Background/Purpose: Janus kinase (JAK) inhibitors are immunosuppressive medications that target the JAK-STAT signaling pathway. Tofacitinib (Xeljanz) was the first JAK inhibitor approved for the treatment of rheumatoid arthritis (RA) in November 2012. Additional JAK inhibitors such as baricitinib (Olumiant) and upadacitinib (Rinvoq) were later approved for the treatment of RA in May 2018 and August 2019, respectively. Shortly after the FDA approved tofacitinib, randomized clinical safety trials found a higher incidence of venous thromboembolic events within the first year of treatment. In 2019 the FDA released a Boxed Warning stating the increased risk of serious heart-related problems and cancers in those treated with tofacitinib. Here we compare the number of adverse cardiovascular events in those patients started on a JAK inhibitor (tofacitinib, baricitinib, upadacitinib) within two major health systems in Northeast Ohio.

Methods: SlicerDicer in EPIC at University Hospitals (Cleveland, OH) and MetroHealth (Cleveland, OH) were used to identify patients who were prescribed a JAK inhibitor (tofacitinib, baricitinib, upadacitinib) who were 18 years or older from November 2012 (first approval of tofacitinib) through May 2025. Subsequently, adverse cardiovascular event (venous thromboembolic event, stroke, ischemic heart disease, heart failure, cardiac arrest, and tachyarrhythmia) were identified using problem list and emergency department diagnosis as narrowing filters. Adverse cardiovascular events were measured from 1 week to 52 weeks after JAK inhibitor initiation.

Results: We identified 2788 patients (University Hospitals, n = 1917; MetroHealth, n = 871) treated with JAK inhibitors (tofacitinib, baricitinib, upadacitinib) of which 294 patients (University Hospitals, n = 226; MetroHealth, n = 68) were diagnosed with an adverse cardiovascular event within 1 year of treatment initiation. The majority of patients were 65 years or older (< 65 years old, n = 131; > 65 years old, n = 163), with 28% males and 72% females. The incidence of adverse cardiovascular events of those on a JAK inhibitor at University Hospitals and MetroHealth collectively was 11%. Yearly trends from November 2012 to May 2025 favored an increase in the number of adverse cardiovascular events following the 2019 FDA Boxed Warning.

Conclusion: JAK inhibitors (tofacitinib, upadacitinib and baricitinib) have been shown to be associated with increased reporting of VTE, stroke, ischemic heart disease, heart failure, cardiac arrest and tachyarrhythmia within the first year of treatment initiation. Our data from two major health systems in Northeast Ohio suggests an incidence of 11%, which is higher than commonly reported. Next steps will include adjudicating patient charts in EPIC SlicerDicer in order to validate and broaden our dataset in EPIC Cosmos. As the FDA approval for JAK inhibitors has expanded beyond inflammatory conditions such as rheumatoid arthritis and psoriatic arthritis to include gastrointestinal and dermatological conditions such as ulcerative colitis and atopic dermatitis, all prescribers have an obligation to familiarize themselves with the increased risk of adverse cardiovascular events demonstrated in this population.

Figure 1. Proportion of adverse cardiovascular (CV) events. A) Proportion of adverse CV events of patients on JAK inhibitors, T-test, *p < 0.05. B) Proportion of adverse CV events of patients on JAK inhibitors relative to sex (female vs male), T-test, *p < 0.05. C) Proportion of adverse CV events of patients on JAK inhibitors relative to age ( < 65 years old vs > 65 years old), no significance between age groups.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-retrospective-study-of-adverse-cardiovascular-events-in-patients-started-on-jak-inhibitors-at-two-major-health-systems-in-northeast-ohio-analysis-of-the-2019-jak-inhibitors-fda-boxed-warning-for-in/