.
• There are data to support roles for hepatitis B and reports of a higher
frequency of exposure to parvovirus B19 and cytomegalovirus in PAN
patients compared with control populations.
• HIV has also been implicated, and PAN-like illnesses have been
reported in association with cancers and haematological malignancies.
However, in childhood, associations between PAN and these infections
or other conditions are rare.
• Bacterial superantigens may play a role in some cases.
• Occasional reports suggest immunization as a cause, but this is not
proven.
Clinical features of PAN
A diagnosis is made by considering all clinical features in a patient, only
some of which may be classification criteria. Clinical manifestations (and
investigation findings) can be very confusing, especially in the early phase
of the disease with absence of conclusive diagnostic evidence.
• The main systemic clinical features of PAN are malaise, fever, weight
loss, skin rash, myalgia, abdominal pain, and arthropathy.
• Skin lesions are variable, and may masquerade as those of HSP or
erythema multiforma. The cutaneous features described in a recent
international classification exercise for PAN in children occurred
commonly and were defined as follows:
• Livedo reticularis—purplish reticular pattern usually irregularly
distributed around subcutaneous fat lobules, often more prominent
with cooling.
• Skin nodules—tender subcutaneous nodules.
 POLYARTERITIS NODOSA (PAN) 193

• Superficial skin infarctions—superficial skin ulcers (involving skin and

superficial subcutaneous tissue) or other minor ischaemic changes
(nailbed infarctions, splinter haemorrhages, digital pulp necrosis).
• Deep skin infarctions—deep skin ulcers (involving deep
subcutaneous tissue and underlying structures), digital phalanx or
other peripheral tissue (nose and ear tips) necrosis/gangrene.
• Renal manifestations such as haematuria, proteinuria, and
hypertension.
• GI features and abdominal pain are relatively common and include:
• Indeterminate intestinal inflammation: intestinal inflammation
without characteristic histological features of either ulcerative colitis
or Crohn’s disease. NB: routine mucosal gut biopsies rarely detect
overt vasculitis since the small- and medium-sized arteries lie below
the mucosa.
• GI haemorrhage (upper and lower).
• Intestinal perforation.
• Panreatitis.
• Neurological features such as focal defects, hemiplegia, visual loss,
mononeuritis multiplex; and organic psychosis may be present.
• Other important clinical features include: ischaemic heart and testicular
pain. Rupture of arterial aneurysms can cause retroperitoneal and
peritoneal bleeding, with perirenal haematomata being a recognized
manifestation of this phenomenon, although this is rare.
Differential diagnosis
• Other p vasculitides: HSP, WG, MPA, KD. See b relevant chapters,
HSP p 179, WG p 188, MPA p 188, KD p 183.
• Autoimmune or autoinflammatory diseases:
• JIA—particularly the systemic form.
• JDM.
• SLE.
• Undifferentiated connective tissue disease.
• Sarcoidosis.
• Behçet’s disease.
• Infections:
• Bacterial, particularly streptococcal infections, and sub-acute
bacterial endocarditis.
• Viral—many: specifically look for hepatitis B/C, CMV, EBV,
parvovirus B19 and consider HIV.
• Malignancy: lymphoma, leukaemia, and other malignancies can
mimic PAN.
Diagnostic laboratory and radiological investigation
Blood tests
• Anaemia, polymorphonuclear leucocytosis, thrombocytosis, i ESR and
CRP.
• Platelets are hyperaggregable.
• Circulating immune complexes or cryoglobulins may be present.
• Positive hepatitis B serology in children is unusual in association with
PAN but can occur.
194 CHAPTER 4 Systemic diseases

• ANCA are not thought to play a major part in the causality of PAN,
but there are reports demonstrating their presence in some adults and
children with PAN.
• The presence of cytoplasmic ANCA (C-ANCA) with antibodies
to proteinase 3 in a patient suspected of having PAN makes it
mandatory to eliminate WG as a diagnosis.
• Likewise, a significant titre of perinuclear ANCA (P-ANCA) with
antibodies to myeloperoxidase would necessitate steps to eliminate
microscopic polyangiitis (MPA) as the diagnosis.
Tissue biopsy
• Biopsy material is diagnostically important, especially skin or muscle,
although tissue biopsy has overall low diagnostic sensitivity since the
disease is patchy and vasculitis can be easily missed.
• The characteristic histopathological changes of PAN are fibrinoid
necrosis of the walls of medium or small arteries, with a marked
inflammatory response within or surrounding the vessel (Fig. 4.6).
• However, absence of such changes would not exclude the diagnosis,
as the vasculitic features are variable and affected tissue may not have
been sampled.
• Renal biopsy is usually not helpful and carries a greater risk than usual
of bleeding and the formation of arteriovenous fistulae.
Radiological tests
• The most valuable investigative procedure is catheter-selective visceral
digital subtraction arteriography to include flush aortogram and
selective renal, hepatic, and mesenteric arteriography. This should be
performed and interpreted only by those with expertise in this test in
paediatric patients.
• Arteriography findings include aneurysms, segmental narrowing,
and variations in the calibre of arteries, together with pruning of the
peripheral renal vascular tree (Fig. 4.7).
• Treatment with prior corticosteroids will alter the arteriography
and can result in false negatives.
• Non-invasive arteriography such as CT or MR angiography (CTA/
MRA) are not as sensitive as catheter arteriography for the
detection of medium-sized vessel vasculitis such as PAN (discussed
later in this list).
• Consider formal cerebral arteriography if clinical and MRI features
suggest cerebral vasculitis (see b Cerebral vasculitis, p 209).
• Indirect evidence of the presence of medium-size artery vasculitis
affecting renal arteries may be obtained by demonstrating patchy
areas within the renal parenchyma of d isotope uptake on Tc-99m
dimercaptosuccinic acid (DMSA) scanning of the kidneys.
• Magnetic resonance angiography (MRA) usually fails to detect
aneurysms of small- and medium-sized muscular arteries, although it
may demonstrate large intra- and extrarenal aneurysms and stenoses/
occlusions of the main renal arteries, and areas of ischaemia and
infarction.
• A caveat is that MRA may overestimate vascular stenotic lesions—
CTA may also reveal larger aneurysms and arterial occlusive lesions
 POLYARTERITIS NODOSA (PAN) 195

and demonstrate areas of renal cortical ischaemia and infarction,

but at the expense of high ionizing radiation exposure with less
sensitivity than catheter arteriography.
• Echocardiography can be useful for the identification of pericarditis,
valve insufficiency, myocarditis, or coronary artery abnormalities.

Fig. 4.6 (See also Colour plate 1.) PAN—skin biopsy.

Pruning of peripheral
arteries

Small aneurysms

Large aneurysm

Perfusion defect Arterial cut-off

Fig. 4.7 PAN—renal arteriogram.

196 CHAPTER 4 Systemic diseases

Treatment
(See b The standard treatment of childhood vasculitis, p 174, for specific
drug doses and protocols, and b BSPAR guidelines for treatments used
in paediatric rheumatology, p 415.)
• In most patients, it is appropriate to treat aggressively to induce
remission (typically 3–6 months), followed by less aggressive therapy
to maintain remission (typically 18–24 months).
• In those presenting with mild predominantly cutaneous disease (see
b Cutaneous PAN, p 198), corticosteroid alone may be appropriate, with
careful monitoring of clinical and laboratory parameters as this is weaned.
• Induction therapy: high-dose corticosteroid with an additional
cytotoxic agent such as cyclophosphamide:
• Cyclophosphamide is usually given as pulsed monthly IV injections
for up to 6 months or for shorter periods in children if remission is
achieved.
• Oral cyclophosphamide 2mg/kg per day for 2–3 months is an
alternative, although for other vasculitides the IV regimen has been
shown to have a more favourable therapeutic index.
• Aspirin 1–5mg/kg/day as an antiplatelet agent may be considered.
• Maintenance therapy: once remission is achieved, therapy with daily
low-dose prednisolone and oral azathioprine is frequently used for up
to 18–24 months.
• Other maintenance agents include MTX, MMF, and ciclosporin.
• Some advocate alternate day low-dose prednisolone in the
maintenance phase with the intention of limiting steroid toxicity
such as growth impairment although data to support this approach
are limited.
• Adjunctive plasma exchange can be used in life-threatening situations
(see b Vasculitis treatment, p 174).
• Biologic agents such as infliximab or rituximab have been used for
those unresponsive to conventional therapy.
• Treatment response can be assessed using a modified Birmingham
Vasculitis Activity Score (BVAS); the paediatric version of BVAS,
or ‘PVAS’, is currently still being validated; and by monitoring of
conventional acute phase reactants, urinary sediment, BP, and growth.
Outcome
• PAN, unlike some other vasculitides such as WG, appears to be a
condition in which permanent remission can be achieved. Relapses can
occur, but despite these, a real possibility of cure can be anticipated.
• However, if treatment is delayed or inadequate, life-threatening
complications can occur due to the vasculitic process.
• Severe complications, especially infections, can occur from
immunosuppressive treatment.
• In comparison with the almost 100% mortality rate in the pre-
steroid era, mortality rates as low as 1.1% were reported in a recent
retrospective multicentre analysis. However, this may not truly reflect
mortality in circumstances of severe disease because 30% of patients in
that series were considered to have predominantly cutaneous PAN.
• A mortality rate of 10% was recently recorded from a major tertiary
referral centre seeing predominantly children with aggressive advanced
disease.
 POLYARTERITIS NODOSA (PAN) 197

• Late morbidity can occur years after childhood PAN from chronic vascular
injury, possibly resulting in premature atherosclerosis. This remains a
cause for concern and an area of ongoing research.
Further reading
Dillon MJ, Eleftheriou D, Brogan PA. Medium-size-vessel vasculitis. Pediatr Nephrol 2010;
25(9):1641–52.
Ozen S, Anton J, Arisoy N, et al. Juvenile polyarteritis: results of a multicenter survey of 110 children.
J Pediatr 2004; 145:517–22.
198 CHAPTER 4 Systemic diseases

Cutaneous polyarteritis nodosa (cPAN)

Background and clinical features
• cPAN is a form of vasculitis affecting small- and medium-sized vessels
limited to the skin.
• It is characterized by the presence of fever; subcutaneous nodular,
painful, non-purpuric lesions with or without livedo reticularis
occurring predominantly in the lower extremities; with no systemic
involvement (except for myalgia, arthralgia, and non-erosive arthritis).
• In a recent international survey of childhood vasculitis, approximately
1/3 of children identified as having PAN were categorized as cPAN.
• The clinical course is characterized by periodic exacerbations and
remissions that may persist for many years.
• Skin biopsy shows features identical to systemic PAN.
• ANCA are usually negative and the condition is often associated with
serological or microbiological evidence of streptococcal infection.
• There is debate as to whether the condition should be classed as a
separate entity or as a part of the spectrum of PAN since a proportion
of cases appear to evolve into full-blown PAN.
Treatment of cPAN
• NSAIDs may suffice.
• Some require moderate doses of oral steroids.
• When streptococcal infection is implicated, penicillin may be effective.
• Some recommend continuing prophylactic penicillin throughout
childhood, as relapses are common and occur in up to 25% of cases
in association with further streptococcal infections.
• When there is a lack of response to the above, or concerns about
possible steroid toxicity, other agents may be considered:
• IVIg has been successfully used.
• Alternatives with anecdotal success for cPAN therapy include
colchicine, hydroxychloroquine, azathioprine, MTX, dapsone
(beware haemolytic anaemia as a relatively common and severe side
effect of this agent), cyclophosphamide, and pentoxifylline.
Outcome of cPAN
• A minority of patients experience a persistence of cutaneous lesions
through childhood.
• Overall it is uncommon for the condition to progress to PAN.
• However, it is mandatory for such patients to remain under surveillance
to detect any evidence of developing systemic disease that would be an
indication for intensification of treatment as per that of PAN.
Further reading
Dillon MJ, Eleftheriou D, Brogan PA. Medium-size-vessel vasculitis. Pediatr Nephrol 2010;
25(9):1641–52.
Ozen S, Anton J, Arisoy N, et al. Juvenile polyarteritis: results of a multicenter survey
of 110 children. J Pediatr 2004; 145:517–22.
 TAKAYASU ARTERITIS 199

Takayasu arteritis
Background
• Takayasu arteritis (TA) is an idiopathic, chronic inflammation of the
large vessels, affecting the aorta and its major branches.
• The disease is named after Mikito Takayasu, a Japanese
ophthalmologist, who first described an association between retinal
peri-papillary arterio-venous anastomoses and absent radial pulses.
• Other names include ‘pulseless disease’, aortic arch syndrome, or
idiopathic aortoarteritis.
• Classification criteria are provided in the b Vasculitis classification, p 168.
Epidemiology
• TA is more prevalent in Asian and African populations, and is rarer
in Europe and North America. Most studies report an incidence
of 1–3 per million/year in Caucasian populations—in Japan the
estimated incidence is up to 100 times higher: 1 per 3000/year.
• In adult studies there is a 9:1 5 predominance. In children however
gender ratios vary amongst different studies. A recent study from
Southeast Asia and Africa report a 5:4 ratio of 2:1.
• TA is a rare vasculitis in children. Age of onset may range from infancy
to middle age. The peak period of onset is in the 3rd decade of life.
Aetiopathogenesis
• The cause remains unknown.
• Genetic factors may play a role, and there are several reports of
familial TA including in identical twins.
• HLA associations include: HLA-A10, HLA-B5, HLA-Bw52,
HLA-DR2, and HLADR4 in Japan and Korea; HLA B22 association
has been described in the US population.
• The presence of HLA Bw52 has been associated with coronary
artery and myocardial involvement and worse prognosis.
• TA is described in association with RA, ulcerative colitis, and other
auto-immune diseases suggesting an autoimmune mechanism for the
pathogenesis of the disease.
• Circulating anti-aortic endothelial cell antibodies in patients with TA
have been reported; their exact role however is yet to be determined.
Histopathology
• TA is characterized by granulomatous inflammation of all layers of the
arterial vessels (panarteritis).
• Inflammation of the tunica intima is followed by intimal hyperplasia
leading to stenoses or occlusions.
• Destruction of tunica elastica and muscularis cause dilatation and
aneurysms.
• Endothelial cell damage leads to a prothrombotic tendency.
• The lesions have a patchy distribution.
• The initial finding is neutrophil infiltration of the adventitia and
cuffing of the vasa vasorum with proliferation and penetration of the
latter within the tunica intima.
200 CHAPTER 4 Systemic diseases

• Various mixed chronic inflammatory cells including T cells

contribute to granuloma formation in the tunica media and
adventitia mediated by the release of interferon-G and TNFA.
• Later, the adventitia and media are replaced by fibrous sclerotic
tissue and the intima undergoes acellular thickening, thus narrowing
the vessel’s lumen and contributing to ischaemia.
• In paediatric series:
• Occlusions and stenoses were present in 98% of the patients while
aneurysms were only seen in 15.6% of the patients.
• Post-stenotic dilatations were present in 34% of cases.
• Lesions are most commonly seen in the subclavian arteries (90%),
the common carotids (60%), the abdominal aorta (45%), the aortic
arch (35%), and the renal arteries (35%); pulmonary arteries are
involved in 25% of the cases.
Clinical features
Acute phase
Non-specific features of systemic inflammation (systemic, pre-stenotic
phase). In children, up to 65% of TA present abruptly with systemic features:
• Pyrexia, malaise, weight loss, headache, arthralgias and/or myalgias.
• Rash (erythema nodosum, pyoderma gangrenosum).
• Arthritis.
• Myocarditis causing congestive heart failure (± hypertension) or valvular
involvement (aortic valve most commonly affected followed by mitral
valve).
• Myocardial infarction.
• Hypertension.
• Hypercoagulable state: thrombotic tendency.
Chronic phase
Features and signs s to vessel occlusion and ischaemia (stenotic phase):
• Asymmetric or absent pulses; a measured difference of >10mmHg on
4-limb BP monitoring is likely to indicate arterial occlusion.
• Systemic hypertension: commonest finding.
• Arterial bruits.
• Congestive heart failure s to hypertension and/or aortic regurgitation
when the valve is affected.
• Angiodynia: localized tenderness on palpation of the affected arteries.
• Claudication.
• Coronary angina.
• Mesenteric angina presenting with abdominal pain and diarrhoea from
malabsorption.
• Recurrent chest pain from chronic dissection of the thoracic aorta or
pulmonary arteritis.
• Pulmonary hypertension.
CNS involvement
May be attributed to ischaemia ± hypertension: dizziness, or headache;
seizures; transient ischaemic attacks, stroke.
 TAKAYASU ARTERITIS 201

Eye involvement
• Diplopia, blurry vision, amaurosis, visual field defect. Fundoscopy
findings include:
• Retinal haemorrhage
• Micro aneurysms of the peripheral retina
• Optic atrophy.
Renal involvement
• Renal hypertension s to renal artery stenosis with s glomerular
damage.
• Chronic renal failure.
• Amyloidosis.
• Glomerulonephritis (GN) has been described in association with
TA: IgA nephropathy; membranoproliferative GN; crescentic GN;
mesangioproliferative GN.
Differential diagnoses
• Other vasculitides including medium- and small-vessel vasculitis:
Kawasaki disease; polyarteritis nodosa; Wegener’s granulomatosis is
also recognized cause of aortitis.
• Infections:
• Bacterial endocarditis
• Septicaemia without true endocarditis
• TB
• Syphilis
• HIV
• Borelliosis (Lyme disease)
• Brucellosis (very rare).
• Other autoimmune or autoinflammatory diseases: SLE; rheumatic
fever; sarcoidosis; Blau’s syndrome.
• Non-inflammatory large vessel vasculopathy of congenital cause.
Treatment with immunosuppression will be ineffective and could be
harmful:
• Fibromuscular dysplasia
• William’s syndrome
• Congenital coartctation of the aorta
• Congenital mid-aortic syndrome
• Ehler–Danlos type IV
• Marfan syndrome
• Neurofibromatosis type I.
• Other: post radiation therapy.
Laboratory investigations (also see b Vasculitis
investigation, p 172)
• Normochromic normocytic anaemia, leucocytosis, thrombocytosis;
raised ESR, raised CRP—may not be present in chronic (stenotic)
phase of illness.
• Elevated transaminases and hypoalbuminaemia.
• Deranged renal function tests in cases of renal involvement.
• Poyclonal hyperglobulinaemia.
202 CHAPTER 4 Systemic diseases

Further tests required to exclude other causes mimicking

TA or for disease monitoring
• Regular 4-limb BP measurement (preferably with a manual
sphygnomanometer).
• In cases of significant peripheral artery stenosis, central BP
measurements may be required.
• Renal function tests, urinalysis.
• Auto-immune screen.
• Baseline immunology tests including lymphocyte subsets, nitroblue
tetrazolium (NBT) test.
• Blood cultures (acute phase).
• Mantoux test or interferon gamma releasing assays (IGRA).
• Syphilis serology.
• Tissue biopsy, rarely performed but should include microbiological
culture, 16S and 18S ribosomal PCR if available to exclude bacterial and
fungal infection respectively.
Imaging
• An echocardiogram (and ECG) and a CXR are simple 1st-line imaging
tests and should be performed in all cases where TA is suspected.
• Conventional digital subtraction catheter arteriography is the method
used routinely for obtaining a generalized arterial survey when TA
is suspected, but essentially only provides ‘lumenography’ with no
imaging of arterial wall pathology.
• MRI and MRA, and CTA, or a combination of these may help accurately
diagnose TA and monitor disease activity, and (for MRA and CTA)
provide cross-sectional aortic wall images allowing detection of arterial
wall thickness and intramural inflammation.
• MRI and MRA are gradually replacing conventional angiography in
most centres and are useful for diagnosis and follow-up.
• However, MR lacks sensitivity in evaluation of the distal aortic
branches, and may overestimate the degree of arterial stenosis,
especially in small children.
• Cardiac MRI is increasingly employed to look for valvular
involvement and/or myocarditis.
• Angiographic findings form the basis of one classification for TA
(Takayasu Conference, 1994):
• Type I. Classic pulseless type that affects blood vessels of aortic arch;
involving the brachiocephalic trunk, carotid, and subclavian arteries.
• Type II. Affects middle aorta (thoracic and abdominal aorta).
• Type III. Affects aortic arch and abdominal aorta.
• Type IV. Affects pulmonary artery in addition to any of the above
types.
• Type V. Includes patients with involvement of the coronary arteries.
• Doppler USS:
• High resolution duplex US technology is a valuable tool in
evaluation and follow-up of TA.
• This modality offers high-resolution imaging of the vascular wall and
can be useful for the detection of i wall thickness.
 TAKAYASU ARTERITIS 203

18
• F-FDG-PET co-registered with CTA can be a powerful technique
combining information relating to the metabolic activity of the arterial
wall (18F-FDG uptake detected using PET) with detailed lumenography
(CTA) thus providing information on disease activity and anatomy. This
technique is not available in all centres, and carries a high radiation
exposure limiting its use for routine follow-up of disease activity.
Diagnosis
The diagnosis of TA is based on clinical and laboratory findings of systemic
inflammation and/or of large-vessel ischaemia, raised and angiographic
demonstration of lesions in the aorta or its major branches, with exclu-
sion of other causes listed in the differential diagnosis.
Treatment (also see b Vasculitis treatment, p 174)
• Early diagnosis and aggressive treatment is fundamental for the
outcome of the disease, although new lesions can continue to develop
even in the presence of clinical remission in 60% of cases.
• Vascular damage already established in some patients will usually not
respond to medical treatment.
• Medical management of TA includes: high-dose corticosteroids,
usually in combination with MTX or cyclophosphamide for induction
of remission. Maintenance agents include MTX, azathioprine, or more
recently MMF. There are case reports of benefit with the use of
infliximab.
Hypertension
• At least 40% of TA patients are hypertensive.
• Optimal control of hypertension is essential in the longer term since it
is a major contributor to long-term morbidity.
• Medical treatment of hypertension in TA may be challenging since
renovascular hypertension may not respond to medical therapy alone.
Seek specialist advice from a paediatric nephrologist.
• Revascularization procedures may be required.
Revascularization and other surgical procedures
Techniques include:
• Angioplasty (including percutaneous transluminal angioplasty; or patch
angioplasty), arterial bypass procedures, endarterectomy, arterial
stenting, cardiac valve repair/replacement
• Surgery during the acute phase of the disease carries significant risk of
re-occlusion and procedural complication, so should be deferred until
the acute phase is treated
• These techniques should only be undertaken in centres with expertise.
Indications for revascularization include:
• Hypertension from stenotic coarctation of the aorta or renovascular
disease.
• End-organ ischaemia or peripheral limb ischaemia.
• Cerebral ischaemia.
• Aortic or other arterial aneurysms, or aortic regurgitation.
204 CHAPTER 4 Systemic diseases

Prognosis
• There is usually a significant time lag (approximately 18 months,
occasionally much longer) between initial presentation and diagnosis
of TA in children. Arterial damage accrues during this pre-diagnostic
phase, and influences prognosis.
• The course of the disease is variable, but most patients experience
new lesions over time. Typically vascular inflammation persists even in
patients thought to be clinically in remission.
• Aortic valve insufficiency and congestive heart failure are reported in 25%.
• Vascular claudication limiting activities occurs in up to 40%.
• Long-term mortality ranges from 10–30%:
• The main causes of death include congestive cardiac failure,
myocardial infarction, aneurysm rupture, or renal failure.
• After commencement of treatment approximately 60% will respond to
corticosteroids while 40% will relapse when these are tapered off.
• Poor prognostic factors are severe aortic regurgitation, severe
hypertension, cardiac failure, and aneurysms.
Further reading
Gulati A, Bagga A. Large vessel vasculitis. Paed Nephrol 2010 25:1037–48.
 BEHÇET’S DISEASE 205

Behçet’s disease
Behçet’s disease (BD) is a multisystem disease with a classic triad of recurrent
oral aphthous ulcers, genital ulcers, and uveitis, which may also affect the skin,
joints, GI tract, and CNS. Both small- and large-vessel vasculitis occurs, and in
some patients there is a propensity to arterial and venous thromboses. Many
now regard BD within the spectrum of autoinflammatory diseases.
Pathophysiology
• Unknown.
• BD has geographical variability, being more commonly found in the
Mediterranean, Middle East, and Japan than in the USA and the UK.
• Likely auto inflammatory condition with possible environmental
triggers in genetically susceptible individuals.
• HLA-B51 is significantly associated with BD.
• Recent studies also implicate the familial Mediterranean fever gene
(MEFV) as an additional genetic susceptibility factor in some patients.
• Other genetic associations including MICA and TNF genes are thought
to be the result of linkage disequilibrium with the HLA-B 51 gene, and
are thus not causally associated.
• Pathergy: the skin hyper-reactivity response or pathergy test is not
pathognomic of BD but may be an important diagnostic indicator.
Early or pathergy-induced cutaneous lesions in BD show a neutrophilic
vascular reaction. This may be vascular or perivascular with a diffuse
dermal neutrophilic infiltrate. Longstanding lesions may show a
lymphocytic vasculitis. A typical pathergy test protocol is described
later in this section.
Diagnostic criteria
The presence of recurrent oral aphthae (>3 times in one year), plus 2 of
the following in the absence of other systemic diseases:
• Recurrent genital aphthae
• Eye lesions (uveitis or retinal vasculitis)
• Skin lesions
• Positive pathergy test.
Clinical features
Almost any organ can be involved due to the vasculitis affecting both arteries
and veins of all sizes:
• Oral ulcers—painful, occur singly or in crops, affect lips, gingivae,
buccal mucosa and tongue, last 1–2 weeks.
• Genital ulcers—affect scrotum in 4, vulva in 5, may result in scarring.
• Cutaneous lesions may be erythema nodosum-like, papulopustular,
vesicular, abscesses, erythema multiforme-like eruptions, folliculitis,
thrombophlebitis. Less commonly are pyoderma gangrenosum-type
lesions, palpable purpura, purulent bullae, bullous necrotizing vasculitis
and Sweet syndrome-like lesions.
• Ocular—iridocyclitis affecting the anterior segment or chorioretinitis,
optic papillitis, retinal thrombophlebitis, arteritis.
• Arthralgia and arthritis usually affecting knees and ankles.
206 CHAPTER 4 Systemic diseases

• GI—nausea, vomiting, diarrhoea, weight loss. May mimic inflammatory

bowel disease. Ulcers may occur anywhere but usually affect ileum and
caecum.
• Neurological—headaches, paralysis, hyperparaesthesia, dementia,
behavioural disorders, psychiatric problems, cerebellar signs, peripheral
nerve palsies. Underlying pathology includes meningoencephalitis,
cerebral venous thrombosis and ‘benign intracranial hypertension’,
parenchymal inflammatory brain disease without obvious vasculitis
(‘neuro-Behçet’s’), and true arterial vasculitis.
• Cardiovascular—myocarditis, pericarditis.
• Vascular—arterial or venous occlusions, varices, aneurysms.
• Pulmonary arterial aneurysms are of particular concern in adults
with BD, and can present with haemoptysis mimicking pulmonary
embolism, but anticoagulation can be fatal in this situation so
beware this diagnostic pitfall.
• Respiratory—pulmonary infiltrates may be associated with pulmonary
haemorrhage.
• Nephro-urological—haematuria and proteinuria (which may cause
nephrotic syndrome), urethritis, orchitis, and epididymitis.
• Haematological—thrombocytopenia, neutropenia.
• Systemic—malaise, anorexia, weight loss.
Investigations
• FBC, CRP, ESR, routine clinical chemistry, thrombophilia screen (to
exclude other causes of thrombosis), urinalysis.
• IgG, A, and M to exclude common variable immunodeficiency or other
cause of low immunoglobulins (can present with oral ulcers).
• ANA, ds-DNA antibodies, RF, C3 and C4, ANCA, anticardiolipin
antibodies, and antiphospholipid antibody are negative or normal but
should be performed to exclude other autoimmune disease.
• Consider IgD and genetic testing for hyper IgD syndrome in atypical
cases of suspected BD.
• Skin pathergy test—A 20-gauge needle is inserted obliquely 5mm into
the skin of the anterior forearm. The presence of erythema, papules,
erythematous papules, or pustules at 24–48h indicate a positive test result.
• MRI of the brain including MR arteriography and venography should
be considered early for those with headaches to exclude neuro-BD or
cerebral venous thrombosis.
Treatment
Evidence in children is limited. EULAR recommendations for treatment in
adults are based on limited evidence and were not designed with children
in mind, but provide a framework for the management of children. See
Table 4.5.
General principles of treatment of BD in the young.
• Tailored to the individual and reflecting organ involvement and severity.
• Least toxic therapies should be tried first.
• Oral ulcers should be treated with topical agents before considering
systemic drugs.
• Anti-TNFA agents (etanercept, infliximab, and adalimumab) are
increasingly used before thalidomide in children.
 BEHÇET’S DISEASE 207

• Thalidomide is still used on a named-patient basis for children and

adolescents with BD, typically for severe and resistant oral and/
or genital ulceration, although it may also benefit other systemic
symptoms of BD. Peripheral neuropathy and teratogenicity limit its use.
• Suggested dosing regimen: 0.5–1mg/kg (maximum 100mg) orally
once a week at nighttime (to avoid daytime drowsiness). i dose by
adding another daily dose every week until symptoms controlled or
until dose of 1mg/kg daily (whichever achieved first).
• Exclude pregnancy, and check peripheral nerve conduction studies
prior to starting thereafter repeating nerve conduction 3–6-monthly
(or after every 10g of total accumulative dose). Stop immediately if
symptoms of neuropathy (e.g. numbness, tingling) develop.
• Remember that teratogenic risk also applies to mothers/female
carers who handle the drug- full precautions always must be advised.
• The L isomer lenalidomide may be less toxic but have greater (or
comparable) efficacy, but experience in paediatric BD is limited.
Prognosis—variable
• Eye disease can result in long-term visual impairment.
• Course may be worse in children than adults.
• 4 tend to be more severely affected.
• Reported mortality of 3%, usually due to vascular complications.
Patient and parental support, including information sheets for children and
adults can be found at: M http://www.behcets.org.uk.

Table 4.5 EULAR 2008 recommendations for the treatment of

Behçet’s disease*
Recommendation Category
of evidence
1. Eye involvement: any patient with BD and inflammatory eye Ib
disease affecting the posterior segment should be on a treatment
regimen that includes azathioprine and systemic corticosteroids
2. Refractory eye involvement: if the patient has severe eye Ib/IIb
disease defined as >2 lines of drop in visual acuity on a 10/10
scale and/or retinal disease it is recommended that either
ciclosporin or infliximab be used in combination with azathioprine
and corticosteroids; alternatively interferon-A with or without
corticosteroids could be used instead
3. Major vessel disease: there is no firm evidence to guide the III
management of major vessel disease in BD. For the management
of acute deep vein thrombosis immunosuppressive agents
such as corticosteroids, azathioprine, cyclophosphamide, or
ciclosporin are recommended. For the management of
pulmonary and peripheral arterial aneurysms, cyclophosphamide
and corticosteroids are recommended
(continued )
208 CHAPTER 4 Systemic diseases

Table 4.5 (Contd.)

Recommendation Category
of evidence
4. Anticoagulation: there are no controlled data on, or evidence IV
of benefit from uncontrolled experience with anticoagulants,
antiplatelet,or anti-fibrinolytic agents and management of deep vein
thrombosis or for the use of anticoagulation for the arterial lesions
of BD
5. Gastrointestinal involvement: there is no evidence-based III
treatment that can be recommended for the management of GI
involvement of BD. Agents such as sulfasalazine, corticosteroids,
azathioprine, TNFA antagonists and thalidomide should be tried
first before surgery, except in emergencies
6. Joint involvement: in most patients with BD, arthritis can be Ib
managed with colchicine
7. Neurological involvement: there are no controlled data III
to guide the management of CNS involvement in BD. For
parenchymal involvement agents to be tried may include
corticosteroids, interferon-A, azathioprine, cyclophosphamide,
MTX, and TNFA antagonists. For dural sinus thrombosis
corticosteroids are recommended
8. Ciclosporin neurotoxicity: ciclosporin should not be used in III
BD patients with CNS involvement unless necessary for intra
ocular inflammation
9. Mucocutaneous involvement: the decision to treat skin and Ib
mucosal involvement will depend on the perceived severity
by the doctor and patient. Mucocutaneous involvement
should be treated according to the dominant or codominant
lesions present.
Topical measures (i.e. topical corticosteroids) should be the 1st-line
treatment for isolated oral and genital ulcers
Acne like lesions are usually of cosmetic concern only. Thus, topical
measures as used in acne vulgaris are sufficient
Colchicine should be preferred when the dominant lesion is
erythema nodosum
Leg ulcers in BD might have different causes. Treatment should be
planned accordingly
Azathioprine, IFNA and TNFA antagonists may be considered in
resistant cases
CNS, central nervous system; IFN, interferon; TNF, tumour necrosis factor.
Categories of evidence: Ia: meta-analysis of randomized controlled trials; Ib: randomized
controlled trial; IIa: controlled study without randomization; IIb: quasi-experimental study; III:
non-experimental descriptive studies such as comparative, correlation and case-control studies;
IV: expert committee reports or opinion or clinical experience of respected authorities or both.
*
Adapted from: Hatemi G, Silman A, Bang D, et al. EULAR recommendations for the
management of Behcet disease. Ann Rheum Dis 2008; 67:1656–62.
 CENTRAL NERVOUS SYSTEM VASCULITIS IN CHILDREN 209

Central nervous system vasculitis

in children
Background
• Central nervous system (CNS) vasculitis in children is an increasingly
recognized inflammatory brain disease that continues to pose great
diagnostic and therapeutic challenges. CNS vasculitis may occur as a p
disease that is isolated to the CNS (primary angiitis of the CNS, PACNS) or
as a s manifestation of an underlying systemic condition.
• The most common systemic inflammatory diseases and infections that
may cause s CNS vasculitis are summarized in Box 4.1.
Diagnostic criteria
Diagnostic criteria for PACNS in adults were proposed by Calabrese et al.
in 1992 and they include the following:
• An acquired neurological deficit.
• Angiographic and/or histopathological features of angiitis within the
CNS, and
• No evidence of systemic condition associated with these findings.
Although a paediatric case definition of PACNS in children (cPACNS) has
not been proposed, most reported cases fit the Calabrese et al. criteria.
cPACNS is broadly subdivided into two forms of the disease:
• Large–medium-vessel vasculitis (further divided into progressive
and non-progressive, according to angiographic evidence of disease
progression 3 months after diagnosis).
• Small-vessel vasculitis.
Epidemiology
The true incidence of cPACNS is difficult to establish as the condition is
rare and there is lack of consensus on diagnostic criteria.
Clinical features
The clinical presentation of cPACNS is heterogeneous, with some chil-
dren presenting with a rapidly progressive neurological deficit, whereas
others have a slowly evolving disease course over weeks or months. Most
common presenting features (in isolation or in various combinations)
include the following:
• Acute severe headache.
• Focal neurological deficit.
• Gross motor deficit, hemiparesis.
• Cranial nerve involvement and optic neuritis.
• Concentration and cognitive deficits, behaviour, and personality changes.
• New onset of seizures.
• Acute loss of consciousness and symptoms of i intracranial pressure
caused by either intracerebral or subarachnoid haemorrhage, or a CNS
mass lesion.
• Movement abnormalities.
• Constitutional symptoms (fever, fatigue, weight loss) are uncommon
but can present in a minority of patients with small vessel vasculitis.
210 CHAPTER 4 Systemic diseases

Box 4.1 Secondary central nervous system vasculitis in

children
Inflammatory disorders
• Systemic lupus erythematosus
• Behçet’s disease
• Sjögren’s syndrome
• Juvenile dermatomyositis
• Scleroderma
• Inflammatory bowel disease.
Systemic vasculitides
• Polyarteritis nodosa
• Kawasaki disease
• Henoch–Schönlein purpura
• ANCA-associated vasculitides: Wegener’s granulomatosis; microscopic
polyangiitis; Churg–Strauss syndrome.
Infectious/post-infectious
• Bacterial:
• Streptococcus pneumoniae
• Salmonella spp.
• Mycoplasma pneumonia
• Mycobacterium tuberculosis
• Treponema pallidum
• Viral:
• Hepatitis C virus
• Cytomegalovirus
• Epstein–Barr virus
• HIV
• Parvovirus B19
• Varicella zoster virus
• Enterovirus
• Spirochete
• Borrelia burgdorferi.
• Fungal:
• Candida albicans
• Aspergillus.
Other
• Malignancy
• Graft-versus-host disease.
 CENTRAL NERVOUS SYSTEM VASCULITIS IN CHILDREN 211

Differential diagnosis
CNS vasculitis can be mimicked in both its clinical presentation and radio-
logical manifestations by a number of inflammatory and non-inflammatory
disorders, summarized in Box 4.2.
Investigations
The aim of the diagnostic work-up in patients with suspected cPACNS is
to exclude causes of s CNS vasculitis or other neuro-inflammatory condi-
tions that can present in the same way. In general there are no consistent
or reliable laboratory abnormalities in children with cPACNS, and normal
inflammatory markers by no means exclude an active vasculitic process in
the CNS. The following investigations should be considered:
Laboratory investigations
• FBC and blood film, haemoglobin electrophoresis/sickle cell screen if
patient is black or of Mediterranean ethnicity.
• ESR and CRP.
• ANA/dsDNA, ENA.
• ANCA.
• C3 and C4 levels.
• IgG, IgA, IgM.
• Clotting screen.
• Full thrombophilia screen including:
• Lupus anticoagulant and anticardiolipin antibodies
• Protein C
• Protein S
• Antithrombin
• APC resistance ratio
• Factor V Leiden
• Methylenetetrahydrofolate reductase (MTHFR) and prothrombin
G20210A gene mutations
• Von Willebrand antigen levels may be elevated
• CSF studies to establish cell count, protein levels, and exclude
infection. CSF opening pressure should also be measured; CSF
oligoclonal bands (simultaneous serum testing for total IgG required)
• Plasma amino-acids and plasma homocysteine
• Plasma lactate and ammonia
• Alpha galactosidase A (to exclude Fabry’s disease)
• Serology for mycoplasma, Borrelia burgdorferi, VZV.
• Ophthalmology assessment to look for retinal vasculitis, infection, or
other inflammatory disease.
• Echocardiogram and ECG.
• Imaging studies:
• MRI brain/spine and MRA.
• MRI in cPACNS reveals areas of acute ischemia in a vascular
distribution when large–medium vessels are affected. In cases
of small-vessel disease, the lesions may be multifocal and not
necessarily conform to a specific vascular distribution.
• The parenchymal lesions may involve both grey and white matter,
and meningeal enhancement has also been described.
212 CHAPTER 4 Systemic diseases

• Diffusion weighted imaging (DWI) identifies areas of ischaemia in

large-vessel disease.
• MRA provides an assessment of the vasculature and may reveal
beading, tortuosity, stenosis, and occlusion of the vessels.
• Conventional catheter arteriography (CA) continues to be the
radiological gold-standard for identifying cerebrovascular changes
in patients with suspected CNS vasculitis and is more sensitive than
MRA at detecting distal lesions that affect small calibre vessels, and
for lesions in the posterior part of the brain.
• Brain biopsy for confirmation of vasculitis should be considered
in difficult cases, but is rarely performed in children due to the
invasiveness of the procedure. It should however be strongly
considered in cases of high clinical suspicion but with negative
arteriography findings or in cases of poor response to therapy.
• Biopsy findings characteristically reveal segmental, non-
granulomatous, intramural infiltration of arteries, arterioles,
capillaries, or venules.
• Non-lesional biopsy may be considered when lesions identified on
imaging are not easily accessible.
Treatment
There are no randomized control trials (RCTs) to guide therapy.
• Current therapeutic recommendations are based on those for systemic
vasculitis (see b Vasculitis therapy, p 174) and include:
• 6 months’ induction therapy with IV cyclophosphamide:
500–1000mg/m2 (max 1.2g) every 3–4 weeks (usually 7 doses);
corticosteroids and antiplatelet doses of aspirin, followed by
• 1–2yr maintenance therapy with azathioprine (1.5–3mg/kg/day),
low dose daily or alternate day corticosteroid, and continuation
of aspirin.
• MMF has also been reported to be effective in some cases to
maintain remission.
• Full anticoagulation may need to be considered on an individual patient
basis.
• Treatment of large-vessel non-progressive disease remains
controversial. There may be a role for steroids and aspirin without
cytotoxic immunosuppression.
Outcome
• A recent study of 62 children with cPACNS suggested a poorer
prognosis for patients presenting with: 1) a neurocognitive dysfunction,
2) multifocal parenchymal lesions on MRI, or 3) evidence of distal
stenoses on arteriography.
• Further long-term follow-up studies are necessary to accurately define
the prognosis of this condition in children.
 CENTRAL NERVOUS SYSTEM VASCULITIS IN CHILDREN 213

Box 4.2 Mimics of CNS vasculitis in children

• Arterial dissection
• Thromboembolic disease (congenital heart disease, inherited
thrombophilia)
• Antiphospholipid syndrome
• Sickle cell disease
• Moyamoya disease (cerebral arteriopathy characterized by
progressive steno-occlusive changes at the terminal portions of the
bilateral internal carotid arteries with arterial collateral vessels at the
base of the brain)
• Fibromuscular dysplasia
• Fabry’s disease
• Sneddon’s syndrome (morphologically fixed livedo reticularis and
cerebrovascular accidents)
• CADASIL (cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy)
• Susac’s syndrome (acute encephalopathy, branch retinal artery
occlusions and sensorineural hearing loss)
• Amyloid angiopathy
• Neurofibromatosis type I
• Hyperhomocysteinaemia
• Drug-exposure (cocaine, amphetamine, methylphenidate)
• Metabolic diseases:
• Mitochondrial diseases
• Leucodystrophies
• Mucopolysaccharidoses
• Multiple sclerosis
• Acute disseminated encephalomyelitis (ADEM)
• Devic’s disease/neuromyelitis optica (CNS demyelinating condition
affecting predominantly the spinal cord and optic nerves characterized
by the presence of aquaporin-4 water channel IgG antibodies)
• Vitamin B12 deficiency
• Rasmussen syndrome (neurological disorder characterized intractable
focal seizures, progressive hemiplegia and increasing cognitive
impairement)
• Sarcoidosis
• Coeliac disease
• 1° and 2° haemophagocytic lymphohistiocytosis (HLH)
• Progressive multifocal leukoencephalopathy (JC virus)
• Lymphoma
• Glioma
• Migraine/vasospasm
• Post radiation therapy for CNS tumour.

Further reading
Elbers J, Benseler SM. Central nervous system vasculitis in children. Curr Opin Rheumatol 2008;
20:47–54.
214 CHAPTER 4 Systemic diseases

Other vasculitides
Background
The EULAR/PReS endorsed consensus criteria for the classification of
childhood vasculitides include a category of “other vasculitides’’ for vas-
culitides where an aetiological process was defined, or in which no other
classification category was appropriate (see b p 168). These include:
• Behçet’s disease
• Vasculitis s to infection (including hepatitis B-associated PAN),
malignancies, and drugs, including hypersensitivity vasculitis
• Vasculitis associated with connective tissue diseases
• Cogan’s syndrome
• cPACNS
• Unclassified vasculitides.
Isolated cutaneous leucocytoclastic vasculitis, and hypocomplementic
urticarial vasculitis are also described in this chapter. Behçet’s disease and
cPACNS are described in their respective chapters.
Vasculitis secondary to infection, malignancies, and drugs,
including hypersensitivity vasculitis
Vasculitis secondary to infection
• Many viruses (HIV, parvovirus B19, cytomegalovirus, varicella-zoster
virus, and human T-cell lymphotropic virus- HTLV1) can be responsible
for systemic vasculitis, the most frequent being hepatitis B virus-related
polyarteritis nodosa (HBV-PAN), even though its incidence has d over
the past few decades.
• Mixed cryoglobulinemia has been shown to be associated with hepatitis
C virus (HCV) infection in adults, but has not been reported in
children.
• Some bacteria, fungi, or parasites can also cause vasculitis, mainly by
direct invasion of blood vessels or septic embolization.
• Effective antimicrobial drugs are mandatory to treat bacterial,
parasitic or fungal infections, while the combination of antiviral agents
(vidarabine, interferon-A) and plasma exchange has been proven to be
effective against HBV-PAN.
Vasculitis secondary to drugs, including hypersensitivity vasculitis
• Therapeutic agents from virtually every pharmacological class have
been implicated in the development of drug-induced vasculitis.
• Typically presents with cutaneous vasculitis alone (palpable purpura,
macules, plaques, bullae and ulcers), low grade fever, arthralgia, and
microcopic haematuria.
• More rarely can present with life-threatening systemic involvement,
which may result in a severe and sometimes fatal illness.
• Withdrawal of the offending agent alone is often sufficient to induce
prompt resolution of clinical manifestations.
• Steroids may be used for systemic involvement and azathioprine or
other immunosuppressants may be appropriate for refractory disease.
 OTHER VASCULITIDES 215

Vasculitis secondary to malignancy

• In some patients, vasculitis occurs during the course of or prior to
malignancies, most often haematological rather than solid tumours.
Evidence of autoantibodies, immune complexes, and complement
consumption is typically absent.
• Vasculitis may also occasionally be a complication of chemotherapy,
radiation therapy, and bone marrow transplantation.
Vasculitis associated with connective tissue diseases
• Vasculitis s to connective tissue disorders in children most commonly
arises in the context of pre-existing SLE, p Sjögren’s syndrome (SS),
systemic sclerosis, relapsing polychondritis, p antiphospholipid syndrome,
juvenile dermatomyositis, or mixed connective tissue (see b specific
chapters on each of these entities, SLE p 223, Sjogren's syndrome
p 277, systemic sclerosis p 260, antiphospholipid syndrome p 279,
mixed connective tissue or overlap syndromes p 275).
• The vasculitis may involve vessels of any size, but small-vessel
involvement is predominant.
• Patterns of involvement vary with the associated underlying disorder,
and range from isolated cutaneous involvement to life-threatening
internal organ involvement.
• When vasculitis occurs in the setting of a pre-existing connective
tissue disorder, it often correlates with disease severity and portends
a poorer prognosis. Prompt recognition and treatment of vasculitis
can dramatically improve the outcome for these patients.
Isolated cutaneous leucocytoclastic vasculitis
• This refers to cutaneous leucocytoclastic vasculitis without systemic
vasculitis or glomerulonephritis.
• Histologically leucocytoclastic vasculitis appears as a neutrophil
infiltration in and around small vessels, with neutrophil fragmentation
(often referred to as ‘nuclear dust’ or leucocytoclasis), fibrin
deposition, and endothelial cell necrosis.
• Treatment may require corticosteroids, colchicine, hydroxychloroquine,
azathioprine, MTX or rarely dapsone (beware severe haemolytic
anaemia and/or methaemoglobinaemia with dapsone).
Hypocomplementaemic urticarial vasculitis syndrome
• Hypocomplementaemic urticarial vasculitis syndrome (HUVS) is
an uncommon immune complex–mediated entity characterized by
urticaria with persistent acquired hypocomplementaemia.
• The disease is extremely rare in the paediatric population.
• In patients with HUVS, systemic findings include leucocytoclastic
vasculitis, angio-oedema, laryngeal oedema, pulmonary involvement
(interstitial lung disease, haemoptysis, pleural effusions), arthritis,
arthralgia, glomerulonephritis, and uveitis.
• Laboratory findings include low levels of C1q, C2, C3, and C4. The
binding of C1q antibodies to immune complexes is thought to be
important in the pathogenesis of renal disease in HUVS.
• Treatment is individualized and is based on disease severity and will
typically include corticosteroids and other immunosuppressive agents
such as azathioprine or cyclophosphamide.
216 CHAPTER 4 Systemic diseases

• Patients may have significant morbidity and mortality, most commonly

caused by chronic obstructive pulmonary disease and acute laryngeal
oedema.
Cogan’s syndrome
• Cogan syndrome is a rare syndrome of:
• Interstitial keratitis.
• Vestibuloauditory symptoms (hearing loss and balance problems).
• Occasionally aortitis.
• The cause is unknown, although autoantibodies and small-vessel
vasculitis have been implicated.
• Typical Cogan’s is characterized by:
• Ocular involvement: primarily interstitial keratitis and occasionally
conjunctivitis, uveitis, or subconjuctival haemorrhage.
• Audiovestibular involvement giving a clinical picture similar to
Ménière’s disease accompanied with progressive hearing loss of
hearing, usually ending in deafness within 1–3 months.
• Other symptoms include fever, loss of weight, cardiac involvement
(aortic insufficiency reported to up to 15% of patients), myalgia,
arthralgia, mucocutaneous manifestations, GI and neurological
involvement.
• The differential diagnosis is:
• Vogt–Koyanagi–Harada syndrome (audiovestibular involvement
with uveitis, vitiligo, alopecia).
• Susac syndrome (retinocochleocerebral vasculopathy, presenting
with acute or subacute encephalopathy, branch retinal artery
occlusions and sensorineural hearing loss as a result of small infarcts
in the brain, retina and cochlea).
• Other vasculitides.
• Relapsing polychondritis.
• SLE or Sjögren’s may cause similar symptoms.
• During attacks patients may have raised inflammatory markers.
Detection of antibodies against corneal or inner ear antigens has been
studied in small case series.
• Treatment includes corticosteroid therapy, while other
immunosuppressants such as MTX, cyclophosphamide have been used
with variable efficacy. Cochlear implantation may ultimately be necessary
for hearing loss, and physiotherapy is required for the vestibular symptoms.
• The course of the disease is variable, with some patients experiencing
episodes of ocular and audiovestibular symptoms at variable intervals
with complete remission in between. In the longer term 790% of
patients suffer severe hearing loss while long-term ocular sequelae
are rare. Systemic involvement is associated with the worst prognosis
and can develop years after the initial onset of symptoms justifying
prolonged close monitoring.
Further reading
Jara LJ, Navarro, C, Medina, G, et al, Hypocomplementemic urticarial vasculitis syndrome Curr
Rheumatol Rep 2009, 11:410–15.
Ozen S. The ‘other’ vasculitis syndromes and kidney involvement. Pediatr Nephrol 2010; 25(9):1633–9.
Grasland A, Pouchot J, Hachulla E, et al, Typical and atypical Cogan’s s syndrome: 32 cases and
review of the literature, Rheumatology 2004; 43:1007–15.
 VASCULITIS MIMICS: NON-INFLAMMATORY VASCULOPATHIES 217

Vasculitis mimics: non-inflammatory

vasculopathies
Background
There are numerous non-inflammatory vasculopathies that may mimic
the clinical, laboratory, radiological, and/or pathological features of the
p vasculitides. Some will have associated musculoskeletal manifestations
and will be referred to the paediatric rheumatologist. Awareness of these
mimics is essential to avoid the use of unnecessary and potentially harmful
immunosuppression and to direct management to the correct underlying
cause of disease. The commonest of these vasculitis mimics are discussed
in this section. Mimics of CNS vasculitis are covered in b p 213.
Fibromuscular dysplasia (FMD)
• FMD is a non-inflammatory vasculopathy leading to stenoses of
small- and medium-sized arteries, sometimes with poststenotic
dilatation resembling aneurysms. It is a major differential diagnosis
for Takayasu disease.
• FMD has been detected in almost every vascular bed although the
most commonly affected are renal arteries (60–75%) followed by
the cervico-cranial arteries (25–30%), non-renal visceral arteries (5%),
and arteries in the extremities (5%). Intracranial arterial poststenotic
dilatations have been reported in 7% of adult patients, but rarely in
children.
• Patients can remain asymptomatic or present with signs of vascular
insufficiency such as hypertension, stroke, abdominal pain, or claudication.
• The pathological classification for FMD is based on the arterial layer
involved. Medial fibroplasia accounts for 80–90% of all cases and is
characterized by a ‘string of beads’ appearance on angiography due to
alternating areas of stenosis and aneurysmal dilatation involving the
mid-to-distal portions of the vessel.
• It can be difficult to differentiate diffuse intimal FMD from large-
vessel vasculitis, since their angiographic appearance can be similar.
Histological examination may be required in these cases.
• Imaging investigations to be considered include:
• Renal ultrasonography and Doppler studies.
• CTA and MRA have been increasingly used for non-invasive imaging
of the vascular tree.
• However, selective catheter arteriography continues to be the
radiological gold standard for delineating the extent of vascular
involvement.
• Cerebral perfusion scans or other measures to exclude cerebral
arterial insufficiency should be carried out before angioplasty or
surgical correction of renal artery stenosis to relieve hypertension,
since a drop in BP can precipitate stroke in this situation.
• The management of hypertension associated with renal artery
FMD involves antihypertensive therapy and revascularization with
percutaneous angioplasty or other revascularization procedures for
patients with significant renal artery stenosis, severe hypertension with
218 CHAPTER 4 Systemic diseases

inadequate response, or intolerance of antihypertensive medication.

Management of dissecting carotid artery due to FMD includes
antiplatelet therapy and percutaneous angioplasty or surgical repair for
patients with signs of cerebral vascular insufficiency.
Vasculopathies involving the TGFB-signalling pathway
Marfan syndrome
• Incidence of Marfan syndrome is reported to be 1 in 10,000.
• Marfan syndrome results from mutations in the fibrillin-1 (FBN1) gene
on chromosome 15, which encodes the glycoprotein fibrillin. Recent
studies have suggested that abnormalities in the transforming growth
factor-beta (TGFB)-signalling pathway may represent a final common
pathway for the development of the Marfan phenotype.
• Affected patients are usually taller and thinner than their family
members. Their limbs are disproportionately long compared with
the trunk (dolichostenomelia). Arachnodactyly, pectus excavatum, or
carinatum are common features (Fig. 4.8).
• Ocular findings include ectopia lentis, flat cornea, cataract, glaucoma,
retinal detachment.
• Cardiovascular involvement is the most serious complication associated
with Marfan syndrome and comprises aortic root dilatation, aortic
dissection involving the ascending aorta, and mitral valve prolapse.
• Patients can also present with spontaneous pneumothorax, stretch marks
(striae atrophicae in the lower back), recurrent or incisional hernia, and
dural ectasia.
Management: seek expert cardiological advice
The paediatric rheumatologist should be aware that evidence now sug-
gests that the vasculopathy of Marfan syndrome is associated with dysreg-
ulation of TGFB, and that this can be blocked using angiotensin II receptor
1 blockade (AT1 antagonists) such as losartan. Animal and human data
have demonstrated that this can significantly slow the progression of
aortic root dilatation and prolong life. Thus early referral to a paediatric
cardiologist is essential. Other management of the vasculopathy under
expert paediatric cardiology supervision may include:
• General measures: moderate restriction of physical activity,
endocarditis prophylaxis, echocardiography at annual intervals.
• Beta-blocker therapy (propanolol 2–4mg/kg/day in divided doses) should
be considered at any age if the aorta is dilated, but prophylactic treatment
may be more effective in those with an aortic diameter of <4cm.
• ACE inhibitors (enalapril 0.08mg/kg/day—up to 5mg) reduce central
arterial pressure and conduit arterial stiffness and may be useful.
• Prophylactic aortic root surgery should be considered when the aortic
diameter at the sinus of Valsalva is >5cm.
 VASCULITIS MIMICS: NON-INFLAMMATORY VASCULOPATHIES 219

Fig. 4.8 Pectus excavatum of moderate severity.

Loeys–Dietz syndrome
• Loeys–Dietz syndrome is considered an autosomal dominant disorder
associated with mutations in either of the TGFB receptors (TGFB
R1/TGFB R2).
• 2 subtypes of Loeys–Dietz syndrome have been identified:
• Loeys–Dietz syndrome type I patients have both craniofacial and
vascular disorders. The most characteristic craniofacial findings
are hypertelorism and broad or bifid uvula or cleft palate, 2 of
the 3 components of the clinical triad that also includes arterial
aneurysms and tortuosity.
• Loeys–Dietz syndrome type II patients may have a bifid uvula but do
not have a cleft palate, craniosynostosis, or hypertelorism.
• Additional manifestations include blue sclera, malar hypoplasia,
exotropia, and retrognathia. Cervical spine instability, pectus deformity,
arachnodactyly, craniosynostosis, scoliosis, and joint laxity are some
of the many musculoskeletal manifestations. Patients may also have
congenital cardiac anomalies (bicuspid aortic valve).
• Due to the high risk of death from aortic aneurysm rupture, patients
should be followed closely to monitor aneurysm formation, which can
then be corrected with vascular surgery.
• The role of TGFB antagonism is currently being explored in this
condition too.
220 CHAPTER 4 Systemic diseases

Ehler–Danlos syndrome (vasculopathic EDS) type IV

• EDS type IV is an autosomal dominant disorder that results from
mutations in the type III pro-collagen gene (COL3A1).
• Although joint and skin laxity is not common, patients often have easy
bruising, thin skin with visible veins, or characteristic facial features (loss
of subcutaneous fat and collagen, referred to as acrogeria).
• Arterial complications may include aortic or other arterial aneurysm,
dissection, and carotico-cavernous sinus fistulae. Patients can present
acutely with life-threatening rupture of the intestines, the gravid uterus,
or other viscera.
• There is currently no preventative treatment for this condition but
close follow-up to monitor aneurysm formation is recommended.
Grange syndrome
• Grange syndrome is an hereditary disorder that is associated with
a variable combination of multiple arterial stenoses and aneurysms,
brachydactyly, and syndactyly of the hands and feet, bone fragility
consistent with a mild form of osteogenesis imperfecta, learning
disability, and cardiac defects (PDA, VSD, bicuspid aortic valve).
• No underlying genetic defect has yet been determined.
Susac’s syndrome
• Susac’s syndrome is a microangiopathy of unclear aetiology that is
more frequently reported in young adult 5.
• Susac’s syndrome is characterized by the typical clinical triad of acute
or subacute encephalopathy, branch retinal artery occlusions, and
sensorineural hearing loss that results from small infarcts in the brain,
retina, and cochlea.
• Typical findings on brain MRI are multiple small white-matter
hyperintensities; grey-matter involvement may also be seen. CSF analysis
usually reveals a lymphocytic pleocytosis and elevated protein levels.
Histological evidence of microangiopathic infarct is seen, without
evidence of vasculitis or thrombosis.
Degos disease (DD)
• DD, also known as malignant atrophic papulosis, is characterized by
thrombo-occlusive vasculopathy affecting the skin and various internal
organs.
• DD has been described in 2 forms: the limited benign cutaneous and
the lethal multiorgan systemic variant.
• In the skin, DD initially manifests with erythematous, pink or red
papules that leave scars with pathognomonic, central, porcelain white
atrophic centres.
• In the systemic form, GI involvement has been reported in the majority
of patients and may manifest as abdominal pain, GI bleeding or bowel
perforation. Central and peripheral nervous system, heart, lung, eye,
pancreas, adrenal gland, and kidney involvement have been described.
• There has been no proven effective treatment for DD. Antiplatelet
agents including aspirin and dipyridamole have been reported to reduce
the formation of new skin lesions but there is no evidence in their role
to prevent systemic complications. Immunosuppressants, anticoagulants,
 VASCULITIS MIMICS: NON-INFLAMMATORY VASCULOPATHIES 221

and plasma exchange have been shown to be ineffective. Since

corticosteroids may worsen other forms of occlusive vasculopathy, they
should be used with caution in DD. Prompt surgical intervention is often
needed for bowel infarction, perforation, or intracranial haemorrhage.
• The systemic form has a poorer prognosis and is usually fatal within the
first 2yr after diagnosis because of major organ involvement.
Livedoid vasculopathy (LV)
• LV is an occlusive vasculopathy characterized by thrombosis and
ulceration of the lower extremities.
• While the aetiology of LV remains unclear, it likely has a prothrombotic
pathogenesis. Factor V Leiden mutation, heterozygous protein C
deficiency, and hyperhomocysteinaemia have been associated with LV.
In addition, plasminogen activator inhibitor (PAI)–1 promoter 4G/4G
genotype has also been linked to the disease.
• Skin biopsies reveal segmental hyalinizing vascular involvement of
thickened dermal blood vessels, endothelial proliferation, and focal
thrombosis without nuclear dust. No true vasculitis is evident.
• The initial clinical findings are typically painful purpuric macules or
papules on the ankles and the adjacent dorsum of the feet. Patients
may have a history of livedo reticularis on their lower legs. The initial
lesions, which often appear in clusters or groups, eventually ulcerate
over a period of months and years and form irregular patterns of
superficial ulcers. When the ulcers finally heal, they leave behind
atrophic porcelain-white scars, which are referred to as ‘atrophie
blanche’.
• Small- and medium-sized vasculitides, such as isolated cutaneous
leucocytoclastic vasculitis and PAN occasionally present with ulceration
resulting in ivory-white, stellate scarring on the lower limbs and may be
difficult to differentiate from LV.
• A number of therapies have been employed with variable effect:
• Corticosteroids in combination with pentoxifyllin have been used
in cases of widespread LV. Pentoxifyllin is believed to enhance the
blood flow in the capillaries, making red blood cells more flexible
and thereby reducing viscosity effectively. However, anecdotally
some report that corticosteroids can worsen the occlusive
vasculopathy associated with LV.
• As thrombogenic mechanisms may be involved in the disease
pathogenesis, anticoagulant therapy (low-molecular-weight heparin,
warfarin) and aspirin are often tried, but with variable efficacy.
• Hyperbaric oxygen therapy has been used in intractable cases of LV
with good effect in some cases.
222 CHAPTER 4 Systemic diseases

Pseudoxanthoma elasticum (PXE)

• PXE is a rare, genetic disorder characterized by progressive
calcification and fragmentation of elastic fibres in the skin, the retina,
and the cardiovascular system, which is termed as elastorrhexia.
• PXE is caused by mutations in the ATP-binding cassette transporter
C6 (ABCC6) also known as multidrug resistance-associated protein 6
(MRP6) gene.
• Patients present with:
• Characteristic skin lesions that can appear during childhood. These
are small, yellow papules of 1–5mm in diameter in a linear or
reticular pattern which may coalesce to form plaques. The skin has a
cobblestone-like appearance. These skin changes are first noted on
the lateral part of the neck and later can involve any part of the body.
• Ocular manifestations: angioid streaks of the retina, which are slate
grey to reddish brown curvilinear bands radiating from the optic disc.
• Cardiovascular manifestations include: calcification of the elastica
media and intima of the blood vessels leading to a variety of physical
findings, mitral valve prolapse.
• Renal artery involvement leads to hypertension.
• Mucosal involvement leading to GI haemorrhage.
• There is currently no treatment available for PXE.
Further reading
Eamonn S. Molloy and Carol A. Langford. Vasculitis mimics. Curr Opin Rheumatol 2008; 20:29–34.
 JSLE: EPIDEMIOLOGY AND AETIOLOGY 223

JSLE: epidemiology and aetiology

• Systemic lupus erythematosus (SLE) is a multisystem autoimmune
disorder characterized by widespread inflammation and damage to any
organ. It is a complex disease with marked heterogeneity, causing mild
to life-threatening disease in any combination of organ systems and is
remitting and relapsing with an unpredictable natural history.
• Approximately 15–20% of patients with lupus present before the age of
18 and form the cohort known as juvenile-onset SLE (JSLE).This group
has a higher severity of disease and accrues more organ damage than
adults (Box 4.3).

