Risk of venous thromboembolism with upadacitinib in rheumatoid arthritis: a meta-analysis

Upadacitinib, a selective Janus kinase (JAK) inhibitor, has become an effective therapeutic option for rheumatoid arthritis (RA). However, venous thromboembolism (VTE) represents a potentially life-threatening complication associated with JAK inhibition, and uncertainties remain regarding the risk of specific VTE subtypes with upadacitinib, including non-fatal pulmonary embolism (nPE), non-fatal deep vein thrombosis (nDVT), and concurrent pulmonary embolism and deep vein thrombosis (cPE-DVT). This meta-analysis was performed to systematically assess the risks of these individual VTE subtypes in patients with RA receiving upadacitinib relative to comparator treatments. We systematically searched databases, including PubMed, Embase, and the Cochrane Library, for relevant randomized controlled trials (RCTs) in RA patients that reported VTE and its subtypes. Meta-analysis was conducted using the Mantel-Haenszel (M-H) fixed-effects model to calculate risk ratios (RR) with 95% confidence intervals (CI) due to low heterogeneity. A total of 4 RCTs involving 4201 patients were included in this meta-analysis. The results showed that no significant differences were observed between the upadacitinib and control groups in the risk of total VTE (0.79% vs. 0.78%; RR=0.93, 95%CI: 0.47-1.83, P=0.82), nPE (0.32% vs. 0.42%; RR=0.72, 95%CI: 0.28-1.83, P=0.49), nDVT (0.34% vs. 0.33%; RR=0.97, 95%CI: 0.32-2.96, P=0.96), or cPE-DVT (0.20% vs. 0.11%; RR=1.32, 95%CI: 0.20-8.62, P=0.77). Heterogeneity was absent across all analyses (I² = 0% for all outcomes). In this meta-analysis of RCTs, upadacitinib did not demonstrate a significantly increased risk of VTE or its subtypes compared to controls in the studied RA population. Despite the low overall incidence and lack of signal in this cohort, the potential VTE risk highlighted by the FDA boxed warning necessitates careful patient selection based on comorbidities and dosage.