clinical topic updates

Thrombotic Risk in Rheumatoid Arthritis: Is It Increased by Janus Kinase Inhibitors?

by Jonathan Kay, MD

Overview

Rheumatoid arthritis (RA) is associated with an increased risk of thromboembolism characterized by an approximately 2-fold increased risk of pulmonary embolism (PE) or deep vein thrombosis (DVT). The risk of thromboembolism is also increased in patients who are treated with Janus kinase (JAK) inhibitors compared with those receiving placebo.

Expert Commentary

Jonathan Kay, MD

Professor of Medicine and Population and Quantitative Health Sciences
Timothy S. and Elaine L. Peterson Chair in Rheumatology
Director of Clinical Research, Rheumatology
University of Massachusetts Medical School
Worcester, MA

“There is a boxed safety warning for this class of medications stating that thrombotic events, including DVT, PE, and arterial thrombosis, have occurred in patients taking JAK inhibitors to treat inflammatory conditions.”

Jonathan Kay, MD

Patients with RA have an increased risk of venous thromboembolism (VTE) compared with the general population. In an analysis comparing approximately 10,000 patients with RA with a matched cohort of nearly 100,000 individuals without RA in the United Kingdom, those with RA had an approximately 2-fold increased risk of PE or DVT. A retrospective cohort study using US insurance claims yielded similar findings. Notably, these studies were conducted prior to the introduction of JAK inhibitors.

Analyses suggest that JAK inhibitors are associated with an increased risk of VTE. For example, a meta-analysis of placebo-controlled clinical trials found that, compared with placebo, JAK inhibitors are associated with a 4-fold increased risk of thromboembolic events across disease states. Accordingly, there is a boxed safety warning for this class of medications stating that thrombotic events, including DVT, PE, and arterial thrombosis, have occurred in patients taking JAK inhibitors to treat inflammatory conditions. This is based primarily on experience with tofacitinib and baricitinib. An analysis found that treatment with the 10-mg twice-daily dose of tofacitinib, a dose that is higher than the dose approved by the US Food and Drug Administration, was associated with an increased risk of all-cause mortality and PE compared with tumor necrosis factor inhibitor treatment, while the 5-mg twice-daily dose had a safety profile similar to that of tumor necrosis factor inhibitor therapy. This increased risk was observed in patients aged 50 years and older who had at least 1 cardiovascular risk factor. In contrast, another analysis of patients in the tofacitinib clinical trial program found no increased risk of thromboembolic events. However, patients who participated in these clinical trials were selected to exclude those with significant comorbidities. Baricitinib has also been shown to be associated with a dose-dependent increased risk of PE/DVT. Several cases of PE/DVT have been reported in patients taking baricitinib 4 mg daily, but the 2-mg daily dose was associated with a rate of VTE similar to that of placebo. For upadacitinib, an analysis of data from the clinical trial program found no increased risk of VTE compared with methotrexate or adalimumab.

JAK inhibitors are among the many immunomodulatory agents that are being studied as potential treatments for the cytokine storm that may occur in SARS-CoV-2 infection. However, since endothelial cell dysfunction is thought to contribute to the development of complications of COVID-19, including VTE, vigilance is warranted when using JAK inhibitors to treat patients with COVID-19.

References

Bilal J, Riaz IB, Sadiq M, et al. Risk of thromboembolism with Janus kinase inhibitors: a systematic review and meta-analysis of randomized placebo controlled trials [abstract 2393]. Arthritis Rheumatol. 2019;71(suppl 10). Accessed September 20, 2020. https://acrabstracts.org/abstract/risk-of-thromboembolism-with-janus-kinase-inhibitors-a-systematic-review-and-meta-analysis-of-randomized-placebo-controlled-trials/

Choi HK, Rho Y-H, Zhu Y, et al. The risk of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a UK population-based outpatient cohort study. Ann Rheum Dis. 2013;72(7):1182-1187. doi:10.1136/annrheumdis-2012-201669

Choy E, McInnes I, Cush J, et al. MACE and VTE across multiple upadacitinib studies in rheumatoid arthritis: integrated analysis from the SELECT phase 3 clinical program [abstract 846]. Arthritis Rheumatol. 2019;71(suppl 10). Accessed September 20, 2020. https://acrabstracts.org/abstract/mace-and-vte-across-multiple-upadacitinib-studies-in-rheumatoid-arthritis-integrated-analysis-from-the-select-phase-3-clinical-program/

Huertas A, Montani D, Savale L, et al. Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)? Eur Respir J. 2020;56(1):2001634. doi:10.1183/13993003.01634-2020

Kim SC, Schneeweiss S, Liu J, Solomon DH. Risk of venous thromboembolism in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2013;65(10):1600-1607. doi:10.1002/acr.22039

Kim SC, Solomon DH, Liu J, Franklin JM, Glynn RJ, Schneeweiss S. Risk of venous thromboembolism in patients with rheumatoid arthritis: initiating disease-modifying antirheumatic drugs. Am J Med. 2015;128(5):539.e7-539.e17. doi:10.1016/j.amjmed.2014.11.025

Mehta P, Ciurtin C, Scully M, Levi M, Chambers RC. JAK inhibitors in COVID-19: need for vigilance regarding increased inherent thrombotic risk. Eur Respir J. 2020;2001919. doi:10.1183/13993003.01919-2020

Taylor PC, Weinblatt ME, Bermester GR, et al. Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis. Arthritis Rheumatol. 2019;71(7):1042-1055. doi:10.1002/art.40841

Xie W, Zhang Z. Tofacitinib in cardiovascular outcomes: friend or foe? Rheumatology (Oxford). 2020;59(8):1797-1798. doi:10.1093/rheumatology/keaa090

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