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Ann Rheum Dis. Oct 2004; 63(10): 1227–1231.
PMCID: PMC1754756

Methotrexate related adverse effects in patients with rheumatoid arthritis are associated with the A1298C polymorphism of the MTHFR gene


Background: There is an association between C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene and methotrexate related toxicity.

Objective: To examine the relations between the recently described A1298C polymorphism of the MTHFR gene, plasma homocysteine, methotrexate toxicity, and disease activity in patients with rheumatoid arthritis.

Design: A cross sectional study on 93 methotrexate treated patients with rheumatoid arthritis, comprising a clinical interview and physical examination to determine disease activity and methotrexate related adverse reactions. Genotype analysis of the MTHFR gene was carried out and fasting plasma homocysteine and serum folate concentrations were measured. The data were analysed using univariate analysis. Allele and genotype distributions were compared with those of a healthy control group.

Results: The frequency of the 1298CC genotype (24.7%) in the rheumatoid study group was greater than expected in the general population (12.8%, p<0.001). This genotype was associated with a significantly low rate of methotrexate related side effects. The odds ratio for side effects in patients with wild type 1298AA genotype v 1298CC genotype was 5.24 (95% confidence interval, 1.38 to 20). No correlation of disease activity variables or plasma homocysteine with MTHFR A1298C and C677T polymorphisms was observed.

Conclusions: 1298CC polymorphism was more common in methotrexate treated rheumatoid patients than expected in the population, and was associated with a reduction in methotrexate related adverse effects. The A1298C polymorphism of the MTHFR gene may indicate a need to adjust the dose of methotrexate given to patients with rheumatoid arthritis.

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Selected References

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  • Kremer JM. Methotrexate and emerging therapies. Rheum Dis Clin North Am. 1998 Aug;24(3):651–658. [PubMed]
  • Weinblatt ME, Maier AL, Fraser PA, Coblyn JS. Longterm prospective study of methotrexate in rheumatoid arthritis: conclusion after 132 months of therapy. J Rheumatol. 1998 Feb;25(2):238–242. [PubMed]
  • Cronstein BN. The mechanism of action of methotrexate. Rheum Dis Clin North Am. 1997 Nov;23(4):739–755. [PubMed]
  • Goldman ID, Matherly LH. The cellular pharmacology of methotrexate. Pharmacol Ther. 1985;28(1):77–102. [PubMed]
  • D'Angelo A, Selhub J. Homocysteine and thrombotic disease. Blood. 1997 Jul 1;90(1):1–11. [PubMed]
  • Roubenoff R, Dellaripa P, Nadeau MR, Abad LW, Muldoon BA, Selhub J, Rosenberg IH. Abnormal homocysteine metabolism in rheumatoid arthritis. Arthritis Rheum. 1997 Apr;40(4):718–722. [PubMed]
  • Hernanz A, Plaza A, Martín-Mola E, De Miguel E. Increased plasma levels of homocysteine and other thiol compounds in rheumatoid arthritis women. Clin Biochem. 1999 Feb;32(1):65–70. [PubMed]
  • Morgan SL, Baggott JE, Refsum H, Ueland PM. Homocysteine levels in patients with rheumatoid arthritis treated with low-dose methotrexate. Clin Pharmacol Ther. 1991 Nov;50(5 Pt 1):547–556. [PubMed]
  • Haagsma CJ, Blom HJ, van Riel PL, van't Hof MA, Giesendorf BA, van Oppenraaij-Emmerzaal D, van de Putte LB. Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis. 1999 Feb;58(2):79–84. [PMC free article] [PubMed]
  • Morgan SL, Baggott JE, Lee JY, Alarcón GS. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention. J Rheumatol. 1998 Mar;25(3):441–446. [PubMed]
  • van Ede AE, Laan RFJM, Blom HJ, Boers GHJ, Haagsma CJ, Thomas CMG, De Boo TM, van de Putte LBA. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatology (Oxford) 2002 Jun;41(6):658–665. [PubMed]
  • Jensen Ole Kudsk, Rasmussen Claus, Mollerup Frank, Christensen Peder Bjerg, Hansen Henrik, Ekelund Suzanne, Thulstrup Ane Marie. Hyperhomocysteinemia in rheumatoid arthritis: influence of methotrexate treatment and folic acid supplementation. J Rheumatol. 2002 Aug;29(8):1615–1618. [PubMed]
  • Ulrich CM, Yasui Y, Storb R, Schubert MM, Wagner JL, Bigler J, Ariail KS, Keener CL, Li S, Liu H, et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood. 2001 Jul 1;98(1):231–234. [PubMed]
  • Toffoli G, Veronesi A, Boiocchi M, Crivellari D. MTHFR gene polymorphism and severe toxicity during adjuvant treatment of early breast cancer with cyclophosphamide, methotrexate, and fluorouracil (CMF) Ann Oncol. 2000 Mar;11(3):373–374. [PubMed]
  • Toffoli Giuseppe, Russo Antonio, Innocenti Federico, Corona Giuseppe, Tumolo Salvatore, Sartor Franca, Mini Enrico, Boiocchi Mauro. Effect of methylenetetrahydrofolate reductase 677C-->T polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients. Int J Cancer. 2003 Jan 20;103(3):294–299. [PubMed]
  • van Ede AE, Laan RF, Blom HJ, Huizinga TW, Haagsma CJ, Giesendorf BA, de Boo TM, van de Putte LB. The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum. 2001 Nov;44(11):2525–2530. [PubMed]
  • Urano Wako, Taniguchi Atsuo, Yamanaka Hisashi, Tanaka Eiichi, Nakajima Hiroshi, Matsuda Yuko, Akama Hideto, Kitamura Yutaka, Kamatani Naoyuki. Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses. Pharmacogenetics. 2002 Apr;12(3):183–190. [PubMed]
  • van der Put NM, Gabreëls F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998 May;62(5):1044–1051. [PMC free article] [PubMed]
  • Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998 Jul;64(3):169–172. [PubMed]
  • Friedman G, Goldschmidt N, Friedlander Y, Ben-Yehuda A, Selhub J, Babaey S, Mendel M, Kidron M, Bar-On H. A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations. J Nutr. 1999 Sep;129(9):1656–1661. [PubMed]
  • Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. [PubMed]
  • van Riel PL. Provisional guidelines for measuring disease activity in clinical trials on rheumatoid arthritis. Br J Rheumatol. 1992 Dec;31(12):793–794. [PubMed]
  • Araki A, Sako Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr. 1987 Nov 27;422:43–52. [PubMed]
  • van Ede AE, Laan RF, Rood MJ, Huizinga TW, van de Laar MA, van Denderen CJ, Westgeest TA, Romme TC, de Rooij DJ, Jacobs MJ, et al. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2001 Jul;44(7):1515–1524. [PubMed]
  • Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, Koopman WJ, Krumdieck CL, Alarcón GS. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med. 1994 Dec 1;121(11):833–841. [PubMed]
  • Shpichinetsky V, Raz I, Friedlander Y, Goldschmidt N, Wexler ID, Ben-Yehuda A, Friedman G. The association between two common mutations C677T and A1298C in human methylenetetrahydrofolate reductase gene and the risk for diabetic nephropathy in type II diabetic patients. J Nutr. 2000 Oct;130(10):2493–2497. [PubMed]

Figures and Tables

Figure 1
 Relation between plasma homocysteine and serum folate concentrations for various A1298C polymorphisms. Regression lines represent the relation between plasma homocysteine concentration (µmol/l) and serum folate (ng/ml) for various A1298C ...

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