Efficacy of synthetic and biological DMARDs: a systematic literature review informing the 2025 update of the EULAR recommendations for the management of rheumatoid arthritis

OBJECTIVES: This systematic literature review (SLR) updated evidence on the efficacy of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) to inform the 2025 update of the European Alliance of Associations for Rheumatology (EULAR) management recommendations for rheumatoid arthritis (RA). METHODS: Medline (PubMed), Embase (OVID), Cochrane Central Register of Controlled Trials, and Web of Science were searched for randomised controlled trials (RCTs) of conventional-synthetic, biological, and targeted-synthetic DMARDs (csDMARDs, bDMARDs, tsDMARDs), as well as GCs and biosimilars, published from 14 January 2022 to 22 January 2025. Additional searches on DMARDs, GCs, and antifibrotics for RA-associated interstitial lung disease (RA ILD), and on DMARDs and GCs for preventing RA in at-risk individuals, were conducted from database inception to 22 January 2025. RESULTS: A total of 12,567 references were identified; 390 full-texts were reviewed, and 72 studies were included. Phase 3-4 RCTs evaluated csDMARDs (hydroxychloroquine, iguratimod, leflunomide, and methotrexate), bDMARDs (abatacept, otilimab, and ozoralizumab), and tsDMARDs (ivarmacitinib, peficitinib, and tofacitinib). Twelve novel compounds were assessed in phase 2 RCTs, and 3 articles investigated GCs. Strategic trials compared conventional therapies with bDMARD- or tsDMARD-based strategies and explored precision-medicine approaches such as synovial biopsy-guided treatment and therapeutic drug monitoring. Additional evidence addressed DMARD tapering. Two RCTs assessed antifibrotics (nintedanib and pirfenidone) for RA ILD, and 7 studies evaluated DMARDs for RA prevention in at-risk populations. CONCLUSIONS: This SLR, together with the safety review, informed the 2025 update of the EULAR RA management recommendations. Although few phase 3 trials on novel agents were available, strategic and head-to-head studies provided important insights that enabled further refinement of the established treatment algorithm.