{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:56:53Z","timestamp":1790751413681,"version":"4.1.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Within TriNetX, adults with RA aged \u226550 years and \u22651 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\u2013Meier 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In 18,757 matched pairs, JAKi was not associated with excess MACE (HR 1.002, 0.923\u20131.088; +2.11 per 1,000). All-cause mortality, a secondary outcome, was higher with JAKi (HR 1.158, 1.058\u20131.268;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.0014; +10.4 per 1,000; E-value 1.586), whereas heart failure hospitalization (HR 1.019, 0.955\u20131.088) and VTE (HR 1.054, 0.961\u20131.156) did not differ; the negative control showed no excess (HR 0.934, 0.867\u20131.007). 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\u20131.809; 198 events). A three-component composite including death was non-significant (HR 1.058, 0.992\u20131.127). No consistent effect modification was seen by sex, cardiovascular risk burden, or index year.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1908442","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:06:29Z","timestamp":1790748389000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cardiovascular and mortality outcomes with JAK versus TNF inhibitors in rheumatoid arthritis: a target trial emulation (CARDINAL-RA)"],"prefix":"10.3389","volume":"17","author":[{"given":"Rachael","family":"McClenahan","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Reading Hospital","place":["West Reading, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laith","family":"Alamlih","sequence":"additional","affiliation":[{"name":"Internal Medicine Department, Faculty of Medicine, Al-Quds University","place":["Jerusalem, Palestine"]},{"name":"Rheumatology Department, Al-Mezan Specialty Hospital","place":["Hebron, Palestine"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27425","article-title":"Is the incidence of rheumatoid arthritis rising? Results from Olmsted County, Minnesota, 1955-2007","volume":"62","author":"Myasoedova","year":"2010","journal-title":"Arthritis Rheum"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/art.24092","article-title":"Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies","volume":"59","author":"Avi\u00f1a-Zubieta","year":"2008","journal-title":"Arthritis Rheum"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0b013e32834ff2fd","article-title":"Risk factors for cardiovascular disease in rheumatoid arthritis","volume":"24","author":"Gabriel","year":"2012","journal-title":"Curr Opin Rheumatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2014-206624","article-title":"The effects of tumor necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic 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cardiovascular disease: a post hoc analysis from ORAL Surveillance","volume":"82","author":"Charles-Schoeman","year":"2023","journal-title":"Ann Rheum Dis"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2023-003630","article-title":"Comparative cardiovascular safety with janus kinase inhibitors and biological disease-modifying antirheumatic drugs as used in clinical practice: an observational cohort study from Sweden in patients with rheumatoid arthritis","volume":"9","author":"Bower","year":"2023","journal-title":"RMD Open"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/art.43188","article-title":"Incidence of major adverse cardiovascular events in patients with rheumatoid arthritis treated with JAK inhibitors compared with biologic disease-modifying antirheumatic drugs: data from an international collaboration of registries","volume":"77","author":"Aymon","year":"2025","journal-title":"Arthritis 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