Review

Immunoglobulin use in neurology: a

practical approach
Mahima Kapoor ‍ ‍ ,1 Anthony Khoo ‍ ‍ ,2,3 Michael P T Lunn ‍ ‍ ,4,5
Stephen Reddel,6 Aisling S Carr5

► Additional supplemental ABSTRACT and therefore, is given as regular pulses

material is published online
Human immunoglobulin, delivered either over years in chronic use. In acute use, it
only. To view, please visit the
journal online (https://​doi.​org/​ intravenously (IVIg) or subcutaneously, is can modulate a postinfective, monophasic
10.​1136/​pn-​2022-​003655). used to treat a range of immune-­mediated response (in Guillain-­ Barré syndrome,
1
neurological disorders. It has a role in acute GBS) or act as a bridging therapy while
Neuroscience / FMNHS / School
of Translational Medicine,
or subacute inflammatory disease control introducing other immunosuppressants
Monash University, Melbourne, and as a maintenance therapy in chronic and waiting for them to come to effect
Victoria, Australia
2
disease management. This review considers (myasthenia gravis crisis or autoimmune
Flinders University College of
Medicine and Public Health,
mechanisms of IVIg action and the evidence for encephalitis).4
Adelaide, South Australia, IVIg in neurological conditions. We use Guillain-­ IVIg is pooled normal polyspecific
Australia Barré syndrome and chronic inflammatory human IgG obtained from healthy
3
Department of Neurology, demyelinating polyradiculoneuropathy (CIDP) donors. Pooled plasma from 1000 to
Flinders Medical Centre, Bedford as frameworks to demonstrate an approach
Park, South Australia, Australia 100 000 donors is fractionated into ther-
4
Centre for Neuromuscular to IVIg use in acute and chronic dysimmune apeutic plasma proteins such as immu-
Diseases, National Hospital for neurological conditions across two different noglobulins, clotting factors, albumin
Neurology and Neurosurgery, healthcare systems: the UK and Australia. We and others for clinical use in differing
London, UK
5
UCL Queen Square Institute
highlight the benefits and limitations of IVIg indications.5 Stabilising agents are added
of Neurology, Faculty of Brain and focus on practical considerations such as and then purification processes remove
Sciences, University College informed consent, managing risks and adverse known bloodborne pathogens. In the
London, London, UK effects, optimal dosing and monitoring response.
6
ANZAC Research Institute, 1980s, there was one case of HIV trans-
We use these basic clinical practice principles mission and a small number of cases
Central Clinical School,
University of Sydney, Sydney, to discuss the judicious use of an expensive of hepatitis C transmission.6 Since the
New South Wales, Australia and scarce blood product with international introduction of careful donor screening
relevance. programmes and the standardisation of
Correspondence to
Aisling S Carr, MRC Centre purification processes in IVIg production,
for Neuromuscular Diseases, no further cases of transmission have been
National Hospital of Neurology
and Neurosurgery, London, UK; INTRODUCTION recorded. Until June 2023, UK donors
A
​ isling.​carr@​nhs.​net Intravenous immunoglobulin (IVIg) treats were not used as source plasma because
a range of immune-­mediated neurological of the potential risk of transmission of
Accepted 3 July 2024
disorders with good evidence for clin- new-­variant Creutzfeldt-­Jakob disease
ical efficacy in diseases affecting the full resulting in dependence on IVIg importa-
neuroanatomical spectrum from muscle tion. There have been no reported cases
to brain (table 1). Neurologists in the of prion disease transmitted via IVIg.
UK prescribed over 2.5 million grams in IVIg supply is maintained and protected
2021/2022 across approximately 4500 at national level for obligate IVIg users
patients, mostly as maintenance therapy (eg, primary and secondary immune defi-
for chronic inflammatory neuropathy, ciency states, or multifocal motor neurop-
where it results in meaningful reductions athy with conduction block (MMNCB))
in disability.1 2 As IVIg is a limited and by using IVIg only where it is therapeu-
© Author(s) (or their
employer(s)) 2024. No expensive resource (£70/g in the UK and tically effective, considering alternative
commercial re-­use. See rights $A54.8/g in Australia), we neurologists treatments when available and suitable,
and permissions. Published optimising doses and stopping when
by BMJ.
should try to ensure our use is appro-
priate, judicious and dose-­ minimised to no longer required. This is the basis for
To cite: Kapoor M, Khoo A, protect availability for all.3 It is important the IVIg commissioning guidelines in
Lunn MPT, et al. Pract Neurol
Epub ahead of print: [please to remember that IVIg is only immu- both the UK and Australia.1 Long-­term
include Day Month Year]. nomodulatory, it is not immunosup- IVIg treatment results in a significant
doi:10.1136/pn-2022-003655 pressing. It does not induce remission, financial burden. Over £300 million and

