This review provides a comprehensive overview of genetic variations influencing the efficacy and side effects of methotrexate (MTX) treatment in rheumatoid arthritis (RA) patients. It synthesizes findings on the associations between genetic polymorphisms and MTX therapy outcomes, aiming to identify potential genetic markers for enhancing treatment and personalized strategies in RA. The review highlights genetic variations associated with MTX therapy effects. Gene variants involved in MTX transport, including reduced folate carrier 1 (RFC1) and ABC transporters, are associated with treatment response. Specific RFC1 and ABCB1 variants are associated with improved MTX efficacy. Polymorphisms in genes regulating MTX metabolism, such as thymidylate synthase (TYMS) and methylenetetrahydrofolate reductase (MTHFR), predict MTX efficacy and toxicity risks. In addition, genes affecting MTX's mechanistic pathways, such as the adenosine signaling cascade, influence clinical outcomes. While the evidence is preliminary, this review suggests the potential of genetic testing to guide personalized MTX therapy in RA, leading to improved efficacy and reduced side effects. However, further research with diverse cohorts is needed to confirm these findings and establish the applicability of pharmacogenomic-based therapeutic approaches for RA patients receiving MTX. RA is a chronic autoimmune disease treated with MTX as the cornerstone therapy, but patient responses vary. This comprehensive review examines genetic variations influencing the efficacy and toxicity of MTX in RA patients. This study synthesizes findings from pharmacogenetic research on genetic polymorphisms and MTX outcomes through a rigorous literature review using databases such as PubMed and Web of Science.
IJPRAS