Box 4.3 Differences between JSLE and adult-onset SLE

• Children have more severe disease at onset than adults.
• Higher rates of organ involvement and more aggressive clinical course.
• Higher use of corticosteroids and immunosuppressive therapies.
• Accrue more organ damage, related to disease and corticosteroid use.
• Higher mortality rates.
• i incidence of renal, neurological, and haematological disease.
• Effects of disease and treatments on growth and physical and
psychological development.

Epidemiology
• The annual incidence of SLE per 100,000 children and young people
ranges from 0.36–0.8 although this probably underestimates the actual
number as many cases go unrecognized, have mild disease, or do
not fulfil diagnostic criteria. 5:4 ratio varies with age, being 8:1 after
puberty and 4:1 before 10yr of age. JSLE is rare before 5yr of age. The
incidence of SLE appears to be higher in non-white children especially
Black, Hispanic, and Asian children.
• Outcome has improved over recent years from 5yr survival of 60–90%
in the 1980s to nearer 95% now. However, long-term outcome and
cardiovascular morbidity from premature atherosclerosis is yet to be
determined.
• Male children, early-onset of disease and ethnicity are associated with
worse outcome.
Aetiology
• JSLE is the archetypal paediatric systemic autoimmune disease,
illustrated by its complex clinical, molecular, and genetic characteristics.
The cause of JSLE remains unknown. The principal underlying disorder
in JSLE is impaired cellular and humoral immune response. Hormonal
and environmental factors act on genetically susceptible individuals
over time resulting in development of autoimmunity, eventually leading
to disease progression (Box 4.4 and Fig. 4.9).
• The multitude of presenting and clinical features of lupus reflects the
complex pathogenesis of SLE.
224 CHAPTER 4 Systemic diseases

Box 4.4 Genetic, immunological, and environmental

factors contributing to the development of lupus
Genetic factors
• Siblings of patients with SLE have 10–20-fold i risk of developing
disease.
• Monozygous twins have 24% concordance rate versus 2%
heterozygote pairs.
• Familial autoimmunity is a risk factor for SLE (odds ratio 4.1
with 1 relative, 11.3 with 2 or more relatives).
• Homozygous deficiency of C1q, C1r, C1s, C4, and C2 are strongest
susceptibility factors for SLE in humans (80% prevalence for C1 or C4
molecules).
• i susceptibility to SLE is associated with an increasing number of
recognized candidate genes, including HLA haplotypes, ITGAM, IFR5,
BLK, STAT4, PTPN22, and FcG receptor polymorphisms.
Immune dysfunction
• B cells and autoantibodies: immune complexes containing anti-DNA
and anti-RNP antibodies activate dendritic cells to produce IFNA
which induces differentiation of B cells into antibody-secreting plasma
cells, perpetuating auto-antibody production and immune complex
production. B cells secrete cytokines and chemokines enhancing the
inflammatory cascade.
• Dendritic cells (DCs): abnormal activation causes selection rather
than deletion of T cells that have receptors to self-antigens.
• T cells: hyperactivity and loss of tolerance, in part due to mutations in
inhibitory receptors on T cells.
• Proinflammatory cytokines levels elevated: interferon-A, IL-6, IL-10,
IL-12, IL-18.
• Apoptosis: impaired clearance of apoptotic cells may lead to
over-presentation of nuclear antigens by DCs to T cells.
• Other: abnormalities in monocytes, NK cells, cytokines, and
immunoglobulins also identified.
Environmental
• Ultra-violet (UV) light can induce flares, possibly by altering DNA
methylation.
• Viruses.
• Hormones.
• Drugs (e.g. procainamide, hydralazine have been shown to impair
T cell DNA methylation leading to i autoreactivity).
 JSLE: EPIDEMIOLOGY AND AETIOLOGY 225

Genetic factors Environmental triggers

Virus
Inhibitory receptors on T cells (PD1)
T
Deficient removal of apoptotic cells
(C1q deficiency)
T
Sequential loss of tolerance Myeloid DCs

pDC activating IC IFN alpha Plasmacytoid

ANA IL-6 DCs
Anti-phospholipid
Anti-Ro/La
Anti-dsDNA
Anti-Sm B
Anti-nuclear
B
RNP B

B cell activating IC
Pre-clinical Disease manifestations
Fig. 4.9 Roles played by both genetic and environmental factors in the development of
paediatric SLE. Genetic alterations may contribute to a progressive loss of tolerance
to nuclear antigens, which has been shown to precede the development of clinical
disease. IFNA will also activate monocytes and other myeloid DC precursors to
become immunogenic DCs able to activate T and B cells. Viruses and other environ-
mental triggers can activate DCs to secrete IFNA which amplifies these loops and
precipitates the development of clinical disease. Adapted from Stichweh D, Arce E,
Pascual V. Update on pediatric systemic lupus erythematosus. Curr Opin Rheumatol
2004; 16:577–87.

Further reading
Crispin JC, Liossis SN, Kis-Toth K, et al. Pathogenesis of human systemic lupus erythematosus:
Recent advances. Trends Mol Med 2010; 16:47–57.
Stichweh D, Arce E, Pascual V. Update on pediatric systemic lupus erythematosus. Curr Opin
Rheumatol 2004; 16:577–87.
226 CHAPTER 4 Systemic diseases

JSLE: clinical features and diagnostic

criteria
Clinical presentation of JSLE
• The clinical manifestations of JSLE are extremely variable. They range
from mild illness characterized by rash, fatigue, and joint pains to life-
threatening organ involvement (Box 4.5)
• Symptoms may be incorrectly attributed to problems such as ‘being a
teenager’, exam stress, anorexia nervosa, or chronic fatigue syndrome.
Diagnosis may be complicated by the evolution of disease over time.

Box 4.5 Presenting features of JSLE

• Constitutional (fever, malaise, weight loss): 40–74%
• Joint pains/arthritis: 20–74%
• Enlarged liver ± spleen: 15–74%
• Renal involvement: 20–82%
• Malar rash: 44–52%
• Lymphadenopathy: 15–30%

Multisystem presentation of JSLE

Careful, multisystem assessment must be carried out in all patients in whom
JSLE is suspected. Potential clinical features are protean, and include:
• Mucocutaneous—malar rash, vasculitic lesions, photosensitive rashes,
nasal/oral ulcers, Raynaud’s phenomenon, alopecia, discoid lesions.
• Systemic—fever, lethargy, weight loss, arthralgia.
• Arthritis (non-erosive).
• Renal—proteinuria, glomerulonephritis, hypertension, renal failure.
• GI tract: hepatosplenomegaly, autoimmune hepatitis, pancreatitis,
diffuse abdominal pain, serositis, colitis, oesophageal dysmotility.
• Cardiopulmonary—pericarditis, myocarditis, pleuritis, interstitial lung
disease, pulmonary haemorrhage.
• Neuropsychiatric—headache, migraine, seizures, depression, cognitive
impairment, stroke, chorea, cranial and peripheral neuropathies.
• Haematological—anaemia, Coombs positivity, thrombocytopenia,
leucopenia.
• Other—lymphadenopathy, ocular (e.g. uveitis, episcleritis, optic neuritis,
retinopathy), antiphospholipid antibodies.
Diagnosis of JSLE
• The diagnosis of JSLE is based on a collection of clinical and laboratory
features. The American College of Rheumatology (ACR) revised
criteria for classification of SLE (Table 4.6) are frequently used for
diagnosis and have been shown to be valid in JSLE:
• The criteria were introduced for the purpose of clinical trials.
• A person can be said to have SLE if any 4 or more of the 11 criteria
are present, serially or simultaneously, during any interval.
• The presence of 4 out of 11 gives 96% sensitivity and specificity for
(adult-onset) SLE.
 JSLE: CLINICAL FEATURES AND DIAGNOSTIC CRITERIA 227

Table 4.6 The ACR revised criteria for classification of SLE

Criteria Definition
Malar rash Fixed erythema, flat or raised, over malar eminences, tending
to spare nasolabial folds
Discoid lupus Erythematous raised patches of adherent keratotic scaling
and follicular plugging. Atrophic scarring may be seen in
older lesions
Photosensitivity Skin rash as a result of unusual reaction to sunlight
Oral or nasal Oral or nasopharyngeal ulcers, usually painless, observed
ulceration by a physician
Non-erosive Non-erosive arthritis involving 2 or more peripheral joints,
arthritis characterized by tenderness, swelling, or effusion
Serositis Pleuritis—pleuritic pain, rub heard or pleural effusion, or
Pericarditis—documented by ECG or rub or pericardial
effusion
Nephritis Persistent proteinuria >0.5g/day or >3+, or:
Cellular casts: red cell, haemoglobin, granular, tubular
or mixed
Neurological Seizures in the absence of offending drugs or metabolic
derangement (e.g. uraemia, ketoacidosis, electrolyte
imbalance), or
Psychosis in the absence of offending drugs or metabolic
derangement (e.g. uraemia, ketoacidosis, electrolyte
imbalance)
Haematological Haemolytic anaemia with reticulocytes, or
Leucopenia <4000 per mm3 on 2 or more occasions, or
Lymphopenia <1500 per mm3 on 2 or more occasions, or
Thrombocytopenia <100,000 per mm3 in absence of
offending drugs
Immunological Anti-DNA antibody, or
Anti-Sm antibody, or
Anti-phospholipid antibodies:
(i) Abnormal anticardiolipin antibody IgG or IgM
(ii) Positive lupus anticoagulant
(iii) False positive for syphilis for >6 months
Anti-nuclear Abnormal titre of ANA at any point in absence of drugs
antibody known to be associated with drug-induced lupus
228 CHAPTER 4 Systemic diseases

• The criteria alone are not a pre-requisite for diagnosis or commencing

treatment in patients where there is a high index of suspicion of JSLE.
Many individuals with 1 or 2 features will develop others later on and
may eventually fulfil the criteria.
• The ability to diagnose JSLE correctly may be challenging especially
in those with an insidious onset of symptoms that are common in
childhood such as joint pains and tiredness.
• Early referral to a clinician with experience and expertise of JSLE
is important to allow prompt and correct diagnosis and the timely
commencement of appropriate therapy to prevent long-term damage.
• The most common ACR criteria found in children are ANA positivity,
arthritis, immunological disorder, haematological disorder, malar rash,
and photosensitivity although many children present with or develop
renal or neurological disease, even if not strictly meeting the ACR
definitions outlined here.
Further reading
Hochberg MC. Updating the American College of Rheumatology revised criteria for the
classification of systemic lupus erythematosus. Arth Rheum 1997; 40:1725.
 ASSESSMENT OF THE CHILD WITH JSLE 229

Assessment of the child with JSLE and

monitoring of disease activity
Assessing disease severity and monitoring outcome
Optimizing disease control depends on assessing disease activity. The
complexity and variability of paediatric lupus makes this difficult. There is
no single ‘gold standard’ biological marker that accurately reflects this. In
the assessment of the child with JSLE it is important to determine the fol-
lowing aspects of their disease across all organ systems:
• Disease activity—potentially reversible with correct therapy.
• Organ damage—reversible or irreversible.
• Effect of lupus on the patient’s quality of life (QoL).
• Concurrent pathology, e.g. infection, drug side effects, disease
complications, concomitant conditions.
Clinical approach to assessment
Careful multisystem assessment must be carried out at each clinical visit:
• History—detailed multi-system symptom enquiry including effect of
disease on social and psychological functioning. Enquire about fatigue.
• Examination—cardiovascular including BP, respiratory, abdominal,
mucocutaneous, musculoskeletal and neurological. Growth, pubertal
staging and development.
• Disease activity score assessment: see Box 4.6.
• SLICC/ACR damage index (annually): see Box 4.6.

Box 4.6 JSLE assessment tools

There are several assessment tools available which can be used serially
in the clinical setting or in clinical studies/trials to assess response and
outcome and allow comparison of therapies.
Lupus Disease Activity Measures
• BILAG (British Isles Lupus Assessment Group)
• SLEDAI (SLE Disease Activity Index)
• SLAM (Systemic Lupus Activity Measure)
• ECLAM (European Community Lupus Activity Measure).
Most widely used are the BILAG and SLEDAI.
Assessment of damage
• The SLICC/ACR damage index (Systemic Lupus International
Cooperating Clinics/American College of Rheumatology).
Function and QoL
• Neither the SLEDAI, BILAG nor SLICC/ACR measure health-related
QoL, degree of disability, or impact of disease.
• The Childhood Health Questionnaire (CHQ) and SF36 can be useful
in assessing general health and well-being. Specific JSLE-related QoL
tools are also being developed.
• The CHAQ (Childhood Health Assessment Questionnaire) measures
function and includes a visual analogue scale (VAS) for pain and
general evaluation of disease.
230 CHAPTER 4 Systemic diseases

Investigations
Routinely at each review, e.g. 3-monthly or more frequently if unwell
• FBC—dHb (anaemia of chronic disease or autoimmune anaemia),
dWCC (i suggests infection or s to stress response/corticosteroids),
dlymphocytes (due to disease or immunosuppression), dplatelets.
• NB: consider macrophage activation syndrome (see b MAS, p 305) if
increasing pancytopenia in sick patient.
• i ESR (if sudden drop in ESR in sick patient, consider MAS).
• Urinalysis—protein or blood in renal involvement. If protein present
need quantitative measure such as spot urinary albumin creatinine ratio
(UACR) or protein creatinine ratio (UPCR).
• Urine MC&S—presence of casts, WCC, RBC, organisms.
• U&Es, LFTs, bone profile, and glucose (consider amylase and lipase in
presence of abdominal pain).
• CRP—if i consider infection. Other causes of raised CRP in the context
of SLE include serositis and polyarthritis.
• Complement—dC3 and C4, levels correlate with disease activity.
• Immunoglobulins—i in acute inflammation.
• ds-DNA—possible direct pathogenic role and titres are measure of
disease activity. Serial measurements of anti-C1q also marker of disease
activity particularly renal disease but test not widely available.
At initial assessment then annually
(*Denotes investigations to perform more frequently in sick patients.)
• Clotting screen* (prolonged in APLS and MAS), fibrinogen* (iin acute
inflammation, d in MAS).
• DAT*—positive in autoimmune haemolytic anaemia.
• Lupus anticoagulant and anticardiolipin IgG and IgM—s APLS.
• TFTs* and thyroid antibodies.
• Lipid profile* (dyslipidaemia i risk of cardiovascular events; i TGs in MAS).
• Vitamin D levels.
• ANA (positive in 95% of SLE), dsDNA (positive in 60%), ENAs—most
common include anti-Ro, anti-La associated with neonatal lupus
syndromes, anti-Sm (anti-‘Smith’, not ‘smooth muscle’ as often
erroneously assumed) associated with renal involvement.
• Immunity status—e.g. measles and varicella IgG.
Further systems investigation should be undertaken at baseline and
when appropriate for select individuals with any disease flare or annual
monitoring of progress
• Renal biopsy.
• ECG, echocardiogram, visceral angiogram, MRA.
• CXR, pulmonary function tests including transfer factor, CT chest.
• Renal USS, renal biopsy, measurement of GFR.
• MRI brain, MRA brain, EEG, psychometric testing.
• Abdominal USS, upper and lower GI endoscopy.
• Bone mineral density scan (DEXA) for those at risk from osteoporosis.
• Skin biopsy.
• Ophthalmology assessment.
• Infection screen e.g. viral serology, urine MC&S, blood cultures, lumbar
puncture, stool MC&S, and virology.
 ASSESSMENT OF THE CHILD WITH JSLE 231

Further reading
Gutierrez-Suarez R, Ruperto N, Gastaldi R et al. A proposal for a pediatric version of the Systemic
Lupus International Collaborating Clinics/American College of Rheumatology Damage Index
based on the analysis of 1,015 patients with juvenile-onset systemic lupus erythematosus.
Arthritis Rheum 2006; 54:2989–96.
Haq I, Isenberg DA. How does one assess and monitor patients with systemic lupus
erythematosus in daily clinical practice? Best Pract Res 2002; 16:181–94.
232 CHAPTER 4 Systemic diseases

JSLE: approach to management

(Also see b Lupus nephritis, p 236.)
General principles
• Management of JSLE requires full MDT engagement by professionals
experienced in paediatric rheumatology including prompt liaison with
other specialists as dictated by disease manifestations.
• As the survival rates for JSLE improve the late complications of both
disease and therapy should be recognized and addressed, such as
premature atherosclerosis (Box 4.7), osteoporosis, neurocognitive
impairment, and potentially i risk of malignancy.
• Early and aggressive therapy is key for treatment of JSLE to improve
outcome and function and reduce organ damage.
• Management should be individualized taking into account patient
preference, tolerance of drugs, and disease presentation. Care should
be taken to explore the burden of disease and treatment on QoL,
education, physical and emotional development. This should improve
patient care and adherence.

Box 4.7 Premature atherosclerosis

• Leads to marked morbidity in young adults—risk to women with SLE
of myocardial infarction (MI) or stroke 6–9× that of healthy controls
and MI rate of 8% observed in 24–43yr-olds who developed SLE in
childhood.
• Risk factors—obesity, smoking, insulin resistance, iBP, renal disease,
dyslipidaemia, inflammation, APLS, vascular disease. Other as yet
undefined non-conventional cardiovascular risk factors arising from
SLE and its treatment are areas of ongoing study.
• Prevention in JSLE needs to begin in childhood—importance of
modifying risk factors, and potential use of statins in JSLE (NB
ongoing trial of atorvastatin in JSLE: The APPLE trial).

Evidence base for management of JSLE

• Paucity of robust epidemiological, clinical cohort studies, and clinical
trial data in JSLE hamper evidence-based management of JSLE. To date,
no large randomized comparative trials have been published in JSLE,
so treatment regimens are based primarily on observational cohort
studies and adult data (Box 4.8).
• International organizations (e.g. PRINTO, CARRA) and national,
collaborative research groups such as the UK JSLE Study Group seek to
improve the evidence base.
• Multinational collaborative paediatric research is essential to define the
efficacy and safety of therapies to improve care for JSLE patients.
• Important data from adult studies can help, which may have larger
cohorts including patients developing SLE in childhood; however,
determining the efficacy and safety within a paediatric population of
new and existing therapies is critical.
 JSLE: APPROACH TO MANAGEMENT 233

Box 4.8 UK JSLE Cohort Study & Repository

Established by the UK JSLE Study Group (M http://www.liv.ac.uk/ukjsle/
index.htm), the study consists of a comprehensive, prospective clinical
data set from patients with JSLE from across the UK. The aims of the UK
JSLE Cohort Study & Repository include:
• To determine the demographics of JSLE across the UK and to
investigate the clinical characteristics of disease presentation, activity,
damage, and response to therapy for a national cohort of JSLE patients.
• To undertake comparative studies with other national lupus cohorts.
• Develop a cohort of patients suitable for recruitment to clinical
interventional trials in JSLE.
• Facilitate international collaborative studies and trials in JSLE.

General management of JSLE

• UV light—advise sun avoidance and prescribe sun block factor 50–60
to reduce flares and photosensitive rashes.
• Vaccination—i risk of infection in JSLE due to drug therapies and JSLE-
associated immune dysfunction. All routine immunizations advised plus
pneumococcal and influenza. NB Live vaccines contraindicated if on
significant immunosuppression.
• Bone health—ensure adequate dietary intake of calcium and vitamin
D. Discourage inactivity. Assess bone density regularly and treat
osteoporosis if present.
Corticosteroids in JSLE
• Corticosteroids are needed initially in all but very mild cases to provide
rapid control of inflammation but are associated with numerous side
effects (osteoporosis, growth retardation, obesity, Cushingoid facies,
cataracts, impaired glucose tolerance) and are a risk factor for damage.
• Steroid-sparing immunosuppressive therapy is started early for prompt
induction of remission and to allow rapid tapering of steroids as clinical
response dictates, with the aim to minimize steroid toxicity.
• Prednisolone used as oral therapy (1–2mg/kg initially then tapered).
In control of acute flares and at induction high-dose pulsed IVMP
may be required (e.g. 30mg/kg on 3 consecutive days) and repeated
as according to response, followed by tapering oral steroids. Weekly
pulsed IVMP (e.g. 30mg/kg/day for 4–6 weeks), followed by tapering
of oral steroids may also be needed. Oral prednisolone may not be
absorbed in gut involvement.
Disease-modifying drugs in JSLE (see b JSLE: renal
involvement, p 236 and b BSPAR guidelines for treatments used
in paediatric rheumatology, p 415)
Choice of DMARDs in JSLE varies with clinician as evidence of superiority
is lacking. Multiple DMARDs may be required in refractory disease.
Hydroxychloroquine (HCQ) e.g. 5–6.5mg/kg/day once a day can be given
(maximum 400mg)
• Advised in all patients unless contraindicated. Adult studies indicate
disease-modifying role and lipid-lowering effect; particularly useful for
skin and joint disease; some patients can be managed with HCQ and
low-dose corticosteroids only.
234 CHAPTER 4 Systemic diseases

Azathioprine (AZA) (e.g. start at 1mg/kg/day, i in increments up to a maximum

of 3mg/kg/day)
• Traditionally the 1st-line steroid-sparing DMARD in moderate disease.
Side effects uncommon but include nausea, fatigue, hair loss, and bone
marrow suppression. Increasingly, many clinicians using MMF before
AZA due to anecdotal evidence of i efficacy and tolerability of MMF,
and emerging evidence from clinical trials (ALMS trial for both renal
and non-renal SLE) in adults (see b Lupus nephritis, p 236).
Mycophenolate mofetil (MMF): (e.g. 10–20mg/kg/day per dose twice daily;
or 600mg/m2 per dose twice daily)
• Increasingly used as induction and/or maintenance of remission therapy
in all but mild disease. Studies in adults with lupus nephritis indicate
it to be as effective but less toxic than cyclophosphamide. Published
data from the JSLE population is limited, although it offers a significant
therapeutic opportunity. It is steroid-sparing, improves renal function,
and reduces disease activity in JSLE. Relatively well-tolerated, main side
effect is GI upset which can be minimized by slow introduction.
Cyclophosphamide (CPM) (e.g. monthly pulsed IV CPM of 500–1000mg/m2
[maximum dose 1.2 g] for 3–6 months)
• ‘Gold standard’ until recently as induction agent for major organ
involvement or life-threatening lupus together with pulsed IVMP.
Marked side effect profile including bone marrow suppression, gonadal
suppression, hair loss, and haemorrhagic cystitis. IV CPM considered
superior to oral CPM. More recently, an alternative approach using
lower cumulative doses of IV CPM (300–500mg/m2, maximum dose
500mg, given every 2 weeks for 6 doses), the so-called ‘Eurolupus
protocol’ have been proposed for induction of remission of JSLE.
Biologic therapies in JSLE
• The advent of biological therapies offers a major therapeutic advance
in the management of JSLE. To date, rituximab, a B-cell depletor has
demonstrated evidence of efficacy in JSLE. Randomized controlled
studies are summarized in the separate section on B cell depletion
therapy in SLE (b p 241), and are given under expert advice only.
Anti-phospholipid syndrome
• If positive anticardiolipin Ab or lupus anticoagulant on 2 occasions
3 months apart commence low-dose aspirin to prevent thrombotic
events.
Other therapies used in refractory JSLE
• Methotrexate (skin and joint disease), ciclosporin (lupus nephritis,
particularly for membranous nephritis, Class V), infliximab, IVIg.
 JSLE: APPROACH TO MANAGEMENT 235

Treatment of severe refractory lupus

• Plasma-exchange—anecdotal evidence of efficacy in severe refractory
lupus.
• Haematopoietic stem cell transplantation(autologous and allogeneic
stem cell transplant, see b Haematopoietic stem cell transplantation,
p 405)—successfully used in severe refractory disease. Associated
with significant mortality rate so only considered in those with severe
disease who have failed conventional therapies.
Further reading
von Scheven E, Bakkaloglu A. What’s new in paediatric SLE? Best Pract Res 2009; 23:699–708.
236 CHAPTER 4 Systemic diseases

JSLE: renal involvement

Introduction
• Renal disease is a major determinant of the long-term outcome of SLE:
• Present in 60–80% of JSLE cases.
• Influences management with immunosuppressive agents.
• Earlier and more severe presentation in patients with JSLE
(compared to adult-onset) SLE.
• Presentation of renal involvement:
• Proteinuria.
• Microscopic (and rarely macroscopic) haematuria.
• Nephrotic syndrome.
• Hypertension.
• Evidence of renal dysfunction—elevated plasma creatinine or
reduced estimated GFR.
• Histopathology of renal involvement with lupus nephritis (LN) cannot
be accurately predicted from clinical and serological markers:
• Renal biopsy is undertaken if deteriorating renal function, significant
proteinuria, haematuria or hypertension, or to delineate thrombotic
microangiopathy.
Investigations
All JSLE patients should be monitored at least every 3 months for evidence
of LN:
• BP measurement.
• Early morning urinary dipstick test.
• Early morning urine albumin:creatinine ratio.
• Consideration of 24h urine collection in adolescent children.
• Markers of renal function (plasma creatinine, estimated GFR, and
serum albumin).
• Routine lupus immunological tests.
Histopathology
Classification of LN facilitates clinical management (in guiding treatment
and conducting RCTs of therapeutic agents) as well as communica-
tion between pathologists and scientists. It standardizes definitions with
uniform and reproducible reporting between centres.
The original World Health Organization classification of LN was developed
in 1974–1975, and modified in 1982 and 1995 with the current histopatho-
logical classification reported by the International Society of Nephrology/
Renal Pathology Society working group in 2003 (Fig. 4.10):
• ISN/RPS Class I LN = minimal mesangial LN.
• ISN/RPS Class II LN = mesangial proliferative LN.
• ISN/RPS Class III LN = focal lupus nephritis, subdivided into:
• III (A) active focal proliferative LN.
• III (A/C) active and sclerotic focal proliferative LN.
• III (C) inactive sclerotic focal lupus nephritis.
• ISN/RPS Class IV LN = diffuse segmental (IV-S) or global (IV-G):
• See Figs. 4.11 and 4.12.
• IV (A) active diffuse segmental or global proliferative LN.
 JSLE: RENAL INVOLVEMENT 237

• IV (A/C) diffuse segmental or global proliferative and sclerotic.

• IV (C) diffuse segmental or global sclerotic lupus nephritis.
• ISN/RPS Class V LN = diffuse membranous LN:
• Class III and Class V changes are reported as Class III + V.
• Class IV and Class V changes are reported as Class IV + V.
• ISN/RPS Class VI LN = advanced sclerotic LN.
• This classification has been validated in JSLE.

Lupus nephritis biopsy

ISN/RPS classification

No endocapillary Endocapillary
hypercellularity hypercellularity

Mesangial Mesangial Subepithelial Involving Involving

deposits only hypercellularity deposits <50% glomeruli ≥50%
Class I Class II Class V Class III* glomeruli

* = include proportion of glomeruli with active

and chronic lesions, necrosis and crescents
If Class V (membranous changes) are seen Segmental Global
with Class III or IV then both are reported distribution distribution
Class IV S* Class IV G*
Class VI denotes advanced sclerosing LN of
end-stage renal failure and is rarely biopsied

Fig. 4.10 Summary of International Society of Nephrology/Renal Pathology Society

classification of lupus nephritis.

Treatment
• The aim of treatment is to induce remission while minimizing side
effects (including infectious complications) and flares of disease activity
in order to improve patient morbidity and mortality.
• Once induction of remission to gain control of disease activity is
achieved then maintenance therapy is utilized to maintain disease
control and minimize therapy related toxicity, including corticosteroid
exposure.
• However, due to the increasing use of MMF instead of IV CYC for
induction of remission, many clinicians are utilizing MMF for both
induction and maintenance phases.
• ISN Class I and II LN:
• The same therapy is employed for those with mild to moderate
SLE without LN and may include azathioprine therapy (see b JSLE:
non-renal involvement, p 236).
• ISN Class III, IV and V LN:
• MMF as 1st-line treatment is a safe and efficacious therapy for SLE
and LN but can cause more diarrhoea despite less overall side
effects than CYC.
238 CHAPTER 4 Systemic diseases

• IV CYC may be reserved for patients with severe multisystem

disease activity or with poor adherence to oral therapy but is
associated with more nausea and vomiting.
• The Aspreva Lupus Management Study (ALMS) showed no
difference in response rate in adults with ISN/RPS Class III, IV and
V who were randomized to MMF or iv CYC in a 24-week induction
study:
— 56% and 53% responded to MMF and IV CYC respectively.
— No significant differences in rates of adverse events, including
infections.
• Plasmapheresis should be considered for children with rapidly
progressive crescentic glomerulonephritis (as well as cerebral
vasculitis or pulmonary haemorrhage).
• B cell depletion with IV rituximab has been shown to be useful for
JSLE patients with severe renal and non-renal disease activity as well
as refractory disease, although its use is not yet supported with RCT
data (see b B-cell depletion therapy).
• ISN Class VI
• The current classification of advanced sclerotic LN implies end-
stage renal failure (CKD5) management with renal replacement
therapy, although immunosuppressive therapies may be utilized to
treat or avoid further non-renal flares of disease activity.
• Maintenance therapy of LN:
• Oral prednisolone 10–15mg alternate days (where possible; some
prefer lower doses of daily prednisolone and there are no hard data
to suggest which is superior).
• Oral hydroxychloroquine 4–6mg⁄kg⁄day (maximum dose 400mg/day).
• Oral AZA 2–3mg/kg once daily, or
• Oral MMF 300–600mg/m2/dose twice daily (usual maximum dose of
2g/day although occasionally 3g/day has been used).
 JSLE: RENAL INVOLVEMENT 239

Fig. 4.11 (See also Colour plate 2.) ISN/RPS Class IV LN (PAS stain, original
magnification ×250). Wire loop (denoted by lower arrow) and hyaline droplet
(upper arrow) change representing massive subendothelial deposits when seen
on light microscopy.

Fig. 4.12 ISN/RPS Class IV LN (electron microscopy). Massive subendothelial

deposit corresponding to a wire-loop lesion (see arrow).

Further reading
Appel G, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for
induction treatment of lupus nephritis. J Am Soc Nephrol 2009; 20:1103–12.
Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic
lupus erythematosus revisited. Kidney Int 2004; 65:521–30.
240 CHAPTER 4 Systemic diseases

Neonatal lupus syndrome

• Autoimmune disease associated with transplacental passage of
maternal auto-antibodies (autoAbs) to SSA/Ro and SSB/La antigens.
• Risk of an infant developing NLS in positive mother is 2% (risk to
subsequent pregnancy is 25%).
Clinical features
• Skin—subacute cutaneous lupus-like lesions, telangiectasia.
• Cardiac—congenital heart block, cardiomyopathy, prolonged QT
interval, sinus bradycardia, cardiac malformations.
• Hepatobiliary—elevation in transaminases, cholestasis, fulminant liver
failure.
• Haematological—thrombocytopenia and less commonly other cytopenias.
Investigation
• Diagnosis is made by identifying relevant clinical features with positive
NLS-associated antibodies in maternal or neonatal serum.
• Skin biopsy may be useful if diagnosis unclear.
Management
• Careful in utero and postnatal monitoring of at-risk pregnancies is
important to ensure appropriate treatment (serial fetal echo; postnatal
ECG).
• Use of maternal fluorinated corticosteroids (dexamethasone or
beclamethasone) which cross the placenta may prevent progression of
incomplete heart block.
• Infants with cardiac disease may need cardiac pacing.
• Skin lesions can be treated with sun avoidance, sun block, and topical
corticosteroids.
Prognosis
• Skin, hepatic and haematological manifestations tend to resolve
spontaneously as maternal autoantibodies disappear from the infant’s
circulation; complete heart block and cardiomyopathy can be life
threatening.
• Affected infants may be at irisk of subsequent autoimmune disease.
Further reading
Lee LA. The clinical spectrum of neonatal lupus. Arch Dermatol Res 2009; 301:107–10.
Pain C, Beresford MW. Neonatal lupus syndrome. Paediatr Child Health 2007; 17:223–7.
 B-CELL-TARGETED THERAPIES FOR SLE 241

B-cell-targeted therapies for systemic

lupus erythematosus
Why target B cells in SLE?
• A minority of patients with SLE will not have a sufficient clinical
response to the present standard treatment with MMF, IV CYC, AZA,
and corticosteroids.
• In these cases there continues to be clinical and laboratory symptoms
and signs of active disease of such a degree that alternative approaches
to treatment would be preferable.
• B cells have critical roles in the pathogenesis of SLE, including cytokine
production, presentation of self-antigen, T-cell activation, and
(indirectly via plasma cells) autoantibody production.
• Recently, several clinical trials have reported different approaches for
the induction of remission in adults with SLE by targeting B cells.
Types of B-cell-targeted therapy
• Currently tested B-cell-targeted therapies include rituximab,
ocrelizumab, belimumab, epratuzumab, and atacicept. The mechanisms
of action of these agents are summarized in Table 4.7.
• The vast majority of the paediatric SLE experience to date is only
with rituximab, with little or no data on the role of other agents in
paediatric patients. Rituximab should only be used in conjunction with
expert advice and in children with SLE resistant to standard therapy;
in rare circumstances, rituximab may be considered for p induction of
remission and there is ongoing controversy as to whether rituximab
should be given with IV CYC for ‘synergistic’ B-cell depletion or not,
and what immunosuppression to follow rituximab therapy with.
Clinical trials of B-cell-targeted therapies in adults with SLE
• Very recently, several important prospective RCTs of B cell-targeted
therapy have been reported in adults (summarized in Table 4.8), with
mixed and perhaps (to many) surprising results.
• Both rituximab trials (EXPLORER and LUNAR) reported negative
results.
• Both belimumab trials reported positive results.
• Methodological aspects of the clinical trials of rituximab could explain
the ‘unexpected’ negative results of the EXPLORER and LUNAR trials
despite early reported open label success in those with SLE resistant to
conventional therapy (including children). Possible reasons include:
• Improvements in the standard care limb of these trials: MMF in
place of IV CYC which may result in a higher than anticipated
response rate thus reducing the power of the study.
• High corticosteroid doses in both the experimental and standard
limbs of the trials.
• Overly optimistic p endpoints and sensitive cut-offs for
non-response.
• Patient heterogeneity including the fact that some patients with
minimal disease activity were included in these trials.
242 CHAPTER 4 Systemic diseases

• The EXPLORER and LUNAR trials do not answer the question

relating to efficacy of rituximab for those with SLE resistant to
standard induction therapy.

Table 4.7 Different types of B cell-targeted therapy

Drug name B cell target Proposed mechanism
of efficacy
Rituximab Chimeric (mouse-human) Depletion of peripheral blood
(see b p 441 monoclonal antibody which B cells, with little or no d in
guidelines) binds specifically to the CD20 serum immunoglobulin because
antigen located on pre-B and plasma cells are spared
mature B lymphocytes, thus
Efficacy thought to be the result
mediating B-cell lysis. CD20
of autoantibody independent
is not expressed on
effects of B cell depletion
plasma cells
including reduced self-antigen
presentation, reduced cytokine
production and d T-cell activation
Ocrelizumab Fully human monoclonal Same as rituximab
antibody against CD20
Belimumab Fully human monoclonal BAFF levels are i in SLE and
antibody against BAFF (B-cell correlate with disease activity-
activating factor, also referred blocking BAFF therefore
to as B-lymphocyte stimulator, reduces pathological B-cell
BLyS). BAFF (and another survival and differentiation
related molecule called APRIL)
are produced mainly by cells
of the innate immune system,
and promote B cell survival
and differentiation
Epratuzumab Fully human monoclonal B-cell depletion so similar in
antibody against CD 22, a action to rituximab
B-cell surface antigen involved
in the regulation of signalling
Atacicept Chimeric molecule with a Has a dramatic inhibitory effect
region which binds both on plasma cells hence reduces
BAFF and APRIL, fused autoantibodies but also reduces
to the constant region immunoglobin—very high rate of
of human IgG1 infections reported in early trials
Table 4.8 Summary of recent RCTs of B-cell-targeted therapy in SLE
Trial name Description Design Primary end point Result Adverse events
EXPLORER The Exploratory Double blind RCT; N=257 all Pre-defined No differences between Safety and tolerability were
Phase II/III SLE receiving PRED, and 1 of AZA, improvement in placebo and RTX similar in patients receiving
Evaluation of MMF, or MTX. Patients were BILAG score groups in the p RTX and those receiving
Rituximab; randomized 2:1 to receive RTX endpoint. Serological placebo
or placebo. Moderate and severe improvement observed
Non-renal lupus trial
LN or CNS lupus excluded in RTX group
LUNAR Lupus Nephritis Double blind RCT; RTX or Proportion of No difference in More severe neutropaenia
Assessment with placebo was added onto standard patients who endpoint between RTX (3.6% RTX vs 0% placebo);

B-CELL-TARGETED THERAPIES FOR SLE

Rituximab therapy with MMF and high- obtained a and placebo groups. and non-serious herpes virus
dose corticosteroids; n=144, 1:1 pre-defined renal Serological improvement infections (15% RTX vs 8%
randomization. Active class III or IV response at observed in RTX group placebo); 4 episodes of serum
LN included; CNS lupus excluded 52 weeks: either sickness occurred in the RTX
CRR, PRR, or NR group
BLISS-52 Belimumab Double blind RCT; n= 865:standard Improvement at Reduced disease activity No difference in adverse
International SLE care (corticosteroids and other week 52 in SRI, and i time to flare for events between placebo and
study- 52 week immunosuppressant) plus either and no worsening both the low- and high- belimumab groups with the
follow-up placebo or belimumab 1mg/kg, or of physician global dose belimumab groups exception of infusion reactions
10mg/kg given at days 0, 14, 28, and assessment score or compared with placebo
every 28 days until week 52. Severe BILAG at week 52
LN and active CNS lupus excluded

(continued )

243
 244
Table 4.8 (Contd.)

CHAPTER 4
Trial name Description Design Primary end point Result Adverse events
BLISS-76 Belimumab Second phase III RCT of belimumab: Reduced disease activity Not yet reported
International SLE identical study design as BLISS-52; and i time to flare in the

Systemic diseases
study- 76 week only difference is that blinding and high dose belimumab
follow-up follow-up remain for an additional group only, compared
24 weeks with placebo at week 52.
Week 76 results not yet
reported
AZA: azathioprine; BILAG: British Isles Lupus Assessment Group score; CNS: central nervous system; CRR: complete renal response; LN: lupus nephritis; MTX: methotrexate; PRED:
prednisone; PRR: partial renal response; MMF: mycophenolate mofetil; NR: non-response; RCT: randomized controlled trial; RTX: rituximab; SRI: SLE-response index.
 B-CELL-TARGETED THERAPIES FOR SLE 245

The use of rituximab in paediatric SLE

• Given the negative recent trial data for rituximab, albeit with positive
retrospective clinical experience with this therapy in children with SLE
resistant to standard therapy, rituximab should only be given upon
expert advice.
• In rare circumstances, rituximab can be considered for p induction of
remission—suggest under expert advice only.
• Adding to the complexity is the still ongoing controversy as to whether
rituximab should be given with IV CYC for ‘synergistic’ B-cell depletion
or not, and what immunosuppression to follow rituximab therapy with.
• Data suggest that B-cell activation in SLE makes these cells more
resistant to antibody-mediated cell killing from agents such as
rituximab, providing an (unproven) argument for combining
rituximab with cyclophosphamide.
• At the time of writing there are no data to provide firm
recommendations on these issues.
• Treat each case on an individual basis.
Patient selection criteria
• Severe active lupus previously treated with standard lupus treatment
either IV CYC or MMF for a minimum of 6 months, or
• As add on to standard induction therapy for those with severe life-
threatening disease- little available evidence of its efficacy in this
context.
• No known severe reaction to humanized chimeric antibodies.
Exclusion criteria
• Chronic active infection.
• Recent severe infection.
• Pregnancy or planned pregnancy.
Rituximab treatment protocol
Rituximab may be given in addition to cyclophosphamide (see above),
except where cumulative cyclophosphamide toxicity, side effects, or other
clinical contraindication preclude this. A suggested protocol is given (also
see Guidelines b Chapter, p 441):
Day 1 and day 15
• Rituximab infusion 750mg/m2 (rounded up to the nearest 100mg).
Max. dose: 1g.
• Premedicate with chlorphenamine (5–10mg) and paracetamol (15mg/kg)
1h prior to the rituximab infusion.
• In addition a dose of methylprednisolone IV 100mg (absolute dose, not
per kg) is given immediately prior to the rituximab infusion.
• This is followed with oral prednisolone for 3 days after the infusion:
30mg, 20mg and 10mg (i.e. days 2, 3, & 4 & days 16, 17, & 18), and then
with the patient’s previous maintenance prednisolone dose.
Day 2 and day 16
• Cyclophosphamide infusion 375mg/m2 as per infusion protocol
(see b p 427).
246 CHAPTER 4 Systemic diseases

Administration of rituximab: practical aspects

• Dilute the required dose with sodium chloride 0.9% or glucose 5%
to a final concentration of 1–4mg/mL.
• The initial infusion rate is 25mg/h, which can be i by increments of
25mg/h every 30min up to a maximum of 200mg/h as tolerated.
Rituximab: side effects
• Serum sickness: fevers and rigors, which usually present within the first
2h. Other reported symptoms include pruritis and rashes, dyspnoea,
bronchospasm, angio-oedema, and transient hypotension.
• In the event of an infusion related adverse event, stop the infusion
and recommence at half the previous rate once the symptoms have
resolved.
• Premedication with chlorphenamine, paracetamol, and
methylprednisolone will reduce the incidence of adverse effects.
• Infections:
• Herpes zoster infection described in children.
• Progressive multifocal leucoencephalopathy caused by JC virus
(a polyoma virus).
• Rituximab associated neutropenia—occurring usually several months
following the administration of rituximab:
• Usually not clinically significant and is self-limited but should be
differentiated with neutropenia from other cause such as active SLE.
• Mechanism remains largely speculative.
Follow-up post rituximab
Follow-up carefully with:
• Clinical status.
• FBC including diff, ESR, CRP, U&Es, and LFTs; UA:UC (minimum of
fortnightly FBC for 6 weeks then monthly).
• ANA, doubled-stranded DNA, C3, C4.
• Screen for B-cell response and hypoagammaglobulinaemia (see
Table 4.9). The use of replacement immunoglobulin in deficient
patients is not standard practice at this stage, but will be continually
monitored. The decision to commence IVIg replacement will be
decided on an individual basis and will depend on the findings of
hypogammaglobulinaemia and/or the occurrence and nature of
infections.
 B-CELL-TARGETED THERAPIES FOR SLE 247

Immune monitoring (Table 4.9) is recommended.

Table 4.9 Monitoring rituximab treatment in patients with SLE

Test Timing (after 1st dose) Notes
Lymphocyte • Days 7–10 Measures T, B (CD19)
subsets • Monthly from 4 months after and NK cells. Must do
first dose until B cells normal FBC same day
Immunoglobulins • Days 7–10
GAM • 2 months after first dose
• Monthly from 4 months after
first dose until B cells normal
Note: B cells express CD19 and CD20, and it is routine to measure CD19 as a B-cell marker.
Rarely (normally in the context of malignancy) B cells may not express CD20 and will not
therefore be eliminated by rituximab. If there is concern that B cells are not eradicated after
7–10 days, routine B cell measurement should be repeated and direct measurement of CD20
may be helpful. This will rarely be required.

Repeat rituximab dosing

• Repeated doses of rituximab are only recommended for those with
evidence of return of disease activity after return of peripheral blood
lymphocytes.
• Hypersensitivity reactions such as serum sickness and anaphylaxis may
be of increasing concern for those re-treated with rituximab.
Further reading
Looney RJ. B-cell targeted therapies for systemic lupus erythematosus. Drugs 2010; 70:529–40.
Podolskaya A, Stadermann M, Pilkington C, et al. B cell depletion therapy for 19 patients with
refractory systemic lupus erythematosus. Arch Dis Child 2008; 93:401–6.
248 CHAPTER 4 Systemic diseases

British Isles Lupus Assessment Group

(BILAG) 2004 Index
The BILAG Index is a measure of disease activity developed initially for
adult-onset SLE using nominal consensus approach and modified several
times to improve its validity and reliability (Table 4.10). The BILAG 2004
validation is ongoing. Across 9 domains, clinicians indicate whether each
parameter is:
• Not present, 0
• Improving, 1
• Same, 2
• Worse, 3 or
• New, 4.
Scoring refers to manifestations present in the last 4 weeks compared to
the previous 4 weeks and to features attributable to SLE disease activity
and not due to damage, drugs, or infection.
(NB For detailed descriptions of definitions of manifestations see BILAG
2004 glossary.)
The BILAG rests on the principle of the physicians’ intent-to-treat in
assigning scores A–E:
• A = Disease necessitating high-dose oral/IV steroids, DMARDs, or
biologics.
• B = Low-dose corticosteroids (equivalent to d20mg/day prednisolone)
and/or HCQ.
• C = Stable mild disease.
• D = Prior involvement of the organ system, no current disease activity.
• E = Organ system never involved.
Several conversion systems have been proposed to translate BILAG
A–E ratings into a BILAG disease activity summary score. Newly revised
scoring for BILAG 2004 is as follows: A = 12; B = 8; C = 1; D = 0; E = 0.
Use of BILAG in JSLE
The original adult-derived ‘Classic’ BILAG index has been used in JSLE
and shown to be sensitive to change in disease activity. However, it was
recognized that adaptation of certain parameters of the original BILAG
needed to take place for use in children (e.g. age-adjusted BP). In addi-
tion, potential scoring problems were noted due to the differences
between paediatric and adult management practices (e.g. timing of renal
biopsy). Validation of the revised BILAG 2004 in a JSLE cohort is currently
underway but it is summarized here in view of its increasing use in clinical
trials of adult-onset SLE.
Further reading
Yee CS, Farewell VT, Isenberg DA et al. Numerical scoring for the BILAG 2004 Index.
Rheumatology 2010; 49(9):1665–9.
Table 4.10 British Isles Lupus Assessment Group (BILAG) 2004 Index
Domain Manifestations* Assessment

BRITISH ISLES LUPUS ASSESSMENT GROUP (BILAG) 2004 INDEX

Constitutional 1. Pyrexia (documented >37.5*C) A Pyrexia recorded as 2 (same), 3 (worse), or 4 (new) and t2 recorded as 2–4: weight
2. Weight loss-unintentional >5% loss, lymphadenopathy/splenomegaly, anorexia
3. Lymphadenopathy/splenomegaly B Pyrexia recorded as 2, 3, or 4 or t2 recorded as 2–4: weight loss, lymphadenopathy/
4. Anorexia
splenomegaly, anorexia but do not fulfil criteria for category A
C Pyrexia recorded as 1 (improving) or t1 recorded as 2 (same), 3 (worse) or 4 (new):
weight loss, lymphadenopathy/splenomegaly, anorexia BUT does not fulfil criteria for
category A or B
D Previous involvement
E No previous involvement
Mucocutaneous 1. Skin eruption—severe A Any of the following recorded as 2 (same), 3 (worse), or 4 (new):
2. Skin eruption—mild Skin eruption—severe
3. Angio-oedema—severe Angio-oedema—severe
4. Angio-oedema—mild Mucosal ulceration—severe
5. Mucosal ulceration—severe Panniculitis/bullous lupus—severe
6. Mucosal ulceration—mild Major cutaneous vasculitis/thrombosis
7. Panniculitis/bullous lupus—severe B Any category A features recorded as 1 (improving) or any of following recorded
8. Panniculitis/bullous lupus—mild as 2 (same), 3 (worse), or 4 (new):
9. Major cutaneous vasculitis/thrombosis Skin eruption—mild
10. Digital infarcts or nodular vasculitis Panniculitis/Bullous lupus—mild
11. Alopecia—severe Digital infarcts or nodular vasculitis
12. Alopecia—mild Alopecia—severe
13. Peri-ungual erythema/chilblains C Any category B features recorded as 1 (improving) or any of the following recorded as t1:
14. Splinter haemorrhages Angio-oedema—mild
Mucosal ulceration—mild

249
(continued )
 250
CHAPTER 4
Table 4.10 (Contd.)
Domain Manifestations* Assessment

Systemic diseases
Alopecia—mild
Periungual erythema/chilblains
Splinter haemorrhages

D Previous involvement
E No previous involvement
Cardiorespiratory 1. Myocarditis—mild A Any of the following recorded as 2 (same), 3 (worse), or 4 (new):
2. Myocarditis/endocarditis + cardiac Myocarditis/endocarditis + cardiac failure
failure Arrhythmia
3. Arrhythmia New valvular dysfunction
4. New valvular dysfunction Cardiac tamponade
5. Pleurisy/pericarditis Pleural effusion with dyspnoea
6. Cardiac tamponade Pulmonary haemorrhage/vasculitis
7. Pleural effusion with dyspnoea Interstitial alveolitis/pneumonitis
8. Pulmonary haemorrhage/vasculitis Shrinking lung syndrome
9. Interstitial alveolitis/pneumonitis Aortitis
10. Shrinking lung syndrome Coronary vasculitis
11. Aortitis B Any category A features recorded as 1 (improving) or pleurisy/pericarditis or mild
12. Coronary vasculitis myocarditis recorded as 2, 3, or 4
C Any category B features recorded as 1 (improving)
D Previous involvement
E No previous involvement
Neuropsychiatric 1. Aseptic meningitis A Any of manifestations numbered 1–11 or status epilepticus or cerebellar ataxia
2. Cerebral vasculitis recorded as 2 (same), 3 (worse), or 4 (new)

BRITISH ISLES LUPUS ASSESSMENT GROUP (BILAG) 2004 INDEX

3. Demyelinating syndrome B Any category A features recorded as 1 (improving) or any of the following recorded
4. Myelopathy as 2 (same), 3 (worse), or 4 (new):
5. Acute confusional state Seizure disorder
6. Psychosis Cerebrovascular disease (not due to vasculitis)
7. Acute inflammatory demyelinating Cognitive dysfunction
polyradiculoneuropathy Movement disorder
8. Mononeuropathy (single/multiplex) Autonomic disorder
9. Cranial neuropathy Lupus headache—severe unremitting
10. Plexopathy Headache due to raised intracranial hypertension
11. Polyneuropathy C Any category B features recorded as 1 (improving)
12. Seizure disorder D Previous involvement
13. Status epilepticus E No previous involvement
14. Cerebrovascular disease (not due to
vasculitis)
15. Cognitive dysfunction
16. Movement disorder
17. Autonomic disorder
18. Cerebellar ataxia (isolated)
19. Lupus headache—severe unremitting
20. Headache from intracranial iBP

(continued )

251
 252
CHAPTER 4
Table 4.10 (Contd.)

Systemic diseases
Domain Manifestations* Assessment
Musculoskeletal 1. Myositis—severe A Severe myositis or severe arthritis recorded as 2 (same), 3 (worse), or 4 (new)
2. Myositis—mild
B Any category A features recorded as 1 (improving) or mild myositis or moderate
3. Arthritis—severe
arthritis/tendonitis/tenosynovitis recorded as 2–4.
4. Arthritis(moderate)/tenosynovitis
5. Arthritis (mild)/arthralgia/myalgia C Any category B features recorded as 1 (improving) or mild arthritis/arthralgia/myalgia
scored as t1
D Previous involvement
E No previous involvement
Gastrointestinal 1. Lupus peritonitis A Any of the following recorded as 2 (same), 3 (worse), or 4 (new):
2. Abdominal serositis or ascites Peritonitis
3. Lupus enteritis/colitis Lupus enteritis/colitis
4. Malabsorption Intestinal pseudo-obstruction
5. Protein losing enteropathy Acute lupus cholecystitis
6. Intestinal pseudo-obstruction Acute lupus pancreatitis
7. Lupus hepatitis B Any category A feature recorded as 1 (improving) or abdominal serositis and/or as-
8. Acute lupus cholecystitis cites, malabsorption, protein losing enteropathy, lupus hepatitis recorded as 2 (same),
9. Acute lupus pancreatitis 3 (worse) or 4 (new)
C Any category B features recorded as 1 (improving)
D Previous involvement
E No previous involvement
Ophthalmic 1. Orbital inflammation/myositis/proptosis A Any of the following recorded as 2 (same), 3 (worse), or 4 (new):
2. Keratitis—severe Orbital inflammation/myositis/proptosis
(Usually scored by

BRITISH ISLES LUPUS ASSESSMENT GROUP (BILAG) 2004 INDEX

3. Keratitis—mild Keratitis—severe
ophthalmologist)
4. Anterior uveitis Posterior uveitis/retinal vasculitis—severe
5. Posterior uveitis/retinal Scleritis—severe
vasculitis—severe Retinal/choroidal vaso-occlusive disease
6. Post. uveitis/retinal vasculitis—mild Optic neuritis
7. Episcleritis Anterior ischaemic optic neuropathy
8. Scleritis—severe B Any category A features recorded as 1 (improving) or any of the following recorded
9. Scleritis—mild as 2 (same), 3 (worse), or 4 (new):
10. Retinal/choroidal vaso-occlusive Keratitis—mild
disease Anterior uveitis
11. Isolated cotton-wool spots Posterior uveitis/retinal vasculitis—mild
12. Optic neuritis Scleritis—mild
13. Anterior ischaemic optic neuropathy C Any category B features recorded as 1 (improving) or episcleritis or isolated
cotton-wool spots (cytoid bodies) recorded as t1
D Previous involvement
E No previous involvement

(continued )

253
 254
CHAPTER 4
Table 4.10 (Contd.)
Domain Manifestations* Assessment
Renal 1. Systolic BP (mmHg) A Two or more of the following providing 1, 4, or 5 is included:

Systemic diseases
2. Diastolic BP (mmHg) 1. Deteriorating proteinuria (severe) defined as:
3. Accelerated hypertension (Y/N) (a) Urine dipstick increased by t2 levels or
4. Urine dipstick protein (+=1, (b) 24h urine protein >1g that has not decreased (improved) by t 25%; or
++=2, +++=3) (c) UPCR >100 mg/mmol that has not decreased (improved) by t 25%; or
5. Urine albumin-creatinine ratio (d) UACR >100 mg/mmol that has not decreased (improved) by t 25%
(UACR) mg/mmol 2. Accelerated hypertension
6. Urine protein-creatinine ratio 3. Deteriorating renal function (severe) defined as
(UPCR) mg/mmol (a) plasma creatinine >130μmol/L and having risen to >130% of previous value;
7. 24h urine protein (gram) or
8. Nephrotic syndrome (Y/N) (b) GFR <80mL/min per 1.73m2 and having fallen to <67% of previous value; or
9. Creatinine (plasma/serum) (c) GFR <50mL/min per 1.73m2, and last time was >50mL/min per 1.73 m2 or
10. GFR (calculated) was not measured
11. Active urinary sediment (Y/N) 4. Active urinary sediment
12. Active nephritis 5. Histological evidence of active nephritis within last 3 months
6. Nephrotic syndrome
B One of the following:
1. One of the category A criteria
2. Proteinuria (that has not fulfilled category A criteria):
(a) Urine dipstick which has risen to t2+ or
(b) 24h urine protein t0.5 g that has not decreased (improved) by t25%; or
(c) UPCR or UACR t50 mg/mmol that has not decreased (improved) by t25%
3. Plasma creatinine >130μmol/L and having risen to t115% but d130% of
previous value
 C One of the following:
1. Mild/stable proteinuria defined as that which has not fulfilled criteria for

BRITISH ISLES LUPUS ASSESSMENT GROUP (BILAG) 2004 INDEX

category A & B
2. Rising BP (>140/90mmHg) which has not fulfilled criteria for category
A & B, defined as systolic rise of t30 mm Hg; and diastolic rise of t15mm Hg
D Previous involvement
E No previous involvement
Haematological 1. Hemoglobin (g/dL) A TTP recorded as 2 (same), 3 (worse), or 4 (new) or evidence of haemolysis and
2. Total WBC (×109/L) Hb <8 g/dL or platelets <25 × 109/L
3. Neutrophils (×109/L) B TTP recorded as 1 (improving) or any of the following:
4. Lymphocytes (×109/L) 1. Evidence of haemolysis and Hb 8–9.9g/dL
5. Platelets (×109/L) 2. Hb <8g/dL (without haemolysis)
6. TTP 3. WCC <1.0 × 109/L
7. Evidence of active haemolysis (Y/N) 4. Neutrophil count <0.5 × 109/L
8. Coombs test positive (Y/N) 5. Platelet count 25–49 × 109/L
C Any 1 of the following:
1. Evidence of haemolysis and Hb t10g/dL
2. Hb 8–10.9 g/dL (without haemolysis)
3. WCC 1–3.9 × 109/L
4. Neutrophil count 0.5–1.9 × 109/L
5. Lymphocyte count <1.0 × 109/L
6. Platelet count 50–149 × 109/L
7. Isolated Coombs’ test positive
D Previous involvement
E No previous involvement
Table adapted from BILAG 2004 Index (Form, Scoring and Glossary available from Rheumatology online via Yee CS, Farewell VT, Isenberg DA et al. Numerical scoring for the BILAG
2004 Index. Rheumatology 2010; 49(9):1665–9.).

255
256 CHAPTER 4 Systemic diseases

SLEDAI 2000 Disease Activity Index

Table 4.11 SLEDAI 2K—check box: if descriptor is present at time of
visit or past 10 days
Weight Descriptor Definition
Recent onset, exclude metabolic,
8  Seizure
infectious or drug causes
Altered ability to function in normal
activity due to severe disturbance
in the perception of reality. Include
hallucinations, incoherence, marked
8  Psychosis loose associations, impoverished
thought content, marked illogical
thinking, bizarre, disorganized, or
catatonic behaviour. Exclude uraemia
and drug causes
Altered mental function with impaired
orientation, memory, or other
intellectual function, with rapid onset
and fluctuating clinical features, inability
Organic brain to sustain attention to environment, plus
8 
syndrome at least 2 of the following: perceptual
disturbance, incoherent speech,
insomnia or daytime drowsiness, or
i or d psychomotor activity. Exclude
metabolic, infectious, or drug causes
Retinal changes of SLE. Include cytoid
bodies, retinal haemorrhages, serous
8  Visual disturbance exudates or haemorrhages in the
choroid, or optic neuritis. Exclude
hypertension, infection, or drug causes
Cranial nerve New onset of sensory or motor
8 
disorder neuropathy involving cranial nerves
Severe, persistent headache, may be
8  Lupus headache migrainous, but must be non-responsive
to narcotic analgesia
New onset of cerebrovascular
8  CVA
accident(s). Exclude arteriosclerosis
Ulceration, gangrene, tender finger
nodules, periungual infarction, splinter
8  Vasculitis
haemorrhages, or biopsy or angiogram
proof of vasculitis
t2 joints with pain and signs of
4  Arthritis inflammation (i.e., tenderness, swelling
or effusion)
 SLEDAI 2000 DISEASE ACTIVITY INDEX 257

Table 4.11 (Contd.)

