PRIMER

Psoriatic arthritis
Oliver FitzGerald   1 ✉, Alexis Ogdie2, Vinod Chandran   3,4, Laura C. Coates5,
Arthur Kavanaugh   6, William Tillett7, Ying Ying Leung8, Maarten deWit   9,
Jose U. Scher   10 and Philip J. Mease   11
Abstract | Psoriatic arthritis (PsA) is a complex inflammatory disease with heterogeneous clinical
features, which complicates psoriasis in 30% of patients. There are no diagnostic criteria or
tests available. Diagnosis is most commonly made by identifying inflammatory musculoskeletal
features in joints, entheses or the spine in the presence of skin and/or nail psoriasis and in the
usual absence of rheumatoid factor and anti-​cyclic citrullinated peptide. The evolution of
psoriasis to PsA may occur in stages, although the mechanisms are unclear. In many patients,
there may be little or no relationship between severity of musculoskeletal inflammation and
severity of skin or nail psoriasis. The reason for this disease heterogeneity may be explained by
differences in genotype, especially in the HLA region. New targeted therapies for PsA have been
approved with additional therapies in development. These developments have substantially
improved both short-​term and long-​term outcomes including a reduction in musculoskeletal
and skin manifestations and in radiographic damage. With efforts underway aimed at improving
our understanding of the molecular basis for the heterogeneity of PsA, a personalized approach
to treating PsA may become possible.

Psoriasis
Psoriatic arthritis (PsA) is a complex inflammatory short-​term and long-​term outcomes, including reduc-
Psoriasis is a skin disease that disease with heterogeneous clinical features that com- tions in musculoskeletal and skin manifestations and
causes itchy, scaly patches plicates skin or nail psoriasis in up to 30% of patients. radiographic damage. These new treatments are at
commonly on the extensor No diagnostic criteria or tests are available for PsA. least in part related to an improved understanding of
aspects of the knees and
Diagnosis is most commonly made by identifying the genetic basis of PsA and the underlying molecular
elbows and in the scalp.
inflammatory musculoskeletal features in the joints, pathways that are activated and contribute to disease
Entheses entheses or the spine in the presence of skin and/or nail expression. For example, genetic studies have confirmed
The enthesis is the site psoriasis, and in the usual absence of rheumatoid factor the association between PsA and single-​nucleotide poly­
of attachment of ligament and anti-​c yclic citrullinated peptide 1 (Table  1). PsA is morphisms in the IL-17/IL-23 pathway4,5. In addi-
to bone.
thought to be the result of interplay between environ- tion, immunopathological studies have demonstrated
Rheumatoid factor mental factors, an individual’s phenotype and genotype the predominance of IL-17-​expressing CD8+ T cells
Rheumatoid factor is an and the adaptive and innate immune systems2. in the synovial fluid of patients with PsA, providing
anti-​immunoglobulin antibody The evolution from psoriasis to the point at which further evidence for the IL-17/IL-23 pathway in PsA
found commonly in patients
the patient meets the criteria for PsA of the Classification pathogenesis6. Furthermore, treatments targeting IL-17
with rheumatoid arthritis.
Criteria for Psoriatic Arthritis (CASPAR) (described in and IL-23 have not only proven particularly effective
Anti-​cyclic citrullinated the section Classification) may occur in stages (Fig. 1). for skin psoriasis but are also effective and licensed for
peptide PsA may develop in up to 30% of patients with psoriasis musculoskeletal manifestations. With efforts underway
This peptide is an antibody attending dermatology clinics3. The link between skin aimed at improving our understanding of the molecular
found commonly in patients
with rheumatoid arthritis.
and musculoskeletal inflammation is certainly established basis for the heterogeneity of PsA, a precision medicine
but the underlying mechanisms are yet unclear. Many approach to treating PsA may not be too far away.
patients with PsA with active disease may have mild pso- In this Primer, we discuss the epidemiology and
riasis and many patients with severe psoriasis may have pathogenesis of PsA and focus on the challenges in its
only mild musculoskeletal features associated with PsA. diagnosis, screening and prevention. In addition, we
The differences in genotype, especially in the HLA region, discuss in detail the current treatment approaches as
✉e-​mail: are considered to explain the heterogeneity of the disease2. well as the impact of PsA on the quality of life (QoL)
[email protected] Several new targeted therapies have been approved and well-​being of patients. The Primer concludes with a
https://doi.org/10.1038/ for use in PsA, with additional therapies in develop- glimpse at what the future holds in terms of unmet needs
s41572-021-00293-​y ment. These advances have substantially improved the and opportunities to address them.

NATURE REvIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:59 1

0123456789();:
Primer

Author addresses of patients with juvenile PsA develop arthritis first and
develop psoriasis later, further complicating the devel-
1
Conway Institute for Biomolecular Research, University College Dublin, Dublin, Ireland. opment of classification systems for use in children15.
2
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Second, the criteria refer to boys or men, although we
3
Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, know that PsA affects both sexes equally. Third, treat-
Toronto, Ontario, Canada.
ment for juvenile idiopathic arthritis may differ from the
4
Departments of Medicine and Laboratory Medicine and Pathobiology, University
of Toronto, Toronto, Ontario, Canada. management of adult PsA. Methotrexate remains
5
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, the first-​line therapy as of 2019, although a 2021 update
University of Oxford, Oxford, UK. of the American College of Rheumatology juvenile idio­
6
Center for Innovative Therapy, Division of Rheumatology, Allergy & Immunology, pathic arthritis treatment guidelines is in progress16.
University of California, San Diego Medical School, San Diego, CA, USA. Many therapies used to treat adult disease have not yet
7
Royal National Hospital for Rheumatic Diseases, Pharmacy and Pharmacology, been approved for use in children.
University of Bath, Bath, UK.
8
Singapore General Hospital, Duke-​NUS Medical School, Singapore, Singapore. Risk factors for PsA
9
GRAPPA Patient Research Partner, Amsterdam, Netherlands. Studies have identified a number of potential risk fac-
10
Department of Medicine, Division of Rheumatology, NYU Grossman School of
tors for the development of PsA among patients with
Medicine, New York, NY, USA.
11
Swedish Medical Center/Providence St. Joseph Health and University of Washington, psoriasis17. These include the following: genetic sus-
Seattle, WA, USA. ceptibility within the HLA region; variants in genes
involved in interferon signalling and NF-​κB signalling18;
comorbidities such as obesity and hyperlipidaemia; and
Epidemiology psoriasis-​related factors such as psoriasis severity, nail
Incidence and prevalence in adults dystrophic changes and potentially psoriasis location19.
The incidence of PsA among patients with psoriasis Understanding the role of these risk factors is an active
ranges from 0.27 to 2.7 per 100 person-​years, depend- area of investigation.
ing on the study and outcome definition7. However, Defining PsA in a population is challenging and
a meta-​analysis found a prevalence of PsA defined might be one of the potential reasons for the variabil-
using CASPAR of 23.8% among patients with psoriasis. ity in prevalence estimates across studies. The CASPAR
PsA is relatively uncommon in the general population classification can only be applied in studies in which
(0.10–0.25% of adults)8. The prevalence of PsA is highest patients are being examined20. However, studying small
among patients 30–60 years of age and affects men and samples (for example, in a dermatology clinic) can be
women equally9. The majority of patients with PsA are associated with selection bias, leading to biased prev-
white; whether this increased incidence is related to a alence estimates. On the other hand, analysing large,
specific genetic underpinning or is in part related to the population-​based datasets is complicated by misclas-
difficulty in diagnosing psoriasis in patients with darker sification bias as classification in this setting relies on
skin colours is unclear10. Of interest, the reported prev- codes for defining PsA (that is, missing diagnoses that
alence of PsA is lower in Asia than in Europe and North have not been recorded in the dataset and simultane-
America, potentially suggesting differences by race ously misdiagnosis of PsA as conditions unrelated to
and/or ethnic group or by environment8. psoriasis (for example, osteoarthritis))19,21,22. The truth
might be somewhere in the middle. Thus, both study
Incidence in children designs must be interpreted in light of these potential
The prevalence and phenotype of PsA is quite dif- limitations, although they are helpful in understanding
ferent among children, in part related to differences not only prevalence and incidence but also outcomes
in the criteria used in different classification sys- and risk factors for PsA.
tems. In the International League of Associations for
Rheumatology (ILAR) classification, the criteria for PsA Comorbidities
and enthesitis-​related arthritis are analogous to those in PsA is associated with several chronic conditions, which
the CASPAR and the Assessment of SpondyloArthritis may affect lifespan and QoL23. Although most studies
international Society systems used in adults; however, have shown that the overall mortality among patients
they are quite different in that a variety of exclusion cri- with PsA is not higher than in the general population,
teria classify patients to other categories depending on cardiovascular comorbidities have a higher prevalence
certain factors11,12. For example, a patient with HLA-​B27, a and can impact lifespan and QoL17. Obesity is particu-
first-​degree relative with HLA-​B27-​associated disease, larly common in patients with PsA, and is significantly
a positive rheumatoid factor or a systemic presentation more prevalent than in patients with psoriasis or rheu-
of juvenile idiopathic arthritis would be excluded from matoid arthritis and the general population17. Obesity
having a diagnosis of PsA12 (Table 2). The ILAR classifi- has a particular impact on function, QoL and response
cation is the most commonly used; however, an alterna- to therapy24. In addition, PsA is associated with an
tive system for classifying juvenile PsA, the Vancouver increased prevalence of cardiovascular risk factors such
criteria, was developed in 1989 but is rarely used as hypertension, hyperlipidaemia, type 2 diabetes melli-
today13,14. Additionally, there are several limitations with tus, and the combination of these (that is, the metabolic
the use of the ILAR system. First, patients are required syndrome) compared with the prevalence in the general
to have a diagnosis of psoriasis to be classified as having population25. Indeed, PsA is associated with an increased
juvenile PsA. This is not withstanding the fact that ~50% incidence of cardiovascular events such as myocardial

2 | Article citation ID: (2021) 7:59 www.nature.com/nrdp

0123456789();:
 Primer

Uveitis
infarction, even after adjusting for traditional risk extra-​articular sites. The mediators for musculoskeletal
Uveitis is inflammation of the factors26. Similarly, patients with PsA are at significantly inflammation may be skin-​derived or there may be a
uveal tract of the eye. increased risk of type 2 diabetes mellitus and fatty liver common trigger causing skin and joint disease (Fig. 2).
disease27,28. These cardiometabolic conditions may also
be associated with increased disease activity17. In addi- HLA-​associated genetic factors
tion, depression and anxiety are common in patients Studies have revealed a strong genetic contribution to
with PsA, each affecting 10–30% of patients29, and the development of psoriasis and PsA. Epidemiological
fibromyalgia or central sensitization is also common, evidence suggests that the recurrence of PsA among
also affecting ~30% of patients30,31. Depression, anxiety first-​d egree relatives of PsA probands (λs 30–48)
and fibromyalgia have a substantial impact on treatment is greater than the recurrence of psoriasis among
outcomes and, therefore, these comorbidities should be first-​degree relatives of psoriasis probands (λs 4–10)36.
identified and managed so as to improve outcomes32,33. However, a new study that investigated single-​nucleotide
PsA is also associated with extra-​articular manifes- polymorphisms from large-​scale genotyping arrays,
tations including uveitis and inflammatory bowel dis- while confirming strong heritability, concluded that
ease (that is, Crohn’s disease and ulcerative colitis)34. there is a stronger contribution from psoriasis37. The
A meta-​analysis showed a prevalence of ~3% of uvei- genetic associations in PsA are found in HLA and
tis and ~3% of inflammatory bowel disease in patients non-​HLA region genes, with the strongest association
with PsA35. These conditions can have a major impact being within the HLA region. HLA-​C*06:02 is found
on treatment selection as not all therapies for PsA cover in ~60% of those with psoriasis but the frequency is
these manifestations. significantly lower than in those with PsA (28%)38.
This same study found that 18% of patients with PsA
Mechanisms/pathophysiology were HLAB*27-​positive, with the frequency of B*27 in
The exact sequence of events leading to the onset and patients with psoriasis in whom PsA has been excluded
progression of human PsA has not yet been delineated. (cutaneous-​only psoriasis; PsC) similar to that in normal
Nevertheless, arthritis has been suggested to be triggered controls. HLA-​B*08 was the major allele in patients with
by a complex interplay between an individual’s genetic PsA (37%) but, interestingly, its frequency was signifi-
predisposition and environmental influences that trig- cantly less in those with PsC (15%)38. A comparison of
gers an immune response, leading to entry and prolif- HLA alleles and amino acid sequences in patients with
eration of immune cells at articular, periarticular and PsA or PsC revealed that the association was most sig-
nificant for HLA-​B amino acid position 45. Of the amino
acid residues at this position, the presence of glutamine
Table 1 | Distinguishing clinical, laboratory and radiographic features of PsA (HLA-​B Glu45) was associated with the highest risk
Feature Psoriatic Rheumatoid Osteoarthritis Ankylosing of developing PsA rather than PsC. Although, among
arthritis arthritis spondylitis the HLA alleles, HLA-​B*27 had the lowest P value, the
Polyarticular Common Very common Common Rare association was less significant than the association with
HLA-​B Glu45. Interestingly, HLA-​B alleles that asso-
Oligoarticular Common Occasional Common Occasional
ciated with PsA, including HLA-​B*27, HLA-​B*38 and
Distal Common Rare Common Rare HLA-​B*39, have glutamine at position 45 (ref.39). Another
interphalangeal study that controlled for age of psoriasis onset showed
joint involvement
that HLA-​C*06:02 is not associated with PsA and that
Axial Common No No Nearly always amino acid position 97 (asparagine or serine) of HLA-​B
spondyloarthritis
differentiates PsA from PsC. Of note, HLA-​B*27 has
Dactylitis Common No No Rare asparagine at position 97 and HLA-​B*07 and HLA-​B*08
Enthesitis Common Rare No Common have serine40.
Psoriasis Very common Rare Rare Occasional HLA class I molecules play a critical role in immune
responses, particularly to viruses, by presenting viral
Nail dystrophy Very common No No Occasional
peptides to CD8+ T cells. Studies have demonstrated the
Rheumatoid Occasional Very common Rare Rare presence of clonally expanded CD8+ T cell populations
factor-​positive in synovial fluid and tissue of patients, indicating a role
aCCP-​positive Rare Very Common Rare Rare for CD8+ T cells in PsA pathogenesis2. The amino acid
Elevated ESR or Common Very common Rare Common residues associated with PsA are in the antigen-​binding
elevated CRP groove of the HLA-​B molecule. The peptides driv-
HLA-​B27 positivity Occasional Rare Rare Very common ing clonal expansions of CD8+ T cells in PsA have not
been identified. But given the structural similarity of
Joint erosiona Common Very common Occasional Occasional
the binding pockets of each of the HLA-​B molecules
Osteoproliferationa Common Rare Common Very associated with PsA producing a negative charge, the
commonb peptide sitting in the B pocket is highly likely to have
Sacroiliitis on Occasional No No Nearly always positively charged amino acids at position 45 (ref.41). The
radiographsa heterogeneous nature of this T cell response has been
aCCP, anti-​cyclic citrullinated peptide; common, 30–60%; CRP, C-​reactive protein; ESR, suggested to further determine the molecular pathways
erythrocyte sedimentation rate; nearly always, >90%; no, not found; occasional, 10–30%;
PsA, psoriatic arthritis; rare, <10%; very common, 60–90%. aIn disease of >2 years duration. that are activated, which ultimately result in charac-
b
Very common in spine or sacroiliacs; occasional in peripheral skeleton. teristic diverse clinical disease expression and possibly

