The role of sequential biologic therapy in rheumatoid arthritis: a systematic review and meta-analysis of efficacy, safety, and predictive factors.

Background: Biologic DMARDs have revolutionized rheumatoid arthritis (RA) management; however, therapeutic switching is often required due to inefficacy or intolerance. This study aimed to systematically evaluate the efficacy, safety, and predictive factors of response to sequential bDMARD therapy in adult RA patients.

Methods: A systematic review and meta-analysis were conducted following PRISMA 2020 guidelines (PROSPERO ID: CRD42025632894). PubMed, Scopus, Web of Science, and Cochrane Library were searched through March 2025. Eligible studies included RCTs and observational cohorts assessing outcomes after switching between bDMARDs. Primary outcomes included clinical efficacy (ACR20/50/70, DAS28, CDAI), safety (adverse events [AEs], serious adverse events [SAEs]), and predictors of therapeutic response. Risk of bias was evaluated using ROB2 and ROBINS-I tools; certainty of evidence was assessed with GRADE. Meta-analyses were performed using random-effects models.

Results: Fifty-seven studies (n > 620,000) were included. Sequential bDMARD use was primarily driven by secondary inefficacy or adverse events. Fifteen studies (n = 11,066) were included in the meta-analysis. Pooled data revealed superior ACR50 response rates in patients receiving b/tsDMARDs compared to controls (RR = 1.89; 95% CI: 1.37-2.61; p < 0.00001), despite high heterogeneity (I² = 91%). Favorable outcomes were associated with seropositivity, early disease duration, and lower baseline activity.

Conclusion: Sequential bDMARD therapy is effective and safe in RA patients requiring a therapeutic switch. Inter-class transitions, particularly following TNF inhibitor failure, may enhance outcomes. Identifying predictors of response underscores the role of personalized treatment strategies in optimizing long-term RA management.