FUTURE Trials Lead to Novel Treatment for Psoriatic Arthritis

Reduction of  the disease burden from skin manifestations of psoriasis may be central to preventing joint damage and structural damage associated with psoriatic arthritis (PsA). Results of the FUTURE 1 trial reported in the October 1, 2015 issue of the New England Journal of Medicine demonstrated that selective inhibition of interleukin-17A (IL-17A) with secukinumab significantly reduced disease burden and severity, resulting in improved quality of life for patients with PsA treated with the monoclonal antibody.¹

Secukinumab is designed to target the TH17 pathway to mediate the psoriatic inflammatory response expressed in the skin, synovium, and enthesis.²  The results of the FUTURE 1 trial demonstrated that selective inhibition of IL-17A with secukinumab significantly reduced disease activity, further supporting the importance of the TH17 pathway in the mechanism of PsA. “The data that comes out from this study is that inhibition of IL-17 yields good results in all the important clinical domains of psoriatic arthritis including arthritis, enthesitis, dactylitis, skin disease, and the ability to inhibit structural damage as measured by radiographic progression,” explained lead author Philip J. Mease, MD, a clinical rheumatologist and director of the Rheumatology Clinical Research Division of Swedish Medical Center in Seattle, Washington. “And it does so as effectively as we have seen previously with the anti-TNF medicines.”

Traditional treatments for psoriasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and disease-modifying antirheumatic  drugs (DMARDs), have also been used for PsA, with moderate efficacy and a high potential for toxicity. Methotrexate (MTX) is the most commonly used DMARD for PsA, despite evidence showing that it is ineffective against many of the cardinal manifestations, including axial disease and enthesitis.³

TNF Inhibitors

The advent of biological drugs and most especially tumor necrosis factor (TNF) inhibitor agents changed the landscape for the treatment of psoriasis and particularly for PsA, where these agents showed improvements in enthesitis as well as a reduction of inflammation in peripheral and axial joints, along with the potential to slow the progression of joint damage.^4,5 American College of Rheumatology 20% improvement (ACR20) responses were significantly improved with TNF inhibitor therapy compared with placebo in clinical trials over 12 to 24 weeks.⁴ Significant improvements in functional status, quality of life measures, and in skin and nail manifestations of psoriasis were also observed.⁴

Despite this, the place for TNF inhibitors has not yet been established in PsA, as comparative studies have not yet been done. The agents are often used as first-line therapies and are more frequently prescribed after an inadequate response to DMARD therapy.³ Currently available TNF inhibitors (entanercept, infliximab, and adalimumab) all appear to show similar benefit, but responses can diminish over time and some patients show no response to treatment. It is not clear whether switching among them can improve outcomes.³

Patients with PsA have been shown to have elevated numbers of circulating TH-17 cells and increased TH-17 levels in synovial fluid, synovium, and in skin plaques, pointing to a role for TH-17 modulation in PsA. According to an article published in Expert Opinion in November of 2015,⁶ authors Boyd and Kavanaugh report that, “Our growing experience with these medications has revolutionized the approach to disease management in PsA,” leading to further investigation of cytokines including IL-12, IL-22, and IL-23, all of which have been implicated in the TH-17 mechanism of PsA.^6,7 One of the most promising directions, however, has been investigation of IL-17 inhibition, due to the impact on a range of clinical manifestations of PsA.