NATURE REvIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:59 3

0123456789();:
Primer

Sacroiliitis
treatment responses. In support of this concept, studies locus at chromosome 5q3; and distinct PsA variants
Inflammation of the sacroiliac have shown associations of HLA genotypes not just with at IL23R, PTPN22 (which encodes a potent inhibitor
joints susceptibility to disease but also with certain disease fea- of T cell activation) and RUNX3 (which is involved in
tures, such as the interval between the onset of psoriasis CD8+ T lymphocyte differentiation)44. Notably, all of
and PsA. For example, HLA-​B*27 is associated with a these PsA-​specific loci involve genes that are involved
short interval between skin manifestations and mus- in immune activation, emphasizing the importance of
culoskeletal disease and HLA-​C*06 is associated with immune dysfunction in PsA pathogenesis.
a longer interval. In addition, B*27:05:02,C*01:02:01 The exact mechanism that results in over-​expression
and B*08:01:01,C*07:01:01 haplotypes are associated of pro-​inflammatory mediators, including cytokines,
with dactylitis; B*27:05:02,C*01:02:01 haplotype is is poorly understood. We do, however, know that
associated with enthesitis; B*27:05:02,C*01:02:01 and active PsA is associated with production of a cascade
B*27:05:02,C*02:02:02 haplotypes are associated with of cytokines including TNF, IL-17 and IL-23 (ref.1). The
symmetrical sacroiliitis and B*08:01:01,C*07:01:01 importance of these cytokines in disease pathogenesis
haplotype with asymmetrical sacroiliitis42. is supported by the efficacy of inhibitors targeting these
cytokines in affecting clinical disease expression. As not
Non-​HLA-​associated genetic factors all patients respond to cytokine inhibition, an improved
Although the strongest genetic associations with PsA understanding of the molecular pathways associated
are with genes within the HLA region, non-​HLA gene with specific disease features may help to better guide
associations are also well described. Many of the genetic treatment choices2.
risk loci reported as associated with PsA susceptibility
are shared with psoriasis, such as IL12B and TRAF3IP2, Environmental factors
which are involved in IL-17 signalling43. This finding A number of environmental factors have been hypoth-
reflects shared molecular pathways mediated by the pre­ esized to be associated with the development of PsA.
sence of cutaneous psoriasis in both phenotypes. The These factors include musculoskeletal injury, obe-
number of shared susceptibility alleles might possibly sity and infection; evidence for the association of PsA
relate to inadequate exclusion of musculoskeletal inflam- with stress or anxiety, alcohol consumption or smok-
mation in patients designated as having PsC. However, ing is controversial45. For years, support for a role of
studies have identified a number of PsA-​specific loci, musculoskeletal injury in disease pathogenesis was
which explains the additional musculoskeletal burden. poor, with case reports or series providing anecdo-
These loci include the following: the presence of glu- tal evidence only. A matched cohort study using data
tamic acid at amino acid position 45 in HLA-​B; a risk from the Health Improvement Network showed that

Future treatment intervention Current treatment intervention

3
Good
Psoriasis with asymptomatic outcome;
synovio-entheseal inflammation remission
on imaging
2 5
1
Preclinical PsA with clinically
Skin and/or immune activation evident disease
nail psoriasis phase or PsA (CASPAR)
4 Poor
Psoriasis with musculoskeletal outcome;
Clinical and/or environmental risk factors symptoms (arthralgia, stiffness) damage
• Obesity
• Biomechanical stress
• Infections (microbiome)
Genetic factors
• First-degree relative with PsA
• HLA-B27 allele

0–10 years

Fig. 1 | Stages in the evolution of psoriasis to psoriatic arthritis. This arthralgia and/or stiffness but without sufficient signs to make a diagnosis
figure illustrates the stages in the evolution of psoriasis to psoriatic arthritis of PsA; and (5) the stage in which patients meet the criteria of the
(PsA). These stages include: (1) patients with skin and/or nail psoriasis only Classification Criteria for Psoriatic Arthritis (CASPAR). The bidirectional
but with risk factors, at present undetermined, for subsequent development arrows reflect the important possibility that some of these stages may be
of PsA; (2) musculoskeletal immune activation phase when cytokines such reversible. At present, treatment is focused on those patients who receive
as IL-23/IL-17 and/or TNF are over-​expressed at a cellular or tissue level; a diagnosis of psoriatic arthritis (stage 5) and have ongoing inflammatory
(3) an asymptomatic stage with evidence of synovio-​entheseal inflammation disease and evidence of radiographic damage. Future treatment
on imaging such as MRI or ultrasonography; (4) a ‘prodromal’ stage in which intervention strategies may target patients at earlier disease stages
patients with psoriasis may have musculoskeletal symptoms such as (stages 1–4).

4 | Article citation ID: (2021) 7:59 www.nature.com/nrdp

0123456789();:
 Primer

Table 2 | Classification systems for psoriatic arthritis and enthesitis-​related arthritis

ILAR enthesitis-​related arthritis ILAR psoriatic arthritis Vancouver psoriatic arthritis
Arthritis and enthesitis or arthritis Arthritis and psoriasis or arthritis and at Arthritis and psoriasis or
or enthesitis plus at least two of the least two of the following: dactylitis; nail arthritis plus at least two of the
following: sacroiliac joint tenderness pitting or onycholysis; family history of following: dactylitis; nail pitting;
or inflammatory back pain; HLA-​B27 psoriasis (first-​degree relative) family history of a first-​degree
positivity; family history (first-​degree or second-​degree relative with
relative) of HLA-​B27-​associated disease; a psoriasis-​like rash
acute and symptomatic anterior uveitis;
arthritis in boys >6 years of age
Exclusions: psoriasis in self or first-​degree Exclusions: onset of arthritis in an Exclusions: none
relative, rheumatoid factor positivity, HLA-​B27-​positive male beginning
systemic JIA after the sixth birthday, family
history (first-​degree relative) of
HLA-​B27-​associated disease,
rheumatoid factor positivity, systemic JIA
ILAR, International League of Associations for Rheumatology; JIA, juvenile idiopathic arthritis.

patients with psoriasis exposed to trauma, especially the relationship between inflammation at the two
bone and joint trauma, had an increased risk of PsA sites is successive (that is, changes in the skin trigger
compared with controls46. Association with trauma musculoskeletal inflammation) or synchronous (that
is not confined to major trauma, which is consistent is, a common trigger leads to skin and musculoskel-
with the hypothesis that microtrauma at entheseal sites etal inflammation). In 70% of patients with PsA, skin
may be a critical disease-​initiating factor47. This find- inflammation predates musculoskeletal inflammation
ing might possibly explain the association between PsA by many years. This latency, if associated with certain
and increasing BMI45, with higher mechanical load at HLA alleles, such as HLA-​C*0602, is associated with a
entheseal sites being a consequence of high BMI. The long interval between the onset of skin inflammation
effects of excess adipose tissue, which includes abundant and musculoskeletal inflammation54. Thus, mediators
pro-​inflammatory mediators, might spill over to other originating in the inflamed skin could trigger musculo-
tissue sites, triggering immune activation. skeletal inflammation. This theory is supported by the
Studies have suggested a role for infection in trig- findings of one study, which demonstrated increased
gering PsA, in particular the association between circulatory skin-​d erived tissue-​r esident memory
streptococcal infection and guttate psoriasis is well CCR10+CD8+ T cells in the peripheral circulation of
established48. In addition, psoriasis and PsA also occur patients with PsA compared with the levels in patients
more commonly and severely in individuals with HIV with PsC55. However, these cells were not enriched
infection, which targets CD4+ T cells but not CD8+ in the synovial fluid55. Another study demonstrated
T cells, than in the general population49. Studies have a high proportion of synovial TC17 cells expressing
examined changes in the microbiome and onset of markers typically associated with homing to the skin
PsA50; however, the findings from these studies have or gut56. Injury to sites of biomechanical stress may be
been inconclusive. Understanding the role of the micro­ the underlying mechanism driving synchronous skin
biota in PsA pathogenesis is an area for further research and musculoskeletal inflammation. Joint disease has
as microbiota-​driven populations of IL-17-​producing been demonstrated to occur simultaneously with or
innate immune cells have been identified in other tis- prior to the onset of skin disease in 30% of patients1.
sues, such as the gastrointestinal tract and periodontal Furthermore, HLA- ​ B *27 is associated with short
tissue51. Furthermore, one study has demonstrated the skin–joint disease latency38,42. Microtrauma at sites of
important influence of the gut microbiota — together increased biomechanical stress leading to enthesitis
and over time — on systemic immune cell dynamics52. may underlie this form of PsA, with skin disease lim-
ited to sites of microtrauma (such as behind the elbows
Immune mediators in PsA and knees) and joint disease triggered at the enthesis.
Given the strong association with HLA class I alleles In fact, enthesitis is hypothesized to be the mechanism
and T helper 17 (TH17) immune response, a model for underlying the diverse musculoskeletal manifestations
pathogenesis of PsA has been proposed whereby primed of PsA or spondyloarthritis including eye and gut
antigen-​presenting cells at sites such as the skin or enthe- inflammation, which is further supported by the associ-
sis engage with innate lymphoid cells and naive T cells, ation between HLA-​B*27 and more severe sonographic
leading to local clonal expansion of TH1 and TH cells and enthesitis in PsA57.
CD8+ cytotoxic T (TC1 and TC17) cells53. The interplay Clonal expansion of T cells in the psoriatic joint is
between the effector T cell subsets, stromal cells and the well described58,59. Indeed, one study demonstrated
cytokine milieu at the local sites determines disease fea- a threefold increase in the population of memory
tures including enthesitis, synovitis, bone and cartilage CD8+ T cells as well as pronounced CD8+ T cell clonal
Synovitis loss, and new bone formation in the axial and peripheral expansion in the joints of patients with PsA compared
Synovitis is inflammation
of the synovial tissue, which is
musculoskeletal system53. with the population in peripheral blood60. These cells
normally a thin layer of tissue The strong relationship between skin and musculo- express cell-​cycle activation, tissue-​homing and tissue
lining the inside of joints. skeletal inflammation raises the question as to whether residency markers, including the skin or gut-​homing

NATURE REvIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:59 5

0123456789();:
Primer

marker ITGA1 (also known as CD49a) and granulysin. The majority of patients with inflammatory arthritis and
CXC-​chemokine receptor 3 (CXCR3) is upregulated psoriasis are likely to have PsA62.
in the expanded synovial CD8+ T cells, and its two lig- Unfortunately, there is a well-​recognized delay in the
ands, CXCL9 and CXCL10, are elevated in PsA synovial diagnosis of PsA even though the majority of patients
fluid60. Elevated CXCL10 is known to predict the future have a preceding condition in the form of skin psori-
development of PsA in patients with PsC61. asis. Data from a UK national audit in 2015 estimated
a median delay of 29 weeks, which was substantially
Diagnosis, screening and prevention longer than in matched patients presenting with rheu-
The first step in caring for patients with PsA is to make matoid arthritis63. This delay in diagnosis has also been
an accurate and timely diagnosis to allow prompt ther- shown to have major implications. For example, another
apy. Multiple factors are considered in the process of UK study found that a delay in diagnosis of 12 months
diagnosing PsA. Typically, these factors may include was associated with increased physical function impair-
patient history, physical examination, laboratory find- ment at 10 years despite active treatment64. A subsequent
ings and imaging results. Although the diagnostic pro- study in Ireland showed that a delay in diagnosis of even
cess may end in a clinician making a binary decision 6 months was associated with a higher chance of periph-
(that is, the disease is present or not), this process is often eral erosive disease and poorer physical function than a
associated with a level of probability of the diagnosis in shorter diagnostic delay65.
relation to other potential differential diagnoses.
The majority of patients manifest psoriasis before Clinical presentation
developing PsA, although this may not have been previ- There are relatively few data concerning the signs and
ously diagnosed. In patients with psoriasis, the key issue symptoms that aid diagnosis of PsA. In 2013, a nominal
is to identify whether inflammatory musculoskeletal group exercise was performed with health-​care pro-
disease (arthritis, enthesitis or spondylitis) is present. fessionals interested in rheumatology and with patient

Mixed cellular TH1 and CD8+

pattern T cell driven
• TNF • TNF (IL-17,
• IL-17 (IL-23p19, IL-23p19, IL-12p40)
T-bet IL-12–IL-23p40) RORγt
CD4+ IL-17
Synovial predominant CD8+ T cell
TH1 cell
• Allele B*08:01:01
and C*07:01:01
• Haplotype
B*08:01:01–C*07:01:01
CD4+
T-bet TH1 cell
RORγt
IL-17
CD8+ T cell PAM
Entheseal- Cutaneous-
predominant predominant
symmetrical • Alleles B*57:01
axial disease and HLA-C*06:02
RORγt • Allele B*27:05:02 RORγt
CD4+ IL-17
TH17 cell CD8+ T cell

TH17 driven RORγt

• IL-17 CD4+
• IL-23p19 TH17 cell
IL-12R CXCR3 IL-23R CD161 CCR5 CCR6
• IL-12–IL-23p40 (TNF)

Fig. 2 | Proposed pathogenetic pathways activated in key subtypes of and haplotype HLA-​B*08:01:01–HLA-​C*07:01:01, CD8+ engagement with TH1
psoriatic disease. Distinct clinical phenotypes of psoriatic disease (PsD) occur cells and responsiveness to TNF inhibition. Cutaneous-​predominant PsD
as a consequence of genetic predisposition, environmental triggers (such as is associated with HLA-​B*57:01 and HLA-​C*06:02, is TH1 cell-​driven and is
biomechanical or metabolic stress, infections and obesity) and local factors responsive to IL-17 and IL-23 inhibition. Entheseal-​predominant psoriasis with
according to disease site (joints, skin, spine or entheses). Amplification of the or without axial disease, which is associated with the HLA-​B*27:05:02 allele,
IL-23–IL-17 axis is initiated via activation of innate cells in the skin, entheses and involves engagement of both TH1 and TH17 cells that produce both TNF and
gastrointestinal tract, ultimately resulting in the expansion of CD4+ and CD8+ IL-17 , and is responsive to TNF and IL-17 inhibition. Psoriatic arthritis mutilans
T helper 1 (TH1) and TH17 cells, which are expanded by IL-23 and IL-12 and (PAM) probably represents a combination of these host genetic factors and
produce TNF and IL-17. Different HLA alleles and/or haplotypes, T cell subsets T cell interactions. CXCR3, CXC-​chemokine receptor 3; CCR, CC-​chemokine
and treatment response profiles are associated with different PsD phenotypes. receptor; IL-12R, IL-12 receptor; IL-23R, IL-23 receptor. Reprinted from ref.53,
Synovial-​predominant PsD is associated with HLA-​B*08:01:01, HLA-​C*07:01:01 Springer Nature Limited.

