Comparative Safety of JAK Inhibitors vs TNF Antagonists in Immune-Mediated Inflammatory Diseases

Importance: Janus kinase (JAK) inhibitors are highly effective medications for several immune-mediated inflammatory diseases (IMIDs). However, safety concerns have led to regulatory restrictions. Objective: To compare the risk of adverse events with JAK inhibitors vs tumor necrosis factor (TNF) antagonists in patients with IMIDs in head-to-head comparative effectiveness studies. Data Sources: For this systematic review and meta-analysis, the Ovid Medline, Ovid EMBASE, and Web of Science databases were searched from inception to June 25, 2025. Study Selection: Head-to-head comparative effectiveness studies of adults (aged ≥18 years) with IMIDs (including rheumatoid arthritis, inflammatory bowel disease, psoriasis or psoriatic arthritis, or spondyloarthropathy) treated with either JAK inhibitors or TNF antagonists were included. Randomized clinical trials, noncomparative observational studies, studies not reporting outcomes of interest or focused solely on specific safety events, and studies with a sample size of less than 500 were excluded. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was followed. Data Extraction and Synthesis: Four investigators independently, and in pairs, abstracted data from included studies. A random-effects meta-analysis was conducted to obtain incidence rates (IRs) and hazard ratios (HRs) for JAK inhibitors vs TNF antagonists for each safety outcome (serious infections, malignant neoplasms, major cardiovascular events [MACEs], or venous thromboembolism [VTE]), adjusting for key confounding variables. Heterogeneity was quantified using the I2 statistic. Risk of bias was assessed by 2 investigators independently using the Newcastle-Ottawa Scale. Main Outcomes and Measures: The primary outcome was risk of serious infections, malignant neoplasms, MACEs, or VTE. Results: This meta-analysis of 42 studies with low to moderate risk of bias included 813 881 patients (median age, 55.7 years [IQR, 53.0-59.0 years] for JAK inhibitor users and 51.5 years [IQR, 42.7-57.4 years] for TNF antagonist users; 76.5% female). For patients using JAK inhibitors vs TNF antagonists, there was no significant difference in risk of serious infections (IR, 3.79 [95% CI, 2.85-5.05] vs 3.03 [2.32-3.95] per 100 person-years; pooled HR, 1.05 [95% CI, 0.97-1.13]), malignant neoplasms (IR, 1.00 [0.77-1.31] vs 0.94 [0.72-1.22] per 100 person-years; pooled HR, 1.02 [0.90-1.16]), or MACEs (IR, 0.72 [0.56-0.92] vs 0.66 [0.49-0.89] per 100 person-years; pooled HR, 0.91 [0.80-1.04]), with minimal to moderate heterogeneity. There was a slightly higher risk of VTE with JAK inhibitors vs TNF antagonists (IR, 0.57 [95% CI, 0.40-0.82] vs 0.52 [0.37-0.73] per 100 person-years; pooled HR, 1.26 [95% CI, 1.03-1.54]). Effect estimates were largely stable across subgroups and on meta-regression. Conclusions and Relevance: The head-to-head studies in this systematic review and meta-analysis did not identify any meaningful difference in the risk of serious infections, malignant neoplasms, or MACEs with JAK inhibitor vs TNF antagonist use across all IMIDs, with low overall incidence. JAK inhibitor use was associated with a slightly higher risk of VTE. Further research, especially long-term studies, is needed to fully elucidate the safety of JAK inhibitors and TNF antagonists across diverse populations and optimize clinical use.