Introduction: The differences in drug efficacy and adverse reactions may be caused by genetic variations in drug metabolism between individuals.
Objectives: The aim of the study was to evaluate the effect of gene polymorphisms on the efficacy of therapy and side effects in patients with rheumatoid arthrit s (RA) treated with methotrexate (MTX).
Patients and methods: A total of 273 Caucasian patients with RA were treated with MTX for at least 6 months or stopped MTX because of adverse effects. Seven polymorphisms (RFC-1 c.80G>A, GGH c.-401C>T, MTHFR c.1298A>C and c.677C>T, TYMS 2R/3R, TYMS 6-bp deletion, and TCII c.593T>C) were examined for their effects on MTX efficacy and toxicity. Genomic DNA was obtained from peripheral blood leukocytes.
Results: Of all patients, 53% reported some adverse effects during at least 1 visit, which led to MTX withdrawal in 17% of the patients. Adverse effects were more frequent in patients with the MTHFR 677T allele than in those with the 677CC genotype (odds ratio [OR], 1.97; P = 0.01) and in those with the GGH 401CC genotype than in those with the GGH 401CT and TT genotypes (OR, 3.8; P = 0.05). Furthermore, the MTHFR 677T allele was associated with increased activity of aminotransferases (OR, 3.4; P = 0.02). MTX-related hepatotoxicity and alopecia were more common in patients with the RFC-1 80AA genotype (OR, 3.5, P = 0.01; OR, 2.4, P = 0.04; respectively). A more rapid positive response to MTX therapy was demonstrated in MTHFR 677CC homozygotes (OR, 3.4; P = 0.001). There were no other associations between single -nucleotide polymorphisms and the efficacy of MTX treatment.
Conclusions: The MTHFR 677CC and GGH 401TT and CT genotypes were associated with a reduction in the number of MTX-related adverse events. Future allele and genotype analyses may help identify the subsets of RA patients with an increased risk of adverse effects.