O015 Il-17 blockade with secukinumab in peripheral spondyloarthritis impacts synovial immunopathology without compromising systemic immune responses

Abstract

Objective: Secukinumab (anti-IL-17A) is an effective therapy for ankylosing spondylitis (AS), psoriatic arthritis (PsA), and the prototypical forms of spondyloarthritis (SpA). This study assessed if secukinumab modulates the immunopathology of target lesions without blunting systemic immune responses, using peripheral SpA (pSpA) as model. Methods: Twenty active peripheral SpA patients were included in a 12-week open-label trial with secukinumab (300 mg weekly for 4 weeks followed by every 4 weeks). Outcomes included clinical response, cytokine production by peripheral blood cells using TruCulture technology, and histological and qPCR analysis of synovial biopsies before and after treatment. Results: All patients completed the 12-week study, without SAEs or severe treatment-related AEs. The efficacy end point, ACR20 response at week 12, was achieved by 13 of 20 patients (13 achieved an ACR20, of which 8 reached ACR50 and 5 ACR70 response), with rapid and significant improvements in all clinical disease activity measurements. Clinical improvement in joint counts was associated with histological decrease in synovial sublining macrophages (P = .028) and neutrophils (P = .004), sensitive synovial biomarkers of inflammatory response in pSpA, as well as with decreased synovial expression of IL-17A (P = .010) but not TNF. Systemically, secukinumab treatment decreased CRP (P < .01) and ESR (P < .01), as well as MMP-3 production in the TruCulture system (P < .01). With exception of IL-17A itself, however, the capacity of peripheral blood cells to produce a broad panel of cytokines and chemokines upon stimulation with microbial antigens was not affected. Conclusion: This mechanism-of-action study in pSpA indicates that clinical improvement upon secukinumab treatment is paralleled by immunomodulation of the inflamed target tissues without compromising systemic immune responses.