Weight Descriptor Definition
Proximal muscle aching weakness,
associated with elevated creatine
4  Myositis phosphokinase/aldolase or
electromyogram changes or a biopsy
showing myositis
4  Urinary casts Haem-granular or red blood cell casts
>5 red blood cells/high power field,
4  Hematuria
Exclude stone, infection or other cause
4  Proteinuria >0.5g/24h
>5 white blood cells/high power field.
4  Pyuria
Exclude infection
2  Rash Inflammatory type rash
2  Alopecia Abnormal, patchy or diffuse loss of hair
2  Mucosal ulcers Oral or nasal ulcerations
Pleuritic chest pain with pleural rub or
2  Pleurisy
effusion, or pleural thickening
Pericardial pain with at least 1 of
the following: rub, effusion, or
2  Pericarditis
electrocardiogram or echocardiogram
confirmation
d in CH50, C3, or C4 below the lower
2  Low complement
limit of normal for testing laboratory
Increased DNA i DNA binding by Farr assay above
2 
binding normal range for testing laboratory
1  Fever >38*C. Exclude infectious cause
<100,000 platelets/× 109/L, exclude drug
1  Thrombocytopenia
causes
<3000 white blood cells/× 109/L,
1  Leucopenia
exclude drug causes
 TOTAL SCORE (Sum of weights next to descriptors marked
present)
*Adapted from: Gladman DD, Ibanez D, Urowitz MB. Systemic lupus erythematosus disease
activity index 2000. J Rheumatol 2002; 29(2):288–91.
258 CHAPTER 4 Systemic diseases

SLICC/ACR Damage Index (paediatric)

Table 4.12 SLICC/ACR Damage Index (paediatric)*
SCORE
(circle)
Ocular (either eye, by clinic assessment)
• Any cataract ever 01
• Retinal change or optic atrophy 01
Neuropsychiatric
• Cognitive impairment or major psychosis 01
• Seizures requiring therapy for 6 months 01
• Cerebral vascular accident ever (score 2 if >1), or resection not 012
for malignancy
• Cranial or peripheral neuropathy (excluding optic) 01
• Transverse myelitis 01
Renal
• Estimated or measured GFR <50% 01
• Proteinuria 24h, t3.5 g or ACR >1000mg/mm or >10mg/mg 01
• End-stage renal disease (regardless of dialysis or transplantation) 3
Pulmonary
• Pulmonary hypertension (right ventricular prominence, or loud P2) 01
• Pulmonary fibrosis (physical and x-ray) 01
• Shrinking lung (x-ray) 01
• Pleural fibrosis (x-ray) 01
• Pulmonary infarction (x-ray) or resection not for malignancy 01
Cardiovascular
• Angina or coronary artery bypass 01
• Myocardial infarction ever (score 2 if >1) 012
• Cardiomyopathy (ventricular dysfunction) 01
• Valvular disease (diastolic murmur, or a systolic murmur >3/6) 01
• Pericarditis × 6 months or pericardiectomy 01
Peripheral vascular
• Claudication × 6 months 01
• Minor tissue loss (pulp space) 01
• Significant tissue loss ever (e.g. loss of digit or limb, resection) 012
(Score 2 if >1)
• Venous thrombosis with swelling, ulceration, or venous stasis 01
Gastrointestinal
• Infarction or resection of bowel (below duodenum), spleen, 012
liver or gall bladder (score 2 if >1)
• Mesenteric insufficiency 01
• Chronic peritonitis 01
• Stricture or upper GI tract surgery ever 01
• Pancreatic insufficiency requiring enzyme replacement or with 01
pseudocyst
 SLICC/ACR DAMAGE INDEX (PAEDIATRIC) 259

Table 4.12 (Contd.)

SCORE
(circle)
Musculoskeletal
• Atrophy or weakness 01
• Deforming or erosive arthritis (including reducible deformities, 01
excluding avascular necrosis)
• Osteoporosis with fracture or vertebral collapse 01
(excluding avascular necrosis)
• Avascular necrosis (score 2 if >1) 012
• Osteomyelitis 01
• Ruptured tendons 01
Skin
• Alopecia 01
• Extensive scarring of panniculum other than scalp and pulp space 01
• Skin ulceration (not due to thrombosis) >6 months 01
Diabetes (regardless of treatment) 01
Malignancy (exclude dysplasia) score 2 if >1 site 012
Premature gonadal failure/secondary amenorrhoea 01
Pubertal stage pre
post
Height (cm) Weight
(kg)
Bone age (yr)
• DEXA scan every 2yr
*
Adapted from: Gutierrez-Suarez R, Ruperto N, Gastaldi R et al: Arthritis Rheum 2006;
54:2989–96; scored by summation of scores for each item in the 12 domains (maximum of 47).
260 CHAPTER 4 Systemic diseases

Scleroderma
The encompassing term scleroderma (literally ‘hard skin’) is characterized
by skin thickening and i collagen and may involve atrophy of subcutaneous
fat and/or deeper tissues. Scleroderma has 2 distinct groupings: localized
scleroderma (LS) and the much rarer juvenile systemic sclerosis (jSSc)—
Table 4.13. Classifications of LS and jSSC are largely clinical and as yet,
there is no universal consensus as to their use in clinical practice or clinical
trials (Tables 4.14 and 4.15).
Assessment and monitoring
There are currently no validated outcomes of severity or disease activity
in LS or jSSc, either of the skin or organ involvement. Current methods of
assessment include;
• Clinical examination (skin, joints, muscles, general examination,
growth).
• Need to consider potential multisystem involvement (Table 4.16):
check BP, urinalysis, pulmonary function tests/transfer factor, ECHO
as baseline and in jSSc, at least annually pending clinical scenario.
• Imaging:
• Serial photographs and measurement of lesions.
• Thermography and capillaroscopy.
• MRI head (especially if facial lesions present).
• Skin US, Laser Doppler flowmetry (not yet validated).
• Blood tests: autoantibodies (Table 4.15 and see b p 263). Muscle
enzymes (b muscle disease, p 266).
 SCLERODERMA 261

Table 4.13 Epidemiology and clinical features

Localized Juvenile systemic sclerosis (jSSc)
scleroderma (LS)
Estimated 3.4 per million 0.27 per million
incidence
Survival Likely normal Estimated 4yr survival is 95% (cardiac and
pulmonary disease)
5:4 ratio Between 1.7:1–2.4:1 2.8:1 or greater
(largest cohort 2.4:1) (largest cohort 3.6:1)
Ethnicity 82–90% Caucasian
Mean age Approx 8yr (range: birth–16yr)
of onset
Delay in diagnosis is common especially in LS as presentation is
often insidious
Clinical Articular (19%)—often More generalized skin changes and may
features distant to skin lesions include widespread visceral involvement
Neurological (4%)— Raynaud’s phenomenon (76%), skin
e.g. epilepsy, headaches, induration (66%), sclerodactyly (55%),
behavioural change, digital tip ulceration (35%),
learning disabilities dysphagia (13%)
Vascular—Raynaud’s 3 subtypes recognized:
Ocular—e.g. uveitis, Limited cutaneous systemic sclerosis
episcleritis, eyelid or (lcSSc)—skin change usually confined
eyelash abnormality to distal arm or leg >head and neck.
Previously often termed ‘CREST’ (calcinosis,
GI (2%) (reflux
Raynaud’s, oesophageal involvement,
oesophagitis)
sclerodactyly, telangiectases)
Respiratory, renal &
Diffuse cutaneous (dcSSc)—skin
cardiac (<1%)
involvement extends to proximal limb
and/or trunk
Overlap syndromes—both lcSSc and dcSSc
may overlap with other connective tissue
diseases (e.g. SLE, Sjögren’s syndrome and
inflammatory muscle disease)
Differential Amyloidosis, eosinophilic faciitis, graft-versus-host-disease, juvenile
diagnosis dermatomyositis, juvenile idiopathic arthritis, [lichen sclerosus
et atrophicus], lipodystrophy, Lyme disease, lupus erythematosus,
mixed connective tissue disease, phenylketonuria, scleredema
262 CHAPTER 4 Systemic diseases

Table 4.14 Localized scleroderma (Mayo Clinic classification)

Localized Subdivision Comment
scleroderma
type (relative
frequency, %)
Plaque Plaque morphoea Most benign subtype (usually on
morphoea the trunk), lesions may be single or
(26%) multiple. Often start as localized
patch of erythema, induration with
erythematous halo or altered skin
pigment
Others—Guttate Skin lesion patterns are variable and
morphoea, differing patterns may coexist
atrophoderma of
Pasini and Pierini,
Keloid morphoea
(nodular morphoea),
[lichen sclerosus et
atrophicus]
Generalized No subdivisions. Plaques confluent or
morphoea affecting >2 separate anatomical sites
(7%)
Bullous No subdivisions
morphoea
(<1%)
Linear Linear morphoea/ Commonest subtype usually affecting
morphoea scleroderma limbs. May also involve face
(65%)
En coup de sabre When face is affected, changes are
(Parry-Romberg) often disfiguring
‘En coup de sabre’ refers to cranial
linear lesion with lack of hair growth
Progressive
in the involved skin; ‘Parry–Romberg
hemifacial atrophy
syndrome’ refers to hemifacial atrophy.
Intracranial brain lesions are rare (e.g.
gadolinium-enhancing lesions, cerebral
vasculitis, raised oligoclonal bands, or
intracranial calcification)
Deep Various Subcutaneous morphoea, eosinophilic
morphoea descriptions fasciitis, morphoea profunda, disabling
(2%) pansclerotic morphoea of children
 SCLERODERMA 263

Table 4.15 Proposed provisional classification criteria of jSSc

(M http://www.pres.org)
Major criterion (1 required)
Proximal skin sclerosis/induration of the skin
Minor criterion (>2 required)
Cutaneous Sclerodactyly
Peripheral vascular Raynaud’s phenomenon, nailfold capillary abnormalities,
digital tip ulcers
Gastrointestinal Dysphagia, gastroesophageal reflux
Cardiac Arrhythmias, heart failure
Renal Renal crisis, new-onset arterial hypertension
Respiratory Pulmonary fibrosis (high-resolution CT/radiography) with
d transfer factor and restrictive lung disease on pulmonary
function tests, pulmonary arterial hypertension
Neurologic Neuropathy, carpal tunnel syndrome
Musculoskeletal Tendon friction rubs, arthritis, myositis
Serological Antinuclear antibodies, jSSc-selective autoantibodies
(anticentromere, anti–topoisomerase I [Scl-70],
antifibrillarin, anti–PMScl, antifibrillin or anti–RNA
polymerase I or III)
These criteria still require validation and particularly with regard to disease subtypes.

Approach to management
• Early disease recognition and referral to an experienced paediatric
rheumatology MDT. There are few placebo controlled trials in children
with scleroderma; therapy decisions are based on reports of clinical
cohorts. Physiotherapy and occupational therapy optimize physical
function to treat and prevent contractures and muscle weakness and
facilitate access to make up and cosmetic approaches if there are
disfiguring skin lesions. Surgery may be complicated by problems with
healing and ischaemia.
• Raynaud’s phenomenon—avoidance of smoking, certain drugs
(e.g. beta blockers) and may be helped by gloves, topical GTN or oral
medication (calcium channel blockers) or iloprost (see b Clinical
guidelines p 409, and b Overlap syndromes, p 275).
• Treatment of skin lesions in LS depends largely on lesion site, size,
depth, and potential for growth impairment when the lesions are
deep and/or over joints and the presence of extra-cutaneous features.
Options include topical treatments (e.g. moisturizers, corticosteroids),
UV phototherapy and systemic immunosuppression are increasingly
used (e.g. corticosteroids, MTX, MMF, and anti-TNF treatment—see
b p 409)—case series have demonstrated efficacy in halting
264 CHAPTER 4 Systemic diseases

progression of skin involvement. Cosmetic procedures in localized

scleroderma may be helpful when growth is complete and lesions
inactive.
• EULAR have recently proposed evidenced-based treatment
recommendations for jSSc (Table 4.16). Treatment of jSSc requires
specialist evaluation and treatment (including iloprost (see b
Epoprostenol/iloprost, p 433, and b Overlap syndromes, p 275) for
Raynauds, DMARDs, and cytotoxics for organ involvement and proton
pump inhibitors for GI symptoms). There are successful case reports of
bone marrow transplantation and autologous haematopoietic stem cell
transplantation (see b AHSCT, p 405).
• Long-term monitoring is imperative and LS often progresses insidiously
and frequently relapses following cessation of drug treatment. LS
evolving into jSSc is reported, albeit very rarely (and possibly cases
were atypical from onset).

Table 4.16 EULAR recommendations for the treatment of SSc

(recommendations for adult and paediatric populations)
Organ system Recommendation Category
of
evidence
SSc-related Dihydropiridine-type calcium antagonists, A
digital usually oral nifedipine, should be considered for
vasculopathy first-line therapy for SSc-RP, and IV iloprost, or
(Raynaud’s other available IV prostanoids for severe SSc-RP
phenomenon
(RP), digital IV prostanoids (in particular iloprost) should A
ulcers) be considered in the treatment of active digital
ulcers in patients with SSc
Bosentan should be considered in diffuse SSc A
with multiple digital ulcers after failure of calcium
antagonists and, usually, prostanoid therapy
SSc-related Bosentan should be strongly considered to treat A/B
pulmonary SSc-PAH (pulmonary hypertension)
arterial
hypertension At present, sitaxentan may also be considered to A/B
(PAH) treat SSc-PAH
Sildenafil may be considered to treat SSc-PAH A/B
Intravenous epoprostenol should be considered A
for the treatment of patients with severe SSc-PAH
SSc-related skin MTX may be considered for treatment of skin A
involvement manifestations of early diffuse SSc
SSc-related In view of the results from 2 high-quality RCTs A
interstitial lung and despite its known toxicity, cyclophosphamide
disease (ILD) should be considered for treatment of SSc-ILD
(interstitial lung disease)
 SCLERODERMA 265

Table 4.16 (Contd.)

Organ system Recommendation Category
of
evidence
SSc-related Despite the lack of RCT, expert consensus is C
renal crisis that ACE inhibitors should be used in the
(SRC) treatment of SRC
4 retrospective studies suggest that steroids are C
associated with a higher risk of SRC. Patients on
steroids should be carefully monitored for BP and
renal function
SSc-related Despite the lack of specific RCT, experts believe B
gastrointestinal that proton pump inhibitors should be used for
disease the prevention of SSc-related gastro-oesophageal
reflux, oesophageal ulcers, and strictures
Despite the lack of specific RCTs, experts believe C
that prokinetic drugs should be used for the
management of SSc-related symptomatic motility
disturbances (dysphagia, gastrointestinal reflux
disease, early satiety, bloating, pseudo-obstruction)
Despite the lack of specific RCT, experts believe D
that, when malabsorption is caused by bacterial
overgrowth, rotating antibiotics may be useful in
SSc patients

Further reading
Herrick AL, Ennis H, Bhushan M, et al. Incidence of childhood linear scleroderma and systemic
sclerosis in the UK and Ireland. Arthritis Care Res (Hoboken) 2010; 62(2):213–18.
Kowal-Bielecka O, Landewé R, Avouac J, et al. EULAR recommendations for the treatment of
systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group EUSTAR).
Ann Rheum Dis 2009; 68(5):620–8.
Zulian F, Athreya BH, Laxer R, et al.; Juvenile Scleroderma Working Group of the Pediatric
Rheumatology European Society (PRES). Juvenile localized scleroderma: clinical and
epidemiological features in 750 children. An international study. Rheumatology (Oxford) 2006;
45(5):614–20.
Zulian F, Woo P, Athreya BH, et al. The Pediatric Rheumatology European Society/American
College of Rheumatology/European League against Rheumatism provisional classification
criteria for juvenile systemic sclerosis. Arthritis Rheum 2007; 57(2):203–12.
266 CHAPTER 4 Systemic diseases

Juvenile dermatomyositis
Juvenile dermatomyositis (JDM) is a rare small-vessel vasculopathy of
childhood. It characteristically affects the skin and muscle but can also
involve the GI system, heart, joints, and other organs. JDM is the most
common of the idiopathic inflammatory myopathies of childhood.
Epidemiology
• The incidence of JDM is between 2 and 3 children per million per year.
• JDM is more commonly seen in girls than boys (2.3:1).
• The mean age of onset is ~7yr; however 25% of cases present before
the age of 4.
• Ethnicity largely reflects that of the population. An analysis of cases
from Great Britain and Ireland has shown an over-representation
amongst the black population relative to population demographics.
• Seasonality, most notably in birth distribution in certain populations,
suggests a role for perinatal environmental factors in the onset of the
illness in later childhood.
Clinical features
• Clinical features form the central basis of the diagnosis of all cases of
JDM. The typical picture is one of:
• Heliotrope rash, periorbital oedema
• Gottron’s papules over the extensor surfaces
• Proximal muscle weakness
• In reality patients can present with any of a number of clinical pictures
including:
• Systemic symptoms (fever, malaise, anorexia, weight loss or irritability)
• Arthritis, myalgia, contractures
• Dysphagia, dyspnoea, dysphonia
• Lipoatrophy, calcinosis, skin ulceration, oedema.
Diagnostic criteria
• The diagnostic criteria defined by Bohan and Peter in 1975 remain
the most widely used today. These criteria require, for a diagnosis
of definite JDM, the presence of 1 of the characteristic rashes in
combination with 3 of the following:
• Symmetric proximal muscle weakness
• Raised serum muscle enzymes (creatine kinase, transaminases,
lactate dehyrogenase, and aldolase)
• Abnormal findings on a muscle biopsy (Fig. 4.13) or electromyogram
(EMG).
• The presence of 1 of the characteristic rashes plus 2 of the other features
provides a diagnosis of probable JDM; rash +1 feature gives possible JDM.
• Over time, changes in clinical practice have made these criteria less
reliable as many children with a diagnosis of JDM may not fulfil the
criteria as a result of a lack of muscle biopsy or EMG. As such the
classification criteria for JDM is under discussion, but may include:
• Abnormal MRI
• Abnormal nailfold capillaroscopy
• Calcinosis
• Dysphonia.
 JUVENILE DERMATOMYOSITIS 267

Monitoring during follow-up

Monitoring of disease activity in JDM involves both global activity moni-
toring, organ specific monitoring and includes the following:
• Assessment of muscle disease activity: muscle strength, contractures,
reduced muscle length.
• Assessment of skin disease activity: rashes, nailbed erythema and
swelling.
• Assessment of other organ disease: arthritis, lung/liver/heart, calcinosis.
inflammation, cuticular overgrowth, nailbed capillary abnormalities.
Global assessment
• JDM Disease Activity Score—assesses the extent and distribution
of cutaneous involvement, muscle weakness, functional status and
vasculopathic manifestations.
• Parent/Patient global assessment of disease activity assessment by
Visual Analogue Score (VAS).
Functional ability
Childhood Health Assessment Questionnaire—see b Outcome measures,
p 41.
Health-related quality of life
Child Health Questionnaire—see b Outcome measures, p 41).
Assessment of muscle disease
The assessment of the extent and severity of muscle involvement is
pivotal to the monitoring of JDM. Assessment of muscle disease activity
and response to therapy can be subdivided.
• Measures of muscle strength—MMT8 (tests 8 muscle groups).
• Measures of muscle functional ability—CMAS.
• Serological measurement of muscle enzymes (this does not always
accurately assist with disease activity monitoring particularly in
long-standing disease).
Childhood Myositis Assessment Scale (CMAS)—(Table 4.17)
• This is an excellent assessment and monitoring tool to assess muscle
strength and function, stamina of muscles, task orientated function.
• The CMAS assesses quality of movement as well as whether the task
can be completed.
• The maximum score is 53 and this indicates a well, fit, young person.
Manual Muscle Test (MMT8)
JDM affects both proximal muscles and distal muscles and so muscle test
have been validated to provide an outcome tool that measures 8 specific
muscle groups, and gives an overall score which can be followed over
time. Current Scoring scales include the Oxford MMT and the Kendall
MMT (Table 4.18).
Assessment of skin disease
• Cutaneous Assessment Tool—assesses skin activity and damage.
• Disease Activity Score.
268 CHAPTER 4 Systemic diseases

Monitoring of extramuscular disease

Myositis Disease Activity Assessment—a combination of a series of organ
specific visual analogue scales and a myositis intention to treat activity
index.
Assessment of damage
Myositis Damage Index—assess the extent of damage in many organ
systems and includes a VAS to quantify the extent of damage (it includes
the assessment of linear growth and pubertal development).
Imaging
MRI is accepted as the most valuable tool in the evaluation of myositis
activity and in differentiation between activity and damage (Fig. 4.14).
Capillaroscopy (see b Nailfold capillaroscopy in rheumatic disease)
Nailfold capillary changes correlate strongly with measures of disease
activity.
Treatment
• The aims of therapy for JDM are to treat the disease, prevent mortality,
and reduce long-term disability and calcinosis.
• The management of JDM continues to vary widely from centre to
centre and evidence base is scant.
• Corticosteroids are the accepted 1st-line therapy, however mode of
administration, dosage, and duration of therapy still varies.
• The early introduction of agents beyond corticosteroids may shorten
disease duration, reduce calcinosis, reduce the likelihood of flares later
in the disease course, and i the chance of remission.
• Corticosteroid therapy is preferably administered by the parenteral
route rather than oral, particularly in patients with vasculopathy as
evidenced by periungal nailfold capillary abnormalities.
• Accepted 1st-line management for a typical case of JDM in the UK
(see b for guidelines)
• Corticosteroids—IV methylprednisolone 10–30mg/kg/day for 3 days
followed by 1–2mg/kg oral prednisolone (weaning dose).
• MTX 15mg/m2 preferably by the subcutaneous route.
• Physical therapy.
• Photoprotective measures.
• Calcium and vitamin D supplementation.
• Hydroxychloroquine at 3–6mg/kg/day.
• 2nd-line agents
• IVIg
• Ciclosporin
• AZA.
• 3rd-line agents
• Cyclophosphamide
• MMF
• Tacrolimus
• Rituximab
• Anti-TNFA agents.
 JUVENILE DERMATOMYOSITIS 269

Table 4.17 Childhood Myositis Assessment Scale (CMAS) scoring

sheet
1. Head elevation (neck flexion): Item
score . . .
0 = Unable
1 = 1–9sec
2 = 10–29sec
3 = 30–59sec
4 = 60–119sec
5 = >2min
No. of seconds . . . . . . . . . . . . . . . . . . .
2. Leg raise/touch object: Item
score . . .
0 = Unable to lift leg off table
1 = Able to clear table, but cannot touch object
2 = Able to lift leg high enough to touch object
3. Straight leg lift/duration: Item
score . . .
0 = Unable
1 = 1–9sec
2 = 10–29sec
3 = 30–59sec
4 = 60–119sec
5 = >2min
No. of seconds . . . . . . . . . . . . . . . . . . .
4. Supine to prone: Item
score . . .
0 = Unable. Has difficulty even turning onto side; able to pull
arms under torso only slightly/not at all
1 = Turns onto side fairly easily, but cannot fully free arms,
but not able to fully assume a prone position
2 = Easily turns onto side; some difficulty freeing arms, but fully
frees them and fully assumes prone position
3 = Easily turns over, free arms with no difficulty
5. Sit-ups: for each type of sit-up enter either ‘0’ (unable) or ‘1’ Item
(able). Then enter the total subscore. Maximum possible item score . . .
score 6.
Hands on thighs, with counterbalance
Hands across chest, with counterbalance
Hands behind head, with counterbalance
Hands on thighs, without counterbalance
Hands across chest, without counterbalance
Hands behind head, without counterbalance

(continued )
270 CHAPTER 4 Systemic diseases

Table 4.17 (Contd.)

6. Supine to sit: Item
score . . .
0 = Unable by self
1 = Much difficulty. Very slow, struggles greatly, barely makes it.
Almost unable
2 = Some difficulty. Able, but is somewhat slow, struggles some
3 = No difficulty
7. Arm raise/straighten: Item
score . . .
0 = Cannot raise wrists
1 = Can raise wrists at least up to the level of the acromioclavicular
joint. but not above top of head
2 = Can raise wrists above top of head. but cannot raise arms straight
above head so that elbows are in full extension
3 = Can raise arms straight above head so that elbows are in full
extension
8. Arm raise/duration: Item
score . . .
Can maintain wrists above top of head for:
0 = Unable
1 = 1–9sec
2 = 10–29sec
3 = 30–59sec
4 = 60–119sec
5 = >120sec
No. of seconds . . . . . . . . . . . . . . . . . . . . .
9. Floor sit: Item
score . . .
Going from a standing position to a sitting position on the floor.
0 = Unable. Afraid to even try, even if allowed to use a chair for
support. Child fears that he/she will collapse, fall into a sit, or harm
self.
1 = Much difficulty. Able, but needs to hold onto a chair for support
during descent. (Unable or unwilling to try if not able to use a chair
for support.)
2 = Some difficulty. Can go from stand to sit without using a chair
for support, but has at least some difficulty during descent. Descends
somewhat slowly and/or apprehensively; may not have full control or
balance as manoeuvres into a sit.
3 = No difficulty. Requires no compensatory manoeuvring.
 JUVENILE DERMATOMYOSITIS 271

Table 4.17 (Contd.)

10. All-fours manoeuvre: Item
score . . .
0 = Unable to go from a prone to an all-fours position.
1 = Barely able to assume and maintain an all-fours position.
2 = Can maintain all-fours position with straight back and head raised
(so as to look straight ahead). But, cannot creep (crawl) forward
3 = Can maintain all fours, look straight ahead, and creep (crawl)
forward
4 = Maintains balance while lifting and extending leg.
11. Floor rise: Item
score . . .
Going from a kneeling position on the floor to a standing position.
0 = Unable, even if allowed to use a chair for support
1 = Much difficulty, Able, but needs to use a chair for support. Unable
if not allowed to use a chair
2 = Moderate difficulty. Able to get up without using a chair for
support, but needs to place one or both hands on thighs/knees or
floor. Unable without using hands
3 = Mild difficulty. Does not need to place hands on knees, thighs, or
floor, but has at least some difficulty during ascent
4 = No difficulty.
12. Chair rises: Item
score . . .
0 = Unable to rise from chair, even if allowed to place hands on sides
of chair seat
l = Much difficulty. Able, but needs to place hands on sides of seat.
Unable if not allowed to place hands on knees/thighs.
2 = Moderate difficulty. Able, but needs to place hands on knees/
thighs. Does not need to place hands on side of seat.
3 = Mild difficulty. Able; does not need to use hands at all, but has at
least some difficulty;
4 = No difficulty
13. Stool step: Item
score . . .
0 = Unable
1 = Much difficulty. Able, but needs to place one hand on exam table
or examiner's hand
2 = Some difficulty. Able; does not need to use exam table for
support, but needs to use hand(s) on knee/thigh
3 = Able. Does not need to use exam table or hand(s) on knee/thigh

(continued )
272 CHAPTER 4 Systemic diseases

Table 4.17 (Contd.)

14. Pick up: Item
score . . .
0 = Unable to bend over and pick up pencil off floor
1 = Much difficulty. Able, but relies heavily on support gained by
placing hand(s) on knees/thighs
2 = Some difficulty. Needs to at least minimally and briefly place
hand(s) on knees/thighs for support and is somewhat slow
3 = No difficulty. No compensatory manoeuvre necessary
TOTAL SCORE (Max = 53) ......

Table 4.18 The MMT Standard Scoring systems (Oxford and Kendall)
(0–10 scale)
Function of the muscle 0–10
scale
No 0
movement
Test Movement in horizontal plane
movement
Moves through partial range of motion 1
Moves through complete range of motion 2
Moves to completion of range against resistance Or
Moves to completion of range and holds against pressure Or 3
Antigravity position
Moves through partial range of motion
Test Gradual release from test position 4
position
Holds test position (no added pressure) 5
Holds test position against slight pressure 6
Holds test position against slight to moderate pressure 7
Holds test position against moderate pressure 8
Holds test position against moderate to strong pressure 9
Holds test position against strong pressure 10
Oxford MMT:
• 0=no muscle action,
• 1=flicker of muscle action,
• 2=muscle action with gravity counterbalance,
• 3=muscle action against gravity,
• 4=muscle action against gravity with some resistance,
• 5=full muscle strength,
• (9=not done)
 JUVENILE DERMATOMYOSITIS 273

Table 4.18 (Contd.)

Function of the muscle 0–10
scale
The 8 muscle groups assessed are:
• Neck flexors (this must be assessed lying flat as this includes gravity)
• Shoulder abductors
• Elbow flexors
• Wrist extensors
• Hip abductors
• Hip extensors
• Ankle dorsiflexors
• Knee extensors
All 8 muscle groups are assessed and the score is added up to give a global score (out of 80).

Fig. 4.13 (Also see Colour plate 3.) Muscle biopsy in JDM.
274 CHAPTER 4 Systemic diseases

Fig. 4.14 MRI of muscles in JDM.

Further reading
Isenberg DA, Allen E, Farewell V, et al. International consensus outcome measures for patients
with idiopathic inflammatory myopathies. Development and initial validation of myositis activity
and damage indices in patients with adult onset disease. Rheumatology (Oxford) 2004; 43:49–54.
Lowry CA, Pilkington CA. Juvenile dermatomyositis: extramuscular manifestations and their
management. Curr Opin Rheumatol 2009; 2: 575–580.
Pilkington C. Clinical assessment in juvenile idiopathic inflammatory myopathies and the
development of disease activity and damage tools. Curr Opin Rheumatol 2004; 16:673–7.
 OVERLAP SYNDROMES 275

Overlap syndromes
Background
• Paediatric and adolescent rheumatology patients may exhibit features
of >1 of the classical autoimmune rheumatic diseases (JIA, SLE, JDM,
systemic sclerosis) (Fig. 4.15). Such patients are often described as
having ‘overlap’ syndromes or ‘undifferentiated’ autoimmune rheumatic
disease (UAIRD)/connective tissue disease.
• Over time, UAIRD may ‘evolve’ so the features of one of the classical
autoimmune diseases predominate.
• Sometimes one AIRD e.g. JDM may ‘evolve’ into another, e.g. SLE.
• Variability of the clinical manifestations over time is a particular feature
of paediatric overlap syndromes, and is more common than in adult
patients.
The paediatric rheumatologist needs to remain vigilant for features of SLE,
myositis, systemic sclerosis, inflammatory arthritis, and vasculitis in any
child with an overlap syndrome, and should avoid a rigid diagnostic label.

JDM

Systemic
SLE
sclerosis

Fig. 4.15 Overlap syndromes.

Mixed connective tissue disease (MCTD)

This specific overlap syndrome is more clearly defined, and characterized
by:
• Puffy, swollen hands (‘sausage fingers’—diffuse swelling of the entire
digit distinct from the articular swelling seen in JIA).
• Raynaud’s phenomenon.
276 CHAPTER 4 Systemic diseases

• High titre speckled pattern ANA on immunofluorescence with

antibodies to U1-RNP:
• A variety of formal diagnostic criteria have been proposed for
MCTD in adults (e.g. Sharp’s, Kasukawa, Porter’s); none have been
validated in children.
• Controversy exists over whether MCTD is a discrete diagnostic
entity because U1-RNP antibodies are also found in SLE, and
follow-up of adult MCTD patients shows that many differentiate
into SLE or SSc. Proponents of MCTD argue that antibodies to
U1-RNP and MCTD have specific immunogenetic associations
(e.g. HLA-DR4) suggesting a distinct pathogenesis.
• Clinical features and their frequencies (derived from synthesis of data from
a number of case series) in juvenile onset MCTD are shown in Table 4.19.
• Mean age of onset of paediatric MCTD is 9–12yr.
• 5 to 4 ratio ~6:1.
• In children, evolution of MCTD is common. Over time arthritis, myositis,
and SLE-like manifestations transition to scleroderma-type features.
• Inflammatory manifestations (e.g. arthritis, myositis) respond better
to immunosuppression and result in less permanent damage than
scleroderma-type manifestations.
• There are conflicting observations from small case series of paediatric
MCTD over whether SLE-like or sclerodermatous features are more
common than in adult MCTD.
• Some studies report a more benign prognosis in paediatric MCTD
compared to adult disease, but other series show the opposite.
• Pulmonary hypertension, a cause of serious morbidity and mortality
in adults, is rare in paediatric disease.

Table 4.19 Clinical features of MCTD

Manifestation Frequency (%)*
Raynaud’s phenomenon 91%
Arthritis 81%
Sclerodermatous skin changes/sclerodactyly 60%
Rash (may be lupus-type or JDM-type) 50–60%
Myositis 52%
Sicca symptoms/parotiditis 40%
Interstitial lung disease 28%
Oesophageal dysmotility 15%
Thrombocytopenia 12%
Pericarditis 12%
Haemolytic anaemia 5%
Pulmonary arterial hypertension 5%
*Frequencies are derived from synthesis of data from a number of case series
 OVERLAP SYNDROMES 277

Sjögren’s syndrome overlap

• 1* Sjögren’s syndrome (pSS) is an autoimmune exocrinopathy
characterized pathologically by focal lymphocytic infiltration of
glandular tissue eventually leading to glandular destruction.
• Some patients have overlapping features of SS and other connective
tissue diseases. The term ‘Sjögren overlap’ has been used to describe
these patients.
• The syndrome manifests clinically as sicca symptoms (dryness of
mucosal surfaces, particularly eyes and mouth).
• Extraglandular features such as arthralgia, hepatic involvement, and
renal tubular acidosis may also occur.
• Both pSS and Sjögren overlap are very rare in children.
Overlap with organ-specific autoimmunity
• Systemic autoimmune disease may overlap with organ-specific
autoimmune disease.
• SLE/autoimmune hepatitis (AIH) overlap is well described.
• Autoimmune hepatitis occurs in 9% of juvenile SLE patients
(compared to only 1% of adult SLE patients).
• In juveniles AIH usually precedes the development of SLE; in adults
the converse is true.
Investigations in patients with overlap syndromes:
These depend on the clinical manifestations. However, consideration
should be given to the following:
• Full immunological work-up at initial presentation to best characterize
disease:
• RF, ANA, ENA, dsDNA, ANCA, anticardiolipin antibodies and lupus
anticoagulant, complement (C3, C4), immunoglobulins G, A, and M.
• Serial measurement of dsDNA & C3/C4; repeat ENA every 2yr as the
autoantibody profile may evolve with time.
• TFTs and anti-thyroid antibodies.
• Coombs’ test.
• Muscle enzymes (CK, LDH, AST).
• Urine dip at all clinic visits; if abnormal request urine microscopy to
look for casts, urine culture, and urine protein:creatinine ratio.
• MRI is a useful non-invasive tool for assessing myositis. Muscle biopsy
remains the ‘gold standard’ but is painful and so often avoided in
children.
• CXR.
• Lung function tests with gas transfer (depending on the age of the
child) to identify interstitial lung disease—consider high resolution CT
of the chest if abnormal.
• Echocardiography to estimate pulmonary artery pressure (PAP) if
pulmonary hypertension suspected.
Treatment
Treatment is tailored to individual manifestations of the child’s disease:
• Arthritis—NSAIDs, MTX, hydroxychloroquine, corticosteroids.
• Rash—hydroxychloroquine, topical treatments including steroids and
tacrolimus.
278 CHAPTER 4 Systemic diseases

• Raynaud’s phenomenon—calcium channel blockers (e.g. nifedipine),

GTN patch, angiotensin II receptor blockers in addition to conservative
measures.
• IV epoprostenol or eporostenol analogue (e.g. iloprost) may be
used in severe cases with digital ischaemia.
• Myositis—steroids, AZA, MTX. IVIg and cyclophosphamide may be
used in severe cases. Rituximab may have a role.
• Interstitial lung disease—steroids, AZA, or MMF, or CPM
• Pulmonary arterial hypertension (PAH)—this carries a poor prognosis.
Consult a cardiologist with experience of PAH.

Iloprost administration: standard regimen is an infusion lasting 6h per

day for 5 consecutive days. See also b BSPAR guidelines for treatments
uses in paediatric rheumatology, p 415.
50 micrograms (0.5mL) Iloprost is mixed with 49.5mL of normal saline
in a syringe driver, giving a solution of 50mcg in 50mL. A fresh solution
should be prepared daily.
Day1
• Commence at 0.5 nanogram/kg/min (1mcg = 1000ng).
• If tolerated, after 30min i to 1 ng/kg/min.
• If tolerated, after further 30min i to 1.5ng/kg/min.
• If tolerated, after further 30min i to 2ng/kg/min. Run at this rate for
the remaining 4.5h.
On subsequent days commence rate at the highest rate tolerated on the
previous day.
Check P/BP/T prior to infusion, every 30min during infusion, and 1h post
infusion.
Common side effects: facial flushing, headaches, nausea & vomiting, diar-
rhoea, sweating, paraesthesia, erythema around infusion site, hypoten-
sion. If mild, reduce rate by 0.5ng/kg/min. If moderate/severe stop the
infusion. It may be possible to re-start at the lowest rate following pre-
medication with paracetamol and an antiemetic.
NB Iloprost is renally excreted: use ½ dose in patients on dialysis.
 ANTIPHOSPHOLIPID SYNDROME (APS) 279

Antiphospholipid syndrome (APS)

Background
• APS is a multisystem autoimmune disease characterized by persistent
positivity of antiphospholipid (aPL) antibodies in the presence of
vascular thrombotic events, pregnancy morbidity, and other clinical
manifestations.
• The APS may occur as an isolated clinical entity (p APS) or in
association with an underlying systemic disease (s APS), most
commonly SLE.
• Paediatric p APS is very rare whilst the prevalence of s APS in
children with SLE is estimated to be 9–14%.
Classification criteria
Preliminary criteria for the classification of paediatric APS are based
on the recently revised classification criteria for the diagnosis of APS in
adults, and include:
• Clinical criteria—vascular thrombosis: 1 or more clinical episodes of
arterial, venous, or small-vessel thrombosis, in any tissue or organ.
Thrombosis must be confirmed by objective validated criteria (i.e.
unequivocal findings of appropriate imaging studies or histopathology).
For histopathological confirmation, thrombosis should be present
without significant evidence of inflammation in the vessel wall.
• Laboratory criteria must be present on 2 or more occasions, at least
12 weeks apart and include:
• Anticardiolipin antibody (ACL) of IgG and/or IgM isotype in serum
or plasma: must be present in medium or high titre (i.e. >40 GPL or
MPL, or >99th percentile)
• Anti-B2 glycoprotein-I antibody of IgG and/or IgM isotype in serum
or plasma: must be present in titre >99th percentile.
• Lupus anticoagulant (LA) in plasma.
Paediatric APS is considered to be present if the clinical criterion and at
least 1 of the laboratory criteria are met.
Pathogenesis
• Exactly how aPL antibodies cause thrombosis, and why some patients
develop thromboses rather than pregnancy morbidity is currently not
known.
• One hypothesis postulates that pathogenic aPL antibodies target and
bind cellular and platelet phospholipids in the presence of certain
serum cofactors such as beta-2 glycoprotein I, leading to cellular
activation and biological effects such as promotion of thrombosis.
• In addition, aPL antibodies cause an i in expression of tissue factor
(a critical pro-thrombotic intermediate in the clotting cascade) in both
monocytes and endothelial cells.
Furthermore, platelet and complement activation as well as endothelial
activation and a ‘second hit’ inflammatory signal may play a role, particu-
larly in those with catastrophic APS (CAPS).
280 CHAPTER 4 Systemic diseases

Clinical features
The clinical manifestations of APS in children include:
• Vascular thrombosis:
• Most commonly this is deep vein thrombosis of the lower limbs.
• More rare are thromboses in the superficial and upper extremity
veins, inferior and superior vena cava, hepatic (Budd–Chiari syndrome)
and portal veins, renal, adrenal, retinal, and intracranial veins.
• Arterial thrombosis, resulting mainly in stroke (20% of all
thrombotic events thromboses) and transient ischaemic attacks
(11% of all thrombotic events), are less common. Other involved
vessels include coronary, subclavian, mesenteric, renal, retinal, and
pedal arteries. Of note is that arterial thrombosis is much more
common in children than in adults.
• Central nervous system symptoms—chorea (always consider APS in
the differential diagnosis of Sydenham’s chorea), dementia, migraine,
intracranial hypertension, neurocognitive deficits, psychosis and
depression, epilepsy, Guillain–Barré syndrome, transverse myelopathy
and optical neuritis.
• Cardiac manifestations—valvulopathy (mitral/aortic valves),
intracardiac thrombosis, coronary artery thrombosis and
cardiomyopathy.
• Haematological disorders—mainly thrombocytopenia and haemolytic
anemia (direct Coombs testing is usually positive in the latter).
• Skin manifestations—livedo reticularis, cutaneous gangrene, skin
ulcers, livedoid vasculopathy (an important occlusive vasculopathy
mimicking vasculitis, although not vasculitic in nature), palmar and
plantar erythema, anetoderma (focal loss of dermal elastic tissue,
resulting in localized areas of flaccid or herniated saclike skin),
Raynaud’s phenomenon.
• Renal manifestations include:
• Renal artery thrombosis.
• Thrombosis in smaller-diameter renal parenchymatous vessels,
resulting in areas of focal cortical, ischaemia and/or necrosis.
• Thrombotic microangiopathy—most characteristic lesion of APS
nephropathy, with distinctive microscopic and ultrastructural changes.
• Thrombosis of the renal veins and inferior vena cava.
• Pulmonary involvement is rare in children with APS, but includes:
pulmonary embolism, intra-alveolar haemorrhages, p thrombosis of
lung vessels, both major and minor, as well as pulmonary capillaritis,
pulmonary hypertension.
• Various GI manifestations have been reported including intestinal
and oesophageal ischaemia and infarction, ischaemic colitis, colonic
ulceration, infarction of the liver, cholecystitis, and mesenteric, hepatic,
and portal vein thrombosis.
• Perinatal APS—rare cases of perinatal thrombosis in infants born to
mothers with APS or mothers with aPL antibodies have been reported,
with the clinical presentation consisting of arterial and venous
thromboses in multiple localizations. Although patients in this subgroup
have diagnostic criteria of APS, their disease behaves differently, is
transitory and does not recur, similar to patients with neonatal SLE.
 ANTIPHOSPHOLIPID SYNDROME (APS) 281

Laboratory investigations
• Clotting screen:
• The first clue to the presence of aPL antibodies is the finding of a
prolonged APTT. If the clotting remains abnormal when the patient’s
plasma is mixed with normal pooled plasma, this is suggestive of the
presence of an inhibitor, the lupus anticoagulant (LA).
• The presence of LA is then confirmed with a phospholipid-sensitive
functional clotting testing, such as the dilute Russell viper venom
test (dRVVT). In part one of the test Russell viper venom directly
activates factor X, but phospholipid is still required to generate
thrombin, so in the presence of PL binding anticardiolipin antibodies
(the LA) clotting is delayed. In the second part of the test the
inhibitory effect of LA on phospholipids can be overcome by adding
an excess of phospholipid to the assay. The clotting times of both
the initial dRVVT assay and the second part of the test are used
to determine a ratio of time with or without phospholipid excess.
A ratio >1.2 is considered positive and implies that the patient may
have aPL antibodies.
• Other tests for measuring aPL antibodies are the enzyme-linked
immunosorbent assay which detects different isotypes of
anticardiolipin antibodies and antibodies to many other phospholipids
(phosphatidylserine, phosphatidylinositol, phosphatidylcholine).
• Another group of antibodies are directed against protein co-factors
that bind the phospholipids, such as beta-2 glycoprotein-1 and annexin.
• Although there is some overlap between all these antibodies, it is
important to use >1 test to detect them.
Treatment
The risk of thrombosis is low in asymptomatic children who are incidentally
found to have positive aPL; high among those in whom thrombosis already
occurred and extremely high in patients with CAPS.
• Aspirin at low doses (2–5mg/kg/once daily) has been used as
prophylaxis in aPL-positive children with autoimmune diseases but
without previous thromboses and in particular to prevent arterial
thromboses.
• Hydroxychloroquine may be protective against the development of
thrombosis in aPL-positive patients with SLE.
• Warfarin: lifelong treatment if one major thrombotic episode has
occurred (such as pulmonary or femoral arterial thrombus) is
recommended, aim for INR 2–3.
Dosing regimen for warfarin is:
• 200 micrograms/kg (max. 10mg) as a single dose on first day.
• Reduce dose to 100 micrograms/kg (max. 5mg) once daily for following
3 days. Note that:
• If INR still below 1.4 use 200 micrograms/kg (max. 10mg) once daily, or
• If INR above 3 use 50 micrograms/kg (max. 2.5mg) once daily, or
• If INR above 3.5 omit dose;
• Dose is then adjusted according to INR, usual maintenance
100–300 micrograms/kg once daily (may need up to 400 micrograms/kg).
282 CHAPTER 4 Systemic diseases

NB initial warfarinization should be covered with full heparinization to

prevent warfarin-induced thrombosis due to inhibition of protein C and
S which occurs at INR levels <2. Heparin is usually given in its low-molec-
ular-weight forms (LMWH) subcutaneously at therapeutic doses. It will
often take up to 10 days to adjust warfarin treatment to obtain the rec-
ommended INR. During this time LMWH treatment is assessed through
monitoring anti-Xa levels to ensure a therapeutic range (0.5–1.0 anti-Xa
units/ml plasma). This is of particular importance in children with renal or
hepatic impairment and severely ill children. Note that LMWH is not as
easy to reverse as unfractionated heparin.
In cases of s APS, treatment of the underlying condition should be initi-
ated in addition to anticoagulation and anti-platelet therapy.
Outcome
In one study, of a large paediatric APS cohort at follow-up of 6.1yr:
• 19% developed recurrent thromboses, which usually occurred in a
similar blood vessel type as initial thrombosis.
• 5% presented with life threatening widespread thrombotic disease
suggestive of CAPS.
• 7% died mainly due to aPL-related thrombotic complications.
Catastrophic APS (CAPS)
• CAPS is a rapidly progressive life-threatening disease causing multiple
organ thromboses and dysfunction in the presence of aPL antibodies,
and is associated with an i mortality despite treatment. The syndrome
is characterized by a diffuse thrombotic microvasculopathy.
• The exact pathogenesis of CAPS remains unclear. One hypothesis
postulates that clots continue to generate thrombin, fibrinolysis is
depressed by an i in plasminogen activator inhibitor type-1 (PAI-1),
and there is consumption of the natural anticoagulant proteins such
as protein C and antithrombin III. In addition, manifestations of the
systemic inflammatory response syndrome are presumed to be due to
excessive cytokine release from affected and necrotic tissues.
• Another specific characteristic of CAPS is that 60% of patients appear
to have a triggering factor especially infections, the commonest
identifiable trigger for CAPS and present in about 25% of cases.
• For treatment of CAPS seek expert advice and consider IVIg (2g/kg),
Pulsed IV methylprednisolone, cyclophosphamide and/or rituximab and
plasma exchange, in addition to full anticoagulation and anti-platelet
therapy as per APS.
• Despite treatment, mortality in CAPS is reported to be as high as 48%.
Further reading
Avcin T, Silverman ED. Antiphospholipid antibodies in pediatric systemic lupus erythematosus and
the antiphospholipid syndrome. Lupus 2007; 16; 627.
Avcin T, Cimaz R, Rozman B; Ped-APS Registry Collaborative Group Lupus. The Ped-APS
Registry: the antiphospholipid syndrome in childhood. Lupus 2009; 18:894–9.
 PAEDIATRIC UVEITIS 283

Paediatric uveitis
• Uveitis is the term for intraocular inflammation, i.e. those layers internal
to the sclera and cornea (see Fig. 4.16 for a diagram of eye anatomy).
• The uveal tract is the vascular layer including the choroid, ciliary body,
and iris (uvea = grape in Greek).
• The term uveitis referred to inflammation of the uveal tract but can
also refer to inflammation of the retina and vitreous.
Aetiology
• The causes can be infectious and non-infectious (Tables 4.20 and 4.21).
• Non-infectious uveitis has an approximate incidence of 4–7/100 000
children.
• The appearance and site of the inflammation may help to determine
the cause, e.g. sarcoidosis is typically a granulomatous anterior or
panuveitis. The investigations to consider depend on the clinical
presentation (Table 4.22).
Masquerade syndromes include:
• Juvenile xanthogranulomatosis—typical histiocytic skin lesions which
may involve the eye, particularly iris
• Diffuse retinoblastoma
• Intraocular foreign body
• Leukaemia
• 1° retinal detachment
• Retinal dystrophy.

Pars plana Sclera Choroid Retina

Eyelids

Cornea Optic
nerve
Iris
Pupil Lens

Anterior chamber
Posterior chamber

Ciliary body
Vitreous

Conjuctiva

Anterior Intermediate Posterior

Fig. 4.16 Anatomy of the eye: Reproduced from M http://www.uveitis.net/patient/

glossary.php, with permission.
284 CHAPTER 4 Systemic diseases

Table 4.20 Infectious causes of paediatric uveitis

Relatively common Relatively uncommon but with
geogrphical variation

• Toxoplasmosis gondii • Lyme disease

• Varicella zoster • Toxocara
• Herpes simplex virus • Histoplasmosis
• Cytomegalovirus • Ascaris
• Tuberculosis • Echovirus
• Bartonella • Fungal infection
• Syphilis

Table 4.21 Non-infectious types of paediatric uveitis

No systemic disease Associated with systemic disease
association
Idiopathic uveitis: the Common:
most common type in • Juvenile idiopathic arthritis (JIA)—
population-based cohorts. typically chronic asymptomatic anterior
uveitis. The most common systemic disease
In children <8yr of age idiopathic
associated with paediatric uveitis worldwide
chronic anterior uveitis is by far
• Enthesitis related arthritis—usually acute
the most common.
anterior uveitis and often carry HLA B27
In those with onset between • Inflammatory bowel disease—anterior
8–15yr of age intermediate and intermediate uveitis
uveitis is relatively more • Sarcoidosis—anterior and pan uveitis.
common, and in older patients Granulomas of uvea frequent
acute anterior uveitis is the • Blau syndrome—if there is a family history
most frequent type, as in adults. of granulomatous disease consider this
autosomal dominant genetic granulomatous
Named uveitis syndromes are
condition involving arthritis, uveitis and
very rare in childhood:
dermatitis with a typical skin rash (NOD2
• Sympathetic ophthalmia—
gene; see b p 300 sarcoid)
trauma to one eye causes
• Tubulointerstitial nephritis uveitis
uveitis in the other eye,
(TINU)—bilateral anterior uveitis and
typically multifocal
acute interstitial nephritis; occasionally
choroiditis and panuveitis
associated with deafness.
 PAEDIATRIC UVEITIS 285

Table 4.21 (Contd.)

No systemic disease Associated with systemic disease
association
Less common
• Acute multifocal placoid • Kawasaki disease—an acute non-
pigment epitheliopathy granulomatous bilateral uveitis which usually
• Fuch’s cyclitis resolves without any specific ocular therapy
• Birdshot retinochoroidopathy and without visual complication
• Other childhood-onset vasculitides: WG,
PAN, scleroderma, SLE, Cogan’s syndrome
(atypical; typical Cogan’s is associated with
interstitial keratitis)
• Behçets disease—posterior and anterior
uveitis is recognized. Rare to have onset of
uveitis in childhood
• Chronic inflammatory neurologic
cutaneous and articular syndrome
(CINCA)—uveitis and papillitis with
chronic disc swelling
• Other periodic fever syndromes
• Vogt–Koyanagi–Harada syndrome—
uveitis, vitiligo, poliosis (= d or absence of
melanin in head hair, eyebrows, or eye-
lashes), neurological and auditory findings
• Multiple sclerosis with intermediate uveitis
is rare in childhood, although intermediate
uveitis is common

Table 4.22 Anatomical classification of uveitis

Uveitis type Inflammation site
Anterior uveitis Anterior segment (i.e. iris ± ciliary body)
Intermediate uveitis Vitreous and retina
Anterior and intermediate Intermediate uveitis with significant anterior uveitis
uveitis
Posterior uveitis Retina or choroid only
Panuveitis Anterior uveitis and posterior uveitis

Uveitis associated with JIA

• JIA is the commonest systemic disease associated with paediatric
uveitis. 15% of children with JIA have uveitis, usually chronic anterior
uveitis and it can occur before, or up to 7yr after the onset of arthritis.
• Predisposing factors include:
• Oligoarticular rather than polyarticular onset.
286 CHAPTER 4 Systemic diseases

• Age at JIA onset <7yr (and especially <4yr), and ANA positivity.
• Uveitis is much less common in sJIA and chronic anterior uveitis
is not typically associated with childhood onset ERA or RA. The
presence of psoriasis may i the risk of chronic anterior uveitis.
• There is no difference known in the course or pattern of uveitis seen in
JIA other than the almost exclusive association of acute anterior uveitis
in those with clinical enthesis related arthritis. All other JIA types, other
than early onset RA develop chronic anterior or chronic anterior and
intermediate uveitis.
• Children <8yr rarely describe unilateral visual loss reliably so screening
for vision in each eye is required.
• JIA uveitis can cause irreversible blindness without changes in the
appearance of the eye or reliably reported symptoms.
• All JIA children should have eye screening with a slit lamp examination
according to the Royal College of Ophthalmologists and BSPAR (see
b Screening, p 148).
• Poor prognostic features for vision include uveitis present prior to
arthritis, severe uveitis at presentation and the failure to achieve early
remission.
• Irreversible complications may occur after only a few weeks of
uncontrolled eye inflammation.
• Complications include raised intraocular pressure, glaucoma, posterior
synechiae, band keratopathy, cataract, retinal detachment, macular
oedema, and hypotony.
• Visual loss may affect up to 25% of JIA uveitis.
• Reducing JIA medication given for arthritis, e.g. MTX may result in a
uveitis flare.
• Raised inflammatory markers in the absence of corresponding articular
signs may represent ocular inflammation.
Treatment modalities in paediatric uveitis (Table 4.23)
The correct treatment of uveitis balances the long-term risk, and effects of
visual loss with the short- and long-term risks of treatment. In most cases
these are not well established. About half of children with JIA-uveitis or
intermediate uveitis do not suffer visual loss despite prolonged inflamma-
tion. Aggressive treatment should be confined to those with a significant
risk of permanent visual loss, and this risk (and the efficacy of available
treatments) may change considerably over the course of disease.
Treatment will depend on causes identified from the investigations previ-
ously described. For idiopathic and autoimmune/autoinflammatory causes,
including uveitis associated with JIA:
• Topical corticosteroids are invariably used when the predominant
site of inflammation is anterior, e.g. prednisolone or dexamethasone
1% drops. They are not indicated when the predominant site is
intermediate or posterior.
• Topical mydriatics are used to reduce the risk of synechiae formation
in anterior uveitis.
• Topical glaucoma agents may be required to reduce intraocular pressure.
• Systemic corticosteroids, e.g. oral prednisolone, short-term high dose to
gain control followed by a reducing course over 4–6 weeks. The need
for long-term systemic steroids needs regular review in growing children.
 PAEDIATRIC UVEITIS 287

• Periocular corticosteroids, e.g. orbital floor steroid injection may be

used where topical steroids are ineffective. Intravitreal steroids are
occasionally used where risk of cataract and glaucoma are low.
• MTX 15mg/m2 once weekly (SC or PO) when topical steroids are
insufficient is frequently used in patients with JIA. Other steroid-sparing
agents used in adult uveitis may be more appropriate in other types of
uveitis.
• Inhibitors of tumour necrosis factor alpha (anti-TNFA) i.e. infliximab
and adalimumab have been used in JIA—uveitis poorly controlled with
MTX. They may be more effective than etanercept or other 2nd-line
immunosuppressants but there is no trial data to confirm this—see
b Biologics, p 393.
• The Interleukin 1 inhibitors, anakinra and canakinumab, have been used
to treat uveitis associated with CAPS (which includes the severe variant
chronic infantile neurological cutaneous arthritis, CINCA).

Table 4.23 Suggested investigations in paediatric uveitis

Suggested first line Suggested second line investigations
investigations
• FBC, blood film • Tissue biopsy—especially of rashes; other including
• ESR, CRP renal biopsy
• Renal function: • CXR
plasma creatinine • Chest CT
and consider formal • Serum ACE
GFR if abnormal • ANCA
• Immunoglobulins • MRI/MRA brain
• ASO titre • Selective visceral arteriography (particularly for PAN,
• ANA see b p 168 Vasculitis)
• Urine analysis for • Pure tone audiometry and assessment of vestibular
blood and protein; function (Cogan’s)
UA:UC if proteinuria • Many others—including specific genetic tests
on dip test dependent on the clinical presentation
• Mantoux and or • To pursue the diagnosis of infectious/malignant
Quantiferon (or causes where the clinical diagnosis is in doubt:
equivalent gamma • PCR (including 16S and 18S ribosomal PCR as
interferon release screening tests for bacterial and fungal infection
assay) respectively) and cytology of ocular fluids is usually
necessary.
• Serology for infectious agent may be helpful to
exclude, but not diagnose, causes of ocular
infection.

