Impact of methylenetetrahydrofolate reductase (MTHFR) A1298C gene polymorphism on the outcome of methotrexate treatment in a sample of Egyptian rheumatoid arthritis patients

Abstract

Background: Methotrexate is the most commonly used disease-modifying anti-rheumatic drug (DMARD) and it is considered the first-line treatment in the management of rheumatoid arthritis (RA). MTX treatment outcome regarding response to the drug and adverse effects in RA patients are not universal. Therefore, it would be beneficial if we could predict the response of patients to MTX before starting MTX treatment in order to determine the patient’s drug-treatment plan.

Objectives: The present study aimed to evaluate the impact of MTHFR A1298C SNP (rs1801131) on the clinical outcome of MTX treatment as regards treatment efficacy and toxicity in a cohort of Egyptian rheumatoid arthritis patients.

Patients and methods: Fifty rheumatoid arthritis patients were included in the present study. Data about patient related variables such as age and sex, disease related variables such as disease duration as well as treatment related variables such as treatment duration, dose of MTX, its route of administration and concomitant use of other drugs (NSAIDs) were obtained. DAS28 was calculated to all patients to assess drug response. MTHFR A1298C polymorphism was investigated using real time 50 nuclease allelic discrimination assay.

Results: Multivariate regression analysis for factors predicting MTX drug response showed that MTHFR A1298C SNP and MTX dose were the most significant independent predictors for MTX treatment response (p = .016, OR = 39.113, 95% C.I = 1.970–776.558, p = .003, OR = 1.667, C.I = 1.184–2.348, respectively). Considering clinicopathological variables; longer disease duration, positive anti-CCP, NSAIDs users, higher MTX doses and longer treatment durations were significantly associated with nonresponse to MTX. Regarding MTX drug toxicity, MTHFR 1298 CC genotype, MTX dose and concomitant use of NSAIDs were significantly associated with MTX drug toxicity (^MCp = .003, p = .031, p = .029, respectively).

Conclusion: Our study proved that MTHFR A1298C SNP can predict clinical outcome of MTX treatment as regards treatment efficacy and toxicity in Egyptian rheumatoid arthritis patients.

Keywords: Rheumatoid arthritis, Methotrexate, Pharmacogenetics, Methylenetetrahydrofolate reductase