Objective To compare the differential reporting disproportionality patterns of cardiovascular adverse events associated with three JAK inhibitors used for the treatment of rheumatoid arthritis (RA).

Methods Reports involving tofacitinib, baricitinib, and upadacitinib were retrieved from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) from the quarter of their respective U.S. approvals through the first quarter of 2026. Analyses were restricted to reports in which the target drug was designated as the primary suspect and the indication was RA. Adverse events were coded using MedDRA preferred terms (PTs), and eligible PTs were prespecified and hierarchically classified into thromboembolic events, ischemic cardiovascular and cerebrovascular events, arrhythmia/heart failure, and abnormalities in blood pressure/lipid monitoring. The reporting odds ratio (ROR) was used as the primary disproportionality measure, with PRR/MHRA, MGPS, and BCPNN applied for consistency assessment. Pairwise comparative reporting odds ratios (cRORs) were calculated for 10 clinically important PTs, and a sensitivity analysis was conducted using a common event-occurrence window from the third quarter of 2019 through the first quarter of 2026.

Results A total of 96,534 RA-related JAK inhibitor reports were included, of which 3,589 unique reports contained at least one cardiovascular-related PT, generating 15,918 cardiovascular PT event records. The proportions of reports containing cardiovascular adverse events were 2.93% for tofacitinib, 9.21% for baricitinib, and 4.89% for upadacitinib (P<0.001). Pairwise comparisons showed that, compared with tofacitinib, baricitinib exhibited greater reporting disproportionality for pulmonary embolism [cROR=6.57, 95%CI (5.22, 8.26)], deep vein thrombosis [cROR=5.71, 95%CI (4.25, 7.68)], heart failure [cROR=2.76, 95%CI (1.61, 4.72)], and transient ischemic attack [cROR=4.42, 95%CI (2.62, 7.44)]. Baricitinib also showed higher cRORs than upadacitinib for these events. Compared with tofacitinib, upadacitinib showed greater reporting disproportionality for thrombosis, myocardial infarction, atrial fibrillation, and transient ischemic attack. In the common-window sensitivity analysis, the directions of the baricitinib-associated differences in pulmonary embolism, deep vein thrombosis, and transient ischemic attack were consistent with those observed in the primary analysis. Exploratory time-to-onset analysis showed a numerically shorter median time to onset for baricitinib-related drug-PT event records.

Conclusion The three JAK inhibitors shared reporting disproportionality patterns for thromboembolic and ischemic cardiovascular and cerebrovascular events. The main differences were observed for baricitinib-associated pulmonary embolism, deep vein thrombosis, and transient ischemic attack, as well as upadacitinib-associated thrombosis and transient ischemic attack. These findings may serve as pharmacovigilance signals requiring further validation. They reflect disproportionality in a spontaneous reporting database and should not be interpreted as estimates of true incidence or as a risk among the drugs.

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