Background Bone and joint damage due to chronic inflammation in the synovium of patients with RA is mediated by IL-6 and other cytokines. IL-6 mediates effects inside the joint and systemically and is blocked by sarilumab, a human mAb blocking the IL-6R?. Safety and efficacy of SC sarilumab (150 or 200 mg q2w) was evaluated in combination with MTX in patients with RA and inadequate response (IR) to MTX (MOBILITY; NCT01061736) or csDMARDs in patients with RA and IR or intolerance to ≥1 TNFi (TARGET; NCT01709578).
Objectives To compare gene expression patterns in circulating blood cells after treatment with sarilumab vs placebo in patients from MOBILITY and TARGET.
Methods Total RNA was isolated from whole blood collected at baseline (predose) and wk 2 posttreatment in patients from MOBILITY (placebo, n=58; sarilumab 150 mg q2w, n=60; sarilumab 200 mg q2w, n=46) and TARGET (placebo, n=19; sarilumab 150 mg q2w, n=27; sarilumab 200 mg q2w, n=16). Gene expression data were generated using microarray analyses (Agilent 8 × 60k platform). Data were processed using the limma package (R Bioconductor). Background correction and quantile normalization were performed and probes with low expression were filtered; 48,109 probes were analyzed. Effect of sarilumab vs placebo on gene expression was assessed in each study using linear mixed models. P values were adjusted using the Benjamini-Hochberg procedure to control false discovery rate (FDR; 5% threshold).
Results After P value adjustment to control FDR at 5%, 2 genes implicated in thrombosis and atherosclerosis (thrombomodulin [THBD] and platelet endothelial cell adhesion molecule 1 [PECAM-1]) were downregulated after treatment with sarilumab 200 mg q2w vs placebo in both studies (Table). These genes decreased with a fold-change (FC) ≤0.8 in both studies (P<0.001). An additional gene associated with coagulation, von Willebrand factor (vWF), was significantly decreased in MTX-IR but not TNF-IR patients. Numerical decreases in gene expression between sarilumab 150 mg q2w and placebo did not reach significance.
Conclusions In patients with active RA, sarilumab may decrease thrombosis-related gene expression in circulating immune cells. Additional analysis of the serum levels of thrombosis risk proteins is needed to test the hypothesis that sarilumab treatment decreases levels of thrombosis risk factors.
Acknowledgements This study was sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. Editorial support was provided by MedThink SciCom and funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc.
Disclosure of Interest C. Paccard Shareholder of: Sanofi R&D, Employee of: Sanofi R&D, J. Msihid Shareholder of: Sanofi R&D, Employee of: Sanofi R&D, A. Brisacier Shareholder of: Sanofi R&D, Employee of: Sanofi R&D, A. Damask Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, C. Paulding Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, M. Zilberstein Shareholder of: Sanofi R&D, Employee of: Sanofi R&D, A. Boyapati Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc