Fibroblast-like Synoviocytes as Therapeutic Targets in Rheumatoid Arthritis: Current Evidence on DMARD-Mediated Modulation

Background/Objectives: Fibroblast-like synoviocytes (FLS) are key contributors to rheumatoid arthritis (RA) pathogenesis, driving synovial inflammation, cartilage degradation, bone erosion and disease persistence. Recent advances have revealed substantial FLS heterogeneity, with distinct fibroblast subsets exhibiting different pathogenic roles within the rheumatoid synovium. Although disease-modifying antirheumatic drugs (DMARDs) constitute the cornerstone of RA treatment, their effects on FLS have not been comprehensively characterised. This review summarises and compares the effects of conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) on RA-FLS. Methods: A non-systematic literature review was conducted to identify studies investigating the effects of DMARDs on RA-FLS. Studies evaluating the impact of csDMARDs, bDMARDs and tsDMARDs on FLS proliferation, apoptosis, migration, invasion, inflammatory mediator production, extracellular matrix remodelling and osteoclastogenic activity were included. Results: Available evidence indicates that DMARDs modulate multiple pathogenic functions of RA-FLS. Methotrexate, leflunomide, hydroxychloroquine and sulfasalazine regulate inflammatory signalling, apoptosis, autophagy and ferroptosis. Biologic agents, particularly tumour necrosis factor alpha (TNF-α) and interleukin (IL)-6 receptor inhibitors, suppress cytokine production, matrix metalloproteinase expression, osteoclastogenic signalling and FLS migration. Targeted synthetic DMARDs, particularly Janus kinase inhibitors (JAKis), exhibit broad activity across inflammatory, angiogenic, metabolic and tissue-destructive pathways. Despite their distinct molecular targets, all DMARD classes ultimately attenuate key pathogenic FLS functions associated with synovial inflammation and joint destruction. Conclusions: JAKis exert broad effects on RA-FLS function in vitro, likely reflecting their ability to block multiple cytokine-dependent signalling pathways. However, clinical evidence linking these effects to patient outcomes remains limited; further validation is therefore required.