Clinical predictors of response to methotrexate in patients with rheumatoid arthritis: A systematic review
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, structural damage, and disability. Methotrexate (MTX) is the first‐line treatment; however, up to one‐third of patients exhibit an inadequate response. This systematic review aimed to identify clinical, serological, genetic, pharmacogenomic, and treatment‐related predictors of MTX response in RA. A systematic search of PubMed/MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted for studies published up to May 22, 2024. Randomized controlled trials, prospective cohort studies, and registry‐based studies evaluating predictors of MTX efficacy were included. In total, 87 studies met the eligibility criteria and were included in the review. Predictors were categorized as demographic/clinical, disease‐related, serological/immunological, genetic/pharmacogenomic, treatment‐related, and emerging. Evidence was synthesized narratively, with consideration of methodological quality and consistency. Consistent predictors of favorable MTX response included lower baseline disease activity, better functional status, early MTX initiation, and absence of erosive disease. Male sex, older age, and moderate alcohol consumption were associated with improved outcomes, although these associations may be influenced by treatment‐related and behavioral confounders, whereas smoking and higher body mass index were linked to reduced efficacy. Several inflammatory and cellular biomarkers were associated with MTX response, although individual pharmacogenetic variants showed limited reproducibility. Treatment‐related factors, including subcutaneous administration, rapid dose escalation, glucocorticoid co‐therapy, and folate supplementation, were associated with improved efficacy and tolerability. Emerging proteomic, epigenetic, and metabolomic signatures demonstrated potential for early response prediction. Overall, early disease control and optimized treatment strategies appear to be more reliable predictors of MTX response than isolated demographic or genetic factors. Integration of clinical predictors with emerging molecular biomarkers may support personalized treatment approaches and earlier identification of MTX non‐responders. CRD42023464365.