Choosing the next option: a scenario-based roadmap for b/tsDMARD sequencing in rheumatoid arthritis

Biologic (b) and targeted synthetic (ts) DMARDs have expanded rheumatoid arthritis (RA) treatment options, but evidence guiding sequencing after b/tsDMARD failure remains heterogeneous and difficult to translate into clinical practice. To provide a pragmatic, scenario-based synthesis to guide next-therapy choice in RA after discontinuation of a b/tsDMARD. We performed a narrative review based on PubMed and Cochrane Library searches (2010–June 2025), including systematic reviews, meta-analyses, randomised controlled trials (RCTs), and real-world studies in adults with RA after ≥ 1 failed targeted therapy. Evidence was organised into predefined clinical scenarios by number and mechanism of prior b/tsDMARD failures and synthesised using a structured framework incorporating study design, consistency, and key limitations. Across scenarios, switching to a drug with other mechanism of action (OMA) or a JAK inhibitor (JAKi) generally showed comparable, and sometimes favourable, effectiveness and persistence versus within-class cycling, particularly after failure of multiple targeted therapies. After first TNF inhibitor (TNFi) failure, both strategies are effective, although most RCTs and observational data tend to favour switching, mainly for persistence. In more treatment-experienced RA, IL-6 inhibitors and JAKi often showed favourable effectiveness and retention, although results were inconsistent. After JAKi failure, limited and largely observational evidence suggests that cycling to a second JAKi may offer higher persistence than switching to a bDMARD. This scenario-based synthesis may offer a useful complement to existing RA recommendations, potentially supporting clinicians in treatment sequencing decisions following b/tsDMARD failure, though further validation in real-world settings would help confirm its applicability.