Question explored with the scientific record
Relative risk of MACE with a jak inhibitor if you are 65 and have rheumatoid arthritis
For a 65-year-old with rheumatoid arthritis, the evidence shows JAK inhibitors carry a higher risk of major adverse cardiovascular events (MACE) compared to TNF inhibitors, though the absolute numbers are modest.
The most direct evidence comes from the ORAL SURVEILLANCE trial, a post-authorization safety study of tofacitinib in rheumatoid arthritis patients over 50 with at least one cardiovascular risk factor. It found MACE occurred in 3.4% of tofacitinib users versus 2.5% of those on TNF inhibitors over the study period [1]. A separate analysis of the same trial reported the rate as 91 per 10,000 person-years for tofacitinib 10 mg twice daily, compared to 73 per 10,000 person-years for anti-TNF therapy [3]. That is a roughly 25% higher rate, not a doubling.
The 2025 network meta-analysis in psoriatic arthritis found JAK inhibitors comparable to adalimumab for MACE risk, but that population is younger and has a different baseline cardiovascular profile than a 65-year-old with RA [2]. The Korean ulcerative colitis study found no difference in MACE between tofacitinib and anti-TNF, but the average age was 41, not 65 [4]. Age matters: a 2008 study found TNF inhibitor users over 65 with prior heart failure had a hazard ratio of 4.19 for heart failure hospitalization versus methotrexate users [8]. A 2019 meta-analysis of biologics in older RA patients found infection odds 1.59 times higher than in younger patients [7].
| Group | MACE rate | Comparison |
|---|---|---|
| Tofacitinib (RA, >50, CV risk) | 3.4% (91/10,000 PY) | vs 2.5% (73/10,000 PY) for anti-TNF [1][3] |
| Tofacitinib 10 mg BID (RA) | 91 per 10,000 PY | vs 73 per 10,000 PY for anti-TNF [3] |
| Tofacitinib (UC, mean age 41) | 2.9% | vs 2.9% for anti-TNF [4] |
The mechanism fits: JAK-STAT signaling is involved in vascular inflammation and myocardial remodeling [5][6]. Blocking it broadly can suppress protective as well as harmful immune responses, and the ORAL SURVEILLANCE trial was required specifically because regulators suspected this risk.
My call: for a 65-year-old with RA, a JAK inhibitor carries a modestly higher MACE risk than a TNF inhibitor, probably around 1.5 extra events per 100 people treated over a few years. The evidence is moderate quality, from one required safety trial and supporting analyses. Confidence: moderate.
Sources used 8
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JAK inhibitors for the treatment of inflammatory bowel disease
Oral JAK inhibitors, notably tofacitinib and upadacitinib, demonstrate strong efficacy in ulcerative colitis and Crohn's disease across randomized trials and real-world studies with rapid symptom relief and mucosal healing, but safety concerns necessitate careful patient selecti…
DOI: 10.58931/cibdt.2023.115 -
Risk of Major Adverse Cardiovascular Events and Thromboembolism Events in Patients with Psoriatic Arthritis on JAK Inhibitors: A Network Meta-Analysis
This network meta-analysis evaluates the risk of major adverse cardiovascular events (MACE) and thromboembolic events (TE) in patients with psoriatic arthritis treated with Janus kinase inhibitors (JAKis) compared to placebo and TNF inhibitors, finding that tofacitinib and upada…
DOI: 10.1007/s40744-025-00783-5 -
Vía JAK-STAT e inhibidores JAK
An accessible overview of the JAK-STAT signaling pathway and JAK inhibitors in dermatology, summarizing mechanisms, approved uses, safety concerns, and regulatory warnings to guide clinical practice.
DOI: 10.47196/da.v28i2.2324 -
Long-Term Safety of Tofacitinib for Treatment of Moderate-to-Severe Ulcerative Colitis: Three Years of Korean National Data
A nationwide Korean population-based cohort study comparing the long-term safety of tofacitinib versus anti-TNF inhibitors for moderate-to-severe ulcerative colitis, finding no significant differences in serious adverse events or thromboembolic/cardiovascular outcomes over ~15–1…
DOI: 10.3346/jkms.2025.40.e259 -
Mechanism of Abnormal Activation of JAK-STAT Signaling Pathway in High-Altitude Polycythemia-Related Heart Failure And Specific Inhibitor Intervention
JAK-STAT overactivation links hypoxia-driven erythropoiesis to myocardial remodeling in high-altitude polycythemia-related heart failure, and selective inhibitors may mitigate these effects.
DOI: 10.32629/jcmr.v6i3.4422 -
AI-based Predictive Signaling Pathway Profiling in Cardiac Fibrosis Suggests a Novel Combinatorial Treatment Strategy
AI-driven analysis maps temporal signaling pathway dynamics in cardiac fibrosis and demonstrates that stage-specific dual inhibition of JAK-STAT and TGF-β improves outcomes after myocardial infarction in mouse models.
DOI: 10.64898/2025.12.04.692460 -
Efficacy and safety of biological agents in the older rheumatoid arthritis patients compared to Young: A systematic review and meta-analysis
A systematic review and meta-analysis comparing efficacy and safety of biologic agents for rheumatoid arthritis in older adults versus younger adults, finding worse safety and efficacy in older patients largely due to higher baseline disease activity and steroid use, with anti-T…
DOI: 10.1016/j.semarthrit.2018.07.009 -
Tumor necrosis factor-α antagonist use and heart failure in elderly patients with rheumatoid arthritis
This study investigates the risk of heart failure hospitalization in elderly rheumatoid arthritis patients using tumor necrosis factor-α antagonists compared to methotrexate, finding a significant increase in risk associated with TNFA use.
DOI: 10.1016/j.ahj.2008.02.025