Although the pathogenesis of psoriatic arthritis (PsA) is not fully understood, the pleiotropic inflammatory cytokine interleukin-6 (IL-6), which has a known role in synovitis, local and systemic inflammation, and the promotion of bone resorption in rheumatoid arthritis (RA), may play a role. Serum levels of IL-6 are increased in patients with psoriasis, and the up-regulation of proinflammatory cytokines, including IL-6, in PsA synovial tissue has been reported. In patients with PsA, IL-6 levels correlate with the number of affected joints, elevation of the erythrocyte sedimentation rate, and C-reactive protein (CRP) level. Additionally, a few case reports of successful use of anti–IL-6 receptor biologic therapy to treat PsA exist, although results have been conflicting. Taken together, these findings make IL-6 a potential therapeutic target in PsA.
Clazakizumab is a monoclonal antibody with high affinity and specificity for IL-6. It has been studied previously as a treatment for RA using intravenous and subcutaneous formulations with encouraging results, and with a safety profile that is consistent with the known pharmacology of IL-6 blockade.
This randomized, double-blind, placebo-controlled, dose-ranging phase IIb study evaluated the efficacy of three doses of clazakizumab administered subcutaneously every four weeks vs. placebo, with or without methotrexate (MTX), in patients with active PsA and an inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs) and/or nonbiologic disease-modifying anti-rheumatic drugs (DMARDs).
Methods: Patients with active PsA and an inadequate response to nonsteroidal anti-inflammatory drugs were randomized (1:1:1:1) to receive subcutaneous placebo or clazakizumab 25 mg, 100 mg, or 200 mg every four weeks, with or without methotrexate. The primary end point was the response rate according to the American College of Rheumatology 20% criteria for improvement (ACR20) at Week 16, with secondary efficacy end points at Weeks 16 and 24.
Results: A total of 165 patients were randomized. At Week 16, the ACR20 response rate was significantly higher with clazakizumab 100 mg vs. placebo (52.4% vs. 29.3%; P 5 0.039). ACR20 response rates at Week 16 were 46.3% with clazakizumab 25 mg (P 5 0.101 vs. placebo) and 39.0% with clazakizumab 200 mg (P 5 0.178 vs. placebo). ACR50/ACR70 response rates were numerically higher with clazakizumab vs. placebo at Weeks 16 and 24. Compared with placebo, clazakizumab treatment significantly improved musculoskeletal manifestations (joint signs and symptoms, enthesitis and dactylitis), with minimal improvements in skin disease, without clear evidence of a dose response. Clazakizumab was well tolerated.
Conclusion: This is the first clinical trial of an IL-6–targeted therapy in PsA. Clazakizumab may be an effective treatment option for musculoskeletal aspects of PsA, but because of the lack of a dose response in this study, further studies are required to confirm the appropriate dose. The safety profile is consistent with the pharmacology of IL-6 blockade and prior clinical experience with this antibody in rheumatoid arthritis.