Firestein: Kelley's Textbook of Rheumatology, 8th ed.

Copyright 2008 W. B. Saunders Company

TREATMENT
In considering treatment strategies for psoriatic arthritis, the diverse nature of the clinical phenotype (peripheral arthritis, skin and nail disease, axial disease, dactylitis and enthesitis) may complicate therapeutic decisions because not all treatments are effective for all of the features, and patients often display a mixture of all of the features simultaneously. GRAPPA published a systematic review of the evidence for treatment strategies in psoriatic arthritis, and this review provides treatment guidelines that are currently being devised. The reader is referred to this GRAPPA publication for a detailed review of the evidence; Figure 72-12 is a proposed preliminary algorithm for treatment choices.[76] Treatment choices may be driven by the disease feature considered most severe at the time of the evaluation. Finally, in reviewing the evidence for therapeutic effect presented next, the recommendations from the Agency for Health Care Policy Research were used where interventions are scored by categories of evidence (level 1 through 4) and strength of recommendation (grade A through D).[77]

Figure 72-12 Preliminary treatment algorithm for the various clinical manifestations in psoriatic arthritis.(From Kavanaugh AF, Ritchlin CT: Systematic review of treatments for psoriatic arthritis: An evidence based approach and basis for treatment guidelines. J Rheumatol 33:14171421, 2006.)

TRADITIONAL AGENTS
Although there is little published evidence of a favorable therapeutic effect in psoriatic arthritis, nonsteroidal anti-inflammatory drugs are most often the agents first used in psoriatic arthritis whatever the clinical phenotype (level 1b, grade A).[78] Expert opinion supports use of nonsteroidal anti-inflammatory drugs, although occasional exacerbations of psoriasis have been reported. The use of systemic corticosteroids is not evidence-based (level 4, grade D), although 24% of patients in one study were taking prednisolone.[79] There are concerns that exacerbations of psoriasis may follow corticosteroid withdrawal. There have been no randomized controlled trials of intra-articular steroids in psoriatic arthritis or of local entheseal or dactylitis injections. Expert opinion indicates that intra-articular steroids can be quite effective, especially in oligoarticular disease or where there is localized entheseal involvement, such as in plantar fasciitis (level 4, grade D). Mild skin disease (PASI <10) is usually controlled with topical steroids or vitamin D derivatives, with the latter best used for maintenance therapy.[80] Systemic therapy is considered in patients with three or more inflamed joints despite conventional therapy as described previously; persistent or treatment-resistant axial, entheseal, or dactylitic disease especially where multiple sites are involved; or moderate or severe psoriasis (PASI >10). Randomized controlled trials of diseasemodifying antirheumatic drugs (DMARDs) are few and limited by size. Based on evidence and expert opinion, nearly all DMARDs may have small-to-moderate beneficial effects on peripheral joints, enthesitis, and dactylitis.[78,81,82] Axial features

and nail disease do not seem to respond.[83] Good or moderate improvements in skin disease have been reported with some of the older systemic agents, such as methotrexate, cyclosporine, sulfasalazine, leflunomide, and acetretin (all level 1b, grade A).[80] The best evidence for DMARD use comes from studies of peripheral joint disease and of psoriasis. There have been six randomized controlled trials of sulfasalazine in psoriatic arthritis (level 1a, grade A), the largest including 221 patients. Fifty-nine percent of patients achieved a therapeutic response (PsARC), but in keeping with other studies a high therapeutic response (42.7%) also was noted in placebo-treated patients.[38] Methotrexate remains for many rheumatologists the DMARD of first choice for patients with psoriatic arthritis, but evidence for its use is limited (level 3, grade B). A small, prospective randomized controlled trial concluded that methotrexate was as effective as cyclosporine, and a more recent study of 72 patients with active psoriatic arthritis and an incomplete response to methotrexate, in which cyclosporine was added in, showed significant differences only in synovitis as detected by MSUS and PASI score in favor of the combination therapy.[26,84] Although evidence for methotrexate is lacking, an open study reported significant reductions in synovial cellular infiltration and in cytokine gene expression after 3 months of therapy.[65] Although there is evidence that cyclosporine may be as effective as methotrexate, its use is limited because its toxicity profile is considered to be high (level 1b, grade B).
[85]

