Influence of methylenetetrahydrofolate reductase polymorphisms on efficacy and toxicity of methotrexate in patients with juvenile idiopathic arthritis

OBJECTIVE: To study the relationship of C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene to toxicity and efficacy of methotrexate (MTX) in patients with juvenile idiopathic arthritis (JIA). METHODS: Single nucleotide polymorphisms of the MTHFR gene were investigated by polymerase chain reaction and restriction enzyme analysis of DNA extracted from peripheral blood cells. The fasting plasma homocysteine concentration was analyzed by enzyme immunoassay. Clinical data of 58 patients with JIA treated with MTX were analyzed retrospectively. RESULTS: The 1298A/A genotype was present in 31 patients, 1298C/C in 4 patients, and 21 patients were heterozygous. The 677C/C genotype was present in 29 patients, 677 T/T in 3 patients, and 26 patients were heterozygous. In patients who presented the C allele of the A1298C polymorphism, improvement with respect to the number of swollen joints, the number of tender joints, and a decrease in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels occurred more frequently than in 1298 A/A homozygous patients (p < 0.05 for ESR, p < 0.01 for CRP, chi-square test). There was no relationship between the C677T polymorphism and the efficacy of MTX treatment. Forty-two adverse events were noted in 26 patients; gastrointestinal symptoms were most common (n = 20), followed by elevated serum levels of transaminases (n = 19) and hair loss (n = 3). There was no cytopenia. Patients with the heterozygous genotype 677C/T exhibited adverse events more frequently than patients with the homozygous C/C genotype (65% vs 31%; p < 0.05, chi-square test). The A1298C polymorphism, however, was not associated with occurrence of adverse events. Plasma homocysteine was elevated in 6 patients with up to 16.9 mmol/l. No association was found to a specific genotype or to adverse events. CONCLUSION: These preliminary data suggest an association of the MTHFR 677C/C polymorphism to a higher tolerability of MTX, and of the 1298A/A to lower clinical efficacy of MTX therapy in JIA.