6 | Article citation ID: (2021) 7:59 www.nature.com/nrdp

0123456789();:
 Primer

Joint erythema
research partners to identify descriptive elements of seems similar to that observed in ankylosing spondylitis,
Joint erythema is one of the inflammatory joint disease. The symptoms identified although asymmetrical sacroiliac involvement is more
features of an inflamed joint or included early morning stiffness for >30 min, joint ten- common80,81.
arthritis when the joint is red in derness, pain aggravated by rest and relieved by exercise,
appearance.
symptoms improved by NSAIDs or corticosteroid use, Classification
Dactylitis joint erythema or warmth and related fatigue. Possible The first classification system developed for PsA was
Dactylitis is sausage-​like clinical signs included joint swelling, limited motion and that of Moll and Wright, which was developed based on
swelling of a finger or toe. joint deformity66. clinical observation, and was the key classification used
In terms of peripheral arthritis, the presentation is until 2006 (ref.62). In the Moll and Wright classification,
similar to that in most forms of inflammatory arthri- PsA is defined as an inflammatory arthritis (peripheral
tis, although the pattern of joint involvement can vary, arthritis and/or sacroiliitis or spondylitis) in the pres-
with oligoarticular and polyarticular patterns described. ence of psoriasis with the (usual) absence of serological
Distal interphalangeal joint involvement is more com- tests for rheumatoid factor62. However, the criteria focus
mon in patients with PsA than in those with other forms on peripheral arthritis rather than on other aspects of the
of inflammatory arthritis67. The clinical presentation of musculoskeletal disease, such as enthesitis, and require
musculoskeletal inflammation can be helpful in differ- a negative rheumatoid factor test, which is an issue in a
entiating between PsA and other forms of inflammatory minority of patients82.
arthritis (Table 1). In addition to peripheral arthritis, Over the decades, a number of other classification
patients often present with inflammation in other musculo­ systems have been developed but none of these classi-
skeletal tissues including the following: enthesitis, fications was utilized widely in clinical research until
observed in up to 67% of patients on presentation68–73; the introduction of the CASPAR system. In 2000,
dactylitis, observed in 12–39% of patients68–74; and axial a large international consortium of rheumatologists
involvement within the axial spondyloarthritis pheno­ came together to develop a new, robust and data-​driven
type, observed in 5–28% of patients at diagnosis but classification, which was finally published in 2006. The
potentially in up to 70% of patients with late-​stage CASPAR system considers a wider range of items for
disease68–73. Although the vast majority of patients inclusion, overlapping with the criteria of Moll and
presenting with PsA have peripheral musculoskeletal Wright but also allows classification of people without
involvement, the prevalence of axial disease in isolation psoriasis (~10% of patients) or with a positive rheuma-
with psoriasis has been reported to be 7–17% in a few toid factor (~15% of patients), provided the patients have
cohorts72,75. other key features of the disease20. In the development
cohort, CASPAR had a high sensitivity and specificity20,
Laboratory testing and these findings have been confirmed in numerous
The reason for the diagnostic delay in PsA compared independent studies subsequently83–85.
with rheumatoid arthritis may be partly related to the In early disease, classification according to CASPAR
lack of specific investigations to confirm the diagnosis may not be as straightforward as in established disease
(Table 1). Primary care physicians typically use inflam- but specificity has been confirmed to be >95%. There is
matory markers including CRP, specific antibodies, an issue of lower sensitivity in early inflammatory arthri-
such as rheumatoid factor, or anti-​citrullinated peptide tis as some typical features may not yet be present71,86. In
to screen patients with possible inflammatory arthritis. particular, typical new bone formation is not common at
Patients with PsA are usually seronegative, although a presentation, thereby limiting the ability to identify the
positive rheumatoid factor or anti-​citrullinated pep- disease. Another issue raised with CASPAR is the heavy
tide does not exclude the condition. At presentation, weighting given to ongoing psoriasis. Whilst the major-
only 33–89% of patients demonstrated elevated CRP ity of patients do fulfil this criterion, the criteria are
levels68,70,75,76; thus, a substantial proportion of patients difficult to meet if a patient’s psoriasis has been treated
do not have raised blood markers despite active disease. and gone into remission. Potentially, a clear diagnosis of
Studies have identified typical imaging features in psoriatic skin or nail disease by a dermatologist should
PsA, which are included in the classification criteria. be given a weighting similar to ongoing active psoriasis.
These imaging features are more prevalent with increas- The next step proposed for the CASPAR classifica-
ing disease duration. In early disease, radiographs often tion is most likely to involve clarifying the ‘stem’ of the
appear normal as bone damage has not occurred and criteria, which state that patients must have inflamma-
therefore radiographs often do not assist in diagnosis. tory articular disease (joint, spine or enthesis). From a
A 2003 study in patients with peripheral arthritis found rheumatology perspective, where we are trying to differ-
that 27% of patients had erosions at presentation, and the entiate PsA from other types of inflammatory arthritis,
findings were similar in the 2015 Tight Control of PsA this is straightforward. Rheumatologists are confident
(TICOPA) study77. However, in both studies, the amount in identifying inflammatory arthritis and can then use
of erosive disease observed was relatively small, affecting CASPAR to confirm if this is likely to be PsA. However,
only a few joints in most of the patients imaged. for dermatologists and primary care physicians, the
Given the potential for axial involvement, imaging of key issue is the diagnosis of inflammatory articular
the spine and sacroiliac joint can also show abnormal- disease in patients who have known psoriasis. Here,
ities in patients with PsA. Again, axial involvement is the psoriasis is often clear, but it may be difficult for
more prevalent in late disease stages, with limited value non-​rheumatologists to accurately differentiate inflam-
in early diagnosis78,79. Sacroiliac joint involvement in PsA matory articular disease (as required for CASPAR)

NATURE REvIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:59 7

0123456789();:
Primer

PEST questionnaire
from other causes of musculoskeletal pain, for example, across different questionnaires93. The CONTEST ques-
A questionnaire designed osteoarthritis and mechanical joint pain. tionnaire, developed from a combination of the best-​
to screen for psoriatic arthritis performing questions in each questionnaire did not
in patients with psoriasis. Prognosis out-​perform the Psoriasis Epidemiology Screening Tool
Predicting outcomes in patients with PsA is based (the PEST questionnaire) in a subsequent study95. Most
on limited data with substantial individual variation. studies have shown high sensitivity and low specificity
Multiple studies have shown that the evolution of PsA as joint symptoms related to other diagnoses are com-
can vary over time with different joint and extra-​articular mon. Studies have also shown difficulty in identifying
involvement87. The pattern of peripheral joint disease patients, in particular those with pure axial disease.
does seem to change over time, with oligoarthritis more Whilst screening tools are not perfect, some studies have
common in patients with early disease than in those with found a reasonable benefit in using them. It is recom-
late disease. In most cases, increased joint involvement mended that the PEST questionnaire, which is the short-
is observed over time with increasing disease duration, est questionnaire available, is used annually in patients
with a high proportion of patients with monoarthritis or with psoriasis in the UK96. The questionnaires also indi-
oligoarthritis showing progression to polyarthritis87,88. rectly provide education to patients with psoriasis who
Involvement of other domains can also change over time, are then aware of the potential for the development of
in particular axial involvement is increasingly common psoriasis-​related arthritis.
with increasing disease duration78,89. However, axial
spondyloarthritis and specifically axial PsA can be dif- Prevention
ficult to diagnose as clear evidence of axial involvement In collaboration between dermatology and rheumatol-
with radiographic changes and restriction of mobility is ogy, studies monitoring patients with psoriasis aiming to
likely to take many years to develop. predict the development of PsA are underway. To date,
Previous studies have identified a number of poor these studies have predominantly confirmed known
prognostic markers in PsA. These markers are often predictors of PsA development97. In large populations,
included in published treatment recommendations to these findings might be used to develop predictive mod-
potentially aid treatment decisions, advising that more els that could be applied to individuals, which would
urgent or aggressive therapy should be started if the allow in-​depth study of the pathogenesis of disease in
poor prognostic markers are present. In terms of periph- a high-​risk population and may elucidate the triggers
eral arthritis, in particular, these markers relate to the involved in this continuum. Potentially, similar to the
number of joints involved (polyarthritis or five or more studies performed in rheumatoid arthritis, interven-
joints), or the presence of dactylitis, high levels of inflam- tional studies trying to prevent the development of
matory markers (for example, CRP) or baseline erosive disease could be established in high-​risk populations.
disease90,91. However, evidence around these risk factors Studies such as these would require collaborative efforts
is insufficient and it is not easy to predict outcomes in to recruit suitably sized populations and should include
individual patients. Many of these studies have focused patient representation within their design to ensure that
solely on radiographic damage as the poor outcome the studies are acceptable to patients and that individual
of interest, which also affects the prognosis. Overall, patients are educated about their potential risk and what
although oligoarthritis is less likely than polyarthritis to this may mean for them in the future.
cause radiographic damage in the hands or feet, it may
have a marked impact on QoL and functional ability92. Management
Prior to the year 2000, the pharmacological treatment
Screening options for PsA were essentially limited to NSAIDs,
Up to 30% of patients with psoriasis may go on to develop glucocorticoids, methotrexate, sulfasalazine and cyclo-
PsA. Although predicting this progression accurately at sporine. Only a few randomized therapeutic trials
an individual level is not currently possible, studies have specifically investigated PsA. Despite known clinical
identified key predictors of PsA development including differences between the conditions, it was assumed that
severity and site of psoriasis (for example, nails, scalp), evidence from clinical trials in rheumatoid arthritis
obesity, smoking and trauma19. Delay in diagnosis may could be extrapolated to PsA. Since the year 2000, the
be a particular issue in patients presenting with limited management of PsA has been revolutionized as a result
disease (for example, oligoarthritis) or involvement in of several developments. These advances include the
other domains, such as axial disease or enthesitis. development of numerous immunologically targeted
Given awareness of the delay in diagnosis and the biological disease-​modifying drugs (bDMARDs) and
associated consequences, education and interventions targeted synthetic drugs (tsDMARDs). Although these
focusing on primary care physicians, dermatologists and drugs were originally developed for the treatment of
patients to promote early diagnosis is ongoing. In par- rheumatoid arthritis, they have shown efficacy in other
ticular, studies have employed screening questionnaires conditions, including psoriasis, PsA and axial spondylo­
to identify potential patients with PsA, usually from arthritis. In addition, by identifying the importance of
amongst patients with psoriasis. A number of screen­ing pro-​inflammatory mediators and pathways, research
questionnaires have been developed but their sensitivity on the immunopathogenesis of PsA has helped reinforce
and specificity are limited93,94. Comparative studies, for the rationale for the effectiveness of targeted immuno­
example the CONTEST study, have shown similar levels therapies, and has also suggested new treatments.
of sensitivity (74.5–76.6%) and specificity (29.7–38.5%) Furthermore, research on the clinical aspects of PsA

