Using pharmacogenetics to predict methotrexate response in rheumatoid arthritis patients

Methotrexate (MTX) is a folate antagonist and a first-line drug for the treatment of rheumatoid arthritis (RA). However, in up to 30% of cases, MTX monotherapy is insufficient, while a further 30% of patients suffer with severe adverse effects. Despite extensive clinical evidence, it is not currently possible to predict therapy outcomes and drug toxicity for MTX. Therefore, to establish biomarkers of toxicity and successful disease remission, pharmacogenomic approaches are rapidly becoming more popular.

This review summarizes recent pharmacogenomic studies evaluating MTX efficacy and toxicity. In recent years, multiple genetic alterations associated with MTX therapy outcomes and toxicity have been identified in genes associated with MTX metabolism and effector pathways. However, the data are inconsistent and require further validation.

To date, several single nucleotide polymorphisms (SNPs) have been linked with MTX efficacy. However, thanks to equivocal data, pharmacogenomic testing in routine clinical practice remains a distant prospect. Genome-wide association studies (GWAS) could facilitate the evaluation of current SNPs, and support searches for new genetic variations Once achieved, only then will it be possible to introduce more personalized and individualized therapies for RA patients.