REVIEWS Advances in the management of psoriatic arthritis Ignazio Olivieri, Salvatore D’Angelo, Carlo Palazzi and Angela Padula Abstract | Psoriatic arthritis (PsA), which affects musculoskeletal structures, skin and nails, is a heterogeneous chronic inflammatory disease with a wide clinical spectrum and variable course. Patients with PsA are more likely than healthy individuals to have metabolic syndrome or cardiovascular disease. To include these comorbidities, ‘psoriatic disease’ has been suggested as an umbrella term. The management of PsA has changed tremendously over the past decade owing to early diagnosis and improvement in treatment strategies, including, early referral from dermatologists and primary-care physicians to rheumatologists, early initiation of therapy, treating to the target of remission or low disease activity, and advances in pharmacological therapy. Outcome assessment is also improving, because of validated instruments for clinical disease manifestations. The commercialization of TNF blockers, including adalimumab, etanercept, golimumab and infliximab, is representative of a revolution in the treatment of PsA. A new anti-TNF agent, certolizumab pegol, and a fully human monoclonal antibody against IL‑12 and IL‑23, ustekinumab, are approved for the treatment of active PsA. The efficacy of ustekinumab suggests that inhibiting the type 17 T helper pathway might be an alternative to blocking TNF. PsA management must now use improved measures to predict patient outcomes and define remission, and develop better-targeted therapies. Olivieri, I. et al. Nat. Rev. Rheumatol. advance online publication 8 July 2014; doi:10.1038/nrrheum.2014.106
Introduction
Rheumatology Department of Lucania, San Carlo Hospital of Potenza, Via Potito Petrone Snc, Potenza 85100, Italy (I.O., S.D., A.P.). Rheumatology Department of Lucania, Madonna delle Grazie Hospital of Matera, Contrada Cattedra Ambulante Snc, Matera 75100, Italy (C.P.) Correspondence to: I.O. ignazioolivieri@ tiscalinet.it
Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory disease with a wide clinical spectrum and a variable clinical course.1 This disease affects musculo skeletal structures, including the skin, nails, joints, enthe ses, synovial sheaths of tendons and the axial skeleton (Figure 1). Patients with PsA can also have ocular and intestinal complications,2,3 and an increased prevalence of metabolic syndrome, obesity, insulin resistance, type 2 diabetes mellitus, hyperlipidaemia, hypertension and cardiovascular disease is associated with PsA.4 The term ‘psoriatic disease’ is a new and generally accepted desig nation that covers all these clinical characteristics.5 This Review will focus on musculoskeletal manifestations of psoriatic disease, that is, PsA. Currently, PsA is classi fied as a type of spondyloarthritis, even if the symmetric polyarthritis form resembling rheumatoid arthritis (RA) does not meet the Assessment in Spondyloarthritis international Society (ASAS) criteria for axial and peripheral disease.6,7 The prevalence of psoriasis is 2–3% and PsA occurs in about one-third of patients with psoriasis,1 indicating that many individuals (prevalence ~0.5–1.0%) with PsA are undiagnosed. PsA is deforming and destructive in approximately 40–60% of patients, with early manifesta tions of disease appearing as joint damage (erosions and Competing interests All authors declare that they have received honoraria from Abbvie, Bristol–Myers Squibb, MSD, Pfizer, Roche, and UCB to attend scientific meetings. The authors have received no payment in preparation of this manuscript.
bone proliferation).8–11 Patients with PsA have a reduced quality of life, functional impairment, psychosocial dis ability and are at greater risk of death in comparison with the general population.11–13 Over the past decade, the management of PsA has con siderably improved as a result of earlier detection of PsA in patients with psoriasis by dermatologists, and several clinical advances: development of targets for treatment; valid outcome measures for each disease domain (that is, peripheral arthritis and enthesitis, dactylitis, spondylitis, nail and skin lesions); composite measures, including several disease domains; and an expanded range of treat ment options (Figure 2). In this article, our aim is to review published data and highlight work in progress on advances in PsA diagnosis, treatment and outcome measurements.
Management strategies Early screening and referral Clinical manifestations of PsA include peripheral arthri tis, peripheral enthesitis, dactylitis and other forms of tenosynovitis, and axial symptoms (Figure 1). However, a period of preclinical or occult disease can occur.14,15 In the majority of patients, skin and nail lesions appear before musculoskeletal manifestations, therefore, primarycare physicians and dermatologists have the potential to identify patients suitable for referral to rheumatolo gists for early diagnosis and treatment of PsA. Studies in dermatology clinics suggest that the majority of patients with PsA remain undiagnosed until examination by a rheumatologist.16–18
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REVIEWS 15 questions for the assessment of symptoms and func tional capacity.19 The PASE total score ranges from a minimum of 15 points to a maximum of 75. A score of 47 was the optimal cut-off point (82% sensitivity, 73% specificity) for distinguishing PsA from non-PsA. This tool was validated in a study with a larger sample size (190 participants), with 76% sensitivity and specificity, at a cut-off of 44.20 The Toronto Psoriatic Arthritis Screen (ToPAS) questionnaire was developed and validated in five groups of patients (from PsA, rheumatology, derma tology and family medicine clinics, and a phototherapy centre), achieving 87% sensitivity and 93% specificity for the identification of PsA.21 A subsequent version (ToPAS2), in which questions on axial disease were modified and pictures of inflamed joints as well as dac tylitis were added, had better sensitivity (96%) and speci ficity (99%).22 The Psoriatic Epidemiology Screening Tool (PEST), which has 92% sensitivity and 78% speci ficity, was developed in a primary-care-based population with psoriasis and includes five questions and a cartoon of a manikin for patients to identify areas of tenderness.23 The Psoriatic Arthritis Screening Questionnaire (PASQ) has 10 weighted questions and a manikin for identifi cation of affected joints.24 The validation of the paper version of PASQ had 93% sensitivity and 75% specificity, and the subsequent electronic version had higher sensi tivity (98%) and the same specificity (75%).24 Published in 2012, the Early Arthritis for Psoriatic patients (EARP) questionnaire is reliable and is faster and simpler to administer than PASE.25 In some studies, PASE, ToPAS and PEST have been compared in study populations of patients with psori asis different from those in which the single screening instruments were initially developed and validated, and sensitivity and specificity values have been found to be lower than previously reported.18,26,27 Quantifying the effect of musculoskeletal symptoms of PsA on func tion and quality of life might improve the specificity of these screening tools, permitting the differentiation of PsA from other rheumatic diseases.22 On the whole, these screening questionnaires have good, and roughly equivalent, specificity and sensitivity in the development cohorts, but further studies suggest that in the clinic they do not perform as well.18,26,27 Therefore, these tools iden tify many cases of musculoskeletal disease other than PsA, and can place an increased burden on rheumatol ogy services. On the other hand, they do not ‘capture’ all patients with early or subtle disease, such as non polyarticular (oligoarticular, spinal and entheseal) forms. Further refinement of these questionnaires is therefore needed to enhance their specificity and sensitivity.