8 | Article citation ID: (2021) 7:59 www.nature.com/nrdp

0123456789();:
 Primer

Table 3 | Outcome measures in clinical trials in PsA of non-​pharmacological therapies, including physical
and occupational therapy, psychotherapy and dietary
Domains Instruments approaches including weight reduction is beyond the
Arthritis 68/66 T/S joint count, ACR20/50/70 response, DAS28, scope of this Primer. These non-​pharmacological treat-
PsARC, PsAJAI, DAPSA, cDAPSA ments should be pursued in parallel with pharmacological
Enthesitis Leeds Enthesitis Index, SPARCC, MASES, four-​pointa treatment.
Dactylitis Leeds Dactylitis Index, Dactylitis Count, Dactylitis
Severity Score Adjunctive treatments
Axial spondyloarthritis BASDAI, BASFI, BASMI NSAIDs. NSAIDs are frequently used for symptomatic
improvement of pain associated with arthritis and peri­
Skin, nails PASI, target lesion, physician global, PSI, PSD, NAPSI, articular manifestations of PsA. Interestingly, and in
mNAPSI, nail VAS
contrast to rheumatoid arthritis, there is very little evi-
Composite — multidomain MDA, VLDA, PASDAS, CPDAI, GRACE dence addressing NSAID efficacy specifically in PsA.
Pain VAS, NRS One 12-​week RCT investigating the efficacy of celecoxib
Patient global VAS (joint global, skin + joints global), NRS did not demonstrate statistical superiority of cele­
coxib over placebo102. Nevertheless, many years of clinical
Physician global VAS (joint global, skin + joints global), NRS
experience suggests that NSAIDs can be a useful adjunct
Physical function HAQ, HAQ-​S, SF-36 PF, PROMIS-​PF in the management of various domains of PsA, includ-
HRQoL SF-36, PSAID, PsAQoL, DLQI, EQ5D, PROMIS-​Profiles ing peripheral arthritis, axial arthritis, enthesitis and
Fatigue FACIT-​Fatigue, VAS, PROMIS-​Fatigue dactylitis. Indeed, in axial disease, the lack of efficacy of
conventional synthetic DMARDs (csDMARDs) leaves
Participation PROMIS-​Social roles and participation
NSAIDs as the mainstay of therapy. Before the advent
Acute phase reactant ESR, CRP of biological agents, NSAIDs were commonly included
Structural damage Plain radiography (modified Sharp or van der Heijde– as concomitant therapies in trials of DMARDs in PsA.
Sharp), MRI, US
Work or home productivity WPAI, WPS Glucocorticoids. Although topical steroid medications
Data from refs81–83. ACR, American College of Rheumatology; BASDAI, Bath Ankylosing are commonly used to treat psoriasis and intra-​articular
Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; steroids used to treat flares in one or a few joints, sys-
BASMI, Bath Ankylosing Spondylitis Metrology Index; cDAPSA, clinical Disease Activity in temic steroids are not as commonly used in PsA as in
Psoriatic Arthritis; CPDAI, Composite Psoriatic Disease Activity Index; CRP, C-​reactive protein;
DAPSA, Disease Activity in Psoriatic Arthritis; DAS, Disease Activity Score; DLQI, Dermatology rheumatoid arthritis. In PsA, there is a need for caution
Life Quality Index; EQ5D, EuroQol five dimensions; ESR, erythrocyte sedimentation rate; when considering steroids for local tendon or enthe-
FACIT, Functional Assessment of Chronic Illness Therapy; GRACE, GRAPPA Composite Exercise; seal injection, as longer-​term efficacy is questionable
GRAPPA, Group for Research and Assessment of Psoriasis and Psoriatic Arthritis; HAQ, Health
Assessment Questionnaire; HAQ-​S, Health Assessment Questionnaire–Spondyloarthritis; owing to reports of tendon rupture103. The concern for
HRQoL, health-​related quality of life; MASES, Maastricht Ankylosing Spondylitis Enthesis steroid use in PsA partly comes from anecdotal experi-
Score; MDA, minimal disease activity; mNAPSI, Modified Nail Psoriasis Severity Index;
NAPSI, Nail Psoriasis Severity Index; NRS, numeric rating scale; PASDAS, Psoriatic Arthritis ence showing that skin psoriasis can flare dramatically
Disease Activity Score; PF, physical functioning; PROMIS, Patient-​Reported Outcomes upon abrupt discontinuation of steroids, usually at very
Measurement Information System; PsA, psoriatic arthritis; PSAID, Psoriatic Arthritis Impact high doses104.
of Disease; PsAJAI, Psoriatic Arthritis Joint Activity Index; PsAQoL, Psoriatic Arthritis Quality of
Life Index; PsARC, Psoriatic Arthritis Response Criteria; PASI, Psoriasis Area and Severity
Index; PSI, Psoriasis Symptom Inventory; PSD, Psoriasis Symptom Diary; SF-36, Short-​Form 36; Conventional synthetic DMARDs
SPARCC, Spondyloarthritis Research Consortium of Canada; T/S, tender/swollen; Methotrexate. Although methotrexate has been one
US, ultrasonography; VAS, visual analogue scale; VLDA, very low disease activity; WPAI,
Work Productivity and Activity Index; WPS, Work Productivity Survey. aUsed in the impact study. of the most widely used medications for PsA since the
1980s, very few studies have investigated the efficacy
has led to an increased appreciation of the complex of methotrexate in PsA105–107 (Box  1). Assessment of
and heterogeneous nature of the disease in individual the findings of these few studies suggested that doses
patients including peripheral arthritis, axial arthritis, of methotrexate of 15 mg/week or higher may be more
enthesitis, dactylitis, spondylitis, skin and nail psoriasis, effective than lower doses in PsA. In the Methotrexate
iritis and inflammatory bowel disease. These domains in Psoriatic Arthritis (MIPA) trial published in 2012,
need to be assessed individually to ensure that different the primary end point was not significantly different
manifestations are being treated appropriately. between patients receiving methotrexate and those
In addition, since the early 2000s, the development of receiving placebo108. However, design issues includ-
reliable and validated outcome measures to assess PsA ing the dose of methotrexate used affected assessment
clinical domains has helped optimize assessment in clin- of the data from that study. In addition, a subset analysis
ical trials98–101 (Table 3). Advances in imaging, including showed that methotrexate was effective in patients with
ultrasonography and MRI, have allowed more precise PsA whose disease was similar to rheumatoid arthritis
visualization of tissue inflammation and joint damage. (that is, polyarticular disease, with elevated acute phase
Besides standard randomized controlled trials (RCTs), reactants). In the study of etanercept and methotrexate
Treatment to target of strategy trials such as treatment to target of remission in combination or as monotherapy in patients with pso-
remission and head-​to-​head comparative trials are increasingly riatic arthritis (SEAM-​PsA) trial, methotrexate seemed
Treatment to target of being performed. In this section, we summarize the to perform well, achieving levels of articular, entheseal
remission is where treatment is
escalated according to patient
pharmacological treatment of PsA, focusing on specific and skin responses numerically close to those achieved
response until a target of classes of drugs, followed by a summary of treatment with TNF inhibition; of note, there was no placebo
remission has been achieved. recommendations and treatment strategies. A review comparator 109. Based on evidence from the SEAM

NATURE REvIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:59 9

0123456789();:
Primer

Box 1 | PsA therapeutic groups5 Biological DMARDs

TNF inhibitors. TNF is a pro-​inflammatory cytokine
Adjunctive therapies with myriad impacts on various aspects of the inflam-
• NSAIDs, glucocorticosteroids (oral, intra-​articular, matory and immune responses. TNF inhibitors (TNFi)
intramuscular or topical administration) are a landmark breakthrough in the therapy of PsA.
• Conventional synthetic DMARDs (cs-​DMARDs) Following success observed in rheumatoid arthritis,
• Methotrexate, sulfasalazine, leflunomide, cyclosporine the first evidence for this benefit in PsA came from a
• biological DMARDs (bDMARDs) trial demonstrating the effectiveness of etanercept in
• TNF inhibitors both articular and psoriasis domains113. Soon after,
-- Etanercepta, infliximaba, adalimumaba, golimumab, one study showed improvement in articular and pso-
certolizumab riasis domains as well as physical function, dactylitis
• IL-12/IL-23 inhibitors and enthesitis with infliximab therapy; in addition, the
-- Ustekinumab treatment slowed the progression of radiographic dam-
• IL-17 inhibitors age to peripheral joints in PsA114. Subsequently, studied
-- Secukinumab, ixekizumab, brodalumabb, TNFi, including adalimumab, golimumab and certo-
bimekizumabc lizumab, also showed efficacy across all PsA domains.
• IL-23 inhibitors All TNFi have also demonstrated benefit in ankylosing
-- Guselkumab, risankizumabb, tildrakizumabb spondylitis, used as surrogate evidence for efficacy in
• T cell modulator the axial component of PsA. With the introduction of
-- Abatacept biosimilar versions of several TNFi in many countries
around the world, the acquisition costs have decreased,
Targeted synthetic DMARDs
an important consideration that affects the utilization
• PDE4 inhibitor (apremilast)
of biological agents. Important, albeit infrequent, seri-
• JAK inhibitors (tofacitinib, upadacitinib; baricitinibc, ous side effects with TNFi include infection, including
filgotinibc)
opportunistic infection (particularly tuberculosis), and
a
Biosimilars available in 2021. bApproved for the treatment autoimmune reactions115.
of psoriasis but not psoriatic arthritis (PsA) at the time of
publication. cIn development. IL-12 or IL-23 inhibition. Ustekinumab is a human
IgG1 monoclonal antibody that binds to the common
p40 subunit of IL-12 and IL-23, the former involved
study as well as experience from global clinical practice, in differentiation and activation of TH1 cells and the
methotrexate remains an important therapy, especially latter in differentiation and activation of TH17 cells.
in parts of the world with limited health-​care resources. Downregulating these pathways can lead to reduction
When used with certain biological therapies, methotrex- of several key cytokines in the pathogenesis of pso-
ate can reduce immunogenicity. Nevertheless, metho- riasis and PsA, including IL-23, IL-17 and TNF. The
trexate can be associated with tolerability issues, such as efficacy of ustekinumab in PsA was confirmed in two
nausea, diarrhoea and fatigue, and laboratory monitor- phase III trials, across domains116,117. Of note, in derma-
ing for safety issues (for example, liver, haematological) tology, ustekinumab was the first biological agent that
is necessary. showed efficacy in skin psoriasis greater than that of
TNFi. Ustekinumab failed to show benefit in ankylosing
Sulfasalazine. Sulfasalazine is an oral medication that spondylitis118, although previously subjective axial symp-
has been shown to have modest efficacy in arthritis but toms did improve in a subset of patients with PsA119.
no significant benefit was demonstrated in psoriasis in Whether axial arthritis in PsA differs from ankylosing
an RCT110. Gastrointestinal tolerability issues as well spondylitis or whether the outcome measures used can
as allergic reactions may limit its utility, and labora- detect improvement in extra-​axial domains is a matter of
tory monitoring (for example, haematological, liver) is discussion. The safety profile of ustekinumab is benign
standard. overall, with low rates of serious infection.

Leflunomide. Leflunomide is an oral pyrimidine IL-17 inhibitors. IL-17 includes a family of related
antagonist, which has shown efficacy in arthritis end cytokines; IL-17A and IL-17F seem to be the most
points in a single placebo-​controlled study involving involved in pathogenesis of inflammatory disease.
190 patients with PsA111. Studies have demonstrated less IL-17 is produced by a wide variety of cells in the innate
robust results in other domains of PsA, especially skin. immune system including natural killer cells, γδ T cells,
Laboratory monitoring for liver function tests and blood neutrophils and mast cells, which line barrier sites such
counts is required. as the gut, skin and lung. Several, but not all, of these cell
types are activated by IL-23 produced by keratinocytes,
Cyclosporine. Cyclosporine is a calcineurin inhibitor macrophages and dendritic cells in response to micro-
that has demonstrated greater benefit in skin psoriasis bial agents. IL-17 plays a key part in preserving barrier
than in PsA but can also be effective for articular man- function in the gut and integrity of the epithelium.
ifestations. Laboratory monitoring for renal toxicity Two IL-17A inhibitors are currently approved for the
is needed, and hypertension can limit its use in some treatment of PsA in many jurisdictions. Secukinumab
patients112. is a human monoclonal IgG1 antibody that binds to

10 | Article citation ID: (2021) 7:59 www.nature.com/nrdp

0123456789();:
 Primer

IL-17A. All clinical domains of PsA demonstrated sig- Apremilast has a benign safety profile with no serious
nificant improvement, including particularly robust adverse effects such as infection, and does not need
improvement in psoriasis and in axial disease in PsA120. laboratory monitoring.
Ixekizumab is an IgG4 humanized monoclonal antibody
to IL-17A that has also shown efficacy in all clinical JAK inhibitors. The JAK–STAT kinase intracellular
domains of PsA, similar to that of secukinumab. In head-​ signalling system is critical for the induction of cellular
to-​head trials of both these agents against adalimumab, activation by cytokines involved in PsA pathogenesis,
skin psoriasis improved more with IL-17 inhibitors and including IL-23, IL-6 and IL-15. There are four JAK
articular domains were comparable121,122. Brodalumab molecules — JAK1, JAK2, JAK3 and TYK2. The first
is a human antibody that binds to the IL-17 receptor, JAK inhibitor to be approved for the treatment of PsA,
thereby resulting in broad inhibition of the IL-17 family. tofacitinib (which inhibits JAK3 and JAK1 more than
Brodalumab has been approved for the treatment of pso- JAK2), is effective in musculoskeletal domains and
riasis in many countries. Brodalumab has shown efficacy modestly beneficial for skin lesions137–139. The safety
in PsA similar to that of the other IL-17 inhibitors123,124. profile is similar to that seen in the treatment of rheu-
Bimekizumab, a humanized IgG1 monoclonal antibody matoid arthritis, which includes the risk of serious infec-
that binds to IL-17A and IL-17F, has shown efficacy in tion, the need for laboratory monitoring of liver function
all clinical domains of PsA in a phase II study and is tests and blood counts, and rare adverse effect of lym-
currently in phase III development125. phoma. Evidence suggests an increased risk of throm-
boembolic events if the medication is used at higher
IL-23 inhibitors. The first IL-23 inhibitor to be approved than the recommended dose, which may be a class
worldwide for the treatment of PsA is guselkumab, effect139. Other JAK inhibitors in development for the
a p19 IL-23 inhibitor that specifically targets IL-23 treatment of PsA include the selective JAK1 inhibitors,
(distinct from ustekinumab, which binds to the p40 upadacitinib and filgotinib140,141, and the TYK2 inhibitor,
unit and inhibits IL-12 and IL-23). IL-23 is a key pro-​ deucravacitinib142,143. Whether differential selectivity for
inflammatory cytokine in psoriasis and, indeed, its JAK isoforms impacts efficacy across domains of PsA or
inhibition yields the most complete reduction of pso- toxicity remains to be determined.
riasis manifestations compared with other biological
agents126. Efficacy data in arthritis, enthesitis and dac- Treatment strategies
tylitis domains of PsA is robust, similar to the data from Treat-​to-​target. As in other fields of medicine, striving
RCTs of TNFi and IL-17 inhibitors127,128. A sub-​study for a treatment target of remission has become common
of patients with back pain and radiographic evidence of practice if possible, or low disease activity if not. Such a
sacroiliitis demonstrated symptomatic improvement strategy yields optimal short-​term and long-​term out-
of spinal pain (Bath Ankylosing Spondylitis Disease comes for the patient. Numerous treat-​to-​target trials
Activity Index, BASDAI question 2 )129. This prelimi- have been conducted in rheumatoid arthritis, utiliz-
nary finding in patients with axial PsA will be further ing quantifiable measures of disease activity, typically
explored as studies of IL-23 inhibitors in ankylosing including numerically assessed physical examinations,
spondylitis failed to demonstrate efficacy compared such as joint counts, quantified patient self-​assessment
with placebo, suggesting that IL-23 is not a driver of and laboratory measures of disease activity, such as
inflammation in that condition130. Phase II studies CRP. The Tight Control of Psoriatic Arthritis (TICOPA)
of risankizumab131 and tildrakizumab132 demonstrated trial77, conducted in patients with early-​stage PsA, com-
results consistent with those of the phase III studies of pared patients evaluated monthly and requiring inten-
guselkumab. Studies have shown minimal evidence sification of treatment if a goal of Minimal Disease
of serious infection with IL-23 inhibitors. Activity (MDA) activity was not met with patients eval-
uated every 3 months without such a target of treatment.
Costimulatory blockade. Abatacept (CTLA4 immuno- After 48 weeks, the patients in the treat-​to-​target group
globulin) is a recombinant human fusion protein that demonstrated superior treatment results, supporting
binds to CD80/CD86 on antigen-​presenting cells, pre- this goal of treatment in clinical practice. Notably, many
venting interaction with CD28 on T cells. A phase III treat-​to-​target studies are tautological, in as much as the
trial in which the majority of patients had failed treat- requirement to alter therapy to achieve a goal results in
ment with TNF inhibitors demonstrated modest benefit greater achievement of the goal using similar metrics.
of abatacept in arthritis and minimal benefit in psoriasis Factors such as longer-​term outcomes, safety consider-
compared with placebo133. Although the effects of abat- ations and pharmacoeconomic assessments should also
acept are modest, one advantage of the medication is its be taken into account in therapeutic decision-​making.
relatively benign safety profile.
Treatment recommendations. Four international
Targeted synthetic DMARDs organizations have published and updated PsA treat-
PDE4 inhibitor. The oral phosphodiesterase 4 (PDE4) ment recommendations — the Group for Research
inhibitor apremilast may downregulate a number of and Assessment of Psoriasis and Psoriatic Arthritis
BASDAI question 2 key pro-​inflammatory cytokines involved in the patho- (GRAPPA), the European League Against Rheumatism
A questionnaire commonly
used to assess disease activity
genesis of psoriasis and PsA, including TNF and IL-23. (EULAR), and the American College of Rheumatology
in patients with ankylosing Studies have shown modest efficacy of apremilast in pso- and National Psoriasis Foundation in collaboration
spondylitis. riatic skin lesions, arthritis, enthesitis and dactylitis134–136. (ACR–NPF). The GRAPPA recommendations144 were

