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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. PROSPERO REGISTRATION NUMBER: CRD42024593584.