Risk of Stroke with Rinvoq (Upadacitinib)
Rinvoq (upadacitinib) carries an increased risk of major adverse cardiovascular events (MACE) including stroke, particularly in patients aged ≥50 years with cardiovascular risk factors, though the absolute risk remains low in most populations.
Regulatory Warnings and Key Safety Data
The FDA drug label for Rinvoq explicitly warns that the medication may increase the risk of MACE including myocardial infarction, stroke, and cardiovascular death 1. This warning stems primarily from the ORAL Surveillance study, which evaluated the JAK inhibitor tofacitinib (not upadacitinib directly) in rheumatoid arthritis patients aged ≥50 years with at least one cardiovascular risk factor. In that study, JAK inhibitors showed higher rates of MACE compared to TNF antagonists 2.
The European Medicines Agency recommends cautious use of JAK inhibitors as first-line agents in patients at risk for adverse cardiovascular outcomes, specifically:
- Age ≥65 years
- Current or previous long-term smokers
- History of cardiovascular disease (such as heart attack or stroke)
- History of cancer 2, 3
Evidence from Clinical Studies
Postmarketing Surveillance Data
A 2024 FDA adverse event reporting system (FAERS) analysis found that JAK inhibitors, including upadacitinib, were associated with increased reporting of stroke compared to biologic DMARDs (adj.ROR=1.25,95% CI: 1.16-1.34) 4. When comparing different JAK inhibitors, stroke was more frequently reported with upadacitinib and baricitinib than tofacitinib 4. Notably, most adverse cardiovascular events occurred within the first year of treatment initiation 4.
Meta-Analyses and Randomized Controlled Trials
Multiple meta-analyses provide reassuring data:
A 2026 meta-analysis of 8 RCTs (4,433 patients) in spondyloarthritis and inflammatory bowel disease found upadacitinib was not associated with increased MACE risk (RR 0.35; 95% CI 0.05-2.19) 5, though the wide confidence intervals reflect low event rates and limited precision
A 2022 meta-analysis of 19 RCTs (10,656 patients) demonstrated no significant effect on MACE during ≤52-week follow-up (RR: 0.62; 95% CI: 0.24-1.60) 6
In the SELECT-MONOTHERAPY trial, 3 adjudicated MACE occurred (including 1 fatal hemorrhagic stroke with upadacitinib 15 mg) among 648 patients over 14 weeks 7
Real-World IBD Data
A 2026 study of older IBD patients (≥50 years) with baseline cardiovascular risk factors found no major adverse cardiovascular events occurred over 188 patient-years of upadacitinib exposure 8. This provides some reassurance for the IBD population specifically.
Clinical Algorithm for Risk Assessment
Before prescribing Rinvoq, stratify stroke risk:
High-Risk Patients (Use Only if No Alternatives)
- Age ≥65 years
- Prior stroke or TIA
- Current/long-term smokers
- Established cardiovascular disease
- Multiple cardiovascular risk factors (hypertension, diabetes, hyperlipidemia)
Moderate-Risk Patients (Use with Caution)
- Age 50-64 years with ≥1 cardiovascular risk factor
- Family history of premature cardiovascular disease
- Obesity (high BMI)
Lower-Risk Patients (Standard Monitoring)
- Age <50 years
- No cardiovascular risk factors
- No smoking history
Practical Considerations
The absolute risk of stroke remains low across most populations studied. The British Society of Gastroenterology notes that general precautions regarding JAK inhibitors should be applied regarding cardiovascular and thrombotic events 3. The AGA guidelines emphasize that in patients at high risk of major adverse cardiovascular events, JAK inhibitors should be used cautiously 2.
Common Pitfall
Do not assume all JAK inhibitors carry identical stroke risk profiles. While considered a class effect, postmarketing data suggest upadacitinib may have higher stroke reporting rates than tofacitinib 4. However, this must be interpreted cautiously given differences in patient populations and reporting biases.
Monitoring Recommendations
- Instruct patients, especially those with cardiovascular risk factors, to be alert for signs and symptoms of cardiovascular events 1
- Seek immediate medical attention for sudden neurological symptoms
- Consider baseline cardiovascular risk assessment (SCORE2 or equivalent) before initiation 9
- The FDA label specifically instructs patients to contact their healthcare provider immediately if they develop cardiovascular symptoms 1
Bottom line: While regulatory warnings exist based on class effects observed with tofacitinib, the absolute stroke risk with upadacitinib appears low in most populations. Reserve use for patients without suitable alternatives if they are ≥65 years or have significant cardiovascular risk factors including prior stroke.