We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Methotrexate pharmacogenetics in rheumatoid arthritis: a status report

    Fardina Malik

    Alton Memorial Hospital, Alton, IL 62002, USA

    &
    Prabha Ranganathan

    * Author for correspondence

    Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Ave, Campus PO Box 8045, St Louis, MO 63110, USA.

    Published Online:https://doi.org/10.2217/pgs.12.214

    Methotrexate (MTX), an antifolate drug, is the first-line disease-modifying agent for the treatment of rheumatoid arthritis (RA) worldwide. MTX has excellent long-term efficacy, tolerability and safety. Early initiation of MTX in patients with RA controls joint destruction and slows progression of disease. However, the clinical response to MTX and frequency of adverse effects from the drug exhibit marked interpatient variability. Over the past decade, there has been a quest to identify genetic markers that reliably predict MTX efficacy and toxicity and help optimize MTX therapy in RA; that is, the field of MTX pharmacogenetics. This review will summarize key pharmacogenetic studies examining SNPs in the genes encoding enzymes in the MTX cellular pathway and their association with MTX response in RA. As evident from this review, MTX pharmacogenetics in RA remains a muddled field, mostly due to inconsistent results from several small underpowered studies.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    References

    • Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses. Arthritis Rheum.33,1449–1461 (1990).
    • Kremer JM, Phelps CT. Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis. Update after a mean of 90 months. Arthritis Rheum.35,138–145 (1992).
    • Weinblatt ME, Maier AL, Fraser PA, Coblyn JS. Longterm prospective study of methotrexate in rheumatoid arthritis: conclusion after 132 months of therapy. J. Rheumatol.25,238–242 (1998).
    • Weinblatt ME, Keystone EC, Furst DE et al. Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum.48(1),35–45 (2003).
    • Bathon JM, Martin RW, Fleischmann RM et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N. Engl. J. Med.343(22),1586–1593 (2000).
    • Finckh A, Liang MH, van Herckenrode CM, de Pablo P. Long-term impact of early treatment on radiographic progression in rheumatoid arthritis: a meta-analysis. Arthritis Rheum.55(6),864–872 (2006).
    • Ranganathan P, McLeod HL. Methotrexate pharmacogenetics: the first step toward individualized therapy in rheumatoid arthritis. Arthritis Rheum.54(5),1366–1377 (2006).
    • Galivan J. Evidence for the cytotoxic activity of polyglutamate derivatives of methotrexate. Mol. Pharmacol.17(1),105–110 (1980).
    • van Ede AE, Laan RF, Blom HJ et al. Methotrexate in rheumatoid arthritis: an update with focus on mechanisms involved in toxicity. Semin. Arthritis Rheum.27(5),277–292 (1998).
    • 10  Szeto DW, Cheng YC, Rosowsky A et al. Human thymidylate synthetase – III. Effects of methotrexate and folate analogs. Biochem. Pharmacol.28(17),2633–2637 (1979).
    • 11  Chan ES, Cronstein BN. Molecular action of methotrexate in inflammatory diseases. Arthritis Res.4(4),266–273 (2002).
    • 12  Kang SS, Zhou J, Wong PW, Kowalisyn J, Strokosch G. Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am. J. Hum. Genet.43(4),414–421 (1988).
    • 13  Dervieux T, Greenstein N, Kremer J. Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum.54(10),3095–3103 (2006).
    • 14  Kurzawski M, Pawlik A, Safranow K, Herczynska M, Drozdzik M. 677C>T and 1298A>C MTHFR polymorphisms affect methotrexate treatment outcome in rheumatoid arthritis. Pharmacogenomics8(11),1551–1559 (2007).
    • 15  Wessels JA, de Vries-Bouwstra JK, Heijmans BT et al. Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum.54(4),1087–1095 (2006).▪ First paper to examine associations of genetic variants in the adenosine pathway and methotrexate (MTX) treatment outcomes in rheumatoid arthritis (RA) patients.
    • 16  Urano W, Taniguchi A, Yamanaka H et al. 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. Pharmacogenetics12(3),183–190 (2002).
    • 17  Taniguchi A, Urano W, Tanaka E et al. Validation of the associations between single nucleotide polymorphisms or haplotypes and responses to disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a proposal for prospective pharmacogenomic study in clinical practice. Pharmacogenet. Genomics17(6),383–390 (2007).
    • 18  Kim SK, Jun JB, El-Sohemy A, Bae SC. Cost–effectiveness analysis of MTHFR polymorphism screening by polymerase chain reaction in Korean patients with rheumatoid arthritis receiving methotrexate. J. Rheumatol.33(7),1266–1274 (2006).
    • 19  Xiao H, Xu J, Zhou X et al. Associations between the genetic polymorphisms of MTHFR and outcomes of methotrexate treatment in rheumatoid arthritis. Clin. Exp. Rheumatol.28(5),728–733 (2010).