NATURE REvIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:59 11

0123456789();:
Primer

developed by rheumatologists, dermatologists and active domains, whilst being cognizant of potential
patients with PsA and are organized across the domains adverse events. A greater understanding of the disease
of PsA, including peripheral arthritis, axial disease, pathophysiology has allowed us to precisely target key
enthesitis, dactylitis, skin psoriasis and nail psoriasis, cellular and cytokine pathways. Treatment effect with
as well as inflammatory bowel disease and uveitis. The any single agent may wane; hence, multiple classes of
EULAR guidelines145 overall yield recommendations medicine and choices of individual agents are needed to
similar to the GRAPPA recommendations, but are sustain treatment targets.
arranged in an algorithm sequence from early and/or
mild disease to more advanced disease in patients in Quality of life
whom previous treatments have failed. The ACR–NPF PsA has a substantial negative impact on physical func-
guidelines146 used a strict Grades of Recommendation tion and QoL (Box  2). The concept of QoL extends
Assessment, Development and Evaluation (GRADE) beyond the physical manifestations of disease to include
approach. The guidelines choose one class or group emotional well-​being, self-​esteem, participation in work
of medicines ahead of another, allowing for variances and activities as well as non-​health issues such as finan-
depending on contextual factors, such as the presence of cial security, spiritual well-​being and environmental
severe skin disease. One key difference among the three safety (Fig. 3). PsA has a similar effect on QoL to that
guidelines is the recommendation to use TNFi prior to observed in rheumatoid arthritis despite generally being
csDMARDs, based on efficacy and safety data from clin- a less destructive arthropathy. The negative effect of PsA
ical trials. In the absence of head-​to-​head trials available seems to be due to the accumulated burden of skin, joint,
when these guidelines were developed, the majority of entheseal, axial disease, comorbidities and flare147,148.
recommendations are considered ‘conditional’ as the Pain is ranked consistently in qualitative studies as the
comparative evidence is indirect. Importantly, there are top priority in patients as an outcome of treatment, but
also additional regional and societal guidelines, devel- fatigue, physical function, ability to work and social
oped with less rigor, which present the clinician with a participation all rank highly149,150. An observational
heterogeneous group of treatment guidelines to follow. study in patients with early PsA and rheumatoid arthri-
Overall, there are numerous biopharmacological tis has shown that despite severe disease at diagnosis,
therapeutic options for the management of PsA. Most near-​normalization of health-​related QoL is observed in
treatment options have the potential to be effective in patients with rheumatoid arthritis after 5 years but not
all clinical domains of the disease. However, in many in those with PsA, possibly owing to diagnostic delay151.
patients, cross-​domain efficacy can be variable, efficacy The delay in diagnosis in PsA is longer than that in rheu-
may not be achieved or may soon be lost, and true remis- matoid arthritis and is associated with worse clinical and
sion is not frequent. Clinicians must, therefore, assess functional outcomes64,65.
each domain on a regular basis and aim to achieve
remission or low disease activity across the different Assessment of QoL
The understanding of treatment outcomes important
to patients has advanced considerably since the 2010s.
Box 2 | Patient experience Improving QoL is clearly a high-​priority outcome of
treatment for patients150. All RCTs and observational
The statement provided has not been edited and the patient’s emphases remain
in place. studies of PsA have confirmed the importance of assess-
The advent of effective DMARDs has changed the perspective of people with ing QoL152. Instruments for measuring QoL may be
psoriatic arthritis (PsA) for the better. When I was diagnosed with PsA after a delay generic, applicable across diseases or the general pop-
of 5 years suffering from severe psoriasis and unexplained joint pain, I was left with ulation, or disease-​specific, attributing the measured
indomethacin. It could not prevent serious damage of one knee, a radical synovectomy effect to the particular disease under consideration.
followed by a total knee replacement ten years later. I lost my job as a company trainer Disease-​specific QoL instruments cover concerns that
and became depressed, hardly able to take care of my family. are specific and relevant to the group of patients with
Starting anti-​TNF became a life-​changing event. I joined a local patient hydrotherapy the condition. Generic measures of QoL commonly
group and became a volunteer at an arthritis patient organization. I got to know used in PsA include the Medical Outcome Study 36-​item
other patients and their stories inspired me to read information about rheumatology
short form questionnaire (SF-36)153 and the EuroQoL
research. It made me aware about my responsibility for my own health. Too long I had
unconditionally followed my rheumatologist’s advice and still feeling isolated and five dimensions questionnaire (EQ5D)154. The SF-36
loosing many friends. Receiving an effective treatment motivated me to give something scores eight subdomains and aggregates the score into
back to society and changed my perspective on health care delivery and research. two summary domains of physical and mental health,
I learned the principles of self-​management, which enabled me to cope better with and there are data supporting its validity in PsA100. The
residual symptoms and limitations. For me remission is not the ultimate goal if that EQ5D is available as an index (with country-​specific
means to further increase the methotrexate dose. Communication with my adjustments) or visual analogue scale. Disease-​specific
rheumatologist is improved, I dare to ask more questions and we discuss existing instruments include the Psoriatic Arthritis Quality
guidelines. Sometimes a specialized arthritis nurse monitors my disease, and it is good of Life (PsAQoL) index155 and the Psoriatic Arthritis
to see that she not only asks how my joints are doing but also asks for skin symptoms. Impact of Disease (PSAID) score149. The PSAID has been
Over the years the diagnosis and care of people with PsA has improved. I have
provisionally recommended by the Outcome Measures
developed a positive outlook on my future and, despite the fact that we have not found
the Holy Grail of curing the disease, I am optimistic about the perspective for newly in Rheumatology (OMERACT) for use in RCTs and
diagnosed people who is promising. observational studies in PsA156. The PSAID can be used
in the 9-​item or 12-​item versions, and captures infor-
-​Anon
mation in 0–10 numerical rating scales for pain, fatigue,

12 | Article citation ID: (2021) 7:59 www.nature.com/nrdp

0123456789();:
 Primer

Financial burden
Patients’ experiences of the disease vary considerably.
One of the concerns of patients is the financial impact
of the disease152,160. Psoriasis alone has a considerable
Psychological
• Depression impact on socioeconomic status161. The impact of PsA
• Anxiety on finances may be through lost work productivity162,163,
• Embarrassment direct medical costs, and insurance and pension costs,
and the broader financial impact on the family. Up to
50% of people with PsA become unemployed and those
able to attend work report reduced effectiveness (presen-
teeism)164. A study of work disability found that treatment
of active PsA was associated with a 40% improvement in
work disability following 6 months of treatment with bio-
Quality logical therapy165. In a Danish study of health-​care and
of life public transfer (allowance) costs in patients with PsA,
for PsA
the relative risk for being on disability pension 5 years
Physical Social prior to PsA diagnosis was 1.36 (95% CI 1.24–1.49) com-
• Pain • Work and productivity pared with the general population, rising to 1.60 (95%
• Psoriasis • Financial burden CI 1.49–1.72) at the time of diagnosis and 2.69 (95% CI
• Fatigue • Social participation 2.40–3.02) 10 years after diagnosis, where 21.8% of the
• Physical function • Stigmatization
• Stiffness • Intimacy and/or patients with PsA received disability pension166.
• Flare sexual relationships
Psychological impact of PsA
People living with PsA suffer from a range of psycholog-
ical impacts including disturbed sleep, fatigue, low-​level
stress, depression, mood and behavioural changes, and
Fig. 3 | The complex model of quality of life for patients with PsA. The negative poor body image162. Responses to pain differ between
impact of psoriatic arthritis (PsA) on the quality of life (QoL) occurs through a complex individuals, depending on a variety of psychological
interplay of physical, psychological and social domains. The Venn diagram lists the factors including each individual’s personality struc-
individual elements that impact QoL within each domain. ture, cognition and attention to pain162. Fatigue is now
recognized as one of the core domains to be measured
skin, work, function, discomfort, sleep, coping, anxiety, in RCTs in PsA, and fatigue seems to negatively affect
embarrassment, social participation and depression patients’ QoL and work167–169. Anxiety and depression are
individually and as a summary score. known to be prevalent amongst people living with PsA.
In a systematic literature review of 24 studies including
Personal and professional QoL 31,227 people with PsA, the pooled estimate of the pro-
With the development of improved patient-​reported portion of individuals living with anxiety was 33% (95%
measures of QoL, such as the PSAID, large observational CI 17–53%) and of those living with depression was up
studies to quantify the impact of disease on QoL have to 51%170.
been feasible. Despite being on treatment, a global study
in 1,286 patients from eight countries identified high Multidisciplinary patient care
levels of residual disease impact, including moderate or The burden of PsA beyond musculoskeletal manifes-
major impacts of PsA on physical activity (78%), ability tations has been increasingly recognized. This need
to perform certain activities (76%), work productivity highlights the importance of a patient-​centred holis-
(62%) and career path (57%)157. Skin or nail symptoms tic approach in the care of patients living with PsA.
occurred in 80% of patients. Overall, 69% of patients Different models of multidisciplinary care led by rheu-
reported that PsA had a moderate to major impact on matologists or dermatologists, together with specialized
emotional or mental well-​being, 56% on romantic rela- nurses, psychologists and various therapists, have been
tionships or intimacy, and 44% on relationships with explored171. The evidence showing favourable outcomes
family and friends. Social impacts included emotional are preliminary172, and further studies to better under-
distress (58%), social shame or disapproval (32%) and stand sustainable outcomes are required. Nonetheless,
cessation of participation in social activities (45%)157. awareness of the multidimensional needs of these
The relative impact of each domain of the disease is patients remains the key to improving their care.
uncertain. Evidence suggests that joint pain is most
strongly associated with reduced QoL in people with Outlook
PsA but that resolution of skin disease is required for Although the field of PsA has continued to evolve sub-
optimal QoL. Pain from joint disease is often ranked stantially over the past two decades, a number of out-
as the highest priority to patients and was the highest standing gaps in basic, translational and clinical research
ranked outcome in the PSAID development studies and remain unmet. There are several knowledge-​based needs
a UK multicentre study149,150. However, improving skin for further basic or translational advances in the field.
and joint disease symptoms is important to achieving First, a more detailed characterization of genetic and
optimal improvement in QoL158,159. environmental factors that determine disease initiation

NATURE REvIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:59 13

0123456789();:
Primer

is needed1. Although several genome-​wide association in this endeavour, including spatial transcriptomics178,
studies have contributed to the understanding of disease ECCITE-​seq179 and other variations of single-​cell res-
pathogenesis, multiple questions are yet to be answered. olution sequencing technologies. In turn, these tech-
For instance, why the concordance rate for PsA is <20% nologies can aid in precision medicine approaches and
in monozygotic twins and the precise role of epigenetic treatment strategies based on synovial biopsy and/or
modifications, environmental exposures, biomechanical synovial fluid cellular or molecular pathways. Critically,
stress and infections (including gut and skin dysbiosis) big data analytics that incorporate clinical, genetic, envi-
in the triggering of synovio-​entheseal disease are yet to ronmental and immunological variables into predictive
be determined. Furthermore, the cellular and molecular algorithms for diagnostics and therapeutics are emerg-
drivers of disease perpetuation remain to be fully eluci- ing and should serve as examples for bringing precision
dated. This understanding is of high relevance as most medicine initiatives into the management of PsA.
of the latest advances in therapeutics were derived from As these tools become available, applying the knowl-
the discovery of a handful of unique, disease-​specific tar- edge generated into avenues for new therapeutic par-
gets, most notably IL-17 and IL-23 cytokines and/or their adigms will be essential. As discussed, the current
receptors. A more expansive and detailed characterization approach of monotherapy strategies to improve the
of T resident memory cells56, innate cells (that is γδ T cells, outcomes of a multidomain, multicytokine condition,
innate lymphoid cells and natural killer cells)173 and newly such as PsA, may be inadequate. Altering the treatment
discovered players should include not only their mole­ strategies by implementing multitarget approaches may
cular and functional capacity, but also their spatial inter- prove more efficacious180. Such combination therapy
actions, homing features and migratory patterns so that has shown efficacy in multiple neoplastic syndromes
their function or contribution in various compartments and is currently being tested in related conditions, such
can be studied and therapeutically addressed. as inflammatory bowel disease. A concrete example is
Concomitantly, there are multiple challenges to be the VEGA trial, which is testing the hypothesis that the
elucidated in the clinical realm. These include the need biological combination of a TNF inhibitor and an IL-23
for further characterization of factors associated with the inhibitor might be superior to monotherapy181.
development of PsA and the common definition of states Ultimately, the success of these endeavours will be
that precede clinically overt synovio-​enthesitis (that is, dependent on innovative work performed by clini-
what constitutes preclinical PsA). A related concept per- cal and translational researchers and industry part-
tains to the adequate timing of potential immunomod- ners, most likely through a team science approach.
ulatory interventions and even preventive strategies19. Multiple programmes have been launched that incor-
Another issue that is yet to be addressed is the meaning porate private–public partnerships to advance the
of imaging abnormalities present in patients with pso- field through collaborative efforts, using novel multi-
riasis without musculoskeletal symptoms174,175. A third disciplinary strategies. These programmes include the
unmet need involves the distinction between various NPF’s Psoriasis Prevention Initiative; the European
phenotypes of PsA and other forms of inflammatory Union’s Innovative Medicines Initiative (IMI)182 and the
arthritis (for example, axial PsA and axial spondylo­ Accelerating Medicines Partnership (AMP)183. IMI is
arthritis)176. Critically, and despite the achievement of a partnership between the European Commission and
remarkable outcomes in clearance of the skin with the the European Federation of Pharmaceutical Industries
newer generation of biological agents (such as IL-23 and and Associations. AMP is an NIH-​led pre-​competitive
IL-17 blockers), the use of the same molecular strategies effort including government, industry, academia and
has not proven superior to TNF blockade in terms of non-​profit organizations to harness collective capabil-
ameliorating peripheral arthritis or axial disease177. ities, scale and resources towards the development of
To overcome these challenges, multiple complemen- new therapies for complex, heterogeneous diseases. All
tary and potentially synergistic priorities are envisioned. three programmes have funded (or propose to fund)
First, incorporating digital biomarkers into the clinical large consortia of investigators in the field, which,
journey of patients with psoriatic disease should help combined with individual efforts, will be fundamental
address progression from psoriasis to PsA, flares and to enhancing the understanding of PsA pathogenesis,
treatment response. Second, an in-​depth study of cells diagnostics and new targets for better treatments as well
and associated inflammatory mediators that modulate as preventive strategies.
disease in the synovial, entheseal and axial tissues is
gradually materializing. Several platforms promise to aid Published online xx xx xxxx