Kapoor M, et al. Pract Neurol 2024;0:1–15. doi:10.1136/pn-2022-003655 1

Review

Table 1 Evidence-­based neurological indications for IVIg and primary outcomes

Outcomes from highest level
Condition Indications for IVIg evidence IVIg dose Reference
72
G
  BS Significant functional impairment ↓ Disability at 4 weeks 2 g/kg over 5 days
↓ Time to:
► Unaided walking
► Stopping assisted ventilation
73
CIDP Significant functional impairment, OR ↓ Disability at 6 weeks Induction: 2 g/kg over 2–5 days
Relapse after stopping IVIg therapy ↓ Disability at 24 weeks Maintenance (IVIg): 1 g/kg × 3
Improvement in mRS score weeks IVIg
Maintenance (SCIg): 0.2–0.4 g/
kg weekly, or patient’s
equivalent IVIg dose (1:1).
42
Multifocal motor neuropathy Significant functional impairment ↑ Muscle strength and ↓ Induction: 2 g/kg induction
functional disability Maintenance: 1–2 g/kg × 4
weeks
74
Myasthenia gravis Myasthenic crisis/impending ↑QMG score at days 14–28 Induction: 1–2 g/kg over
myasthenic crisis 2–5 days
Before surgery in those with Maintenance: 0.4–1 g/kg × 4–6
advanced disease or bulbar/ weeks
respiratory involvement
Maintenance therapy when other
treatments ineffective
13
LEMS Significant disability where ↑Muscle strength at 2–4 weeks Induction: 2 g/kg induction over
symptomatic therapy insufficient 2 days
Maintenance: 0.4–1 g/kg × 4–6
weeks
75
Autoimmune encephalitis Confirmed or suspected autoimmune Better mRS score and fewer Induction: 2 g/kg over 5 days
encephalitis with functional relapses Maintenance: 0.4–1 g/kg × 4
impairment weeks
76
Dermatomyositis Severe weakness unresponsive to ↑Total improvement score at 2 g/kg over 2–5 days × 4 weeks
other treatment week 16
77
Polymyositis Severe weakness unresponsive to Mean muscle strength (no 2 g/kg over 2 days × 4 weeks
other treatment randomised trials)
78
Stiff-­person syndrome Significant functional disability Reduced stiffness and 2 g/kg over 2 days × 4 weeks
heightened sensitivity scores
79
Rasmussen’s encephalitis Significant disability and Delayed deterioration as Induction: 0.4 g/kg/day for
corticosteroids have failed or are measured by hemispheric ratio 3 days
contraindicated and Motricity index Maintenance: 0.4 g/kg × 4
weeks
Inclusion body myositis (IBM) Biopsy proven inclusion body myositis Evidence limited to case series
with dysphagia and expert opinion. When used
Necrotising autoimmune myopathy Significant weakness unresponsive to in exceptional circumstances
or in conjunction with corticosteroids suggested outcome measures
listed in local commissioning
Opsoclonus–myoclonus syndrome Significant disability and
criteria
corticosteroids have failed or are
contraindicated
Neuromyotonia Symptomatic patients with significant
disability
Neuromyelitis optica spectrum disorders Acute relapse with significant
disability and corticosteroids and/
or plasma exchange have failed/
unavailable
Autoimmune autonomic ganglionopathy Acute autonomic failure with positive
ganglionic acetylcholine receptor
antibodies
Adapted from Criteria for Clinical Use of Immunoglobulin in Australia. National Blood Authority. Accessible athttps://www.criteria.blood.gov.au/(accessed 26 April 2023)
and Commissioning Criteria Policy for the use of therapeutic Immunoglobulin in England. Accessible at https://www.england.nhs.uk/publication/commissioning-criteria-
policy-for-the-use-of-therapeutic-immunoglobulin-ig-in-england-2021/(accessed 26 April 2023).
CIDP, chronic inflammatory demyelinating polyneuropathy; GBS, Guillain-­Barré syndrome; IVIg, intravenous immunoglobulin; LEMS, Lambert-­Eaton myasthenic syndrome;
MMN, multifocal motor neuropathy; mRS, modified Rankin Score; QMG, Quantitative Myasthenia Gravis.

$A582.3 million per annum are spent on this therapy generally well tolerated, it is not completely risk-­free,
alone. IVIg is in the top 10 high-­cost National Health which is another essential element in ongoing thera-
Service (NHS)-­commissioned drugs. Although IVIg is peutic decision-­making.

2 Kapoor M, et al. Pract Neurol 2024;0:1–15. doi:10.1136/pn-2022-003655

 Review

This review considers mechanisms of IVIg action, Mechanisms of action

and an approach to IVIg use in GBS and chronic IVIg is effective across a broad range of different
inflammatory demyelinating polyradiculoneurop- neurological (table 1) and non-­neurological immune-­
athy (CIDP) as working examples due to their prev- mediated disorders. Despite their heterogeneity,
alence and readers’ familiarity. We discuss patient many of these conditions share pathogenic pathways
consent, monitoring clinical response, patient safety involving complement-­ mediated, cellular and/or
and therapeutic alternatives, referencing depart- humoral autoimmunity.
mental approaches in London (National Hospital IVIg has multiple putative mechanisms of action
for Neurology and Neurosurgery) and major periph-
given that it is not a manufactured molecule with
eral nerve specialist centres in Australia (Sydney and
specific and directed function and effect. The appre-
Melbourne) with potential for extrapolation to other
ciation of some of these mechanisms can help us clini-
neurological conditions and other countries worldwide
with similar healthcare systems. We acknowledge the cians understand how and why IVIg exerts its effect
infrastructure and staffing required to support these and how we might best measure response when using
models and discuss potential financial benefits that can it therapeutically (figure 1). Central mechanisms of
justify this approach. Practical and emerging alterna- IVIg include:
tives to IVIg have been discussed in recent editions of ► Complement and cytokine inhibition by sequestration.
this journal.7 8 ► Anti-­idiotypic antibody activity.

Figure 1 Mechanisms of IgG in autoimmune and inflammatory neurological diseases (A) Fab mechanisms; (i) IgG inhibits
complement cascade by binding autoantibodies to target, and accelerating clearance before the autoantibodies can activate
complement, IgG can also directly inhibit complement cascade. The inhibition of membrane attack complex (MAC) deposition in
the endomysial capillaries is a key reason for IgG’s effectiveness in dermatomyositis; (ii) Neutralisation of cytokines, complement and
other inflammatory-­inducing molecules as well as antibodies to pathogens and toxins; these (and others) are the multiple reasons
that IgG is effective in inflammatory neuropathies, particularly chronic inflammatory demyelinating polyradiculoneuropathy (CIDP);
(iii) Anti-­idiotypic antibodies present in Ig interact with regions of other antibodies to form idiotypic-­anti-­idiotypic complexes. The
effect of these antibodies on autoantibodies and also on B-­cell-­mediated antibody production are relevant in antibody-­mediated
diseases such as myasthenia gravis, neuromyelitis optica spectrum disorder and antibody-­mediated neuropathies. (B) Fc portion
mechanisms; i) Compete for saturation of FcRn receptors and accelerate IgG and autoantibody degradation. FcRn inhibitors
capture this mechanism and have been shown to be safe and effective in myasthenia gravis; (ii, iv) Activates anti-­inflammatory Fcy
receptor iib, which also impact B cell responsiveness. Again, this may be relevant in antibody-­mediated neurological diseases; (iii)
IgG competes with immune complexes to bind Fc portion receptors on macrophages; (v) Saturation and modulation of Fc portion
receptors; (vi) IgG influences the T cell balance towards immune tolerance. The immunopathogenesis of CIDP and Guillain-­Barré
syndrome (GBS) are complex and not completely defined but all of these mechanisms of IgG contribute to its efficacy in CIDP and
GBS. Adapted from: Gelfand E. W80, Hou, Y. B, et al 81. Created with BioRender.com.