Standardizing uveitis measurement for research

• Currently there are no standardized criteria for measuring paediatric
uveitis activity in clinical studies.
• Proposed standardized terms and grades for adult uveitis were
published in 2005.
Further reading
Standardization of Uveitis Nomenclature for Reporting Clinical Data. Results of the First
Workshop. Am J Ophthalmol 2005; 140:509–16.
288 CHAPTER 4 Systemic diseases

Periodic fever syndromes/

autoinflammatory disease
Introduction
The periodic fever syndromes are disorders of innate immunity, some-
times referred to as autoinflammatory diseases.
They are characterized by the following:
• Recurring episodes of fever and constitutional upset, but with normal
health between attacks.
• Systemic inflammatory symptoms affecting the:
• Serosal surfaces
• Joints
• Skin
• Eyes.
• Symptoms are always accompanied by biochemical markers of
inflammation such as raised ESR, CRP, and leucocytosis.
• The various syndromes are compatible with near-normal life
expectancy, except for the risk of developing amyloid A (AA)
amyloidosis in later life.
• Despite similarities in symptoms, the syndromes have differing
aetiologies, inheritance, duration, and clinical features.
• The hereditary periodic fever syndromes are associated with mutations
in genes involved in innate immunity and generally the onset is early
in childhood affecting both sexes equally. 7 major syndromes are
currently recognized (summarized in Table 4.24):
• Familial Mediterranean fever (FMF)
• TNF receptor-associated period syndrome (TRAPS)
• Mevalonate kinase deficiency (MKD) (also known as
hyperimmunoglobulin D and periodic fever syndrome (HIDS))
• Cryopyrin associated periodic syndrome (CAPS) (subdivided into
Familial cold autoinflammatory syndrome (FCAS), Muckle–Wells
syndrome (MWS) and chronic infantile, neurological, cutaneous
and articular syndrome/neonatal onset multisystem inflammatory
disease (CINCA/NOMID))
• Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA)
syndrome
• Deficiency of IL-1 receptor antagonist (DIRA)
• Blau syndrome/early onset sarcoidosis (EOS).
• There are now completely effective treatments for most patients with
FMF, CAPS, and DIRA and although not always quite as effective, good
treatments are available for the majority of the other syndromes too.
• Disorders of unknown aetiology which share some features with the
inherited syndromes include:
• Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis
(PFAPA) syndrome
• Behçet’s disease
• Chronic recurrent multifocal osteomyelitis (CRMO)—(see b
CRMO, p 297)
• Systemic juvenile idiopathic arthritis (sJIA)—see b JIA and MAS, p 305.
Table 4.24 Hereditary periodic fever syndromes
Periodic Gene Mode of Predominant Usual Potential Distinctive Typical Typical Characteristic Treatment
fever inheritance ethnic age at precipitants clinical duration frequency laboratory
syndrome groups onset of attacks features of attacks of attacks abnormalities
FMF MEFV Autosomal Eastern Childhood/ Usually none Short severe 1–3 days Variable Marked acute Colchicine
recessive Mediterranean early adult attacks phase response
Chromosome 16 Occasionally
(dominant in during attacks
menstruation, Colchicine
rare families)
fasting, stress, responsive
trauma
Erysipelas like
erythema
TRAPS TNFRSF1A Autosomal Northern Childhood/ Usually none Prolonged More than Variable, Marked acute Etanercept
dominant, can European but early adult symptoms a week, may be phase response
Chromosome 12 High-dose
be de novo reported in may be very continuous during attacks.
corticosteroids
many ethnic prolonged Low levels of
groups soluble TNFR1
when well
HIDS MVK Autosomal Northern Infancy Immunizations Diarrhoea and 3–7 days 1–2-monthly Elevated IgD Anti-TNF
recessive European lympha- & IgA, acute and anti IL-1
Chromosome 12
denopathy phase therapies
response, and
mevalonate
aciduria
during attacks

(continued )
Table 4.24 (Contd.)
Periodic Gene Mode of Predominant Usual Potential Distinctive Typical Typical Characteristic Treatment
fever inheritance ethnic age at precipitants clinical duration frequency laboratory
syndrome groups onset of attacks features of attacks of attacks abnormalities
CAPS NLRP3 Autosomal Northern Neonatal/ Marked Severity Continuous Often daily Varying but
dominant or European infancy diurnal spectrum often worse marked acute
Chromosome 1
sporadic variation including: in the phase response
evenings most of the
Cold Urticarial
time
environment rash
but less
Conjunctivitis
marked than
in FCAS Sensorineural
deafness
Aseptic
chronic
meningitis
Deforming
arthropathy
PAPA PSTPIP1 (CD2BP1) Autosomal Northern Childhood None Pyogenic Intermittent Variable, Acute phase Anti-TNF
dominant European arthritis, attacks with and may be response therapy or anti
Chromosome 15
(only 3 families pyoderma migratory continuous during IL-1 therapies
reported) gangrenosum arthritis attacks
Cystic acne
DIRA IL1RN Autosomal Hispanic and Neonatal None Sterile Continuous Continuous Marked IL-1ra
recessive European multifocal acute phase
Chromosome 2
(few families osteomyelitis, response
reported) periostitis, and
pustulosis
Blau NOD2 (CARD15) Autosomal None Childhood None Granulomatous Continuous Continuous Sustained Corticosteroids
syndrome dominant polyarthritis, modest acute
Chromosome 16
iritis, and phase
dermatitis response
292 CHAPTER 4 Systemic diseases

Inherited fever syndromes

Familial Mediterranean fever is commonest in Middle Eastern populations
(prevalence 1/250 to 1/1000) but occurs worldwide. It is inherited reces-
sively due to mutations in the MEFV gene on chromosome 16.
Clinical features
• Attacks occur irregularly and may be precipitated by minor physical or
emotional stress, the menstrual cycle, or diet.
• Attacks resolve within 72h and the clinical features are:
• Fever
• Aseptic peritonitis in 85%
• Pleuritic chest pain in 40%
• Erysipelas-like rash occurs in 20%
• Meningitic headache rarely
• Orchitis rarely
• Joint involvement is rare and generally mild affecting the lower
limbs.
• Acute attacks are accompanied by a neutrophil leucocytosis and a
dramatic acute phase response.
• Protracted febrile myalgia is a very rare complication, characterized by
severe pain musculature and can be accompanied by a vasculitic rash; it
usually responds to high-dose corticosteroid therapy.
Diagnosis
Supported by DNA analysis but remains clinical and centres on the history
of recurrent self-limiting attacks of fever and serositis that are prevented
by colchicine.
Treatment
• Colchicine has now been licensed by the US Food and Drug
administration for the prophylactic treatment of FMF from the age of
4yr upwards.
• Continuous use prevents or substantially reduces symptoms of FMF in
at least 95%, and almost completely eliminates the risk of developing
AA amyloidosis.
• The mechanism of action of colchicine remains incompletely
understood but most patients respond to between 250 microgrammes
and 2mg daily.
Long-term complications
• Life-long treatment is required but in general the long-term outlook is
excellent.
• Prior to colchicine, 60% of Turkish patients developed AA amyloidosis,
effective long-term colchicine prophylaxis should completely prevent
this.
• Destructive arthritis is very rare.
• Growth, educational achievement and fertility appear to be normal
for both sexes once treated, but otherwise severe disruption to
development, education and family life results from the recurrent
attacks.
 PERIODIC FEVER SYNDROMES/AUTOINFLAMMATORY DISEASE 293

Tumour necrosis factor-receptor associated periodic syndrome (TRAPS) is

very rare with an estimated prevalence of about 1 per million in Europe.
It is an autosomal dominant disease where there is usually a family history.
It occurs in many ethnic groups and presentation is usually before the age
of 4yr.
Clinical features
TRAPS attacks are often far less distinct than in FMF and may be precipi-
tated by minor stress, travel, the menstrual cycle or diet. Typical features
are:
• Prolonged attacks lasting 1–3 weeks (symptoms are near continuous in
30%).
• 750% give no clear family history.
• >95% of patients experience fever.
• 80% classically have arthralgia and myalgia often with centripetal
migration.
• Abdominal pain occurs in 80% of patients.
• Rash (erythematous, oedematous plaques, discrete reticulate or
serpiginous lesions) occurs in 70% of patients.
• Other features include:
• Headache
• Pleuritic pain
• Lymphadenopathy
• Conjunctivitis and periorbital oedema.
• Symptoms are accompanied by a marked acute phase response.
Diagnosis
Genetic testing is central to diagnosis. One difficulty is interpretation of
the significance of 2 common polymorphisms, R92Q (Caucasian) and
P46L (African/Arab origin). Both are present in 74% of normal population
but can be associated with a mild inflammatory syndrome.
Treatment
• Acute attacks respond to high-dose corticosteroids but this does not
reduce the frequency of attacks.
• Etanercept is useful in some patients, but infliximab and other
monoclonal antibodies to TNF exacerbate the attacks.
• IL-1 blockade seems to be the most effective treatment: recombinant
IL-1 Ra (anakinra) is effective in 780% cases but needs to be injected
daily. Long-acting IL-1 blocking agents such as canakinumab may be
used more frequently for TRAPS in the future.
Long-term complications
• Life-long treatment is required but, in general, the long-term out look
is good.
• Without effective long-term treatment >25% patients developed AA
amyloidosis.
• Growth, educational achievement, and fertility appear to be
near normal for both sexes only if treated. Otherwise the child’s
development, education, and family life are severely compromised.
294 CHAPTER 4 Systemic diseases

Mevalonate kinase deficiency (MKD) also known as hyperimmunoglobulin

D periodic fever syndrome (HIDS) is an autosomal recessive disease. MVK
is the enzyme after HMG CoA reductase, most mutations found in this
syndrome reduce enzyme activity by >90%. Mutations resulting in near
complete absence of enzyme activity cause a much more severe disease
called mevalonic aciduria (MVA) with severe mental retardation. MKD is
extremely rare, most patients are North European with a concentration
in Holland and indeed it used to be called ‘Dutch fever’, although it occurs
in other ethnicities. Usually the onset of MKD is below 1yr of age.
Clinical features
• Attacks occur irregularly and may be precipitated by vaccination, minor
trauma, surgery, or stress.
• Attacks last 4–7 days and consist of:
• Fever
• Unilateral or bilateral cervical lymphadenopathy
• Abdominal pain with vomiting and diarrhoea
• Headache, arthralgia, large joint arthritis, erythematous macules and
papules, and aphthous ulcers are also common
• History of high fevers or a full attack with vaccination.
• Attacks are often less severe in adult life.
Diagnosis
• A high serum IgD, IgE, and IgA concentration are seen although these
are not specific.
• Presence of mevalonic acid in the urine during attacks.
• A mutation in both alleles of the MVK gene can be identified in most
patients.
Treatment
• Etanercept is useful in some patients.
• IL-1 blockade seems to be the most effective treatment anecdotally.
Recombinant IL-1 Ra (anakinra) can either be used continuously or to
abort attacks.
• Statins do not appear to be useful
Long-term complications
• Symptoms may partially improve with age.
• AA amyloidosis has been reported but appears less common than in
FMF, TRAPS, or CAPS.
Cryopyrin associated periodic syndrome (CAPS)
CAPS comprises an overlapping severity spectrum ranging from mild to
severe otherwise known as familial cold autoinflammatory syndrome
(FCAS); Muckle–Wells syndrome (MWS); and chronic infantile neuro-
logical, cutaneous, and articular syndrome (CINCA), which is known in
the US as neonatal onset multisystem inflammatory disease (NOMID).
CAPS is associated with mutations in NLRP3/CIAS1 on chromosome
1q44, encoding a key component of the IL-1 activation complex, called the
inflammasome. Dominant inheritance occurs in about 75% of patients with
FCAS and MWS, whereas CINCA is usually due to de novo mutations.
Most reported patients are Caucasian but cases have been described from
 PERIODIC FEVER SYNDROMES/AUTOINFLAMMATORY DISEASE 295

South Asia and elsewhere. Onset of disease is usually in early infancy,

often from birth, and there is no sex bias.
Clinical features
• In FCAS, attacks of fever, urticarial rash, arthralgia, and conjunctivitis
are precipitated by exposure to cold or damp conditions.
• In MWS, attacks usually occur daily often in the afternoon and evenings
although there may be a degree of cold exacerbation. Acute symptoms
are fever, urticarial rash, arthralgia and myalgia, conjunctivitis, headache,
and fatigue. The rash can be persistent. Deafness occurs later and is
often missed in the early stages.
• In CINCA/NOIMID there is continuous inflammation with additional
severe chronic aseptic meningitis, raised intracranial pressure, uveitis,
deafness, and arthropathy.
Diagnosis
Patients with FCAS and MWS have mutations in NLRP3. Mutations are
present in only 50% of CINCA/NOMID patients.
Treatment
The treatment of choice is IL-1 blockade with anakinra or with 2 other
licensed therapies: the fully human anti-IL-1beta antibody canakinumab; or
IL-1 Trap (rilonacept).
Long-term complications
• AA amyloidosis occurs in 725% of patients.
• Complications of chronic CNS inflammation—these are most severe in
CINCA but are also seen in MWS:
• Sensorineural deafness in 40%
• Blindness due to optic atrophy or uveitis
• Developmental delay.
• Arthropathy causes cartilage and bony overgrowth especially affecting
the patella. Joint destruction can occur. In 17%, clubbing of the finger
nails is seen.
Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA)
syndrome
• This is an exceptionally rare autosomal dominant disease caused by
mutations in the proline serine threonine phosphatase-interacting
protein 1 (PTSTPIP) gene encoding a protein also known as CD2
binding protein 1 (CB2BP1).
• The underlying pathogenesis remains poorly understood although
there is evidence that CD2BP1 interacts with pyrin.
• It is characterized clinically by severe acne and recurrent pustular
sterile arthritis which typically occurs after minor trauma.
• Early reports suggest that therapy with anakinra may be effective,
especially for the skin lesions.
Deficiency of the IL-1 receptor antagonist (DIRA)
• This autosomal recessive disease was first described in 2009 with very
few affected families known and is due to mutations in IL1RN resulting
in a total deficiency of IL-1 receptor antagonist.
296 CHAPTER 4 Systemic diseases

• Presents in the immediate neonatal period with a pustular rash, joint

swelling, osteolytic lesions, and periosteitis typically affecting the distal
ribs and the long bones.
• Treatment is anakinra with good responses seen in all cases treated
so far.
Blau syndrome (see b Sarcoidosis, p 300)
• A sarcoid-like autosomal dominant syndrome with granulomatous
infiltration of the skin, joints and sometimes viscera associated with
uveitis.
• Histologically it is indistinguishable from sarcoid and is associated with
missense mutations in NOD2/CARD15.
• Treatment is with corticosteroids.
Periodic fever, aphthous stomatitis, pharyngitis and
adenitis (PFAPA)
• This was first described in 1987 (as Marshall’s syndrome) and is of
unknown aetiology. It is the most common periodic fever syndrome
in the paediatric age group and does not appear to be a monogenetic
disease.
• The diagnosis is clinical and is suggested by the presence of the
following in the absence of evidence of recurrent upper respiratory
tract infections or cyclic neutropenia:
• Regular recurrent fever of early onset
• Oral apthous ulcers
• Cervical lymphadenopathy
• Pharyngitis
• The 1st-line treatment of PFAPA is a single dose of corticosteroid
(1–2mg/kg given at the start of the attack). Alternative treatments
include tonsillectomy (approximately 50% success reported.
Colchicine, cimetidine, or anakinra maybe useful but the response is
unpredictable.
• In general the prognosis is good and most children will outgrow their
symptoms by adolescence.
 CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS 297

Chronic recurrent multifocal

osteomyelitis
Background
• CRMO is an auto-inflammatory disorder associated with non-infective
painful inflammation of bones and may be associated with SAPHO
syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis),
sacroiliitis, psoriasis, or inflammatory bowel disease, with reported
frequency of association of CRMO with SAPHO syndrome or psoriasis
varying from 7.5–23%.
• The presence of HLA-B27 is i (21% reported) suggesting an overlap
between CRMO/SAPHO and spondyloarthropathies; indeed some
patients may develop persistent arthritis typical of enthesitis related
arthritis (see b JIA, p 129).
• The diagnosis of CRMO is based on a combination of clinical,
radiological, and histopathological features. The major and minor
diagnostic criteria of non-bacterial osteitis (NBO) are included in
Table 4.25.
Clinical presentations
• Predominantly a disease of young 5 (85% girls, mean age of 10yr)
although can occur de novo in adults.
• Typically, acute or insidious onset with unifocal or multifocal bone
pain, nocturnal pain, and sometimes fever and bony lesions may be
associated with an asymmetrical inflammatory arthritis. Inflammatory
markers may be raised and are useful to follow disease activity. ANA is
usually negative and HLA B27 may be positive.
• Lesions can occur at any site, lower limbs are most frequently affected,
followed by clavicle, spine, ribs, and mandible (median number of bony
lesions is 3.5). Isolated swelling of the medial clavicle is common.
• Persistence of disease is i with greater number of initial bony lesions
and in younger children (median duration of active disease 2–3yr).
Management
• The main differential is exclusion of infection and malignancy and often
requires multi-specialist input (including radiology, infectious diseases,
orthopaedics, and paediatric rheumatology).
• X-ray may be non-specific (e.g. soft tissue swelling, localized
osteopenia, periosteal reaction or bony expansion)—typically lytic and
sclerotic lesions in the metaphyses of long bones and medial clavicles
are observed (Fig. 4.17).
• Radioisotope bone scan detects ‘hot spots’ as evidence of inflammatory
change (Fig. 4.18).
• MRI with gadolinium contrast is very sensitive to inflammatory changes
and best identified on T1 sequences.
• Bone biopsy may be necessary to exclude infection or malignancy, and
is recommended in most cases.
• There are no validated disease activity scores in CRMO, but in practice,
the degree of clinical involvement, pain scores, acute phase reactants,
298 CHAPTER 4 Systemic diseases

impact on physical function (e.g. CHAQ see b p 45), and imaging (and
especially MRI) are most helpful.
• There are no clinical trials to guide medical therapy:
• Antibiotics have not been shown to be effective.
• NSAIDS may be an effective 1st-line treatment for symptom control.
• Pamidronate (see b p 431), helps reduce symptoms in acute
CRMO and efficacy may be related to anti-osteoclastic and/or anti-
inflammatory activity. Regular infusions do not appear to reduce the
frequency or severity of flares.
• Corticosteroids can be useful particularly if there is associated
arthritis or synovitis.
• MTX has not been shown to reduce the severity or frequency of
flares but may improve any associated arthritis.
• Anti-TNF therapy (see b p 393) is used in severe cases
unresponsive to pamidronate with clinical improvement reported
albeit in small case series only.

Table 4.25 Major and minor criteria for non-bacterial osteitis (NBO)
Major diagnostic criteria Minor diagnostic criteria
Radiologically proven osteolytic/ Normal blood count, systemically well
sclerotic bone lesion
Multifocal bone lesions Mild/moderate elevation CRP or ESR
Palmoplantar pustulosis (PPP) or Observation time >6 months
psoriasis
Sterile bone biopsy with signs Hyperostosis
of inflammation and/or fibrosis,
sclerosis
Other autoimmune disease (excluding
PPP or psoriasis)
1st- or 2nd-degree relatives with autoimmune,
auto-inflammatory disease or NBO
NBO confirmed by 2 major criteria or 1 major and 3 minor criteria.

Further reading
Jansson A, Renner ED, Ramser J, et al. Classification of non-bacterial osteitis. Rheumatology 2007;
46:154–60.
 CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS 299

(a) (b)

Fig. 4.17 Plain radiographs of (a) right and (b) left clavicle. Left clavicle shows
cortical expansion and sclerosis (arrow).

Fig. 4.18 Radioisotope bone scan showing i uptake in left clavicle.

300 CHAPTER 4 Systemic diseases

Sarcoidosis
Background
• Idiopathic multisystemic inflammatory disease with non-caseating
granulomata in affected tissues.
• The cause is unknown; aberrant host responses (under genetic control)
to infection (undefined organism) remain the main hypotheses.
Candidate genes may reside in loci that influence regulation of
antigen presentation and/or T-cell function resulting in i granulomata
formation and fibrosis.
• There is an i incidence of other autoimmune diseases in patients with
sarcoidosis.
Epidemiology
• Prevalence varies worldwide and by age: primarily a disease of
20–40yr-olds. Twice as common in 5.
• The disease is more common in Japanese and black children, although
this racial distribution varies with geographic location. Sarcoid is seen
more commonly in developed than underdeveloped areas.
• In Denmark, where the disease has a high prevalence, the incidence in
children <15yr was 0.22–0.27 per 100 000/yr; 0.06 per 100,000 children
aged <4yr; and i gradually with age to 1.02 per 100,000 in children aged
14–15yr.
Genetics of sarcoidosis
• There is an i incidence of sarcoidosis in certain families.
• An HLA association has been described including DQB1*0603,
DQB1*0604, and DPB1*0201.
• In the USA, familial clusters are observed in African Americans in 19%,
compared to 5% in white families.
• Monozygotic twins are 2–4× more concordant for disease than
dizygotic twins.
• Recent studies suggest a unique candidate gene BTNL2 in the MHC II
region on chromosome 6.
• Specific HLA genotypes appear to confer a predisposition to disease
phenotype. For example, HLA-DQB1*0201 and HLA-DRB1*0301 are
associated with acute disease and a good prognosis.
Relationship between early-onset sarcoidosis (EOS) and
Blau’s syndrome
• EOS refers to young children with disease onset in the first 5yr of life.
These children differ from those with sarcoidosis of later presentation.
• EOS typically presents with the classic triad of rash, arthritis, and
uveitis (in that order), but without apparent pulmonary involvement
or hilar lymphadenopathy.
• EOS typically presents in the 1st year of life.
• Uveitis, which occurs in more than half the children with EOS, is
relatively less common in patients with later onset disease.
• Blau’s syndrome—autosomal dominant granulomatous disease with an
identical clinical phenotype to EOS.
 SARCOIDOSIS 301

• Recent data suggest that EOS and Blau's syndrome represent the same
disease since both share genetic mutations in the nucleotide binding
oligomerization domain 2 gene (NOD2, also referred to as the CARD15
gene).
• The NOD2 gene probably has no major effect on sarcoidosis
susceptibility in older patients, however.
Clinical features
Multisystemic disease so presentation can vary greatly.
• Multisystemic presentation—older children usually present in a similar
manner as adults with lymphadenopathy, pulmonary involvement, and
systemic symptoms (fever, malaise, fatigue and weight loss), in contrast
to the presentation of EOS described previously.
• Renal and biochemical findings:
• Renal involvement is rare in children and adults, and may be
asymptomatic. Renal involvement is usually s to hypercalcaemia
and/or hypercalciuria (occurring in ~30% of paediatric sarcoid cases)
rather than renal infiltration with granulomata.
• Polyuria, enuresis (s nephrogenic diabetes insipidus from
hypercalcaemia).
• Hypercalcaemia ± hypercalciuria.
• Hypercalciuria in the absence of hypercalcaemia.
• Nephrocalcinosis and nephrolithiasis (only if hypercalciuria).
• Bilateral enlargement of the kidneys.
• Tubulointerstitial nephritis.
• Rarely glomerular lesions: classically membranous
glomerulonephritis, but crescentic nephritis also reported.
• Pulmonary disease—is the most commonly involved organ.
• Chronic cough with or without dyspnoea.
• Bilateral hilar lymphadenopathy with or without parenchymal
involvement is the most common radiographic finding.
• The hilar lymphadenopathy is usually symmetrical.
• Parenchymal disease, pleural effusions, and atelectasis occur less
commonly in children than in adults (25% of affected adults are
affected with these).
• Nearly 50% of all children with sarcoidosis demonstrate restrictive
lung disease on pulmonary function tests.
• An obstructive pattern s to intrabronchial granuloma or
mediastinal lymph node airway compression may occasionally be
observed.
• Lymphadenopathy and hepatosplenomegaly—lymphadenopathy,
including retroperitoneal lymphadenopathy, is commonly observed,
and can occur with or without hepatosplenomegaly.
• Skin disease—77% of young children; and 24–40% of older children:
• Sarcoid should be considered in the differential diagnosis of unusual
skin lesions in children.
• Most common is a cutaneous eruption with soft, yellowish-brown
flat-topped papules found most frequently on the face. Larger
violatious plaque-like lesions may be found on the trunk and
extremities. Erythema nodosum is reported in 31%.
302 CHAPTER 4 Systemic diseases

• Other lesions include nodules and subcutaneous tumours, hyper- or

hypopigmented lesions, and ulcers.
• Eye disease—it should be remembered that young children may be
asymptomatic although blind in one eye at presentation. All of the
following described in sarcoid:
• Uveitis—general term used to describe inflammation of the uvea
(comprising iris, ciliary body, and choroid).
• Iridocyclitis (inflammation of the iris and ciliary body).
• Posterior uveitis—predominantly choroid but not iridocyclitis.
• Lacrimal gland swelling, conjunctival granulomata.
• Vitritis, chorioretinitis, optic neuritis.
• Proptosis, interstitial keratitis.
• Musculoskeletal disease—affects 15–58% of affected children:
• Arthralgia.
• Arthritis, usually affecting multiple joints: boggy teno-synovitis with
relatively painless effusion and little or no overlying erythema of
skin. Erosive changes on x-ray usually absent.
• Bone cysts (especially small bones of hand and foot).
• Muscle involvement can occur but is unusual.
• Neurological—neurosarcoid is rare in children but is described.
Encephalopathy and seizures; cranial nerve involvement; cerebral
mass lesion (rare in posterior fossa); spinal cord involvement; aseptic
meningitis; obstructive hydrocephalus.
• Other—parotid enlargement (with uveitis sometimes called ‘uveo-
parotid fever’); rectal prolapse; sicca syndrome; testicular mass;
pericardial effusion; myocardial involvement, and granulomatous large
and medium-size vessel vasculitis.
Differential diagnosis
• Infection causing granulomatous inflammation, including:
• Mycobacterium tuberculosis, leprosy, histoplasmosis, blastomycosis.
• Chronic granulomatous disease (exclude with nitroblue tetrazolium
test).
• Blau’s syndrome.
• sJIA.
• Granulomatous small-vessel vasculitis including Wegener’s
granulomatosis, and Churg–Strauss syndrome.
• Crohn’s disease may rarely be confused with sarcoidosis.
• Lymphoma.
• Berylliosis: inhalation of beryllium has been associated with a
granulomatous lung disease known as chronic beryllium disease (CBD).
Laboratory findings and investigations
No single test is diagnostic of sarcoid, and ultimately tissue diagnosis and
the exclusion of other diseases that can mimic sarcoid is required. The
historical Kveim–Siltzbach test, whereby intradermal injection of a splenic
extract from a known sarcoid patient resulted in sarcoid granulomata in
a suspected case, is antiquated, and the standard test reagent no longer
available. Observed findings and useful investigations include:
• Leucopenia, thrombocytosis, eosinophilia relatively common, high ESR
and CRP.
 SARCOIDOSIS 303

• Hypercalcaemia—varies from 2–60% of cases. The mechanism of

this appears to be that abnormal pulmonary macrophages synthesize
1,25 (OH)2 vitamin D from 25-hydroxy vitamin D, and are relatively
insensitive to feedback by hypercalcaemia.
• Abnormal liver function.
• Raised UA:UC ratio, tubular function abnormalities.
• Raised serum angiotensin converting enzyme (sACE). Epithelial cells in
the granulomas produce sACE, which thus may be elevated. This can
also be used to monitor response to therapy, but is neither absolutely
sensitive, nor specific.
• Recent studies have suggested that serum chitotriosidase
concentrations may be a useful marker for monitoring disease activity
in sarcoidosis but this remains a research tool at present.
• Mantoux test (to exclude TB). NB Sarcoid patients commonly
demonstrate anergy (no response) to purified protein derivatives of
Mycobacterium tuberculosis even if previously exposed.
• Nitroblue tetrazolium (NBT) test (alternatively a flow cytometric
test of neutrophil oxidative metabolism using dihydrorhodamine) to
exclude chronic granulomatous disease.
• Eye screen for uveitis.
• X-rays of affected bones and joints.
• CXR—standard screen for pulmonary sarcoid.
• i sensitivity of detection of pulmonary involvement with high-
resolution CT of chest.
• Pulmonary function tests including transfer factor.
• MRI of brain for suspected neurosarcoid.
• FDG-PET scanning may be useful in assessing the extent of organ
involvement and planning diagnostic biopsy.
• Tissue biopsy—skin, lung, salivary glands, muscle. Occasionally renal
biopsy.
• ECG and echocardiogram for suspected cardiac involvement. Cardiac
MRI may also have a role in this context.
Treatment
• Acute transient disease requires rest and NSAIDs.
• Chronic and/or severe multisystemic disease requires corticosteroid
therapy, e.g. 0.5–2mg/kg daily prednisolone, tapering over 2–3 months.
• An additional immunosuppressant agent may be required for persistent
progressive sarcoidosis: MTX, or AZA.
• An RCT of MTX in 24 adults with sarcoid demonstrated steroid
sparing efficacy.
• Occasionally cyclophosphamide or ciclosporin have been used for
more aggressive disease.
• Biologic therapy including anti-TNFA has been used in some severe
cases.
• Ocular involvement usually responds to corticosteroid administered
locally, or systemically.
304 CHAPTER 4 Systemic diseases

Prognosis
• Guarded prognosis for young children with EOS—nearly all develop
long-term morbidity from uveitis, polyarthritis, or other organ
involvement.
• Older children have a variable prognosis, dependent on organ
involvement, geography, sex, and race.
• A recurrence after >1yr of remission is uncommon, but can occur and
may develop at any age and in any organ.
• Long-term follow-up of 46 Caucasian Danish children reported
78% complete recovery; 11% still had chronic active disease with
multiorgan involvement; 7% died; and 4% were recovered but
with residual organ damage including unilateral loss of vision and
abnormal chest radiography.
• The presence of erythema nodosum was associated with a good
prognosis, and CNS sarcoidosis was associated with a poor
prognosis.
• In patients without persisting active disease, health-related QoL
scores were similar to the reference population.
• In another series of 19 children followed-up for a mean of 21yr:
37% had persistent abnormalities on CXR, 68% had impaired lung
function, and 63% had abnormal findings on echocardiography.
Further reading
Marcille R, McCarthy M, Barton J, et al. Long-term outcome of pediatric sarcoidosis with emphasis
on pulmonary status. Chest 1992; 102:1444–9.
Milman N, Hoffman AL. Childhood sarcoidosis: long-term follow-up. Eur Respir J 2008; 31:592–598.
Shetty AK, Gedalia A. Childhood sarcoidosis: a rare but fascinating disorder. Pediatric
Rheumatology 2008, 6:16.
 MACROPHAGE ACTIVATION SYNDROME 305

Macrophage activation syndrome

Introduction
MAS is the term used for s haemophagocytic lymphohistiocytosis (HLH)
occurring in rheumatological diseases. It is potentially fatal with reported
mortality rates of 8–22%.
Pathophysiology
• The exact pathophysiology remains unknown.
• It includes dysregulation of T lymphocytes, natural killer (NK) cells,
excessive cytokine production, abnormal proliferation of macrophages,
cytopenias, and coagulopathy.
• Macrophages phagocytose haematopoietic cells in the bone marrow.
• Proposed triggers for MAS include infections (see following list)
and in the context of sJIA some medications, e.g. NSAIDs, but
importantly MAS can also precipitated by persistently active inflammatory
rheumatologic disease alone.
Potential infective triggers of MAS
• Epstein–Barr virus
• Varicella zoster virus
• Coxsackie virus
• Parvovirus B19
• Hepatitis A virus
• Salmonella enteritidis
• Enterococcus.
Diagnosis
• Early recognition and treatment is important on account of the
significant morbidity and mortality.
• Diagnosis is often difficult because the features of MAS are similar to
the underlying active rheumatological inflammatory disease (Table 4.26).
• The diagnostic criteria of the Histiocyte Society (Box 4.9) are the most
universally recognized but have multiple limitations. The criteria are
not absolute and need to be interpreted in the context of the clinical
case. For example, in sJIA relative reductions of blood counts are more
important than the absolute degree of cytopenia.
• Diagnosis can be made in the absence of bone marrow
haemophagocytosis, and in the absence of absolute cytopenia.
Rheumatological diseases which may be complicated
by MAS
Commonly
• sJIA (most commonly)
• SLE
• Kawasaki disease.
Less commonly
• JDM
• Polyarticular JIA
• PAN
306 CHAPTER 4 Systemic diseases

• SSc
• MCTD
• Sarcoidosis
• Sjögren’s syndrome
• CINCA.
Characteristic clinical features
• Unremitting high fever
• Hepatosplenomegaly
• CNS dysfunction (irritability, disorientation, headache, seizures, coma)
• Purpuric rash or haemorrhages.
Other clinical features
• Renal involvement
• Lymphadenopathy.

Box 4.9 Diagnostic guideline for haemophagocytic

lymphohistiocytosis: HLH 2004 protocol
Establish the diagnosis if either (1) or (2) is fulfilled:
(1) A molecular diagnosis consistent with HLH.
(2) Diagnostic criteria for HLH fulfilled (5 or more out of the 8 criteria):
• (a) Fever
• (b) Splenomegaly
• (c) Cytopenias (affecting t 2 of 3 lineages in the peripheral blood:
• (i) Haemoglobin <9.0g/dL (in infants <4 weeks: haemoglobin
<10.0 g/dL)
• (ii) Platelets <100 × 109/L
• (iii) Neutrophils <1.0 × 109/L
• (d) Hypertriglyceridaemia and/or hypofibrinogenaemia: fasting
triglycerides t3.0mmol/L (>265mg/dL), fibrinogen d1.5g/L
• (e) Haemophagocytosis in bone marrow, spleen, lymph nodes or
cerebrospinal fluid: no evidence of malignancy
• (f) Low or absent natural killer cell activity (according to local
laboratory reference)
• (g) Elevated ferritin (t500mcg/L)
• (h) Soluble CD25 (i.e. soluble interleukin-2 receptor) above
normal limits for age.
Adapted with permission from Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and
therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;
48:124–31.
 MACROPHAGE ACTIVATION SYNDROME 307

Recognized haematological features

• Low haemoglobin
• Low WCC and neutrophil count
• Low platelets
• Normal or falling ESR
• Raised liver transaminases
• Prolonged PT and PTT
• Low fibrinogen
• Very high ferritin (>500 microgrammes/L possible HLH, and >10,000
microgrammes/L very likely HLH)
• High D-dimers
• Raised LDH
• Low albumin
• Raised triglycerides
• Raised sCD25 and CD163
• Low NK cell activity
• Bone marrow haemophagocytosis
• Abnormal perforin and MUNC expression—although usually associated
with p HLH this may also be a feature of 2° HLH in sJIA.
Important: laboratory values recognized to be falling or to be incongruous
with the level of inflammation clinically evident may allow earlier recognition
of developing MAS.
Management
1st-line—successful alone in almost 50% of cases:
• Supportive treatment—very important in all cases.
• Corticosteroid is the essential 1st-line treatment and should be started
immediately with pulse high-dose methylprednisolone (30mg/kg/day
with a maximum dose of 1g). This may be required for several days and
is followed by maintenance oral prednisolone at least 1mg/kg/day or
the equivalent corticosteroid intravenously depending on the patient
condition.
2nd-line—chosen depending on progress and extent of multiorgan
involvement:
• Ciclosporin 3–5mg/kg/day PO or 1–2mg/kg/day IV.
• IVIg 1–2g/kg—also useful when diagnosis is unclear, i.e. whether this is
true MAS or sepsis.
• Etoposide 150mg/m2 twice weekly (day 1 and 4) for the first 2 weeks then
once-weekly for another 6 weeks—effective, however concerns exist
regarding reported risk of 2nd malignancies. In patients with refractory
disease therapy based on protocols for p HLH might be required.
Alternative 2nd-line management options with biologics—some successful
treatment has been reported with biologics including anakinra and
etanercept however outcome data is currently limited:
• Etanercept 0.4mg/kg (maximum 25mg) twice-weekly SC injection
• Anakinra 2mg/kg (maximum 100mg) once daily SC injection. Higher
doses have been used anecdotally, mainly for MAS 2° to sJIA—seek
expert advice
308 CHAPTER 4 Systemic diseases

Table 4.26 Comparison of clinical and laboratory features of sJIA and

MAS
Feature sJIA MAS
Fever pattern Quotidian Unremitting
Rash Evanescent, Petechial or
maculopapular purpuric
Hepatosplenomegaly Yes Yes
Lymphadenopathy Yes Yes
Arthritis Yes No
Serositis Yes No
Encephalopathy No Yes
White cells and High Low
neutrophil count
Haemoglobin Normal or low Low
Platelets High Low
ESR High Normal or sudden fall
Bilirubin Normal Normal or high
ALT/AST Normal or slightly high High
PT Normal Prolonged
PTT Normal Prolonged
Fibrinogen High Low
Ferritin Normal or high High or very high
D-dimers High Very high
 PRIMARY IMMUNODEFICIENCY 309

Primary immunodeficiency and

rheumatological disease
1* immunodeficiency disorders (PID) are characterized by:
• Unusual susceptibility to (and recurrent) infections presenting from
birth/early childhood.
• Deregulation of immune functions resulting in:
• Autoimmunity (mediated by auto-reactive B or T lymphocytes) or as
• ‘Auto-inflammatory’ disorders (see b Periodic fever syndromes/
autoinflammatory disease, p 288) with episodes of seemingly
unprovoked inflammation, without presence of auto-reactive B or
T lymphocytes (Figure 4.19).
• Many of the conditions recognized are summarized in Box 4.10.

Systemic
inflammation

Vasculitis Enteropathy

Autoinflammatory
/autoimmune
presentation of
PID
Organ specific
Arthritis
autoimmunity

Cytopenias

Fig. 4.19 Auto-immune/-inflammatory presentation of PID.

The most common clinical features (i.e. when to

‘think of ’ PID)
• Chronic (non-septic) arthritis and features of systemic autoimmunity
(fever, vasculitis, dermatomyositis, and SLE-like syndromes), as well as
organ-specific autoimmunity, in particular cytopenias, are described
in well-defined PID syndromes (e.g. Wiskott–Aldrich and DiGeorge
syndromes, the (clinical and genetic), continuum of selective IgA
deficiency and common variable immunodeficiency (CVID), hyper-IgM
syndrome(s) due to class-switch recombination (CSR) process failures.
• Vasculitis, cytopenias, and features of Omenn syndrome are associated
with ‘leaky’ mutations (less-severe mutations are called ‘leaky’ mutations
because some function still ‘leaks through’ into the phenotype) in genes
causing severe combined immunodeficiency (SCID).
• Different features of autoimmunity and/or immune dysregulation,
including vasculitis, are increasingly reported in patients with other, less
well-defined ‘combined immunodeficiencies (CID)’, some of which have
recently been characterized (e.g. Aicardi–Goutiere syndrome [AGS],
spondyloenchondrodysplasia [SPENCD]).
310 CHAPTER 4 Systemic diseases

• Monogenic autoimmune diseases presenting with autoimmunity as the main

feature of the underlying p (monogenic) immunodeficiency:
• Autoimmune lymphoproliferative syndrome (ALPS) is due to
mutations of genes involved in the apoptosis (programmed cell
death pathway), can present clinically with features of systemic
autoimmunity such as SLE.
• Autoimmune polyendocrinopathy, candidasis, ectodermal dystrophy
(APECED) and immunodysregulation, polyendocrinopathy,
enteropathy, X-linked (IPEX) syndromes present with organ-specific
autoimmunity (i.e. polyendocrinopathy, enteropathy, cytopaenias):
— APECED or APS-1 (autoimmune polyendocrinopathy syndrome
type 1) are due to mutations in AIRE (autoimmune regulator)
which plays a crucial role in central (thymic) tolerance.
— IPEX syndrome is due to mutations in FOXP3 which plays a
crucial role in peripheral tolerance.
• ‘Classical’ disorders of the innate immunity’ include disorders of
phagocyte function (e.g. chronic granulomatous disease [CGD]) and/or
the classical complement activation pathway (in particular deficiencies of
C1q-r-s, C2, C1 esterase inhibitor) which may present with autoimmune
features such as SLE-like or dermatomyositis-like syndromes.
• Newly defined innate immune system disorders:
• Mutations (causing loss of function) of genes coding for different
molecules of innate immune system signalling pathways, normally
leading to an effective inflammatory process by releasing pro-
inflammatory cytokines (such as IL-1 and -6) are characterized by
‘peculiar’ absence of the inflammatory response (no fever or rise
in CRP) in the light of an overwhelming, usually bacterial infection.
(NEMO, IRAK4, MyD88).
• In contrast, the ‘gain-of-function’ mutations of the genes involved
in the same process of IL-1 production, but via intracellular
‘inflammasomes’ (such as NLRP3), cause unprovoked and ongoing
inflammation and manifest with fevers, rashes, arthritis, vasculitis and
bone lesions, the clinical hallmark of cryopyrin associated periodic
fever syndrome (CAPS) and other auto-inflammatory syndromes (see
b Periodic fever syndromes/autoinflammatory disease, p 288).
• Although not as often as expected, some of these patients do present
with autoimmune features such as colitis in NEMO mutation(s)
(otherwise presenting with ectodermal dysplasia [EDA-ID]).
• Uncontrolled macrophage activation leading to haemophagocytic
lymphohistiocytosis (HLH) results from mutations of several genes
involved in perforin-related cytolysis, intracellular vesicle trafficking
(Chediak–Higashi, Griscelli and Hermansky–Pudlak syndromes) and/or
signalling (lymphoproliferative syndromes; X-linked and/or autosomal
recessive). Whilst these p immunodeficiency disorders were recently
re-classified as auto-inflammatory syndromes, some patients with
clinically well defined rheumatological conditions such as sJIA and/or
SLE can present with similar features of MAS (see b MAS, p 305).
• Current and future research into this area provides new insights in
the underlying pathophysiology, and hopefully will result in successful
targeted therapies such as the use of IL-1 blockade in CAPS (see
b Periodic fever syndromes/autoinflammatory disease, p 288), IL-1,
IL-6 and TNFA blockade in JIA.
 PRIMARY IMMUNODEFICIENCY 311

Further reading
Henderson C, Goldbach-Mansky R. Monogenic IL-1 mediated autoinflammatory and
immunodeficiency syndromes: Finding the right balance in response to danger signals. Clin
Immunol 2010; 135:210–22.
Notarangelo LD, Fischer A, Geha RS et al. Primary immunodeficiencies: 2009 update. J Allergy Clin
Immunol 2009; 124:1161–78.

Box 4.10 PID with features of autoimmunity and/or

rheumatic/connective tissue disorders
Well-defined PID syndromes
• Selective IgA deficiency—common variable immunodeficiency
• DiGeorge syndrome (Table 4.28)
• Wiskott–Aldrich syndrome
• Hyper-IgM syndromes (class-switch recombination (CSR) deficiencies)
• Severe combined immunodeficiency syndromes (SCID).
Innate immune system disorders
‘Classical’
• Neutrophil disorders (chronic granulomatous disease—CGD)
• Complement disorders (classical activation pathway component
deficiencies—C1-q-r,-s, C2, C4, C5-8, C1 esterase inhibitor).
‘Newly defined’
• TLR/IL-1 receptor (TIR) signalling pathway (IRAK4; MyD88; NEMO).
Haemophagocytic syndromes (‘macrophage activation’)
• Perforin-related cytolysis (perforin, syntaxin-11, UNC 13-D, UNC 18–2)
• Intracellular vesicle trafficking (Chediak–Higashi, Griscelli,
Hermansky–Pudlak syndromes)
• Intracellular signalling (lymphoproliferaive syndromes; X-linked
(SH2DIA and XIAP) and/or autosomal recessive (ITK).
Monogenic autoimmune diseases
• Autoimmune lymphoproliferative syndrome (ALPS)
• Immune dysregulation polyendocrinopathy enteropathy X-linked
syndrome (IPEX)
• Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy
syndrome (APECED)/autoimmune polyendocrinopathy syndrome
type I (APS I).
Auto-inflammatory disorders (see b Periodic fever syndromes/
autoinflammatory disease, p 288)
• Cryopyrin-associated periodic fever syndromes (CAPS):
• Chronic infantile neurological cutaneous and articular syndrome
(CINCA)/neonatal-onset multisystem inflammatory disease (NOMID)
• Mevalonic kinase deficiency (MKD)/hyper-IgD syndrome (HIDS)
• TNF receptor-associated periodic fever syndrome (TRAPS)
• Deficiency of IL-1 receptor antagonist (DIRA)
• Chronic recurrent multifocal osteomyelitis (CRMO)
• Majeed syndrome
• NOD2-associated granulomatous inflammatory syndromes (early
onset sarcoidosis (EOS); Blau syndrome; Crohn’s disease).
Newly defined (combined) immunodeficiencies
• Aicardi–Goutieres syndrome (AGS)
• Spondyloenchondrodysplasia (SPENCD).
312 CHAPTER 4 Systemic diseases

Mucopolysaccharidoses (MPS) and

mucolipidoses (ML)
• Rare progressive storage disorders with a spectrum of clinical
features (Table 4.27) varying from facial dysmorphism, bone dysplasia,
hepatosplenomegaly, neurological abnormalities, developmental
regression, and a reduced life expectancy at the severe end of the
clinical spectrum to an almost normal clinical phenotype and life
span in patients with more attenuated disease.
• MPS is due to a reduction of activity in lysosomal enzymes which break
down glycosaminoglycans (GAGs)—long chains of carbohydrates that
help build bone, cartilage, tendons, corneas, skin, and connective tissue.
Over time, GAGs in 3 different forms—dermatan sulfate (DS), heparan
sulfate (HS), or keratan sulfate (KS)—accumulate in the cells, blood and
connective tissues resulting in progressive skeletal dysplasia, dwarfism,
marked coarsening of the facial features. In addition, deposition of GAG
leads to corneal clouding and neurological deterioration.
• ML is due to multiple enzyme deficiencies 2° to failure of targeting of
enzymes to lysosome.
• Phenotypic variability (heterogeneity) is very much a feature of MPS
disease and within each specific enzyme deficiency there is a very wide
spectrum of clinical effects.
Differential diagnosis
• Arthrogryposis
• Juvenile polymyositis and dermatomyositis
• Scleroderma and SSc
• JIA
• Skeletal dysplasia
• Osteogenesis imperfecta.
Investigations
• Prenatal—chorionic villus biopsy at around 12th week of pregnancy
• Amniocentesis: measuring the enzyme activity in cultured amniotic
cells in the 15–16th week of gestation or GAGs in cell-free fluid.
• Postnatal—urinary glycosaminoglycan as screening test (GAG):
• White blood cell enzyme assay and cultured cells.
• Urine oligos and blood gastrin in mucolipidoses.
• Mutation analysis—possible for all disorders listed.
• Imaging—skeletal survey—dysostosis multiplex:
• Large skull with thickened calvaria, premature suture closure,
j-shaped sella turcica, and shallow orbits:
— Short, thickened, and irregular clavicles
— Short, wide, and trapezoid shaped phalanges
— Oar-shaped ribs
— Anterior hypoplasia of the lumbar vertebrae with kyphosis
— Poorly formed pelvis with small femoral heads and coxa valga
— Enlarged diaphyses of long bones and irregular metaphyses
— Abnormal spacing of teeth with dentigerous cysts.
 MPS AND ML 313

• MRI scan: hydrocephalus, white matter change, cerebral atrophy,

arachnoid cysts
• Echocardiogram: valvular heart disease, ventricular wall thickening
• Neurophysiology:
• Electroretinography: retinal degeneration
• Nerve conduction study: carpal tunnel syndrome.
• Audiology—conductive and neuro-sensory hearing loss.
Management
Apart from MPS I specific treatment is limited for MPS and ML that involve
the CNS. In such patients, management has been limited to a supportive
one in improving QoL for the child.
Early identification and diagnosis (Fig. 4.20) of the condition is essential
and follow-up will require the involvement of multi-agency expertise in
specialties including: paediatrician specialized in metabolic disorder, ortho-
paedic surgeon, ENT surgeon, neurologist, physiotherapist, occupational
therapist, cardiologist, and rheumatologist.
Enzyme replacement therapy (ERT)
• Laronidase therapy i catabolism of GAGs, which accumulate with MPS I.
Laronidase therapy has shown to improve walking capacity and pulmonary
function.
• Idursulfase is a purified form of human iduronate-2-sulfatase, a
lysosomal enzyme. It is used to replace insufficient levels of the
lysosomal enzyme iduronate-2-sulfatase in MPS II, Hunter syndrome.
• Galsulfase is a recombinant form of galactosamine 4 sulphate sulphatase.
It is used as replacement therapy in MPS VI (Maroteaux–Lamy syndrome).
All ERTs are administered by weekly IV infusions. ERT for MPS IVA is at
an advanced stage of development and intra thecal ERT for MPS IIIA is in
early phase II/III clinical trials.
Haematopoietic stem cell transplantation
Offered to severely affected patients, usually Hurler disease, and is shown
to improve life span. Skeletal manifestations, cardiac valve lesions, and
corneal clouding do not improve with stem cell transplantation.
Hearing and vision
• Hearing aids, grommet placement, and visual aids are beneficial.
• Corneal grafting.
Respiratory
• Sleep apnoea may necessitate treatment with high-pressure CPAP with
supplementary oxygen.
• Tracheostomy.
Central nervous system
• Ventriculoperitoneal(VP) shunting is indicated in moderate to severe
hydrocephalus.
• Carpal tunnel syndrome with surgical decompression of median nerve.
 314
Table 4.27 Classification and clinical features

CHAPTER 4
Types Name Inheritance Enzyme defect Clinical manifestations
MPS

Systemic diseases
IH Hurler AR Alpha-L iduronidase Corneal clouding, coarse facies, dysostosis multiplex, hernia, kyphosis,
hepatomegaly, severe mental retardation
IS Scheie AR Alpha-L iduronidase Joint contractures, corneal clouding, valvular abnormalities, carpel tunnel
syndrome, hernia
IHS Hurler/ AR Alpha-L iduronidase Mild learning disability, mild organ and skeletal involvement
Scheie
II Hunter XR Iduronate sulfatase Coarse facial features, skeletal deformities (such as claw hand), joint
stiffness, retinal degeneration, hydrocephalus, mental retardation
IIIA Sanfilippo AR Heparan N-sulfatase Subtypes are not distinguishable clinically, hyperactivity, mental
deterioration, developmental delay, coarse hair, hirsutism, mild
IIIB Sanfilippo AR Alpha-N-acetylglucosaminidase hepatosplenomegaly, and enlarged head. Severely disturbed social
IIIC Sanfilippo AR Acetyl CoA:alpha-glucosaminide behaviour occurred later in life (e.g. uncontrollable hyperactivity,
acetyltransferase destructive physical aggression)

IIID Sanfilippo AR N-acetylglucosamine 6-sulfatase

IVA Morquio AR N-acetylgalactosamine-6-sulfate Skeletal involvement with spondyloepiphyseal dysplasia, genu valgum,
sulfatase short stature, spinal curvature, odontoid hypoplasia, ligamentous laxity
and atlantoaxial instability. Normal intelligence.
IVB Morquio AR Beta-galactosidase Mild skeletal involvement, normal life span
VI Maroteaux-Lamy AR N-acetylgalactosamine-4-sulfatase Corneal clouding, coarse facies, joint stiffness, skeletal deformities, heart
valvular disease and normal intelligence
VII Sly AR Beta-glucuronidase Severe form with hydrops fetalis and hepatosplenomegaly in the neonatal
period. Corneal clouding, coarse facies, macrocephaly, metatarsus adductus,
prominent sternum, pelvic hypoplasia, hepatosplenomegaly, and hernias.
IX AR Hyaluronidase Mild short stature and multiple periarticular soft-tissue masses
Mucolipidoses
ML I Sialidosis I AR Neuraminidase Myoclonus and ataxia associated with a macular cherry-red spot,
dementia in later life
ML II I cell AR *Phosphotransferase (mutation Course facies, hepatomegaly, skeletal dysplasia and severe learning
in GNTAB gene alpha sub unit) difficulties
ML III Pseudo-Hurler AR *Phosphotransferase (mutation Hepatosplenomegaly, dysostosis multiplex, cardiac valve lesion
polydystrophy in GNTAB gene either alpha
ML III alpha/beta or beta subunits)
ML III Pseudo-Hurler AR *Phosphotransferase (mutation Learning impairment, cardiac valvular lesion, skeletal disease
polydystrophy in GNPTG gene)
ML III gamma

MPS AND ML
ML IV AR Unknown Motor impairment, severe mental retardation, retinal degeneration,
corneal clouding, iron deficiency anaemia and achlorhydria with elevated
blood gastrin levels
*
UDP-N-acetylglucosamine: lysosomal hydrolase N-acetylglucosamine-1-phosphotransferase (GNPTAB) enzyme deficiency—enzyme requires the action of 2 genes GNTAB and
GNPTG. Mutations in GNTAB are associated with ML II and ML III alpha/beta and mutations in GNPTG cause ML III gamma.

315
316 CHAPTER 4 Systemic diseases

Cardiovascular
• Valve replacement surgery. Bacterial endocarditis prophylaxis may be
necessary
• Routine evaluation of ventricular function, wall thickness.
Orthopaedic
• Soft tissue surgery with release of contractures
• Corrective osteotomy: valgus deformity
• Posterior spinal decompression and fusion: kyphosis or atlantoaxial
subluxation.
Further reading
Manger B. Rheumatological manifestations are the key in early diagnosis of mucopolysaccharidosis
type I. Eur Musculoskeletal Rev 2008; 1–6.
 MPS AND ML 317

Joint contractures?

Yes
From birth?* Evolving?
Consider poly/
Yes Yes dermatomyositis
Weakness, myalgia, ↑
Consider muscle enzymes? Yes
arthrogryposis
or other
genetic disorder Skin Consider
stiffness?** Yes scleroderma

Obvious inflammation?
(redness, swelling, effusion)
Consider
No arthritis (JIA, RA)
Yes
Other evidence of inflammation?
• Fever, ↑ ESR
• Elevated ANA
• Pain proportional to degree of stiffness Yes
• Responsive to NSAIDS
No

Urinary Elevated uGAG or

Test unavailable? GAG
analysis† abnormal pattern?
Yes Yes
Any of the following?
• Comeal clouding
• Umbilical or inguinal hernia Consider MPS
Yes disorder
• Heart murmur
• Carpal tunnel syndrome
• Recurrent respiratory
and/or ear infections
IDUA or
other enzyme
assay(s)

Fig. 4.20 Diagnostic algorithm for attenuated mucopolysaccharidoses. *Newborn

infants with the most severe form of MPS I (Hurler syndrome), although normal
appearing, often have radiological evidence of bone and joint abnormalities. **Note
that overall skin texture in patients with MPS I can be thickened and rough. MPS II
and rarely MPS I can be associated with a distinctive skin lesion consisting of white
‘pebbly’ papules 2–10mm in diameter, sometimes coalescing in ridges. †Authors
recommend both quantitative and qualitative (GAG profile) analysis in a reputable
laboratory. False negatives can occur with spot screening. IDUA: A-L-iduronidase;
uGAG: urinary glycosaminoglycan; JIA: juvenile idiopathic arthritis; RA: rheumatoid
arthritis. Reproduced from Cimaz R, Coppa GV, Koné-Paut I, et al. Joint contractures
in the absence of inflammation may indicate mucopolysaccharidosis Paediatr
Rheumatol 2009; 7:18.
318 CHAPTER 4 Systemic diseases

Chromosomal abnormalities and

associated musculoskeletal morbidity
• Children with chromosomal problems may have significant
musculoskeletal (MSK) problems.
• These are often overlooked, especially in the presence of learning
difficulties, developmental delay, and other complex needs where the
child cannot communicate symptoms and observed motor problems
may be ascribed to neurological or other cause.
• Examples of the most common conditions and associated MSK
morbidity are given in Table 4.28. The frequency of MSK abnormalities
in these conditions is often poorly defined.
• It is important to consider other differentials including metabolic
disorders and skeletal dysplasias (see b p 333) especially in the
presence of contractures.
• Most chromosomal problems are also associated with
hypermobility, dysmorphism, and short stature.
• Inflammatory arthritis in these children is managed in a similar way to
JIA (see b p 155, p 159, and Table 4.29) and require input from an
experienced MDT.
• The use of MTX and biologics in this patient group requires
caution as some conditions are prone to malignancy (e.g. Down’s
syndrome) and anecdotally, these children appear less tolerant of
MTX. However, most patients derive benefit from these agents
where indicated, and the presence of a chromosomal abnormality
per se is not a contraindication to the use of DMARDS or biologics
for inflammatory arthritis in this context.
 CHROMOSOMAL ABNORMALITIES 319

Table 4.28 Chromosomal conditions and musculoskeletal (MSK)

problems
Chromosomal MSK abnormalities MSK presentations and
condition clinical features
Down’s Inflammatory arthritis Limp, leg-length discrepancy,
syndrome • Poly or oligo motor delay. May express
articular no pain, instead behavioural
(Trisomy 21)
• Psoriatic changes, e.g. reluctance to hold
Learning • Small and large hands, reversion to earlier
difficulties, joints stage of development, morning
upslanting Cervical spine instability: stiffness.Joint swelling, d or
palpebral fissures, • Atlanto axial ‘normal’ range of movement
epicanthic folds, • Occipital cervical (remember these children are
brachycephaly, Hip dislocation/ normally markedly hypermobile
cardiac subluxation therefore an observed ‘normal’
abnormalities General hypotonia: range of joint movement,
• Joint hypermobility especially if symmetrical, may
• Pes planus (flat feet) actually signify loss of movement)
• Patella dislocation Associated psoriatic rash ±nail
• Scoliosis pitting
Other:
Asymptomatic, neck pain,
• Short stature
limited neck mobility/torticollis,
• Metatarsus
sensory deficit, hyper-reflexia,
primus varus
• Brachydactyly spasticity
Limp, antalgic gait, motor delay
Clumsiness, poor-coordination,
generalized hypotonia, front of
feet pointing away from each
other, may be asymptomatic
Big toe bending inwards
Short fingers
DiGeorge Inflammatory arthritis Limp, leg-length discrepancy,
syndrome Micrognathia and motor delay.
(22q11 deletion) retrognathia Pain, joint swelling, d range of
Immunodeficiency movement
Scoliosis, short
T-cell dysfunction, stature Malocclusion, difficulty brushing
IgA deficiency teeth
hypocalcaemia, Feeding difficulties, dentist
facial, pharyngeal recognizes problem.
and cardiac
abnormalities Postural shift, altered function,
back pain
Turner’s Inflammatory arthritis: Limp, leg-length discrepancy.
syndrome poly or oligo Pain, joint swelling, d range of
(X0) Cubitus valgus movement
Webbed neck, Clinodactyly, Wide carrying angle at elbows
low hair line, brachydactyly Curved 5th fingers
horseshoe kidney, Blunt fingertips Short fingers
lymphoedema
Micrognathia Small jaw, malocclusion
Short stature

(continued )
320 CHAPTER 4 Systemic diseases

Table 4.28 (Contd.)

Chromosomal MSK abnormalities MSK presentations and
condition clinical features
Trisomy 8 Joint contractures— Restricted joints—e.g.
Learning difficulties camptodactyly, fixed flexion deformity of
thick lips, deep-set clinodactyly interphalangeal joint of little
and prominent ears, Scoliosis fingers
pectus excavatum Absent patella Curved 5th fingers
(mild clinical Micrognathia Postural shift
features often Small jaw, malocclusion
associated with
mosacism)
18p syndrome Inflammatory or Limp, leg-length discrepancy,
Learning difficulties, non-inflammatory pain, morning stiffness, joint
IgA deficiency arthritis of large joints swelling, d range of movement
Short stature
Cystic fibrosis Arthralgia Troublesome joint pain,
(CF)—see b p 323 Inflammatory arthritis: occasionally related to
Mutations for CF ciprofloxacin use
• Oligo or polyarticular
transmembrane Limp, pain, joint swelling, d
• Relapsing range of movement
conductance
transporter, Hypertrophic Can be associated with
chromosome 7 pulmonary erythema nodosum
osteoarthropathy
Detected on Joint pain and swelling. Consider
screening, failure in long-standing CF and marked
to thrive, chronic finger clubbing.
respiratory symptoms,
malabsorption
Neurofibromatosis Scoliosis & kyphosis Usually presents before 10yr of
(NF) Short stature age, May be an incidental clinical
NF1 gene— finding, back pain, postural shift
Pseudoarthrosis of the
chromosome 17 tibia or forearm Bowing of leg or arm
2 or more of the Bone/soft tissue Asymmetrical limb length/
following: t6 café hypertrophy macrodactyly
au lait spots, t2
neurofibromata,
axillary or inguinal
freckling, optic
glioma, t2 Leish
nodules, osseous
dysplasia on the
sphenoid bone or
cortex of a long
bone, 1st-degree
relative with NF
 CHROMOSOMAL ABNORMALITIES 321

Table 4.28 (Contd.)

Chromosomal MSK abnormalities MSK presentations and
condition clinical features
NF2 gene—long Spinal tumour Difficulty walking, pain, postural
arm chromosome 22 shift, loss or altered function,
Usually presents in neurological signs
adults but childhood
cases are reported.
May present with VIII
nerve masses, family
history NF2, presence
of t2 neurofibroma,
meningioma, glioma,
schwannoma, juvenile
posterior capsular
lenticular opacity

Table 4.29 Chromosomal conditions and MSK problems:

an overview approach to management
MSK problem MSK radiological Management
investigations & features
Inflammatory If clinical uncertainty, US Referral to a paediatric
arthritis or contrast-enhanced MRI rheumatology MDT for
to identify joint effusions & confirmation of diagnosis,
synovial enhancement. medical treatment and access
to ophthalmology for uveitis
Plain films are of limited
screening.
use until long-standing
arthritis has caused Consider broad spectrum of
significant joint damage such autoimmune disorders
as joint space narrowing and
erosions
Cervical spine Cervical spine plain Close surveillance,
Instability radiograph—as showing i neurosurgical referral
atlanto-dental interval on
Advice to avoid contact sports
lateral flexion/extension
and to wear a neck collar
view (normal <8yr <4mm,
when travelling in a car.
>8yr <3mm)
MRI may show ligamentous
swelling suggestive of
instability. CT may show
malalignment of vertebrae in
the neutral position
Hip dislocation/ Hip plain radiograph—flared Referral to orthopaedics
subluxation iliac wings, hip dysplasia
and or dislocation
Hip US may be useful in
younger children

(continued )
322 CHAPTER 4 Systemic diseases

Table 4.29 (Contd.)

MSK problem MSK radiological Management
investigations & features
Abnormal foot Radiology of limited use Referral to orthotics/podiatry
positioning or orthopaedics.
Scoliosis Spinal plain radiograph Referral to orthopaedics or
spinal surgeon
Hypermobilty Radiology of limited use Referral to hypermobility MDT
—physiotherapy and
occupational therapy
Joint Radiology of limited use Referral to physiotherapy &
contractures occupational therapy
Consider orthopaedic referral
to improve function if severe
Abnormal finger Radiology of limited use Referral for occupational
positions e.g. therapy for hand function
camptodactyly/ assessment and aids
clinodactyly
Micrognathia Orthopantomogram may Referral to orthodontics
show malalignment of the or maxillary facial surgeons
Jaw malocclusion
teeth and small mandible depending on severity
Short stature Ensure plotted on appropriate
growth chart (e.g. Turner’s and
Down’s syndromes). Referral
to endocrinologist for growth
hormone consideration (e.g. in
Turner’s syndrome)
 ARTHRITIS AND CYSTIC FIBROSIS 323

Arthritis and other musculoskeletal

features associated with cystic fibrosis
Many patients (reported as 13%) with cystic fibrosis (CF) will have mus-
culoskeletal complaints; with increasing prevalence of rheumatic symptoms
with age, CF lung disease severity, and infection with Pseudomonas aeruginosa
and Aspergillus fumigatus. CF arthropathy is reported in 2–8.5% of patients
and hypertrophic osteoarthropathy in 2–7% of patients. Undoubtedly
patients with chronic lung disease are more likely to be physically decondi-
tioned and this tends to associate with generalized musculoskeletal pain and
being prone to mechanical/non-inflammatory musculoskeletal complaints.
Musculoskeletal manifestations in CF tend to be one of the following
categories:
• Cystic fibrosis-related inflammatory arthritis:
• Transient recurrent arthritis: with rash/without rash.
• Persistent/chronic inflammatory arthritis.
• Hypertrophic osteoarthropathy (HOA).
• Metabolic bone disease (osteopenia/osteoporosis/osteomalacia/renal
osteodystrophy)
• Cystic fibrosis associated with sarcoidosis
• Non-inflammatory musculoskeletal pain (often due to physical
deconditioning).

