clinical topic updates
Venous Thromboembolism Risk From Higher Doses of Janus Kinase Inhibitors
High doses of Janus kinase (JAK) inhibitors have been associated with an increased risk of venous thromboembolism (VTE), although the mechanism of this effect is unknown.
Professor of Medicine and Population and Quantitative Health Sciences
“An unmet need is to understand the mechanism whereby VTE occurs in individuals with RA, especially those treated with JAK inhibitors.”
JAK inhibitors have been associated with the occurrence of VTE and pulmonary embolism (PE). A safety review of the US Food and Drug Administration (FDA) Adverse Event Reporting System was conducted to assess postmarketing reporting rates for thromboembolic risks for tofacitinib, tofacitinib extended-release, and ruxolitinib. Data indicated that pulmonary thrombosis may potentially be a class-wide issue for JAK inhibitors. The FDA issued a boxed warning for tofacitinib in July 2019, stating that there was an increase in VTE with the 10-mg-twice-daily dosing regimen, which is higher than the 5-mg-twice-daily dose for which the drug is approved by the FDA to treat rheumatoid arthritis (RA). However, an analysis of data from clinical trials by Mease and colleagues found no greater risk of deep vein thrombosis or PE among patients with RA, psoriasis, psoriatic arthritis, or ulcerative colitis treated with tofacitinib, as compared with those treated with other therapies. Baricitinib was approved with a boxed warning for thrombosis, including deep venous thrombosis and PE, and the product label indicates that an increased risk of these events has been observed relative to placebo. With upadacitinib, a JAK1-selective agent, the boxed warning for thrombosis refers to "patients treated for inflammatory conditions with JAK inhibitors."
The risk of VTE is already increased in patients with RA, relative to the general population. Thus, an unmet need is to understand the mechanism whereby VTE occurs in individuals with RA, especially those treated with JAK inhibitors. This is crucial to determine what testing might be appropriate to identify which patients might be at risk for developing VTE and to initiate appropriate therapy to mitigate this risk, thereby allowing safe and effective treatment to control their disease activity. Patients with RA who have a history of cardiovascular events or VTE and those who are older and/or obese seem to be at an increased risk of VTE.
Future research should aim to elucidate the mechanism of JAK inhibitor-associated VTE. Data from such studies should help to guide the appropriate use of these effective medications and to facilitate prevention and intervention strategies to decrease the occurrence of VTE. In my practice, I avoid using JAK inhibitors to treat patients with RA who have risk factors for VTE, such as obesity and immobility. I counsel patients who are initiating treatment with a JAK inhibitor about the potential risk of developing VTE, but I also inform them that such events can occur in patients with RA independently of treatment with a JAK inhibitor.
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). https://acrabstracts.org/abstract/mace-and-vte-across-multiple-upadacitinib-studies-in-rheumatoid-arthritis-integrated-analysis-from-the-select-phase-3-clinical-program/. Accessed January 6, 2020.
Desai RJ, Pawar A, Weinblatt ME, Kim SC. Comparative risk of venous thromboembolism in rheumatoid arthritis patients receiving tofacitinib versus those receiving tumor necrosis factor inhibitors: an observational cohort study. Arthritis Rheumatol. 2019;71(6):892-900.
Liang H, Danwada R, Guo D, et al. Incidence of inpatient venous thromboembolism in treated patients with rheumatoid arthritis and the association with switching biologic or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) in the real-world setting. RMD Open. 2019;5(2):e001013.
Mease PJ, Kremer J, Cohen S, et al. Incidence of thromboembolic events in the tofacitinib rheumatoid arthritis, psoriasis, psoriatic arthritis and ulcerative colitis development programmes [abstract SAT0243]. Ann Rheum Dis. 2018;77(suppl 2):983.
Mogul A, Corsi K, McAuliffe L. Baricitinib: the second FDA-approved JAK inhibitor for the treatment of rheumatoid arthritis. Ann Pharmacother. 2019;53(9):947-953.
Taylor PC, Weinblatt ME, Burmester GR, et al. Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis. Arthritis Rheumatol. 2019;71(7):1042-1055.