Key points ■■ The management of psoriatic arthritis (PsA) is advancing, owing to progress in treatment strategies and outcome assessment ■■ Early referral, diagnosis and initiation of treatment for PsA are crucial for the optimization of management strategies ■■ As for treatment of rheumatoid arthritis, PsA should be treated-to-the-target of remission or to the alternative target of low disease activity ■■ Validated tools to measure the cutaneous and musculoskeletal manifestations of psoriatic disease now exist, and EULAR and GRAPPA recommend useful therapeutic algorithms to account for the main clinical presentation of the disease ■■ The five approved TNF inhibitors are effective at reducing the signs and symptoms of PsA, and can slow the progression of joint damage ■■ The IL‑12 and IL‑23 inhibitor ustekinumab, which has been licensed, offers an alternative treatment option for patients with PsA
With the aim of helping the dermatologist, various screening tools, including self-administered question naires, have been developed over the past 10 years for the identification of musculoskeletal manifestations of psoriatic disease (Table 1).19–25 The first proposed screening tool was the Psoriatic Arthritis Screening and Evaluation (PASE), which was developed in a combined dermatology and rheumatology clinic and consists of
Axial disease ■ NSAIDs ■ Physiotherapy ■ Biologic agents: TNF inhibitor
Skin and nail disease ■ Topical treatments ■ Psoralen + UVA/UVB ■ DMARDs: Methotrexate Ciclosporin ■ Biologic agents: TNF inhibitor
Peripheral arthritis ■ NSAIDs ■ Intra-articular steroids ■ DMARDs: Methotrexate Ciclosporin Sulphasalazine Leflunomide ■ Biologic agents: TNF inhibitor
Dactylitis ■ NSAIDs ■ Steroid injection ■ Biologic agents: TNF inhibitor
Enthesitis ■ NSAIDs ■ Steroid injection ■ Biologic agents: TNF inhibitor
◀
Figure 1 | PsA manifestations and corresponding treatment. Clinical manifestations of psoriatic disease include peripheral arthritis, peripheral enthesitis, dactylitis and other forms of tenosynovitis, spondylitis, and skin and nail lesions. Therapeutic options for the various manifestations of psoriatic disease are listed, according to the GRAPPA recommendations.49 Abbreviations: GRAPPA, Group for Research and Assessment of Psoriasis and Psoriatic Arthritis; PsA, psoriatic arthritis.
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REVIEWS Pharmacological therapies ■ TNF inhibitors (infliximab, etanercept, adalimumab, golimumab, certolizumab pegol) ■ IL-12/IL-23 inhibitor (ustekinumab) ■ Investigational drugs: IL-17 inhibitors (brodalumab, ixekizumab), phosphodiesterase 4 inhibitor (apremilast)
Outcome assessment ■ Validated outcome measures for each disease domain (peripheral arthritis and enthesitis, dactylitis, spondylitis, nail and skin lesions) ■ Minimal disease activity criteria ■ Composite disease activity indices (DAPSA, CPDAI, PASDAS and AMDF) Advances in the management of PsA
Treatment strategies ■ Early referral ■ Early diagnosis and early treatment ■ Treat-to-target approach ■ Tight control ■ Dissemination of recommendations
Figure 2 | Advances in PsA management. The management of PsA is evolving noticeably as a consequence of many factors: the improvement in treatment strategies, including early referral from dermatologists and primary-care physicians; early diagnosis; early beginning of therapy; treating to the target of remission or low disease activity; intensive management with tight control; and the dissemination of international treatment recommendations. The progression in the outcome assessment due to validated instruments for several disease manifestations and advances in pharmacological therapy are also contributing to advances in PsA management. Abbreviations: AMDF, Arithmetic Mean of Desirability Functions; CPDAI, Composite Psoriatic Disease Activity Index; DAPSA, Disease Activity index for Psoriatic Arthritis; PASDAS, Psoriatic Arthritis Disease Activity Score; PsA, psoriatic arthritis.
Early diagnosis A diagnosis of PsA should be considered every time a patient with psoriasis or a family history of psoriasis has peripheral arthritis, especially oligoarticular arthritis or that involving the distal interphalangeal joints, periph eral enthesitis, tenosynovitis, dactylitis or inflammatory spinal pain. No diagnostic criteria are available for PsA, only clas sification criteria. In 2006, the Classification for Psoriatic Arthritis (CASPAR) criteria were created.28 Although not diagnostic criteria, in everyday clinical practice the CASPAR criteria should be considered, but diagnosis can still be made even if the criteria are not met. Given that the presence of psoriasis is included in both the ASAS and CASPAR criteria, there is some over lap;29 therefore, the same patients could be classified as having PsA (according to CASPAR criteria) or periph eral spondyloarthritis (according to ASAS criteria). The CASPAR criteria, which are more specific and sensitive, and are more universally accepted, than previously pub lished classification criteria for PsA,30 were developed using data from a population with long-standing disease (mean duration 12.5 years).28 Studies have established that the CASPAR criteria can identify patients with early disease.29,31–33 Similar to other classification criteria pri marily used for clinical and epidemiological studies, the CASPAR criteria are referenced in clinical practice (Box 1). Another value of these criteria is that, even in the absence of psoriasis, they classify patients as having PsA if other distinctive traits are present, particularly
if a patient has a first-degree or second-degree relative with psoriasis.