Kapoor M, et al. Pract Neurol 2024;0:1–15. doi:10.1136/pn-2022-003655 3

Review
► FcRn (neonatal Fc receptor) saturation accelerates the by engagement of the Fc fragment of antibodies with
clearance of pathogenic antibodies. differing affinity and specificity.18 The inhibitory FcγIIR
► Downregulation of costimulatory molecules/inhibitory and FcγIIIR bind with low affinity, and therefore, only
cell effect.9–12 when IgG concentrations are very high—for example
These mechanisms can be broadly considered as after IVIg infusion. They are important checkpoints in
mediated by either the Fab fragment or Fc fragment of immune homeostasis through T cell, plasma cell and
the Ig molecule (figure 1). Antibodies are glycosylated macrophage inhibition (figure 1F). There is a role for
proteins, the position and extent of the glycosyla- this mechanism in CIDP where macrophage activation
tion determining isotype: IgA, IgE, IgG or IgM. The contributes to demyelination and is a histological hall-
heavy chains provide the structural framework for mark of the disease.19
the molecule and are constant within isotypes. The Fc Given the constant flux and vast reserve within
fragment exerts cellular effects via engagement with the immune system, IVIg with a half-­life of approxi-
surface receptors (Fc receptors, figure 1A). The light mately 3 weeks will have a short-­term impact on these
chains provide antigen specificity via three hyper- immune functions and so requires regular infusion at
variable loops known as complementary determining appropriate intervals (at least 6 weekly) to achieve
regions, evenly distributed between four less variable maintenance symptom control in chronic disease.
framework regions. The complementary determining The complexity of these putative mechanisms goes
regions provide a specific antigen recognition site on some way to explain how IVIg had therapeutic effi-
the Fab fragment surface and the hypervariability of cacy across a range of neuromuscular diseases with
these regions enables antibodies to recognise an almost differing pathogenesis but also gives a possible reason
unlimited number of antigens (figure 1B). for the variation in time to clinical response depending
It is this huge variability that facilitates the seques- on the effect on target tissue.
tration of soluble immuno-­active molecules including These mechanisms also provide an appreciation of
cytokines, chemokines and elements of the comple- IVIg’s limitations. IVIg is not effective when the patho-
ment cascade (figure 1C). Activation of the comple- genic antibody is predominantly of the IgG4 subclass
ment cascade is a key pathogenic mechanism of (eg, muscle-­ specific tyrosine kinase myasthenia and
dermatomyositis, CIDP and GBS. In these conditions, autoimmune nodopathies). IgG4 antibodies do not
complement-­ mediated membrane attack complex activate the complement cascade, bind to inhibitory
formation and macrophage activation are central to Fcγ receptors or cause antibody-­ dependent cellular
muscle and nerve damage.13–15 Anti-­idiotypic antibody cytotoxicity.12 Similarly, while IVIg has some T-­ cell
activity refers to the ability of infused IVIg molecules inhibitory effects, these are influenced by affinity and
to bind pathogenic autoantibodies and increase their avidity of the Fc fragment as well as many other immune
clearance (figure 1D). In vitro, IVIg has been shown molecules such as cytokines. We could consider IVIg’s
in autoimmune myasthenia gravis to sequester acetyl- predominant mechanism (as detailed above) as modu-
choline receptor antibodies from patient serum but lating humoral and complement-­mediated pathways,
the relative contribution of anti-­idiotype antibodies to which may explain why paraneoplastic syndromes
efficacy of IVIg in clinical practice is not known.9 16 with diagnostic serological antibodies to intracellular
The Fc fragment may also modulate endogenous anti- antigens (such as anti-­Hu and anti-­Yo) which are not
body levels via saturation of the FcRn. An important primarily pathogenic, respond less well than those
differentiating feature of IgG molecules is their ability with humorally targeted cell surface epitopes (such as
to bind to FcRn which protects them from lysosomal NMDA-­R encephalitis).20
degradation and is the mechanism by which IgG half-­
life is extended to 3 weeks compared with just a few
days for other immunoglobulin subtypes (figure 1E). Starting IVIg
The infusion of large volumes of exogenous IVIg satu- IVIg should be used only where there is a clear diag-
rates these protective receptors resulting in increased nosis of an IVIg responsive condition, with compat-
removal of pathogenic antibodies. This is the basis of ible clinical and laboratory support, where there is
mechanism of action of efgartigimod and rozanolixi- not a better alternative and where benefit is likely to
zumab (molecule specific FcRn inhibitors) which have outweigh risk. Once IVIg has been administered, diag-
very recently been shown to be effective in autoim- nostic clues can be obscured, and false positive sero-
mune myasthenia gravis, Lambert-­Eaton myasthenic logical responses appear. For example, antibodies to
syndrome, N-­methyl-­D -­aspartate receptor (NMDA-­R) hepatitis B, syphilis and Lyme disease, and antineutro-
encephalitis and CIDP.13 14 However, the UK and phil cytoplasmic antibodies can all be transfused.21 All
Australia do not have established formal approval for relevant serology should be performed before giving
clinical use of the molecules in all these conditions.15 17 IVIg, even in the most acute setting if possible (table 2).
The Fc gamma receptor family (FcγR) is broadly This is particularly relevant to hepatitis B serology as
expressed by haematopoietic cells, with activating or detection of core antibody, which may be transmitted
inhibitory influence on immune effector cells mediated by the Ig, complicates giving other immunotherapy