Transient recurrent arthritis (most common)

Transient recurrent arthritis does not seem to be related to the severity
of lung involvement as it can occur in mild to severe lung disease. The
pathogenesis of this arthritis has not been well established. It is suspected
that the presence of immune complexes may play a role in joint and skin
involvement in CF.
Clinical features
• Painless/painful joint swelling with restricted movement:
• Joints affected (in order of reducing frequency)—knees, ankles,
wrists, PIPJs of hands, shoulders, elbows, and hips.
• Episodes lasting 1–10 days.
• Recurrent at intervals of weeks to months.
• Mostly monoarticular but can be oligo- or polyarticular.
• Unrelated to severity of lung disease.
• With our without rash (often vasculitic), which if present can be (in
reducing order of frequency):
• Pruritic ± painful erythematosus nodules, commonest over anterior
tibia
• Purpura (more commonly over legs)
• General erythematous macular-papular rash
• Erythema nodosum.
Investigations
• Acute phase reactants may be raised.
• ANA usually negative, RF negative.
324 CHAPTER 4 Systemic diseases

• No HLA association.
• Hypergammaglobulinaemia/raised complement in patients with
vasculitis-associated arthritis.
• Amylase is useful to measure as there is a rare association of
pancreatitis, panniculitis, and arthritis.
• Biopsy of rash may demonstrate vasculitis.
Management
• Shared care with paediatric respiratory team.
• Symptom relief:
• NSAID (caution may induce bronchoconstriction and supervised
trial may be necessary). If not suitable for NSAIDS, then regular
paracetamol.
• Physical therapy (physiotherapy and occupational therapy).
Pending severity and nature of arthropathy (inflammatory versus non-
inflammatory), consider short course of oral corticosteroids or intra-articular
corticosteroids (see b p 390).
Persistent chronic inflammatory arthritis
Clinical features
• Usually in patients with progressive lung disease and clubbing.
• Similar to clinical features of JIA, typically polyarthritis (may be RF+ve),
and often affecting small joints of hands and feet.
• May have tenderness of distal long bones (HOA—see following
section).
• Lethargy, joint pain and stiffness, functional limitation.
Management
• Shared care with paediatric respiratory team.
• Screening joint assessment (pGALS) as a minimum followed by full joint
examination for pattern of joint involvement.
• Investigations:
• Assessment of severity of lung disease and possible infective flare.
• FBC and acute phase reactants may show evidence of inflammation.
• RF (titre may rise with progressive lung disease).
• Treat infective flares of lung disease first.
• Symptom control.
• Consider systemic corticosteroids and DMARDs similar to JIA
(see b p 415) with persistent severe joint involvement, with early
physiotherapy in addition.
Hypertrophic osteoarthropathy
Clinical features
• Excessive proliferation of skin and bone at distal ends and digital
clubbing.
• Symptoms worse at time of acute infective exacerbations.
• Can be mild to severe, and usually in older children.
• Variable relation to severity of lung disease:
• Bone pain and burning sensation in distal extremities, which can be
severe.
 ARTHRITIS AND CYSTIC FIBROSIS 325

• May be associated joint disease (most likely knees, ankles, wrists,

and metacarpals).
• Clubbing in all cases and tenderness along distal long bones (tibia and
radius); radiographs of long bones:
• Acute changes—periosteal reaction of tubular bone separated from
underlying cortex by thin radiolucent line at ends of long bones.
• Chronic changes—mid shafts of long bones with new bone
formation fused with cortex of shaft and no intermediate band of
radiolucency.
• May have acne, hyperhydrosis, coarse facial features (s to hypertrophy
of soft tissue).
• Differential diagnosis: thyroid acropathy, acromegaly.
Management
• Shared care with paediatric respiratory team.
• Treat underlying infective exacerbations of lung disease.
• Symptom control and active physiotherapy.
• Pending severity of symptoms, consider:
• Oral corticosteroids or
• Pamidronate (see b p 427) has been used in isolated, refractory
cases and proven to be effective. If used, a preceding full bone
profile and DEXA scan should be performed.
Metabolic bone disease
• Multiple risk factors include malabsorption of vitamin D, corticosteroid
use, diet and reduced physical activity, chronic ill health, and chronic
renal impairment in some patients.
• May be asymptomatic (most cases) or may present with
musculoskeletal pain (often without joint swelling), muscle pain and
fatigue, low trauma fractures.
• Assessment and management—see b Metabolic bone disease, p 330.
Cystic fibrosis and vasculitis
• Systemic vasculitis occasionally complicates CF, the cause of which is
unknown but presumably reflects an aberrant immune response to
chronic infection or drug therapy, or both.
• The vasculitis is predominantly cutaneous, but occasionally is more
widespread with both cerebral and renal involvement (renal failure and
focal glomerular sclerosis and capsular adhesions) reported.
• Arthritis may be a feature.
Further reading
Botton E, Saraux A, Laselve H, et al. Musculoskeletal manifestations in cystic fibrosis. Joint Bone
Spine 2003; 70(5):327–35.
Garke LA, Bell SC. Pamidronate results in symptom control of hypertrophic pulmonary
osteoarthropathy in cystic fibrosis. Chest 2002; 121:1363–4.
Koch AK, Bromme S, Wollschlager B, et al. Musculoskeletal manifestations and rheumatic
symptoms in patients with cystic fibrosis (CF) no observations of CF-specific arthropathy.
J Rheumatology 2008; 35(9):1882–91.
Schidlow DV, Goldsmith DP, Palmer J, et al. Arthritis in cystic fibrosis. Arch Dis Child 1984;
59:377–9.
326 CHAPTER 4 Systemic diseases

Inflammatory bowel disease and

musculoskeletal features
Introduction
• Musculoskeletal symptoms in inflammatory bowel disease (IBD)
are common and include arthralgia, myalgia, peripheral arthropathy,
enthesitis, sacroiliitis, and spondylitis.
• Non-inflammatory MSK pain can be the result of deconditioning and
general debilitation in IBD.
• Glucocorticoid and chronic disease-related osteopenia and s
hypertrophic osteoarthropathy may also result in MSK pain.
• Inflammatory arthropathy is uncommon.
• Features of arthropathy may occur before, during or after the
presentation of clinical features suggestive of IBD.
Definitions
• Ulcerative colitis (UC)—diffuse mucosal inflammation limited to the colon.
• Crohn’s disease (CD)—patchy transmural inflammation affecting any
part of the GI tract.
• Indeterminate colitis (IC)—10% of children with IBD affecting the colon
cannot be classified as there are some features of both conditions.
• Arthropathy of inflammatory bowel disease—any non-infectious
arthropathy occurring before or during the course of UC, IC, or CD.
• Clinical features, see Table 4.30.
Epidemiology
• Collective incidence of IBD <16yr olds in UK is 5.2 per 100,000 (60%
CD, 28% UC and 12% IC). Mean age at presentation: 11.9yr (58% are
boys, 4% are <5yr). 25% of all IBD presents in children and young
people.
• Family history—29% have a t1 relative with IBD (greatest in those
presenting before 3yr old).
• Arthralgia and myalgia are common (1/3 of patients and often coincide
with disease activity)—this may reflect the incidence of MSK pain in
healthy adolescents.
• Incidence of arthropathy in IBD variable (2.4–21%) and there is no
observed difference between UC and CD.
Physical features that may also be present/occur
Anal fistula/anal abscess (CD), growth failure/delayed puberty (CD), erythema
nodosum/rash (CD), liver disease, appendicitis, toxic megacolon (UC),
uveitis.
 IBD AND MUSCULOSKELETAL FEATURES 327

Table 4.30 Clinical features of IBD at presentation

Symptoms or sign CD (%) IC (%) UC (%)
Common symptoms
Abdominal pain 72 75 62
Diarrhoea 56 78 74
Bleeding 22 68 84
Weight loss 58 35 31
Lethargy 27 14 12
Anorexia 25 13 6
Arthropathy 7 4 6
Other symptoms
Nausea/vomiting, constipation/soiling, psychiatric
symptoms, s amenorrhea

Peripheral arthritis
• Oligoarthritis affecting knees and ankles most common. Occasionally
affects multiple joints, including small joints of hands and TMJs.
• Episodes of arthritis tend to be short (1–2 weeks).
• Onset of arthritis does not correlate with activity of IBD and may
occur before, during, or unrelated to flare of bowel disease.
• Persistent arthritis is more likely to reflect poor control of bowel
disease.
• Arthritis is rarely persistent, progressive, or erosive.
Sacroiliitis and spondyloarthropathy (axial skeletal
involvement)
MSK symptoms with back pain and generalized idiopathic (non-inflammatory)
pain are common in IBD and important to distinguish from inflammatory
back pain.
• May begin as a peripheral inflammatory arthritis and progress to
involve sacroiliac joints, hips, and lumbosacral spine.
• Disease does not reflect activity of IBD, and may be progressive
despite good control of IBD.
• Associated with the presence of HLA B27.
• May progress to ankylosing spondylitis (3–7%) albeit with no difference
between UC and CD for the prevalence of axial spine involvement.
Diagnosis and investigation
See: Guideline for the investigation and management of IBD in children in
the United Kingdom (M http://bspghan.org.uk/). A high level of suspicion
from a history suggestive of arthritis accompanied by any of the listed pre-
senting clinical features of IBD. Consider IBD in the child who is intolerant
of NSAIDs.
• Presence of anaemia, raised acute phase reactants, and low albumin.
328 CHAPTER 4 Systemic diseases

• Perinuclear antineutrophil cytoplasmic antibodies (pANCA) and

anti-Saccharomyces cerevisiae antibodies (ASCA), may help distinguish
between UC and CD (pANCA 68% of UC; ASCA 81% of CD).
• MRI of sacroiliac joints and spine help distinguish non-specific MSK pain
from true sacroiliitis and spondylitis—x-rays are not helpful in
the adolescent patient as the epiphyses do not fuse until mid-20s.
Management
• Control of IBD usually results in resolution of peripheral arthritis.
• If persistent peripheral arthritis, then intra-articular steroids are
effective.
• Axial disease may (or may not) benefit from sulfasalazine or MTX.
• Persistent arthritis, axial disease, or resistant IBD may respond to
parenteral MTX, AZA, or anti-TNF such as infliximab (there are
reports that IBD has developed whilst on treatment with etanercept).
 Chapter 5 329

Bone diseases, skeletal

dysplasias, disorders
of collagen

Metabolic bone diseases 330

Skeletal dysplasias 333
The osteochondroses 343
Heritable disorders of connective tissue 346
330 CHAPTER 5 Bone diseases, skeletal dysplasias

Metabolic bone diseases

Primary osteoporosis
Osteogenesis imperfecta (OI)
• Principal features are bone fragility and low bone mass leading to
fractures and bone deformity with growth retardation.
• Ligamentous laxity, dentinogenesis imperfecta, and blue scleral hue are
variable features. 90% of OI dominantly inherited due to defects in the
type I collagen genes COL1A1 and COL1A2.
Idiopathic juvenile osteoporosis
15–20% due to heterozygous mutations in low-density lipoprotein
receptor related protein 5 (LRP5) gene, rest unknown. Typically presents
pre/early puberty with metaphyseal and vertebral crush fractures.
Rare disorders presenting in the neonatal period with fractures
All have other features that help distinguish them from OI. These disor-
ders include:
• Akinesia
• Spinal muscular atrophy with arthrogryposis
• Neurofibromatosis
• Cytomegalovirus inclusion disease
• Caffey’s disease
• I-cell disease (mucolipidosis II).
Bone active treatment is with bisphosphonates to i bone mass, reduce
bone pain, and improve vertebral size and shape:
• Infants and those with more severe disease, or where growth will
soon cease more often receive IV therapy—pamidronate 9–12mg/kg/yr
(see b Guidelines, p 431).
• Oral therapy in milder cases with risedronate (1–2mg/kg/week) is safe
and effective. Other bisphosphonates are used but the evidence base is
less clear.
Secondary osteoporosis
Inflammatory conditions (e.g.)
• Inflammatory bowel disease—bone loss and fractures more common
in Crohn’s disease than in ulcerative colitis, before and after starting
glucocorticoids.
• Juvenile arthritis—up to 7% of children with inflammatory joint disease
have vertebral crush fracture prior to use of glucocorticoids. Main
clinical feature is back pain.
• Cystic fibrosis—bone mass loss after 1st decade with concomitant i in
fracture risk.
Use of glucocorticoids
• i fracture risk when taking oral glucocorticoids irrespective of
underlying condition.
• Complex actions on skeleton—reduce cortical bone turnover leading to
retention of older, more heavily mineralized bone that i DXA-measured
 METABOLIC BONE DISEASES 331

bone mass; loss of trabecular bone, leading to i risk of fractures in

vertebrae.
• Resolution of risk 3–6 months after steroid cessation.
Disuse
• Cerebral palsy—long bone fractures occur in major bones during
handling; bones are narrow with thin cortices.
• Duchenne muscular dystrophy—low bone mass s to disuse and
corticosteroids; fractures occur whilst still mobile, but i in frequency
once boy becomes immobile. Bone loss i when steroid dose higher.
• Epidermolysis bullosa—bone loss due to immobility.
Endocrine disturbance
• Anorexia nervosa—low bone mass may not be apparent in childhood/
adolescence—low bone mass consistently reported in adult women
who were anorexic as teenagers.
• Cushing’s syndrome—low bone mass and fractures reported, vertebral
crush fractures resolve on treatment of underlying disorder.
• Turner’s syndrome—no evidence of low bone mass or fractures until
young adulthood.
Haematology/oncology
• Acute leukaemia—i fracture risk and bone loss both at diagnosis and
during treatment.
• Post chemotherapy for childhood cancer. Studies suggest that
chemotherapy alone does not lead to i later fracture risk—risk is i in
those receiving radiotherapy.
• Thalassaemia.
• Post-transplantation.
Osteomalacia/rickets
• Clinical features—bowed limbs, metaphyseal swelling, bossed forehead,
pain.
• Vast majority are due to lack of vitamin D, resulting from poor sunlight
exposure or dietary inadequacy; more common in darker-skinned
individuals living in colder climates.
• Vitamin D deficiency results in myopathy and musculoskeletal aches
and pains; infants are usually miserable. Investigations: serum Ca, PO4,
ALP, PTH, and 25OH vitamin D.
• The threshold for deficiency in asymptomatic individuals is debated
widely; a typical cut-off is 25mmol/L 25OH vitamin D. Above this,
either treatment or supplementation (200–400U/d) is given. Sufficiency
is generally accepted as being >75mmol/L.
• Treatment is with ergo/cholecalciferol daily for 2 months. <2yr 3000U/
day; 2–10yr 6000U/day; 10+y 10,000U/day.
• Inherited forms of rickets often associated with i circulating FGF-23,
which promotes phosphaturia and inhibits renal production of the
vitamin D metabolite 1,25 dihydroxyvitamin D; this group includes
X-linked hypophosphataemic rickets, and children with McCune–
Albright syndrome/polyostotic fibrous dysplasia. Replacement with oral
phosphate in divided doses (40–50mg/kg) and 1,25 dihydroxyvitamin D
or 1-A calcidol (30–50ng/kg).
332 CHAPTER 5 Bone diseases, skeletal dysplasias

Osteopetrosis
• i bone mass due to failure to resorb bone.
• Severe cases present with bone marrow failure and incipient blindness at
3–6 months—urgent decompression of optic nerves may be required.
• Some respond well to bone marrow transplantation.
• Milder forms present later in life—nerve compression and poor
fracture healing are significant problems.
Avascular necrosis
• Commonest site affected is the femoral head (other sites described in
b The osteochondroses, p 343).
• Thought to be due to interruption to blood supply to the femoral
head.
• Affects approximately 1in 1000 children, 4 more than 5 (4:1), usually
between 3–12yr. 5–10% of cases are bilateral.
• Presenting features—deep hip or referred pain to the knee especially
with exercise, may present with limp.
• Diagnosis is by radiograph; however MRI results in earlier detection.
• Treatment—conservative in early disease. Surgical intervention may be
required.
• Prognosis—relatively good in the very young and with early detection.
Older children and those with significant deformities of the femoral
head develop premature osteoarthritis.
Bone densitometry
• DXA is most commonly used to assess bone density, but cannot
measure tissue depth; hence adjustment procedures are often applied
to account for body size.
• No simple algorithm is available that fully corrects this problem.
• Small children will have lower values than large children; hence
adjusting for body size seems logical, but may be confounded when the
underlying disease affects growth. Sequential measurements (usually
2-yearly) assessed alongside a growth chart are helpful in assessing
bone mass trajectory in response to therapy.
• Indications for the use of DXA in 1° and 2° osteoporosis in children,
along with comprehensive supporting evidence, are given on the
International Society for Clinical Densitometry (ISCD) website: M http://
www.iscd.org/visitors/pdfs/ISCD2007OfficialPositions-Pediatric.pdf.
 SKELETAL DYSPLASIAS 333

Skeletal dysplasias
Background
A group of several hundred clinically and genetically heterogeneous disor-
ders causing generalized abnormalities of bone growth and/or bone mod-
elling. The majority are rare with one of a small number (710) conditions
present in most affected individuals. Usually present with 1 or more of:
• Short stature (usually disproportionate)
• Bone deformity/joint malalignment
• Joint (or generalized bone) pain or limitation of movement
• Abnormal gait
• Recurrent fractures
• Significant family history.
Healthcare needs, associated features, prognosis, and recurrence risks in
other family members are dependant on specific diagnosis.
Assessment
History
• Pre- and postnatal growth pattern—age at which abnormalities first
noted.
• Age of onset and progression of symptoms.
• Associated features including abnormalities of vision, hearing, teeth,
palate, development, neurological function.
• Effect on physical and psychosocial functioning.
• Three-generation family history including, parental heights, evidence of
short stature, early onset ‘arthritis’, joint replacement at young age, and
consanguinity.
Examination
• Height, weight, head circumference.
• Skeletal proportion—span, where possible sitting height (subischial leg
length = height − sitting height) or upper and lower segments (US, LS)
and US/LS.
• (LS measured from symphysis pubis to floor, US = height − LS).
• (Centile charts are available for sitting height and subischial leg
length. US/LS normally >1.0 until age 10yr, 1.0 at 10yr, <1.0 after
10yr (see M http://www.castlemeadpublications.com).
• If limbs are short it is important to note which segment(s) are
affected: i.e. if the proximal segment (shoulder to elbow, or hip to
knee) is short, e.g. in achondroplasia—rhizomelic shortening, middle
segment (elbow to wrist, knee to ankle); mesomelic, distal segment
(hands, feet); acromelic; or all segments micromelic.
• Hands and feet—brachydactyly, polydactyly, talipes, joint limitation/
deformity.
• Joint function, spine (assess for kyphosis, scoliosis, i lumbar lordosis),
gait.
• General examination—including particularly vision, hearing, palate,
teeth, heart, abdominal organomegaly, dysmorphic facial features and
development.
334 CHAPTER 5 Bone diseases, skeletal dysplasias

Investigation
• Radiological skeletal survey—discuss exact composition with local
radiologist but likely to include:
• Anterior–posterior (AP) and lateral skull.
• PA chest.
• AP and lateral spine.
• AP pelvis and bilateral hips.
• AP 1 upper limb and 1 lower limb.
• AP of left hand and wrist (both if hands affected).
• Other views as clinically indicated—consider views of cervical spine
in flexion and extension where there is significant spine involvement.
• Biochemical assessment including vitamin D levels if abnormal bone
density or metaphyseal abnormalities (nutritional rickets is frequently
misdiagnosed as a metaphyseal dysplasia).
• Metabolic investigation if features of storage disorder (coarse facies,
organomegaly, dysostosis multiplex, developmental delay.
• Chromosome analysis—if associated malformations and/or cognitive
developmental delay.
• DNA analysis—rarely indicated. May be helpful in specific circumstances
or where prenatal diagnosis in future pregnancies is requested. Discuss
with clinical genetics.
Differential diagnosis
• Most skeletal dysplasias result in disproportionate short stature with
specific clinical and radiographic features:
• Expert assessment of x-rays may be required (discuss with radiology
or European Skeletal Dysplasia Network: M http:www.esdn.org).
• Radiographic changes may not be present in infancy and may
disappear after puberty—previous x-rays may be helpful.
• Consider other causes of short stature—endocrine, chronic illness,
syndromic, constitutional delay of growth and puberty particularly
if short stature is proportionate 9 delayed bone age ± non-skeletal
features (including cognitive delay).
• Consider overall diagnostic group (Table 5.1). Common diagnoses only are
described for full classification of skeletal dysplasias (for more information
see b Further reading, p 342).
Management
• Multidisciplinary team including rheumatology, orthopaedics, radiology,
clinical genetics, physiotherapy, occupational therapy, ENT, paediatrics,
neurosurgery.
• Diagnosis will help identify likely natural history and healthcare needs.
Anticipatory management important—e.g. kyphosis in achondroplasia,
retinal detachment in spondyloepiphyseal dysplasia congenita (SEDc).
• Surgical intervention is not always required.
• Pain is a major feature of many bone dysplasias and is often poorly
controlled:
• Pain may be 1* presenting feature, e.g. joint pain in multiple epiphyseal
dysplasia (MED), generalized bone pain in Engelmann disease:
— May not respond to usual analgesics.
 SKELETAL DYSPLASIAS 335

— Appropriate physiotherapy may be more helpful.

• Steroid treatment can be very effective in, e.g. Engelmann disease.
• Most bone dysplasias are heritable—discuss with family and offer
referral to clinical genetics.
• Support available for family from several organizations (see b Useful
contacts, p 342).
Table 5.1 Skeletal dysplasias
Clinical/ Clinical features Radiological features Inheritance/ Other features
radiographic group molecular genetics
Short limbs/‘normal’ trunk
Achondroplasia/ • Short limbs (rhizomelic) • Large calvaria, dsize foramen AD—mostly new dominant Risk of hydrocephalus and foramen
hypochondroplasia • Macrocephaly magnum with unaffected parents magnum stenosis in early years.
• Thoraco-lumbar kyphosis in • dinterpediculate distance, short Lumbar stenosis in adulthood
Mutations in FGFR3
infancy, lordosis later pedicles
Obstructive sleep apnoea common
• Trident hand • Flat, round iliac bones, notch-like
• delbow extension sacroiliac groove Achondroplasia/
• Tibial bowing • Short tubular bones hypochondroplasia may be
• Brachydactyly difficult to differentiate clinically
Pseudoachondroplasia • Short limbs (micromelic) • Delayed epiphyseal ossification, AD—many new dominant Not related to achondroplasia
• Brachydactyly flat irregular epiphyses
Mutations in COMP Present with waddling gait and
• Extreme joint hypermobility • Biconcave vertebrae, later
later hip and knee pain. At risk of
• Normal head size/shape platyspondyly, anterior vertebral
cervical spine instability
• Kyphoscoliosis tongue
• Waddling gait • Brachydactyly Overlaps with severe multiple
• Knee deformity (wind swept) epiphyseal dysplasia
Dyschondrosteosis • Madelung deformity of upper • Madelung deformity AD Very variable phenotype
limbs with limitation of pronation • Bowing of forearm and lower leg
Deletion or mutations in Growth velocity may increase on
supination bones
SHOX treatment with hGH
• Mesomelic shortening
• Radial, tibial bowing Important to differentiate from
• May present as ‘isolated’ familial short stature
familial short stature
Short trunk with ‘normal’ limbs
Spondyloepiphyseal • Short spine and neck, barrel • Delayed ossification of skeleton, AD Motor development may
dysplasia congenita chest, pectus carinatum, absence of various ossification be delayed, but cognitive
Mutations/deletion/
(SEDc) genu valgum centres (e.g. pelvis, vertebral development normal
duplication of COL2A1
• Hands and feet clinically normal bodies, femoral head and neck) Small thorax may cause
• Flattened midface • Odontoid hypoplasia, Spectrum of allelic disorders
respiratory complications
• 9 myopia, cleft palate, club feet kyphoscoliosis includes Kniest dysplasia,
• Coxa vara AD spondyloarthropathy, Risk of atlanto-axial dislocation
stickler syndrome COL2 and spinal cord compression
type, achondrogenesis II,
High myopia associated with
hypochondrogenesis
retinal detachment
Progressive • Short trunk • Platyspondyly, ± scoliosis AR An important differential for JIA
pseudorheumatoid • Progressive large joint • Enlarged epiphyses initially. Mutations in WISP3 especially where there is a family
arthropathy of contracture Later develop cystic lesions history
childhood • Contracture of small joints of with flattening
Differentiating factors include
(spondyloepiphyseal hands and feet with soft tissue • Enlarged epiphyses and
platyspondyly and the absence of
dysplasia tarda with swelling metaphyses of bones of hands
erosions and periostitis
progressive and feet with osteoporosis but
arthropathy) no periostitis Progressive joint contracture
and osteoarthrosis may lead to
decreased mobility and the need
for joint replacement
(continued )
Table 5.1 (Contd.)
Clinical/ Clinical features Radiological features Inheritance/ Other features
radiographic group molecular genetics
Brachyolmia • Short trunk, scoliosis, • Platyspondyly Heterogeneous Type 1: corneal opacities
mild short stature • Short ilia Both AR and AD forms Type 2: calcification of falx cerebri
• Clinically and genetically • 9 longitudinal striations of documented Type 3: severe kyphoscoliosis
heterogeneous metaphyses of large long bones Type 1: AR
• Types 1–3 (e.g. femur) Type 2: AR
Type 3: AD, TRPV4
Short trunk with short limbs
Kniest dysplasia • Short limbs, joint enlargement, • Platyspondyly, anterior AD, mutations in COL2A1 Complications include chronic
djoint mobility wedging of vertebral bodies (most are deletions otitis media, retinal detachment,
• Dorsal kyphosis, ilumbar lordosis, • Broad, hypoplastic ilia resulting in truncated cataracts, joint contractures, early
thoracic scoliosis • Broad, short femoral necks type II collagen) arthrosis
• Flattened midface, depressed nasal • Delayed ossification of capital
bridge, femoral epiphyses
• 9 cleft palate, myopia, deafness, • Short tubular bones, broad
clubfeet metaphyses, deformed epiphyses
Diastrophic dysplasia • Wide phenotypic variability • Flat dysplastic epiphysis with AR Perinatal and infant mortality i
• Short limbs wide metaphyses
Mutations in DTDST Risk of medullary compression
• Multiple joint contractures • Delta shaped distal femoral/
from cervical kyphosis (present at
• Proximal hypermobile thumbs radial metaphyses
birth but usually resolves by 77y)
(‘hitchhiker thumb’, deformity • Short, wide, long bones
of 1st metacarpal) • Deformities of metacarpals, Clubfeet often difficult to
• Clubfeet metatarsals, and phalanges manage and resistant to surgical
• Cysts of external ear (in first • Progressive thoraco-lumbar correction
12 weeks of life), subsequently kyphoscoliosis, cervical kyphosis
Joint contracture is progressive
cauliflower deformity of pinnae and may recur after surgical
• Progressive kyphoscoliosis release
• 9 cleft palate
Epiphyseal disorders
Multiple epiphyseal • Very variable phenotype • Delayed epiphyseal ossification Mostly AD Poor correlation between
dysplasia (MED) • Joint pain • Flattened irregular epiphyses Mutations in: phenotype and genotype. Very
• Hypermobile joints, especially in • Mild irregularity and flattening COMP variable even within families
hands of vertebrae in severe cases MATN3 Overlaps with mild
• dmobility, waddling gait
Col9A1/A2/A3 pseudoachondroplasia severe end
Rare AR form of MED spectrum
Mutations in:
DTDST
(continued )
Table 5.1 (Contd.)
Clinical/ Clinical features Radiological features Inheritance/ Other features
radiographic group molecular genetics
Metaphyseal dysplasias
Metaphyseal dysplasia, • Bowed legs, waddling gait • Short tubular bones AD May be difficult to differentiate
Schmid type • Normal epiphyseal development • Broad irregular metaphyses Mutations is COL10A1 clinically and radiographically
• Brachydactyly hips worse than knees from rickets. Always check
• Lordosis • Coxa vara, short femoral necks biochemistry including vitamin
• Brachydactyly D levels
• ± mild platyspondyly
Cartilage–hair • dlength at birth • Short tubular bones AR Risk of cervical spine instability
hypoplasia • Fine, sparse hair/eyebrows/lashes • Metaphyseal dysplasia of tubular Mutations in RMRP All features variable including
• Brachydactyly with hypermobile bones knees more than hips severity of immunodeficiency
hands • Mild platyspondyly Probable i risk of malignancy in
• delbow extension • Brachydactyly with cone-shaped adulthood, e.g. lymphoma.
• Ligamentous laxity epiphyses
• Recurrent infections (children)
secondary to din vitro T-cell function
• Particularly at risk from varicella
infection
• Hirschsprung’s disease
Skeletal dysplasias with dbone density
Osteogenesis • Recurrent low trauma fracture • Generalized hypomineralization Mostly AD Vital to differentiate from non
imperfecta • Bone deformity • Wormian bones in skull Mutations in COL1A1/A2 accidental injury. Requires expert
• Blue sclerae and dentinogenesis Very rare AR forms assessment. Both diagnoses may
imperfecta may be present be present
• Back pain Management of severe OI
• Very variable phenotype with revolutionized by use of IV
multiple types based on clinical bisphosphonates
features
Skeletal dysplasias with ibone density
Osteopetrosis • Very variable phenotype • Generalized increase in bone AR—severe neonatal form Mutation analysis is important
• Severe infantile density especially at skull base Mutations in: in neonatal forms as it may
• Intermediate childhood onset • ‘Bone within a bone’ CLCN7 determine suitability for definitive
• Mild late onset • ‘Rugger jersey’ spine TCIRG1 treatment by BMT. Urgent
• Low trauma fractures OST assessment is required
• Cranial nerve impingement AD—later onset forms
Neurosurgical assessment
• Bone marrow failure Mutations in:
required
• Early dental decay and loss CLCN7
LRP5
AD, autosomal dominant; AR, autosomal recessive.
342 CHAPTER 5 Bone diseases, skeletal dysplasias

Further reading
Superti-Furga A, Unger S, the Nosology Group of the International Skeletal Dysplasia Society.
Nosology and classification of genetic skeletal disorders. Am J Med Genet 2006; 143A:1–18.
Trotter TL, Hall JG. Health supervision for children with achondroplasia. Pediatrics 2005;
116:771–83.

Useful contacts
European Skeletal Dysplasia Network—online diagnostic resource: M http://www.esdn.org.
Little People of America—support organization: M http://www.lpaonline.org.
Restricted Growth Association—support organization: M http://www.restrictedgrowth.co.uk.
 THE OSTEOCHONDROSES 343

The osteochondroses
Definition
Historically, the term ‘osteochondrosis’ or ‘osteochondritidis’ has been
applied to a heterogeneous group of conditions characterized by a dis-
turbance in endochondral ossification in an area in which previously
growth had been normal; such changes have been observed in almost
every growth centre (epiphysis or apophysis) in the body and the different
sites are often associated with eponyms. The degree of articular cartilage
involvement varies and in some localized cases the term osteochondritis
dissecans (OCD) is used (Table 5.2). Also see b Metabolic bone disease,
p 330.
Aetiology
The initial event or combination of events that leads to the disorder in
endochondral ossification is unknown and hence these conditions are
considered idiopathic in origin:
• Both a vascular and a traumatic aetiology have been proposed.
• The vascular theory is certainly part of the process in Legg–Perthes and
• Repetitive microtrauma is implicated in OCD and Osgood–Schlatter’s
amongst others.
Pathology
Histologically, the affected area shows many of the features of ischaemic
necrosis affecting both bone and cartilage:
• Necrosis.
• Revascularization.
• Invasion with granulation tissue.
• Osteoclastic resorption of dead bone.
• Osteoid replacement along necrotic trabeculae.
• Formation of mature lamellar bone
In OCD, the process is more localized:
• Segmental epiphyseal necrosis may lead to physical separation of an
osteoarticular fragment in which the bony fragment may be very small.
• Once separated this fragment may continue to grow as the articular
cartilage is nourished by the synovial fluid.
When the history, clinical examination, and imaging are typical then bone
biopsy is not required.
Clinical features
Overall, the natural history for the osteochondroses (as distinct from
OCD) is well defined and generally the outcomes are predictable and
often good. The specific symptoms vary from site to site and with age of
onset of the condition. Symptoms and signs may include:
• Local or referred pain.
• Swelling and symptoms of inflammation such as tenderness and warmth.
• Joint stiffness, with or without a limp.
344 CHAPTER 5 Bone diseases, skeletal dysplasias

Table 5.2 The osteochrondroses

Eponym Site
Lower limb Kohler Navicular
Freiberg 2nd metatarsal head (or 3rd/4th)
Sever Calcaneal apophysis
Osgood–Schlatter Tibial apophysis
Upper limb Panner Capitellum
Keinboch Lunate
Spine Schuermann Vertebral end plates
Others *Blount Proximal tibial physis
*
Legg–Calve–Perthes Proximal (capital) femoral epiphysis
Osteochondritis dissecans Knee (distal femoral condyle and
patella), talus, capitellum
*
Most paediatric orthopaedic surgeons consider these two conditions as separate entities—
the natural history of these two conditions is more severe and the management strategies
significantly more aggressive.

Features on imaging
The exact features vary with the anatomical site involved but some plain
radiographic changes are common:
• Early signs include a d in size, change in shape, i in density or irregularity
of the bony epiphysis/apophysis. Often the whole bony area is involved.
• Later bone resorption is seen as fragmentation.
• With continued re-ossification the radiographic appearances may
return to normal.
• With delay in revascularization, non-union may lead to separation of
an osteochondral fragment as seen in OCD (where the process is
localized so that the rest of the epiphysis appears normal).
The MRI features vary depending on the stage of the disease process and
the site of involvement but bone oedema is common. Small subchondral
fractures might be identified and early identification of fragment separa-
tion for OCD lesions may be helpful. MRI and/or bone scans can be useful
in diagnosing other pathologies (see b Pitfalls, p 345).
 THE OSTEOCHONDROSES 345

Natural history and treatment recommendations

Most osteochondroses are benign, self-limiting processes; treatment is
usually symptomatic and conservative. Symptoms may take some time to
resolve and with apophyseal lesions this may not occur until after physeal
fusion. Beware of ‘over-treatment’. Management includes the following:
• Family/patient education.
• Relative rest from exercise—encourage sporting ‘warm up and cool
down’.
• Analgesic and/or anti-inflammatory medication as required.
In selected cases:
• Physiotherapy, support bandaging, bracing (perhaps in Scheuermann’s
disease) may help.
• Treatment of Blount’s and Legg–Perthes requires referral to an
orthopaedic surgeon.
The management of OCD lesions can be more complex: symptoms such
as locking, sharp pain, and ‘giving way’ of the joint with signs of an effusion
warrant an orthopaedic opinion. Surgical options include:
• Pinning in situ for the lesion that is not separated.
• Drilling to enhance revascularization.
• Replacement of the loose fragment (or removal).
• Debridement of craters/ulcers if the fragment has been ‘lost’.
• Consideration of techniques such as ACI or MACI (autologous
chondrocyte implantation or matrix-induced ACI).
Pitfalls
• Children are not used to ‘chronic’ pain and parents do not like to see
their child limping. For both it can be a depressing/frustrating time.
• If the child has a ‘disease’ label, then parents expect treatment for it.
It is unfortunate that most of the eponyms imply that OCD is a disease
state rather than a usually benign condition that disrupts normal
growth temporarily.
• Remember that some of the radiological features described such as
fragmentation of the calcaneal apophysis (in Sever’s disease) and the
tibial tubercle (in Osgood–Schlatter’s) may also be seen in normal,
asymptomatic children.
• Thus it is important to determine whether or not the radiographic
features are a ‘red herring’: does the clinical history and examination
match the imaging results?
• For localized pain and swelling in a child the differential diagnosis
must always include:
• Tumour.
• Bone and joint infection.
346 CHAPTER 5 Bone diseases, skeletal dysplasias

Heritable disorders of connective tissue

A number of inherited disorders of connective tissue may present to pae-
diatric rheumatology services with biomechanical pain related to muscu-
loskeletal features.
• The majority of these conditions are recognizable by their clinical
features.
• It is important to identify those patients with conditions that may
predispose to potentially preventable causes of morbidity and
mortality.
• A physiotherapy-led multidisciplinary approach with attention to
strengthening areas of weakness and pacing activities is effective for
patients with significant musculoskeletal symptoms.
• Emerging new therapeutic drug approaches are being used in Marfan
syndrome to limit cardiovascular complications.
Marfan syndrome
Background
• Inherited disorder of fibrillin transmitted as an autosomal dominant trait.
• Incidence 1:5000, panethnic, no sex predilection.
• Marfan syndrome is fully penetrant with variable expression.
Pathophysiology
• Caused by mutations in Fibrillin-1 gene (FBN1), located on
chromosome 15.
• Fibrillin-1 is a glycoprotein which aggregates to form complex
extracellular structures called microfibrils which are essential for elastic
fibre maintenance in postnatal life.
• Abnormal microfibrils weaken the aortic wall and other structures
such as the suspensory ligament of the lens, ligaments, lung airways,
and spinal dura.
• Recent studies suggest that abnormalities in FBN1 lead to dysregulation
of transforming growth factor-beta (TGF-B) and that many of the
multisystem manifestations including cardiovascular complications
relate to excess TGF-B signalling.
• Severe neonatal Marfan syndrome is associated with a cluster of
mutations between exons 24–32 of FBN1 but there are no other
established correlations between genotype and phenotype.
Clinical features
A diagnosis of Marfan syndrome is based on the revised Ghent nosology.
• Systemic features and differential diagnosis are shown in Tables 5.3
and 5.4.
• In the absence of family history, Marfan syndrome is diagnosed when
there is:
• Aortic root dilatation or dissection (z score >2) and ectopia lentis.
• Aortic root dilatation or dissection and FBN1 mutation.
• Aortic root dilatation or dissection and t7 points on systemic
features score.
• Ectopia lentis and FBN1 mutation known to be associated with
aortic root dilatation or dissection.
 HERITABLE DISORDERS OF CONNECTIVE TISSUE 347

• In the presence of family history Marfan syndrome is diagnosed when

there is ectopia lentis or t7 points on systemic features score or aortic
root dilatation/dissection.
• Caveat: when the diagnosis of Marfan syndrome is made without a
known mutation in FBN1, discriminating features of vEDS, SGS, or
LDS must not be present (Table 5.3) and appropriate diagnostic tests
performed if indicated.
• Patients <20yr with borderline aortic root measurements and a family
history of Marfan syndrome or a known FBN1 mutation are defined
as having potential Marfan syndrome and require close cardiology
follow-up to detect progressive aortic root dilatation.
• Patients with musculoskeletal features typical of Marfan syndrome
without further organ involvement are classified as having a Marfanoid
habitus.
• Neonatal Marfan syndrome is not a separate entity but represents the
most severe end of the Marfan syndrome spectrum.
Investigations
• A high rate of new mutations means a clinically useful genetic screening
test has not been developed.
• ECG and echocardiogram are indicated in patients with Marfanoid
habitus to identify potential cardiac involvement.
Management
• Antihypertensive treatment with B-blockers to delay or prevent aortic
root dilatation and dissection is the current standard of medical care.
• Elective aortic graft surgery is recommended for patients with an aortic
diameter of t5cm or rapidly progressive dilatation.
• Losartan is an angiotensin II receptor blocker which has also been shown
to block TGF-B signalling. Recent animal studies and one case series
of 18 children with progressive aortic root dilatation unresponsive to
standard therapy suggest that Losartan may reduce or halt progression
of aortic root dilatation in these patients.
348 CHAPTER 5 Bone diseases, skeletal dysplasias

Table 5.3 Scoring system for systemic features of Marfan syndrome

(Revised Ghent nosology)
Feature Points Feature Points
Wrist or thumb sign* 1 Pneumothorax 2
Wrist and thumb sign 3 Dural ectasia 2
Pectus carinatum 2 Protrusio acetabuli 2
Pectus excavatum or chest 1 Reduced upper:lower 1
asymmetry segment ratio and increased
armspan:height ratio and no
severe scoliosis
Hindfoot deformity 2 Scoliosis or thoracolumbar 1
kyphosis
Pes planus 1 Reduced elbow extension 1
Facial features 3/5 from: 1 Skin striae 1
dolichocephaly, enopthalmos,
downslanting palpebral fissures,
malar hypoplasia, retrognathia
Myopia >3 dioptres 1 Mitral valve prolapse 1
Maximum score = 20 points. t7 points indicates systemic involvement.
*
The thumb sign is positive if the thumb, when completely opposed within the clenched hand,
projects beyond the ulnar border.
The wrist sign is positive if the distal phalanges of the 1st and 5th digits of 1 hand overlap when
wrapped around the opposite wrist.
 HERITABLE DISORDERS OF CONNECTIVE TISSUE 349

Table 5.4 Differential diagnosis of Marfan syndrome

Differential diagnosis Gene Discriminating features
Loeys–Dietz syndrome TGFBR1/2 Bifid uvula/cleft palate, arterial
(LDS) tortuosity, hypertelorism, diffuse
aortic and arterial aneurysms,
craniosynostosis, clubfoot, cervical
spine instability, thin and velvety
skin, easy bruising
Shprintzen–Goldberg FBN1 and others Craniosynostosis, mental retardation
syndrome (SGS)
Congenital contractural FBN2 Crumpled ears, contractures
arachnodactyly (CCA)
Weill–Marchesani FBN1 and Microspherophakia, brachydactyly,
syndrome (WMS) ADAMTS10 joint stiffness
Ectopia lentis FBN1 Lack of aortic root dilatation
syndrome (ELS) LTBP2
ADAMTSL4
Homocystinuria CBS Thrombosis, mental retardation
Familial thoracic aortic TGFBR1/2, Lack of Marfanoid skeletal features,
aneurysm syndrome ACTA2, MYH11 livedo reticularis, iris flocculi
(FTAA)
Arterial tortuosity SLC2A10 Generalized arterial tortuosity,
syndrome (ATS) arterial stenosis, facial dysmorphism
Ehlers–Danlos COL3A1, COL1A2, Middle-sized artery aneurysm,
syndromes (vascular, PLOD1 severe valvular insufficiency,
valvular, kyphoscoliotic) translucent skin, dystrophic scars,
facial characteristics
350 CHAPTER 5 Bone diseases, skeletal dysplasias

Ehlers–Danlos syndromes (EDS)

• The EDS are a heterogeneous group of disorders characterized by
hyperextensible skin, hypermobility, dislocations, poor wound healing,
wide thin scars, tissue fragility and easy bruising.
• Diagnostic criteria and clinical features for EDS are shown in Table 5.5.
• Patients who present with biomechanical pain and are found to have
joint hypermobility and soft, mildly extensible skin have previously
been classified as EDS type III or ‘hypermobile type EDS’; the label may
cause unnecessary anxiety for patients and families and current UK
practice is to describe these patients as having joint hypermobility and
biomechanical pain.
Osteogenesis imperfecta
• Children with mild subtypes of osteogenesis imperfecta (OI) are usually
of average stature and have a history of minimal trauma fractures.
• Family members with OI type 1 have been identified who have never
sustained a fracture and these patients may present with hypermobility
and musculoskeletal symptoms.
• Clinical and laboratory discriminating features are shown in Table 5.6.
Table 5.5 Diagnostic criteria for Ehlers–Danlos syndromes
Type and inheritance Major features Minor features Laboratory
Classical Skin hyperextensibility Smooth velvety skin Abnormalities in skin collagen under
electron microscopy
AD Widened atrophic scars Molluscoid pseudotumors
Abnormal collagen type V
Joint hypermobility Subcutaneous spheroids
30% due to mutation in tenascin

HERITABLE DISORDERS OF CONNECTIVE TISSUE

Complications of joint hypermobility (sprains,
subluxations/dislocations, pes planus)
Muscle hypotonia
Delayed gross motor development
Easy bruising
Manifestations of tissue extensibility and fragility
Postoperative hernia
Positive family history
Vascular Thin, translucent skin Acrogeria Abnormal type 3 collagen
AD Arterial/intestinal/uterine Hypermobility of small joints COL3A1 mutation
fragility or rupture
Tendon and muscle rupture
Extensive bruising
Talipes equinovarus
Characteristic facial appearance
Early onset varicose veins
Arteriovenous, carotid-cavernous sinus fistula

(continued )

351
 352
CHAPTER 5
Bone diseases, skeletal dysplasias
Table 5.5 (Contd.)
Type and inheritance Major features Minor features Laboratory
Pneumothorax
Gingival recession
Positive family history or sudden death in close relatives
Hypermobility Generalized joint hypermobility Recurring joint dislocations
AD Hyperextensible or smooth, Chronic joint or limb pain
velvety skin
Positive family history
Kyphoscoliotic Generalized joint laxity Tissue fragility, including atrophic scars Urinalysis for lysylpyridinoline and
hydroxylysylpyridinoline
AR Severe muscle hypotonia at birth Easy bruising
Scoliosis at birth, progressive Arterial rupture
Scleral fragility and rupture of Marfan-like habitus
the ocular globe
Microcornea
Osteopenia
Family history
Arthrochalasia Severe generalised joint Skin hyperextensibility Skin biopsy and demonstration of
hypermobility with recurrent abnormal collagen type 1
AD Tissue fragility, including atrophic scars
subluxations
Easy bruising
Congenital hip dislocation
Muscle hypotonia
Kyphoscoliosis
Radiologically demonstrated mild osteopenia

HERITABLE DISORDERS OF CONNECTIVE TISSUE

Dermatosparaxis Severe skin fragility Soft doughy skin texture Demonstration of abnormal
collagen 1 chains in skin
AR Sagging, redundant skin Easy bruising
Premature rupture of fetal membranes
Large hernias (inguinal and umbilical)
For a diagnosis to be made a patient must have one or more of the major criteria. Presence of minor criteria is ‘suggestive’ of a diagnosis. Items in bold are distinguishing features of
that particular subtype of Ehlers–Danlos syndrome.

353
354 CHAPTER 5 Bone diseases, skeletal dysplasias

Table 5.6 Disorders predisposing to bone fragility which can be

associated with joint hypermobility (see b Metabolic bone diseases,
p 330)
Type and Discriminatory Other features Laboratory
inheritance features
Osteogenesis Blue sclera Kyphoscoliosis Reduction
imperfecta Hypermobility, Arcus cornea in synthesis
type I AD especially Hearing impairment of type I
of small joints procollagen
Metatarsus varus
Wormian bones Abnormalities
Easy bruising in COL1A1
in 70% Fractures from
Generalized minimal trauma
osteopenia on DEXA Opalescent dentine
Osteogenesis White sclera Progressive long COL1A1 or
imperfecta Fractures from bone deformity COL1A2
type IV AD minimal trauma Joint hypermobility mutations
Short stature Opalescent dentine which reduce
collagen
Wormian bones stability
in 50–70%

Further reading
Loeys BL, Dietz HC, Braverman AC, et al. The Revised Ghent Nosology for the Marfan syndrome.
J Med Genet 2010; 47:476–85.
 Chapter 6 355

Infection and
immunization

Tuberculosis and mycobacterial disease (see also

b Infections in the immunocompromised, p 70,
b Bone and joint infections, p 64, and b Pyrexia of
unknown origin, p 94) 356
Rheumatic fever 363
Lyme disease 368
Varicella zoster infections 371
Immunization schedules and the immunocompromised 374
356 CHAPTER 6 Infection and immunization

Tuberculosis and mycobacterial disease

There are 3 main scenarios to consider:
• Latent TB infection (LTBI).
• 1* musculoskeletal TB and reactivation of LTBI as a result of drug-
induced immune-suppression.
• Reactive immunological phenomena associated with Mycobacterium
tuberculosis (MTB) and/or antimycobacterial therapy.
LTBI
• Following infection with MTB, 95% of individuals will develop LTBI,
hosting live MTB in the absence of clinical manifestations (Fig. 6.1).
In LTBI, MTB is deemed a state of non-replicating persistence or low
replication contained by a highly organized infiltrate called a granuloma
constituted by mycobacteria-containing macrophages surrounded by
activated lymphocytes.
• Tumor necrosis factor (TNF) plays multiple roles in the host’s ability
to respond against the infection with MTB including responsibility for
granuloma formation and maintenance.
• MTB are kept at bay long term in most immunocompetent individuals.
However, MTB remains viable and a change of host’s immune
response such as immune-suppression with TNF antagonists may lead
to granuloma disintegration and uncontrolled replication of MTB to
produce TB disease.
• A review of the current knowledge of the risk of TB in relationship to
TNF antagonists published by the Tuberculosis Network European
Trials Group (M http://www.ncbi.nlm.nih.gov/pubmed/20530046) can
be summarized as follows:
• The risk of TB in adults with RA treated with TNF antagonists is i
d25x with risk likely i from the disease itself and the use of non-
biological immunosuppressants.
• The risk of TB may be i in children exposed to TNF antagonists
although data (8 years to date) reports very few cases. This may
be because children treated with biologics have so far been in
countries with a very low risk of TB.
• TNF antagonists efficacious against granulomatous conditions
(Crohn’s disease and sarcoidosis) such as infliximab and adalimumab
are more likely to cause TB reactivation than etanercept.
• Screening for LTBI is currently recommended for all candidates
prior to starting anti-TNF therapies (see b p 393). Consequently
paediatric rheumatologists have to manage children with positive
immunodiagnostic tests for TB in absence of clinical symptoms.
 TUBERCULOSIS AND MYCOBACTERIAL DISEASE 357

Exposure to MTB

Infection
10–30%
Non-infection Following inhalation it first
70–90% multiplies in the lungs and then
disseminates to regional lymph
nodes (primary complex)

Non-specific immunity controls

infection initially
After 4–8 weeks, cell-mediated
immunity develops and will
determine further course

Active TB LTBI
5–10% 90–95% Transient infection with
Immunity fails to control MTB Immunity controls MTB clearance?
replication (in half of individuals replication and with the Immunity eradicates the
active disease develops within formation of granuloma walls infection
first 2 years from exposure) it off to an asymptomatic focus

Re-activated TB Persistent LTBI

5% 90%
Changes in host’s immune Longterm immune control
response lead to A large proportion of
uncontrolled replication granuloma will eventually
become sterile

Fig. 6.1 Pathogenesis of TB following exposure to MTB in immunocompetent

individuals.
358 CHAPTER 6 Infection and immunization

Diagnosis
• Immunodiagnostic tests for TB, either tuberculin skin tests (TSTs) such
as Mantoux and/or the newest T-cell based interferon-G release assays
(IGRAs), measure adaptive immune response to MTB infection and
neither of them distinguish active TB disease from LTBI. In the absence
of a gold standard for the detection of LTBI these immunodiagnostic
tests are used as ‘proxy measures’ for LTBI.
• A positive TST (i.e. Mantoux) indicates a cellular immune response
to MTB antigens.
• TST induration >5mm indicates infection in individuals without
BCG vaccination and t15mm with BCG. Variable ‘cut-offs’ between
>5 to >10 exist (e.g. World Health Organization).
• IGRAs measure interferon G released by T cells (QuantiFERON-TB
Gold) or T cells releasing interferon G (T-SPOT.TB) in response
to MTB-specific antigens. Both include a positive control and a
negative control to helps differentiate a true negative response
from anergy (i.e. in children or immune-suppressed patients). IGRAs
compared to TSTs are more specific (i.e. do not cross-react with
BCG strains and environmental mycobacteria), are more reliable to
test immunosuppressed patients, and are likely to be more accurate
in diagnosing LTBI in children than TSTs.
• There are current no published guidelines on how to best screen
children prior starting anti-TNFA.
• Most paediatric rheumatology local guidelines are modelled on
adult recommendations.
• Expert opinion support simultaneous TST, IGRAs, CXR and offering
treatment if any test is positive.
Treatment
• Preventive chemotherapy should be offered to all individuals receiving
TNFA antagonists in the presence of evidence of LTBI. Recommended
prophylactic treatments for LTBI (all ages) in the UK include 3 months
of rifampicin and isoniazid or 6 months of isoniazid.
• TNFA antagonist treatment can be initiated after 4 weeks of treatment
for LTBI has been completed.
Primary musculoskeletal TB and reactivation of LTBI as a
result of drug-induced immune-suppression
• There are an estimated 1.3 million cases of TB annually in children
resulting in 450,000 deaths.
• Overall notification rates for TB in children have been rising in Europe
over the last decade, mostly due to a significant rise in Eastern Europe
and some specific areas such as London, whilst notification rates for
Western Europe including the UK in general have been declining.
• Musculoskeletal TB is rare in developed countries and epidemiological
data is scarce especially in the paediatric population. 2–5% of children
with TB have musculoskeletal involvement.
• In untreated 1* MTB infection the average risk of developing bone
lesions for all children under the age of 5yr is 71–2% in 2yr.
• TB is caused by MTB, rarely by M. bovis (see Fig. 6.1).
 TUBERCULOSIS AND MYCOBACTERIAL DISEASE 359

• During the formation of the 1* complex and for some months after, in
many individuals bacilli escape intermittently into the bloodstream and
may lodge anywhere in the body, but particularly in the CNS, bones, or
the kidneys.
• If circumstances favour the organism rather than the host (i.e. young
age or poor nutrition), then the cells of the reticular endothelial
system do not control the disease and haematogenous spread lead to a
localized lesion or multiple lesions (miliary disease).
• Bone or joint disease is usually the result of lymphohaematogenous
spread from a 1* focus, usually pulmonary. Rarely, direct invasion
by extension from adjacent lymph nodes or lung may cause spinal
disease. Lesions can be found <3 months but usually occur within 1–3yr
of the 1* infection and hence evidence of concomitant pulmonary
involvement is not always found.
• Infection develops in the metaphyses, bone may be destroyed eroding
through into the adjacent joint space and epiphyseal growth plates are
at risk of damage.
• In spinal TB, 3 different patterns of vertebral body infection have
been described—anterior, paradiscal, and central. Subsequent spread
involves intervertebral discs and narrowing of the disc space.
• Abscesses frequently develop in advanced disease, following tissue
planes from vertebrae into the retropharyngeal space, lung, psoas
sheath, perineum, or gluteal region or may extend posteriorly into the
spinal canal.
• Healing is by formation of fibrous tissue and calcification may be seen.
Clinical presentation
• Often indolent and non-specific often leading to significant diagnostic
delay.
• Manifestations of musculoskeletal TB include spondylitis, osteomyelitis,
and septic arthritis.
• TB spondylitis (‘Pott’s disease’) accounts for 50% of TB involvement
of the musculoskeletal system in adults although data is unclear in
children.
• Thoracic and lumbar lesions are most common. Pain is the presenting
symptom producing alteration of gait or posture s to muscle spasm.
Young children unable to localize the pain may cry when moved or
picked up, or refuse to sit or walk. Vertebral collapse may results in
kyphosis. Paraplegia is usually due to spinal cord compression either by
oedema, abscess, granulation tissue or sequestra.
• Extra-axial osteomyelitis is responsible for 20% of musculoskeletal TB,
in children commonly involving the metaphysis of femur, tibia, skull,
and small bones of hands and feet (i.e. dactylitis). Osteomyelitis can be
associated with septic arthritis and overlying soft tissue abscess or can
occur without joint involvement in any bone but more often in the long
bones or in dactylitis. Soft tissue swelling is seen, followed by a non-
tender mass attached to bone. Dactylitis usually presents as painless or
mildly painful swelling mostly involving the proximal phalanges or the
metacarpal bones. TB osteomyelitis is most commonly a single focus
process in the immune-competent host.
360 CHAPTER 6 Infection and immunization

• Septic arthritis, although rare, is particularly relevant due to the

frequent monoarticular nature (90% of cases), common involvement
of large weight-bearing joints, and insidious manifestations rendering it
difficult to differentiate from oligoarticular JIA. Involvement of the small
joints of hands and fingers are often described in children and immune-
suppressed patients. Onset is gradual with joints initially becoming
swollen, then limitation of movement, followed by pain, stiffness, and
alteration of gait.
• Because of the rarity of musculoskeletal TB in Western countries,
there are no current recommendations to rule out TB in children
presenting with mono-arthritis. However unusual features such as
proliferative synovitis with subtle signs of inflammation, peri-articular
abscesses and draining sinuses and/or lack of response to intra-articular
steroids should prompt investigations to rule out TB.
• Other musculoskeletal manifestations including tenosynovitis, bursitis,
and muscle abscesses are rarer and often a result of continuous
spreading from adjacent bony and articular lesions.
• For children on TNF antagonists, due to the i risk of reactivation of
LTBI, paediatric rheumatologists need to be aware of presentations of
TB in the immune-suppressed host which are similar to those of 1*
TB albeit with an i frequency of multifocal articular and bone lesions.
Diagnosis (Fig. 6.2)
• The triad of a history of TB contact, positive Mantoux test, and
suggestive CXR changes is highly suggestive for a diagnosis of TB. Plain
x-ray skeletal survey is often abnormal and therefore essential and
cost-effective. Typical x-ray features include:
• Lytic lesions with poorly defined edge.
• Absent or minimal reactive sclerosis.
• Juxta-articular osteopenia, narrowing of joint space and adjacent
soft tissue involvement.
• In dactylitis there is usually enlargement of the bone with periosteal
thickening and destruction of the spongiosa giving a cystic
appearance (‘spina ventosa’).
• Plain x-ray of the spine may show disc space narrowing, anterior
vertebral scalloping or variable degrees of destruction with kyphosis.
• Definitive diagnosis relies on culture of the organism. Open biopsy
or fine needle aspiration of bone, or synovial fluid aspiration and
synovial biopsy obtain specimens. The differential diagnosis is broad
but includes bacterial and fungal infection, syphilis, and bone tumours
including sarcomas and sarcoidosis.
 TUBERCULOSIS AND MYCOBACTERIAL DISEASE 361

• Local prevalence rate?

Assess likelihood of MT infection • History of contact (in non/low endemic regions and young children a
household contact is more likely)?

• Cough >2–3 weeks not improving after 1 course of antibiotics, fever,

Ask for systemic manifestations * weight loss, night sweat

• CXR
Look for concurrent pulmonary TB ** • Chest CT if equivocal findings on CXR

Look for radiological evidence of • Radiographic skeletal survey

musculo-skeletal TB and identify site • CT scan (better for defining bone involvement)
for biopsy • MRI (better for defining articular and soft tissue involvement)

Assess supporting immunological • Tuberculin skin test

evidence *** • Interferon G release assay

Look for hystological evidence if • Granulomatous inflammatory changes (multinucleated giant cells,
tissue specimen possible histiocytes and chronic inflammatory cells)

• Acid fast bacilli in direct smear microscopy (synovial fluid)

Attempt bacteriological confirmation
• Culture of tissue specimen

Fig. 6.2 Diagnosis of musculoskeletal TB.

*Systemic manifestations will be absent unless disseminated TB or concurrent
pulmonary involvement.
** The coexistence of pulmonary TB is reported in 30–50% of cases. If a pulmonary
lesion is identified, attempt specimen collection (sputum in older children, gastric
aspiration and/or nasopharyngeal aspirate in young children) and detection of acid
fast bacilli in direct smear microscopy and culture; these yield a positive result in
only 20–50% of cases.
*** Both TSTs and IGRAs lack sensitivity to reliably distinguish between TB and LTBI
in a patient with TB-like illness. Either test is therefore an adjunct to other tests for
diagnosing TB disease. A recent UK study failed to show that IGRA are more sensitive
than TST>15 mm in diagnosing active TB but confirmed that combining both tests
identified more than 90% of culture-confirmed cases.

Treatment
• Due to the difficulty in bacteriological confirmation of TB disease
in children, treatment should be started if the histology and clinical
picture are consistent without waiting for the results of the cultures,
and should be completed even if the culture results are negative if an
alternative aetiology is not identified.
• The standard regimen recommended from NICE to treat active
musculoskeletal TB in all ages is 6 months of isoniazid and rifampicin
initially plus pyrazinamide and ethambutol for the first 2 months.
• Reactivated TB disease in association with immunosuppression is
treated as 1* TB.
• If TNF antagonists required in children with active TB, a full course of
anti-tuberculous treatment should be completed before initiation.
• The role of surgery in spinal TB is debatable; it is indicated to establish
a diagnosis and in those with active disease and neurological deficit
requiring decompression. Drainage may be useful in joint involvement
362 CHAPTER 6 Infection and immunization

to relieve pressure. Radical resection/bone grafting may be considered

if there is destruction of t2 vertebral bodies.
• Bed rest and immobilization are no longer recommended.
Prognosis
MTB does not produce proteolytic enzymes that easily destroy cartilage
(contrast to bacterial infection). Therefore a good response to treatment
and return to normal function is expected if the diagnosis is made early.
Reactive immunological conditions (in association with MTB
infections and anti-mycobacterial therapy)
• Erythema nodosum is a not uncommon hypersensitivity reaction to MTB.
• Poncet’s disease, a rare aseptic reactive polyarthritis usually seen
in the context of active pulmonary TB, has been described. Other
hypersensitivity reactions to MTB include ocular manifestations such
as conjunctivitis and phlyctenular keratoconjunctivitis (redness, tearing
and foreign body sensation) and interstitial keratitis.
• Drug-induced lupus has been described in association with isoniazid
and rifampin therapy. Reactive phenomena tend to resolve with
discontinuation of the offending drug.
 RHEUMATIC FEVER 363

Rheumatic fever
Introduction
• Acute rheumatic fever (ARF) is an auto-immune consequence s
to infection with group A Streptococcus (GAS), causing a sub-acute
generalized inflammatory response and an illness that affects mainly the
heart, joints, brain, and skin.
• ARF results from a complex interplay between susceptible hosts,
virulence of GAS strain, and environmental features (Fig. 6.3).
• The prognosis of rheumatic fever is almost solely determined by
its cardiac sequelae. Cardiac involvement leads to rheumatic heart
disease (RHD). People who have had ARF previously are at higher
risk of subsequent episodes which may cause further cardiac
valve damage.
• Arthritis occurs early and more frequently in large joints. Lower
extremities are generally affected initially followed by upper
extremities. It is often, but not always, transient and self limiting.

Environment
(overcrowding,
hygiene etc.)

Virulence of
Genetic
GAS strain
susceptibility
(cell wall, M
protein etc.)

Fig. 6.3 ARF pathogenesis.

