Background/Purpose: IL-17A blockade is an effective therapy for AS and PsA, the prototypical forms of spondyloarthritis(SpA). How IL-17A blockade affects the systemic and local immune responses in SpA remains incompletely understood. Our aim was 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)

Methods: 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(bsl) to wk4 and then every 4wks. TruCulture tubes with SEB and zymosan were drawn at bsl, day3, and wk12. Synovial biopsies were obtained by needle arthroscopy at bsl and wk12, analyzed by immunohistochemistry(IHC) and qPCR

Results: The 20 pSpA patients were 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. Two SAEs occurred in the extension: tonsillitis (suspected related to study drug) and myocardial infarction (non related), both fully recovered. Secukinumab induced a rapid and highly significant improvement in SJC(median bsl: 2,5[IQR1-4] vs wk12: 0,5[IQR0-1]p=0.001), TJC(6[2-8] vs 0,5[0-3]p<0.001); VAS pt global(46[28-65] vs 13[6-24]p<0.001). 18/20patients reached EULAR good or moderate DAS response(Resp) at wk 12(10 good, and 8 moderate Resp). In parallel, improvements of 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), 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) was seen. This was associated with decreased production of MMP-3, a validated biomarker of inflammation in pSpA^{,(VanDooren,A&R,2004)} by peripheral blood cells in the TruCulture system(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. Contrasting 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 macrophage infiltrate of the synovial sublining (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.^{(Kruithof, A&R, 2005)}  mRNA analysis of synovial biopsies before and after 12wks of secukimumab shows a decrease in IL-17A but not TNF expression

Conclusion: This mechanistic 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