Treat-to-target approach Whether early aggressive therapy is effective in the management of PsA has not yet been established. How ever, a general feeling exists within the rheumatology community that early intervention could achieve the main objectives of reducing pain, improving physi cal function and quality of life, and preventing joint damage.34–36 Patients with RA are currently treated-totarget.37 ‘Remission’ or ‘low disease activity’ have been identified as treatment targets on the basis of the results of systematic literature reviews.38 The target of clinical remission is to avoid joint erosion and subsequent dis ability. In PsA, bone damage is characterized by erosions and new bone formation; therefore, the RA treatment model, which only includes erosions, could not work for the treatment of patients with PsA. An international task force of experts has suggested treat-to-target recommendations for spondyloarthritis, including PsA.39 These recommendations include five overarching principles, nine common items for axial spondyloarthritis, peripheral spondyloarthritis and PsA, and two specific items for each of the three forms of spondyloarthritis.39 Unlike RA, the recommendations for spondyloarthritis are not based on firm evidence and should only be considered as expert opinion (consensus) because no trials comparing therapy adapted to reach a definite target with routine outpatient care for patients with spondyloarthritis or PsA have been performed.40 The main target of the proposed recommendations is remission (inactive disease). However, as remission is not easy to achieve in all patients, especially in those with long-standing disease, consensus group experts have agreed that ‘low disease activity’ could be an alternative target.39 Validated criteria for remission are not currently available for PsA, but for ‘minimal disease activity’, cri teria have been endorsed by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA; Box 2).41 These criteria include measure ments of joint, entheseal and skin involvement, together with patient-reported outcomes and a functional ability to assess disease activity. Tight control Modern imaging techniques highlight the link between inflammation and subsequent joint damage in RA.42 The TICORA (Tight Control of RA) study 43 demon strated that intensive management with tight control of the disease (see Box 3 for definitions) reduces disease activity, and damage progression (as measured by radio graphy), and improves physical function and quality of life compared with routine care that has no defined therap eutic protocol. By contrast, the relationship between inflammation and structural damage in PsA has not yet been studied with imaging techniques. However, cohort studies have demonstrated that active joint involvement and previous articular injury are predictive of disease progression and damage.44,45 Biologic drugs
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REVIEWS Table 1 | Characteristics of PsA screening tools Screening tool
Setting
Questions (n)
Visual cues
Cut-off score
Sensitivity (%)
Specificity (%)
Inclusion of axial involvement
Inclusion of nail or skin involvement
PASE19,20
Dermatology and rheumatology clinic
15
No
4719 4420
8219 7620
7319 7620
Yes (being developed)
No
ToPAS21 ToPAS222
Phototherapy centres and rheumatology, PsA, dermatology and family medicine clinics
12 12
Pictures of skin and nail lesions; (also inflamed joints and dactylitic fingers in ToPAS2)
8 8
8721 9622
9321 9922
Yes Yes (questions modified in ToPAS2)
Yes Yes
PEST23
Primary-carebased population with psoriasis
5
A manikin (to specify areas of tenderness)
3
92
78
Yes
Yes
PASQ24
Dermatology and rheumatology clinic
10
A manikin (for joint areas involved)
7
93 98 (electronic version)
75 75 (electronic version)
Yes
Yes
EARP25
Dermatology clinic
10
No
3
85
92
Yes
No
Abbreviations: EARP, Early ARthritis for Psoriatic patients; PASE, Psoriatic Arthritis Screening Evaluation; PASQ, Psoriatic Arthritis Screening Questionnaire; PEST, Psoriatic Epidemiology Screening Tool; PsA, psoriatic arthritis; ToPAS, Toronto Psoriatic Arthritis Screen.
Box 1 | CASPAR classification criteria28 Criteria fulfilled with three or more points from the following five categories in patients with inflammatory articular disease (current psoriasis = 2, other items = 1): ■■ Psoriasis: current psoriasis, personal history of psoriasis or family history of psoriasis ■■ Psoriatic nail dystrophy ■■ A negative test for rheumatoid factor ■■ Dactylitis (current or previous) ■■ Radiographical evidence of new juxta-articular bone formation
that can suppress inflammation have greatly improved the outcome of patients with PsA.35 Preliminary results of the TICOPA (Tight Control of Psoriatic Arthritis) study of 206 patients with early PsA, who had not previously been exposed to conven tional or biologic DMARDs, were published in 2013.46,47 Enrolled patients were randomly assigned to receive either standard care (12‑week assessments and treatment deemed appropriate by the treating clinician) or inten sive management (4‑week assessments and p rotocol-led treatment with dose continuation and escalation deter mined by minimal disease activity criteria). By week 48, more patients in the tight-control group than in the standard-care group (62% and 45%, respectively) had achieved an ACR20 response (ACR criteria for a 20% improvement).47 Control of the skin manifestations of psoriasis, measured with the PsA skin index 75 (a 75% reduction in the PASI score), was also better in the tightcontrol group than in the standard-care group (59% and 33%, respectively). Biologic therapies were more fre quently used, and more adverse events (nausea, infec tions and abnormalities in liver function) were seen in the tight-control group.47 These data show that a treatto-target strategy is more effective than standard care for
reducing disease activity in the skin and joints of patients with early PsA.
Treatment recommendations Two sets of international algorithms have been developed for the management of PsA: the EULAR48 and GRAPPA49 recommendations. In addition, a series of national guide lines that focus predominantly on the use of biologic agents for patients with PsA have been published.50–54 The EULAR recommendations, which are based on evidence from systematic literature reviews and expert opinions, direct rheumatologists to choose the best medication for the severity of each clinical presentation of PsA (arthri tis, enthesitis and axial disease), by using a step-by-step approach (Figure 3).48 The GRAPPA recommendations were developed with dermatologists to treat the various manifestations of psoriatic disease, including skin and nail lesions (Figure 1).49 An added value of the GRAPPA recommendations is that all the prevalent manifesta tions of PsA, such as peripheral arthritis, spondylitis, peripheral enthesitis, dactylitis and cutaneous lesions, are graded as mild, moderate or severe.
