Influence of MTHFR C677T polymorphism on methotrexate monotherapy discontinuation in rheumatoid arthritis patients: results from the GAPAID European project.

Objectives: Methotrexate (MTX) is the most widely prescribed drug for rheumatoid arthritis (RA) patients, but 45% of them discontinue therapy within two years, either due to inefficacy or toxicity. Several authors have reported contradictory results related to C677T polymorphism in the MTHFR gene and response to MTX in RA. The purpose of this study was to further explore this genotype-response association in a European RA population.

Methods: This retrospective longitudinal study included a total of 269 RA patients from Italy and Hungary, of whom 73.2% had available data on MTX treatment (197 patients). C677T polymorphism (rs1801133) was genotyped by quantitative PCR using TaqMan assays. Genotype association analysis and Kaplan-Meier method were used for statistical comparisons between patients continuing and patients who abandoned MTX treatment.

Results: A total of 85 out of the 197 RA patients (43%) abandoned MTX treatment by the time of analysis. No significant genotype-MTX discontinuation association was found for the overall population, either at the end of the study (p=0.375), or during the follow-up (p=0.324). When the analysis was restricted to the 68 patients on MTX monotherapy, a borderline association (OR 3.15, 95% CI 0.93-10.67, p=0.057) was noted with the recessive genetic model. In agreement with that, a Kaplan-Meier analysis showed a significantly shorter time-to-discontinuation of MTX monotherapy for homozygous carriers of the T-allele (p=0.042).

Conclusions: These results demonstrate that the C677T polymorphism in the MTHFR gene is involved in MTX monotherapy discontinuation in a multicentre European patient cohort, confirming previous results.