Pharmacogenetics of methotrexate in rheumatoid arthritis: A systematic review

Abstract

Abstract Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by inflammation of multiple joints, leading to destruction of cartilage and juxta articular bone. It eventually leads to deformity, disability, and impaired quality of life. Methotrexate (MTX) has a reported response rate of 33–65%, and this variability may be explained by genetic variations (polymorphisms) in the metabolic pathway of this drug. To evaluate possible relationships between polymorphisms in the metabolic pathway and response to MTX in patients with RA. Methodology A systematic search and review of the literature was conducted. A total of 29 studies that evaluated polymorphisms in the metabolic pathway of MTX were included, due to their full text and methodological quality. Results Of the 29 studies, five were systematic reviews and/or meta-analyses, three of which clinical trials none was triple blind and only one was double-blind, six were cohort, seven were case–control, and eight cross sectional. The polymorphism identified were: methylene tetrahydrofolate reductase, dihydrofolate reductase, thymidylate synthase, 5-amino-imidazole-4-carboxamide ribonucleotide formyl transferase (AICAR formyltransferase), 5-aminoimidazole-4-carboxamide polymorphisms formyltransferase/IMP cyclohydrolase ribonucleotide (ATIC) identified conveyors attached to ATP cassette (ABC ATP-binding cassette), folylpoly-glutamate, glutamyl hydrolase, reduced folate carrier (RFC-SLC10A1). The dihydrofolate reductase and methylene tetrahydrofolate reductase polymorphism were shown to be associated with increased MTX toxicity. RFC and C677T polymorphisms are associated with better efficacy of MTX. Conclusions The polymorphisms of methylene tetrahydrofolate reductase, C677T and RFC1-G80A generate increased efficacy and toxicity in patients treated with MTX. However, for the other polymorphisms, although studies show statistically significant associations, they are not conclusive and some are contradictory. This justifies conducting multicenter studies to assess the presence and association with the effectiveness or toxicity in patients with RA treated with MTX.