Outcome measures in clinical trials In the past two decades, the assessment of PsA has progressed because of the need to have valid outcome measures for clinical trials. Validated instruments cur rently exist to measure all the clinical manifestations of psoriatic disease (Figure 2).55 In addition, measures of physical function, quality of life, fatigue and structural damage exist. The Outcome Measures in Rheumatology (OMERACT) initiative established a core set of assess ment measures that should be used in all rheumatology clinical trials.56 PsA is a complex, heterogeneous disease; therefore, in addition to the measurement of each clinical domain,
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REVIEWS Box 2 | GRAPPA measures of minimal disease activity41 A patient is classified as having ‘minimal disease activity’ when achieving 5 of 7 following criteria: ■■ Tender joint count ≤1 ■■ Swollen joint count ≤1 ■■ Psoriasis Activity and Severity Index ≤1 or body surface area ≤3 ■■ Patient pain visual analogue score ≤15 ■■ Patient global disease activity visual analogue score ≤20 ■■ Health assessment questionnaire ≤0.5 ■■ Tender entheseal points ≤1
Box 3 | Treat to target and tight control ■■ ‘Tight control’ can be defined as a treatment strategy of aggressive management with close monitoring and appropriate adjustments in treatment using a prespecified outcome measure for decision-making ■■ A ‘treat-to-target’ strategy proposes that the therapeutic target in PsA should be a state of remission or a low disease activity, and that rheumatologists should measure and register disease activity in every clinical visit; if the goal has not been reached, therapy should be adjusted ■■ A careful review of the definitions of ‘treat-to-target’ and ‘tight control’ could lead to the assumption that they describe the same topic—both strategies attempt to adequately control disease by identifying a good therapeutic target
composite measures should be used to give a complete and reliable picture of disease activity. In contrast to RA, outcome measures need to cover several manifes tations of PsA, making their derivation and validation arduous. Some composite disease activity measures that are specific for PsA have been tested, such as the Disease Activity index for Psoriatic Arthritis (DAPSA) and the Composite Psoriatic Disease Activity Index (CPDAI).57–59 The GRAPPA Composite Exercise (GRACE) is a study including 503 patients, some of whom needed to switch treatment because of persistent active disease.60,61 These patients were followed-up for 12 months, and a wide variety of patient-completed measures and clinical assessments were obtained at 3, 6 and 12 months. Two new composite measures were acquired from these data, the Psoriatic Arthritis Disease Activity Score (PASDAS) and the Arithmetic Mean of Desirability Functions (AMDF). The PASDAS was developed using statistical techniques and modelling, and is a weighted, generic quality-of-life measure, including articular elements of disease (joint counts, enthesitis and dactylitis) and both patient and physician global (skin and joints) visual ana logue scale (VAS) for pain scores. The AMDF is derived empirically, and is based on core domains chosen by physician-defined cut-offs for disease activity scores. This index includes measurements of both skin and joint domains as well as a specific health-related quality-of-life measurement. The PASDAS and AMDF discriminated better between “inactive” and “active” disease (defined according to the decision to change treatment at baseline) than the existing indices, the DAPSA, CPDAI and the
Disease Activity Score 28‑joint count (DAS28).61 Future steps in the GRACE study will be the calculation of cutoffs for remission and for high, moderate and low disease activity scores.
Pharmacological therapies Therapy for PsA has evolved considerably since the turn of the century (Table 2). Biologic agents, such as TNF inhibitors, lead to substantial clinical responses in skin and musculoskeletal manifestations, they improve quality of life and inhibit structural damage caused by the disease. However, initial treatment for PsA has not changed in the biologic era; anti-TNF drugs are only prescribed after the failure of NSAIDs, steroids and traditional DMARDs. Several new drugs, such as IL‑17 inhibitors and the phosphodiesterase isozyme 4 inhibi tor apremilast, are currently being tested as treatments for PsA.
Licensed drugs NSAIDs and corticosteroids Published randomized controlled trials of NSAIDs for the treatment of patients with PsA are limited, but do support the efficacy of these drugs.62–65 NSAIDs are cur rently used to treat patients with PsA,48,49 and all patients with mild disease, especially in the absence of risk factors for disease progression, should be treated with NSAIDs to relieve joint pain and stiffness. Those not responding to this first level of treatment should be given DMARDs. Intra-articular and local corticosteroid injections, but not systemic administration of corticosteroids, should be used to treat patients with PsA according to the inter national recommendations. 48,49 However, despite the absence of evidence from randomized controlled trials, corticosteroids are used systemically to treat patients who are poorly responsive to NSAIDs or DMARDs. 66 In a study of 220 patients with PsA who received intra- articular corticosteroid injections, the probability of complete remission of tenderness and joint effusion at 3 months was 41.6% and of relapse within 1 year of injection was 25.5%.67 Therefore, intra-articular corti costeroid injections can be very useful in the treatment of persistent monoarthritis or oligoarthritis. Although local steroid injections have not been evaluated in controlled trials, or in case series, they can also be very useful in the treatment of dactylitis and peripheral enthesitis. Conventional DMARDs Conventional DMARDs are recommended to treat patients with peripheral manifestations of PsA, espe cially when the joints are involved, but these drugs are not effective for treating axial disease. 48,49 Although methotrexate (7.5–25 mg per week) is the most widely used DMARD for the treatment of PsA, specific studies of methotrexate treatment for PsA are scarce and their conclusions often contradictory, as outlined in a review in which the authors reported that a substantial clini cal improvement is rarely achieved with 15 mg methotrexate per week.72 Among other DMARDs, ciclosporin, 73–75 lefluno mide76–78 and sulphasalazine79–81 are commonly admin istered to treat the peripheral manifestations of PsA. Although there are few data and almost no head-to-head comparisons, these drugs do not seem to be superior to methotrexate, which should be considered as the first-choice DMARD.48 Other DMARDs can be used successfully when methotrexate fails and, as with metho trexate, they do not influence the progression of damage measured by radiography.48 Data on the use of conventional DMARDs to treat PsA are surprisingly scarce, especially for nonpolyarticular disease. Nevertheless, the difficulty of designing studies of the articular and extra-articular forms of PsA, owing to frequent clinical fluctuations or spontaneous remission, must be emphasized. TNF inhibitors The commercialization of TNF inhibitors is a revolution in the treatment of active PsA. These drugs reduce signs
Table 2 | Traditional and biologic DMARDs licensed for PsA Drug
Structure
Mechanism of action
Dosing regimen
Methotrexate
Small molecule (hippuric acid derivative)
Inhibition of T‑cell and B‑cell functions by decreasing purine synthesis
7.5–25 mg per week (oral, subcutaneous, or intramuscular)
Leflunomide
Small molecule (anilide)
Inhibition of T‑cell activation and proliferation by decreasing de novo synthesis of pyrimidines
20 mg per day (oral)
Sulphasalazine
Small molecule (aminobenzenesulphonamide)
Not known
1–3 g per day (oral)
Ciclosporin
Small molecule (cyclic undecapeptide)
Inhibition of transcription of cytokine genes in activated T cells
2–3 mg/kg per day (oral)
Infliximab
Chimeric monoclonal antibody
TNF inhibition
5 mg per kg at 0, 2, and 6 weeks, then every 8 weeks (intravenous)
Etanercept
Recombinant human TNF receptor (p75)–IgG1 Fc fusion protein
TNF inhibition
50 mg weekly (subcutaneous)
Adalimumab
Human monoclonal antibody
TNF inhibition
40 mg every second week (subcutaneous)
Golimumab
Human monoclonal antibody
TNF inhibition
50 mg every 4 weeks (subcutaneous)
Certolizumab pegol
Pegylated monoclonal antibody
TNF inhibition
400 mg at weeks 0, 2, and 4, then 200 mg every 2 weeks (subcutaneous)
Ustekinumab
Human monoclonal antibody
IL‑12/IL‑23 inhibition
45 mg or 90 mg at week 0, week 4, and every 12 weeks (subcutaneous)
Abbreviation: PsA, psoriatic arthritis.
