Increased VTE Risk with Upadacitinib
Yes, there is a significant increased risk of venous thromboembolism with upadacitinib, occurring in a dose-dependent manner, particularly in patients with pre-existing cardiovascular risk factors. 1
Evidence from Guidelines
The most recent 2025 expert consensus statement from the Annals of the Rheumatic Diseases explicitly states that there is a dose-dependent risk of venous thromboembolic events, especially pulmonary embolism, with JAK inhibition, particularly in patients with risk factors for VTE (Level of Evidence 2b, Strength of Recommendation B). 1 This represents an evolution from earlier guidance, as the increased VTE risk may pertain to all JAK inhibitors, including upadacitinib, as a class effect. 1
The 2025 guidelines emphasize that history of arterial or venous thromboembolic events is now a contraindication (changed from "recurrent VTE" to "history of"), reflecting that both arterial and venous thromboembolism are increased in a dose-dependent manner with JAK inhibitors compared to TNF inhibitors. 1
Regulatory Warnings
The European Medicines Agency (EMA) has issued warnings to use JAK inhibitors with caution in patients with risk factors for VTE. 1 This regulatory action was based on RCT data showing increased VTE risk above the underlying effect of inflammatory disease itself, especially in patients with cardiovascular risk factors. 1
Clinical Trial Data for Upadacitinib
FDA Label Data
In the 12-month exposure dataset, venous thrombosis events (pulmonary embolism or deep vein thrombosis) were reported in 5 patients (0.5 per 100 patient-years) treated with upadacitinib 15 mg and 4 patients (0.4 per 100 patient-years) treated with upadacitinib 30 mg. 2
Integrated Safety Analysis
The integrated analysis from the SELECT phase III rheumatoid arthritis program showed that rates of VTE were similar across upadacitinib doses (0.2-0.4 events per 100 patient-years) when comparing the overall population. 3, 4 However, VTE events were more frequent in higher-risk cohorts (patients aged ≥50 years with ≥1 cardiovascular risk factor) versus the overall population, though rates remained generally similar across treatment groups including adalimumab comparators. 5
Risk Stratification
Most patients experiencing VTE events had two or more baseline cardiovascular risk factors. 4 The 2025 consensus specifically recommends considering:
- History of thromboembolism (whether provoked or unprovoked) 1
- Cardiovascular risk factors 1
- Age (higher age is an important risk factor) 1
Contradictory Evidence
A 2021 meta-analysis of RCT data found pooled incidence rate ratios that did not support VTE warnings for JAK inhibitors as a class (IRR 0.68,95% CI 0.36-1.29). 1 However, this contradicts the guideline recommendations and regulatory warnings, which are based on more comprehensive safety surveillance data and should take precedence in clinical decision-making. 1
Clinical Management
For patients with prior VTE history, concurrent anticoagulation appears protective. A 2024 study demonstrated 9.0 VTE events per 100 patient-years during JAK inhibitor treatment without anticoagulation versus zero events with concurrent anticoagulation (P = 0.020). 6 This suggests that patients with prior VTE who require JAK inhibitors should receive concurrent anticoagulation therapy. 6
Common Pitfalls
- Do not assume the absolute VTE risk is high - while statistically significant and clinically important, the absolute rate remains low (0.2-0.5 events per 100 patient-years). 2, 3, 4
- Do not ignore cardiovascular risk factor assessment - the risk is concentrated in patients with multiple baseline risk factors. 5, 4
- Do not abruptly discontinue if VTE occurs - consider anticoagulation continuation rather than immediate drug cessation, as withdrawal syndrome can occur. 7