Cardiovascular and mortality outcomes with JAK versus TNF inhibitors in rheumatoid arthritis: a target trial emulation (CARDINAL-RA)
- 1Department of Internal Medicine, Reading Hospital , , ,
- 2Internal Medicine Department, Faculty of Medicine, Al-Quds University , ,
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.
Related
- Cardiovascular risk assessment using the DAS28-GGT score in rheumatoid arthritis patients initiating JAK inhibitors: Results from the MAJIK-SFR registry
- Serum Calprotectin as predictor of Rheumatoid Arthritis disease severity and Mortality
- Joint–brain communication in rheumatoid arthritis: glial mechanisms, pain phenotypes, and translational evidence
- Histone lactylation in fibroblast-like synoviocytes drives CXCL1-mediated immune cell recruitment in rheumatoid arthritis
- Identification of a shared PAX5-mediated B-cell regulatory axis in inflammatory bowel disease and rheumatoid arthritis
BibTeX
@article{mcclenahan2026cardiovascular,
title = {{Cardiovascular and mortality outcomes with JAK versus TNF inhibitors in rheumatoid arthritis: a target trial emulation (CARDINAL-RA)}},
author = {Rachael McClenahan and Laith Alamlih},
journal = {Frontiers in immunology},
year = {2026},
month = sep,
doi = {10.3389/fimmu.2026.1908442},
url = {https://europepmc.org/article/PMC/PMC13662084},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cardiovascular and mortality outcomes with JAK versus TNF inhibitors in rheumatoid arthritis: a target trial emulation (CARDINAL-RA)
AU - Rachael McClenahan
AU - Laith Alamlih
PY - 2026
DA - 2026/09/30
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1908442
UR - https://europepmc.org/article/PMC/PMC13662084
AB - 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.
SN - 1664-3224
ER -