Therapeutic approaches for difficult-to-treat rheumatoid arthritis: a systematic literature review of current evidence.

This systematic literature review (SLR) aims to update the evidence regarding therapeutic strategies in difficult-to-treat rheumatoid arthritis (D2T RA), building on the previous SLR informing the European Alliance of Associations for Rheumatology (EULAR) points to consider for the management of D2T RA. Three research questions addressed efficacy or safety of treatments in patients with RA with (1) active disease and limited treatment options; (2) active disease with ≥2 prior biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) and (3) poor health-related quality of life and low objective disease activity (non-pharmacological interventions). MEDLINE, Embase and Cochrane Library were searched until July 2025. Meta-analysis and meta-regression were conducted. We screened 8589 records and included 131 studies. For research question (RQ)1, evidence on DMARD efficacy and safety was synthesised across a wide spectrum of comorbidities including obesity, cardiovascular disease, history of malignancy and respiratory comorbidities. For RQ2, all b/tsDMARDs except otilimab demonstrated better efficacy than placebo (mostly high risk of bias). Meta-regression showed efficacy was maintained for Janus kinase inhibitors (JAKi) despite increasing number of prior bDMARD failures (1 to ≥3). Safety results confirmed the increased occurrence of infection and malignancy with JAKi. For RQ3, limited evidence suggested orthopaedic surgical intervention as a potential non-pharmacological option in patients with D2T RA. This SLR summarised evidence supporting DMARD efficacy/safety across multiple comorbidities. In patients with active RA with ≥2 prior bDMARDs, JAKi offer substantial clinical benefits but require careful risk stratification given cardiovascular and malignancy risks. Furthermore, standardised reporting and dedicated studies on non-pharmacological interventions are urgently needed. CRD42024593584.