4 Kapoor M, et al. Pract Neurol 2024;0:1–15. doi:10.1136/pn-2022-003655

 Review

All the rare but serious complications occur more

Table 2 Blood tests before giving IVIg
often with first doses, or in the acute setting, and
Pre-­IVIg Maintenance IVIg should be included in an informed consent (table 3).
Full blood count Only if clinically indicated Haemolytic anaemia due to infusion of antiblood
Urea and electrolytes type antibodies is usually self-­ limiting. Transient,
Hepatitis serology clinically insignificant variations in white cell counts
Serological tests if there is a consideration commonly arise from cell sequestration and do not
in the differential diagnosis require monitoring. A full blood count at baseline is
IVIg, intravenous immunoglobulin. useful as a reference for later.23 Acute kidney injury
previously occurred with sucrose-­ stabilised prepara-
tions (88% of 114 reports between 1981 and 1998).
The exact incidence of acute kidney injury with prod-
(such as rituximab) and can prompt clinicians to start ucts containing other stabilisers (proline, sorbitol or
antiviral prophylaxis. glycine) is unknown but is much rarer; baseline testing
of renal function is probably sensible.24
Pre-IVIg screening
When using IVIg to treat primary immunodeficiency, Dosing
it is recommended to establish IgA status pretreatment. The traditional induction dose of IVIg is 2 g/kg, given
This is because in those with inherited absolute IgA over 2–5 days preferably calculated to ideal body
deficiency there is a potential for anaphylaxis to very weight to account for the volume of distribution.25
small amounts of IgA that may be present in some IgG Men: ideal body weight (kg)=22×(height in
batches. Measuring the IgA concentration, however, is metres)2.
not required in the acute setting when using IVIg for Women: ideal body weight (kg)=22×(heights in
immunomodulatory purposes. In fact, relative IgA defi- metres–10 cm)2.
ciency (below the lower limit of normal but not absolute In myasthenia gravis, a controlled trial of people
absence of IgA) occurs in 2%–5% in the general popu- treated for an acute severe exacerbation of myas-
lation and has no clinical or IVIg-­related risk implica- thenia found no superiority of 2 g/kg compared
tions. In those with relative IgA deficiency or patients with 1 g/kg.26
with normal IgA concentrations, anaphylactic reactions
can still occur. All patients should be consented to the Monitoring efficacy and safety
possibility of anaphylaxis at a rate of 1 in 10 000 infu- The response to IVIg should be functionally signifi-
sions, reactions being severe in 1 in 100 000.22 cant and measurable with objective clinical outcomes

Table 3 IVIg-­related risks

Rare but serious Common, mild and transient
Rate per infusion Rate per infusion
Anaphylaxis 1:10 000 Flushing, raised BP or HR 5%–15%
► severe 1:100 000

Haemolytic anaemia Less than 1:100 000 Skin reaction 5%–15%

► Plantar pompholyx
► Eczematous
► Urticaria
► Maculopapular

Acute kidney injury Very rare (outside products stabilised with sucrose) Headache 20%
► Migraine like

Aseptic meningitis 1:10 000

► 0.6% lifetime risk per patient

Thromboembolic events
► 3%–10% in acute use
► 7-­fold increase in risk in maintenance use
► Increased in those with elevated cardiovascular risk (QRISK2)

Severe skin reaction Less than 1:100 000

IVIg, intravenous immunoglobulin.

Kapoor M, et al. Pract Neurol 2024;0:1–15. doi:10.1136/pn-2022-003655 5

 Review

Figure 2 Natural History of GBS. GBS, Guillain-­Barré syndrome.

of impairment or disability paired with global impres- Plasma exchange versus IVIg
sions of change from patient and clinician to justify Plasma exchange removes soluble molecules by the ex
benefits, risks and costs. vivo separation of plasma from cells, replacing it with
These principles can be considered and adapted a biofluid substitute. Plasma exchange works in GBS,
depending on the disease being treated, the individual myasthenia gravis and many other humorally mediated
related specifics and
patient characteristics (disease-­ conditions.32 Logistics, personnel and venous access
comorbidities) and whether IVIg is being used in the means IVIg is preferred to plasma exchange in GBS
acute setting or as a long-­term, maintenance therapy treatment in the UK and most developed healthcare
in chronic disease. systems worldwide.33 34
Since plasma exchange very effectively removes
IVIg in acute setting: GBS as a framework IgG there is no rational basis for using this after IVIg.
GBS is a monophasic, postinfective inflammatory Although of theoretical advantage, there is no addi-
neuropathy (figure 2). For moderate to severe GBS, tional benefit to IVIg after plasma exchange where this
2 g/kg IVIg hastens recovery and may help reduce long-­ has been formally tested.35
term morbidity.27 In mild GBS, IVIg has no therapeutic
benefit.28 There are several very helpful and pragmatic Long-term/maintenance IVIg treatment: CIDP as a
scores that can predict GBS severity at presentation and framework
help determine the prognosis and benefits of starting The only chronic, immune-­ mediated neurological
IVIg.29 Pure Miller Fisher syndrome does not warrant disease requiring long-­term treatment where IVIg is
IVIg treatment in most cases as it is self-­resolving.30 the only effective therapy is multifocal motor neurop-
Repeating treatment for GBS should be avoided. A athy with conduction block (MMNCB).36 For other
recent randomised controlled trial of a second dose of neurological diseases (table 1) where IVIg is effective,
IVIg 7–9 days after the first dose in severe GBS found we use it when it is the best option for the individual,
no difference in any of the primary or secondary or when other therapies are not possible or contra-
outcomes between the one-­dose and two-­dose treated indicated. IVIg does not cure autoimmune disease
groups. However, the second dose did more harm, and long-­term use maintains clinical stability37–39 but
with more severe adverse effects including haemolytic regular infusions are required. Dose and regimen can
anaemic and thrombosis.31 When IVIg is used in the be personalised to patient response and tolerance.
acute or subacute phase of inflammatory neurological Therefore, interactive and iterative clinical outcome
conditions, which are not monophasic such as myas- assessment or efficacy monitoring is essential for dose
thenic crisis or autoimmune encephalitis, early initi- adjustment and reappraisal of need is part of long-­term
ation of alternative immunosuppression determined treatment. We discuss an approach to efficacy moni-
by the particular disease is preferable to serial IVIg toring in more detail below. This is particularly relevant
dosing. as 70% of CIDP patients have a relapsing-­remitting