364 CHAPTER 6 Infection and immunization

Epidemiology
• The mean annual incidence is 19/100,000; a higher incidence of
>10/100,000 was reported in Eastern Europe, the Middle East, Asia,
and Australasia and a far lesser incidence of d10/100,000 was found in
Western Europe and North America; the difference is probably due to
improved hygiene standards. In Western Europe and North America,
periodic outbreaks occur rather than an endemic form.
• RHD is the most common form of acquired paediatric heart disease in
the world and thus is the leading cause of cardiac death in the first 5
decades of life. Notably, Kawasaki disease is now the commonest cause
of acquired paediatric heart disease in developed countries including the
UK and North America (see b chapter on Kawasaki disease, p 183).
• Worldwide, an estimated 5–30 million children and young adults have
chronic RHD, and 90,000 patients die from this disease each year.
Clinical features (Table 6.1)

Table 6.1 Clinical features

Musculoskeletal Non- musculoskeletal

• Polyarthritis • Antecedent sore throat

• Arthralgia-migratory • Fever, pallor, weight loss
• Fatigue • Erythema marginatum, SC nodules
• Malaise • Neurological involvement—Sydenham’s chorea
• Motor dysfunction • Irritability and personality change—PANDAS
• Headache
• Epistaxis
• Abdominal pain, vomiting
• Rheumatic pneumonia
• Chest pain (valvulitis, carditis), orthopnoea
• Microscopic haematuria, pyuria

Modified Jones criteria

The Duckett Jones criteria (revised by the American Heart Association,
and now referred to as the modified Jones criteria: the latest updated
revised criteria were published in 1992) are guidelines to assist the physician
to diagnose ARF:
• If evidence of a preceding GAS infection (positive throat culture for
GAS, positive rapid streptococcal antigen test, elevated or rising
streptococcal antibody titre, most often antistreptolysin O) plus
• Presence of 2 major criteria; or 1 major and 2 minor criteria (Table 6.2)
is suggestive of ARF.
 RHEUMATIC FEVER 365

Table 6.2 Modified Jones criteria in diagnosing ARF

Major manifestations Minor manifestations
1. Carditis* 1. Arthralgia
2. Polyarthritis 2. Fever
3. Chorea 3. Elevated acute phase reactants (ESR, CRP)
4. Erythema marginatum 4. Prolonged PR interval
5. Subcutaneous nodules
*
Data were insufficient to allow echocardiographic documentation of mitral or aortic
regurgitation in the absence of auscultatory findings as the sole criterion for valvulitis.

Investigations
• White blood cell count.
• ESR (repeat weekly once diagnosis confirmed).
• CRP.
• Blood cultures if febrile.
• ECG.
• CXR.
• Echocardiogram (repeat as necessary in 2–4 weeks if equivocal or if
serious carditis).
• Throat swab (preferably before giving antibiotics)—culture for group
A Streptococcus.
• Anti-streptococcal serology: both anti-streptolysin O and anti-DNase
B titres, if available (repeat 10–14 days later if 1st test not confirmatory).

Management
Antibiotics
• Oral penicillin V (1–6yr: 125mg qds; 6–12yr: 250mg qds; 12–18yr: 500mg
qds) should be commenced in all cases while the diagnosis is being
established.
• Oral erythromycin (2–8yr: 250mg qds; 8–18yr: 500mg qds) used in cases
with reliably documented penicillin allergy.
• To reliably eradicate GAS, antibiotics should be given for the full 10 days.
Arthritis/arthralgia
Controlled trials show response with salicylates or NSAIDS often within
hours and almost always within 3 days (Level II). Mild arthralgia and fever
may respond to paracetamol alone.
366 CHAPTER 6 Infection and immunization

Carditis/heart failure
• Diuretics/fluid restriction for mild-moderate failure.
• ACE inhibitors for more severe failure, particularly if aortic
regurgitation present.
• Glucocorticoids optional for severe carditis.
• Digoxin if atrial fibrillation present.
• There is little experience with B-blockers in heart failure due to acute
carditis, and their use is not recommended (Grade D evidence).
• Bed rest.
Chorea
• Sydenham’s chorea is self-limited.
• Carbamazepine can be used initially for severe chorea and valproic acid
be considered for refractory cases (Level III 2, Grade B).
• Medication should be continued for 2–4 weeks after chorea has
subsided and then withdrawn.
• Remember that antiphospholipid syndrome (APS) can cause cardiac
valve pathology (including the mitral valve) and chorea and thus may
mimic rheumatic fever (see b APS, p 279).
Valve surgery
• Usually deferred until active inflammation has subsided.
• Rarely, valve leaflet or chordae tendinae rupture leads to severe
regurgitation which requires emergency surgery.
• Valve replacement, rather than repair, is usually performed during the
acute episode, because of the technical difficulties of repairing friable,
inflamed tissue.
Prevention
• 1* prophylaxis: ARF episodes can be prevented by antibiotic treatment
of GAS throat infections.
• s prophylaxis: to prevent recurrent episodes of ARF in patients with
credible history of ARF or RHD, s prophylaxis is recommended.
• Register based co-coordinated control programs with regular
(3-weekly) IM benzathine penicillin G (1.2 MU or 600,000 U if
<20kg) in association with education is effective.
• Alternatives include oral phenoxymethylpenicillin (1 month–6yr:
125mg bd; 6–18yr: 250mg bd.), or erythromycin (1 month–2yr:
125mg bd; 2–18yr: 250mg bd.).
• A vaccine for GAS is in development.
Differentiation from post streptococcal reactive
arthritis (PSRA)
• PSRA is a term coined in 1980s to differentiate a group of patients
from ARF with no/less incidence of carditis and where modified Jones
criteria are usually not met.
• The incidence of ARF in the USA and Western Europe is d, and PSRA
is more prevalent.
 RHEUMATIC FEVER 367

• PSRA patients are generally older, have a longer interval between

group A Streptococcus infection and symptom onset, and respond less
dramatically to salicylates than ARF patients.
• The course of PSRA is characterized by arthritis that, in contrast to
ARF, is additive, non-migratory and is frequently chronic.
• Extra-articular manifestations including renal involvement can be present
with PSRA.
Further reading
Barash J, Mashiach E, Navon-Elkan P, et al. Differentiation of post-streptococcal reactive arthritis
from acute rheumatic fever. J Pediatr 2008; 153:696–9.
Ferrieri P. Proceedings of the Jones Criteria workshop. Circulation 2002; 106:2521–3.
Tibazarwa, KB, Volmink, JA, Mayosi BM. Incidence of acute rheumatic fever in the world: a systematic
review of population-based studies. Heart 2008; 94:1534–40.
368 CHAPTER 6 Infection and immunization

Lyme disease
Lyme disease is caused by infection from the spirochaete Borrelia burgdorferi,
transmitted by the bite of the Ixodes tick, and can affect the skin, joints,
nervous system, and heart.
For the rheumatologist the task is to distinguish the arthritis caused by
Lyme disease (most commonly a monoarthritis affecting the knee) from
that due to other diseases such as JIA, septic arthritis, or TB (Table 6.3).
If this distinction is correctly made, and appropriate treatment delivered,
Lyme disease in children usually has an excellent prognosis. However, the
rheumatologist also needs to be aware of the ongoing controversy sur-
rounding the phenomenon of ‘chronic Lyme disease’ and the evidence
base behind it.
Aetiology and epidemiology
• Borrelia burgdorferi is transmitted by a bite from a tick of the Ixodes
genus, after the tick has been attached for more than 24h. The patient
is often unaware of having been bitten.
• The tick is mainly found in temperate regions of Europe, NE USA, Asia,
most commonly in or near densely forested areas. The incidence of
Lyme disease is approximately 69 per 100,000 but may be as high as
1:100 in hyperendemic areas.
Clinical presentation
Early localized—erythema chronicum migrans
• First presentation in 89% of children.
• Days to weeks after tick bite.
• Expanding over days to weeks, 8–50cm in diameter.
• May be associated with flu-like symptoms.
Early disseminated
• Weeks after infection.
• Neurological: facial nerve palsy, lymphocytic meningitis, rarely
meningoencephalitis.
• Cardiac: conduction defects.
• Articular: arthralgia.
Late disease
• Predominantly articular; chronic cutaneous and neurological features
can occur but are uncommon, especially in children, who are more
likely to have arthritis as the sole presenting problem.
• Occurs weeks to months after initial infection.
• Arthritis—most commonly single knee with intermittent, relatively
painless large effusions lasting days/weeks, remitting and recurring course.
• Small joints not affected.
 LYME DISEASE 369

Table 6.3 Clinical features of Lyme arthritis compared with septic

arthritis and JIA
Lyme arthritis Septic arthritis JIA
History of tick bite/travel May be associated
to forested area exposure with rash, uveitis,
to ticks autoantibodies
Monoarthritis, large joints Monoarthritis, any joint Any joints may be affected,
any number
Small joints not affected
Intermittent/recurrent Persistent symptoms Persistent symptoms
symptoms >6 weeks
WBC, ESR, CRP may WBC, ESR, CRP raised. WBC, ESR, CRP may be
be normal or raised. Not normal or raised. May be
May be febrile
febrile in late disease febrile
May be relatively painless, Extremely painful, often May be relatively painless,
not usually stiff unable to weight-bear commonly stiff
High synovial fluid WBC Very high synovial fluid Moderately raised synovial
white blood cell count. fluid WBC
Organisms cultured
NB Always consider TB in cases of monoarthritis (see b TB, p 356).

Diagnosis
Need clinical features plus history of exposure plus positive serology.
Serology
• Enzyme immunoassay for IgG is sensitive but not specific—if positive,
do Western blot (immunoblot is highly specific as well as sensitive).
Arthritis is a late stage finding, so by the time this occurs IgG levels are
high on Western blot, and serology is therefore reliable.
• If Western-blot negative, then a positive/indeterminate enzyme
immunoassay is a false positive.
Joint fluid assessment
• Helpful in excluding septic arthritis.
• PCR for Borrelia burgdorferi DNA is very useful in previously untreated
patients, with higher positivity on synovial tissue than fluid. Culture of
B. burgdorferi rarely successful from joint fluid/synovial biopsy.
370 CHAPTER 6 Infection and immunization

Treatment (Box 6.1)

Box 6.1 Summary of IDSA treatment guidelines*
• 4 weeks of:
• Oral doxycycline 1–2mg/kg bd if >12yr.
• Oral amoxycillin 50mg/kg/day in 3 doses if <12yr.
• For meningitis/peripheral nerve involvement 2 weeks of IV
antibiotics* (ceftriaxone).
• For meningoencephalitis 3 weeks of IV antibiotics** (ceftrioxone or
cefotaxime).
*
Based on Infectious Diseases Society of America guidelines (2006): M http://www.idsociety.
org/lymedisease.htm.
**
Ceftriaxone 75–100mg/kg od or IV cefotaxime 50mg/kg tds.

• If persistent symptoms after 3 months try a second 4-week course of

oral or IV antibiotics.
• Thereafter, if persistent symptoms try NSAIDs, IA steroid injections, or
DMARD.
Prognosis
• Children treated according to the IDSA guidelines summarized in
Box 6.1 have an excellent prognosis, and do not go on to develop
chronic arthritis, joint deformities, or recurrence of infection.
• Some patient groups and practitioners advocate that Lyme disease can
manifest as a chronic illness, able to evade conventional medical tests
and treatments.
• There is no evidence to support this view, or to show that persistent
arthritis is due to continuing or refractory infection, and therefore
amenable to prolonged courses of antibiotics.
• The paediatric rheumatologist needs to be aware that non-accredited
laboratories/clinics sometimes incorrectly make a diagnosis of chronic
Lyme disease in patients with medically unexplained symptoms
based on substandard or inherently unreliable tests.
• In the UK the Department of Health have provided specific
guidance on this difficult subject, found at: M http://www.hpa.
org.uk/Topics/InfectiousDiseases/InfectionsAZ/LymeDisease/
GeneralInformation/lym020UnorthodoxPractices/.
 VARICELLA ZOSTER INFECTIONS 371

Varicella zoster infections

1* infection with varicella zoster virus (VZV) causes varicella (chickenpox),
while its reactivation from latency produces zoster (shingles). Cellular
immunocompromise dramatically i the risk of severe and disseminated
varicella, including potentially fatal pneumonitis, encephalitis, and hepatitis.
In children who have already acquired VZV, immunosuppression i both
the rate and severity of zoster; 2nd episodes of varicella are also well-
described. VZV disease therefore requires active management in chil-
dren with present or anticipated immunosuppression. Children may be
immunosuppressed due to their underlying diagnosis (e.g. JSLE with lym-
phopenia) or more commonly due to therapy. Relevant immunosuppres-
sive drugs include systemic corticosteroids (equivalent to prednisolone
1mg/kg/day for 1 month or 2mg/kg/day for 1 week within the previous 3
months), azathioprine, ciclosporin, methotrexate, cyclophosphamide and
biologics e.g. anti-TNF therapy, anakinra, tocilizumab etc.
Assessment of VZV immunity
• At diagnosis, assess VZV susceptibility in the patient and family
members by eliciting a history of varicella and/or zoster.
• Check VZV serology at diagnosis/prior to commencing
immunosuppressive therapy.
• Young children with no history of varicella (or receipt of varicella
vaccine—unusual in the UK) are very likely to be seronegative.
Counselling/education
• Families should be warned of the dangers of VZV in immunosuppressed
children (see b Biologics, p 393).
• The need to avoid exposure should be reinforced; varicella vaccination
of any other susceptible family members should be advised.
• Families should be advised to contact their medical team immediately
in the event of known exposure or suspected VZV disease.
Active vaccination
• The live attenuated varicella vaccine is safe and effective in healthy
children above 1yr of age. For optimal protection, 2 doses are advised
at least 4 weeks apart.
• Consider vaccinating currently immunocompetent but VZV-susceptible
patients who are likely to require immunosuppression later in the
disease course (but not for at least 3 weeks). In recently diagnosed
oligo-JIA—suggest varicella vaccination at time of joint injection (and
can be done at the time of the general anaesthetic). The 2nd dose can
be considered 4 weeks later.
• Vaccination is contraindicated in the immunocompromised but not
in their healthy varicella-susceptible household contacts—preventing
varicella in healthy sibs is an important step towards protecting the
immunosuppressed child. Pre- and post- serology are not required in
healthy children; the lack of a history of chicken pox in the young child
is a good surrogate for being non immune and vaccination is advised.
Should vaccine-associated rash develop (<5%), there is a small risk of
transmission which should be managed as for wild type exposure of the
immunocompromised individual.
372 CHAPTER 6 Infection and immunization

Post-exposure prophylaxis
• If significant exposure to VZV is recognized, post-exposure
prophylaxis should be given to all immunosuppressed patients who
are seronegative. (Significant exposure is defined as any household
or nosocomial contact with VZV; any face to face contact or 15min
in same room as index case of varicella from 48h before rash until all
spots crusted over; and contact with exposed dermatomal zoster or
any zoster in the immunocompromised.)
• Good evidence supports the use of VZIG as prophylaxis when
administered early (<72h) after exposure; in the UK, stocks are held by
HPA laboratories or their equivalent who will advise on its appropriate
use. See Fig. 6.4 and ‘The Green Book’ (see b Further reading, p 373).
• High-dose oral aciclovir from <7 to 21 days post-exposure is currently
used as an alternative or adjunct to VZIG in some UK centres and
should be offered if no VZIG has been given within 72h of exposure;
however the evidence base for its use as single agent, post-exposure
prophylaxis in the immunocompromised is poor.
• Consider post-exposure prophylaxis using aciclovir in VZV-
seropositives who are severely immunosuppressed, e.g. patients on
a combination of steroids and biologics or cyclophosphamide.
• Neither VZIG nor aciclovir is completely effective in preventing varicella;
clinical infection may follow after a prolonged incubation period (21–28
days post-exposure) and although usually mild, may occasionally be severe.
• Irrespective of serostatus and prophylaxis after exposure, families
should be advised to examine the patient daily for spots and report any
suspicion of illness immediately (including non-specific symptoms such
as fever, back/abdominal pain as well as rash).
Treatment
• Prompt initiation of antiviral therapy contains viral replication and
reduces the risk of dissemination in both varicella and zoster.
• Immunosuppressed children with suspected VZV disease should be
admitted without delay to an isolation cubicle for IV aciclovir and
general supportive care.
• Suggested laboratory work-up includes FBC, liver and renal function;
consider baseline CXR.
• IV aciclovir dose is 500mg/m2 8-hourly (3 months–12yr), 10mg/kg
8-hourly (12–18yr). Recommended duration of therapy is at least
7 days; persist with IV therapy until fever and constitutional symptoms
have resolved and no new spots have appeared for 48h.
• Remember to consider the possible need for post-exposure
prophylaxis among susceptible nosocomial contacts.
 VARICELLA ZOSTER INFECTIONS 373

Further advice
Paediatric infectious disease specialists, virologists, public health agencies (in the UK see: M http://
www.hpa.org.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1287147556958).

Further reading
Chapter 34, Varicella. In Salisbury D, Ramsay M, Noakes K (eds) Immunisation against infectious
disease – ‘The Green Book’. London: The Stationery Office; 2006, 421–42. Available at: M http://
www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/
DH_079917.
Fisher J, Bate J, Hambleton S. Preventing varicella in children with cancer; what is the evidence?
Curr Opin Infect Dis 2011; 24(3):203–11.
Royal College of Paediatrics and Child Health. Immunisation of the Immunocompromised Child: Best
Practice Statement. London: Royal College of Paediatrics and Child Health, 2002. Available on
BSPAR website: M http://www.bspar.org.uk/pages/clinical_guidelines.asp.

Pre-exposure
All patients likely to
require immuno- ASSESS VZV IMMUNITY
suppressive therapy HISTORY ± SEROLOGY

VZV-susceptible VZV-immune

Immunocompetent for at
COUNSEL RE AVOIDANCE
least the next 3 weeks?
OF EXPOSURE & ACTIONS IF
Yes No EXPOSED/DISEASE

VACCINATE VZV-
SUSCEPTIBLE FAMILY
GIVE VARICELLA VACCINE MEMBERS

Post-exposure ASSESS VZV IMMUNITY

HISTORY ± SEROLOGY

VZV-susceptible VZV-immune

Immunocompetent for at
least the next 3 weeks? If heavily immuno-
suppressed
Yes No

IF <72 H SINCE EXPOSURE, <72 h since exposure?

CONSIDER VARICELLA
VACCINE Yes No

Give high-dose oral aciclovir

Urgently give IM VZIG until 21 days following the
Dose: initial contact
250 mg for <5 yrs of age Dose:
500 mg for 5–10 yrs of age If heavily immuno- 200 mg QDS (<2 yrs of age)
750 mg for >10 yrs of age suppressed, add 400 mg QDS (2–6 yrs)
800 mg QDS (>6 yrs)

ALL EXPOSED IMMUNOSUPPRESSED PATIENTS: advice on what to do if child develops varicella

Fig. 6.4 Guidelines for the prevention of severe VZV infection in the
immunocompromromised child.
374 CHAPTER 6 Infection and immunization

Immunization schedules and the

immunocompromised
General principles which guide immunization of children who are taking
immunosuppressive treatments (such as MTX, MMF, azathioprine, cyclo-
phosphamide, biological agents, and systemic corticosteroids) include the
following:
• The routine childhood immunization schedule should be followed with
the exception (in general) of live vaccines.
• Live vaccines may be given once the child has been off systemic
corticosteroid treatment for >3 months, and off other or combination
immunosuppressive treatment for >6 months.
• The dose and duration of systemic corticosteroid treatment that
results in significant immunosuppression is usually considered to be
prednisolone 2mg/kg/day for >1 week, or 1mg/kg/day for >1month.
• Influenza vaccine should be given annually each autumn.
• If circumstances permit, varicella zoster antibody status should be checked
prior to starting immunosuppressive treatment; where appropriate, varicella
zoster vaccine should be given at this time (see b Varicella, p 371).
• Consider giving varicella zoster vaccine to seronegative family members
to provide indirect protection for susceptible patients.
• Administration of live vaccines (except MMR and BCG) to siblings of
immunocompromised patients, especially live oral polio vaccine (OPV),
should be avoided. Patients should also avoid close physical contact
with children vaccinated with OPV for approximately 4–6 weeks
following administration.
Table 6.4 includes a list of vaccines recommended in the UK national
schedule for healthy individuals, and states their suitability in the patient
taking immunosuppressive treatment. Table 6.5 lists other vaccines that
are available and their suitability for the immunosuppressed patient.
Live vaccines may be given to immunocompromised children in exceptional
circumstances (e.g. a child returning to a home country where yellow fever
is endemic). However it is strongly advised to seek specialist advice before
taking such a decision. In children taking immunosuppressive treatment there
is evidence of good efficacy and safety for the use of inactivated vaccines.
Transient flares of disease have been reported.
 IMMUNIZATION SCHEDULES AND THE IMMUNOCOMPROMISED 375

Table 6.4 Vaccines recommended in the UK national schedule for

healthy individuals
Age Immunization (vaccine given) Type Suitability for the
Live/ child who is taking
inactivated immunosuppression
2 months DTP/polio/Hib (diphtheria, tetanus, Inactivated Can be given
pertussis (whooping cough), polio,
and Haemophilus influenzae
type b)—all-in-one injection
PCV (pneumococcal conjugate Inactivated Can be given
vaccine)—in a separate injection
3 months DTP/polio/Hib (2nd dose) Inactivated Can be given
MenC (meningitis C)—in a Inactivated Can be given
separate injection
4 months DTP/polio/Hib (3rd dose) Inactivated Can be given
MenC (2nd dose)—in a separate Inactivated Can be given
injection
PCV (2nd dose)—in a separate Inactivated Can be given
injection
Around Hib/MenC (combined as one Inactivated Can be given
12 months injection—4th dose of Hib and
3rd dose of MenC)
Around MMR (measles, mumps and Live Contraindicated
13 months rubella—combined as one injection)
PCV (3rd dose)—in a separate Inactivated Can be given
injection
Around 'Pre-school' booster of: Inactivated Can be given
3yr and DTP/polio (diphtheria, tetanus,
4 months pertussis and polio)
MMR (2nd dose)—in a separate Live Contraindicated
injection
Around HPV (human papillomavirus)— Inactivated Can be given
12–13yr three injections
(girls)
The 2nd injection is given 1–2 months
after the 1st one. The 3rd is given
about 6 months after the 1st one
Around Td/Polio booster (a combined Inactivated Can be given
13–18yr injection of tetanus, low-dose
diphtheria, and polio)
Adults H. influenzae and PCV if aged Inactivated Can be given
65 or over or in a high-risk group
Td/polio—at any age if you were
not fully immunized as a child
376 CHAPTER 6 Infection and immunization

Table 6.5 Other vaccines that are available and their suitability in the
immunocompromised
Vaccine Targeted population Type Suitability for the
(Live/ child who is taking
inactivated) immunosuppression
BCG Susceptible population Live Contraindicated
Varicella Varicella non-immune Live Contraindicated
patients with high risk
or their close contacts
Hepatitis B Children at high risk of Inactivated Can be given
exposure to virus or
complications of disease/
babies born to infected
mothers
Influenza vaccine Children at i risk of Inactivated Strongly
(currently available morbidity and mortality recommended
as combination from influenza infection
with pandemic
H1N1 strain)
Measles Those who decline MMR Live Contraindicated
Mumps Live Contraindicated
Rabies Exposure to animals Inactivated Can be given
suspected to be infected
Yellow fever Children >9 months of Live Contraindicated
age travelling to Yellow
fever endemic zones
Typhoid Children >1yr travelling Inactivated Can be given
to areas endemic to Vi vaccine
typhoid
Live Contraindicated
Ty21a oral
vaccine

Further reading
Royal College of Paediatrics and Child Health. Immunisation of the Immunocompromised Child: Best
Practice Statement. London: Royal College of Paediatrics and Child Health, 2002. Available on
BSPAR website: M http://www.bspar.org.uk/pages/clinical_guidelines.asp.
Salisbury D, Ramsay M, Noakes K (eds) Immunisation against infectious disease – ‘The Green Book’
M http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/
DH_079917.
Heijstek MW, Ott de Bruir LM, Bijl M, et al. EULAR recommendations for vaccination in paediatric
patients with rheumatic diseases. Ann Rheum Dis 2011; 70(10):1704–12.
 Chapter 7 377

The multidisciplinary
approach to management

The multidisciplinary team 378

The role of the clinical nurse specialist 380
The role of the physiotherapist 382
The role of the occupational therapist 384
The role of the podiatrist 385
Transitional care 387
378 CHAPTER 7 The multidisciplinary approach

The multidisciplinary team

• The experienced MDT is integral to the holistic management of
children and young people with rheumatic disease with the patient
and family at the centre (Fig. 7.1) with input from specialist consultant,
specialist nurse, paediatric physiotherapist and paediatric occupational
therapist.
• In the context of JIA the role of the MDT is paramount with children and
emphasized in the BSPAR Standards of Care (see b Chapter 9, p 409).
The composition of the paediatric rheumatology MDT may vary from centre
to centre and may often involve a managed clinical network with colleagues
in primary, community, and hospital care. The roles of the members of
the MDT may overlap and are often complementary. The BSPAR position
statement outlines the requirements for training and expertise for the
MDT. The clinical roles of the nurse specialist, physiotherapist, occupa-
tional therapist, and podiatrist are detailed in the rest of this chapter and
reference to the important other members of the MDT are given in other
chapters in the handbook (see b Pain, p 87) for the role of the clinical
psychologist in the context of chronic pain management). The roles of the
parent and child/young person in research are also given.

Sp
con eciali
GP sul st
tan
ts
Consultant
Social work

School

Patient Physio
Family
and OT

Nurse
specialist

Psychology

Fig. 7.1 Patient-centred MDT management.

 THE MULTIDISCIPLINARY TEAM 379

The paediatric rheumatology MDT

Core members
Access to named member required by every child or young person
with JIA:
• Paediatric rheumatologist
• Ophthalmologist
• GP
• Paediatric rheumatology clinical nurse specialist
• Paediatric physiotherapist
• Paediatric clinical psychologist
• Paediatric occupational therapist
• Podiatrist
• Health visitor or school nurse
• The child and parent/carer.
The extended team
Access to named member required if clinically indicated:
• Shared care delivery (paediatrician with an interest in rheumatology
or adult rheumatologist)
• Adult rheumatologist for transitional care
• Children’s community nursing team
• Play therapist/youth worker
• Special educational needs coordinator
• Orthodontist/dentist/maxillofacial surgeon
• Orthopaedic surgeon
• Endocrinologist.
NB The extended team may work in conjunction with a paediatrician
with an interest in paediatric rheumatology or an adult rheumatologist
with an interest in paediatric rheumatology (operating within a formal
paediatric rheumatology clinical network).

Further reading
Baildam EM, Davidson JE. BSPAR Position Statement on Professional working in Paediatric
Rheumatology. Rheumatology (Oxford) 2008; 47(6):743–4. M http://www.bspar.org.uk/downloads/
clinical_guidelines/Final_BSPAR_Position_Statement_on_Professionals_working_in_Paediatric_
Rheumatology_Teams.pdf.
Davies K, Cleary G, Foster HE, et al. on behalf of the British Society of Paediatric and Adolescent
Rheumatology: BSPAR Standards of Care for children and young people with Juvenile Idiopathic
Arthritis. Rheumatology 2010; 49(7):1406–8. M http://www.bspar.org.uk/downloads/clinical_
guidelines/Standards_of_Care.pdf.
380 CHAPTER 7 The multidisciplinary approach

The role of the clinical nurse specialist

The specialist nursing team is integral to the clinical service in paediatric
rheumatology and such nurses will be qualified as children’s nurses with
varied training background and experiences. The role of the specialist
nurse has evolved rapidly largely as a result of the era of potent immu-
nosuppression such as biologics and the more pro-active pharmacological
approach to management of paediatric rheumatic diseases. The role of
the clinical nurse specialist (CNS) is described in the British Society for
Paediatric and Adolescent Rheumatology (BSPAR) Position Statement
(see b Further reading, p 381) albeit details of the roles and responsibili-
ties may vary between local services.
Such roles may include:
Clinical coordination
• Holistic care for the child and young person with chronic illness, acting
as patient and family advocate in clinical decision-making.
• Clinical care for children with complex illness and often involving other
specialist services including child protection as necessary.
• Clinical networks and regional shared care services.
• MDT meetings and their documentation.
• Day-case administration of infusions such as biologics, cyclophosphamide
pamidronate.
• DMARDs and biologic therapy monitoring and liaising with home delivery
services.
• Telephone helpline and triage of queries.
• Transitional care and transfer to adult services.
Other clinical roles
• Nurse-led review clinics.
• Joint injections and delivery of Entonox®.
Clinical governance
• Clinical guideline development and audit to deliver high-quality care.
• Patient information leaflets and educational resources.
• Development of proformas and checklists for use of biologics in
accordance with national guidance (see b Approvals for use of biologics
therapies, p 393 and p 399).
Training and education
• Disease and treatment education for patients and their families, medical
and allied health colleagues involved in shared care (community,
general paediatric and primary care).
• Disease and treatment education to school and educational services.
• Training and support for patients and families regarding
immunosuppressive treatments and home administration where
appropriate.
 THE ROLE OF THE CLINICAL NURSE SPECIALIST 381

Service development
• National guidance on clinical services development through national
bodies (such as BSPAR in the UK) and links with other professional
bodies (e.g. Royal College of Nursing—see b Further reading, below).
• Development of training programmes for parenteral methotrexate for
nurses to train patients and families.
• Liaising with pharmaceutical companies to develop information packs
and devices that are appropriate for use in children and young people.
Research
• Contribution to clinical research priority setting within national
professional bodies (such as BSPAR and CSG).
• Participation in obtaining informed consent and data collection for
clinical trials, registries, and clinical research activities.
• Support for children and families taking part in clinical trials.
Further reading
Baildam EM, Davidson, JE. BSPAR Position Statement on Professional working in Paediatric
Rheumatology. Rheumatology (Oxford) 2008; 47(6):743–4.
The following documents are available on the BSPAR website (M http://www.bspar.org.uk).
Department of Health (2004) National Service Framework for Children, Young People and Maternity
Services. London: DoH.
Royal College of Nursing. Adolescent transition care – Guidance for nursing staff. London: RCN,
2004.
Royal College of Nursing. Administering subcutaneous methotrexate for inflammatory arthritis:
Guidance for nurses. London: RCN, 2007.
Royal College of Nursing. Assessing, managing and monitoring biologic therapies for inflammatory
arthritis. London: RCN, 2009.
Royal College of Paediatrics and Child Health. Bridging the Gaps: Health care for Adolescents.
London: RCPCH, 2003.
382 CHAPTER 7 The multidisciplinary approach

The role of the physiotherapist

Generic roles of the physiotherapist
• Assessment of musculoskeletal system:
• Joints—active disease, range of movement, abnormal biomechanics.
• Muscles—strength, stamina, length, and biomechanics and normal
patterns of movement.
• Generalized stamina and fitness.
• Balance, proprioception, and gait.
• Physiotherapy treatment can:
• Reduce pain, reduce fatigue, and i energy.
• Improve or maintain joint range of movement, minimize joint
deformity.
• i or maximize muscle strength and function, i generalized fitness.
• Improve balance and proprioception, restore normal gait patterns.
• Family and patient education:
• Pain management, disease management, goal setting and pacing.
• Ensure full participation with school, family and friends, advice re
sport and physical activity.
Condition-specific focus
Juvenile idiopathic arthritis
• Combined with medical management aim to maintain full range of
movement in all joints.
• Maintain full muscle strength for all muscle groups.
• Re-education balance and proprioception, re-educate gait.
• Regain full fitness to ensure full participation with all sport and physical
activities.
Juvenile dermatomyositis
• Physiotherapy combined with medical management and ideally started
at the time of diagnosis:
• Muscle function assessments (see b JDMS, p 266).
• Maintenance of full muscle length/joint range (splinting, stretching,
active movement).
• Encouraging muscle function immediately; advice on safe handling
and mobility.
• Graduated and progressive, resisted specific muscle strengthening
programme with re-education balance, proprioception, and gait with
aim to regain to full fitness to ensure optimal participation.
Juvenile systemic lupus erythematosus
• i general fitness to reduce fatigue.
Juvenile scleroderma
• Assessment and monitoring of progression combined with medical
management:
• Stretches to maintain joint range, muscle length, skin mobility.
• Deep tissue massage, wax treatment, and specific muscle strength
training.
 THE ROLE OF THE PHYSIOTHERAPIST 383

Non-inflammatory musculoskeletal pain syndromes

• Hypermobility/anterior knee pain/back pain—please see appropriate
other b chapters for details of the conditions, p 117 and p 124.
• Assessment of biomechanical changes, specifically muscle function.
• Explanation for young person and family about pain and treatment
goals and objectives—regain full specific muscle strength/stamina
with progressive/resisted specific muscle training, high reps and low
weights emphasized.
• Pain management techniques, restore balance and proprioception,
re-educate gait.
• Complex regional pain syndrome:
• Family education about disease and treatment; function despite pain
approach.
• Regain normal movement of affected limb immediately to reduce
pain—desensitization is most effective through regaining normal
movement and muscle strength.
• Regain all physical, social, and psychological function.
• Chronic fatigue:
• Education about paced approach to life, specific strength training,
global fitness training.
• Training to be ‘fit for life’.
384 CHAPTER 7 The multidisciplinary approach

The role of the occupational therapist

The occupational therapist (OT) works within the MDT to encourage,
motivate, and support patients and their families through periods of change
to promote functional independence appropriate to their developmental
age and stage, encompassing their life roles within their environments
to lead full, satisfying lives. The therapeutic relationship forged with the
family is likely to be long term and the success of that relationship is central
to promoting the functional independence, social inclusion, and sense of
well-being an individual associates with their self-actualization. The OT is
functionally not diagnostically led, and uses a holistic assessment using a
bio-psychosocial approach. The roles of the OT may be summarized as
follows:
Clinical role
• To encourage, motivate, and support the young person and their
family, especially at the point of diagnosis or transition to enable
functional independence and self-advocacy.
• Provide specific disease education for the young person and their
family at the correct level for their understanding/needs.
• To carry out a holistic standardized assessment (such as that defined by
BSPAR), with regular monitoring of individual function, appropriate to
the young person’s developmental level—see M http://www.bspar.org.
uk/pages/bspar_home.asp.
• To help the young person manage pain, fatigue, anxiety, and
psychosocial difficulties, through educative coping strategies.
• To act as an advocate, upon the young person’s behalf and support
development of self-esteem and self-confidence in activities of daily
living.
• To provide advice to schools and other educational establishments, in
order to promote inclusion, participation, and fulfilment of the young
person’s potential.
• To promote joint protection strategies during activities of daily living.
• To encourage i physical functioning during periods of acute and
chronic disease activity, utilizing pacing and energy conservation
techniques.
• To carry out a transitional assessment/review prior to transfer to adult
services.
• To provide appropriate upper limb splinting, albeit this is required less
with current treatment approaches.
• Promote evidence based practice, implementing Standards of Care
(e.g. BSPAR Standards of Care in JIA, see b Chapter 9, p 409) and
audit to promote high-quality clinical care.
• Training and education of colleagues working within clinical networks.
• Contribute to the development of evidence-based practice through
research activity and promote the evolving role of the OT within
paediatric rheumatology.
Further reading
Melvin J, Jensen G. Rheumatologic Rehabilitation Series Volume 1: Assessment and Management.
Bethesda, MD: The American Occupational Therapy Association, 1998; p. 308.
 THE ROLE OF THE PODIATRIST 385

The role of the podiatrist

The podiatrist has a specialized role to treat structural and functional
problems in the feet, although there is some overlap with physiotherapists
and orthotists depending on provision of services in the primary and hos-
pital care settings. The podiatrist’s 1° role is to improve the child’s foot
position and function, thus increasing the efficiency of gait and reduce soft
tissue strain and fatigue. The podiatrist can also advise on and treat skin
and nail pathologies that may occur with many of the paediatric rheuma-
tological conditions. A child should be referred to the podiatrist if the foot is
in a poor position leading to an inefficient gait or the foot position is causing
discomfort in the foot or is exacerbating problems in other lower limb joints.
Podiatry therapeutic approaches
• Functional orthosis, footwear advice, and adaptations.
• Gait re-education, exercises, shoe raises, and orthodigital splinting:
• Orthoses modify the foot position and alter the timing of the foot
joint motions during gait and prefabricated orthoses or custom
orthoses can be used.
The healthy paediatric foot (see b Normal variants, p 9)
The healthy child (<6y) will typically have a low-arch profile, bulging
talonavicular joint medially, and a valgus heel position. This is called the
pronated, pes planus, or valgus foot. The healthy foot is fully mobile and
pain-free.
Changes in the foot caused by JIA
• Although possessing individual joint capsules, many of the joints appear
to interconnect and synovitis affecting a single foot joint is the exception
rather than the rule. Synovitis and stiffness in 1 joint is often accompanied
by either reduced movement or a compensatory movement in a
neighbouring joint and thus a good overview of foot mechanics and
function is essential when treating the foot in inflammatory joint disease.
• With rearfoot and midfoot synovitis in JIA, the bony integrity of the
arch is lost and i foot pronation is seen, resulting in an i in soft tissue
strain in the foot, including the anti-pronatory muscles which are
overused in an effort to stabilize the foot. The foot becomes painful
and the gait changes as compensatory movements occur in an effort to
off-load painful areas. The affected joints have reduced range of motion
and fixed deformities may develop.
• Although the pronated foot type is common when rearfoot and midfoot
synovitis is present, many other foot deformities are seen and may be
related to the combination of joints affected, to local tenosynovitis, to
muscle weakness, or be related to the impact of the more proximal joints
on the foot (such as genu valgum and fixed flexion deformities at the hip
which influence the foot position).
• Inflammatory joint disease can affect other synovial structures in the foot:
• Tenosynovitis often occurs in conditions such as JIA.
• Swelling in the rearfoot needs careful examination to differentiate
ankle or subtalar synovitis from tenosynovitis of tibialis anterior,
tibialis posterior, or peroneal involvement.
386 CHAPTER 7 The multidisciplinary approach

• Although not common, bursitis can occur in the forefoot with

RF+ve JIA.
• Enthesitis of the Achilles and plantar fascia insertion is frequently
seen in enthesitis-related arthritis and responds well to shock
absorbing, custom orthoses.
Leg-length discrepancy in JIA
• This is much less observed with prompt access to appropriate care.
• The asymmetry created by the leg-length discrepancy can have a
large impact on the musculoskeletal system with initial compensation
mechanisms occurring in the feet and impacting on the knee, pelvis, and
spinal positions.
• As a rule of thumb, when a leg-length discrepancy is seen to create
asymmetry in gait or joint positions, it should be treated by a full length
raise within or placed externally on the sole of the shoe. Such asymmetry
is usually observed when a leg-length difference exceeds 1cm.
Compensatory gait change from pain
• Changes in gait occur as the child attempts to reduce the pain and
discomfort of walking. These changes may become habitual and remain
even when the joint disease has improved.
• It is the role of the podiatrist to assess the child’s gait and use
re-education or shoe adaptations to improve gait efficiency.
The foot in other rheumatological conditions
• Conditions such as JDM and SLE can affect the feet and require
assessment and treatment by a podiatrist
• Muscle weakness associated with JDM may affect the feet by causing
an i in the degree of subtalar joint pronation, and s contracture
(tendoachilles) can cause gait changes and again, excessive foot pronation.
Choice of footwear for children with inflammatory
foot disease
• A podiatrist will not prescribe orthoses until the footwear is suitable
for the child.
• Good footwear is important for all children to wear, particularly in the
presence of joint inflammation or where the foot position requires
supporting to reduce soft tissue strain.
• There is no single make of shoe that can be recommended for children
therefore it is important to direct the child and parents towards local
shoe shops where the staff have a good knowledge of fitting ‘difficult’
feet, are familiar with fitting a shoe with or without orthoses, and have
a range of shoes that they can try.
• A supportive shoe will have a deep heel counter so that the shoe fits
snugly up to the malleoli. The heel counter should be strong when
squeezed. A fastening mechanism is needed to hold the foot into the
strong heel counter and the sole should have some shock absorbing
properties.
• A boot is sometimes recommended when extra support is needed as
they often have stronger support, higher into the heel counter.
 TRANSITIONAL CARE 387

Transitional care
Definitions
• Transition is a multifaceted active process that attends to the medical,
psychosocial, and educational/vocational needs of adolescents as they
move from child into adult care.
• Transfer to adult services is a single event within this process.
Transition (key principles)
• Is an active, future-focused process with the aim to maximize life-long
functioning and potential of young people.
• Is young person-centred and inclusive of parents/care-givers.
• Involves paediatric and adult hospital services as well as primary care,
education, social and youth services, and voluntary agencies.
• Is age and developmentally appropriate recognizing the 3 phases of
adolescent development: early (11–13yr), mid (14–16yr) and late
(17–19yr) as well as emerging adulthood (20–25yr).
• Includes knowledge and skills training for the young person in health
and disease education, communication, decision-making, assertiveness,
self-care, and self-management.
• Is based on a resilience framework to enhance sense of control and
interdependence in healthcare.
Interdependence of adolescent healthcare and transitional care
Transitional care is only one part of adolescent rheumatology care and core
principles of adolescent medicine should underpin transitional care including:
• Acknowledgement of the reciprocal influences of adolescent
development and the rheumatic condition in question.
• The importance of routine psychosocial screening of all adolescents
(e.g. the HEEADS screening tool - Home, Exercise, Education,
Activities, Drugs, Sexual health).
• Giving young people the opportunity to be seen independently.
• Respecting and assuring their rights to confidentiality.
• Effective use of strategies including motivational interviewing
(see M http://www.motivationalinterview.org).
• Adolescent rheumatology services should meet the ‘You’re Welcome’
quality criteria of accessibility, publicity, confidentiality and consent,
environment, staff training, joined-up working, monitoring/evaluation
involving young people, and adolescent health issues for young
person-friendly health services (see M http://www.dh.gov.uk).
Core components of transitional care in rheumatology
• Written departmental transition policy agreed with all key stakeholders
including young people and parents/care-givers.
• Transition lead professional.
• Transition care coordinator.
• MDT.
• Individualized transition plans—examples given at M http://www.bspar.
org.uk/pages/adolescentrheum.asp.
• Education, skills training, and informational resources for young people,
parents, and professionals.
388 CHAPTER 7 The multidisciplinary approach

• Informed adult rheumatology/ophthalmology/orthopaedic/renal

services, and primary health care.
• Links with education/vocational/youth/social services and voluntary agencies.
• Administrative support including transfer summaries, tracking
mechanisms to confirm attendance at first 2 adult clinic appointments.
• Monitoring, evaluation, and audit of services involving young people.
Individualized transition plans
Individualized transition plans should consider the following issues in a
developmentally appropriate context and through education, assessment
of understanding, skills-training, and sign-posting to young people:
• Health issues:
• Specific to rheumatic disease: disease knowledge, treatment, outcome,
pain and fatigue management, independent healthcare utilization,
self-medication and adherence, procedural pain management etc.
• Generic health: exercise, healthy eating, sleep, sexual health,
smoking, alcohol, recreational/illegal drug use, emotional well-being.
• Psychosocial issues—household chores, independence, self-care,
mobility, benefits, driving, leisure activities, social and peer support,
self-esteem, body image, bullying, coping strategies.
• Educational/vocational issues:
• Impact of condition, disclosure, rights, Disability Discrimination Act.
• Career plan, work experience, career counselling.
• Family issues—concept of transition, knowledge of condition and
impact on adolescent development, transitional care needs.
Transition models
• Different models of transition exist depending on the local health
services and resources.
• A developmental transition model includes an adolescent clinic
(11–16yr) and young adult clinic (16–25yr).
• Evidence suggests an early start, ideally in early adolescence.
• The timing of transfer should be flexible, acknowledging disease status,
readiness and maturity of the young person, and completion of growth
and development.
• An evidence-based transitional care programme showed short-term
benefits in rheumatology. Further research is needed to determine
long-term outcomes and effectiveness of the young adult clinic model.
Futher reading
BSPAR website: M http://www.bspar.org.uk/pages/adolescentrheum.asp for transitional care documents.
Department of Health. You’re welcome quality criteria. Making health services young people friendly.
London: DoH, 2007. M http://www.dh.gov.uk.
Department of Health. Transition: Getting it right for Young People. Improving the transition of
young people with long-term conditions from childrens’ to adult health services. London: DoH, 2006.
M http://www.dh.gov.uk/transition.
DREAM Team website: M http://www.dreamteam-uk.org.
e-Learning for Healthcare website: M http://www.e-lfh.org.uk.
Goldenring JM, Rosen DS. Getting into adolescent heads: an essential update. Contemp Pediatr
2004; 21(1):64–90.
HEEADSSS and Motivational Interviewing: M http://www.motivationalinterview.webs.com/.
McDonagh JE. Young people first, juvenile idiopathic arthritis second: Transitional care in
rheumatology. Arthritis Rheum 2008; 59(8):1162–70.
Youthhealthtalk! Website: M http://www.youthhealthtalk.org.
 Chapter 8 389

Specialized therapeutic
approaches

Corticosteroid intra-articular injections 390

Biologic therapies for paediatric rheumatological diseases 393
Approvals for use of biologic therapies 399
Medicines for children and paediatric rheumatology 401
Haematopoietic stem cell transplantation 405
(See also b BSPAR guidelines for treatments used in paediatric
rheumatology, p 415)
390 CHAPTER 8 Specialized therapeutic approaches

Corticosteroid intra-articular injections

Intra-articular corticosteroid injections are increasingly used as they
allow rapid symptom control and allow time for other therapies, such as
methotrexate (MTX) to have their effect. They often remove the need for
the use of oral or IV corticosteroids and avoidance of side effects. There is
no limit to the number of joints that can be injected at any one time or the
total dose of corticosteroid.
Anaesthesia and analgesia
Various modalities are available:
• General anaesthetic is needed for multiple joints or in younger children.
• Inhaled nitrous oxide (Entonox® ) is useful in older children and
for 1–4 joints.
• ‘Wide awake’ is feasible in older children and adolescents—ethyl chloride
topical spray gives local skin anaesthesia.
• Sedation is not recommended and difficult to achieve adequately—
general anaesthetic is a much safer option.
Choice and dose of intra-articular corticosteroid (see
b Intra-articular corticosteroid use in JIA, p 445)
• Triamcinolone hexacetonide (TH) is the drug of choice with longer
duration of remission, less systemic absorption, and without i in
local side effects compared to other more soluble corticosteroid
preparations. TH is available from specialist suppliers (check with your
pharmacy). Triamcinolone acetonide (TA; Kenolog® ), is an acceptable
alternative but produces many more systemic side effects due to
i systemic absorption. Other corticosteroid preparations are not
recommended.
• Corticosteroid doses (given assuming TH is used) depends on body
weight and the joint injected:
• Large joints (knees, shoulders, hips): 1mg per kg per joint (max.
40mg/joint)—larger doses may be used in older larger patients
albeit expert advice is recommended.
• Medium joints (ankles, subtalars, elbows, wrists,) 0.5mg per kg per
joint (max. 30mg/joint).
• Temporomandibular joint 0.25mg per kg per joint.
• Small joints (fingers and toes) 0.04–1mg total dose per joint.
These dosages can be safely rounded up or down and should be doubled
when using TA—there is no maximum total dose that can be used at one
time, but if TA is used, then there is a significant likelihood of systemic side
effects with larger total doses.
Side effects of intra-articular corticosteroids
• Systemic:
• Transient increases in BP, appetite and weight gain are described
and more likely with TA. Striae from weight gain are uncommon.
• Local:
• Subcutaneous atrophy—most likely with joints with a small intra-
articular volume such as fingers, wrists, and subtalar joints.
• Sepsis—very small risk (<1 in 10,000 with good aseptic technique).
 CORTICOSTEROID INTRA-ARTICULAR INJECTIONS 391

• Peri-articular calcification—observed on x-ray but unlikely to cause

clinical symptoms.
• Cartilage growth disturbance—may occur if corticosteroids are
incorrectly placed into growing cartilage.
• Correct needle placement and appropriate dosage will reduce but
not eradicate local side effects.
Procedure
• Informed consent/assent must be recorded in the patient’s case notes
and irrespective of the type of anaesthesia used.
• Aseptic technique—operator should have clean hands and wear sterile
gloves. Gowns and masks are not necessary. Steroid preparation
should be drawn up in a 2mL syringe (or 1mL syringe for PIPJs, MCPJs,
and MTPJs).
• Needle size:
• 21-gauge for shoulders, knees, ankles, and subtalars, 23-gauge for
wrists and TMJs, 25-gauge for PIPJs, MCPJs, and MTPJs, Spinal needle
should be used for the hips.
• The needle should be placed into the joint capsule and attempts
to aspirate the joint should be made—drawing back synovial
fluid confirms needle placement, but the lack of fluid does not
necessarily mean that the needle is not in the correct place. Once
the operator is happy with the placement of the needle, 50% of
the corticosteroid should be injected; the remaining corticosteroid
should be injected after waiting a few seconds. The operator should
then wait for a further 30sec before removing the needle and then
pressing lightly on the injection site.
• Never force an injection: if there is a need to use force then it is
likely that the needle is incorrectly placed and the procedure should
be abandoned and then restarted.
• The use of an image intensifier or US can be used to aid correct
needle placement.
Post-injection management
• Injected joints should be rested for 24h postoperatively—there is no
need for bed rest but patients should defer from taking part in vigorous
exercise for 48h postoperatively.
• Patients and carers should have clear instructions on who to call in the
event of any postoperative complications developing.
Site of injection
• It is important to learn under the guidance of an experienced clinician
with opportunities initially to observe and then perform under
supervision.
• Knee: the needle is inserted approximately 1cm medial (or lateral) to
the patella, at the level of the junction of the upper 2/3 and lower 1/3.
The needle is directed slightly caudally and at an angle to go under the
patella.
• Ankle: the needle is inserted anteriorly just lateral to the extensor
hallucis longus tendon.
392 CHAPTER 8 Specialized therapeutic approaches

• Subtalar: the needle is inserted perpendicularly into the space just

distal to the lateral malleolus.
• Hip: a line should be drawn between the anterior superior iliac crest
(ASIC) and the pubic tubercle. A 2nd line should be drawn from the
ASIC towards the medial border of the patella. A 3rd line should be
drawn perpendicularly from the mid-point of the 1st line until it bisects
the 2nd line. That bisection point is the site of needle entry. The needle
is then directed towards the mid-point of the original line and at an
angle of 60° to the skin. The needle should be slowly inserted until
it hits bone. The needle should then be lying against the neck of the
femur. The needle placement should be checked with fluoroscopy
prior to injection of the drug.
• TMJ: the needle is placed a few millimetres anterior to the tragus and
advanced until it hits the joint just distal to the head of the mandible.
• Shoulder: the needle is inserted anteriorly just lateral to the corocoid
process and superior to the head of the humerus.
• Elbow: with the elbow flexed to 90° the needle is inserted between the
epicondyles and above the olecranon process.
• Wrist: the needle is inserted just distal to the end of the radius angled
at 60° to the dorsal forearm with the wrist slightly palmar flexed.
• Small joints of fingers and toes: these joints should only be injected
by experienced clinicians. Needle placement should be confirmed by
image intensifier or US.
Further reading
Ryder CAJ, Southwood TR, Malleson PN. Intra-articular corticosteroid injections. In Szer I,
Kimura Y, Malleson PN, et al. (eds.) Arthritis in Children and Adolescents. Oxford: Oxford
University Press, 2006; pp. 442–7.
 BIOLOGIC THERAPIES 393

Biologic therapies for paediatric

rheumatological diseases
Biologic agents are genetically engineered drugs designed to target specific
areas of the immune system which are implicated in disease aetiology by
selectively blocking inflammatory pathways. They include monoclonal
antibodies, soluble cytokine receptors and recombinant receptor antagonists
(Table 8.1).
It is recognized that early aggressive management of paediatric rheumato-
logical disease is needed to improve short-term and long-term outcomes
and this has been much aided by the advent of biologics, particularly in
patients who fail conventional treatment with DMARDs. However, a pro-
portion of children do not respond to initial biologic, flare after period of
quiescence, or suffer adverse events necessitating cessation of drug.
In JIA the efficacy of biologics has been shown in recent landmark clinical
trials made possible by international multicentre collaboration. There
are many reports of efficacy and safety in off-label use of biologics for a
range of paediatric rheumatological diseases. There is concern about rare
adverse events and long-term safety of biologics with emerging cases of
infection, autoimmune disease, malignancy, and demyelination, which high-
lights the important role of Registries to document efficacy and long-term
safety as adverse events may not be identified in short-term clinical trials.
NICE guidance on biologic therapies for JIA in the UK
(see b p 399)
• Use of etanercept approved (2002) for children aged 4–17yr with active
polyarticular-course JIA who fail to respond adequately to, or who have
proved intolerant of, MTX (see M http://www.nice.org.uk/nicemedia/
pdf/JIA-PDF.pdf). Initiation of treatment should be in accordance
with relevant sections of the British Paediatric Rheumatology Group
(BPRG) protocol (now BSPAR) (see Appendix D in NICE guidelines),
undertaken by an experienced consultant together with a nurse
specialist who is able to teach families injection techniques.
• Infliximab not currently licensed for JIA in the UK and NICE have
withdrawn infliximab from appraisal at this time.
• Abatacept, tocilizumab, and adalimumab have been licensed but not yet
appraised by NICE for use in JIA.
• Use of biologics for treatment of JDM, JSLE, CAPs, and vasculitis is
currently off-label and not under NICE guidance: see relevant chapters.
Table 8.1 Current use of biologics in paediatric rheumatological diseases (see p b Guidelines and protocols, p 415)
Biologic agent Mode of action Administration Commonly used doses Current indications Licensed indications
#Polyarticular
Abatacept Humanized selective IV infusion 10mg/kg at 0,2,4 weeks JIA (excluding In USA and EU for refractory
T cell co-stimulatory then 4-weekly afterwards ERA and PsA; not included in polyarticular JIA >6yr
modulator RCT). †JIA-associated uveitis
Adalimumab Humanized soluble SC 24mg/m2 up to 40mg #Polyarticular JIA. †JIA- EMEA*licence for refractory
anti-TNF monoclonal fortnightly associated uveitis. †Systemic polyarticular JIA in 4–17yr age.
antibody vasculitis. †CRMO/SAPHO
Anakinra Humanized SC 2mg/kg daily (max. 100mg) #Systemic JIA. Off label
anti-IL1 receptor † Cryopyrin-associated
antagonist periodic syndromes (CAPS)**
†
CRMO/SAPHO
Canakinumab Human anti– SC 2–4mg/kg up to 150mg # CAPS. In adults and children with
IL-1B monoclonal 8-weekly # in progress
SJIA CAPS in EU
antibody
4mg/kg, 4-weekly SJIA
# EMEA licence for refractory
Etanercept Soluble TNF p75 SC 0.4mg/kg twice week Polyarticular JIA (reduced
receptor fusion protein (max. 25mg twice-weekly). efficacy in SJIA) polyarticular JIA in age 4–17yr
†ERA. †PsA
†
NICE approval.
JIA <4yr of age. †Systemic
vasculitis Licensed >2yr in USA
† CRMO/SAPHO
Infliximab Chimeric human murine IV infusion 6mg/kg. #Refractory polyarticular JIA. Off label
anti-TNF monoclonal †JIA-associateduveitis.
Initially at 0, 2, & 6 weeks;
antibody †Refractory JDM. Sarcoid
then at intervals of †Systemic vasculitis.
4–8-weekly depending
†
on clinical response PSA, ERA
†Behçet’s
#Refractory Kawasaki’s disease
†CRMO/SAPHO

# In adults and children with CAPS

Rilonacept Soluble fusion protein SC Initial dose 4.4 mg/kg (max. CAPS
†SJIA in EU & USA (t12yr age); not yet
of IL-1 receptor and 320mg) then once-weekly
IgG Fc at 2.2 mg/kg (max. 160mg) available in UK.
Rituximab Anti-CD20 antibody IV infusion (often used 750mg/m2 (max. 1g) †
JSLE. †SJIA Off label
synergistically with on day 0 and day 14 Refractory polyarticular JIA
(B cell depletor) †Refractory JDM
cyclophosphamide &
methylprednisolone †
Systemic vasculitis
Tocilizumab Humanized anti-IL-6 IV infusion 8mg/kg 2–4-weekly >30Kg #Systemic JIA Off label
receptor monoclonal 12mg/kg <30Kg
antibody (fortnightly initially)
*
EMEA, European Medicines Agency (M http://www.ema.europa.eu).
** Cryopyrin-associated periodic syndromes (CAPS) includes familial cold-induced autoinflammatory syndrome, Muckle–Wells syndrome, and chronic infantile neurologic, cutaneous, articular

(CINCA) syndrome (also known as neonatal-onset multisystem inflammatory disease [NOMID]).

