Schmeling H et al. (2005) Influence of methylenetetrahydrofolate reductase polymorphisms on efficacy and toxicity of methotrexate in patients with juvenile idiopathic arthritis. J Rheumatol 32: 1832–1836

Although methotrexate (MTX) is the most commonly prescribed disease-modifying drug for juvenile idiopathic arthritis (JIA), its mechanism of action is unclear. MTX acts as a folate antagonist and exerts at least some of its anti-inflammatory effects via folate metabolism. A number of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene have effects on folate metabolism and some have been associated with adverse drug reactions. In this study, the MTHFR polymorphisms C677T and A1298C were assessed for correlation with toxicity and efficacy in 58 patients with JIA who had been treated with oral MTX for at least 3 months.

The C allele of the A1298C polymorphism was found to be associated with better efficacy (more frequent reductions in swollen and tender joints, erythrocyte sedimentation rate and C-reactive protein levels) compared with 1298A/A homozygous genotype. The 677C/T genotype was associated with greater MTX toxicity (gastrointestinal symptoms, elevated serum transaminases and hair loss) and the 677C/C polymorphism with higher tolerability to MTX. The risk of having at least one adverse event was fourfold higher in patients with the MTHFR 677C/T genotype compared with those with the 677C/C genotype.

Although these data are preliminary, they imply a link between polymorphisms in the MTHFR gene and the efficacy and safety of MTX in patients with JIA. The determination of genotype might be clinically useful in estimating the risk of adverse events and treatment failure.