6 Kapoor M, et al. Pract Neurol 2024;0:1–15. doi:10.1136/pn-2022-003655

 Review

course with potential for spontaneous remission.40 placebo-­controlled, parallel-­group phase III study to
41
The aim of IVIg treatment is to maintain clinical investigate the efficacy, safety and tolerability of two
improvement while the disease is active. All clinically different doses of IgPro20 (Subcutaneous Immuno-
stable CIDP patients on a stable IVIg regimen for over globulin for the Treatment of Chronic Inflamma-
12 months should be considered for an IVIg holiday tory Demyelinating Polyneuropathy (PATH Study))
or cessation trial. In contrast, remission is rare in showed higher IVIg doses increased the proportion of
MMNCB, and adjustment of IVIg dose and regimen responders providing a precedent for an individualised
may be required to optimise control.42 When consid- dosing approach.47
ering starting IVIg, patients need information on After demonstrating objective IVIg response, we
expected response, approach to monitoring, natural suspend IVIg and review the patient immediately on
history and treatment options/treatment alternatives report of symptomatic relapse, which we identify
with future cessation or IVIg holidays in mind, as through the examples of functional improvement
well side effect profile and management of risks. We that the patient noted with IVIg induction (regaining
provide example patient information booklets on IVIg the ability to turn a key in a lock, ease of walking
(online supplemental file 1) and subcutaneous immu- up a flight of stairs or getting out of a bath inde-
noglobulin (SCIg) (online supplemental file 2). There pendently). Then we re-­record objective evidence
is also a range of short patient information videos of deterioration to provide validity to their subjec-
that we have developed freely available on the UCLH tive but personally important functional change.
YouTube channel (http://m.youtube.com/playlist?list=​ The infusion interval or frequency for maintenance
PLazCbfp_tqxzeGN3NYRsf-CzN4sC8PffaW). treatment is then set to approximately 1 week before
that when documented relapse occurs.
Is IVIg the best first-line treatment in CIDP? Response is re-­ achieved with a further 2 g/kg
Clinician and patient need to weigh up treatment in induction dose and then 20% reductions are made
the context of diagnosis, comorbidity, risk, benefit and on sequential infusions until the individual again
resource. Corticosteroids, IVIg and plasma exchange reports deterioration. Again, objective evidence of
are all potential first-­line therapies for CIDP, and each significant functional change is recorded, rescue
is effective in 60%–70% of patients.7 43 IVIg, however, treatment to previous response baseline is given
generally works more quickly (mean 6 weeks from and the maintenance dose is set at deterioration
treatment vs 4 months with corticosteroids). Pulsed dose×1.2.
intravenous methylprednisolone for 6 months is more Once a patient is established on their minimum
likely to induce remission (50% stable 12 months after maintenance regimen, IVIg can be delivered in the
cessation) compared with IVIg at 2 g/kg/month for 6 hospital, by home infusion through a central venous
months in a head-­to-­head clinical trial. In the IVIg access device or with trained infusion partner/cannu-
subgroup, 80% relapsed and required retreatment.39 lating partner, or by converting to SCIg at home.
We support patient preference taking into account
lifestyle impact of the various treatment options, their
regimens and the side effect profiles.1 Transitioning to SCIg
Patient motivation, dexterity, concordance and
IVIg Induction support networks are important for successful SCIg
A 2 g/kg initiation dose followed by a second 2 g/kg transition. SCIg is given as a 1:1 equivalent dose to
dose at 6 weeks or two 1 g/kg doses 3 weeks apart maintenance monthly IVIg fractionated to weekly
captures almost all IVIg responders.44 45 In clinical or fortnightly infusions (maximum of 40 g per infu-
practice, we use the Lunn algorithm and capture sion). For example, if a patient receives 30 g every
evidence of clinical response with objective clinical 3 weeks of IVIg, the SCIg dose equivalent would be
outcomes measures recorded at 2 weeks after the third 10 g weekly. A first SCIg dose is given 1 week after
infusion (figure 3).46 If there is no clinically signifi- the last IVIg with a transfer to the homecare setting
cant objective improvement, the diagnosis is revisited after a short training period. Fewer than 10% of
and/or another first-­line treatment instituted. See the patients transfer back to IVIg but some fail. The
section below on efficacy monitoring for details on the side effect profile with SCIg is better with fewer
definition of clinical response. headaches and less peridose fluctuation reported. 48
49
Occasional patients require intravenous ‘top-­up’
IVIg maintenance boluses. 49 A successful and effective SCIg service
There is much heterogeneity within the pathogen- typically needs a clinical nurse specialist for initial
esis of CIDP, as it represents a spectrum of treatable training and ongoing out-­ o f-­
h ospital support.
inflammatory neuropathy rather than one disease Patients report significant improvements in quality
entity. Therefore, it is unsurprising that there is not of life and financial gains from not having to travel
a ‘one-­ size-­
fits-­
all’ approach to IVIg dosing and to hospital for treatment and time off work. More
regimen. The randomised, multicentre, double-­blind, patient-­f ocused information is available in the

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Review

Figure 3 Our approach to IVIg use for patients with CIDP. CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; IVIg,
intravenous immunoglobulin.

patient information booklets and YouTube patient validated in CIDP with a defined minimum clini-
information videos mentioned earlier. cally important difference (MCID) (table 4). MCID
is helpful clinimetric construct defined as ‘a change
Efficacy monitoring in CIDP
that is considered meaningful and worthwhile by
All patients on long-­term IVIg or SCIg should be
the patient such that they would consider repeating
in a regular clinical monitoring programme; at a
the intervention’. 52 The 10 m timed was validated
minimum frequency of annually for hospital treated
patients and 6-­ m onthly for homecare. Placebo in a multiple sclerosis cohort but has helpful MCID
responses to IVIg are between 11% and 43% in data in that setting and is part of the recommended
CIDP and accurate, objective clinical monitoring is monitoring scores listed on the UK national IVIg
an essential element of IVIg decision-­m aking.50 In commissioning guidelines for its easy applicability
the UK, the IVIg commissioning guideline recom- and functional relevance to patients with CIDP.
mends annual assessment with at least three vali-
dated, disease-­specific clinical outcome measures
from an approved list. 51 These data are reported
to a national IVIg database, required for NHS Table 4 MCID for CIDP scores
England reimbursement of Trust IVIg spend. The Type of test MCID
most frequently used outcome measures in CIDP CIDP I-­RODS Patient-­reported outcome ±4
include Medical Research Council (MRC)-­ s um MRC-­sum score Strength testing ±2
score, Inflammatory Rasch‐built Overall Disability Hand dynamometry Strength test ±8 kPa
Scale (I-­RODS), 10 m timed walk and manual grip CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; I-­
strength. Grip strength and I-­R ODS are disease-­ RODS, Inflammatory Rasch‐built Overall Disability Scale; MCID, minimum
specific clinical outcome scores that have been clinically important difference; MRC, Medical Research Council.