1. Ritchlin, C. T., Colbert, R. A. & Gladman, D. D. 4. Bowes, J. et al. Confirmation of TNIP1 and IL23A as 7. Alinaghi, F. et al. Prevalence of psoriatic arthritis
Psoriatic arthritis. N. Engl. J. Med. 376, 2095–2096 susceptibility loci for psoriatic arthritis. Ann. Rheum. in patients with psoriasis: a systematic review and
(2017). Dis. 70, 1641–1644 (2011). meta-​analysis of observational and clinical studies.
A comprehensive review of psoriatic arthritis. 5. Hüffmeier, U. et al. Common variants at TRAF3IP2 are J. Am. Acad. Dermatol. 80, 251–265 (2019).
2. Winchester, R. & FitzGerald, O. The many faces associated with susceptibility to psoriatic arthritis and 8. Scotti, L., Franchi, M., Marchesoni, A. & Corrao, G.
of psoriatic arthritis: their genetic determinism. psoriasis. Nat. Genet. 42, 996–999 (2010). Prevalence and incidence of psoriatic arthritis: a
Rheumatology 59, i4–i9 (2020). 6. Menon, B. et al. Interleukin-17+CD8+ T cells are systematic review and meta-​analysis. Semin. Arthritis
3. Haroon, M., Kirby, B. & FitzGerald, O. High enriched in the joints of patients with psoriatic Rheum. 48, 28–34 (2018).
prevalence of psoriatic arthritis in patients with severe arthritis and correlate with disease activity and 9. Ogdie, A. et al. Prevalence and treatment patterns
psoriasis with suboptimal performance of screening joint damage progression. Arthritis Rheumatol. 66, of psoriatic arthritis in the UK. Rheumatology 52,
questionnaires. Ann. Rheum. Dis. 72, 736–740 (2013). 1272–1281 (2014). 568–575 (2013).
This paper demonstrates the large number This paper highlights the importance of IL-17- 10. Kaufman, B. P. & Alexis, A. F. Psoriasis in skin of color:
of patients with psoriatic arthritis attending producing CD8+ T cells in psoriatic arthritis Insights into the epidemiology, clinical presentation,
dermatology clinics. pathogenesis. genetics, quality-​of-life impact, and treatment of

14 | Article citation ID: (2021) 7:59 www.nature.com/nrdp

0123456789();:
 Primer

psoriasis in non-​white racial/ethnic groups. Am. J. 33. Elsawy, N. A., Helal, A. H., Abd ElHamid, H. A. & 55. Leijten, E. F. et al. Tissue-​resident memory CD8+
Clin. Dermatol 19, 405–423 (2018). Yousra Hisham, A.-F. Fibromyalgia in patients with T cells from skin differentiate psoriatic arthritis from
11. Weiss, P. F. & Roth, J. Juvenile- versus adult-​onset psoriatic arthritis: impact on disease activity indices, psoriasis. Arthritis Rheumatol. 73, 1220–1232
spondyloarthritis: similar, but different. Rheum. Dis. fatigue and health-​related quality of life. Int. J. Rheum. (2021).
Clin. North. Am. 46, 241–257 (2020). Dis. 24, 189–196 (2021). 56. Steel, K. J. A. et al. Polyfunctional, proinflammatory,
12. Petty, R. E. et al. International League of Associations 34. Bengtsson, K. et al. Incidence of extra-​articular tissue-​resident memory phenotype and function of
for Rheumatology classification of juvenile idiopathic manifestations in ankylosing spondylitis, psoriatic synovial interleukin-17A+CD8+ T cells in psoriatic
arthritis: second revision, Edmonton, 2001. arthritis and undifferentiated spondyloarthritis: arthritis. Arthritis Rheumatol. 72, 435–447 (2020).
J. Rheumatol. 31, 390–392 (2004). results from a national register-​based cohort study. 57. Polachek, A. et al. The association between HLA
13. Stoll, M. L., Lio, P., Sundel, R. P. & Nigrovic, P. Rheumatology 60, 2725–2734 (2021). genetic susceptibility markers and sonographic
Comparison of Vancouver and International League 35. Bradley, P. et al. Prevalence of extra-​articular enthesitis in psoriatic arthritis. Arthritis Rheumatol.
of Associations for Rheumatology classification criteria manifestations in psoriatic arthritis: a systematic 70, 756–762 (2018); erratum 71, 625 (2019).
for juvenile psoriatic arthritis. Arthritis Rheum. 59, review and meta-​analysis. Rheumatology 59, 58. Costello, P. J. et al. Psoriatic arthritis joint fluids
51–58 (2008). 2199–2206 (2020). are characterized by CD8 and CD4 T cell clonal
14. Southwood, T. R. et al. Psoriatic arthritis in children. 36. O’Rielly, D. D. & Rahman, P. Genetic, epigenetic and expansions appear antigen driven. J. Immunol. 166,
Arthritis Rheum. 8, 1007–1013 (1989). pharmacogenetic aspects of psoriasis and psoriatic 2878–2886 (2001).
15. Brandon, T. G., Manos, C. K., Xiao, R., Ogdie, A. & arthritis. Rheum. Dis. Clin. North Am. 41, 623–642 59. Cañete, J. D. et al. Ectopic lymphoid neogenesis in
Weiss, P. F. Pediatric psoriatic arthritis: a population-​ (2015). psoriatic arthritis. Ann. Rheum. Dis. 66, 720–726
based cohort study of risk factors for onset and 37. Li, Q. et al. Quantifying differences in heritability (2007).
subsequent risk of inflammatory comorbidities. among psoriatic arthritis (PsA), cutaneous psoriasis 60. Penkava, F. et al. Single-​cell sequencing reveals clonal
J. Psoriasis Psoriatic Arthritis 3, 131–136 (2018). (PsC) and psoriasis vulgaris (PsV). Sci. Rep. 10, 4925 expansions of pro-​inflammatory synovial CD8 T cells
16. Ringold, S. et al. 2019 American College of (2020). expressing tissue-​homing receptors in psoriatic
Rheumatology/Arthritis Foundation guideline for the 38. Winchester, R. et al. HLA associations reveal genetic arthritis. Nat. Commun. 11, 4767 (2020).
treatment of juvenile idiopathic arthritis: therapeutic heterogeneity in psoriatic arthritis and in the psoriasis 61. Abji, F., Pollock, R. A., Liang, K., Chandran, V. &
approaches for non-​systemic polyarthritis, sacroiliitis, phenotype. Arthritis Rheum. 64, 1134–1144 (2012). Gladman, D. D. Brief report: CXCL10 is a possible
and enthesitis. Arthritis Rheumatol. 71, 846–863 An important study of the HLA genetic associations biomarker for the development of psoriatic arthritis
(2019). in patients with psoriatic arthritis in comparison to among patients with psoriasis. Arthritis Rheumatol.
17. Karmacharya, P., Chakradhar, R. & Ogdie, A. The those with psoriasis only. 68, 2911–2916 (2016).
epidemiology of psoriatic arthritis: a literature review. 39. Okada, Y. et al. Fine mapping major histocompatibility 62. Moll, J. M. H. & Wright, V. Psoriatic arthritis. Semin.
Best. Pract. Res Clin. Rheumatol. 75, 101692 (2021). complex associations in psoriasis and its clinical Arthritis Rheum. 3, 55–78 (1973).
18. O’Rielly, D. D., Jani, M., Rahman, P. & Elder, J. subtypes. Am. J. Hum. Genet. 95, 162–172 (2014). 63. Holland, R. et al. Psoriatic arthritis is associated with
The genetics of psoriasis and psoriatic arthritis. 40. Bowes, J. et al. Cross-​phenotype association diagnostic delay and worse outcome at three months
J. Rheumatol. Suppl. 95, 46–50 (2019). mapping of the MHC identifies genetic variants when compared to rheumatoid arthritis: results from
19. Scher, J. U., Ogdie, A., Merola, J. F. & Ritchlin, C. that differentiate psoriatic arthritis from psoriasis. the UK National Audit for Inflammatory Arthritis
Preventing psoriatic arthritis: focusing on patients Ann. Rheum. Dis. 76, 1774–1779 (2017). [abstract FRI0514]. Ann. Rheum. Dis. 76, 685 (2017).
with psoriasis at increased risk of transition. Nat. Rev. 41. Winchester, R. & Fitzgerald, O. MHC class I 64. Tillett, W. et al. Smoking and delay to diagnosis are
Rheumatol. 15, 153–166 (2019). associations beyond HLA-​B27: the peptide binding associated with poorer functional outcome in psoriatic
This review is state of the art in assessing early hypothesis of psoriatic arthritis and its implications arthritis. Ann. Rheum. Dis. 72, 1358–1361 (2013).
psoriatic arthritis, risk factors and strategies for disease pathogenesis. Curr. Opin. Rheumatol. 32, 65. Haroon, M., Gallagher, P. & FitzGerald, O. Diagnostic
for future disease prevention. 330–336 (2020). delay of more than 6 months contributes to poor
20. Taylor, W. et al. Classification criteria for psoriatic 42. Haroon, M., Winchester, R., Giles, J. T., Heffernan, E. radiographic and functional outcome in psoriatic
arthritis: development of new criteria from a large & FitzGerald, O. Certain class I HLA alleles and arthritis. Ann. Rheum. Dis. 74, 1045–1050 (2015).
international study. Arthritis Rheum. 54, 2665–2673 haplotypes implicated in susceptibility play a role in 66. Mease, P. J., Garg, A., Helliwell, P. S., Park, J. J. &
(2006). determining specific features of the psoriatic arthritis Gladman, D. D. Development of criteria to distinguish
An important description of the CASPAR phenotype. Ann. Rheum. Dis. 75, 155–162 (2016). inflammatory from noninflammatory arthritis,
classification criteria. 43. Bowes, J. et al. Dense genotyping of immune-​related enthesitis, dactylitis, and spondylitis: a report from
21. Villani, A. P. et al. Prevalence of undiagnosed psoriatic susceptibility loci reveals new insights into the genetics the GRAPPA 2013 Annual Meeting. J. Rheumatol. 41,
arthritis among psoriasis patients: systematic review of psoriatic arthritis. Nat. Commun. 6, 7741 (2015). 1249–1251 (2014).
and meta-​analysis. J. Am. Acad. Dermatol. 73, 44. Apel, M. et al. Variants in RUNX3 contribute to 67. Eder, L. & Gladman, D. D. Psoriatic arthritis:
242–248 (2015). susceptibility to psoriatic arthritis, exhibiting further phenotypic variance and nosology. Curr. Rheumatol.
22. Ogdie, A. The preclinical phase of PsA: a challenge for common ground with ankylosing spondylitis. Arthritis Rep. 15, 316 (2013).
the epidemiologist. Ann. Rheum. Dis. 76, 1481–1483 Rheum. 65, 1224–1231 (2013). 68. Bonifati, C. et al. The diagnosis of early psoriatic
(2017). 45. Green, A. et al. Modifiable risk factors and the arthritis in an outpatient dermatological centre
23. Gupta, S., Syrimi, Z., Hughes, D. M. & Zhao, S. S. development of psoriatic arthritis in people with for psoriasis. J. Eur. Acad. Dermatol. Venereol. 26,
Comorbidities in psoriatic arthritis: a systematic psoriasis. Br. J. Dermatol. 182, 714–720 (2020). 627–633 (2012).
review and meta-​analysis. Rheumatol. Int. 41, An important sudy of modifiable risk factors for the 69. Kane, D., Stafford, L., Bresnihan, B. & FitzGerald, O. A
275–284 (2021). development of psoriatic arthritis in patients with prospective, clinical and radiological study of early
24. Kumthekar, A. & Ogdie, A. Obesity and psoriatic psoriasis. psoriatic arthritis: an early synovitis clinic experience.
arthritis: a narrative review. Rheumatol. Ther. 7, 46. Thorarensen, S. M. et al. Physical trauma recorded in Rheumatology 42, 1460–1468 (2003).
447–456 (2020). primary care is associated with the onset of psoriatic 70. Moghaddassi, M., Shahram, F., Chams-​Davatchi, C.,
25. Karmacharya, P., Ogdie, A. & Eder, L. Psoriatic arthritis among patients with psoriasis. Ann. Rheum. Najafizadeh, S. R. & Davatchi, F. Different aspects of
arthritis and the association with cardiometabolic Dis. 76, 521–525 (2017). psoriasis: analysis of 150 Iranian patients. Arch. Iran.
disease: a narrative review. Ther. Adv. Musculoskelet. 47. Schett, G. et al. Enthesitis: from pathophysiology Med. 12, 279–283 (2009).
Dis. 13, 1759720X21998279 (2021). to treatment. Nat. Rev. Rheumatol. 13, 731–741 71. Coates, L. C. et al. Sensitivity and specificity of the
26. Ogdie, A. & Weiss, P. The epidemiology of psoriatic (2017). classification of psoriatic arthritis criteria in early
arthritis. Rheum. Dis. Clin. North Am. 41, 545–568 48. Teng, Y. et al. Infection-​provoked psoriasis: induced psoriatic arthritis. Arthritis Rheum. 64, 3150–3155
(2015). or aggravated (Review). Exp. Ther. Med. 21, 567 (2012).
27. Dubreuil, M. et al. Diabetes incidence in psoriatic (2021). 72. Niccoli, L. et al. Frequency of iridocyclitis in patients
arthritis, psoriasis and rheumatoid arthritis: a UK 49. FitzGerald, O., Haroon, M., Giles, J. T. & Winchester, R. with early psoriatic arthritis: a prospective, follow up
population-​based cohort study. Rheumatology 53, Concepts of pathogenesis in psoriatic arthritis: study. Int. J. Rheum. Dis. 15, 414–418 (2012).
346–352 (2014). genotype determines clinical phenotype. Arthritis Res. 73. Reich, K., Kruger, K., Mossner, R. & Augustin, M.
28. Ogdie, A. et al. Risk of incident liver disease in Ther. 17, 115 (2015). Epidemiology and clinical pattern of psoriatic
patients with psoriasis, psoriatic arthritis, and 50. Gilis, E. et al. The role of the microbiome in gut arthritis in Germany: a prospective interdisciplinary
rheumatoid arthritis: a population-​based study. and joint inflammation in psoriatic arthritis and epidemiological study of 1511 patients with plaque-​
Physiol. Behav. 176, 139–148 (2019). spondyloarthritis. J. Rheumatol. Suppl. 94, 36–39 type psoriasis. Br. J. Dermatol. 160, 1040–1047
29. Lukmanji, A., Basmadjian, R. B., Vallerand, I. A., (2018). (2009).
Patten, S. B. & Tang, K. Risk of depression in patients 51. Abusleme, L. & Moutsopoulos, N. IL-17: overview and 74. Gladman, D. D., Ziouzina, O., Thavaneswaran, A.
with psoriatic disease: a systematic review and meta-​ role in oral immunity and microbiome. Oral. Dis. 23, & Chandran, V. Dactylitis in psoriatic arthritis:
analysis. J. Cutan. Med. Surg. 25, 257–270 (2020). 854–865 (2017). prevalence and response to therapy in the biologic
30. Mease, P. J. Fibromyalgia, a missed comorbidity in 52. Schluter, J. et al. The gut microbiota is associated era. J. Rheumatol. 40, 1357–1359 (2013).
spondyloarthritis: prevalence and impact on with immune cell dynamics in humans. Nature 588, 75. Torre Alonso, J. C. et al. Psoriatic arthritis (PA):
assessment and treatment. Curr. Opin. Rheumatol. 303–307 (2020). a clinical, immunological and radiological study
29, 304–310 (2017). 53. Jadon, D. R., Stober, C., Pennington, S. R. & of 180 patients. Br. J. Rheumatol. 30, 245–250
31. Lubrano, E., Scriffignano, S., Morelli, R. & Perrotta, F. FitzGerald, O. Applying precision medicine to (1991).
Assessment of widespread and extra-​articular pain in unmet clinical needs in psoriatic disease. Nat. Rev. 76. Scarpa, R. et al. Early psoriatic arthritis: the clinical
psoriatic arthritis: a case-​control study. J. Rheumatol. Rheumatol. 16, 609–627 (2020). spectrum. J. Rheumatol. 35, 137–141 (2008).
https://doi.org/10.3899/jrheum.201163 (2021). This article discusses unmet clinical needs in 77. Coates, L. C. et al. Effect of tight control of
32. Michelsen, B. et al. Do depression and anxiety reduce psoriatic arthritis focusing on joint damage and inflammation in early psoriatic arthritis (TICOPA):
the likelihood of remission in rheumatoid arthritis treatment response prediction. a UK multicentre, open-​label, randomised controlled
and psoriatic arthritis? Data from the prospective 54. Queiro, R. et al. HLA-​C locus alleles may modulate the trial. Lancet 386, 2589–2598 (2015).
multicentre NOR-​DMARD study. Ann. Rheum. Dis. 76, clinical expression of psoriatic arthritis. Arthritis Res. 78. Chandran, V., Barrett, J., Schentag, C. T., Farewell, V. T.
1906–1910 (2017). Ther. 8, R185 (2006). & Gladman, D. D. Axial psoriatic arthritis: update on a