Level of evidence for efficacy and safety: # indicated clinical trial performed, † indicates case series or observational studies, no symbol indicates clinical use but no paediatric data published.
NB Within clinical trials polyarticular refers to any subtype of JIA that involves t4 joints including EOJIA, SJIA, ERA, as well as RF+ve and R|F−ve polyarthritis.
396 CHAPTER 8 Specialized therapeutic approaches

Assessment checklist prior to commencing biologic therapy

• Education (verbal and written; ideally provided by rheumatology CNS):
• Age appropriate, in format that family understand, with time for
reflection to make informed decision.
• Include knowledge of medication/side effects, dose needed (mg/
mL), appropriate storage of medication (if keeping at home) and
safe disposal of medication/equipment.
• A frank and honest discussion is required to maintain trust between
child and healthcare workers (e.g. adalimumab and anakinra
injections may hurt).
• Blood screen:
• FBC, ESR, U&E, LFT, CRP, antibody screen (ANA, anti dsDNA, anti
ENA, anticardiolipin), hepatitis serology, immunity status (measles,
varicella IgG).
• Measurements:
• Accurate height, weight, and surface area to calculate dose of
medication.
• Plot growth chart.
• Risk assessment for tuberculosis (see b TB, p 356):
• History—recent visits or previous residence in high-risk countries/
close family/friend contact/past history of TB.
• Baseline CXR for all patients 9 Mantoux (if not on
immunosuppressant/steroid therapy).
• Consider immunological testing (T spot or Quantiferon),
particularly if high index of suspicion. If positive, treat TB before
starting biologic therapy—seek expert advice.
• Sexual health and contraception:
• Effects of biologic therapy on developing foetus unknown and
pregnancy should be avoided. Education needed for all young
people with potential of being sexually active (best provided by
rheumatology CNS).
• Meaning of confidentiality should be explained to young person and
practiced by health professionals.
• Training on SC injections if applicable:
• The CNS/nurse teaching the patient/family must have experience
and training in giving SC injections and be confident in ability to
teach the patient/family, ensuring competence and safety.
• Important to review injection technique especially if apparent
waning of clinical response.
• Dealing with needle phobia where applicable:
• Suitable environment, allowing element of control with help of play
specialist 9 psychologist.
• Arrange delivery/pick up of medication/equipment:
• Homecare delivery services are available to regularly supply.
medication direct to the patient’s home and collect waste/sharps bins.
• Some companies provide a teaching/assessing service for home
administration.
• Safety checks:
• Families must understand the importance of safe handling and
disposal of medication and equipment.
 BIOLOGIC THERAPIES 397

• Vaccinations:
• Consider varicella vaccination for non-immune patients if able to
delay start of biologic treatment and vaccination not contra-indicated
by other immunosuppressive therapy (see b Varicella, p 371).
• Families need explicit and written instruction if child is non-immune
(e.g. varicella or measles).
• Live vaccinations (including MMR, varicella, BCG, yellow fever)
should not be given to patients on biologic therapy or for 6 months
after treatment has finished (see b Immunizations, p 355).
• Killed vaccinations can be administered safely and are
recommended (annual flu vaccine, 5-yearly pneumococcal vaccine,
human papillomavirus vaccine).
• Counselling regarding infection:
• Essential that patient and family understand importance of seeking
medical advice quickly in event of infection. Biologic treatment
may predispose to serious manifestations of common bacterial
infections and a low threshold for antibiotics is prudent. Consider
opportunistic and atypical infections (see b Infection and the
immunocompromised, p 374).
• Withhold biologic treatment if child has an infection with raised
temperature, but remember that serious infection may be present
in the absence of pyrexia in a child receiving immunosuppression.
• Varicella infection and varicella exposure in the non-immune (see
b Varicella, p 371). In the event of infection, biologic therapy
should be stopped until the child is well and the chicken pox lesions
have crusted over. If the patient is varicella non-immune and there
has been close (family) contacts with chicken pox, give prophylactic
VZIG or acyclovir (see b Varicella, p 371) but the biologic therapy
can be continued if the child does not develop lesions beyond
the incubation period. It is advisable for a child’s school/nursery
to inform the family if there is a chicken pox outbreak. Consider
vaccination of healthy siblings.
• Exclude TB prior to starting biologic treatment and have low
threshold for investigating for TB if symptomatic on treatment.
See b TB, p 356.
• Baseline ‘core set criteria’ (see b Outcome measures, p 41 and p 165)
• Clearly documented before starting biologic treatment and monitor
regularly throughout (recommended 3-monthly for first year).
• Supply contact details:
• Patient/family should need contact details for the hospital/local
services including who to contact at weekends/bank holidays if
necessary.
• Follow-up appointments and blood monitoring:
• Recommended to be at least every 3 months for the first year.
• Families to be of clinic dates and plans for blood monitoring before
discharge.
• Families to have CNS helpline number.
• Families to have written instructions when to seek healthcare if
child unwell (e.g. febrile) and have open access to day units as
necessary.
398 CHAPTER 8 Specialized therapeutic approaches

• Monitoring and reporting treatment response adverse events:

• For etanercept the BSPAR Biologics and New Drugs Registry:
M http://www.bspar.org.uk.
• Other agents used in JIA (and in the future, other diseases) the
Biologics for Children with Rheumatic Diseases Registry: M http://
www.medicine.manchester.ac.uk/musculoskeletal/research/arc/
clinicalepidemiology/pharmacoepidemiology/bcrd.
• In the UK suspected adverse reactions are reported through the
‘Yellow card scheme’: M http://yellowcard.mhra.gov.uk.
Further reading
Beresford MW, Baildam EM. New advances in the management of juvenile idiopathic arthritis – 2:
The era of biologicals. Arch Dis Child Educ Pract Ed 2009; 94:151–6.
Gartlehner G, Hansen RA, Jonas BL, et al. Biologics for the treatment of juvenile idiopathic arthritis:
A systematic review and critical analysis of the evidence. Clin Rheumatol 2008; 27:67–76.
Woo P. Theoretical and practical basis for early aggressive therapy in paediatric autoimmune disorders.
Curr Opin Rheumatol 2009; 21:552–7.
 APPROVALS FOR USE OF BIOLOGIC THERAPIES 399

Approvals for use of biologic therapies

Etanercept and adalimumab in juvenile idiopathic arthritis
(JIA): NICE guidelines (M www.nice.org.uk)
• NICE is funded by the Department of Health (UK) to provide
independent appraisal of licensed therapies based on efficacy and cost
effectiveness.
• Amongst the biologics, to date only etanercept (Enbrel® ) has been
fully appraised by NICE (2002: M http://guidance.nice.org.uk/TA35/
Guidance/pdf/English)—see Tables 8.2 and 8.3.
• Adalimumab (Humira® ) gained its licence for use in JIA in September
2008, is on the NICE portfolio but has yet to be appraised—see
Tables 8.2 and 8.3.
• NICE advocates that patients on these biologics undergo long-term
monitoring and surveillance (see b Biologics and guidelines, p 415):
• For etanercept, the BSPAR Biologics and New Drug Registry:
M http://www.bspar.org.uk/pages/home.asp
• All other biologics, the Extended Biologics Registry: M http://
www.medicine.manchester.ac.uk/musculoskeletal/research/arc/
clinicalepidemiology/pharmacoepidemiology/bcrd.
400 CHAPTER 8 Specialized therapeutic approaches

Table 8.2 Indications for etanercept and adalimumab as per NICE

guidance
Etanercept Children aged 4 to 17 years who have active JIA in t5 joints
and whose condition has not responded adequately to MTX (3
months at a dosage of parenteral MTX = 20mg per m2 once-
weekly unless toxicity occurs) or those who have been unable to
tolerate treatment with MTX. Etanercept is also licensed for use
in psoriasis in children over 8yr
Adalimumab Albeit licensed for the treatment of active polyarticular juvenile
idiopathic arthritis, in children and adolescents aged 4 to 17
years, NICE guidance stipulates that Adalimumab may be used in
young people aged 13 to 17 years who have active polyarticular
JIA, in combination with MTX. Adalimumab can be given as
a mono-therapy where there is intolerance to MTX or when
continued treatment with MTX is inappropriate. Adalimumab is
licensed for the treatment of uveitis in adults in the USA

Table 8.3 Preparations available

Etanercept • 25mg paediatric vial and solvent—multi-dose (x2)
• 25mg vial and solvent—single use
• 50mg pre-filled syringe
• 50mg pre-filled pen device (MYCLIC)
Adalimumab • 40mg pre-filled syringe
• 40mg pre-filled pen device

Further reading
Royal College of Nursing. Assessing, managing and monitoring biologic therapies for inflammatory
arthritis: guidance for rheumatology practitioners. London: RCN, 2009. M http://www.rcn.org.uk.
 MEDICINES FOR CHILDREN AND PAEDIATRIC RHEUMATOLOGY 401

Medicines for children and paediatric

rheumatology
• Many drugs prescribed for children are used outside the terms of
their product licence (‘off-label’) or are not licensed for any use in the
applicable country.
• It is the responsibility of the prescriber to ensure an appropriate
evidence base for safety and efficacy exists for an unlicensed use and
specific guidance is provided by the General Medical Council (M http://
www.gmc.org.uk).
• The Summary of Product Characteristics (SmPC) for the drug product
in question (M http://www.medicines.org.uk/emc) should be consulted
to ascertain the licensed indications, dosages, precautions, and possible
side effects.
Paediatric pharmacokinetics
Growth and development influence the absorption, distribution, metabolism,
and excretion (ADME) of drugs requiring constant adjustment of dosage
regimens from birth to adolescence. In addition, it should be noted that:
• Absorption and bioavailability are influenced by the choice of
formulation, route, fed/fasted state, and concomitant medication for
the oral route and by the need for manipulation of the dosage form,
which will additionally affect dose accuracy.
• Metabolism and excretion can be affected by the complexity of some
multi-system auto-immune, auto-inflammatory disorders where
renal and hepatic involvement may be part of the underlying disease
process (e.g. SLE, sJIA, systemic vasculitides) and by concomitant
medications that induce or inhibit drug metabolizing enzymes or affect
renal function, thus impacting upon efficacy and toxicity which may
necessitate dose adjustment or monitoring.
• Drugs with a narrow therapeutic index require close monitoring and
dose adjustment (e.g. MTX, ciclosporin). Conditions such as nephrotic
syndrome can affect drug excretion.
Safety issues
• Manual handling and inadvertent exposure to cytotoxic drugs
(MTX, azathioprine, cyclophosphamide) must be avoided. Cytotoxic
injectables should be prepared in the pharmacy in accordance with
national guidance and local management policy on safe preparation and
administration.
• If manipulation (e.g. opening capsules or breaking tablets) is
required, it should be referred to the pharmacy.
• Be aware of different product strengths available (e.g. MTX tablets
and unlicensed MTX oral liquids) that can lead to dosing errors. Patients
and carers should be educated to check every new prescription,
dispensed product, and dosing instructions. Recommendations in
safety alerts issued for MTX should be complied with. For primary
care transfer, discharge letters should specify the strength to prescribe
(plus manufacturer if difficult to source) and relevant monitoring.
402 CHAPTER 8 Specialized therapeutic approaches

• Monoclonal antibody (mAb) products should be treated as

biohazardous—insufficient data exists on low-level long-term exposure
to mAbs. Safe preparation and handling guidelines should be followed
to minimize staff contamination and patient cross-contamination.
Dose calculation
Children’s doses are usually calculated based on body weight (mg/kg) or
body surface area (BSA) (mg/m2) and should be obtained from appropriate
paediatric formularies (e.g. BNFC). Several formulae of variable accuracy
for estimation of BSA are available. The 2 commonly used equations are
the Mosteller equation that provides a simple calculation for BSA based
on height and weight and the Boyd equation (used in the BNFC tables)
based on weight alone. Points to note:
• For overweight patients (e.g. those exposed to high doses/long-term
corticosteroids): consider whether actual body weight or ideal body
weight is appropriate to use.
• For NSAIDS, use body weight. Round doses if appropriate to avoid
manipulation of dosage forms which leads to dose inaccuracies.
• For drugs with a narrow therapeutic index (NTI) (e.g. cytotoxics),
use BSA.
• Consider when dose capping is required—the total daily dose should
not exceed the maximum adult daily dose.
• When both body weight and BSA are used for dose calculation, ensure
consistency. Check local guidelines on which measure is to be used.
• MTX often causes nausea and vomiting when given orally at higher
doses. Consider switching from the oral to SC route to improve
tolerability and bioavailability. Currently, the corresponding oral dose is
used for the SC route.
• Due to differences in bioavailability between brands, certain oral drug
products are not interchangeable (e.g. ciclosporin). Where brand
switching is necessary blood levels should be monitored. Such status
is usually stated in the BNFC. In general, switching oral formulations,
e.g. tablets to liquid (even within the same brand), can affect
bioavailability. Check for information on bioequivalence of different
formulations of a specific brand in its SmPC.
Considerations for the drug classes used: see b Guidelines,
p 415
• NSAIDs—the choice of NSAID depends on its side effect profile,
individual efficacy and tolerance, and availability of age-appropriate
formulations.
• Analgesics—step-up protocols from paracetamol, codeine, co-codamol
to opioid analgesics must be followed and used as an adjunct to
NSAIDs.
• Steroids—for oral therapy the minimum effective dose should be
used. Long-term steroid use has osteoporotic side effects, calcium
and vitamin D supplementation and the use of bisphosphonates for
prevention and treatment should be considered.
 MEDICINES FOR CHILDREN AND PAEDIATRIC RHEUMATOLOGY 403

• Cytotoxic immunosuppressants
• Cyclophosphamide: toxic effects such as malignancy and infertility
are related to cumulative doses therefore update the cumulative
dose sheet in patient notes after each dose and dose cap as
appropriate; consider fluid tolerance issues.
• MTX: always prescribe the same strength formulation (i.e. 2.5mg
tablets) and pay attention to the dosing interval (weekly doses).
Homecare providers can greatly improve patient and parent
convenience by reducing hospital visits. However, training must be
provided and the suitability and competence of the patient/carer to
administer medication must be assessed in advance.
• Immunoglobulin: for IgG replacement therapy be aware that infusion
rates vary for the different brands available. Access to immunoglobulin
is restricted due to availability/supply issues. Refer to the local/national
guidance on clinical prioritization and managing supplies.
• Biologics: biosimilars (similar biological medicinal products) must not be
treated as generics since they cannot be proven to have identical clinical
characteristics (differences in starting materials, manufacturing processes,
and immunogenic reactions). Thus, biosimilars are not interchangeable
and must not be substituted without appropriate patient monitoring. The
brand intended must be made clear on prescriptions. SC as opposed to
IV administration enables the child not to miss school.
Issues to consider when selecting oral dosage forms
See Table 8.4.
404 CHAPTER 8 Specialized therapeutic approaches

Table 8.4 Advantages and disadvantages of different dosage forms

Dosage Advantages Disadvantages
form
Tablets and • Portable, more palatable than • Fixed dose
capsules liquids especially for drugs • Swallowing difficulty
where taste is an issue • Unavailability of higher strength
• Lower contamination risks products may require several
(cytotoxics) than liquids to be taken or a single unit to
(spills/breakages) be manipulated for lower doses
Dispersible • Overcomes swallowing • Fixed dose
tablets difficulty • Limited strengths available
• More portable than liquids • Taking proportion of liquid
leads to poor dose uniformity
& reproducibility
Sustained • Reduces number of daily • Fixed dose, lack of paediatric
release doses, avoids school time PK data in most cases
tablets & doses, interference with • Dosage forms cannot be
capsules activities or sleep manipulated
• May improve compliance • Lack of efficacy may complicate
dose escalation and add-on
therapy (e.g. pain management)
Oral liquids • Dose flexibility, usually • Palatability, may contain
flavoured, can be administered unsuitable excipients such as
via feeding tubes alcohol, preservatives, colours
• Overcomes swallowing • Inconvenient/bulky for travel
difficulty
• May provide better/more
consistent absorption than
solids for patients with GI
problems
Effervescent • More convenient to carry • Palatability
products than liquids • Need to be fully dissolved in
• Forms a liquid: overcomes large volume of liquid
swallowing difficulty • Compliance with ingesting
large volume
• Usually have high Na+/K+—
unsuitable for certain groups
(e.g. renal patients)
 HAEMATOPOIETIC STEM CELL TRANSPLANTATION 405

Haematopoietic stem cell

transplantation
• In a small proportion of affected children, rheumatic disease is
severe and/or resistant to conventional treatments—these children
often develop significant side effects from the long-term treatment
with multiple, and often combined disease-modifying agents (both
immunosuppressive and anti-inflammatory) such as corticosteroids,
MTX, cyclophosphamide, and whilst undergoing therapeutic trials of
multiple new biologic agents.
• Even in the era of biologics, this small group of children may benefit
from haematopoietic stem cell transplantation (HSCT) and national
guidance is available. However, autologous HSCT is still regarded as
‘experimental’ treatment and as a rule offered as a ‘last chance’ option,
whilst allogeneic HSCT is ‘generally not recommended’.
Autologous T-cell depleted (TCD) HSCT
The hypothesis
Deletion of presumed auto-aggressive lymphocyte clones—immunosup-
pressive conditioning (usually anti-T lymphocyte globulin-ATG, and cyclo-
phosphamide or fludarabine).
T-cell depletion (usually by CD34+cell selection)
Newly developing lymphocyte population leads to ‘re-setting’ of the
immune system, i.e. self-tolerance.
The evidence
TCD auto-HSCT for JIA induces complete remission (CR):
• Immediate improvement of acute inflammation, due to the
immunosuppressive conditioning regimen.
• Subsequent improvement in disease activity (CR >50%), due to
‘immunomodulation’ (re-establishment of immune tolerance):
• Albeit may be a transient effect.
• Significant transplant-related mortality (TRM).
Emerging potential weakness of the hypothesis for sJIA
• Disease recurrence following long-term remission (7–9yr) post-autologous
HSCT for sJIA.
• Many now regard sJIA as an autoinflammatory disease.
• Some patients with sJIA have a genetic predisposition to
haemophagocytic lymphonistiocytosis (HLH) and there may be some
overlap between sJIA/severe macrophage activation syndrome (MAS)
with primary HLH patients.
• Induction of self-tolerance by autologous HSCT may thus only provide
partial or temporary improvement in those patients.
• Allogeneic HSCT may arguably be a more logical approach in this
subgroup—an area of ongoing debate in the rheumatological and
transplant communities.
406 CHAPTER 8 Specialized therapeutic approaches

Inclusion criteria for autologous TCD HSCT for JIA

Severity of disease and persistent disease activity
• Any JIA subtype with a polyarticular course, with persisting active
inflammatory disease, total disease duration >1yr, active disease
>6 months.
• The persistence of active disease should be despite immunosuppressive
medication or only controlled with unacceptable drug toxicity (see
following section).
• The patient must be in a satisfactory general condition—significant
end-organ disease (e.g. from amyloidosis, hypertension, other major
organ involvement, immunosuppression-related, or other pathology)
may or may not preclude autologous HSCT.
• Patients with sJIA should not have uncontrolled active systemic
features due to i risk of MAS at conditioning (see b Macrophage
activation syndrome, p 305).
• There should be no evidence of active ongoing infection, including with
opportunistic organisms.
• Consideration should be given to the potential for improvement in
functional disability (previously established joint/bone damage cannot
be restored).
• Psychosocial factors need to be considered by the referring team who
are likely to know the child and family well, and are best placed to
judge how they would cope with autologous HSCT.
Failure of immunosuppressive and anti-inflammatory therapy
• It is difficult to define ‘failure of treatment’ as treatment options
are ever increasing. The key point is to think ahead for severe and
‘refractory’ cases as the process of auto-HSCT takes time.
• Conventional immunosuppressive treatment for JIA is MTX, and in the
era of emerging novel therapies most patients, prior to consideration
of auto-HSCT, will have failed >1 biological therapy and a trial of
parenteral MTX, each for at least 3–6 months before being deemed
‘failure’.
• The use of combination therapy, changing from one anti-TNF drug to
another, or considering other biologics such as anti-IL-1 or anti-IL6
‘blockade’ should be considered before auto-HSCT. The downside is
that if these approaches fail, disease and therapy-related damage may
accrue.
• An informal discussion with the transplant team and referral for
independent assessment may be helpful when dealing with a child with
severe, persistently active JIA who has failed immunosuppressive and
anti-inflammatory therapy—i.e. disease uncontrolled on:
• Systemic corticosteroids (>0.3mg/kg/day) and/or repeated IV pulses
of methylprednisolone (30mg/kg/day) or
• High-dose MTX (t15mg/m2/week) given parenterally
for >3 months or
• Biologics such as etanercept or other novel/biologic drugs, given at
appropriate doses for >3–6 months.
 HAEMATOPOIETIC STEM CELL TRANSPLANTATION 407

Drug toxicity or intolerance to medication as defined by any of

the following:
• Evidence of corticosteroid toxicity.
• Intolerance of MTX (e.g. unacceptable nausea/vomiting despite anti-
emetic medication, psychological intervention, and trial of parenteral
route; alopecia; severe mucosal ulceration).
• Unacceptable elevation in liver enzymes related to MTX or drug
induced cytopenia or other toxicity, e.g. renal toxicity or hypertension
related to ciclosporin.
Allogeneic HSCT for severe childhood autoimmune
disorders)
• Benefit—potentially curative procedure, based on very few case reports:
• Initially procedures were intended for treatment of coincidental
malignancy.
• Subsequently, procedures undertaken for intentional treatment of
severe and recalcitrant autoimmune disorders.
• Retrospective survey of 35 patients (EBMT Working Party for
Autoimmune Disorders):
• Complete response in 55%; partial response in further 24%.
• Transplant-related mortality (TRM) 720%.
• Risk of acute/chronic graft-versus-host disease (GvHD) 740%
• The risk:benefit ratio—may be further improved:
• Reduced intensity conditioning (more immunosuppressive, less
myeloablative) and
• Better GvHD prophylaxis (cyclosporin A, mycophenolate mofetil).
Notes on HSCT for autoimmune disorders and clinical
outcomes
• TRM associated with autologous TCD HSCT is higher (710–15%) than
for non-TCD (73–5%), almost comparable to that of allogeneic HSCT.
• The most likely reason for this is the combined effect of
conditioning immunosuppression and T-cell depletion, leading to a
severe and prolonged T-cell immunodeficiency state (6–12 months).
• Autologous TCD HSCT for autoimmune disorders should not be
regarded any longer as ‘experimental treatment’ and should be offered
earlier in the course of the disease:
• If this approach is still considered a treatment option, it should
be brought forward to avoid i risks of TRM from infectious
complications (occurring as a cumulative result of long-term and
combined immunosuppression).
• Experience with allogeneic HSCT for monogenic autoimmune
disorders (IPEX—immunodysregulation, polyendocrinopathy,
enteropathy, X-linked syndrome; ALPS—autoimmune
lymphoproliferative syndrome) is good
• 10 patients; 1% TRM; follow-up 1–6yr (Abinun M et al., unpublished
data).
• Until more evidence is available (from ongoing and planned clinical
trials), allogeneic HSCT for autoimmune disorders should only be
offered to selective patients in specialized centres.
408 CHAPTER 8 Specialized therapeutic approaches

Further reading
Foster HE, Davidson J, Baildam E, et al. Autologous haematopoeitic stem cell rescue (AHSCR)
for severe rheumatic disease in children: guidance for BSPAR members-Executive summary.
Rheumatology 2006; 45:1570–1.
Ljungman P, Bregni M, Brune M, et al. Allogeneic and autologous transplantation for haematological
diseases, solid tumours and immune disorders: current practice in Europe 2009. Bone Marrow
Transplant 2010; 45:219–34.
Milanetti F, Abinun M, Voltarelli JC, et al. Autologous hematopoietic stem cell transplantation for
childhood autoimmune disease. Pediatr Clin North Am 2010; 57:239–71.
 Chapter 9 409

British Society of
Paediatric and Adolescent
Rheumatology clinical
guidelines and protocols

BSPAR Standards of Care for children and young

people with JIA 410
BSPAR drug information leaflets for parents and families 412
BSPAR guidelines for treatments used in paediatric
rheumatology 415
Non-steroidal anti-inflammatory drugs (NSAIDs) 416
Disease-modifying anti-rheumatic drugs (DMARDs) 418
Azathioprine 423
Ciclosporin 425
Intravenous cyclophosphamide 427
Pamidronate 431
Epoprostenol/iloprost 433
Etanercept (Enbrel®) 434
Other anti-TNF-A: adalimumab (Humira®) and infliximab
(Remicade®) 436
Anti-IL-1 treatments: anakinra (Kineret®), rilonacept
(Regeneron®), and canakinumab (Ilaris®) 437
Abatacept (Orencia®) 439
Anti-IL-6 treatment: tocilizumab (Ro-Actemra®) 440
Anti-B-cell therapies: rituximab (Mabthera®) 441
Systemic corticosteroids (oral, intramuscular,
and intravenous) 443
Intra-articular corticosteroid use in JIA 445
410 CHAPTER 9 BSPAR clinical guidelines and protocols

BSPAR Standards of Care for children

and young people with JIA
• The BSPAR Standards of Care (SOC) for JIA are based on the
fundamental principle that all children and young people with JIA
have the right to equitable access to the highest quality of integrated
services (M http://www.bspar.org.uk/downloads/clinical_guidelines/
Standards_of_Care.pdf).
• The SOC are primarily aimed at professionals working in paediatric
rheumatology, designed to support clinical service development, and
delivery in conjunction with colleagues and funding bodies and by being
in the public domain, promote awareness of good clinical practice to
parents and families affected by JIA. Key standards include:
Standards to improve access, early diagnosis and treatment
• All healthcare practitioners likely to come into contact with a child
with JIA should acquire the necessary clinical skills and knowledge to
recognize the condition early.
• Musculoskeletal clinical examination should be included in education
and training of medical students and hospital trainees.
• All children and young people with suspected JIA should be referred
to a paediatric rheumatology team (PRT) d6 weeks of the onset of
symptoms and should be seen by the PRT d4 weeks of referral, with
45min allocated for the first appointment.
• On diagnosis all children and young people with JIA should have
prompt access to a multidisciplinary PRT who must have appropriate
experience and training as defined by the appropriate professional
bodies.
• On diagnosis all children/young people with JIA should have a full
assessment of their disease, general health, psychosocial, educational,
and pain management needs.
• On confirmation of the diagnosis:
• Within 6 weeks all patients should have a slit lamp examination
performed by an experienced paediatric ophthalmologist or
optometrist.
• Where required, IA corticosteroid injections should be performed
by a member of the PRT in d6 weeks and SC MTX should be
available within d4 weeks.
Standards to empower patients and their families by
improving information, access to support, and knowledge
• Children and young people with JIA and their families will be
encouraged to participate in disease management.
• Information for patients and families must be provided to inform
decision-making, and optimize their physical, psychosocial, and
emotional development. Information should be provided:
• In a variety of formats, be developmentally appropriate, and
presented in clear simple language avoiding jargon.
• About JIA, treatment options, and general health issues.
• About the members of the PRT and how to access them.
 BSPAR STANDARDS OF CARE 411

Standards to improve access to ongoing and responsive

treatment and support
• Patients with active disease should be assessed at intervals not greater
than 4 months apart.
• Patients should have regular ophthalmology reviews in accordance
with BSPAR/Royal College Guidelines (see Chapter 9 and b Uveitis
screening in JIA, p 148).
• Each patient should have an individualized care plan (pathways for
treatment, information on what to do in the event of worsening
symptoms), details of national or local support groups, and provision of
information for schools and employers.
• Patients and families should have:
• Access to their named MDT members with direct and easy access
during flares of disease.
• A dedicated telephone helpline managed by the PR clinical nurse
specialist.
• The opportunity to participate in clinical research and clinical trials.
• Paediatric rheumatology clinical networks should have referral
pathways, guidelines, and framework for clinical governance.
• Drugs used for the treatment of JIA must be prescribed and monitored
in accordance with BSPAR/NICE guidelines (see b Biologics, NICE,
p 393 and p 399) and should be available without undue delay.
• Specialist surgery should be performed by a surgeon with training in the
management of JIA and communicating with children and adolescents
and who is linked to the paediatric rheumatology clinical network.
Standards to maximize independence, inclusion, and quality
of life
• The psychosocial well-being of the child/young person with JIA and
their family should be addressed by all professionals (health, education,
and community).
• The PRT should encourage and facilitate age-appropriate participation
in interests, sport, and community life.
• The educational setting (school and college) should ensure full
inclusion of the child/young person with JIA.
• Young people with JIA should be supported to develop the skills to
move into employment.
• The child/young person with JIA and their families should be provided
with support/strategies to manage distressing aspects of their
treatment.
• The child/young person with JIA should be given the skills to disclose
their arthritis to others, should they choose to do so.
• Age- and developmentally-appropriate individualized transitional care
for the child/young person with JIA, should take place reflecting early,
mid, and late phases of adolescent development (see b Transitional
care, p 387).
Further reading
Davies K, Cleary G, Foster H, et al. on behalf of the British Society of Paediatric and Adolescent
Rheumatology: BSPAR standards of care for children and young people with juvenile idiopathic
arthritis. Rheumatology 2010 49(7):1406–8.
412 CHAPTER 9 BSPAR clinical guidelines and protocols

BSPAR drug information leaflets for

parents and families
Medication is a major component in the treatment of rheumatic dis-
eases and medicine taking is an area in which patients and carers should
be enabled to make informed choices and decisions. A market research
survey in 2003 (M http://www.ipsos-mori.com/default.aspx) found that
patients want more medicines information than they get and that they
want it from a variety of sources.
The clinical nurse specialist (CNS) plays a major role in patient and family
education about medicines. This is integral to optimizing adherence and it
is important that both patients and carers understand why a drug is being
prescribed, the risks and benefits, and the importance of monitoring. The
CNS needs to have a good understanding of the medicine that is being
prescribed including:
• Pre-screening that may be required prior to commencement of drug.
• How to report adverse events (e.g. yellow card system) and awareness
of drug alerts (M http://www.medicines.org.uk).
• How to access psychological support/counselling for non-adherence.
• Shared care guidelines with local and tertiary services.
Drug information should initially be given verbally and key messages rein-
forced with patient information leaflets (PILs) and where appropriate
‘signposting’ to relevant websites. Guidance for PILs is available (M http://
www.mhra.gov.uk) and should be:
• Fit for purpose, i.e. appropriate for the intended target group.
• Proof read by a pharmacist for content accuracy.
• Readability assessed (M http://www.plainenglish.co.uk).
• Inclusive of public and patient involvement (M http://www.dh.gov.uk).
A series of PILs are available on the BSPAR website (M http://www.bspar.
org.uk)—these are evidence-based where possible, and consensus-derived
from the BSPAR paediatric rheumatology CNS group.
They highlight aspects of drug education that should be covered:
• Formulary and generic names of the drug.
• Drug interactions, contraindications, side effects, monitoring required
(blood tests).
• Counselling as appropriate; sexual health, contraception and pregnancy
(to both sexes, M http://www.brook.org.uk, http://www.fpa.org.uk),
alcohol, and smoking (M http://www.units.nhs.uk).
• Potential risk of infection. ‘Do’s and don’ts’, when to seek medical
attention and travel information (taking medication abroad, insurance
and contact if become unwell).
• Immunizations and impact on live vaccines.
 BSPAR DRUG INFORMATION LEAFLETS 413

Specific points relevant to paediatric rheumatology practice

(see b Medicines for children, p 401)
NSAIDs
• Formulations available, e.g. liquid, tablet, melt, and its suitability for the
patient and family.
• Consideration should be given to dose intervals, e.g. fitting around the
school day.
• Gastric protection—NSAIDs should be administered with or after
food. Gastroprotective drugs may be required, especially if symptoms
occur or prophylactically if on combination therapies such as
prednisolone.
• Sun protection against pseudoporphyria with naproxen.
Corticosteroids
• Gastric protection (as for NSAIDs).
• Weight gain—dietary advice for the whole family.
• Body image and risk of bullying—psychology/counselling support
(M http://www.bullyingonline.org).
• Changes in mood and behaviour.
• Acne—clindamycin ointment.
• Osteoporosis—activity levels, calcium and vitamin D intake.
DMARDs
• Blood monitoring (see b BSPAR drug guidelines, p 415).
• Sexual health and pregnancy (consult latest product literature).
• Infection risks.
• Avoidance of live vaccinations.
• Potential hair loss with cyclophosphamide, MTX, hydroxchloroquine
sulphate, MMF.
• Safe handling and disposal as per local guidelines especially MTX and
cyclophosphamide.
• Potential i risk of certain cancers.
Methotrexate
• Use 2.5mg tablets where possible to minimize confusion and
medication errors.
• Parenteral administration—RCN document: M http://www.rcn.org.uk.
• Nausea—the use of antiemetics, change time of dosing and/or split the
dose over 24h.
• Liver toxicity—alcohol advice and counselling: M http://www.
need2know.co.uk.
Biologics
(M http://www.rcn.org.uk: assessing, managing, and monitoring biologic
therapies).
• Need for pre-treament screening, e.g. TB.
• Long-term unknown side effects.
• Potential risks of malignancy.
• Risk of serious infections—when to seek medical advice.
• Avoidance of live vaccines.
• Regular blood monitoring.
414 CHAPTER 9 BSPAR clinical guidelines and protocols

• Sexual health and pregnancy.

• When to stop or omit—i.e. surgery, active infection—temperature
>38*C.
• Injection site reactions for SC drugs—apply cold packs pre- and
postinjection, antihistamine cream/oral antihistamines.
• IV infusion reactions including potential anaphylaxis.

Issues to consider for all DMARDs and biologic therapies

(see b Biologics, p 393)
Blood monitoring
• Age of child.
• Difficulty with venous access.
• Capabilities of local services.
• Distance from home.
• Play therapy/psychology input.
• As infrequent as possible.
• Local anaesthetics, e.g. Ametop®, cold spray.
• Establish a monitoring agreement.
Travel
• Vaccinations required.
• Letter re: medications.
• Adequate supply of drug.
• Travel insurance.
• Clinic letter/carriage of medicines.

This section covers some of the issues that should be considered when giving
information about treatments. It is important that patients and families feel
empowered about their treatment and it is their right to be given a balanced
view of all the information available so that they can make informed choices.
 BSPAR GUIDELINES FOR TREATMENTS 415

BSPAR guidelines for treatments used

in paediatric rheumatology
A current list of available classes of treatments is provided: readers are
directed to recommended drug formularies (M http://www.cbnf.org.uk)
for more details and current guidelines and patient information leaflets
are available on the BSPAR website (M http://www.bspar.org.uk).
• NSAIDs.
• Corticosteroids (oral, IV, IA and IM).
• Conventional DMARDs: MTX, sulphasalazine, hydroxychloroquine.
• Other immunosuppressive agents: azathioprine, ciclosporin, MMF,
cyclophosphamide.
• Other agents: pamidronate, epoprostenol.
• Biologic agents:
• Anti-TNF: etanercept, infliximab, adalimumab.
• T-cell co-stimulatory blockers: abatacept.
• IL-1 blockade: anakinra, rilanocept, canakinumab.
• IL-6 blockade: tocilizumab.
• Anti-B-cell therapy: rituximab.
• Autologous or allogeneic haemopoietic stem cell rescue—see b p 405.
416 CHAPTER 9 BSPAR clinical guidelines and protocols

Non-steroidal anti-inflammatory drugs

(NSAIDs)
• The choice of NSAIDs is based on taste, formulation, convenience of
dosing regimen, and side effect profile (Table 9.1). No Cox-2 inhibitors
are licensed for use in children.
• Slow-release preparations given in the evening may be helpful for early
morning stiffness.
• High-dose ibuprofen is helpful for symptomatic relief of pericarditis.
• Check for drug interactions before use (e.g. ACE inhibitors: i risk of
hyperkalaemia and renal damage; warfarin: effect enhanced by NSAIDs;
MTX: elimination can be reduced by NSAIDs albeit unlikely to be
relevant in clinical practice).
• Check for contraindications:
• Absolute (rare)—active or previous peptic ulceration or GI
bleeding. Severe heart failure, moderate to severe renal impairment.
• Relative—asthma, coagulation defects. Renal, cardiac, or hepatic
impairment.
• Side effects are rare but include:
• GI—nausea, abdominal pain, rarely bleeding, ulceration.
• Ibuprofen has the lowest risk. Apparent intolerance of NSAIDs
should raise concern of GI pathology (e.g. Helicobacter pylori
disease, inflammatory bowel disease).
• Central nervous system—headache, hyperactivity, dizziness, vertigo,
anxiety depression, tinnitus may occur.
• Haematological—blood disorders are rare albeit bleeding times
may be prolonged.
• Renal—may provoke renal failure, hypertension in pre-existing renal
impairment. Rarely papillary necrosis or tubulointerstitial nephritis
(later interstitial fibrosis) leading to renal impairment.
• Skin—NSAIDs may cause pseudoporphyria (photosensitive
blistering rash leaving scars—most common with naproxen and in
fair-skinned individuals.
• Other rare side effects—hepatic damage, alveolitis, pulmonary
eosinophilia, pancreatitis, eye changes, Stevens–Johnson syndrome,
toxic epidermal necrolysis.
 NSAIDs 417

Table 9.1 Dosage/administration/formulations

Drug Age Dose Formulations Comments
Ibuprofen >3 months 5–10mg/kg/ Tablet Weakest NSAID, but
dose Suspension least side effects
3–4 doses/day Syrup May be used up to
Max. total 6 doses/day in sJIA
2.4g/day only
Associated with
aseptic meningitis
in SLE
Use sugar-free syrups
where possible
Naproxen >2yr 5–7.5mg/kg/ Tablets Good efficacy.
dose Suspension Generally low
2 doses/day may be incidence of side
Max. total available as effects but associated
1g daily special order with pseudoporphyria
in JIA
Diclofenac >6 months 1.5–2.5mg/kg/ Tablets Similar actions
dose Dispersible and side effects to
2–3 doses/day tablets naproxen
Max. total Suppositories May trigger hepatic
150mg/day porphyria

Piroxicam See ‘Dose’ Dose depends Tablets More GI side effects,

on patient’s Dispersible more serious skin
weight: tabs reactions
<15kg: 5mg Also available Should not be used
16–25kg: 10mg as ‘melts’ 1st line and should
26–45kg: 15mg only be initiated
by physicians
>46kg: 20mg experienced in
One dose/day treating rheumatic
Max. total disease
20mg/day Treatment should
be reviewed after
2 weeks and
periodically thereafter
Indomethacin >1 month 0.5– 1mg/kg/ Capsules Mostly used to treat
dose (2mg/kg Suppositories enthesitis-related
under specialist Suspension arthritis and sJIA
supervision) High incidence of
2 doses/day side effects
Max. total
200mg/day
418 CHAPTER 9 BSPAR clinical guidelines and protocols

Disease-modifying anti-rheumatic drugs

(DMARDs)
Methotrexate (MTX)
MTX is the 1st-line DMARD for JIA and used in many other chronic condi-
tions (see b JIA, p 129). MTX is a folate antagonist but the mechanism of
action as a DMARD is unclear.
Pre-treatment considerations
• FBC, liver transaminase levels, serum creatinine.
• Varicella immunity status (consider also checking measles status)—see
b Varicella, p 371):
• Consider immunization before treatment starts if child is non-
immune.
• Consider testing for TB in high-risk individuals p 356.
• Important aspects of patient education:
• Patients taking MTX are immunosuppressed—effect for t3 months
after cessation.
• Live vaccines contraindicated; inactivated vaccines are safe, but may
have reduced efficacy. Annual flu vaccine and 5-yearly pneumovax
advised. See b Vaccines, p 374.
• Alcohol and MTX; no safe proven drinking limit in children. In older
patients, 5 units/week regarded as safe.
• MTX is a teratogen; pregnancy must be avoided; male patients
should not father a child. Reliable contraception advised.
• Folic acid supplementation may reduce side effects (weekly 5mg dose
3 days after MTX or 1mg/day [except MTX day]).
Contraindications
• Absolute:
• Active bacterial infection, especially active TB, active herpes-zoster
infection, acute hepatitis B or C, active life-threatening fungal infections.
• Planning (or in) pregnancy, breastfeeding.
• Relative: chronic hepatitis B or C, hepatic disease, renal disease.
Drug interactions
• Trimethoprim-containing antibiotics are avoided in practice (i risk of
toxicity).
• NSAIDs may potentiate MTX toxicity. In practice, however, rarely a
clinical problem.
Side effects
• Bone marrow suppression: rare, but potentially fatal. More likely after
the 1st year MTX.
• Hepatotoxicity: irreversible liver damage extremely rare in children.
Transient elevation of liver enzymes is common (often intercurrent
infection).
• Pulmonary fibrosis and renal toxicity: extremely rare in children.
• Nausea, vomiting, and anorexia are very common: may be helped
by ondansetron (given 1h before MTX) or dividing the weekly dose
 DMARDs 419

and giving 12h apart or administering at night or switch to SC route or

daily folic acid (except MTX dosing day). Clinical psychology may help
anticipatory nausea.
• Headaches, hair loss, mood changes. Less common.
Dosage/administration
• Usual starting dose 10–15mg/m2/once weekly SC, orally, or IV. Doses
up to 25mg/m2/dose are used but efficacy unclear and side effects
common at higher doses.
• SC route gives optimal bioavailability. IM administration not
recommended.
Monitoring
• FBC, and either aspartate (AST), or alanine (ALT) aminotransferase
levels at 2–4 monthly intervals. Serum creatinine at 6-monthly intervals.
• The recommendations from BSPAR in Table 9.2 are consensus based.
Table 9.2 BSPAR monitoring recommendations
Monitoring parameter Action
AST or ALT >3x upper limit of normal Consider omitting MTX for 1–2
reference range weeks and repeating blood test
WCC <3.0 x 109/L (or steadily falling) May necessitate dose reduction, or
rarely discontinuation. Avoid abrupt
Neutrophils <1.5 x 109/L (or steadily cessation as may result in disease
falling) flare
Lymphocytes <0.5 x 109/L (or steadily Consider other more common
falling) causes for abnormal blood test
results
Platelets <150 x 109/L (or steadily falling)
New or worsening unexplained Consider omitting MTX whilst
dyspnoea or cough investigating cause
Rising creatinine (falling creatinine Seek renal opinion
clearance)
Rash or unexplained bruising, Patient must be reviewed by medical
temperature above 38.5°C or chicken team prior to continuing with MTX
pox contact in non-immune patients

Sulphasalazine (SSZ)
The mechanism of action of SSZ is unclear. Despite a licence for use in
JIA, it is not widely used.
Pre-treatment investigations
FBC, U&Es, creatinine, LFTs.
Contraindications
Absolute
• Hypersensitivity to sulphonamides, co-trimoxazole or aspirin.
• Children <2 years, severe renal failure.
420 CHAPTER 9 BSPAR clinical guidelines and protocols

Relative
• Systemic JIA—use has been associated with macrophage activation
syndrome.
• G6PD deficiency: risk of haemolysis.
• Moderate renal impairment: crystalluria may develop—ensure high
fluid intake.
• Slow acetylators: potential risk of drug-induced lupus—withdraw SSZ if
clinically suspected (symptoms usually resolve on drug withdrawal).
• Pregnancy: assess risk:benefit ratio, folic acid supplementation should
be offered to all pregnant women taking SSZ and total dose should not
exceed 2g/day.
Side effects
Up to 20% of children experience dose-related side effects:
• GI disturbance (most common)—nausea, anorexia, dyspepsia, diarrhoea.
• Dermatological—photosensitive rash, hypersensitivity reactions, oral
ulcers.
• Haematological—neutropenia, thrombocytopenia, macrocytic anaemia,
pancytopenia.
• Drug-induced SLE, Raynaud’s, interstitial pneumonitis, fibrosing
alveolitis, hepatitis.
• Staining of soft contact lenses and orange discoloration of urine.
• Reversible oligospermia.
• Others: fever, headache, dizziness.
Dosage/administration
• 1st week: 5mg/kg twice daily
• 2nd week: 10mg/kg twice daily
• 3rd week: 20mg/kg twice daily
• Maintenance dose: 20–25mg/kg twice daily. Max. dose 2g/day (2–12yr)
or 3g/day (12–18 yr). Time to response: minimum of 3 months.
Monitoring
• Check for G6PD before starting.
• After checking FBC and LFTs monthly for 3 months the same
monitoring regime as for MTX is recommended.
Hydroxychloroquine
• Hydroxychloroquine is an anti-malarial quinolone with some immuno-
modulatory effects.
• Evidence of benefit in SLE including modifying cardiovascular risk
(see b JSLE, p 226). It is also particularly useful for skin and joint
disease, and may help reduce fatigue.
Pre-treatment considerations
• Baseline bloods including FBC, U&Es, LFTs.
• Baseline ophthalmology review (see b Monitoring, p 148).
Contraindications
Absolute
• Severe renal impairment—creatinine clearance <10mL/min/1.73m2.
• Pre existing maculopathy.
 DMARDs 421

Relative
• Mild/moderate renal impairment—reduce dose on prolonged use.
• Neurological disorders (especially a history of epilepsy).
• Liver disease—avoid concurrent use of hepatotoxic drugs.
• Severe GI disorders.
• Porphyria.
• G6PD deficiency.
• Quinine sensitivity.
• May exacerbate psoriasis and aggravate myasthenia gravis.
Drug interactions
Major
• i risk of ventricular arrhythmias with: amiodarone, moxifloxacin.
• i risk of seizures with: antiepileptics, mefloquine.
• May i plasma concentrations of: digoxin, ciclosporin.
• Avoid other antimalarials: artemether/lumefantrine.
Minor
• Inhibits the effects of: agalsidase beta (used in Fabry’s disease),
laronidase (used in mucopolysaccaridosis), neostigmine, pyridostigmine.
• Effect reduced by: kaolin, antacids.
• Plasma concentrations i by cimetidine.
Side effects
• GI disturbance- nausea, diarrhoea, anorexia, abdominal cramps.
• Headache, skin reactions—rash, pruritis. Rarely pigmentary changes,
bleaching of hair and hair loss. Visual changes.
• Other: ECG changes, convulsions, ototoxicity.
• Rarely: blood disorders, psychological disturbance, myopathy,
Steven–Johnson syndrome, acute generalized exanthematous
pustulosis, exfoliative dermatitis, photosensitivity, hepatic damage.
Dosage/administration
Child 1 month–18yr: 5–6.5mg/kg once daily. Max. dose: 400mg once daily.
Monitoring
• Blood monitoring—not routinely required.
• Assessment and monitoring of vision: the incidence of
hydroxychloroquine-induced retinopathy is very low and dependent
on the maximum dose and duration of treatment. Visual side effects
are dose related. The risk of HCQ retinal toxicity is exceedingly rare.
In the UK, the Royal College of Ophthalmologists recommend baseline
assessment of renal and liver function, inquiry about visual symptoms,
and recording of near visual acuity at each visit and measurement of
visual acuity annually. A yearly sight test including colour vision (local
optician) is recommended.
Fertility/pregnancy/breastfeeding
• Pregnancy: not necessary to withdraw antimalarial drug during
pregnancy if rheumatological disease is well controlled. However,
manufacturer advises to avoid—possibly i risk of cochlear damage.
• Breastfeeding: avoid—risk of toxicity to infant.
422 CHAPTER 9 BSPAR clinical guidelines and protocols

Mycophenolate mofetil (MMF)

MMF is a newer DMARD. It is mainly used in SLE, esp. renal. Sometimes
also used for other connective tissue diseases including scleroderma and
uveitis.
Pre-treatment consideration/testing
FBC, differential WBC, U&Es, creatinine, LFTs, ESR.
Contraindications
Absolute
• Pregnancy (avoid for 6 weeks after discontinuing).
Relative
• Breastfeeding (manufacturer advises avoid).
Drug interactions
• Absorption MMF d by antacids and cholestyramine.
• Absorption of phenytoin d by MMF.
• i risk agranulocytosis in combination with clozapine.
• i plasma concentration of acyclovir, and possibly ganciclovir.
Side effects
• GI: usually diarrhoea/vomiting, but risk of ulceration/haemorrhage/
perforation.
• Infections: viral, bacterial, and fungal all more.
• Hypertension: consider lower dose.
• Thrombocytopenia <150 Stop. Beware falling trend.
• Neutropenia <2.0 Stop. Beware falling trend.
• Oedema.
• s malignancies: both benign and malignant skin and lympho-proliferative
are reported.
Dosage
Take on empty stomach:
• Children 600mg/m2 twice daily (max 1g twice daily).
• Adults 1g twice a day.
Monitoring
FBC and U&Es weekly for 4 weeks, twice-monthly for 2 months, then
monthly.
 AZATHIOPRINE 423

Azathioprine
Azathioprine is mainly used primarily to treat patients with vasculitis or
inflammatory bowel disease. It takes approximately 2–4 months to achieve
its effect.
Pre-treatment consideration/testing
• FBC, U&Es, creatinine, LFTs, urinalysis, zoster immune status,
thiopurine methyltransferase (TPMT) activity.
• In renal or hepatic impairment dose should be reduced and frequency
of blood monitoring for toxicity i.
• Severe myelosuppression may occur due to TPMT deficiency, an enzyme
necessary in the catabolic pathway for azathioprine. Pre treatment testing
of TPMT activity identifies those with TPMT deficiency (azathioprine
contraindicated), low activity (azathioprine recommended to be started
at a lower dose and i with careful monitoring) and normal activity (full
azathioprine dose can be commenced). Myelosuppression can also
occur in individuals with normal TPMT activity and therefore ongoing
monitoring in all patients is recommended.
• Theoretical i risk of malignancy.
Contraindications
Absolute
• Hypersensitivity to azathioprine or mercaptopurine (as per BNF
contraindications).
• TPMT deficiency.
Relative
• TPMT low activity (prescribe at lower dose, see ‘Pre-treatment
considerations/testing’).
• Pregnancy.
Drug interactions
Major
• Allopurinol—enhanced effects and i toxicity of azathioprine when
given with allopurinol (reduce dose of azathioprine to 1/4 of the usual
dose).
• i haematological toxicity seen with trimethoprim and co-trimoxazole.
• Avoid concurrent use of other drugs that suppress the bone marrow.
Minor
• For a full list of drug interactions please refer to the BNFC.
Side effects
• Nausea/vomiting/diarrhoea—usually dose-related, responds to
reducing the dose. Occasional patients show an idiosyncratic reaction
with abdominal pain and severe vomiting; in these patients azathioprine
must be discontinued permanently.
• Haematological—bone marrow suppression usually dose related. Sore
throat, bruising, severe mouth ulcers or fever necessitates an urgent FBC.
424 CHAPTER 9 BSPAR clinical guidelines and protocols

Stop treatment and discuss with rheumatologist caring for the

patient if:
• White cell count <3.5 x 109/L.
• Neutrophil count <1.5 x 109/L.
• Platelet count <150 x 109/L.
• Rashes/mouth ulcers—usually mild but severe rash or mucosal
ulceration is an indication to stop treatment.
• Hair loss—this is usually insignificant and reversible on stopping.
• Liver toxicity—this is an occasional problem. If liver transaminases are
>2x levels then azathioprine should be stopped.
• Flu-like Illness—this may be s to azathioprine immune-mediated
reaction and the drug should be stopped.
Dosage/administration
• Starting dose: 1mg/kg/day (max. 50mg) taken with/after food. Total
daily dose may be given in 2 divided doses.
• Increments: 0.5–1mg/kg/day every 2–4 weeks if no side effects,
depending on clinical condition and response.
• Maximum: 3mg/kg/day (doses of >200mg/day in adults are seldom
necessary).
Monitoring
All patients on azathioprine should carry monitoring cards in which the
results of each blood test are recorded.
• FBC and LFTs should be checked fortnightly for the first 8 weeks and
for 4 weeks after an i in the dose. FBC should be checked monthly
once the dose is stable.
• LFTs should be checked 3-monthly once the dose is stable except in
hepatic impairment when LFTs should be checked monthly.
Fertility/pregnancy/breastfeeding
• There have been reports of premature birth and low birth-weight
following exposure to azathioprine, particularly in combination with
corticosteroids. Spontaneous abortion has been reported following
maternal or paternal exposure.
• Azathioprine is teratogenic in animal studies.
• Breastfeeding—teratogenic metabolite present in milk in low
concentration but no evidence of harm in small studies—consider if
potential benefit outweighs risk.
 CICLOSPORIN 425

Ciclosporin
Ciclosporin (cyclosporin) is a DMARD used occasionally in the treatment of
JIA and JDM. Its use is most limited by renal toxicity and cosmetic problems
with hirsutism.
Pre-treatment consideration/testing
• FBC and differential WCC, U&Es, creatinine, LFTs, fasting lipids
• Calculated GFR
• Urinalysis
• BP.
Contraindications
Absolute
• Renal failure
• Liver failure
• Uncontrolled hypertension
• Uncontrolled infection
• Malignancy
• Severe electrolyte imbalance
• Concomitant use of tacrolimus or rosuvastatin.
Drug interactions
There are multiple drug interactions. See b Further reading, p. 430, for
full listing.
• Always halve the dose of diclofenac if ciclosporin is co-prescribed.
• Care is also needed with other potentially nephrotoxic drugs,
e.g. aminoglycosides, amphotericin, ciprofloxacin, trimethoprim,
vancomycin.
• Ciclosporin levels can be i by erythromycin, clarithromycin,
ketoconazole, fluconazole, oral contraceptives, methylprednisolone
(high dose), hydroxychloroquine.
• Ciclosporin levels can be d by carbamazepine, phenytoin, rifampicin,
St John’s wort.
Side effects
Common
• Hypertension
• Renal dysfunction—dose-dependent rise in serum creatinine and urea
in first few weeks of therapy
• Hyperlipidaemia, hypercholesterolaemia
• Tremor, headache
• Nausea, vomiting, abdominal pain, diarrhoea, anorexia, gingival hyperplasia
• Hepatic dysfunction
• Hyperuricaemia, hyperkalaemia, hypomagnesaemia
• Paraesthesia
• Hypertrichosis
• Muscle cramps, myalgia, fatigue
• Immunosuppression and infections—viral, bacterial, fungal and parasitic.
Other less common side effects listed in BNFC but may include a possible
i risk of s neoplasia.
426 CHAPTER 9 BSPAR clinical guidelines and protocols

Dosage/administration
Switching between formulations without close monitoring may lead to
clinically important changes in blood-ciclosporin concentration. Therefore
prescribing and dispensing of ciclosporin should be by brand name to avoid
inadvertent switching. If it is necessary to switch a patient to a different
brand or formulation of ciclosporin, the patient should be monitored closely
for changes in blood-ciclosporin concentration, serum creatinine, and BP.
Dose
2–4mg/kg/day in 2 divided doses gradually i over 6 weeks according to
response, tolerance, and blood level to a maximum dose 6mg/kg daily.
If no clinical response at maximum tolerated dose for 3 months, then
withdraw treatment.
• The total daily dose is given in 2 doses 12h apart, taken with food or
drink.
• Grapefruit juice should be avoided for 1h prior to administration.
Do not mix with grapefruit juice.
• Mix the oral solution with orange/apple juice (to improve taste) or
with water immediately before administration.
• Do not administer via a nasogastric tube (interaction with plastic).
• Do not keep oral liquid in the fridge. Keep at room temperature
(15–25°C).
Monitoring
• Routine monitoring of ciclosporin levels not usually necessary once
desired level and steady state achieved unless concerns regarding
adherence to therapy.
• U&Es, creatinine—every 2 weeks until dose and trend stable, then
monthly.
• Creatinine rise >30% from baseline, or fall in calculated GFR of
>10%—withhold and discuss with specialist team.
• Potassium rises above reference range—withhold and discuss with
specialist team.
• LFTs—once a month until dose and trend stable for 3 months, then
3 monthly.
• FBC—once a month until dose and trend stable for 3 months, then
3 monthly. If platelets <150 × 109/L or abnormal bruising withhold
and discuss with specialist team.
• Fasting lipids—no clear guideline in children but suggested every
6 months.
• BP should be checked at every clinic visit. Treat BP if >95th centile
for age on 2 consecutive readings 2 weeks apart. If BP cannot be
controlled, stop ciclosporin.
Fertility/pregnancy/breastfeeding
Ciclosporin does cross the placenta but limited data available from organ
transplant recipients indicate that, compared with other immunosuppressive
agents, ciclosporin treatment imposes no i risk of adverse effects on the
course and outcome of pregnancy.
Ciclosporin is excreted in breast milk and breastfeeding should be avoided.
 INTRAVENOUS CYCLOPHOSPHAMIDE 427

Intravenous cyclophosphamide
Cytotoxic drugs such as cyclophosphamide act predominantly on rapidly
dividing cells, such as T lymphocytes, and are therefore immunosuppressive
and anti-inflammatory, as well as having anti-cancer properties. Pulse IV
cyclophosphamide may be used for the treatment of some vasculitic disor-
ders: polyarteritis, systemic lupus erythematous (SLE), dermatomyositis.
Potential adverse effects
• Includes bone marrow suppression, gastrointestinal (GI) symptoms,
haemorrhagic cystitis, and hair loss. Males may be rendered
azoospermic. Amenorrhoea and female infertility can occur with an
increase in risk with increasing age over 25 years.
• Cyclophosphamide is contraindicated in pregnancy.
• Contact with infectious diseases should be avoided as far as possible
during the period of cyclophosphamide therapy and infections should
be treated vigorously.
Dose
Cyclophosphamide IV 500–1000mg/m2 per dose (based on National Institutes
of Health (NIH) protocol, usual starting dose 500mg/m2; maximum dose
1.2g).
The NIH protocol is often used but alternative regimens exist including
the Birmingham Vasculitis protocol of which there are several modified
versions. One example is as follows:
• Dose: 15mg/kg (maximum 1g) of cyclophosphamide given by IV
bolus over 15mins every 2 weeks for 3 doses, then every 3 weeks for
3 doses, then every 4 weeks for 3 doses.
• After each dose of cyclophosphamide the patient may also receive
30mg/kg of methylprednisolone (maximum 1g) over 6hrs in their post-
hydration fluid.
• The use of Ondansetron and MESNA is the same as for the NIH
protocol.
Investigations
Each dose is preceded by a full blood count, urea & electrolytes (U&Es),
liver function tests (LFTs), and creatinine. Dosage should be reduced or
delayed if there is evidence of bone marrow suppression, particularly if
neutrophils are less than 1.5 × 109L. Bone marrow suppression is most
likely to occur 7–10 days following administration of the dose so the full
blood count should be checked at this time. Urine should be monitored
for haematuria and proteinuria throughout the treatment period.
Administration
• The dose is given with sodium 2-mercapto-ethanesulphonate (mesna)
cover (120% of cyclophosphamide dose) with IV hydration, to reduce
the incidence of haemorrhagic cystitis, and with ondansetron to reduce
nausea.
• Mesna is a sulphydryl-containing compound that is excreted
in the urine. Co-administration with alkylating agents, such as
cyclophosphamide significantly reduces their urotoxic effects by
reacting with the metabolites in the urinary system.
428 CHAPTER 9 BSPAR clinical guidelines and protocols

• For patients with a history of haemorrhagic cystitis the total mesna

dose may be increased in 20% increments up to 180%. Administration
time for the cyclophosphamide is increased, and the hydration time
may also be increased to 16–20h.
• For those patients who have an allergic reaction to mesna a revised
protocol is used: give IV cyclophosphamide over 1h. Omit mesna,
but ensure patient is adequately hydrated and increase hydration
fluids to 125mL/m2/h for 12h.
Sequence of administration
See cyclophosphamide infusion chart, Fig. 9.1.
• 15min before cyclophosphamide slow IV bolus of ondansetron 5mg/m2
(max 8mg), and
• Mesna (20% cyclophosphamide dose) IV bolus over 15min.
• Cyclophosphamide (20mg/mL concentration) given over at least 10min
via 3-way tap into hydration fluids, with the patient supine.
• Hydration with: mesna (100% cyclophosphamide dose) in 2.5%
glucose/0.45% NaCl run over 12h at 85mL/m2/h.
• Ondansetron 4mg (4–12 years) or 8mg (over 12 years) orally twice a
day for 2 days if required.
• If emesis is a problem an IV dose of dexamethasone 100microgram/kg
(maximum 4mg) may also be given.
Take care to ensure that the IV cannula is correctly sited and that saline
flushes in easily before administering cyclophosphamide. If extravasation
occurs the duty plastic surgery team is contacted.
Personal protective equipment
Personal protective equipment (PPE) is necessary when preparing, han-
dling, and administering cytotoxic drugs, to minimize the risk of accidental
contamination.

WARD
INTRAVENOUS PRESCRIPTION CHART

CHEMOTHERAPY
SURNAME FIRST HOSP D.O.B. WEIGHT: DATE: HEIGHT SURF ALLERGIES?
NAME NUMBER AGE WEIGHT: DATE: AREA

DATE
DURA- DRS NURSE
DATE IV FLUID VOLUME ADDITIVES RATE & NOTES
TION SIG UNIT
TIME

CYCLOPHOSPHAMIDE
–0:15 Ondansetron_______mg Slow IV 5mg/m2
bolus (max 8mg)

–0:15 Mesna_____________mg Slow IV Over 20% Cyclo-

bolus 15 mins phosphamide
dose
0:00 Cyclophosphamide___mg Slow IV Over Give via 3-way
bolus at least tap into hydration
10 mins fluids

0:00 Glucose 2.5%/ ml Mesna_____________mg Hydration rate =

ml/hr 12hr 2
85ml/m /hr
Sodium Chloride
(________mg per 500ml Mesna dose
0.45% bag or_________mg per =100%
1000ml bag) Cyclophosphamide
dose

Fig. 9.1 Cyclophosphamide infusion chart.

