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Cardiovascular risks associated with Janus kinase inhibitors: peering outside the black box

  • Perspectives in Rheumatology
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Abstract

Considerable controversy related to the cardiovascular safety of Janus kinase inhibitors (JAKinibs) has arisen following the results of the ORAL Surveillance trial. In this trial of rheumatoid arthritis (RA) ≥ 50 years with at least one prevalent cardiovascular disease (CVD) risk factor, tofacitinib was not found to be non-inferior to tumour necrosis factor-alpha inhibitors (TNFi) with regards to the risk for major adverse cardiovascular events (MACE), venous thromboembolism (VTE) or malignancy. Following the results of ORAL Surveillance, the United States Food and Drug Administration (US FDA) issued a boxed warning regarding increased risks of MACE, VTE and malignancy with tofacitinib, baricitinib or upadacitinib in inflammatory arthritis or ulcerative colitis. Analysis of data from other trials (including long-term follow-up studies) of tofacitinib in RA, psoriasis, psoriatic arthritis, spondyloarthritis and inflammatory bowel diseases suggests an overall similar risk of MACE or VTE with tofacitinib when compared with TNFi. In specific patient populations with risk factors for or prior history of MACE or VTE, the risk of subsequent MACE or VTE with tofacitinib use is considerably heightened. Post-hoc analyses from ORAL Surveillance presented at the recent EULAR meeting further help to delineate patients with RA at increased risk of MACE/VTE with tofacitinib. Based on the available literature from trials and long-term follow-up studies of baricitinib and upadacitinib, there exists insufficient evidence to extend the warning of MACE/VTE with tofacitinib to these drugs. Ongoing post-marketing surveillance studies of JAKinibs in immune-mediated inflammatory diseases should help clarify CVD risk with JAKinibs.

Key Points

• The ORAL Surveillance trial failed to demonstrate non-inferiority regarding CVD and malignancy risk for tofacitinib versus TNFi, in rheumatoid arthritis ≥ 50 years old with prevalent CVD risk factors.

• Information from various other trials and their long-term extensions suggest similar risk for MACE or VTE with tofacitinib and TNFi in overall patients with RA; heightened MACE/VTE risk likely applies to specific patient populations.

• Post-hoc analyses of ORAL Surveillance suggest a heightened risk for MACE and VTE with tofacitinib in older RA patients with prior MACE/VTE events or risk factors.

• Trials of baricitinib and upadacitinib do not appear to reveal an increased risk of CVD or VTE with these drugs at their usual doses than with TNFi or placebo; ongoing post-marketing surveillance studies might further clarify CVD/VTE risk with these drugs.

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Data availability

Data pertaining to the article shall be shared on reasonable request to the corresponding author (Durga Prasanna Misra, durgapmisra@gmail.com).

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Authors and Affiliations

  1. Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow-226014, India

    Durga Prasanna Misra & Vikas Agarwal

  2. Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow-226014, India

    Gaurav Pande

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The conception and design of the study – DPM, VA.

Acquisition of data, analysis and interpretation of data – DPM, GP.

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Revising it critically for important intellectual content – VA.

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Misra, D.P., Pande, G. & Agarwal, V. Cardiovascular risks associated with Janus kinase inhibitors: peering outside the black box. Clin Rheumatol 42, 621–632 (2023). https://doi.org/10.1007/s10067-022-06415-5

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