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

A Systematic Review and Network Meta-Analysis

Carlos Alves, PhD; Ana Penedones, PhD; Diogo Mendes, PhD; Francisco Batel Marques, PhD


J Clin Rheumatol. 2022;28(2):69-76. 

In This Article

Abstract and Introduction


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.


Rheumatoid arthritis is an autoimmune disease affecting approximately 5 in every 1000 adults worldwide.[1] Methotrexate, a conventional synthetic disease-modifying antirheumatic drug (csDMARD), is an effective option and is commonly used as first-line antirheumatic alternative.[2] If the disease activity remains moderate to high, additional treatment with other csDMARDs or the initiation of a biological DMARD should be considered.[1,2] Over the last years, the targeted synthetic DMARD (tsDMARD) Janus kinase (JAK) inhibitors (JKIs) have been introduced in the market and are recommended in the treatment of patients who failed initial treatment with a csDMARD.[2]

The safety of JKIs has been on the spotlight since the first medicines were authorized. Even though tofacitinib has been introduced in the US market almost a decade ago (2012), iatrogenic concerns delayed its approval by the European Medicines Agency until 2017.[3] In the same year, European Medicines Agency granted marketing authorization to baricitinib.[3] However, the US Food and Drug Administration rejected the initial application for baricitinib as a result of an unfavorable overall benefit-risk assessment.[4] After reevaluating new data, the regulatory authority approved baricitinib 2 mg, but not the 4-mg dose because of a potential risk of venous thromboembolism.[5] A black-box warning for the risk of thrombosis was additionally placed in the label of baricitinib 2 mg.[6]

In 2021, preliminary evidence on the cardiovascular safety of JKIs arose from the ORAL surveillance (study A3921133), a postmarketing, phase IV randomized controlled trial (RCT) including a population with rheumatoid arthritis and at least 1 cardiovascular risk factor.[7] In this study, patients were randomized to tofacitinib (5 or 10 mg) or tumor necrosis factor inhibitors (TNFis), etanercept or adalimumab, and major adverse cardiovascular events (MACEs) and malignancies were the elected coprimary endpoints. According to the results, tofacitinib was associated with an increased incidence of myocardial compared with TNF-α inhibitors among patients with rheumatoid arthritis who were 50 years or older, with at least 1 additional cardiovascular risk factor.[7] Letters were sent to physicians advising them to consider those risks when prescribing tofacitinib.[7]

New JKIs upadacitinib and filgotinib received market authorization from European Union over the past 2 years.[8,9] Major adverse cardiovascular events and venous thromboembolic events are considered important potential risks on all JKIs risk management plans, and all medicines from this class are under additional safety monitoring.[10] Clinical investigation of JKIs peficitinib safety is ongoing.[11] A previous meta-analysis of RCTs did not reveal a significant change in the risks of cardiovascular events and venous thromboembolic events in patients with rheumatoid arthritis treated with JKIs, but the relative cardiovascular safety of these drugs compared with every other remains unclear due to lack of head-to-head comparisons.[12] Therefore, it is important to compare the risk of cardiovascular events between the JKIs as these medicines represent a pharmacological novelty.

This systematic review and network meta-analysis aimed to compare the relative safety of the different JKIs with regard to the risk of cardiovascular and venous thromboembolism in patients with rheumatoid arthritis.