8 Kapoor M, et al. Pract Neurol 2024;0:1–15. doi:10.1136/pn-2022-003655

 Review
MRC sum score remotely (figure 4).57 Improvements in grip strength
The MRC score is non-­ linear in its estimation of correlate with patients’ judgement of change in their
individual muscle strength but a well-­established and global health and are more sensitive than the Inflam-
familiar measurement for all neurologists. The MRC matory Neuropathy Cause And Treatment score.58
sum score summates the qualitative strength scores of Correct and uniform performance is important.58–60
6–8 pairs of muscles to a maximum total of between
60 and 80.53 The addition of first dorsal interosseous
10 m timed walk
brings the standard MRC-­ SS up to 70 and better
The 10 m walk should begin from a standing start
represents the pattern of weakness in neuropathy.
and average three attempts recorded in seconds. It is
Despite its lack of clinimetric validity, it is quick and
important to avoid as many uncontrolled variables as
easy for any practicing neurologist to perform and
possible by ensuring that the individual is wearing the
can help confirm deficits as attributable to neurop-
same orthotics or using the same walking aid at each
athy and consistent with CIDP and identifies change
visit. A multiple sclerosis cohort established a change
over time. Common age-­related phenomena, such as
of ±17% as the MCID in a timed 24-­foot walk test.
Parkinsonism or non-­neurological issues such as osteo-
We apply this MCID to neuropathy patients too,
arthritis, can contribute to reported disability in the
although the calculation has come from a different
individual (such as walking difficulties, ‘trouble with
cohort and applies to a different distance.59 The 10 m
grip’ or fine motor tasks) and can be picked up by
timed walk with this MCID is included in the NHSE
completing the other components of a traditional clin-
Clinical Commissioning Policy. In clinical practice,
ical neurological assessment in addition to the MRC
changes in more than one outcome measure, as well as
power examination.
patient and doctor’s assessment of clinical status will
also determine treatment pathway.51
Inflammatory Rasch‐built Overall Disability Scale
The I-­RODS assesses functional limitations and is vali-
dated for GBS, CIDP and monoclonal gammopathy of Definition of clinical change/stability
uncertain significance-­ associated neuropathy. There Serial measures of any score will create some noise
are separate, disease-­specific scales used for multifocal around the baseline, so sensible interpretation is
motor neuropathy and POEMS (peripheral neurop- required to detect meaningful change; this is the basis
athy (P), organomegaly (O), endocrinopathy (E), a of the recommendation for using at least three scores
monoclonal plasma cell disorder (M), skin changes (S)) together for a better overall impression. In a study
neuropathy.54–56 These probability questionnaires are examining outcome measure variability in a group
easily and quickly applied in clinical practice, taking of CIDP patients deemed clinically stable by their
only 2–3 min. The questionnaire and its transforma- treating neurologist in a peripheral nerve specialist
tion model are freely available online. The raw sum service, a between-­visit I-­RODS greater than MCID
score is transformed into a linear 100-­point scale with change was seen in 44.2% of datapoints. There was
an MCID of ±4.55 less fluctuation in grip strength and MRC sumscore.34
It is acceptable to ignore individual score fluctuations
Grip strength but acknowledge clinical change when more than one
Hand weakness can be measured with simple hand-­ score moves in the same direction and supports the
held dynamometers and complements disability assess- patient reported subjective impression. Our criteria
ments such as I-­RODS and can be reliably performed for objective evidence of change are:

Figure 4 Technique for measuring grip strength with the Martin Vigorimeter.

Kapoor M, et al. Pract Neurol 2024;0:1–15. doi:10.1136/pn-2022-003655 9

Review
► Greater than MCID change in more than one outcome optimisation after IVIg induction. We reassure patients
measure. that re-­establishing the previous baseline is achievable
► Sub-­MCID change in 2–3 outcome measures in the same with prompt retreatment.65 It also helps to discuss
direction. how risk of IVIg complications can increase with age,
► Patient subjective impression/clinician’s overall in particular risk of thromboembolic events in the
impression. maintenance IVIg cohort which is sevenfold higher
Objective, reliable and responsive serological than that of the general population.66 It is important to
biomarkers of disease activity in CIDP would simplify acknowledge the huge potential cost savings associated
assessment. The mean concentrations of plasma neuro- with identifying patients in remission who no longer
filament light chain reduced in groups of treatment-­ require regular IVIg maintenance therapy.
naïve patients after starting treatment; treated patients In a retrospective study of 33 attempted IVIg
with unstable symptoms had higher mean values than cessation trials in our CIDP maintenance cohort,
stable treated patients.61 However, neurofilament light 36.6% (12/33) of these clinically stable patients on
chain is non-­ specific and not sufficiently sensitive stable IVIg had successful withdrawal of treatment
or temporally responsive to use in clinical practice. with no deterioration over 6 months follow-­up:
Although peripherin shows promise in GBS with close IVIg independent. 65 All IVIg-­ d ependent patients
temporal association with onset of clinical change and achieved previous baseline, 50% within 1 week of
severity, and no central nervous system expression, it restarting treatment. One-­ third of deteriorators
has not yet shown meaningful and measurable change required a rescue bolus dose (2 g/kg) while the rest
in CIDP.62 were restabilised with their previous maintenance
regimen. Gradual dose reduction can also achieve
IVIg cessation trials successful outcomes, but time from the decision
In CIDP, there is potential for spontaneous remission, to stop to actual treatment cessation can be years,
even after a period of treatment dependence.63 Long-­ with a mean cost of £113 623 extra IVIg spend
term natural history studies show that 11% of CIDP per person. 65 Sudden cessation also facilitates the
patients may remain clinically stable and off therapy for clear recording of objective change in a more defin-
more than 5 years (cure) and 20% in remission or clin- itive way than gradual reduction and removes the
ically stable and off treatment for less than 5 years.64 potential for overinterpretation of small variations
When IVIg maintenance treatment is optimised, it in symptoms by both patients and clinicians that
is impossible to clinically differentiate patients with can cause nervousness in gradual reduction.67 An
excellent disease control (dependent on maintenance appropriate infrastructure is required to support
IVIg—active, treated CIDP), from disease in remission this approach and to rescue patients promptly;
with unnecessary IVIg (burnt out/ inactive CIDP).65 this includes clinical nurse specialist, consultant
In clinically stable patients with no peridose change time and access to day care unit for retreatment if
in clinical outcome measures and no change in IVIg required. Our own cost-­a nalysis study in the UK
dose or regimen over 12 months, IVIg withdrawal of routine annual IVIg cessation trials in stable
with close clinical monitoring is a recommendation in CIDP patient on IVIg maintenance showed poten-
the 2021 NHS England IVIg commissioning guidelines tial optimal cost savings of £850 000–£1 710 000
but requires appropriate infrastructure to promptly on IVIg spend and day care unit admission costs
identify and restart treatment in those who deterio- per year. This was a real-­ l ife clinical practice
rate. This is supported by the lack of deterioration in study examining the potential saving from optimal
placebo groups of multiple randomised control trials compliance with national IVIg commissioning
in CIDP where clinical monitoring was optimised, and recommendations to perform annual IVIg cessa-
inclusion criteria were strict and scrutinised: tion compared with proportion of patients who
► No relapse in 37% of placebo group in PATH (SCIg vs consented to IVIg cessation despite counselling and
IVIg as maintenance in CIDP). good support infrastructure. There were no iden-
► No relapse in 46% of placebo group in ADHERE (efgar- tifiable differences between those who consented
tigimod vs placebo). to cessation trial and those who did not, and no
► No relapse in 40% of placebo group in rozanolixizumab differences between those revealed to have active
for CIDP. disease once treatment was stopped and those in
We inform all new patients of the potential for remis- remission.
sion and cessation trials are a routine aspect of our
IVIg treatment algorithm (figure 3). Discussing with- Adverse effects and their management
drawal can be challenging in those on long-­standing All serious complications are more common with
regular treatment, especially if there is fixed disability first dose and when IVIg is used in the acute setting
due to axonal loss. We provide reassurance on how (table 3). In maintenance IVIg, proactive manage-
to access clinical reassessment in the event of deteri- ment of common, mild, transient side effects is
oration, in the same manner as we approach dosing important for tolerability.