NATURE REvIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:59 15

0123456789();:
Primer

longterm prospective study. J. Rheumatol. 36, Leeds Enthesitis Index (LEI), Spondyloarthritis post-​hoc analyses from two phase III, multicentre,
2744–2750 (2009). Research Consortium of Canada (SPARCC), Maastricht double-​blind, placebo-​controlled studies (PSUMMIT-1/
79. Battistone, M. J., Manaster, B. J., Reda, D. J. & Ankylosing Spondylitis Enthesis Score (MASES), Leeds PSUMMIT-2). Ann. Rheum. Dis. 75, 1984–1988
Clegg, D. O. The prevalence of sacroilitis in psoriatic Dactylitis Index (LDI), Patient Global for Psoriatic (2016).
arthritis: new perspectives from a large, multicenter Arthritis, Dermatology Life Quality Index (DLQI), 120. Baraliakos, X. et al. Secukinumab in patients with
cohort. A Department of Veterans Affairs Cooperative Psoriatic Arthritis Quality of Life (PsAQOL), Functional psoriatic arthritis and axial manifestations: results
Study. Skelet. Radiol. 28, 196–201 (1999). Assessment of Chronic Illness Therapy–Fatigue from the double-​blind, randomised, phase 3
80. Helliwell, P. S., Hickling, P. & Wright, V. Do the (FACIT-​F), Psoriatic Arthritis Response Criteria (PsARC), MAXIMISE trial. Ann. Rheum. Dis. 80, 582–590
radiological changes of classic ankylosing spondylitis Psoriatic Arthritis Joint Activity Index (PsAJAI), (2021).
differ from the changes found in the spondylitis Disease Activity in Psoriatic Arthritis (DAPSA), and 121. Mease, P. J. et al. A head-​to-head comparison of the
associated with inflammatory bowel disease, psoriasis, Composite Psoriatic Disease Activity Index (CPDAI). efficacy and safety of ixekizumab and adalimumab in
and reactive arthritis? Ann. Rheum. Dis. 57, 135–140 Arthritis Care Res. 63 (Suppl. 1), 64–85 (2011). biological-​naïve patients with active psoriatic arthritis:
(1998). 101. Mease, P. & van der, H. D. Joint damage in psoriatic 24-week results of a randomised, open-​label, blinded-​
81. Jadon, D. R. et al. Axial disease in psoriatic arthritis arthritis: how is it assessed and can it be prevented? assessor trial. Ann. Rheum. Dis. 79, 123–131 (2020).
study: defining the clinical and radiographic phenotype Int. J. Adv. Rheumatol. 4, 38–48 (2006). This is the first head-​to-head trial of an anti-​TNF
of psoriatic spondyloarthritis. Ann. Rheum. Dis. 76, 102. Kivitz, A. J. et al. A comparison of the efficacy and therapy versus an anti-​IL-17 inhibitor.
701–707 (2017). safety of celecoxib 200 mg and celecoxib 400 mg 122. McInnes, I. B. et al. Secukinumab versus adalimumab
82. Gladman, D. D., Shuckett, R., Russell, M. L., once daily in treating the signs and symptoms of for treatment of active psoriatic arthritis (EXCEED):
Thorne, J. C. & Schachter, R. K. Psoriatic arthritis psoriatic arthritis. Semin. Arthritis Rheum. 37, a double-​blind, parallel-​group, randomised, active-​
(PSA)–an analysis of 220 patients. Q. J. Med. 62, 164–173 (2007). controlled, phase 3b trial. Lancet 395, 1496–1505
127–141 (1987). 103. Dean, B. J. et al. The risks and benefits of (2020).
83. Congi, L. & Roussou, E. Clinical application of the glucocorticoid treatment for tendinopathy: a 123. Mease, P. J. et al. Brodalumab, an anti-​IL17RA
CASPAR criteria for psoriatic arthritis compared systematic review of the effects of local glucocorticoid monoclonal antibody, in psoriatic arthritis. N. Engl.
to other existing criteria. Clin. Exp. Rheumatol. 28, on tendon. Semin. Arthritis Rheum. 43, 570–576 J. Med. 370, 2295–2306 (2014).
304–310 (2010). (2014). 124. Mease, P. J. et al. Brodalumab in psoriatic arthritis:
84. Tillett, W. et al. The classification for psoriatic 104. Ritchlin, C. T. et al. Treatment recommendations for results from the randomised phase III AMVISION-1
arthritis (CASPAR) criteria–a retrospective feasibility, psoriatic arthritis. Ann. Rheum. Dis. 68, 1387–1394 and AMVISION-2 trials. Ann. Rheum. Dis. 80,
sensitivity, and specificity study. J. Rheumatol. 39, (2009). 185–193 (2021).
154–156 (2012). 105. Mease, P. J. Biologic therapy for psoriatic arthritis. 125. Ritchlin, C. T. et al. Bimekizumab in patients with
85. Chandran, V., Schentag, C. T. & Gladman, D. D. Rheum. Dis. Clin. North Am. 41, 723–738 (2015). active psoriatic arthritis: results from a 48-week,
Sensitivity of the classification of psoriatic arthritis 106. Ceponis, A. & Kavanaugh, A. Use of methotrexate in randomised, double-​blind, placebo-​controlled,
criteria in early psoriatic arthritis. Arthritis Rheum. 57, patients with psoriatic arthritis. Clin. Exp. Rheumatol. dose-ranging phase 2b trial. Lancet 395, 427–440
1560–1563 (2007). 28 (Suppl. 1), 132–137 (2010). (2020).
86. van den Berg, R., van Gaalen, F., 107. Mease, P. J. Spondyloarthritis: is methotrexate 126. Bachelez, H. Interleukin 23 inhibitors for psoriasis:
van der Helm-​van Mil, A., Huizinga, T. & van der effective in psoriatic arthritis? Nat. Rev. Rheumatol. 8, not just another number. Lancet 390, 208–210
Heijde, D. Performance of classification criteria for 251–252 (2012). (2017).
peripheral spondyloarthritis and psoriatic arthritis in 108. Kingsley, G. H. et al. A randomized placebo-​controlled 127. Deodhar, A. et al. Guselkumab in patients with
the Leiden Early Arthritis cohort. Ann. Rheum. Dis. 71, trial of methotrexate in psoriatic arthritis. Rheumatol active psoriatic arthritis who were biologic-​naive
1366–1369 (2012). 51, 1368–1377 (2012). or had previously received TNFα inhibitor treatment
87. Jones, S. M. et al. Psoriatic arthritis: outcome of 109. Mease, P. J. et al. Etanercept and methotrexate as (DISCOVER-1): a double-​blind, randomised, placebo-
disease subsets and relationship of joint disease to monotherapy or in combination for psoriatic arthritis: controlled phase 3 trial. Lancet 395, 1115–1125
nail and skin disease. Br. J. Rheumatol. 33, 834–839 primary results from a randomized, controlled 2020).
(1994). phase III trial. Arthritis Rheumatol. 71, 1112–1124 128. Mease, P. J. et al. Guselkumab in biologic-​naive
88. Marsal, S. et al. Clinical, radiographic and HLA (2019). patients with active psoriatic arthritis (DISCOVER-2):
associations as markers for different patterns of 110. Clegg, D. O. et al. Comparison of sulfasalazine and a double-​blind, randomised, placebo-​controlled phase
psoriatic arthritis. Rheumatol 38, 332–337 (1999). placebo in the treatment of psoriatic arthritis. A 3 trial. Lancet 395, 1126–1136 (2020).
89. Chandran, V., Tolusso, D. C., Cook, R. J. & Department of Veterans Affairs Cooperative Study. 129. McInnes, I. B. et al. Efficacy and safety of guselkumab,
Gladman, D. D. Risk factors for axial inflammatory Arthritis Rheum. 39, 2013–2020 (1996). an interleukin-23p19-specific monoclonal antibody,
arthritis in patients with psoriatic arthritis. 111. Kaltwasser, J. P. et al. Efficacy and safety of through one year in biologic-​naive patients with
J. Rheumatol. 37, 809–815 (2010). leflunomide in the treatment of psoriatic arthritis and psoriatic arthritis. Arthritis Rheumatol. 73, 604–616
90. Gladman, D. D. & Farewell, V. T. Progression psoriasis: a multinational, double-​blind, randomized, (2021).
in psoriatic arthritis: role of time varying clinical placebo-​controlled clinical trial. Arthritis Rheum. 50, 130. Mease, P. Ustekinumab fails to show efficacy in
indicators. J. Rheumatol. 26, 2409–2413 (1999). 1939–1950 (2004). a phase III axial spondyloarthritis program: the
91. Brockbank, J. E., Stein, M., Schentag, C. T. & 112. Mease, P. J. & Armstrong, A. W. Managing importance of negative results. Arthritis Rheumatol.
Gladman, D. D. Dactylitis in psoriatic arthritis: patients with psoriatic disease: the diagnosis and 71, 179–181 (2019).
a marker for disease severity? Ann. Rheum. Dis. 64, pharmacologic treatment of psoriatic arthritis in 131. Mease, P. Efficacy and safety of risankizumab,
188–190 (2005). patients with psoriasis. Drugs 74, 423–441 (2014). a selective il-23p19 inhibitor, in patients with active
92. Wervers, K. et al. Influence of disease manifestations 113. Mease, P. J. et al. Etanercept in the treatment of psoriatic arthritis over 24 weeks: results from a
on health-​related quality of life in early psoriatic psoriatic arthritis and psoriasis: a randomised trial. phase 2 trial. Ann. Rheum. Dis. 77, 200–201 (2018).
arthritis. J. Rheumatol. 45, 1526–1531 (2018). Lancet 356, 985–990 (2000). 132. Mease, P. J. et al. Efficacy and safety of tildrakizumab
93. Coates, L. C. et al. Comparison of three screening tools This is an early randomized trial of a biological in patients with active psoriatic arthritis: results of a
to detect psoriatic arthritis in patients with psoriasis agent in the treatment of psoriatic arthritis. randomised, double-​blind, placebo-​controlled, multiple-​
(CONTEST study). Br. J. Dermatol. 168, 802–807 114. Antoni, C. E. et al. Sustained benefits of infliximab dose, 52-week phase IIb study. Ann. Rheum Dis. https://
(2013). therapy for dermatologic and articular manifestations doi.org/10.1136/annrheumdis-2020-219014 (2021).
94. Haroon, M., Kirby, B. & Fitzgerald, O. High prevalence of psoriatic arthritis: results from the infliximab 133. Mease, P. J. et al. Efficacy and safety of abatacept,
of psoriatic arthritis in patients with severe psoriasis multinational psoriatic arthritis controlled trial a T-​cell modulator, in a randomised, double-​blind,
with suboptimal performance of screening (IMPACT). Arthritis Rheum. 52, 1227–1236 (2005). placebo-​controlled, phase III study in psoriatic
questionnaires. Ann. Rheum. Dis. https://doi.org/ 115. Fénix-​Caballero, S. et al. Direct and indirect arthritis. Ann. Rheum. Dis. 76, 1550–1558 (2017).
10.1136/annrheumdis-2012-201706 (2012). comparison of the efficacy and safety of adalimumab, 134. Kavanaugh, A. et al. Treatment of psoriatic arthritis
95. Coates, L. C. et al. Assessment of two screening tools etanercept, infliximab and golimumab in psoriatic in a phase 3 randomised, placebo-​controlled trial with
to identify psoriatic arthritis in patients with psoriasis. arthritis. J. Clin. Pharm. Ther. 38, 286–293 (2013). apremilast, an oral phosphodiesterase 4 inhibitor.
J. Eur. Acad. Dermatol. Venereol. 32, 1530–1534 116. McInnes, I. B. et al. Efficacy and safety of ustekinumab Ann. Rheum. Dis. 73, 1020–1026 (2014).
(2018). in patients with active psoriatic arthritis: 1 year results 135. Cutolo, M. et al. A phase III, randomized, controlled
96. National Institute for Health and Care Excellence. of the phase 3, multicentre, double-​blind, placebo-​ trial of apremilast in patients with psoriatic arthritis:
Psoriasis: assessment and management. Clinical controlled PSUMMIT 1 trial. Lancet 382, 780–789 results of the PALACE 2 trial. J. Rheumatol. 43,
guideline 153 (NICE, 2012). (2013). 1724–1734 (2016).
97. Eder, L. et al. The incidence and risk factors 117. Ritchlin, C. et al. Efficacy and safety of the anti-​ 136. Edwards, C. J. et al. Apremilast, an oral
for psoriatic arthritis in patients with psoriasis: IL-12/23 p40 monoclonal antibody, ustekinumab, phosphodiesterase 4 inhibitor, in patients with
a prospective cohort study. Arthritis Rheumatol. 68, in patients with active psoriatic arthritis despite psoriatic arthritis and current skin involvement:
915–923 (2016). conventional non-​biological and biological anti-​tumour a phase III, randomised, controlled trial (PALACE 3).
98. Orbai, A.-M. et al. Updating the psoriatic arthritis necrosis factor therapy: 6-month and 1-year results Ann. Rheum. Dis. 75, 1065–1073 (2016).
(PsA) core domain set: a report from the PsA of the phase 3, multicentre, double-​blind, placebo-​ 137. Mease, P. et al. Tofacitinib or adalimumab versus
workshop at OMERACT 2016. J. Rheumatol. 44, controlled, randomised PSUMMIT 2 trial. placebo for psoriatic arthritis. N. Engl. J. Med. 377,
1522–1528 (2017). Ann. Rheum. Dis. 73, 990–999 (2014). 1537–1550 (2017).
99. Ogdie, A., Coates, L. C. & Mease, P. Measuring 118. Deodhar, A. et al. Three multicenter, randomized, 138. Gladman, D. et al. Tofacitinib for psoriatic arthritis in
outcomes in psoriatic arthritis. Arthritis Care Res. 72 double-​blind, placebo-​controlled studies evaluating patients with an inadequate response to TNF inhibitors.
(Suppl. 1), 82–109 (2020). the efficacy and safety of ustekinumab in axial N. Engl. J. Med. 377, 1525–1536 (2017).
100. Mease, P. J. Measures of psoriatic arthritis: Tender spondyloarthritis. Arthritis Rheumatol. 71, 258–270 139. Mease, P. et al. Incidence of venous and arterial
and Swollen Joint Assessment, Psoriasis Area and (2019). thromboembolic events reported in the tofacitinib
Severity Index (PASI), Nail Psoriasis Severity Index 119. Kavanaugh, A. et al. Efficacy and safety of rheumatoid arthritis, psoriasis and psoriatic arthritis
(NAPSI), Modified Nail Psoriasis Severity Index ustekinumab in psoriatic arthritis patients with development programmes and from real-​world data.
(mNAPSI), Mander/Newcastle Enthesitis Index (MEI), peripheral arthritis and physician-​reported spondylitis: Ann. Rheum. Dis. 79, 1400–1413 (2020).

