Risk of Cardiovascular and Venous Thromboembolic Events Associated With Janus Kinase Inhibitors in Rheumatoid Arthritis: A Systematic Review and Network Meta-analysis.

Abstract

The Janus kinases are cytoplasmic tyrosine kinases associated with membrane cytokine receptors that mediate signaling of multiple cytokines and growth factors, contributing to the pathogenesis of multiple autoimmune disorders. Janus kinase inhibitors (JKIs) are a new class of targeted therapies with proven efficacy in treating rheumatoid arthritis but are associated with an increased risk of infections. This study is aimed at assessing the risk of cardiovascular and venous thromboembolic events associated with JKIs in patients with rheumatoid arthritis. PUBMED, EMBASE, Cochrane Library, and clinicaltrials.gov were searched to identify randomized controlled trials evaluating the efficacy and safety of JKIs in patients with rheumatoid arthritis. The outcomes assessed were the risk of major adverse cardiovascular events, venous thromboembolic events, and any cardiovascular event. Sensitivity analysis disaggregated the results according to background therapy, JKI licensed doses, and studies' methodological quality. Forty-two randomized controlled trials met the inclusion criteria. No statistically significant risk differences were observed between the JKIs for any of the assessed outcomes. Compared with placebo, tofacitinib (odds ratio, 0.32; 95% confidence interval, 0.11-0.89) reduces the risk of venous thromboembolism. The results of the sensitivity analysis are in line with the initial findings. Current evidence suggests that the risk of cardiovascular and venous thromboembolic events is similar among the JKIs. Postmarketing pharmacovigilance evidence will be of utmost importance in confirming the cardiovascular safety of these drugs.