10 Kapoor M, et al. Pract Neurol 2024;0:1–15. doi:10.1136/pn-2022-003655

 Review

Flushing, heart rate and blood pressure fluc- preinfusion and postinfusion blood tests in our
tuations typically respond to slowing the rate maintenance IVIg cohort. A study of almost 2000
of infusion. The common post-­ I VIg headache immunoglobulin treatment episodes in two UK
has a migraine phenotype and can improve with inflammatory neuropathy cohorts found no clini-
migraine lifestyle advice such as increasing oral cally significant episodes of haemolysis, thrombo-
hydration, avoiding caffeine and using simple cytopaenia, neutropenia, hyponatraemia or acute
analgesia on infusion days and for 3–5 days after. renal impairment on routine preinfusion and post-
Regular prophylactic paracetamol or ibuprofen is infusion full blood count and urea and electrolyte
sometimes required and occasionally ‘as-­required’ monitoring. 23
triptans and migraine prophylaxis (amitriptyline, The most serious potential complication of long-­
etc) are indicated. In resistant headaches, fraction- term IVIg is the increased risk of thromboembolic
ation of the dose by dividing it in half and infusing events. Small case series report IVIg-­r elated venous
twice as often (on the same monthly g/kg/month and/or arterial thromboembolic events occur-
dose) can help. This approach may allow those ring in 3%–11% of cases. A 10-­year retrospective
who experience severe headaches on the first dose single-­
c entre study showed a sevenfold increase
to tolerate treatment in the longer term. Changing
in incidence in thromboembolism in a cohort of
to SCIg also fractionates the dose, reducing occur-
maintenance IVIg patients when compared with
rence of treatment-­associated headache.
contemporaneous population-­b ased rates. 66 There
Most skin reactions are mild and transient.
were no demographic, IVIg dose or frequency-­
Occasionally topical corticosteroids or oral anti-
related differences or CIDP-­a ssociated differences
histamines are helpful if there is reoccurrence
between those who had an event and those who did
with regular treatments. Changing to another
brand is not usually helpful. There may be some not, but cardiovascular risk factors were signifi-
variation in side effects experienced from one cantly more prevalent in the event group. A large-­
batch to another, even with the same IVIg brand. scale population biobank study has shown IVIg
All side effects are more common when a patient exposure is strongly associated with risk of further
has a mild coexistent illness such as a viral infec- thrombotic events in individuals with prior history
tion or urinary tract infection, and therefore, we of myocardial infarction, transient ischaemic
postpone routine IVIg for a few days or a week if attack or stroke.70 In patients requiring main-
patients present for infusion with a temperature or tenance IVIg (with clear evidence of Ig response
any infective symptoms. 68 We use a brief screening and no viable alternative treatment), we now
proforma and traffic light system to stratify risk routinely assess cardiovascular risk pretreatment
in our maintenance IVIg cohort (figure 5). 69 We and suggest strict compliance with medications and
only perform pre-­IVIg blood tests in those with non-­p harmacological measures as per local guide-
symptoms or recent medication changes that lines for secondary prevention of cardiovascular
might raise concern. We do not perform routine disease.70

Figure 5 Traffic light risk stratification system (poster presented at British Peripheral Nerve Society (BPNS), Société Francophone
du Nerf Périphérique (SFNP) Joint meeting 2020). AE, adverse event; CVD, cardiovascular disease; Hb, haemoglobin; VTE, venous
thromboembolism.

Kapoor M, et al. Pract Neurol 2024;0:1–15. doi:10.1136/pn-2022-003655 11

Review

Table 5 Financial justification of IVIg cessation based on NHS pay rates and NHS England Clinical Commissioning Guidelines
Staffing costs Spend
Per annum Per month Per annum
Band 7 CNS (FT) £45 996.00 IVIg £70/g 1 g/kg/month £3780.00 £63 000.00
(75 kg)
Consultant threshold 5 (1.5 PA/week) £13 478.40 DCU £384 £384.00 £4608.00
Total £59 471.40 £67 608.00
CNS, Clinical Nurse Specialist; DCU, Day Care Unit; IVIg, intravenous immunoglobulin; NHS, National Health Service; PA, Programmed Activities.