    • 20  van Ede AE, Laan RF, Blom HJ et al. 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.44(11),2525–2530 (2001).
    • 21  Weisman MH, Furst DE, Park GS et al. Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis. Arthritis Rheum.54(2),607–612 (2006).
    • 22  Ranganathan P, Culverhouse R, Marsh S et al. Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis. J. Rheumatol.35(4),572–579 (2008).
    • 23  Cáliz R, del Amo J, Balsa A et al. The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population. Scand. J. Rheumatol.41(1),10–14 (2012).
    • 24  van der Put NM, Gabreels F, Stevens EM et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am. J. Hum. Genet.62(5),1044–1051 (1998).
    • 25  Kato T, Hamada A, Mori S et al. Genetic polymorphisms in metabolic and cellular transport pathway of methotrexate impact clinical outcome of methotrexate monotherapy in Japanese patients with rheumatoid arthritis. Drug Metab. Pharmacokinet.27(2),192–199 (2012).
    • 26  Berkun Y, Levartovsky D, Rubinow A et al. Methotrexate related adverse effects in patients with rheumatoid arthritis are associated with the A1298C polymorphism of the MTHFR gene. Ann. Rheum. Dis.63(10),1227–1231 (2004).
    • 27  Hughes LB, Beasley TM, Patel H et al. Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis. Ann. Rheum. Dis.65(9),1213–1218 (2006).
    • 28  Bohanec Grabar P, Logar D, Lestan B et al. Genetic determinants of methotrexate toxicity in rheumatoid arthritis patients: a study of polymorphisms affecting methotrexate transport and folate metabolism. Eur. J. Clin. Pharmacol.64(11),1057–1068 (2008).
    • 29  Mena JP, Salazar-Páramo M, González-López L et al. Polymorphisms C677T and A1298C in the MTHFR gene in Mexican patients with rheumatoid arthritis treated with methotrexate: implication with elevation of transaminases. Pharmacogenomics J.11(4),287–291 (2011).
    • 30  Chango A, Emery-Fillon N, de Courcy GP et al. A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol. Genet. Metab.70(4),310–315 (2000).
    • 31  Dervieux T, Kremer J, Lein DO et al. Contribution of common polymorphisms in reduced folate carrier and γ-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis. Pharmacogenetics14(11),733–739 (2004).
    • 32  Hayashi H, Fujimaki C, Daimon T, Tsuboi S, Matsuyama T, Itoh K. Genetic polymorphisms in folate pathway enzymes as a possible marker for predicting the outcome of methotrexate therapy in Japanese patients with rheumatoid arthritis. J. Clin. Pharm. Ther.34(3),355–361 (2009).
    • 33  Drozdzik M, Rudas T, Pawlik A, Gornik W, Kurzawski M, Herczynska M. Reduced folate carrier-1 80G>A polymorphism affects methotrexate treatment outcome in rheumatoid arthritis. Pharmacogenomics J.7(6),404–407 (2007).
    • 34  Grabar PB, Rojko S, Logar D, Dolzan V. Genetic determinants of methotrexate treatment in rheumatoid arthritis patients: a study of polymorphisms in the adenosine pathway. Ann. Rheum. Dis.69(5),931–932 (2010).
    • 35  Fisher MC, Cronstein BN. Metaanalysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity. J. Rheumatol.36(3),539–545 (2009).
    • 36  Owen SA, Lunt M, Bowes J et al.MTHFR gene polymorphisms and outcome of methotrexate treatment in patients with rheumatoid arthritis: analysis of key polymorphisms and meta-analysis of C677T and A1298C polymorphisms. Pharmacogenomics J. doi:10.1038/tpj.2011.42 (2011) (Epub ahead of print).
    • 37  Dervieux T, Wessels JA, van der Straaten T et al. Gene–gene interactions in folate and adenosine biosynthesis pathways affect methotrexate efficacy and tolerability in rheumatoid arthritis. Pharmacogenet. Genomics19(12),935–944 (2009)..
    • 38  Dervieux T, Wessels JA, Kremer JM et al. Patterns of interaction between genetic and nongenetic attributes and methotrexate efficacy in rheumatoid arthritis. Pharmacogenet. Genomics22(1),1–9 (2012).▪ Examines the effects of interactions between genetic and nongenetic attributes on MTX response in a large cohort of RA patients.
    • 39  Tabor HK, Risch NJ, Myers RM. Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat. Rev. Genet.3(5),391–397 (2002).
    • 40  Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K. A comprehensive review of genetic association studies. Genet. Med.4(2),45–61 (2002).
    • 41  Evans WE, Johnson JA. Pharmacogenomics: the inherited basis for interindividual differences in drug response. Annu. Rev. Genomics Hum. Genet.2,9–39 (2001).▪ Comprehensive review on pharmacogenomics.
    • 42  Lee YC, Cui J, Costenbader KH, Shadick NA, Weinblatt ME, Karlson EW. Investigation of candidate polymorphisms and disease activity in rheumatoid arthritis patients on methotrexate. Rheumatology (Oxford)48(6),613–617 (2009).