Perhaps the best randomized controlled trial in psoriatic arthritis of a DMARD is with leflunomide (level 1b, grade A).[86] This trial included 190 patients who received either leflunomide or placebo for 24 weeks. Fifty-nine percent of patients treated with leflunomide compared with 30% of patients given placebo met the primary response criteria (PsARC) with significant, although small improvements in other individual parameters, including joint scores, health assessment questionnaire, PASI, and Dermatology Life Quality Index. Regarding some older DMARDs, such as gold salts and antimalarials, there is no evidence of treatment benefit; exacerbation of psoriasis is reported, and they cannot be recommended. One small randomized controlled trial with azathioprine suggested benefit with a reduction in Ritchie score (level 2b, grade B). Finally, apart from the cyclosporine/methotrexate study referred to earlier, there is little or no evidence that DMARD combination therapy is either beneficial or safe in psoriatic arthritis. With the exception of psoriasis, there is a paucity of evidence that DMARDs are beneficial for the other features of psoriatic arthritis, including dactylitis, axial disease, or enthesitis. The absence of evidence does not mean the absence of an effect, however. Further randomized controlled trials specifically examining these features in psoriatic arthritis are required. In psoriasis, methotrexate and cyclosporine have been shown to be highly and probably equally effective (level 1b, grade A).[80] Adverse effects, in particular with cyclosporine, may limit usage in some patients.

BIOLOGICS
The approach to treatment in psoriatic arthritis has changed considerably with the introduction of biologic therapies. As a result of numerous large, well-conducted, randomized controlled trials, there is now accumulating evidence that anti-TNF treatments are effective in controlling peripheral arthritis symptoms and signs,

improving quality of life, and preventing radiologic progression (overall level 1b, grade A).[78] Patients receiving 25 mg subcutaneously twice weekly of etanercept had significant improvements in ACR-20 responses (59% versus 15%) at 12 weeks compared with placebo.[87] At 12 months, radiographic disease progression (modified total Sharp score) was inhibited in the etanercept group (0.03 unit) compared with worsening of +1.00 unit in the placebo group. Although the anti-TNF therapies have not been compared in any study, the effect on peripheral arthritis seems to be similar. There also is evidence that anti-TNF therapies are effective for other disease features, such as nail disease, enthesitis, and dactylitis.[81,82,88] These studies are limited by the absence of a validated instrument to measure these features. With psoriasis, the effects of anti-TNF therapies can be quite dramatic.[89] In particular with the antibody therapy, highly significant improvements in PASI scores were achieved (e.g., PASI = 75 in 59% of adalimumab-treated patients versus 1% of placebo-treated patients after 24 weeks, and PASI = 90 in 50%).[90] Alefacept is a fusion protein of soluble lymphocyte function antigen 3 with Fc fragments of IgG1. Alefacept was the first biologic agent approved for moderate-tosevere psoriasis (level 1b, grade A). Efficacy was dose dependent and slow, but PASI = 75 was achieved in 33% of patients at some point.[91] More recently, alefacept in combination with methotrexate was evaluated in 185 patients with active psoriatic arthritis.[92] At 6 months, 54% of alefacept-treated patients versus 23% of placebotreated patients achieved an ACR-20 response. Finally, efalizumab, a humanized monoclonal antibody targeting the CD11a component of lymphocyte function antigen 1, also has been approved for psoriasis with PASI = 75 achieved in 22% to 39% in randomized controlled trials.[89] To date, there is no evidence for beneficial effect of efalizumab in other psoriatic arthritis disease manifestations.

Future Directions
The surge of interest in new therapies for psoriatic arthritis is most welcome, in particular for patients with poor prognostic features (polyarticular disease, elevated erythrocyte sedimentation rate, dactylitis, and progressive change on radiograph) who fail to respond to standard treatment approaches. Much additional research on currently available agents and on new treatments is required. New instruments to measure key outcome domains, such as enthesitis, need to be developed and validated, and comparisons of newer agents with standard DMARDs, such as methotrexate, are required to inform treatment decisions. GRAPPA is currently developing treatment guidelines based on current evidence, but there are many gaps in our knowledge, and expert opinion is the best available guide in many situations. It is hoped, however, that guidelines or recommendations can be agreed on that would help inform the physician when treating psoriatic arthritis and its diverse clinical manifestations.
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