Cardiovascular and mortality outcomes with JAK versus TNF inhibitors in rheumatoid arthritis: a target trial emulation (CARDINAL-RA)

Why clinicians should know about it

• Picked for Immunology and Allergy (top studies of the week, 18 October 2026): Target trial emulation compares JAKi vs TNFi outcomes

Abstract

OBJECTIVES: This study aims to compare cardiovascular and mortality outcomes of Janus kinase inhibitors (JAKi) versus tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) at elevated cardiovascular risk using target trial emulation. METHODS: Within TriNetX, adults with RA aged ≥50 years and ≥1 cardiovascular risk factor initiating JAKi or TNFi were compared in a new-user, active-comparator design. Improved 1:1 propensity score matching incorporated demographics, cardiovascular risk factors, comorbidities, individual conventional synthetic DMARDs, oral corticosteroids, prior non-TNF biologic exposure, and baseline inflammatory markers. The primary outcome was MACE (nonfatal myocardial infarction or nonfatal ischemic stroke); the secondary outcomes were all-cause mortality, heart failure hospitalization, and venous thromboembolism (VTE), with cataract as a prespecified negative control. Follow-up began 90 days after initiation. Cox models estimated hazard ratios, with 5-year Kaplan-Meier cumulative incidences and absolute risk differences per 1,000. Cohorts were separately matched by agent, sex, cardiovascular-risk stratum, and index era; E-values quantified sensitivity to unmeasured confounding. RESULTS: In 18,757 matched pairs, JAKi was not associated with excess MACE (HR 1.002, 0.923-1.088; +2.11 per 1,000). All-cause mortality, a secondary outcome, was higher with JAKi (HR 1.158, 1.058-1.268; p = 0.0014; +10.4 per 1,000; E-value 1.586), whereas heart failure hospitalization (HR 1.019, 0.955-1.088) and VTE (HR 1.054, 0.961-1.156) did not differ; the negative control showed no excess (HR 0.934, 0.867-1.007). No agent showed a significant excess in MACE or mortality (mortality HR 1.052 tofacitinib, 1.213 baricitinib, and 1.090 upadacitinib); the only nominally significant agent-level finding was VTE with baricitinib (HR 1.364, 1.028-1.809; 198 events). A three-component composite including death was non-significant (HR 1.058, 0.992-1.127). No consistent effect modification was seen by sex, cardiovascular risk burden, or index year. CONCLUSION: JAKi initiation was not associated with excess MACE (primary outcome), heart failure hospitalization, or VTE. A modest excess in all-cause mortality was observed as a secondary outcome, with no signal for any individual agent. This association was of modest robustness (E-value 1.586) and was not reproduced in any agent-specific cohort, so residual channeling bias cannot be excluded. The null MACE result should not be read as class-wide cardiovascular safety reassurance nor the mortality signal as an established causal effect.

Abstract as published, via PubMed.