    • 43  Takatori R, Takahashi KA, Tokunaga D et al.ABCB1 C3435T polymorphism influences methotrexate sensitivity in rheumatoid arthritis patients. Clin. Exp. Rheumatol.24(5),546–554 (2006).
    • 44  Drozdzik M, Rudas T, Pawlik A et al. The effect of 3435C>T MDR1 gene polymorphism on rheumatoid arthritis treatment with disease-modifying antirheumatic drugs. Eur. J. Clin. Pharmacol.62(11),933–937 (2006).
    • 45  Kooloos WM, Wessels JA, van der Straaten T, Allaart CF, Huizinga TW, Guchelaar HJ. Functional polymorphisms and methotrexate treatment outcome in recent-onset rheumatoid arthritis. Pharmacogenomics11(2),163–175 (2010).
    • 46  Owen SA, Hider SL, Martin P, Bruce IN, Barton A, Thomson W. Genetic polymorphisms in key methotrexate pathway genes are associated with response to treatment in rheumatoid arthritis patients. Pharmacogenomics J. doi:10.1038/tpj.2012.7 (2012) (Epub ahead of print).▪ Interesting study examining the effect of a large number of SNPs (129) in ten MTX pathway genes on MTX response in RA.
    • 47  van der Straaten RJ, Wessels JA, de Vries-Bouwstra JK et al. Exploratory analysis of four polymorphisms in human GGH and FPGS genes and their effect in methotrexate-treated rheumatoid arthritis patients. Pharmacogenomics8(2),141–150 (2007).
    • 48  Wessels JA, van der Kooij SM, le Cessie S et al.; Pharmacogenetics Collaborative Research Group. A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis. Arthritis Rheum.56(6),1765–1775 (2007).
    • 49  Lopez-Lopez E, Martin-Guerrero I, Ballesteros J, Garcia-Orad A. A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia. Pharmacogenomics J. doi:10.1038/tpj.2012.44 (2012) (Epub ahead of print).
    • 50  Lasecka L, Dixon PH, Molokhia M et al. 667C>T and 1298A>C polymorphisms of MTHFR do not predict response to methotrexate in patients with gestational trophoblastic neoplasia. Gynecol. Oncol.123(3),605–609 (2011).
    • 51  Sohn KJ, Croxford R, Yates Z, Lucock M, Kim YI. Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J. Natl Cancer Inst.96(2),134–144 (2004).
    • 52  De Mattia E, Toffoli G. C677T and A1298C MTHFR polymorphisms, a challenge for antifolate and fluoropyrimidine-based therapy personalisation. Eur. J. Cancer45(8),1333–1351 (2009).
    • 53  Plenge RM, Seielstad M, Padyukov L et al.TRAF1-C5 as a risk locus for rheumatoid arthritis – a genome wide study. N. Engl. J. Med.357,1199–1209 (2007).
    • 54  Stahl EA, Raychaudhuri S, Remmers EF et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet.42,508–514 (2010).
    • 55  Ranganathan P. An update on methotrexate pharmacogenetics in rheumatoid arthritis. Pharmacogenomics9(4),439–451 (2008).
    • 56  Kumagai K, Hiyama K, Oyama T, Maeda H, Kohno N. Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis. Int. J. Mol. Med.11(5),593–600 (2003).
    • 57  Aggarwal P, Naik S, Mishra KP, Aggarwal A, Misra R. Correlation between methotrexate efficacy & toxicity with C677T polymorphism of the methylenetetrahydrofolate gene in rheumatoid arthritis patients on folate supplementation. Indian J. Med. Res.124(5),521–526 (2006).▪ First paper to generate a toxigenetic index to monitor MTX adverse effects in RA.
    • 58  Ghodke Y, Chopra A, Joshi K, Patwardhan B. Are thymidylate synthase and methylene tetrahydrofolate reductase genes linked with methotrexate response (efficacy, toxicity) in Indian (Asian) rheumatoid arthritis patients? Clin. Rheumatol.27(6),787–789 (2008).
    • 59  Inoue S, Hashiguchi M, Takagi K, Kawai S, Mochizuki M. Preliminary study to identify the predictive factors for the response to methotrexate therapy in patients with rheumatoid arthritis. Yakugaku Zasshi129(7),843–849 (2009).
    • 60  Taraborelli M, Andreoli L, Archetti S, Ferrari M, Cattaneo R, Tincani A. Methylenetetrahydrofolate reductase polymorphisms and methotrexate: no association with response to therapy nor with drug-related adverse events in an Italian population of rheumatic patients. Clin. Exp. Rheumatol.27(3),499–502 (2009).
    • 61  Urano W, Furuya T, Inoue E et al. Associations between methotrexate treatment and methylenetetrahydrofolate reductase gene polymorphisms with incident fractures in Japanese female rheumatoid arthritis patients. J. Bone Miner. Metab.27(5),574–583 (2009).
    • 62  Stamp LK, Chapman PT, O’Donnell JL et al. Polymorphisms within the folate pathway predict folate concentrations but are not associated with disease activity in rheumatoid arthritis patients on methotrexate. Pharmacogenet. Genomics20(6),367–376 (2010).
    • 63  Sharma S, Das M, Kumar A et al. Purine biosynthetic pathway genes and methotrexate response in rheumatoid arthritis patients among north Indians. Pharmacogenet. Genomics19(10),823–828 (2009).