 INTRAVENOUS CYCLOPHOSPHAMIDE 429

Infection and the patient on cyclophosphamide

Patients receiving cyclophosphamide are highly vulnerable to all infections,
and the manifestations of infection may be less clinically obvious. This is
particularly important in those pa-tients with indwelling venous catheters.
Prophylaxis
Should be commenced at the start of therapy and should only be dis-
continued after discussion with the consultant paediatric rheumatologist/
nephrologist, and not within 2 months of finishing treatment:
• Bacterial: Once-daily co-trimoxazole (Septrin®). Children under
5yrs should receive 240mg od, and those over 5yrs 480mg od. Patients
unable to take co-trimoxazole may be offered once-daily azithromycin
10mg/kg (max 250mg) as an alternative.
• Fungal: Patients with JSLE and those with complex immu-nosuppression,
especially if neutropaenic (total neutrophil count <1.0) should receive
once-daily itraconazole prophy-laxis 5mg/kg/day. To protect against
Aspergillus a trough level of >0.5mg/L is needed so the level should
be checked after 1–2 weeks of treatment and the dose altered
accordingly.
• Viral: Prophylaxis against herpes viruses with acyclovir is not routinely
needed but non-immune children with complex immunosuppression,
especially if lymphopaenic (<1) may benefit. Children in contact (same
room for >15mins, or face to face contact) with varicella or measles
should be dealt with as follows:
Known immunity
No treatment but child must be fully undressed and examined by parent/
carer twice a day and if spots develop admitted to hospital. For children
who are very heavily immunosuppressed with a Varicella contact consider
giving prophylactic oral acy-clovir 10mg/kg/dose qds for 7 days (discuss
with consultant first).
Unknown/non-immune
Within 72 hrs of exposure these children may be given either of the
following:
Exposure to varicella:
• Zoster immunoglobulin (ZIG): consider IVIG if child is throm-
bocytopaenic as IM ZIG may cause excessive bruising
• <5yrs of age: 250mg
• 5–10yrs: 500mg
• >10yrs: 750mg
• Oral acyclovir 10mg/kg/dose QDS for 7 days.
Exposure to measles:
Children are infectious from 3 days before onset of rash until desquamation
(usually ~4days). Children within 6 days (most effective if within 3 days) of
contact should receive Normal Human Immunoglobulin (HI):
- Normal HI
• <1yr: 250mg IM
• 1-2yr: 500mg IM
• >2yr: 750mg IM
- Standard immunoglobulin may be used only if Normal HI not available.
Dose is 0.2mg/kg given IV.
430 CHAPTER 9 BSPAR clinical guidelines and protocols

Patients taking cyclophosphamide should have access to urgent

paediatric assessment with
- Single episode of fever >38.5C
- Two episodes of fever > 38C within 24hrs
- Close contact with infectious disease (e.g. varicella). This normally
refers to ‘kissing contacts’ such as close family members rather than
school friends, but patients are also at risk if they have been in the
same room as an infectious person for longer than 15mins. If in doubt
parents should seek advice (see b Varicella zoster infections, p 371).
- Parental/patient concern. Especially in the presence of symptoms that
may indicate infection (even without docu-mented pyrexia) such as
nausea, vomiting, diarrhoea, cough, coryza.
- Any evidence (even 1 spot) of chickenpox, zoster (shingles), or herpes
simplex (cold sore).
In all circumstances where an acute infection is suspected the patient
MUST be reviewed on the paediatric ward as soon as possible (ideally
within the hour) and the following checked
- FBC (note however that, although profoundly immunosup-pressed,
the WCC may be: normal; low due to previous cyclophosphamide; or
raised due to steroid therapy)
- ESR and CRP
- U+E, Creatinine and LFT’s
- Blood cultures
- Urine cultures.
Other investigations such as throat swabs, cough swabs, viral PCR, lumbar
puncture etc. should be done if clinically indi-cated but are not routine,
however if respiratory signs are present (e.g. hypoxia, tachypnoea) then
pneumocystis infec-tion must be considered. These patients will almost
always need admission and IV antibiotics. They must be discussed with
the consultant paediatric rheumatologist/nephrologist if admitted during
normal working hours. Antibiotic regimes may vary according to indi-
vidual circumstances but in general the following regimes are applicable in
patients with normal renal function (for patients with impaired renal func-
tion this must be discussed with the nephrologist on-call before starting
treatment):
- Central line in situ: teicoplanin 6mg/kg 12hrly for 3 doses then once-
daily and meropenem 20mg/kg tds (max 2g)
- No Central line: ceftazidime 50mg/kg tds (max. 2g) and gentamycin
5mg/kg od, or meropenem 20mg/kg tds (max 1g) and gentamycin 5mg/
kg od
- Varicella (chickenpox or shingles): IV acyclovir 500mg/m2/dose
8-hrly for at least 5 days, and then prophy-laxis with oral acyclovir
10mg/kg/dose twice a day until at least 2 months after finishing
cyclophosphamide.
Further reading
Boumpas I., Austin HA, 3rd, Vaughan EM, et al. (1993). Risk for sustained amenorrhea in patients
with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy.
Ann Intern Med 119: 366–9.
Brogan PA, and Dillon MJ (2000). The use of immunosuppressive and cytotoxic drugs in
non-malignant disease. Arch Dis Child 83: 259–64.
 PAMIDRONATE 431

Pamidronate
Pamidronate is one of bisphosphonate family of drugs. It works by inhibiting
the action of osteoclasts and thus promoting i in bone density. In children
it has a long-standing role in the treatment of children with osteogenesis
imperfecta (but has also been used to treat congenital or steroid-induced
osteoporosis, bone pain due to osteoporotic vertebral or sacral insufficiency
fractures (see b Metabolic bone disease, p 330), chronic recurrent multi-
focal osteomyelitis (CRMO), and synovitis acne pustulosis hyperostosis
osteitis syndrome (SAPHO) (see b CRMO, p 297).
Contraindications
Absolute
Patient must not be hypo-calcaemic and should be taking regular calcium
and vitamin D3 supplements.
Relative
Caution must be used in renal impairment. Patients should be well
hydrated and pamidronate should not be given if creatinine clearance is
<30mL/min/1.73m2.
Drug interactions
i risk of hypocalcaemia when given with aminoglycoside antibiotics.
Side effects
(See BNFC for full listing.)
• Hypocalcaemia—maximum effect occurs a few days post administration.
• Hypophosphataemia.
• Fever and flu-like reactions.
• Transient bone pain- this can be quite severe.
• Nausea, vomiting, headaches, arthralgias, myalgias, diarrhoea, and rash.
• Acute renal failure has been reported, especially in pre-existing renal
impairment.
Dosage and administration
• Usual dose is 1mg/kg given once a day for 3 days every 3 months.
However, because of the risk of fever and flu-like reactions the dose
on the 1st day of the first ever infusion given is often reduced to 0.5mg/kg.
All subsequent doses are 1mg/kg.
• Pamidronate is dissolved in a 250mL bag of 0.9% saline and given by IV
infusion over 2h. In patients requiring lower fluid volumes the maximum
stated concentration is 60mg/250mL for Aredia® and 90mg/250mL for
Medac® and longer infusion times may be needed accordingly.
Monitoring
• Patients with osteoporosis or osteogenesis imperfecta should all
have a DEXA scan done before starting pamidronate and yearly
whilst receiving ongoing treatment. Children with CRMO or SAPHO
syndromes do not need this checking.
• Before commencing infusion—check FBC, ESR, U&Es, LFTs, Ca, Mg, CRP.
432 CHAPTER 9 BSPAR clinical guidelines and protocols

• During infusion—monitor temperature, pulse and BP:

• At baseline.
• After 15 min, 30min, 1h, 90min, and at completion.
• Children should remain for 1h after completion of pamidronate infusion.
 EPOPROSTENOL/ILOPROST 433

Epoprostenol/iloprost
Epoprostenol (prostacyclin), and its synthetic analogue iloprost may be
used to treat severe Raynaud’s syndrome where digital infarction is likely.
Both are given by IV infusion via a syringe driver to ensure accurate and
consistent dosing (see b Overlap syndromes, p 275).
Contraindications
• Absolute: severe coronary heart disease, pulmonary veno-occlusive
disease where there is risk of haemorrhage.
• Relative: half the dose of iloprost in liver disease.
Side effects
• Hypotension
• Facial flushing
• Bradycardia
• Nausea
• Sweating
• Abdominal discomfort
• Headaches.
Dosage
Epoprostenol
Between 1–5 nanogrammes (ng) per kilogramme (kg) bodyweight per
minute (1–5ng/kg/min).
• The rate is started at 1ng/kg/min.
• i rate every 20min as tolerated up to 5ng/kg/min.
• Once the maximum rate is achieved this is continued for a further 5–7h
(depending on tolerance and patient convenience). This is given daily,
for 1–5 days. Dose of 1–20ng/kg/min (or higher) continuously for many
days have been used to treat peripheral ischaemia due to vasculitis,
under expert supervision only.
Iloprost
Between 0.5–2ng/kg/min. Start at 0.5ng/kg/min and increase as for epopros-
tenol to maximum of 2ng/kg/min. Run for 6h/day for 3–5 days.
Monitoring
Postural hypotension may be marked and patients should be nursed lying
down.
BP and pulse should be measured:
• Every 20min for the first hour.
• Every 30min thereafter until finished.
Fertility/pregnancy/breastfeeding
Toxic in animal studies during pregnancy so manufacturers advise to avoid,
no information available for breastfeeding.
434 CHAPTER 9 BSPAR clinical guidelines and protocols

Etanercept (Enbrel®)
(See b Biologics, NICE, p 399.)
Clinical/drug information summary
• Blocks the action of the pro-inflammatory cytokine TNF-A.
• Licensed for use in JIA and approved by NICE (M http://www.nice.org.uk)
for children whose disease is not well controlled by, or who are
intolerant of SC MTX. Etanercept may take between 2–12 weeks to
become effective.
Pre-treatment investigations
• Before starting etanercept the following should be checked:
• FBC, U&Es, creatinine, LFTs.
• Auto-antibody screen including baseline ANA and anti-dsDNA.
• TB screening: this may take several forms but most include a
combination from CXR, Mantoux test, and/or Quantiferon-GOLD
or similar immunological test.
• Varicella zoster immune status—as for MTX.
• Before starting etanercept the patient/carer must be informed of the
following:
• Pregnancy and breastfeeding—there is insufficient data to suggest
either are safe.
• Diet—patients are particularly susceptible to Salmonella and Listeria
food-poisoning.
• Immunizations—as for MTX.
• Tattoos and body piercing—these are strongly discouraged.
There is an i risk of soft tissue infections described in children
taking anti-TNF treatment.
• Chronic active infection or recent severe infection.
• Known/suspected TB.
• Previous history of demyelinating disease.
• Previous history of, or susceptibility to, malignancy.
Drug interactions
There are no specific drug interactions reported for this drug but combining
its use alongside other ‘biologic’ treatments is not recommended.
Side effects
• Immunosuppression—particularly soft tissue infections, and
re-activation of latent TB.
• Good skin/nail care important (ingrowing toenails can become
infected).
• Injection site inflammation is common, but usually improves with
continued use.
• Generally well tolerated. Reports of exacerbation of eczema,
headache, dizziness, rash, abdominal pain, or indigestion.
• Neutropenia.
• Demyelinating diseases—case reports but causal relationship with
etanercept is unclear.
 ETANERCEPT (ENBREL ® ) 435

• Malignancy—theoretical concern but no evidence to date in paediatric

use.
• Anecdotal reports of worsening of pre-existing uveitis, or de novo
uveitis.
Dosage and administration
• Dose: usual starting dose 0.4mg/kg given SC twice a week—may be i
up to 0.8mg/kg if necessary in refractory disease.
• Maximum dose: usually 25mg twice a week, but doses up to 50mg
twice-weekly have been used.
Formulation
There are several different formulations of etanercept available from the
manufacturer. All are injected SC.
• 25mg vial of dry powder with accompanying water for home
reconstitution.
• 25mg/50mg pre-filled syringes and 50mg auto-injector pen—not yet
licensed for children.
Monitoring
FBC, ESR, U&Es, LFTs, CRP, ANA, and anti-dsDNA should be checked
every 3 months for the first year on etanercept. Thereafter the frequency
of monitoring may be reduced to 6–12-monthly. Those who do develop
anti-dsDNA antibodies without clinical features of SLE should continue to
receive treatment but should be monitored more closely. Those developing
any features of SLE should stop taking the drug. The same response to
abnormal results/side effects as with MTX should be used.
436 CHAPTER 9 BSPAR clinical guidelines and protocols

Other anti-TNF-A: adalimumab

(Humira®) and infliximab (Remicade®)
Adalimumab is a fully humanized monoclonal antibody; infliximab is a
chimeric monoclonal antibody. Both work by binding to the receptor for
the TNF-A and thus preventing its action. Adalimumab is licensed for use in
children aged 4–17 years with JIA whose disease is not well controlled by,
or who are intolerant of SC MTX.
Infliximab is not licensed but in practice both are widely used for children
with JIA whose arthritis justifies treatment with an anti-TNF drug but for
whom the risk of a flare of their uveitis would exclude the use of etanercept.
Both may take between 2–12 weeks to become effective after commencing
treatment or a dose increase
Pre-treatment investigations/contraindication/drug
interactions
As for etanercept.
Side effects
• As for etanercept except that neither are associated with an i risk of
flares of uveitis. Indeed both are most often used to treat uveitis that
complicates JIA.
• The formation of human anti-chimeric antibodies (HACA) may prevent
long-term use of infliximab but the risk of this may be lessened if MTX
is co-administered.
• The risk of hypersensitivity reactions is greater with Infliximab.
Dosage and administration
Adalimumab
• Usual starting dose is 24mg/m2 (usually rounded to the nearest 10mg)
given SC every 14 days. Weekly treatment is sometimes used in adults.
• Maximum dose 40mg alternate weeks.
Infliximab
• Usual starting dose is 6mg/kg given IV.
• 2nd dose is usually given 2 weeks after the first. Thereafter doses may
be given at 3–8-week intervals depending on severity of symptoms and
therapeutic response. Most children require 4–6-weekly dose intervals.
• Dose range 3–10mg/kg.
• Co-treatment with MTX recommended.
Formulation
• Adalimumab—40mg pre-filled syringe.
• Infliximab—100mg dry powder for reconstitution.
Monitoring As for etanercept.
Note Pergolimumab and certolizumab are other anti-TNF treatments,
but are not yet available in the UK and are therefore not dealt with in
this chapter.
 ANTI-IL-1 TREATMENTS 437

Anti-IL-1 treatments: anakinra

(Kineret®), rilonacept (Regeneron®),
and canakinumab (Ilaris®)
Anakinra, rilonacept, and canakinumab bind to IL-1B to inhibit its activity.
None are licensed in the UK for use in children but nonetheless anak-
inra is the 1st-line therapy for children with cryopyrin-associated periodic
syndrome (CAPS) and evidence to support its use in sJIA is now very
strong and it is increasingly being used as a 1st-line therapy.
Rilonacept and cankinumab are authorized in the EU for treatment of
CAPS in adults and children t12yr but are not currently licensed in sJIA.
Pre-treatment investigations
As for etanercept.
Contraindications/drug interactions
As for etanercept except:
• No documented dietary restrictions.
• For anakinra:
• Patients with known hypersensitivity to E coli-derived proteins.
• Latex allergy—needle cover (natural rubber) may induce allergic
reactions.
Side effects
Most common is injection site reaction (redness, swelling, and pain). The
incidence of this appears to be much lower with canakinumab. Other mild
side effects reported include coryza, headache, nausea, diarrhoea, sinusitis,
arthralgia, flu-like symptoms, and abdominal pain.
All can cause serious side effects including:
• Infections—cellulitis, pneumonia (especially in asthmatics), and bone
and joint infections.
• Neutropenia.
• Hypersensitivity reactions—hypersensitivity reactions including
anaphylactic reactions, angio-oedema, urticaria, rash, and pruritis have
been reported rarely.
• Malignancies—the role of IL-1 blockers in the possible development of
malignancy is unknown.
Dosage and administration
Anakinra
• Dose: usual starting dose is 1–2mg/kg or 60mg/m2 given daily SC, max.
dose 100mg daily.
• Moderate—severe renal failure may need a lower dose or
alternate-day dosing.
• Can be used alongside MTX, but not recommended for use with other
‘biologics’.
438 CHAPTER 9 BSPAR clinical guidelines and protocols

Canakinumab
Dose is 2–4mg/kg (max.150mg) injected SC every 4 weeks. Higher doses
can be used in children with CAPS under expert supervision only.
Rilonacept
1st dose 4.4mg/kg injected SC; subsequent doses 2.2mg/kg, max. 320mg,
which is followed a week later by once-weekly injections of 2.2mg/kg
(max. 160mg).
Formulation
• Anakinra: 100mg in 0.67mL pre-filled syringes
• Canakinumab: 150mg dry powder for reconstitution with 1mL water
for injections
• Rilonacept: 80mg dry powder for reconstitution in 1mL water for
injections
Monitoring
As for etanercept.
 ABATACEPT (ORENCIA ® ) 439

Abatacept (Orencia®)
Abatacept (Orencia®) blocks the co-stimulatory pathway between T cells
and antigen-presenting cells. It is licensed for use in children with JIA over
the age of 6yr whose disease is not well controlled by, or who are intolerant
of SC MTX. It can be used as monotherapy, or in combination with MTX.
Time to respond 73 months.
Pre-treatment investigations/contraindications
As for etanercept, except demyelinating disorders not reported with
abatacept.
Drug interactions
Patients receiving both abatacept, and another biologic therapy such as
anti-TNF had a much higher risk of serious infection. Thus combination of
abatacept with other biologic agents is not recommended.
Side effects
• Most common are headache, upper respiratory tract infection, sore
throat, and nausea.
• Other side effects may include diarrhoea, cough, fever, and abdominal
pain.
• Abatacept can cause serious side effects including:
• Serious infections: pneumonia, infections caused by viruses, bacteria,
or fungi.
• Allergic reactions: can occur at the time of infusion or can be
delayed (even next day)—pre-dosing with hydrocortisone may
reduce this risk.
• Malignancies: exact relationship is unclear.
• Respiratory problems have been reported in adults with chronic
obstructive lung disease.
Dosage and administration
• Dose: usual starting dose is 10mg/kg given IV. Max. dose 1g
• 2nd dose is usually given 2 weeks after the 1st, thereafter at 4- weekly
intervals.
Monitoring
As for etanercept.
440 CHAPTER 9 BSPAR clinical guidelines and protocols

Anti-IL-6 treatment: tocilizumab

(Ro-Actemra®)
Tocilizumab is recombinant humanized anti-human IL-6 receptor mono-
clonal antibody, binds specifically to both soluble and membrane-bound
IL-6 receptors (sIL-6R and mIL-6R), and inhibits sIL-6R and mIL-6R-
mediated signalling. Used to treat severe JIA, including sJIA. In May 2011
the committee for Medicinal Products for Human Use recommended that
tocilizumab (Ro Actemra, Roche) is indicated for the treatment of active
systemic juvenile idiopathic arthritis (JIA) in patients aged 2 years and
older, who have responded inadequately to previous therapy with non-
steroidal anti-inflammatory drugs (NSAIDs) and systemic corticosteroids.
Pre-treatment investigations/contraindications/drug
interactions/monitoring
As for etanercept.
Side effects
Most common are infusion reactions and pre-dosing with hydrocortisone is
advised. Tocilizumab has also been reported to cause severe infections (pneu-
monia, varicella), deranged LFTs (ALT/AST and bilirubin) and neutropenia.
Dosage and administration
Doses usually 4-weekly but 2-weekly in sJIA has been used:
• <30kg body weight—dose: 10–12mg/kg given by IV infusion over 1h.
• >30kg body weight—dose: 8mg/kg/dose given by IV infusion over 1h.
 ANTI-B-CELL THERAPIES 441

Anti-B-cell therapies: rituximab

(Mabthera®)
(See b on anti-B cell therapy in SLE, p 241.)
Chimeric monoclonal antibody directed against B cells, binds to CD20
antigen located on pre-B and mature B lymphocytes, thus causing B-cell
lysis. Counter-intuitively, the main efficacy in autoimmune disease is
thought not to be due to reduced autoantibody production. Rituximab
spares B cell progenitors (and antibody secreting plasma cells), and B cells
reappear 4–12 months after therapy. However memory B cells can remain
suppressed for 2 years. Rituximab is licensed for use in adults with RA but
not in children. Reports of good effect in adolescents with poly-articular
JIA (RF+ve), treatment-resistant (JSLE), JDM, and some forms of vascu-
litis (particularly ANCA associated). Takes approximately 3 months to be
effective.
Pre-treatment investigations/contraindications/cautions—as
for etanercept plus:
• Check BP before, during, and after treatment.
• Pregnancy is contraindicated and recommended that breastfeeding is
avoided.
• Patients with a history of cardiovascular or renal impairment may
require dose reduction.
• Live vaccines are currently contraindicated post rituximab whilst B cells
are depleted.
• Anti-CD 19 and immunoglobulins should also be measured, see
‘Monitoring’, and in the b Anti B cell therapy in SLE, p 241.
Drug interactions
Renal toxicity has been reported in combination with cisplatin in clinical
trials.
Side effects
• Infusion reactions (fever, rigor, dyspnoea and bronchospasm, pruritis and
rashes, angio-oedema, and transient hypotension) usually present d12h.
• Pre-medication with chlorphenamine, paracetamol and
hydrocortisone may reduce the incidence of infusion reactions.
• A decline in immunoglobulin levels may make children more
susceptible to infections, especially varicella.
Dosage and administration
• Dose: 2 doses of 750mg/m2 (maximum dose 1g) given by IV infusion 2
weeks apart. Other regimens, e.g. 375mg/m2 weekly for 4 weeks have
been described.
• Dilute the required dose with sodium chloride 0.9% or glucose 5%
to a final concentration of 1–4mg/mL. The initial infusion rate is
25mg/h, which can be i by increments of 25mg/h every 30min up to
a maximum of 200mg/h as tolerated.
• In SLE each rituximab may be followed the next day by 375mg/m2 of IV
cyclophosphamide: see b Anti B cell therapy in SLE, p 241.
442 CHAPTER 9 BSPAR clinical guidelines and protocols

• In JIA concomitant use of MTX is recommended.

• Maximum dose per infusion is 1g.
• Re-treatment: conventionally re-treatment with rituximab is considered
once peripheral B-cell count is >2%. However conventional flow
cytometry may be insensitive and ‘lesional’ B cells can be present even
if peripheral B-cell count is still <2%, thus re-treatment before formal
recovery of B-cell numbers may be warranted if clinical features of
active disease return before B-cell numbers have recovered to >2%.
Monitoring
As a minimum, the following immune monitoring is recommended:
• Lymphocyte subsets requesting CD19 (or CD20 if available) On day
7–10 after infusion, then monthly from 4 months after first dose until
peripheral B cells return (repopulation may occur earlier than
4 months, particularly in SLE).
• Immunoglobulins (GAM): day 7–10; 2 months after 1st dose; then
monthly from 4 months after 1st dose until B cells return.
 SYSTEMIC CORTICOSTEROIDS (PO, IM, AND IV) 443

Systemic corticosteroids (oral,

intramuscular, and intravenous)
Systemic corticosteroid therapy is often needed at ‘induction’ or to treat
flares of disease (e.g. polyarticular JIA, sJIA, JSLE, scleroderma, JDM or
vasculitis—see b relevant chapters.
Pre-treatment consideration/testing
• Consider need for prevention and treatment of steroid-induced
osteoporosis with daily vitamin D and calcium supplementation.
Use of activated vitamin D (such as 1-alpha calcidol, or calcitriol) or
bisphosphonates to prevent corticosteroid-induced osteoporosis
cannot yet be routinely recommended, and is the subject of an ongoing
clinical trial in the UK.
• Give steroid card and advice re: chicken pox and measles.
• FBC, ESR, CRP, U&Es, creatinine, glucose, and LFTs (if not done already
as part of disease monitoring). Varicella zoster serology prior to the 1st
dose.
• Avoid live virus vaccines during, and for 3 months after, administration of
oral or IV steroids (live vaccines may be given if patients have received
IA steroids only and >6 weeks before systemic immunosuppression
(e.g. MTX) started.
Contraindications/cautions
Major
• Active peptic ulceration, acute infections.
Minor
• Diabetes, benign intracranial hypertension, previous peptic ulcer
disease, hepatic impairment.
• Reduce the dose or the rate of IV infusion in patients more at risk of
hypertension/renal crisis such as those with SLE nephritis or systemic
sclerosis patients.
• Some advise avoiding high-dose IV methylprednisolone in those
with systemic sclerosis because of the risk of renal hypertensive
crisis. This recommendation is made for adults with this disease in
particular, with little or no data to support this recommendation in
paediatric patients. If in doubt seek expert advice.
Drug interactions
Major
• NSAIDS (including aspirin)— i risk of GI bleeding. Gastroprotection
should be given, usually with a proton pump inhibitor.
• Anticoagulants—corticosteroids may enhance effect of warfarin.
• Ciclosporin—corticosteroids may i plasma levels of ciclosporin.
Minor
• The effect of antihypertensive treatments may be mitigated/negated by
corticosteroids.
444 CHAPTER 9 BSPAR clinical guidelines and protocols

Side effects
• Mild: facial flushing, metallic taste, hyperactivity, mood changes, blurred
vision, tiredness.
• Rare: hypertension (even with IV infusions) and often responds
to slowing infusion rate and only occasionally requires treatment
(e.g. nifedipine).
• Extremely rare: altered conscious state or psychosis, seizures.
Dosage/administration
Intravenous
• Usual dose is 30mg/kg/day IV methylprednisolone (max. 1000mg/day).
• Each dose is normally given over 30–60min in 30–250mL of 0.9%
sodium chloride—and usually given once per day for 3 days.
• This may need to be repeated in subsequent weeks depending on the
nature and severity of the condition being treated.
• Oral steroids are stopped on days that methylprednisolone is given,
and restarted with a weaning regimen appropriate for the individual
and disease being treated.
Intra-muscular
• Usual dose is 1mg/kg, max. 80mg, of triamcinolone acetonide
(Kenolog®).
• Must be given by deep IM injection to the gluteal muscles to try and
avoid causing SC atrophy.
• In larger doses, consider splitting the dose and giving half the dose to
each buttock.
• Pain of administration limits use in children but often tolerated well by
older adolescents.
Oral
• The starting dose is entirely dependent on the disease (and its severity)
being treated, but usually is in the range of 1–2mg/kg/day.
• Aim to wean as quickly as possible thereafter (dependent on clinical
response and toxicity in individual patients).
Monitoring
• Urinalysis for glycosuria prior to 1st dose. If patient is known to have
diabetes, hyperglycaemia should be expected, insulin requirements
will rise and can be unpredictable; blood glucose (BM stix) must be
monitored regularly.
• For IV route only: temperature, pulse, respiratory rate (RR),
BP—before, during and after infusion. If the patient feels unwell, check
TPR, BP, and blood glucose; consider slowing rate of infusion.
 INTRA-ARTICULAR CORTICOSTEROID USE IN JIA 445

Intra-articular corticosteroid use in JIA

(See b JIA, p 129 and b Corticosteroid intra-articular injections, p 390.)
• IA corticosteroid injections:
• Result in minimal systemic steroid absorption.
• Are the treatment of choice for oligo-articular JIA.
• Act as useful bridging agents whilst starting MTX.
• Minimize exposure to systemic corticosteroids.
• Efficacy is good: often t6 months of complete remission in the injected
joint.
• Re-injection d6months is advised if synovitis recurs.
• If recurrent swelling despite 2 injections within 6 months then the
diagnosis and treatment should be reviewed.
Dosage
Triamcinolone hexacetonide
• 1mg/kg/joint for large joints (knees, ankles, elbows, shoulders). Usual
max. 40mg/joint—larger doses may be used in older patients with
resistant disease albeit expert opinion is advised.
• 0.5mg/kg/joint for medium joints (hips, sub-talars, wrists, and TMJs).
• 0.2–2mg/joint for digits.
Triamcinolone acetonide
The dose is double that of triamcinolone hexacetonide, but systemic
absorption is greater.
General notes:
• In young children, or if multiple joints are to be injected, general
anaesthesia is needed.
• Children older than 6–8yr may be able to use Entonox® as adequate
analgesia. Older teenagers may be able to use local anaesthesia such
as EMLA® cream.
• Aseptic technique must be observed at all times. Correct needle
placement should reduce risk of SC atrophy and injection of
corticosteroid into the cartilage that can cause growth disturbance.
X-ray or US imaging may aid accuracy, and is strongly recommended
in deep joints such as hips, and in small joints such as fingers.
• Joint injection followed by casting may help to reduce contractures if
combined with intensive physiotherapy.
Side effects
• Septic arthritis is a potential risk but with good technique,
rarely observed.
• Facial flushing and Cushingoid appearance are transient. Cushing
syndrome and adreno-suppression are very rare.
• Peri-articular calcification may occur (d5% of injections).
• Diabetic patients may notice i insulin requirements transiently after
injections.
446 CHAPTER 9 BSPAR clinical guidelines and protocols

• SC atrophy can occur, mainly smaller joints; skin changes may fade but
unlikely to resolve completely.
• Chemical synovitis may cause i pain and swelling 12–24h post injection
(albeit rarely observed in practice).
• Post-injection pain is uncommon; simple analgesia (with paracetamol)
usually suffices. Post-injection rest is impossible to achieve and should
not be enforced.
 Chapter 10 447

Rashes in paediatric
rheumatology

Systemic JIA 448

Palmar psoriasis in a patient with psoriatic JIA 448
Nail pits and psoriasis in a patient with psoriatic JIA 449
Psoriatic JIA (elbows) 449
Psoriatic JIA (hands) 450
HSP with bilateral ankle swelling 450
Juvenile dermatomyositis with periorbital oedema 451
Severe juvenile dermatomyositis with anterior chest wall
vasculitis—‘shawl sign’ 451
Extensor surface vasculitis in juvenile dermatomyositis 452
Subtle Gottron’s papules in a patient with severe juvenile
dermatomyositis 452
Periungual erythema in undifferentiated connective tissue
disease 453
Systemic vasculitis with pyrexia, livido reticularis, vasculitic rash
with skin necrosis 453
Maculo-papular rash of Epstein–Barr virus associated with
haemophagocytic lymphohistiocytosis (HLH) 454
Erythema nodosum 454
Generalized peeling in Kawasaki disease 455
Purpura in Wegener’s granulomatosis 455
SLE associated with congenital C1q deficiency 456
448 CHAPTER 10 Rashes in paediatric rheumatology

Fig. 10.1 (Also see Plate 4.) Systemic JIA. Note the rash occurring in linear streaks
and exhibiting Koebner phenomenon.

Fig. 10.2 (Also see Plate 5.) Palmar psoriasis in a patient with psoriatic JIA.
 PSORIATIC JIA (ELBOWS) 449

Fig. 10.3 (Also see Plate 6.) Nail pits and psoriasis in a patient with
psoriatic JIA.

Fig. 10.4 (Also see Plate 7.) Psoriatic JIA (elbows).

450 CHAPTER 10 Rashes in paediatric rheumatology

Fig. 10.5 (Also see Plate 8.) Psoriatic JIA (hands).

Fig. 10.6 (Also see Plate 9.) HSP with bilateral ankle swelling.
 SEVERE JDM 451

Fig. 10.7 (Also see Plate 10.) Juvenile dermatomyositis with periorbital oedema.

Fig. 10.8 (Also see Plate 11.) Severe juvenile dermatomyositis with anterior chest
wall vasculitis—‘shawl sign’.
452 CHAPTER 10 Rashes in paediatric rheumatology

Fig. 10.9 (Also see Plate 12.) Extensor surface vasculitis in juvenile
dermatomyositis.

Fig. 10.10 (Also see Plate 13.) Subtle Gottron’s papules in a patient with severe
juvenile dermatomyositis.
 SYSTEMIC VASCULITIS 453

Fig. 10.11 (Also see Plate 14.) Periungual erythema in undifferentiated

connective tissue disease.

Fig. 10.12 (Also see Plate 15.) Systemic vasculitis with pyrexia, livido reticularis,
vasculitic rash with skin necrosis.
454 CHAPTER 10 Rashes in paediatric rheumatology

Fig. 10.13 (Also see Plate 16.) Maculo-papular rash of Epstein–Barr virus
associated with haemophagocytic lymphohistiocytosis (HLH).

Fig. 10.14 (Also see Plate 17.) Erythema nodosum.

 PURPURA FULMINANS IN WG 455

Fig. 10.15 (Also see Plate 18.) Generalized peeling in Kawasaki disease.

Fig. 10.16 (Also see Plate 19.) Purpura in Wegener’s granulomatosis.

456 CHAPTER 10 Rashes in paediatric rheumatology

Fig. 10.17 (Also see Plate 20.) SLE associated with congenital C1q deficiency.
 457

Index

anorexia nervosa 331 anti-Ro 34

A antalgic gait 14 anti-SCL-70 34
abatacept 393–4, 439 anterior knee pain anti-Smith 34
abscess 96 117, 383 anti-TNF-α 71, 73, 153
Achilles tendonitis 122 anti-B-cell therapy 234, 241, APECED syndrome 310
achondroplasia 336 242–3, 247, 441 arterial tortuosity
acromelic shortening 333 anti-C1q antibodies 33 syndrome 349
acute lymphoblastic anti-CCP antibodies 33 arthritis
leukaemia 59, 56–7 anti-CD20 agents, infection ankle and foot 123
acute rheumatic fever 363 risk 71, 73 osteoporosis 330
antibiotic therapy 365 anti-centromere 34 peripheral in inflammatory
arthritis/arthralgia 363, 365 anti-cyclic citrullinated bowel disease 327
carditis 366 protein (anti-CCP) persistent chronic
chorea 366 antibodies 33 inflammatory in cystic
clinical features 364 anti-ds-DNA antibodies 33 fibrosis 324
differentiating from post- anti-histone 34 rheumatic fever 363, 365
streptococcal reactive anti-IL-1 treatments 437 transient recurrent in
arthritis 366 infection risk 71, 73 cystic fibrosis 323
epidemiology 364 anti-IL-6 treatment 440 arthropathy of inflammatory
heart failure 366 infection risk 71, 73 bowel disease 326
investigations 365 anti-La 34 ASP-1 310
management 365 anti-LKM 34 association study 134
modified Jones criteria anti-neutrophil cytoplasmic atacicept 242
364–5 antibodies (ANCA) ataxic gait 14
pathogenesis 363 32; see also ANCA- autoantibodies 32, 34
prevention 366 associated vasculitis autoimmune hepatitis 277
pyrexia of unknown antinuclear antibodies autoimmune
origin 97 (ANA) 32 lymphoproliferative
valve surgery 366 antiphospholipid syndrome (ALPS) 310
adalimumab 393–4, antibodies 33 autoimmune
399–400, 436 antiphospholipid syndrome polyendocrinopathy,
adolescent healthcare 387 279 candidiasis, ectodermal
allele 134 cardiac manifestations 280 dystrophy (APECED)
allodynia 88 catastrophic 282 syndrome 310
allogeneic haematopoietic classification criteria 279 autoimmune
stem cell transplantation clinical features 280 polyendocrinopathy
407 clotting screen 281 type 1 310
allopurinol 423 CNS involvement 280 autoinflammatory disease
American College of dilute Russell viper venom 288–9
Rheumatology (ACR) test 281 autologous stem cell
classification of JIA 139 gastrointestinal transplant 235, 405–6
Core Outcome manifestations 280 autonomic dysfunction 88
Variables 41 haematological disorders avascular necrosis
revised classification 280 112, 332
criteria for SLE 226–7 juvenile SLE 234, 279 azathioprine 175, 234, 423
amyloidosis 154 laboratory investigations
anakinra 394, 437 281
ANCA-associated vasculitis outcome 282 B
188, 190 pathogenesis 279 back pain 58, 89, 100, 383
definitions 188 perinatal 280 Bath Adolescent Pain
investigations 189 pulmonary involvement Questionnaire 88
outcome 191 280 Bath Adolescent Pain
pathogenesis 188 renal manifestations 280 Questionnaire for
treatment 174, 178, 191 skin manifestations 280 Parent 88
ankle treatment 281 B-cell targeted therapy
common problems 121 vascular thrombosis 280 234, 241, 242–3,
corticosteroid injections warfarin therapy 281 247, 441
391 anti-RNP 34
458 INDEX

Behçet’s disease 205 treatment guidelines chronic fatigue 383

clinical features 205 for paediatric chronic granulomatous
cutaneous lesions 205 rheumatology 415 disease 310
diagnostic criteria 205 brucellosis 96 chronic infantile neurologic
eye involvement bruises 55 cutaneous and articular
205, 285 Bulbena scoring system 125 syndrome (CINCA) 98,
gastrointestinal bursitis 386 285, 294
involvement 206 chronic recurrent multifocal
investigations 206 osteomyelitis 297–9
neurological involvement C Churg–Strauss syndrome
206 Caffey’s disease 54 188–9
pathergy 205 Campylobacter 96 ciclosporin 175, 425
pathophysiology 205 canakinumab 394, 437 CINCA 98, 285, 294
prognosis 207 cANCA 32 circumduction gait 14
skin pathergy test 206 candidate gene 134 clinical assessment 4
thalidomide therapy 207 capsules 404 clinical nurse specialist
treatment 178, 206–7 cartilage–hair hypoplasia 380, 412
vascular features 206 340 clubfoot 122
Beighton scoring system 124 CASADIL 213 Cobb angle 104–5
belimumab 242 case–control design 134 Cogan’s syndrome 216
benign bone tumours 62 Castleman’s disease 98 combined
benign joint hypermobility catastrophic APS 282 immunodeficiencies 309
syndrome 3, 124 cat scratch disease 96 complex regional pain
berylliosis 302 causal variant 134 syndrome 3, 89–90, 383
BILAG index 42, 248–9 central nervous system congenital contractural
biologic therapy 393–4 vasculitis 209 arachnodactyly 349
assessment checklist arteriography 212 congenital convex pes
prior to commencing brain biopsy 212 valgus 122
therapy 396 clinical features 209 congenital talipes
biosimilars 403 diagnostic criteria 209 equinovarus 122
infection risk 71, 73 differential diagnosis 211 congenital vertical
JIA 399–400 epidemiology 209 talus 122
juvenile SLE 234 imaging studies 211 connective tissue disease-
NICE guidance 393, investigations 211 associated
399–400 mimics of 213 vasculitis 215
perioperative 153 outcome 212 corticosteroids
prescribing issues 413–14 secondary 210 infection risk 70
vasculitis 174, 178 treatment 212 intra-articular injections
Blau syndrome 284, 291, two forms 209 390, 445
296, 300 cerebral palsy 331 osteoporotic side-effects
BLISS-52 243 Chediak–Higashi syndrome 330, 402
BLISS-76 244 310 perioperative dose
Blount disease 344 chemotherapy-associated adjustment 153
bone densitometry 332 osteoporosis 331 prescribing issues 413
bone infections 64–6, 68, 82 chilblains 54 systemic 443
bone tumours 60–3 Child Activity Limitations crescentic
Bonferroni correction 134 Interview (CALI) 43 glomerulonephritis 177
Borrelia burgdorferi 368 Child Health Questionnaire Crohn’s disease 326
bow legs 10 (CHQ) 43 cryopyrin associated
Boyd equation 402 Childhood Health periodic syndrome
brachyolmia 338 Assessment (CAPS) 290, 294
British Isles Lupus Questionnaire (CHAQ) curly toes 9
Assessment Group 42, 45–6 Cushing’s syndrome 331
(BILAG) index 42, 248–9 Childhood Myositis cutaneous polyarteritis
British Society of Paediatric Assessment Scale nodosa 198
and Adolescent (CMAS) 42, 267, 269 cyclophosphamide 174–5,
Rheumatology (BSPAR) chondromalacia patellae 234, 403
drug information 117 cystic fibrosis 320,
leaflets 412 chondrosarcoma 60 323, 330
methotrexate monitoring chromosomal abnormalities cytomegalovirus (CMV) 96
recommendations 419 318–19, 321 cytoplasmic anti-neutrophil
standards of care in JIA chronic beryllium disease cytoplasmic antibodies
146, 410 302 (cANCA) 32
 INDEX 459

treatment pathway juvenile dermatomyositis

D 161, 164 386
damage measures 42 uveitis 284 juvenile idiopathic arthritis
DAS28 165 uveitis screening 149 385
deficiency of the IL-1 enzyme replacement footwear 386
receptor antagonist therapy 313 formulation of medicines
(DIRA) 291, 295 epidemiology 2; see also 404
Degos disease 54, 220 specific conditions fractures 55, 77–80
dermatoscope 38 epidermolysis bullosa 331 Freiberg’s disease 123, 344
Devic’s disease 213 epoprostenol 433 Functional Status II(R) 43
DEXA 332 epratuzumab 242
diastrophic dysplasia 339 Epstein-Barr virus (EBV) 96
diclofenac 417 EQ5D, 43 G
diffuse idiopathic equinus gait 14 gait
musculoskeletal pain 88 erythema chronicum abnormal patterns 11,
DiGeorge syndrome 319 migrans 368 13–14
dilute Russell viper venom erythema nodosum normal gait development
test 281 362, 454 15–16
disc degeneration 102 etanercept 393–4, 399–400, pain 386
disc prolapse 102 434 gait cycle 11
Disease Activity Score EULAR classification of JIA galsulfase 313
(DAS28) 165 139 genome wide association
disease activity scores EuroQoL 43 study 135
165–6 Ewing’s sarcoma 60–1 genotype 135
disease-modifying anti- EXPLORER 241, 243 gonococcal arthritis 67
rheumatic drugs extractable nuclear antigens Gottron’s papules 452
(DMARDs) 418–19 (ENAs) 34 Grange syndrome 220
infection risk 70 eye grey scale 29
juvenile SLE 233 anatomy 283 Griscelli syndrome 310
prescribing issues 413–14 Behçet’s disease 205, 285 growing pains 66, 92–3
see also specific drugs paediatric uveitis 283–5,
dispersible tablets 404 287
dose calculations 402
Down’s syndrome 153, 319
pseudoxanthoma
elasticum 222
H
drug-induced fever 98 sarcoidosis 302 haemarthrosis 118, 120
drug-induced lupus 362 Takayasu arteritis 201 haematopoietic stem cell
drug-induced vasculitis 214 uveitis screening in JIA transplantation
drug information leaflets 148, 150 313, 405
412 Wegener’s haemophagocytic
Duchenne muscular granulomatosis 189 lymphohistiocytosis 306,
dystrophy 331 310, 454
Dutch fever 294 haplotype 135
dyschondrosteosis 336 F Hardy–Weinberg
equilibrium 135
Faces Pain Scale 88 health status measures 43
factitious illness 98
E familial cold
Henoch-Schönlein
purpura 179
ectopia lentis syndrome 349 autoinflammatory classification criteria
education in pain syndrome 294 170, 179
management 89 familial Mediterranean fever dermatological
effervescent products 404 (FMF) 289, 292 involvement 180
Ehlers–Danlos familial thoracic aortic epidemiology 171, 179
syndromes 220, 349–51 aneurysm syndrome 349 gastrointestinal
18p syndrome 320 fat pad impingement involvement 180
elbow, corticosteroid syndrome 119–20 immunopathology 179
injections 392 femoral head avascular rash 450
Enbrel®, see etanercept necrosis 112, 332 renal involvement
endocarditis 96 fibromuscular dysplasia 217 180–2
endocrine disturbance 331 fibromyalgia 88 rheumatological
enthesitis-related arthritis finger joints, corticosteroid involvement 180
clinical presentation 145 injections 392 suspected non-accidental
foot changes 386 flat feet 9, 121 injury 54
ILAR classification 140 foot treatment 181
management 157 common problems 121 hepatitis 96, 277
460 INDEX

hereditary connective tissue ILAR classification of International League

disease 346, 348–9, JIA 139–40 of Associations for
351, 354 Ilaris®, see canakinumab Rheumatology (ILAR),
hereditary periodic fever iliotibial band problems classification of JIA
syndromes 288–9, 292 119 139–40
Hermansky–Pudlak iloprost 278, 433 intoeing 122
syndrome 310 immunization 71, 374–6 intra-articular corticosteroid
HHV6 96 immunodysregulation, injections 390, 445
high arches 121 polyendocrinopathy, IPEX syndrome 310
hip enteropathy, X-linked isolated cutaneous
corticosteroid injections (IPEX) syndrome 310 leucocytoclastic
392 immunoglobulins 403 vasculitis 215
developmental dysplasia immunosuppression Ixodes tick 368
108 immunization 71, 374–6
musculoskeletal infections 70, 72–3,
ultrasound 30 76, 93 J
pain and problems 106, pyrexia of unknown joint hypermobility 124
108, 111–12 origin 94 Beighton scoring system
history taking 4, 6, 8 tuberculosis 358, 361 124
HIV 96 varicella zoster infections benign joint hypermobility
Hodgkin lymphoma 57 371, 373 syndrome 3, 124
homocystinuria 349 indeterminate colitis 326 Bulbena scoring system
Humira®, see adalimumab individualized transition 125
Hunter syndrome 314 plans 388 chronic pain 88
Hurler/Scheie syndrome indomethacin 417 clinical presentation 125
314 infantile cortical definition 124
Hurler syndrome 314 hyperostosis 54 differential diagnosis 126
hydroxychloroquine 233, infection epidemiology 3, 125
420 bone and joints 64–6, examination 126
hygiene hypothesis 138 68, 82 family history 126
hyperimmunoglobulin D hip problems 112 information for patients
periodic fever syndrome immunocompromised 70, 127
(HIDS) 289, 294 72–3, 76, 93 management 126
hypermobility, see joint juvenile idiopathic arthritis past history 126
hypermobility 138 pathophysiology 125
hypersensitivity 88 macrophage activation physiotherapy 383
hypersensitivity vasculitis syndrome 305 symptoms 125
214 paediatric uveitis 284 joint infections 64–6,
hypertrophic pyrexia of unknown 68, 82
osteoarthropathy 324 origin 96–7 joint pain, differential
hypochondroplasia 336 vasculitis 214 diagnosis 5
hypocomplementaemic inflammation Juvenile Arthritis Damage
urticarial vasculitis knee pain 119 Index (JADI) 42
syndrome 215 persistent joint pain Juvenile Arthritis Disease
following 89 Activity Score
inflammatory bowel disease (JADAS-27) 41, 165
I 98, 284, 326–7, 330 Juvenile Arthritis Functional
ibuprofen 417 inflammatory Assessment Report
I cell mucolipidosis 315 musculoskeletal (JAFAR) 43
idiopathic crescentic conditions Juvenile Arthritis Functional
vasculitis, see renal differentiating from Assessment Scale
limited vasculitis mechanical (JAFAS) 42
idiopathic juvenile presentations 8 Juvenile Arthritis
osteoporosis 330 epidemiology 2 Functionality Scale
idiopathic nocturnal leg infliximab 393, 395, 436 (JAFS) 43
pain 127 inherited connective tissue Juvenile Arthritis Quality
idiopathic uveitis 284 disease 346, 348–9, of Life Questionnaire
idursulfase 313 351, 354 (JAQQ) 43
IL-1 antagonists 437 inherited periodic fever juvenile chronic
infection risk 71, 73 syndromes 288–9, arthritis 139
IL-6 antagonists 440 292 juvenile dermatomyositis
infection risk 71, 73 interferon-γ release assays 266
358 clinical features 266
 INDEX 461

diagnostic criteria 266, 273 infectious trigger 138 environmental factors

epidemiology 3, 266 inflammatory mediators 224–5
extramuscular disease 138 epidemiology 3, 223
monitoring 268 intra-articular genetic factors 224–5
foot changes 386 corticosteroid hydroxychloroquine
Gottron’s papules 452 injections 445 therapy 233
imaging 268, 274 investigation 15, 17 immune dysfunction 224
monitoring 267 leg-length discrepancy 386 investigations 230
muscle biopsy 266, 273 multidisciplinary team management 232–3
muscle disease assessment management 155–6 monitoring 229
267, 269, 272 musculoskeletal multisystem presentation
nailfold capillaroscopy 37 ultrasound 6, 28–30 226
periorbital oedema 451 NICE guidelines for mycophenolate mofetil
physiotherapy 382 biologic therapy therapy 234
pyrexia of unknown 399–400 physiotherapy 382
origin 98 non-HLA/MHC loci plasma exchange 235
shawl sign 451 130, 133 premature atherosclerosis
skin disease assessment occupational therapy 155 232
267 pathogenesis 137–8 renal involvement 236–7,
treatment 268 physiotherapy 155, 382 239
vasculitis 451–2 pregnancy 154 rituximab therapy 234,
juvenile fibromyalgia 88 prognostic indicators 241, 245–7
juvenile idiopathic arthritis 146–7 severe refractory lupus
(JIA) 129 sub-group specific therapy 235
access to care 146 associations 130 SLEDAI 2000 Disease
ACR classification 139 surgery 152 Activity Index 256
adalimumab therapy temporomandibular joint SLICC/ACR Damage
399–400 disease 153 Index (paediatric)
aetiology 137 treatment approaches 258
arthroplasty 152 155–7 UK JSLE Cohort Study &
association studies 130–1 treatment pathways Repository 233
autologous T-cell depleted 159–164 juvenile rheumatoid
haematopoietic stem uveitis 284–5 arthritis 139
cell transplantation uveitis screening 148, 150 juvenile scleroderma,
405–6 juvenile kyphosis 101 see scleroderma
biologic therapy 399–400 juvenile-onset systemic juvenile systemic
BSPAR standards of care lupus erythematosus sclerosis 260–1, 263–4
146, 410 (JSLE)
bursitis 386 ACR revised classification
classification 139–40 criteria 226–7 K
clinical presentation aetiology 223–5 Kawasaki disease 183
141–2 antiphospholipid BCG inoculation site
cytokines 138 syndrome 234, 279 183
diet 155 assessment 229 cardiovascular
disease activity scores autoimmune hepatitis 277 involvement 183
165–6 autologous stem cell clinical features 183
environmental factors 138 transplant 235 coronary arteriography
epidemiology 2 azathioprine therapy 234 185
etanerecept therapy B-cell-targeted therapies differential diagnosis
399–400 234, 241–3, 247 184
ethnicity 2 BILAG index 248–9 epidemiology 171, 183
EULAR classification 139 clinical presentation 226 investigations 184
family conditions 138 comparison with adult- outcome 186
foot changes 385 onset disease 223 pathogenesis 183
genetics 130–1, 133, 137 congenital C1q peeling 455
genome wide association deficiency 456 pyrexia of unknown
studies 130, 135 corticosteroid origin 94, 97
human leucocyte therapy 233 treatment 185, 187
association (HLA) cyclophosphamide uveitis 285
130, 137 therapy 234 Keinboch disease 344
hygiene hypothesis 138 diagnosis 226–7 Kikuchi disease 98
ILAR classification 139–40 disease-modifying Kineret®, see anakinra
immunology 137 drugs 233 Klein’s line 115
462 INDEX

knee musculoskeletal multiple epiphyseal

corticosteroid injections presentations 56–7, dysplasia 339
391 59, 83 multiple sclerosis 285
knock knees 10 pyrexia of unknown musculoskeletal
musculoskeletal origin 97 development 15–16
ultrasound 29 vasculitis 215 musculoskeletal
pain 117, 120, 383 malignant bone tumours disequilibrium 88
Kniest dysplasia 338 60–1 musculoskeletal pain,
knock knees 10 Mantoux test 303, 358 differential diagnosis 5
Kocher’s clinical prediction Manual Muscle Test musculoskeletal
rule 66, 84 (MMT8) 267, 272 ultrasound 6, 28–30
Kohler’s disease 123, 344 Marfan syndrome 218–19, mycobacterial disease 361,
Kveim–Siltzbach test 302 346, 348–9 356–7
Marotaux-Lamy syndrome mycophenolate mofetil 175,
315 234, 422
L Marshall’s syndrome 296
laronidase 313 mastoiditis 96
latent TB infection 356–7 McCune–Albright N
reactivation 358, 361 syndrome 331 nailfold capillaroscopy 37,
leaky mutations 309 Mebthera®, see rituximab 39–40
Legg–Calve–Perthes disease therapy naproxen 417
111, 344 mechanical knee pain neglect 55
leg-length discrepancy 386 117, 120 neonatal lupus syndrome
leptospirosis 97 mechanical presentations, 240
leucocytoclasis 215 differentiating from neonatal onset multisystem
leukaemia 56–7, 59, inflammatory 8 inflammatory
97, 331 medicines disease 294
limping child 81–3, 85–6 drug information leaflets neuroblastoma 58, 97
linkage analysis 135 412 neurofibromatosis 320
linkage disequilibrium 135 prescribing issues 401, neuromuscular
livedoid vasculopathy 221 404, 413–14 assessment 13
livedo reticularis 192 mesomelic shortening 333 neuromyelitis optica 213
localized scleroderma meta-analysis 135 neurosarcoid 302
260–2 metabolic bone disease NF2 gene 321
Loeys–Dietz syndrome 219, 325, 330 NICE guidance, biologic
349 metaphyseal dysplasia, therapies 393, 399–400
loose body 118, 120 Schmid type 340 nitroblue tetrazolium test
lower limb development, metatarsus adductus 121 303
normal variants 9 methotrexate therapy 153, NOMID 294
LUNAR 241, 243 175, 403, 413, 418–19 non-accidental injury 54, 83
lupus nephritis 236–7, 239 mevalonate kinase non-bacterial osteitis 298
Lyme disease 97, 368–70 deficiency (HIDS) non-Hodgkin lymphoma 57
lymph node biopsy 58 289, 294 non-inflammatory
lymphoma 57, 97 mevalonic aciduria 294 musculoskeletal
lymphoproliferative micromelic shortening 333 conditions
syndromes 310 microscopic polyangiitis epidemiology 3
188–9 physiotherapy 383
miliary disease 359 non-inflammatory
M minor allele frequency 135
mixed connective tissue
vasculopathies 217, 219
macrophage activation non-rhabdomyosarcomas
disease 275–6 62–3
syndrome (MAS) 305 modified Jones criteria
clinical features 306, 308 non-steroidal anti-
364–5 inflammatory drugs
diagnosis 305–6 Morquio syndrome 314
haematological features (NSAIDs) 413, 416–17
Mosteller equation 402 nuclear dust 215
307 Moyamoya disease 213
infective triggers 305 MPO-ANCA 32
management 307
pathophysiology 305
Muckle-Wells syndrome O
294
rheumatological diseases mucolipidoses 312, 314, 317 occupational therapy
complicated by 305 mucopolysaccharidoses 155, 384
malaria 97 312, 314, 317 ocrelizumab 242
malignancy multidisciplinary team odds ratio 135
hip problems 108, 111–12 155–6, 378–9 oligoarthritis
 INDEX 463

clinical presentation 143 periodic fever, aphthous Pott’s disease 359

ILAR classification 140 stomatitis, pharyngitis and power calculation 136
management 157 adenitis (PFAPA) 296 power Doppler 29
treatment pathway 160–1 periodic fever syndromes PR3-ANCA 32
opportunistic infection 98, 288–9 pregnancy, JIA 154
71–2, 93 Perthes’ disease 111 pREMS 23–4
oral liquids 404 pes cavus 9, 121 prescribing issues 401, 404,
Orencia®, see abatacept pes planus 385 413–14
orthoses 385 pGALS 18–22 primary angiitis of the CNS
Osgood–Schlatter’s pharmacokinetics 401 209
disease 117, 120, 344 physical examination 4 clinical features 209
osteochondritis dissecans physical function measures diagnostic criteria 209
118, 120, 343–4 42–3 epidemiology 209
osteochondroses 123, 343–4 physical therapy, pain imaging studies 211
osteogenesis imperfecta management 89 investigations 211
330, 341, 350, 354 physiotherapy 155, 382 outcome 212
osteomalacia 331 PID syndromes 309 primary immunodeficiency
osteomyelitis 64–5 piroxicam 417 disorders 309, 311
chronic recurrent plantar fasciitis 123 primary musculoskeletal TB
multifocal 297–9 plasma exchange 235 358, 361
common pathogens 68, 82 plica syndrome 118, 120 primary osteoporosis 330
hip problems 108, 111 podiatrist 385 progressive
musculoskeletal TB 359 polyarteritis nodosa 192 pseudorheumatoid
pyrexia of unknown aetiology 192 arthropathy of
origin 96 arteriography 194–5 childhood 337
types of 65 classification criteria progressive systemic
osteonecrosis 112 170, 192 sclerosis 37
osteopetrosis 332, 341 clinical features 192 pronated foot 385
osteoporosis 153, 330 cutaneous 198 pseudoachondroplasia 336
osteosarcoma 60–1 differential diagnosis 193 pseudo-Hurler
outcome measures 41 echocardiography 195 polydystrophy 315
out-toeing 10 epidemiology 192 pseudoxanthoma elasticum
overlap syndromes 275 gastrointestinal 222
involvement 193 psoriatic arthritis
investigations 193 clinical presentation 144
P livedo reticularis 192 ILAR classification 140
Paediatric Quality of Life magnetic resonance management 157
Inventory (PedsQoL) 43 angiography 194 rash 448–50
paediatric uveitis 283–5, 287 neurological involvement treatment pathway 161
Paediatric Vasculitis Activity 193 psychological therapy, pain
Score (PVAS) 42 outcome 196 management 89–90
Paediatric Vasculitis Damage renal involvement 193 pulmonary capillaritis 191
Index (pVDI) 42 skin lesions 192 pulmonary-renal
pain 87 tissue biopsy 194–5 syndrome 191
assessment 87 treatment 178, 196 purpura fulminans 455
assessment tools 88 polyarthritis management pyogenic sterile arthritis,
chronic pain conditions 88 157 pyoderma gangrenosum
differential diagnosis of polyarthritis (RF-ve) and acne (PAPA)
musculoskeletal pain 5 clinical presentation 144 syndrome 291, 295
gait changes 386 ILAR classification 140 pyrexia of unknown origin
management 89 treatment pathway 161 94, 96
psychologist’s role 89–90 polyarthritis (RF+ve)
pamidronate 427 clinical presentation 143
pANCA 32 ILAR classification 140 Q
Panner disease 344 treatment pathway 162 quality of life measures 43
panniculitis 54 uveitis screening 149
patella dislocation 117, 120 polyostotic fibrous
patellofemoral pain 117, 120 dysplasia 331 R
pathergy 205 Poncet’s disease 362
population stratification rashes 447–56
peg-leg gait 14 Rasmussen syndrome 213
perinuclear anti-neutrophil 135
post-streptococcal reactive Raynaud’s phenomenon
cytoplasmic antibodies 37, 278
(pANCA) 32 arthritis 97, 366
reactive arthritis 67–8, 97
464 INDEX

red flags 8, 62, 100, 103, 121 serum angiotensin spondyloepiphyseal

Regeneron®, see rilonacept converting enzyme dysplasia tarda
Reiter’s disease/ 303 with progressive
syndrome 67 skin disease 301 arthropathy 337
Remicard®, see infliximab treatment 303 spondylolisthesis 101
renal limited vasculitis uveitis 284 spondylosis 101
188–9 Scheie syndrome 314 SSA antibodies 34
rhabdomyosarcomas 62–3 Scheuermann’s disease SSB antibodies 34
rheumatic fever, see acute 101, 344 stem cell transplantation
rheumatic fever Schmorl’s nodes 102 235, 313, 405
rheumatic heart disease 363 scleroderma 260 ‘string of beads’ appearance
rheumatoid factor (RF) 33 assessment 260 217
rhizomelic shortening 333 clinical features 261 subtalar corticosteroid
rickets 331 epidemiology 3, 261 injections 392
rilonacept 395, 437 localized 260–2 sulphasalazine 419
Riser grade 105 management 263–4 Summary of Product
rituximab therapy 395, 441 monitoring 260 Characteristics 401
juvenile-onset SLE 234, nailfold capillaroscopy 37 Susac’s syndrome 216, 220
241, 245–7 physiotherapy 382 sustained release tablets
vasculitis 174 scoliosis 103–5 and capsules 404
Ro-Actemra®, see sepsis 83 synovitis, transient 108,
tocilizumab septic arthritis 64 111
rocker bottom feet 122 common pathogens 68, 82 systemic lupus
rolling sailor gait 14 hip problems 108, 111 erythematosus 223
Kocher’s clinical ACR revised classification
prediction rule 66, 84 criteria 226–7
S pyrexia of unknown B-cell-targeted therapies
sacroiliitis 327 origin 96 241–3, 247
saddlenose deformity tuberculosis 360 nailfold capillaroscopy 37
189–90 Sever’s disease 122, 344 pyrexia of unknown
safety of medicines 401 shawl sign 451 origin 98
Salmonella 96 Shigella 96 see also juvenile-onset
Salter and Harris shoes 386 systemic lupus
classification 79 short limbs 333 erythematosus
Sanfilippo syndrome 314 shoulder, corticosteroid systemic-onset juvenile
SAPHO 297 injections 392 idiopathic arthritis
sarcoidosis 300 Shprintzen–Goldberg clinical presentation 142
Blau’s syndrome 300 syndrome 349 ILAR classification 140
clinical features 301 sialidosis I 315 management 157
differential diagnosis 302 Sinding–Larsen–Johansson pyrexia of unknown
early-onset 300 syndrome 118, 120 origin 97
epidemiology 300 single nucleotide rash 448
eye disease 302 polymorphism 136 treatment pathway 163
genetics 300 sinusitis 96 uveitis screening 149
hepatosplenomegaly 301 Sjögren’s syndrome overlap
hypercalcaemia 303 277
investigations 302 skeletal dysplasias 333, 336 T
Kveim–Siltzbach test 302 skeletal proportion 333 Takayasu arteritis 199
laboratory findings 302 SLEDAI 2000 Disease acute phase 200
lymphadenopathy 301 Activity Index 256 aetiopathogenesis 199
Mantoux test 303 SLICC/ACR Damage Index alternative names 199
multisystemic presentation (paediatric) 258 angiographic classification
301 slipped capital femoral 202
musculoskeletal disease epiphysis 112 chronic phase 200
302 Sly syndrome 315 classification criteria 168,
neurosarcoid 302 smooth muscle antibodies 170, 202
nitroblue tetrazolium 34 clinical features 200
test 303 Sneddon’s syndrome 213 CNS involvement 200
prognosis 304 soft-tissue sarcomas 62–3 diagnosis 203
pulmonary disease 301 spastic gait 14 differential diagnosis 201
pyrexia of unknown spondyloarthropathy 327 Doppler ultrasound 202
origin 98 spondyloepiphyseal epidemiology 199
renal involvement 301 dysplasia congenita 337 eye involvement 201
 INDEX 465

FDG-PET with CTA 203 tubulointerstitial nephritis infection 214

histopathology 199 uveitis 284 investigations 172
hypertension 203 tumour necrosis factor- malignancy 215
imaging studies 202 receptor associated mimics of 217, 219
investigations 201–2 periodic syndrome ‘other vasculitides’ 214
prognosis 204 (TRAPS) 289, 293 pyrexia of unknown
renal involvement 201 tumours origin 98
revascularization 203 back pain 102 rash 453
treatment 203 bone 60–3 standard treatment 174–8
talipes equinovarus 122 hip problem 111–12 suspected non-accidental
tarsal coalition 121 knee pain 119 injury 54
TB spondylitis 359 Turner’s syndrome 319, 331 visual analogue scale 88
T-cell co-stimulation vitamin D deficiency 331
modulators, infection Vogt–Koyanagi–Harada
risk 71, 73 U syndrome 216, 285
temporomandibular ulcerative colitis 326
joint, corticosteroid ultrasound 6, 28–30
injections 392 undifferentiated W
thalidomide 207 autoimmune rheumatic waddling gait 14
thermodysregulation 88 disease/connective tissue warfarin therapy, APS 281
thermography 35–6 disease 37, 275, 453 Wegener’s granulomatosis
thiopurine uveitis, paediatric 283–5, classification criteria 170
methyltransferase 423 287 clinical features 188
thyrotoxicosis 98 uveitis screening 148, 150 definition 188
tibialis posterior tendon, uveo-parotid fever 302 eye involvement 189
MUS 29–30 investigations 189
tip-toe walking 9 purpura fulminans 455
TNF-α inhibitors 71, 73, 153
tocilizumab 395, 440
V renal involvement 189
vaccination 71, 374–6 respiratory tract
toe joints, corticosteroid involvement 189
injections 392 valgus foot 385
varicella vaccine 371 saddlenose deformity
toes, curly 9 189–90
toe-walking gait 14 varicella zoster infections
371, 373, 397 Weill–Marchesani
transient synovitis 108, 111 syndrome 349
transitional care 387 vasculitis
classification 168, 170 Wilm’s tumour 97
transition models 388 wrist, corticosteroid
trauma, hip problems clinical features
suggesting a vasculitic injections 392
108, 112
Trendelenburg gait 14 syndrome 172
CNS, see central nervous
triamcinolone
system vasculitis X
acetonide 390, 445
triamcinolone hexacetonide connective tissue X-linked hypophosphataemic
390, 445 disease 215 rickets 331
trisomy 8, 320 cystic fibrosis 325
drug-induced 214
trisomy 21, 319
tuberculin skin tests 358 epidemiology 171 Y
tuberculosis 96, 356–7, 361 hypersensitivity 214 Yersinia 96