Infrastructure to dose adjustment and treatment withdrawal when

The model proposed in figure 3 is supported by appropriate. These principles can be extrapolated
a regular weekly consultant lead outpatient clinic across the spectrum of dysimmune neurological
and a full-­time clinical nurse specialist in a cohort disorders in which immunoglobulin has been shown
of 110 inflammatory neuropathy patients on main- to have a meaningful therapeutic effect but warns
tenance IVIg and 30 patients on homecare SCIg. against inappropriate use, which can pose risk to
This staffing is required to facilitate routine annual the patients (thromboembolic events and autoim-
reviews, new patient referrals and respond to dete- mune haemolysis), financial impact on the health
rioration in the context of cessation trials and dose service as a whole and might limit access to life-
optimisation after induction. A specialist nurse is saving benefit of immunoglobulin in other condi-
essential in helping to co-­o rdinate care, medication tions such as congenital hypogammaglobulinaemia.
management and education in this out-­o f-­h ospital
model, as well as actioning relapse or symptom
management. If we consider the cost per gram of Key points
IVIg (£70/g) and assume an average maintenance
dose of 1 g/kg/month (£63 000/year for an average ► Intravenous immunoglobulin (IVIg) treats a range
75 kg person), delivered via hospital day care then of immune-­mediated disorders through multiple
this model is financially justifiable based on just mechanisms of action with strong evidence for clinical
one successful cessation trial per year (table 5). efficacy for most indications.
This very basic cost analysis does not quantify ► IVIg is immunomodulatory but not immuno-­
the additional savings related to dose optimisation supressing, it cannot induce remission in chronic
in the individual, infusion unit capacity improve- immune-­mediated neurological diseases but it can
ment through utilisation of an SCIg service or dampen inflammation and improve time to recovery
acknowledge any patient benefit regarding func- in the acute setting (Guillain-­Barré syndrome or
tional improvement, independence or quality of myasthenic crisis) and control symptoms if infused
life. Neither does it take into account alternative regularly in chronic diseases (chronic inflammatory
treatment options for CIDP and the potential for demyelinating polyradiculoneuropathy or multifocal
relapsing-­remitting disease which would require motor neuropathy).
much more complex modelling. But since a signifi- ► IVIg response should be formally recorded with
cant proportion of patients with CIDP are managed disease-­specific outcome measures.
with maintenance IVIg with a disease prevalence of ► IVIg tolerance can be managed with dose
5 per 100 000 persons years, the typical regional fractionation, simple analgesia, alternating batch but
neurosciences centre should be able to support not brand or changing to subcutaneous delivery.
active CIDP patients requiring immunomodulatory ► Severe adverse reactions are rare but include
treatment with this or a similar model.71 autoimmune haemolytic anaemia and anaphylaxis or
increased risk of thromboembolic events, particularly
in those with pre-­existing cardiovascular risk.
CONCLUSION
► IVIg is an expensive and limited resource; its use
We have discussed a practical approach to immuno-
should be limited to where benefit is proven, clear
globulin use as an immunomodulatory therapy in
evidence of efficacy recorded and alternatives
neurology with a particular focus on the inflamma-
considered where possible.
tory neuropathies. We focused on the clinical mani-
► IVIg cessation trials or treatment holidays are the only
festations of Ig response based on mechanism of
way to identify disease remission in long-­term use in
action and disease pathogenesis using an informed
CIDP where 30%–40% evolve to remission over 2–3
approach to bedside decision-­m aking. This allows
years; appropriately supported IVIg cessation trials are
for responsible and safe immunoglobulin prescrip-
safe and bring huge cost savings.
tion and facilitates a sensible and informed approach

12 Kapoor M, et al. Pract Neurol 2024;0:1–15. doi:10.1136/pn-2022-003655

 Review
2 Hughes RAC, Allen D, Makowska A, et al. Pathogenesis of
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Peripher Nerv Syst 2006;11:30–46.
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M., Avau, B., Vankrunkelsven, P., Allen, J. A., Attarian, towards the iceberg? Curr Opin Allergy Clin Immunol
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Contributors MK and AK prepared the first draft of the
manuscript. SR and ASC developed the topic for the article. immunoglobulin in chronic inflammatory demyelinating
All authors contributed to manuscript revisions, and all authors polyradiculoneuropathy (CIDP): mechanisms of action and
read and approved the submitted version. ASC is the guarantor. clinical and genetic considerations. Expert Rev Neurother
Funding MPTL and ASC are supported by UCL Queen Square 2022;22:953–62.
Biomedical Research Centre (BRC). 13 Bain PG, Motomura M, Newsom-­Davis J, et al. Effects of
Competing interests None declared. intravenous immunoglobulin on muscle weakness and calcium-­
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Patient consent for publication Not applicable.
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Provenance and peer review Provenance and peer review. 14 Gresa-­Arribas N, Titulaer MJ, Torrents A, et al. Antibody
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Boston, USA, and Karim Kreft, Cardiff, UK. titres at diagnosis and during follow-­up of anti-­NMDA
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Data availability statement Data sharing not applicable as no
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datasets generated and/or analysed for this study.
15 Yunce M, Katyal N, Monis GF, et al. Neonatal Fc receptor
Supplemental material This content has been supplied by the
blockade as emerging therapy in diseases with plasma exchange
author(s). It has not been vetted by BMJ Publishing Group
Limited (BMJ) and may not have been peer-­reviewed. Any indications. J Clin Apher 2023;38:632–40.
opinions or recommendations discussed are solely those of 16 Fuchs S, Feferman T, Meidler R, et al. A disease-­
the author(s) and are not endorsed by BMJ. BMJ disclaims specific fraction isolated from IVIG is essential for the
all liability and responsibility arising from any reliance placed immunosuppressive effect of IVIG in experimental
on the content. Where the content includes any translated autoimmune myasthenia gravis. J Neuroimmunol
material, BMJ does not warrant the accuracy and reliability of
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Mahima Kapoor http://orcid.org/0000-0001-5498-3426 18 Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of
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