Pharmacogenetic aspects of methotrexate in a cohort of Colombian patients with rheumatoid arthritis.

Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). However, over time, ~40% of patients may experience therapeutic failure or drug toxicity. The genetic variability of the enzymes involved in the MTX metabolic pathway seem to serve an important role in the eventual therapeutic failure or drug toxicity. Depending on the enzymes affected, the toxicity or the therapeutic response may change. The present study reports some of the polymorphisms identified in enzymes in the MTX metabolic pathway that are present in a group of Colombian patients with RA, and assesses the associations of these polymorphisms with toxicity or therapeutic response to the medication. A total of 400 patients with RA were evaluated, of which 76% were women. the average age was 60.7±13.9 years and the duration of the disease was 13.2±10.9 years. The disease activity scoring method, DAS28-CRP, was used to evaluate the therapeutic response. Toxicity was determined based on reports of adverse events during the evaluation of the patients. The single nucleotide polymorphisms (SNPs) assessed using reverse transcription-PCR in the present study were MTHFR C677T, A1298C, ATIC C347G, RFC-1-G80A, FPGS-AG and DHFR-CT. The SNPs of MTHFR C677T (P=0.05) and A1298C (P=0.048) were significantly associated with the efficacy of MTX, and DHFR-CT (P=0.01) and ATIC C347 (P=0.005) were significantly associated with documented toxicity. Haematological, hepatic or renal toxicity was not associated with any of the SNPs. The results obtained in Colombian patients with RA receiving MTX are similar to those reported in other populations; however, the SNPs associated with a lack of response previously reported in the literature were not observed in our data. The SNPs identified in the present study may be used as biomarkers to predict response to MTX in terms of efficacy and toxicity in Colombian patients with RA.