Psoriatic arthritis is clinically heterogeneous, comprising musculoskeletal and dermatological manifestations that might involve arthritis, spondylitis, enthesitis, dactylitis, and psoriasis of skin and nails, and is associated with impaired physical function and poor quality of life.1 Non-steroidal anti-inflammatory drugs (NSAIDs) are typically the first choice in treating psoriatic arthritis symptoms, but have associated safety issues of cardiovascular risk and gastrointestinal toxicity; therefore, physicians initiate conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), preferably methotrexate, early in patients with poor prognostic factors and relevant skin involvement to modify underlying musculoskeletal and skin inflammation.2, 3
Several biological disease modifying anti-rheumatic drugs (bDMARDs) targeting inflammatory cytokines are recommended for patients with psoriatic arthritis with inadequate response to csDMARDs.3, 4 Adalimumab, a human monoclonal antibody against tumour necrosis factor (TNF), is widely used as a first line bDMARD in the treatment of patients with psoriatic arthritis as monotherapy or an add-on to methotrexate.5 Secukinumab, a human monoclonal antibody that directly inhibits IL-17A, has shown substantial improvement in the key clinical domains of psoriatic arthritis, including signs and symptoms, radiographic progression, physical functioning, and quality of life.6, 7, 8 In the treatment of patients with moderate to severe psoriasis and plaque psoriasis, secukinumab has shown greater efficacy versus a TNF inhibitor (etanercept) and an IL-12/23 inhibitor (ustekinumab).9, 10, 11
Research in context
Evidence before this study
Many patients with psoriatic arthritis who have active psoriasis and musculoskeletal symptoms show inadequate clinical responses to conventional synthetic disease-modifying antirheumatic agents (csDMARDs), including methotrexate, in all manifestations of psoriatic arthritis, including arthritis, spondylitis, enthesitis, dactylitis, and psoriasis. Several biological disease-modifying anti-rheumatic drugs (bDMARDs) that target different inflammatory cytokines are recommended for patients with psoriatic arthritis with inadequate response to csDMARDs. Adalimumab, a human monoclonal antibody against tumour necrosis factor (TNF), is widely used as a first-line bDMARD in the treatment of patients with psoriatic arthritis in monotherapy or in combination with methotrexate. We searched PubMed using the terms “psoriatic arthritis”, “biologic”, and “head-to-head” for English language articles published from inception up to Jan 13, 2020, with no limitation or restriction for year of publication or article type. The search results yielded 30 articles, of which nine used matching adjusted indirect comparisons to compare two biologicals, 20 were review articles, and one was a head-to-head comparison of two biologicals in psoriatic arthritis. However, matching adjusted indirect comparisons have an inherent limitation of the methodology used and might lead to different conclusions; therefore, prospective head-to-head trials in psoriatic arthritis are needed to help guide physicians in clinical decision making. A 2020 head-to-head, open label, 24-week trial compared the efficacy and safety of two biologicals—adalimumab and ixekizumab (an IL-17A inhibitor)—in psoriatic arthritis and supported that ixekizumab was superior to adalimumab in achieving combined American College of Rheumatology 50 (ACR50) and Psoriasis Area and Severity Index 100 responses at week 24.
Added value of this study
To our knowledge, EXCEED is the first fully blinded head-to-head trial to evaluate the efficacy and safety of secukinumab (an IL-17A inhibitor) versus adalimumab (an anti-TNF agent) as first-line biological monotherapy in patients with active psoriatic arthritis with a musculoskeletal primary endpoint of ACR20 at week 52. The efficacy data in this study suggest that secukinumab was at least as efficacious as adalimumab in improving musculoskeletal endpoints, provided better responses on skin endpoints, and had a higher retention rate at week 52. No new safety signals were reported for secukinumab and adalimumab.
Implications of all the available evidence
This study presents a considerable volume of comparative efficacy and safety data on two biologicals with different mechanisms of action in the treatment of patients with psoriatic arthritis.
Both adalimumab and secukinumab are approved for treatment of patients with active psoriatic arthritis with or without the use of concomitant methotrexate.5, 6, 12 More than 40% of patients treated with methotrexate discontinue treatment or are non-compliant because of poor tolerability or toxicity, or cannot receive methotrexate because of liver abnormalities related to psoriatic arthritis or concomitant alcohol abuse.13, 14, 15 The European League Against Rheumatism (EULAR) and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommendations differ. EULAR proposes a treatment algorithm, whereas GRAPPA proposes an evidence-based clinical domain approach that includes biologicals with novel mechanisms of action.3, 16 However, there is a paucity of trials to determine which biological treatment should be the initial treatment in patients with psoriatic arthritis upon csDMARD failure or intolerance. The advent of biological therapies with selective mechanisms of action that are approved and widely used in clinical practice has prompted indirect comparison approaches to guide therapy, but these comparisons have methodological limitations.17
Head-to-head trials have shown that IL-17A inhibitors have higher efficacy in treatment of patients with moderate to severe psoriasis and on the skin manifestations of patients with psoriatic arthritis. However, comparative data are lacking on the efficacy of these drugs on musculoskeletal manifestations of psoriatic arthritis and are urgently required. The aim of the EXCEED study was to investigate whether secukinumab 300 mg monotherapy was superior to adalimumab 40 mg monotherapy as first-line bDMARD treatment, thus testing the musculoskeletal endpoint of the American College of Rheumatology (ACR) 20 response as the primary objective in a fully blinded manner. Safety of secukinumab and adalimumab was also assessed.