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REVIEWS and symptoms of inflammation in both peripheral and axial disease.82,83 Four anti-TNF therapies have been used for a number of years (etanercept since 2002, infliximab and adalimumab since 2005 and golimumab since 2009), and these agents have substantially better response rates than placebo (ACR20 response rates of 51–59% with anti-TNF agents versus 9–15% with placebo; PsARC response rates of 62–77% versus 21–31% with placebo) over 12–24 weeks of treatment.82 Equally impressive results have now been achieved with certolizumab pegol in the RAPID-PsA study,84 which showed that the ACR20 response was significantly better in the treated groups than in the placebo group at week 12 (200 mg every 4 weeks, 58%; 400 mg every 4 weeks, 51.9%; placebo, 24.3%; P
Introduction
Rheumatology Department of Lucania, San Carlo Hospital of Potenza, Via Potito Petrone Snc, Potenza 85100, Italy (I.O., S.D., A.P.). Rheumatology Department of Lucania, Madonna delle Grazie Hospital of Matera, Contrada Cattedra Ambulante Snc, Matera 75100, Italy (C.P.) Correspondence to: I.O. ignazioolivieri@ tiscalinet.it
Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory disease with a wide clinical spectrum and a variable clinical course.1 This disease affects musculo skeletal structures, including the skin, nails, joints, enthe ses, synovial sheaths of tendons and the axial skeleton (Figure 1). Patients with PsA can also have ocular and intestinal complications,2,3 and an increased prevalence of metabolic syndrome, obesity, insulin resistance, type 2 diabetes mellitus, hyperlipidaemia, hypertension and cardiovascular disease is associated with PsA.4 The term ‘psoriatic disease’ is a new and generally accepted desig nation that covers all these clinical characteristics.5 This Review will focus on musculoskeletal manifestations of psoriatic disease, that is, PsA. Currently, PsA is classi fied as a type of spondyloarthritis, even if the symmetric polyarthritis form resembling rheumatoid arthritis (RA) does not meet the Assessment in Spondyloarthritis international Society (ASAS) criteria for axial and peripheral disease.6,7 The prevalence of psoriasis is 2–3% and PsA occurs in about one-third of patients with psoriasis,1 indicating that many individuals (prevalence ~0.5–1.0%) with PsA are undiagnosed. PsA is deforming and destructive in approximately 40–60% of patients, with early manifesta tions of disease appearing as joint damage (erosions and Competing interests All authors declare that they have received honoraria from Abbvie, Bristol–Myers Squibb, MSD, Pfizer, Roche, and UCB to attend scientific meetings. The authors have received no payment in preparation of this manuscript.
bone proliferation).8–11 Patients with PsA have a reduced quality of life, functional impairment, psychosocial dis ability and are at greater risk of death in comparison with the general population.11–13 Over the past decade, the management of PsA has con siderably improved as a result of earlier detection of PsA in patients with psoriasis by dermatologists, and several clinical advances: development of targets for treatment; valid outcome measures for each disease domain (that is, peripheral arthritis and enthesitis, dactylitis, spondylitis, nail and skin lesions); composite measures, including several disease domains; and an expanded range of treat ment options (Figure 2). In this article, our aim is to review published data and highlight work in progress on advances in PsA diagnosis, treatment and outcome measurements.
Management strategies Early screening and referral Clinical manifestations of PsA include peripheral arthri tis, peripheral enthesitis, dactylitis and other forms of tenosynovitis, and axial symptoms (Figure 1). However, a period of preclinical or occult disease can occur.14,15 In the majority of patients, skin and nail lesions appear before musculoskeletal manifestations, therefore, primarycare physicians and dermatologists have the potential to identify patients suitable for referral to rheumatolo gists for early diagnosis and treatment of PsA. Studies in dermatology clinics suggest that the majority of patients with PsA remain undiagnosed until examination by a rheumatologist.16–18
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REVIEWS 15 questions for the assessment of symptoms and func tional capacity.19 The PASE total score ranges from a minimum of 15 points to a maximum of 75. A score of 47 was the optimal cut-off point (82% sensitivity, 73% specificity) for distinguishing PsA from non-PsA. This tool was validated in a study with a larger sample size (190 participants), with 76% sensitivity and specificity, at a cut-off of 44.20 The Toronto Psoriatic Arthritis Screen (ToPAS) questionnaire was developed and validated in five groups of patients (from PsA, rheumatology, derma tology and family medicine clinics, and a phototherapy centre), achieving 87% sensitivity and 93% specificity for the identification of PsA.21 A subsequent version (ToPAS2), in which questions on axial disease were modified and pictures of inflamed joints as well as dac tylitis were added, had better sensitivity (96%) and speci ficity (99%).22 The Psoriatic Epidemiology Screening Tool (PEST), which has 92% sensitivity and 78% speci ficity, was developed in a primary-care-based population with psoriasis and includes five questions and a cartoon of a manikin for patients to identify areas of tenderness.23 The Psoriatic Arthritis Screening Questionnaire (PASQ) has 10 weighted questions and a manikin for identifi cation of affected joints.24 The validation of the paper version of PASQ had 93% sensitivity and 75% specificity, and the subsequent electronic version had higher sensi tivity (98%) and the same specificity (75%).24 Published in 2012, the Early Arthritis for Psoriatic patients (EARP) questionnaire is reliable and is faster and simpler to administer than PASE.25 In some studies, PASE, ToPAS and PEST have been compared in study populations of patients with psori asis different from those in which the single screening instruments were initially developed and validated, and sensitivity and specificity values have been found to be lower than previously reported.18,26,27 Quantifying the effect of musculoskeletal symptoms of PsA on func tion and quality of life might improve the specificity of these screening tools, permitting the differentiation of PsA from other rheumatic diseases.22 On the whole, these screening questionnaires have good, and roughly equivalent, specificity and sensitivity in the development cohorts, but further studies suggest that in the clinic they do not perform as well.18,26,27 Therefore, these tools iden tify many cases of musculoskeletal disease other than PsA, and can place an increased burden on rheumatol ogy services. On the other hand, they do not ‘capture’ all patients with early or subtle disease, such as non polyarticular (oligoarticular, spinal and entheseal) forms. Further refinement of these questionnaires is therefore needed to enhance their specificity and sensitivity.
