LAUSR

Background Increased levels of cytokines, including interleukin-6 (IL-6), reflect inflammation and are predictive of therapeutic responses in patients with RA. IL-6 has been implicated in fatigue, pain and depression in RA but a formal association with PROs has not been performed. Sarilumab, a fully human monoclonal antibody directed against IL-6Ra, is approved for treatment of moderate-to-severely active RA. The phase 3 MONARCH randomized controlled trial (NCT01061736) compared the efficacy and safety of sarilumab monotherapy vs adalimumab in RA patients who should not continue methotrexate treatment due to intolerance or inadequate responses. Greater reductions in disease activity and improvements in the clinical signs of RA and physical function were demonstrated with sarilumab vs adalimumab. A better understanding of the association between IL-6 levels and PROs is warranted to evaluate as a biomarker for guiding RA clinical decision-making. Objectives To evaluate, by post-hoc analysis, the potential of baseline IL-6 levels to differentially predict the improvement in PRO with sarilumab vs adalimumab in MONARCH. Methods Serum IL-6 levels were measured at baseline in 300/369 patients in the ITT population. Patients were categorized into high, medium, or low IL-6 tertiles levels. Between-group comparisons of differences at Week 24 in Short Form-36 (SF-36) physical and mental component summaries (PCS, MCS) and domain scores, Functional Assessment of Chronic Illness Therapy (FACIT)-fatigue, and morning stiffness visual analog scale (VAS) measures were performed within each tertile using a linear fixed effect model. In order to evaluate the differential effect of sarilumab vs adalimumab in the baseline high vs low IL-6 groups, an interaction test of treatment-by-baseline IL-6 group analysis was performed using low IL-6 group as the reference. Results At baseline, patients in the high IL-6 tertile presented a significantly worse MCS and morning stiffness scores (P < 0.05). The model interaction comparing high vs low IL-6 tertiles was significant for SF-36 PCS and physical functioning domains, and for morning stiffness. In patients with high IL-6, sarilumab treatment resulted in significant (P < 0.05) improvements vs adalimumab in SF-36 PCS (LS mean [LSM] of the difference: 5.57, 95%CI (2.85, 8.28)) and physical functioning (PF, 16.59 (8.15, 25.03)), role physical (9.44 (0.78, 18.10)), bodily pain (BP, 10.87 (3.92, 17.81)), vitality (8.93 (1.11, 16.74)), and social functioning (12.82 (3.07, 22.58)) domains (all raw values in Figure). Sarilumab also showed significant (P < 0.05) effects vs adalimumab in FACIT-Fatigue (4.86 (1.06, 8.65)) and morning stiffness VAS (-19.93 (-30.30, -9.56)), with LSM changes exceeding minimum clinically important differences (MCID). Conclusion Evaluation of IL-6 biomarker associations with PROs indicate that patients with high IL-6 levels report better improvements with sarilumab vs adalimumab with safety profile consistent with IL-6R blockade. The effects of adalimumab treatment are stable based on IL-6 tertiles but higher with sarilumab, particularly in the high IL-6 tertile group. Effects on PCS scores are mainly driven by the PF domain, consistent with previous reports of marked improvements in pain with high IL-6 levels. Figure * Significant between-group difference in change from baseline (P < 0.05) SF-36 domains: BP, bodily pain; GH, general health; RP, role-physical, MH, mental health; PF, physical functioning; RE, role emotional; SF, social functioning; VT, vitality. Acknowledgement Medical writing support was provided by Gauri Saal, MA Economics, Prime, Knutsford, UK and funded by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interests Vibeke Strand Consultant for: AbbVie, Amgen, Bayer, BMS, Boehringer Ingelheim, Celgene, Celltrion, CORRONA, Crescendo, EMD Serono, Genentech/Roche, GSK, Horizon, Inmedix, Janssen, Kezar, Lilly, Merck, Novartis, Pfizer, Regeneron, Samsung, Sandoz, Sanofi, Servier, UCB., Susan Boklage Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Toshio Kimura Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Florence Joly Shareholder of: Sanofi, Employee of: Sanofi, Anita Boyapati Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Jérôme Msihid Shareholder of: Sanofi, Employee of: Sanofi