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.