Key points ■■ The management of psoriatic arthritis (PsA) is advancing, owing to progress in treatment strategies and outcome assessment ■■ Early referral, diagnosis and initiation of treatment for PsA are crucial for the optimization of management strategies ■■ As for treatment of rheumatoid arthritis, PsA should be treated-to-the-target of remission or to the alternative target of low disease activity ■■ Validated tools to measure the cutaneous and musculoskeletal manifestations of psoriatic disease now exist, and EULAR and GRAPPA recommend useful therapeutic algorithms to account for the main clinical presentation of the disease ■■ The five approved TNF inhibitors are effective at reducing the signs and symptoms of PsA, and can slow the progression of joint damage ■■ The IL‑12 and IL‑23 inhibitor ustekinumab, which has been licensed, offers an alternative treatment option for patients with PsA
With the aim of helping the dermatologist, various screening tools, including self-administered question naires, have been developed over the past 10 years for the identification of musculoskeletal manifestations of psoriatic disease (Table 1).19–25 The first proposed screening tool was the Psoriatic Arthritis Screening and Evaluation (PASE), which was developed in a combined dermatology and rheumatology clinic and consists of
Axial disease ■ NSAIDs ■ Physiotherapy ■ Biologic agents: TNF inhibitor
Skin and nail disease ■ Topical treatments ■ Psoralen + UVA/UVB ■ DMARDs: Methotrexate Ciclosporin ■ Biologic agents: TNF inhibitor
Peripheral arthritis ■ NSAIDs ■ Intra-articular steroids ■ DMARDs: Methotrexate Ciclosporin Sulphasalazine Leflunomide ■ Biologic agents: TNF inhibitor
Dactylitis ■ NSAIDs ■ Steroid injection ■ Biologic agents: TNF inhibitor
Enthesitis ■ NSAIDs ■ Steroid injection ■ Biologic agents: TNF inhibitor
◀
Figure 1 | PsA manifestations and corresponding treatment. Clinical manifestations of psoriatic disease include peripheral arthritis, peripheral enthesitis, dactylitis and other forms of tenosynovitis, spondylitis, and skin and nail lesions. Therapeutic options for the various manifestations of psoriatic disease are listed, according to the GRAPPA recommendations.49 Abbreviations: GRAPPA, Group for Research and Assessment of Psoriasis and Psoriatic Arthritis; PsA, psoriatic arthritis.
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REVIEWS Pharmacological therapies ■ TNF inhibitors (infliximab, etanercept, adalimumab, golimumab, certolizumab pegol) ■ IL-12/IL-23 inhibitor (ustekinumab) ■ Investigational drugs: IL-17 inhibitors (brodalumab, ixekizumab), phosphodiesterase 4 inhibitor (apremilast)
Outcome assessment ■ Validated outcome measures for each disease domain (peripheral arthritis and enthesitis, dactylitis, spondylitis, nail and skin lesions) ■ Minimal disease activity criteria ■ Composite disease activity indices (DAPSA, CPDAI, PASDAS and AMDF) Advances in the management of PsA
Treatment strategies ■ Early referral ■ Early diagnosis and early treatment ■ Treat-to-target approach ■ Tight control ■ Dissemination of recommendations
Figure 2 | Advances in PsA management. The management of PsA is evolving noticeably as a consequence of many factors: the improvement in treatment strategies, including early referral from dermatologists and primary-care physicians; early diagnosis; early beginning of therapy; treating to the target of remission or low disease activity; intensive management with tight control; and the dissemination of international treatment recommendations. The progression in the outcome assessment due to validated instruments for several disease manifestations and advances in pharmacological therapy are also contributing to advances in PsA management. Abbreviations: AMDF, Arithmetic Mean of Desirability Functions; CPDAI, Composite Psoriatic Disease Activity Index; DAPSA, Disease Activity index for Psoriatic Arthritis; PASDAS, Psoriatic Arthritis Disease Activity Score; PsA, psoriatic arthritis.
Early diagnosis A diagnosis of PsA should be considered every time a patient with psoriasis or a family history of psoriasis has peripheral arthritis, especially oligoarticular arthritis or that involving the distal interphalangeal joints, periph eral enthesitis, tenosynovitis, dactylitis or inflammatory spinal pain. No diagnostic criteria are available for PsA, only clas sification criteria. In 2006, the Classification for Psoriatic Arthritis (CASPAR) criteria were created.28 Although not diagnostic criteria, in everyday clinical practice the CASPAR criteria should be considered, but diagnosis can still be made even if the criteria are not met. Given that the presence of psoriasis is included in both the ASAS and CASPAR criteria, there is some over lap;29 therefore, the same patients could be classified as having PsA (according to CASPAR criteria) or periph eral spondyloarthritis (according to ASAS criteria). The CASPAR criteria, which are more specific and sensitive, and are more universally accepted, than previously pub lished classification criteria for PsA,30 were developed using data from a population with long-standing disease (mean duration 12.5 years).28 Studies have established that the CASPAR criteria can identify patients with early disease.29,31–33 Similar to other classification criteria pri marily used for clinical and epidemiological studies, the CASPAR criteria are referenced in clinical practice (Box 1). Another value of these criteria is that, even in the absence of psoriasis, they classify patients as having PsA if other distinctive traits are present, particularly
if a patient has a first-degree or second-degree relative with psoriasis.
