AB0114 Effects of ANTI-IL17A blockade with secukinumab on systemic and local immune responses: a mechanism-of-action study in peripheral spondyloarthritis
Authors: LJJ Van Mens, MG van de Sande, S Menegatti, ICJ Blijdorp, HM de Jong, IA Fluri, TE Latuhihin, AWR van Kuijk, NG Yeremenko, DL Baeten
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> IL-17A blockade is an effective therapy for ankylosing spondylitis (AS) and psoriatic arthritis (PsA), the two prototypical forms of spondyloarthritis (SpA). How IL-17A blockade affects the systemic and local immune responses in SpA remains incompletely understood. <h3>Objectives</h3> To assess the effect of anti-IL17A treatment with secukinumab on the systemic cytokine responses and the synovial immunopathology in SpA patients with peripheral disease (pSpA). <h3>Methods</h3> 20 active SpA patients were included in a 12wk open-label trial followed by 2yrs non-investigational extension. All patients received secukinumab 300mg/wk from baseline to wk4 and then every 4wks. Clinical response was measured 4wkly. TruCulture tubes with SEB and zymosan were drawn at baseline, day3, and wk12. Synovial biopsies were obtained by needle arthroscopy at baseline and wk12, analyzed by immunohistochemistry (IHC) and qPCR. <h3>Results</h3> The 20 pSpA patients consisted of 13 PsA, 3 undifferentiated SpA, 2 AS with peripheral arthritis, 1 reactive arthritis and 1 IBD associated pSpA. There were no SAEs in the 12wk core study. However, two SAEs occurred in the extension of the study: tonsillitis (suspected to be related to study drug) and myocardial infarction (non related), both fully recovered. Secukinumab induced a rapid and highly significant improvement in SJC (Baseline: 2,5 [IQR1–4] vs wk12: 0,5 [IQR0–1]p=0.001), TJC (6 [2–8] vs 0,5 [0–3]p&lt;0.001); VASptglobal (46 [28–65] vs 13 [6–24]p&lt;0.001). 18/20patients reached EULAR DAS response at wk 12 (10 good and 8 moderate responders). This was paralleled by significant improvements in other activity outcomes such as BASDAI (53 [25–63] vs 20 [9–40]p=0.001) and PASI (5,7 [4,5–7,1] vs 0,6 [0,1–1,8]p=0.001). Systemic inflammatory response revealed a decrease in CRP (3,85 [1,35–16,6] vs 2 [1,15–6,3]p=0,001) and ESR (16 [6–35] vs 6 [2,8–16,3]p=0,001), which was associated with decreased production of MMP-3, a validated biomarker of inflammation in pSpA,<sup>1</sup> by peripheral blood cells in the TruCulture system (see figure). With exception of a decrease in IL-17A, the TruCulture system did not reveal any impact of secukinumab on the capacity of peripheral blood cells to produce a broad panel of cytokines and chemokines upon stimulation. In contrast with this preserved systemic immune response, IHC confirmed the positive impact of 12wks of secukinumab on peripheral joint immunopathology as reflected by a significant decrease of infiltration of the synovial sublining with macrophages (2 [1–3] vs 1,5 [1–2]p=0.028) and neutrophils (1 [0,5–3,5] vs 0 [0–1]p=0.004), sensitive synovial biomarkers of treatment response in pSpA.<sup>2</sup> mRNA analysis of synovial biopsies before and after 12wks of secukimumab shows a decrease in IL-17A but not TNF expression. <h3>Conclusions</h3> This mechanism-of-action study indicates that IL-17A blockade with secukinumab has a profound beneficial clinical and biological impact on pSpA without compromising systemic immune responses. Further gene expression analysis will delineate which inflammatory pathways are blocked by secukinumab in the diseased target tissue. <h3>References</h3> van Dooren, Arthritis &amp; Rheumatism, 2004. Kruithof, Arthritis &amp; Rheumatism, 2005. <h3>Disclosure of Interest</h3> L. Van Mens: None declared, M. van de Sande Speakers bureau: Benecke, Takeda, Tillots, MSD, Cellgene, S. Menegatti: None declared, I. Blijdorp: None declared, H. de Jong: None declared, I. Fluri: None declared, T. Latuhihin: None declared, A. van Kuijk Grant/research support from: UCB, Pfizer, MSD, Janssen, Consultant for: Novartis, Celgene, N. Yeremenko: None declared, D. Baeten Grant/research support from: Pfizer, MSD, AbbVie, UCB, Novartis, Janssen, Boehringer Ingelheim, Consultant for: Pfizer, MSD, AbbVie, UCB, Novartis, Janssen, Boehringer Ingelheim, Eli Lilly, Roche, BMS, Glenmark, This study was funded by an unrestricted grant from Novartis, Employee of: UCB