Effect of methylenetetrahydrofolate reductase polymorphism on toxicity and efficacy of methotrexate in patients with rheumatoid arthritis

Objective: Among patients with rheumatoid arthritis (RA) there is high inter-individual variability in the degree of response to methotrexate (MTX) treatment. One possible cause of the differences in the effectiveness and adverse drug reactions is genetic variation. We evaluated the relationship of C677T and A1298C polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene with toxicity and efficacy of MTX in patients with RA.
Material and methods: Genotype analysis of the MTHFR gene was done in 273 Caucasian patients who had been treated with MTX (up to 25 mg per week) and folic acid (5-10 mg per week). All patients had been diagnosed as fulfilling the 1987 ACR criteria. Outcomes were parameters of efficacy of MTX treatment and adverse events. Genomic DNA was obtained from the lymphocytes of peripheral blood. The polymerase chain reaction-restriction fragment length polymorphism assay was applied to determine the genotype of C677T and A1298C polymorphism.
Results: Clinical data of 240 patients with RA treated with MTX were analysed. A good response to therapy was demonstrated in month 6 in 33%, moderate improvement in 43%, and no improvement or deterioration in 24% of patients. 53% of patients described some toxicity during at least one study visit and 16.5% had adverse events leading to MTX withdrawal. Patients with the heterozygous genotype 677CT and homozygous TT genotype exhibited adverse events more frequently than patients with homozygous CC genotype (OR = 1.97, p < 0.01). Furthermore, the MTHFR 677T allele was associated with elevations of aminotransferases (p = 0.02; OR = 3.4). There was no relationship between MTHFR polymorphism and the efficacy of MTX treatment.
Conclusion: MTHFR 677CC polymorphism was associated with a reduction in MTX related adverse effects. This finding indicates that genotyping may help in determining which patients will benefit most from MTX treatment.