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  • Folate Intake Modulation of MTHFR C677T–Influenced Methotrexate Pharmacokinetics in Rheumatoid Arthritis: A Systematic Review

  • Alireza Pourrahim,1,* Mohammad Mahdi Pourrahim,2 Omid Raiesi,3 Alireza Vasiee,4
    1. Student Research Committee, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
    2. Student Research Committee, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
    3. Omid Raiesi
    4. Department of Nursing, Faculty of Nursing and Midwifery, Ilam University of Medical Sciences, Ilam, Iran


  • Introduction: Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) therapy, but its pharmacokinetics are substantially altered by the MTHFR C677T polymorphism, leading to variable exposure and toxicity. Folate supplementation is routinely co-prescribed to mitigate MTX side effects, yet the quantitative impact of folate intake on MTX clearance, systemic exposure, and adverse event rates across MTHFR genotypes remains unclear. This review aggregates existing data to define the extent to which folate modifies MTX pharmacokinetics in RA patients carrying the C677T variant.
  • Methods: We searched PubMed, EMBASE, Web of Science, and Scopus from database inception through June 2025 for clinical trials and cohort studies evaluating folate (folic acid or leucovorin) supplementation and MTX pharmacokinetic parameters in adult RA patients genotyped for MTHFR C677T. Search terms included (“methotrexate” AND “MTHFR C677T” AND “folate” OR “folic acid” OR “leucovorin”) AND (“pharmacokinetics” OR “clearance” OR “AUC” OR “half-life”). Two reviewers independently screened 1,276 records, extracted continuous PK data and adverse event rates, and assessed risk of bias using the Cochrane Risk of Bias tool for RCTs and the Newcastle–Ottawa Scale for observational cohorts. Discrepancies were resolved by consensus, and random-effects meta-analyses provided pooled estimates.
  • Results: Eight studies comprising 1,564 RA patients (folate doses 1–10 mg/week) contributed pharmacokinetic and safety data. Folate supplementation was associated with a pooled increase in MTX clearance of 1.5 L/h (95% CI 1.2–1.8; p < 0.01), a 19.7% reduction in MTX AUC (95% CI –23.4 to –16.1; p < 0.05), and a 0.7-hour decrease in plasma half-life (95% CI –1.0 to –0.4; p < 0.01). The pooled risk ratio for grade ≥ 3 adverse events was 0.53 (95% CI 0.45–0.63; p < 0.01), indicating a 47% overall reduction in severe toxicity with folate co-administration.
  • Conclusion: Aggregate evidence demonstrates that folate supplementation in RA patients carrying MTHFR C677T markedly enhances MTX clearance, lowers systemic exposure, and cuts severe toxicity nearly in half. These findings support standardized folate dosing strategies and suggest that genotype-guided folate supplementation may optimize MTX therapy in RA.
  • Keywords: methotrexate; folate supplementation; MTHFR C677T; pharmacokinetics; rheumatoid arthritis

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