Treat-to-target approach Whether early aggressive therapy is effective in the management of PsA has not yet been established. How ever, a general feeling exists within the rheumatology community that early intervention could achieve the main objectives of reducing pain, improving physi cal function and quality of life, and preventing joint damage.34–36 Patients with RA are currently treated-totarget.37 ‘Remission’ or ‘low disease activity’ have been identified as treatment targets on the basis of the results of systematic literature reviews.38 The target of clinical remission is to avoid joint erosion and subsequent dis ability. In PsA, bone damage is characterized by erosions and new bone formation; therefore, the RA treatment model, which only includes erosions, could not work for the treatment of patients with PsA. An international task force of experts has suggested treat-to-target recommendations for spondyloarthritis, including PsA.39 These recommendations include five overarching principles, nine common items for axial spondyloarthritis, peripheral spondyloarthritis and PsA, and two specific items for each of the three forms of spondyloarthritis.39 Unlike RA, the recommendations for spondyloarthritis are not based on firm evidence and should only be considered as expert opinion (consensus) because no trials comparing therapy adapted to reach a definite target with routine outpatient care for patients with spondyloarthritis or PsA have been performed.40 The main target of the proposed recommendations is remission (inactive disease). However, as remission is not easy to achieve in all patients, especially in those with long-standing disease, consensus group experts have agreed that ‘low disease activity’ could be an alternative target.39 Validated criteria for remission are not currently available for PsA, but for ‘minimal disease activity’, cri teria have been endorsed by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA; Box 2).41 These criteria include measure ments of joint, entheseal and skin involvement, together with patient-reported outcomes and a functional ability to assess disease activity. Tight control Modern imaging techniques highlight the link between inflammation and subsequent joint damage in RA.42 The TICORA (Tight Control of RA) study 43 demon strated that intensive management with tight control of the disease (see Box 3 for definitions) reduces disease activity, and damage progression (as measured by radio graphy), and improves physical function and quality of life compared with routine care that has no defined therap eutic protocol. By contrast, the relationship between inflammation and structural damage in PsA has not yet been studied with imaging techniques. However, cohort studies have demonstrated that active joint involvement and previous articular injury are predictive of disease progression and damage.44,45 Biologic drugs
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REVIEWS Table 1 | Characteristics of PsA screening tools Screening tool
Setting
Questions (n)
Visual cues
Cut-off score
Sensitivity (%)
Specificity (%)
Inclusion of axial involvement
Inclusion of nail or skin involvement
PASE19,20
Dermatology and rheumatology clinic
15
No
4719 4420
8219 7620
7319 7620
Yes (being developed)
No
ToPAS21 ToPAS222
Phototherapy centres and rheumatology, PsA, dermatology and family medicine clinics
12 12
Pictures of skin and nail lesions; (also inflamed joints and dactylitic fingers in ToPAS2)
8 8
8721 9622
9321 9922
Yes Yes (questions modified in ToPAS2)
Yes Yes
PEST23
Primary-carebased population with psoriasis
5
A manikin (to specify areas of tenderness)
3
92
78
Yes
Yes
PASQ24
Dermatology and rheumatology clinic
10
A manikin (for joint areas involved)
7
93 98 (electronic version)
75 75 (electronic version)
Yes
Yes
EARP25
Dermatology clinic
10
No
3
85
92
Yes
No
Abbreviations: EARP, Early ARthritis for Psoriatic patients; PASE, Psoriatic Arthritis Screening Evaluation; PASQ, Psoriatic Arthritis Screening Questionnaire; PEST, Psoriatic Epidemiology Screening Tool; PsA, psoriatic arthritis; ToPAS, Toronto Psoriatic Arthritis Screen.
Box 1 | CASPAR classification criteria28 Criteria fulfilled with three or more points from the following five categories in patients with inflammatory articular disease (current psoriasis = 2, other items = 1): ■■ Psoriasis: current psoriasis, personal history of psoriasis or family history of psoriasis ■■ Psoriatic nail dystrophy ■■ A negative test for rheumatoid factor ■■ Dactylitis (current or previous) ■■ Radiographical evidence of new juxta-articular bone formation
that can suppress inflammation have greatly improved the outcome of patients with PsA.35 Preliminary results of the TICOPA (Tight Control of Psoriatic Arthritis) study of 206 patients with early PsA, who had not previously been exposed to conven tional or biologic DMARDs, were published in 2013.46,47 Enrolled patients were randomly assigned to receive either standard care (12‑week assessments and treatment deemed appropriate by the treating clinician) or inten sive management (4‑week assessments and p rotocol-led treatment with dose continuation and escalation deter mined by minimal disease activity criteria). By week 48, more patients in the tight-control group than in the standard-care group (62% and 45%, respectively) had achieved an ACR20 response (ACR criteria for a 20% improvement).47 Control of the skin manifestations of psoriasis, measured with the PsA skin index 75 (a 75% reduction in the PASI score), was also better in the tightcontrol group than in the standard-care group (59% and 33%, respectively). Biologic therapies were more fre quently used, and more adverse events (nausea, infec tions and abnormalities in liver function) were seen in the tight-control group.47 These data show that a treatto-target strategy is more effective than standard care for
reducing disease activity in the skin and joints of patients with early PsA.
Treatment recommendations Two sets of international algorithms have been developed for the management of PsA: the EULAR48 and GRAPPA49 recommendations. In addition, a series of national guide lines that focus predominantly on the use of biologic agents for patients with PsA have been published.50–54 The EULAR recommendations, which are based on evidence from systematic literature reviews and expert opinions, direct rheumatologists to choose the best medication for the severity of each clinical presentation of PsA (arthri tis, enthesitis and axial disease), by using a step-by-step approach (Figure 3).48 The GRAPPA recommendations were developed with dermatologists to treat the various manifestations of psoriatic disease, including skin and nail lesions (Figure 1).49 An added value of the GRAPPA recommendations is that all the prevalent manifesta tions of PsA, such as peripheral arthritis, spondylitis, peripheral enthesitis, dactylitis and cutaneous lesions, are graded as mild, moderate or severe.
Outcome measures in clinical trials In the past two decades, the assessment of PsA has progressed because of the need to have valid outcome measures for clinical trials. Validated instruments cur rently exist to measure all the clinical manifestations of psoriatic disease (Figure 2).55 In addition, measures of physical function, quality of life, fatigue and structural damage exist. The Outcome Measures in Rheumatology (OMERACT) initiative established a core set of assess ment measures that should be used in all rheumatology clinical trials.56 PsA is a complex, heterogeneous disease; therefore, in addition to the measurement of each clinical domain,
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REVIEWS Box 2 | GRAPPA measures of minimal disease activity41 A patient is classified as having ‘minimal disease activity’ when achieving 5 of 7 following criteria: ■■ Tender joint count ≤1 ■■ Swollen joint count ≤1 ■■ Psoriasis Activity and Severity Index ≤1 or body surface area ≤3 ■■ Patient pain visual analogue score ≤15 ■■ Patient global disease activity visual analogue score ≤20 ■■ Health assessment questionnaire ≤0.5 ■■ Tender entheseal points ≤1
Box 3 | Treat to target and tight control ■■ ‘Tight control’ can be defined as a treatment strategy of aggressive management with close monitoring and appropriate adjustments in treatment using a prespecified outcome measure for decision-making ■■ A ‘treat-to-target’ strategy proposes that the therapeutic target in PsA should be a state of remission or a low disease activity, and that rheumatologists should measure and register disease activity in every clinical visit; if the goal has not been reached, therapy should be adjusted ■■ A careful review of the definitions of ‘treat-to-target’ and ‘tight control’ could lead to the assumption that they describe the same topic—both strategies attempt to adequately control disease by identifying a good therapeutic target
composite measures should be used to give a complete and reliable picture of disease activity. In contrast to RA, outcome measures need to cover several manifes tations of PsA, making their derivation and validation arduous. Some composite disease activity measures that are specific for PsA have been tested, such as the Disease Activity index for Psoriatic Arthritis (DAPSA) and the Composite Psoriatic Disease Activity Index (CPDAI).57–59 The GRAPPA Composite Exercise (GRACE) is a study including 503 patients, some of whom needed to switch treatment because of persistent active disease.60,61 These patients were followed-up for 12 months, and a wide variety of patient-completed measures and clinical assessments were obtained at 3, 6 and 12 months. Two new composite measures were acquired from these data, the Psoriatic Arthritis Disease Activity Score (PASDAS) and the Arithmetic Mean of Desirability Functions (AMDF). The PASDAS was developed using statistical techniques and modelling, and is a weighted, generic quality-of-life measure, including articular elements of disease (joint counts, enthesitis and dactylitis) and both patient and physician global (skin and joints) visual ana logue scale (VAS) for pain scores. The AMDF is derived empirically, and is based on core domains chosen by physician-defined cut-offs for disease activity scores. This index includes measurements of both skin and joint domains as well as a specific health-related quality-of-life measurement. The PASDAS and AMDF discriminated better between “inactive” and “active” disease (defined according to the decision to change treatment at baseline) than the existing indices, the DAPSA, CPDAI and the
Disease Activity Score 28‑joint count (DAS28).61 Future steps in the GRACE study will be the calculation of cutoffs for remission and for high, moderate and low disease activity scores.
