New Therapies for Psoriatic Arthritis

Psoriatic arthritis (PsA) is the second most common inflammatory arthritis and is one of the seronegative spondyloarthropathies. Although cohorts of PsA patients show less radiographic damage than rheumatoid arthritis (RA) patients with comparable disease durations, PsA has a similar impact on quality of life for these patients.¹ Observational studies in PsA have shown that peripheral joint disease activity is a key predictor of future joint damage,² and this has led to an increasing emphasis on treatment of PsA. Traditionally, treatment has relied on disease-modifying antirheumatic drugs (DMARDs) such as methotrexate and sulfasalazine, despite the lack of good-quality evidence of their efficacy. More recently, the treatment of resistant peripheral PsA has been revolutionised by tumour necrosis factor (TNF)-blocking therapies. TNF is a key pro-inflammatory cytokine, and research in PsA has confirmed high levels of TNF in both psoriatic plaques in the skin and synovial fluid taken from active arthritic joints.³ This early research provided a rationale for its use in the treatment of PsA, and clinical trials with this class of drugs have shown excellent clinical benefit. Currently, there are three TNF blockers available in routine clinical practice (etanercept, infliximab and adalimumab), and the evidence from trials of these drugs as well as registry data of their clinical use is discussed in this article. New agents targeting TNF and other key inflammatory mediators are being trialled in psoriasis and PsA, and are also summarised.

These new drugs have had a significant impact on the ability to manage peripheral PsA with evidence-based treatments. However, the vast majority of treatment studies in PsA have concentrated on resistant peripheral polyarticular disease. There has been little research into the typical asymmetrical oligoarticular disease subtype and few studies have concentrated on efficacy in other aspects of psoriatic disease, including dactylitis, enthesitis and spinal involvement. This is due partly to a lack of outcome measures specifically designed and validated for PsA. The majority of treatment studies report outcomes with American College of Rheumatology (ACR) response rates, which have been validated retrospectively for polyarticular peripheral PsA but do not encompass other aspects of the disease. More recently, new outcome measures designed specifically for PsA have been developed, and work is ongoing to develop a composite disease activity measure for PsA. In the future, this should improve the design of trials and provide additional information on the efficacy of treatments for all aspects of the disease.

In the final section of this article, different treatment strategies are discussed. The strategy for the treatment of RA has been revolutionised in recent years, and research in PsA is now investigating the concept of early and aggressive treatment.

Etanercept
Etanercept was the first anti-TNF therapy to be tested in a randomised trial in patients with PsA. Etanercept is a soluble TNF receptor antagonist usually given by weekly subcutaneous injection. The phase
II study of etanercept in active PsA and psoriasis showed an impressive response to treatment with 87% of etanercept-treated patients achieving PsA Response Criteria (PsARC) compared with 23% of placebo-treated patients. There was also a significant improvement in patient-reported disability as measured by the Health Assessment Questionnaire (HAQ) following treatment with etanercept, and patients with substantial skin psoriasis also showed a significant improvement in the Psoriasis Area and Severity Index (PASI) scores. The safety profile seemed acceptable, with no significant increase in adverse events. ⁴ A larger phase III study (n=205) confirmed the articular and cutaneous response to etanercept and, in addition, showed that radiographic disease progression at 12 months was halted by etanercept treatment (mean annualised rate of change in modified Total Sharp Score [mTSS] was -0.03 compared with +1.00 in the placebo group).⁵

Infliximab
Infliximab is a chimeric anti-TNF monoclonal antibody given by intravenous infusion every six to eight weeks. Studies of infliximab in PsA (Infliximab Multinational Psoriatic Arthritis Controlled Trial [IMPACT and IMPACT2]) have shown a significant benefit in peripheral joint disease, physical function, skin psoriasis, enthesitis and dactylitis. ^6,7 The larger phase III study also allowed a more thorough assessment of safety. The overall incidence of adverse events was similar in both groups, although increases in liver function tests were seen more commonly in the infliximab group.⁷

Analysis of the phase II trial suggested a halt in radiographic progression with infliximab therapy, but there was no direct comparison against placebo.⁸ The analysis of joint damage for the IMPACT2 study was more robust, analysing radiographs at baseline, week 24 (prior to cross-over) and week 54. These showed a significant reduction in radiographic damage in the infliximab group compared with placebo at week 24, despite the fact that nearly half of the placebo-treated patients actually entered an ‘early escape’ arm and had received eight weeks of treatment with infliximab.⁷ Repeat radiographs at week 54 showed continued inhibition of joint damage.⁹