Safety of TNF-α inhibitors therapy in patients with rheumatoid arthritis: an umbrella review.

Background: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder that is characterized by progressive synovial inflammation and leads to joint destruction, functional decline, and reduced life expectancy. Although tumor necrosis factor-alpha inhibitors (TNFi) have revolutionized RA management by preventing structural damage, their safety profiles remain controversial. Current safety assessments remain fragmented across isolated meta-analyses, failing to address competing risks or incorporate recent pharmacovigilance data. This study compared the adverse effects of anti-TNF therapy in RA and provided a stratified safety profile for optimal treatment selection. Methods: The research team searched four databases, namely PubMed, Web of Science, EMBASE, and the Cochrane Library, for relevant articles published from January 2000 to March 2025. The review adhered rigorously to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. For each meta-analysis, we recalculated effect sizes as either odds ratio (OR), relative risk (RR) or standardized mean differences (SMD), accompanied by their respective 95% confidence intervals (CIs). Methodological quality of included meta-analyses was evaluated with A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2), while the certainty of evidence was assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. To address potential overlap among primary studies across meta-analyses, the investigators utilized the Graphical Representation of Overlap for Overviews (GROOVE) tool, followed by classification of the synthesized evidence into four levels based on predefined criteria. This umbrella review was prospectively registered on PROSPERO (CRD42025638409). Findings: We synthesized results from 12 meta-analyses. The result indicated that TNF-α inhibitor therapy in RA patients was associated with (a) significantly increased risk of serious infection (OR = 1.63, 95% CI: 1.31, 2.04, p < 0.001, I Interpretation: TNF-α inhibitors are potentially associated with a higher risk of serious infection, while may have beneficial effects on cardiovascular events, myocardial infarction and insulin resistance but no association was found with other indications. However, the inconsistent methodological across studies reduces statistical power and limits the reliability of these findings, which must be interpreted cautiously. Funding: This work was supported by National Key R&D Program of China (No. 2023YFB4606705), National Natural Science Foundation of China (No. 82272611, 82472522, 82072506 and 92268115), Hunan Provincial Science Fund for Distinguished Young Scholars (No. 2024JJ2089), Science and Technology Innovation Program of Hunan Province (No. 2023SK2024) and Natural Science Foundation of Hunan Province (No. 2023JJ30949).