Pharmacological therapies Therapy for PsA has evolved considerably since the turn of the century (Table 2). Biologic agents, such as TNF inhibitors, lead to substantial clinical responses in skin and musculoskeletal manifestations, they improve quality of life and inhibit structural damage caused by the disease. However, initial treatment for PsA has not changed in the biologic era; anti-TNF drugs are only prescribed after the failure of NSAIDs, steroids and traditional DMARDs. Several new drugs, such as IL‑17 inhibitors and the phosphodiesterase isozyme 4 inhibi tor apremilast, are currently being tested as treatments for PsA.
Licensed drugs NSAIDs and corticosteroids Published randomized controlled trials of NSAIDs for the treatment of patients with PsA are limited, but do support the efficacy of these drugs.62–65 NSAIDs are cur rently used to treat patients with PsA,48,49 and all patients with mild disease, especially in the absence of risk factors for disease progression, should be treated with NSAIDs to relieve joint pain and stiffness. Those not responding to this first level of treatment should be given DMARDs. Intra-articular and local corticosteroid injections, but not systemic administration of corticosteroids, should be used to treat patients with PsA according to the inter national recommendations. 48,49 However, despite the absence of evidence from randomized controlled trials, corticosteroids are used systemically to treat patients who are poorly responsive to NSAIDs or DMARDs. 66 In a study of 220 patients with PsA who received intra- articular corticosteroid injections, the probability of complete remission of tenderness and joint effusion at 3 months was 41.6% and of relapse within 1 year of injection was 25.5%.67 Therefore, intra-articular corti costeroid injections can be very useful in the treatment of persistent monoarthritis or oligoarthritis. Although local steroid injections have not been evaluated in controlled trials, or in case series, they can also be very useful in the treatment of dactylitis and peripheral enthesitis. Conventional DMARDs Conventional DMARDs are recommended to treat patients with peripheral manifestations of PsA, espe cially when the joints are involved, but these drugs are not effective for treating axial disease. 48,49 Although methotrexate (7.5–25 mg per week) is the most widely used DMARD for the treatment of PsA, specific studies of methotrexate treatment for PsA are scarce and their conclusions often contradictory, as outlined in a review in which the authors reported that a substantial clini cal improvement is rarely achieved with 15 mg methotrexate per week.72 Among other DMARDs, ciclosporin, 73–75 lefluno mide76–78 and sulphasalazine79–81 are commonly admin istered to treat the peripheral manifestations of PsA. Although there are few data and almost no head-to-head comparisons, these drugs do not seem to be superior to methotrexate, which should be considered as the first-choice DMARD.48 Other DMARDs can be used successfully when methotrexate fails and, as with metho trexate, they do not influence the progression of damage measured by radiography.48 Data on the use of conventional DMARDs to treat PsA are surprisingly scarce, especially for nonpolyarticular disease. Nevertheless, the difficulty of designing studies of the articular and extra-articular forms of PsA, owing to frequent clinical fluctuations or spontaneous remission, must be emphasized. TNF inhibitors The commercialization of TNF inhibitors is a revolution in the treatment of active PsA. These drugs reduce signs
Table 2 | Traditional and biologic DMARDs licensed for PsA Drug
Structure
Mechanism of action
Dosing regimen
Methotrexate
Small molecule (hippuric acid derivative)
Inhibition of T‑cell and B‑cell functions by decreasing purine synthesis
7.5–25 mg per week (oral, subcutaneous, or intramuscular)
Leflunomide
Small molecule (anilide)
Inhibition of T‑cell activation and proliferation by decreasing de novo synthesis of pyrimidines
20 mg per day (oral)
Sulphasalazine
Small molecule (aminobenzenesulphonamide)
Not known
1–3 g per day (oral)
Ciclosporin
Small molecule (cyclic undecapeptide)
Inhibition of transcription of cytokine genes in activated T cells
2–3 mg/kg per day (oral)
Infliximab
Chimeric monoclonal antibody
TNF inhibition
5 mg per kg at 0, 2, and 6 weeks, then every 8 weeks (intravenous)
Etanercept
Recombinant human TNF receptor (p75)–IgG1 Fc fusion protein
TNF inhibition
50 mg weekly (subcutaneous)
Adalimumab
Human monoclonal antibody
TNF inhibition
40 mg every second week (subcutaneous)
Golimumab
Human monoclonal antibody
TNF inhibition
50 mg every 4 weeks (subcutaneous)
Certolizumab pegol
Pegylated monoclonal antibody
TNF inhibition
400 mg at weeks 0, 2, and 4, then 200 mg every 2 weeks (subcutaneous)
Ustekinumab
Human monoclonal antibody
IL‑12/IL‑23 inhibition
45 mg or 90 mg at week 0, week 4, and every 12 weeks (subcutaneous)
Abbreviation: PsA, psoriatic arthritis.
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REVIEWS and symptoms of inflammation in both peripheral and axial disease.82,83 Four anti-TNF therapies have been used for a number of years (etanercept since 2002, infliximab and adalimumab since 2005 and golimumab since 2009), and these agents have substantially better response rates than placebo (ACR20 response rates of 51–59% with anti-TNF agents versus 9–15% with placebo; PsARC response rates of 62–77% versus 21–31% with placebo) over 12–24 weeks of treatment.82 Equally impressive results have now been achieved with certolizumab pegol in the RAPID-PsA study,84 which showed that the ACR20 response was significantly better in the treated groups than in the placebo group at week 12 (200 mg every 4 weeks, 58%; 400 mg every 4 weeks, 51.9%; placebo, 24.3%; P