16 | Article citation ID: (2021) 7:59 www.nature.com/nrdp

0123456789();:
 Primer

140. Mease, P. J. et al. Upadacitinib for psoriatic arthritis patients with psoriatic arthritis: a post hoc analysis of 181. US National Library of Medicine. ClinicalTrials.gov
refractory to biologics: SELECT-​PsA 2. Ann. Rheum. two randomised controlled studies. Ann. Rheum. Dis. https://clinicaltrials.gov/ct2/show/NCT03662542
Dis. 80, 312–320 (2020). 78, 1215–1219 (2019). (2021).
141. Mease, P. et al. Efficacy and safety of filgotinib, a 160. McHugh, N. et al. Evaluation of the economic burden A study of the efficacy and safety of combination
selective Janus kinase 1 inhibitor, in patients with of psoriatic arthritis and the relationship between therapy with guselkumab and golimumab in
active psoriatic arthritis (EQUATOR): results from a functional status and healthcare costs. J. Rheumatol. participants with moderately to severely active
randomised, placebo-​controlled, phase 2 trial. Lancet 47, 701–707 (2020). ulcerative colitis (VEGA).
392, 2367–2377 (2018). 161. Thomsen, S. F., Skov, L., Dodge, R., Hedegaard, M. S. 182. Goldman, M. The innovative medicines initiative:
142. Papp, K. et al. Phase 2 trial of selective tyrosine & Kjellberg, J. Socioeconomic costs and health a European response to the innovation challenge.
kinase 2 inhibition in psoriasis. N. Engl. J. Med. 379, inequalities from psoriasis: a cohort study. Clin. Pharmacol. Ther. 91, 418–425 (2012).
1313–1321 (2018). Dermatology 235, 372–379 (2019). 183. Dolgin, E. Massive NIH–industry project opens
143. Mease P. J., et al. Efficacy and safety of 162. Husni, M. E., Merola, J. F. & Davin, S. The portals to target validation. Nat. Rev. Drug Discov. 18,
deucravacitinib (BMS-986165), an oral, selective psychosocial burden of psoriatic arthritis. 240–242 (2019).
tyrosine kinase 2 inhibitor, in patients with active Semin. Arthritis Rheum. 47, 351–360 (2017).
psoriatic arthritis: results from a phase 2, randomized, 163. Tillett, W. et al. Factors influencing work disability Acknowledgements
double-​blind, placebo-​controlled trial [abstract]. in psoriatic arthritis: first results from a large UK V.C. acknowledges support of the Pfizer Chair Rheumatology
Arthritis Rheumatol. 72 (Suppl. 10), L03 (2020). multicentre study. Rheumatology 54, 157–162 Research Award from the Department of Medicine, University
144. Coates, L. C. et al. Group for Research and (2015). of Toronto. L.C.C. is an NIHR Clinician Scientist funded by a
Assessment of Psoriasis and Psoriatic Arthritis 164. Tillett, W., de-​Vries, C. & McHugh, N. J. Work National Institute for Health Research Clinician Scientist
2015 treatment recommendations for psoriatic disability in psoriatic arthritis: a systematic review. award. The research was supported by the National Institute
arthritis. Arthritis Rheumatol. 68, 1060–1071 Rheumatology 46, 990–995 (2012). for Health Research (NIHR) and the Oxford Biomedical
(2016). 165. Tillett, W. et al. Effect of anti-​TNF and conventional Research Centre (BRC). Y.Y.L. is supported by National
145. Gossec, L. et al. EULAR recommendations for synthetic disease-​modifying anti-​rheumatic drug Medical Research Council, Singapore.
the management of psoriatic arthritis with treatment on work disability and clinical outcome
pharmacological therapies: 2019 update. in a multicentre observational cohort study of Author contributions
Ann. Rheum. Dis. 79, 700–712 (2020). psoriatic arthritis. Rheumatol 56, 603–612 Introduction (O.F. and P.J.M.); Epidemiology (A.O.);
146. Singh, J. A. et al. Special article: 2018 American (2017). Mechanisms/pathophysiology (O.F. and V.C.); Diagnosis,
College of Rheumatology/National Psoriasis 166. Kristensen, L. E. et al. Societal costs and screening and prevention (L.C.C.); Management (P.J.M. and
Foundation guideline for the treatment of psoriatic patients’ experience of health inequities before A.K.); Quality of life (W.T., Y.Y.L. and M.deW.); Outlook
arthritis. Arthritis Rheumatol. 71, 5–32 (2019). and after diagnosis of psoriatic arthritis: a Danish (J.U.S.); Overview of Primer (O.F.).
147. Husted, J. A., Gladman, D. D., Farewell, V. T. & cohort study. Ann. Rheum. Dis. 76, 1495–1501
Cook, R. J. Health-​related quality of life of patients (2017). Competing interests
with psoriatic arthritis: a comparison with 167. Conaghan, P. G. et al. Relationship of pain and O.F. has received research grants and/or consulting fees from
patients with rheumatoid arthritis. Arthritis Rheum. fatigue with health-​related quality of life and work AbbVie, Amgen, Bristol Myers Squibb (BMS), Celgene, Eli Lilly,
45, 151–158 (2001). in patients with psoriatic arthritis on TNFi: results Janssen, Novartis, Pfizer Inc. and UCB. A.O. has consulted for
148. Moverley, A. R., Vinall-​Collier, K. A. & Helliwell, P. S. of a multi-​national real-​world study. RMD Open 6, AbbVie, Amgen, BMS, Celgene, Corrona, Gilead, Janssen,
It’s not just the joints, it’s the whole thing: qualitative e001240 (2020). Lilly, Novartis, Pfizer and UCB, and has received grants from
analysis of patients’ experience of flare in psoriatic 168. Walsh, J. A. et al. Work productivity loss and fatigue Novartis and Pfizer. Her husband has received royalties
arthritis. Rheumatology 54, 1448–1453 (2015). in psoriatic arthritis. J. Rheumatol. 41, 1670–1674 from Novartis. V.C. reports grants and personal fees from
149. Gossec, L. et al. A patient-​derived and patient-​ (2014). Amgen, grants and personal fees from AbbVie, grants and
reported outcome measure for assessing psoriatic 169. Tan, J. S. Q., Fong, W., Kwan, Y. H. & Leung, Y. Y. personal fees from (and other potential interest (spouse
arthritis: elaboration and preliminary validation Prevalence and variables associated with fatigue in employment) in) Eli Lilly and personal fees from BMS, Janssen,
of the psoriatic arthritis impact of disease (PsAID) psoriatic arthritis: a cross-​sectional study. Rheumatol. Novartis, Pfizer and UCB, outside the submitted work. L.C.C.
questionnaire, a 13-country EULAR initiative. Int. 40, 1825–1834 (2020). is a recipient of research funds from AbbVie, Amgen, Celgene,
Ann. Rheum. Dis. 73, 1012–1019 (2014). 170. Zhao, S. S. et al. Systematic review of mental health Gilead, Janssen, Lilly, Novartis, Pfizer and UCB. She has
150. Tillett, W. et al. A multicentre nominal group study comorbidities in psoriatic arthritis. Clin. Rheumatol. received consultancy fees from AbbVie, Amgen, BMS, Boe­hrin­
to rank outcomes important to patients and their 39, 217–225 (2020). ger Ingelheim, Celgene, Domain, Gilead, Janssen, Lilly, Novartis,
representation in existing composite outcome 171. Visalli, E., Crispino, N. & Foti, R. Multidisciplinary Pfizer, Serac and UCB. She reports reimbursement for atten­
measures for psoriatic arthritis. J. Rheumatol. 44, management of psoriatic arthritis: the benefits of a ding a symposium from Janssen and AbbVie, and fees
1445–1452 (2017). comprehensive approach. Adv. Ther. 36, 806–816 for organizing education from UCB. She has received fees for
151. Geijer, M. et al. Health-​related quality of life in early (2019). speaking and hospitality from AbbVie, Amgen, BMS, Biogen,
psoriatic arthritis compared with early rheumatoid 172. Cobo-​Ibanez, T. et al. Multidisciplinary dermatology-​ Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer and
arthritis and a general population. Semin. Arthritis rheumatology management for patients with UCB. A.K. conducted clinical trials sponsored by and/or con-
Rheum. 51, 246–252 (2021). moderate-​to-severe psoriasis and psoriatic arthritis: sulted for Amgen, AbbVie, BMS, Eli Lilly, Janssen, Novartis,
152. Orbai, A.-M. et al. International patient and physician a systematic review. Rheumatol. Int. 36, 221–229 Pfizer and UCB. W.T. has received research grants, and con-
consensus on a psoriatic arthritis core outcome set (2016). sulting or speaker fees from AbbVie, Amgen, Celgene, Eli Lilly,
for clinical trials. Ann. Rheum. Dis. 76, 673–680 173. Soare, A. et al. Cutting edge: homeostasis of innate Janssen, MSD, Novartis, Pfizer and UCB. Y.Y.L. is supported
(2017). lymphoid cells is imbalanced in psoriatic arthritis. by the National Medical Research Council, Singapore. She has
153. Ware, J. E. Jr & Sherbourne, C. D. The MOS 36-item J. Immunol. 200, 1249–1254 (2018). received honoraria from Janssen, AbbVie, Novartis and
short-​form health survey (SF-36). I. Conceptual 174. Kaeley, G. S., Bakewell, C. & Deodhar, A. DKSH. M.deW. has received fees for lectures or consultancy
framework and item selection. Med. Care 30, The importance of ultrasound in identifying and through Stichting Tools from Celgene, Eli Lilly, Pfizer and UCB.
473–483 (1992). differentiating patients with early inflammatory J.U.S. has received funding for investigator-​initiated studies
154. Nord, E. EuroQol: health-​related quality of life arthritis: a narrative review. Arthritis Res. Ther. 22, 1 from Novartis and Janssen and has served as a consultant for
measurement. Valuations of health states by the (2020). Janssen, Novartis, Pfizer, Lilly, AbbVie, Sanofi and UCB. P. J. M.
general public in Norway. Health Policy 18, 25–36 175. Kampylafka, E. et al. Disease interception with has received research grants from AbbVie, Amgen, BMS, Eli
(1991). interleukin-17 inhibition in high-​risk psoriasis patients Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sun and
155. McKenna, S. P. et al. Development of the PsAQoL: with subclinical joint inflammation – data from the UCB. He acts as a consultant with AbbVie, Amgen, Boehringer
a quality of life instrument specific to psoriatic prospective IVEPSA study. Arthritis Res. Ther. 21, 178 Ingelheim, BMS, Eli Lilly, Galapagos, Gilead, GSK, Janssen,
arthritis. Ann. Rheum. Dis. 63, 162–169 (2004). (2019). Novartis, Pfizer, Sun and UCB. He has been a speaker for
156. Holland, R. et al. Psoriatic arthritis impact of disease 176. Feld, J. Is axial psoriatic arthritis distinct from AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer and UCB.
(PsAID12) was provisionally endorsed at Omeract ankylosing spondylitis with and without concomitant
2018 as core instrument to measure psoriatic psoriasis? Rheumatology 59, 1340–1346 (2019). Disclaimer
arthritis-​specific health-​related quality of life 177. Ritchlin, C. & Scher, J. U. Strategies to improve The views expressed are those of the author(s) and not
in randomized controlled trials and longitudinal outcomes in psoriatic arthritis. Curr. Rheumatol. Rep. necessarily those of the NHS, the NIHR or the Department
observational studies. J. Rheumatol. 46, 990–995 21, 72 (2019). of Health.
(2019). 178. Moncada, R. et al. Integrating microarray-​based
157. Coates, L. C. et al. Results of a global, patient-​based spatial transcriptomics and single-​cell RNA-​seq Peer review information
survey assessing the impact of psoriatic arthritis reveals tissue architecture in pancreatic ductal Nature Reviews Disease Primers thanks U. Kiltz, who
discussed in the context of the Psoriatic Arthritis adenocarcinomas. Nat. Biotechnol. 38, 333–342 co-​reviewed with A. Dormann; A.-​M . Orbai; D. Zisman;
Impact of Disease (PsAID) questionnaire. Health Qual. (2020). U. Kalyoncu; and S.Z. Aydin for their contribution to the peer
Life Outcomes 18, 173 (2020). 179. Mimitou, E. P. et al. Multiplexed detection of proteins, review of this work.
158. Tillett, W. et al. Disease characteristics and the burden transcriptomes, clonotypes and CRISPR perturbations
of joint and skin involvement amongst people with in single cells. Nat. Methods 16, 409–412 (2019). Publisher’s note
psoriatic arthritis: a population survey. Rheumatol. 180. Haberman, R. H., Castillo, R. & Scher, J. U. Induction Springer Nature remains neutral with regard to jurisdictional
Ther. 7, 617–637 (2020). of remission in biologic-​naive, severe psoriasis and claims in published maps and institutional affiliations.
159. Kavanaugh, A. et al. The contribution of joint and skin PsA with dual anti-​cytokine combination.
improvements to the health-​related quality of life of Rheumatology 60, e225–e226 (2021). © Springer Nature Limited 2021

NATURE REvIEWS | DISeASe PRIMeRS | Article citation ID: (2021) 7:59 17

0123456789();: