Risk of Cardiovascular and Venous Thromboembolic Events Associated With Janus Kinase Inhibitors in Rheumatoid Arthritis

Abstract

Background/Objective: 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.Methods: 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.Results: 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.Conclusions: 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.

The Risk of Infections Associated With JAK Inhibitors in Rheumatoid Arthritis

“…This systematic review and network meta-analysis followed the Centre for Reviews and Dissemination's guidance for undertaking reviews in health care and was reported in accordance with the PRISMA extension statement for reporting systematic reviews incorporating network meta-analyses of health care interventions (Supplemental Table 1, http://links.lww.com/RHU/A291). 14,15 This systematic review was registered at PROSPERO (CRD42020190440) and at European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS35531), and a protocol was prepared and published in the literature 16 …”

“…14,15 This systematic review was registered at PROSPERO (CRD42020190440) and at European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS35531), and a protocol was prepared and published in the literature. 16…”

Potential Adverse Events Reported With the Janus Kinase Inhibitors Approved for the Treatment of Rheumatoid Arthritis Using Spontaneous Reports and Online Patient Reviews

“…Although JAK inhibitors may increase the risk of thromboembolism events, a recent meta-analysis of randomized clinical trials (RCTs) reported that JAK inhibitors did not significantly change cardiovascular risk, and there was no difference among JAK inhibitors for the occurrence of cardiovascular or thromboembolic events ( Xie et al, 2019 ; Alves et al, 2021 ). However, caution is needed in its interpretation because of the limited follow-up period of the RCTs.…”

Recommendations for risk minimization when using Janus kinase inhibitors for the treatment of chronic inflammatory skin diseases

“…An increased risk of thromboembolic events has been suggested based on study data from individual JAKi 1,9,10 . The actual, individual risk of thromboembolic events during JAKi treatment in dermatological indications is still very low 11,12 .…”