Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Predictive genetic biomarkers for the efficacy of methotrexate in rheumatoid arthritis: a systematic review

Abstract

Multiple pharmacogenetic studies investigated the effectiveness of methotrexate. However, due to the use of nonvalidated outcomes, lack of validation or conflicting results it remains unclear if genetic markers can help to predict response to MTX treatment. Therefore, a systematic review was performed. PubMed was searched for articles reporting potential pharmacogenetic biomarkers associated (p < 0.05) with MTX efficacy using the validated endpoints DAS(28), EULAR, or ACR response criteria. The PICO method was used for study selection, and PRISMA guidelines to prepare the report. Thirty-five studies met the inclusion criteria, providing 39 potential genetic biomarkers in 19 genes. After Bonferroni correction, six genetic biomarkers were associated with the efficacy of MTX: ATIC rs7563206; SLC19A1 rs1051266; DHFR rs836788; TYMS rs2244500, rs2847153, and rs3786362 in at least one study. Only SLC19A1 rs1051266 was replicated in an independent cohort and promising for predicting methotrexate efficacy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Lima A, Bernardes M, Azevedo R, Seabra V, Medeiros R. Moving toward personalized medicine in rheumatoid arthritis: SNPs in methotrexate intracellular pathways are associated with methotrexate therapeutic outcome. Pharmacogenomics. 2016. https://doi.org/10.2217/pgs-2016-0067.

  2. Ulrich CM, Robien K, Sparks R. Pharmacogenetics and folate metabolism—a promising direction. Pharmacogenomics. 2002;3:299–313.

    Article  CAS  PubMed  Google Scholar 

  3. Kawaida R, Yamada R, Kobayashi K, Tokuhiro S, Suzuki A, Kochi Y, et al. CUL1, a component of E3 ubiquitin ligase, alters lymphocyte signal transduction with possible effect on rheumatoid arthritis. Genes Immun. 2005;6:194–202.

    Article  CAS  PubMed  Google Scholar 

  4. Hider SL, Bruce IN, Thomson W. The pharmacogenetics of methotrexate. Rheumatology. 2007;46:1520–4.

    Article  CAS  PubMed  Google Scholar 

  5. Malik F, Ranganathan P. Methotrexate pharmacogenetics in rheumatoid arthritis: a status report R eview. Pharmacogenomics. 2013;14:305–14.

    Article  CAS  PubMed  Google Scholar 

  6. Plant D, Wilson AG, Barton A. Genetic and epigenetic predictors of responsiveness to treatment in RA. Nat Rev Rheumatol. 2014;10:329–37.

    Article  CAS  PubMed  Google Scholar 

  7. Ranganathan P, McLeod HL. Methotrexate pharmacogenetics: the first step toward individualized therapy in rheumatoid arthritis. Arthritis Rheum. 2006;54:1366–77.

    Article  CAS  PubMed  Google Scholar 

  8. Brinker RR, Ranganathan P. Methotrexate pharmacogenetics in rheumatoid arthritis. Clin Exp Rheumatol. 2010;28. https://doi.org/10.3899/jrheum.091095.

  9. Stamp L, Roberts R, Kennedy M, Barclay M, O’Donnell J, Chapman P. The use of low dose methotrexate in rheumatoid arthritis—are we entering a new era of therapeutic drug monitoring and pharmacogenomics? Biomed Pharmacother. 2006;60:678–87.

    Article  CAS  PubMed  Google Scholar 

  10. Zhu H, Deng F-Y, Mo X-B, Qiu Y-H, Lei S-F. Pharmacogenetics and pharmacogenomics for rheumatoid arthritis responsiveness to methotrexate treatment: the 2013 update. Pharmacogenomics. 2014;15:551–66.

    Article  CAS  PubMed  Google Scholar 

  11. Dervieux T, Furst D, Lein DO, Capps R, Smith K, Caldwell J, et al. Pharmacogenetic and metabolite measurements are associated with clinical status in patients with rheumatoid arthritis treated with methotrexate: results of a multicentred cross sectional observational study. Ann Rheum Dis. 2005;64:1180–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ranganath VK, Khanna D, Paulus HE. ACR remission criteria and response criteria. Clin Exp Rheumatol. 2006;24:1909.

  13. Fransen J, van Riel PL. The disease activity score and the EULAR response criteria. Rheum Dis Clin North Am. 2009;35:745–57.

    Article  PubMed  Google Scholar 

  14. Counsell C. Formulating questions and locating primary studies for inclusion in systematic reviews. Ann Intern Med. 1997;127:380–7.

    Article  CAS  PubMed  Google Scholar 

  15. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4:1.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O’Donnell CJ, De Bakker PIW. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics. 2008;24:2938–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Senapati S, Singh S, Das M, Kumar A, Gupta R, Kumar U, et al. Genome-wide analysis of methotrexate pharmacogenomics in rheumatoid arthritis shows multiple novel risk variants and leads for TYMS regulation. Pharmacogenet Genomics. 2014;24:211–9.

    Article  CAS  PubMed  Google Scholar 

  18. Ghodke-Puranik Y, Puranik AS, Shintre P, Joshi K, Patwardhan B, Lamba J, et al. Folate metabolic pathway single nucleotide polymorphisms: a predictive pharmacogenetic marker of methotrexate response in Indian (Asian) patients with rheumatoid arthritis. Pharmacogenomics. 2015;16:2019–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. James HM, Gillis D, Hissaria P, Lester S, Somogyi AA, Cleland LG, et al. Common polymorphisms in the folate pathway predict efficacy of combination regimens containing methotrexate and sulfasalazine in early rheumatoid arthritis. J Rheumatol. 2008;35:562–71.

    CAS  PubMed  Google Scholar 

  20. 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. 2010;69:931–2.

    Article  CAS  PubMed  Google Scholar 

  21. Sharma Shruti, Das Mitashree, Kumar Ashok, Vishal Marwaha, Subramanian Shankar, Paramjeet Singh, et al. Purine biosynthetic pathway genes and methotrexate response in rheumatoid arthritis patients among north Indians. PubMed commons. Pharmacogenet Genomics. 2009;19:823–8.

    Article  CAS  PubMed  Google Scholar 

  22. Wessels JAM, Kooloos WM, De Jonge R, De Vries-Bouwstra JK, Allaart CF, Linssen A, et al. Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis. Arthritis Rheum. 2006;54:2830–9.

    Article  CAS  PubMed  Google Scholar 

  23. 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. 2009;48:613–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kurzawski M, Malinowski D, Szarmach N, Nowak A, Goryniak A, Pawlik A, et al. ATIC missense variant affects response to methotrexate treatment in rheumatoid arthritis patients. Pharmacogenomics. 2016;17:1971–8.

    Article  CAS  PubMed  Google Scholar 

  25. Swierkot J, Bogunia-Kubik K, Nowak B, Bialowas K, Korman L, Gebura K, et al. Analysis of associations between polymorphisms within genes coding for tumour necrosis factor (TNF)-alpha and TNF receptors and responsiveness to TNF-alpha blockers in patients with rheumatoid arthritis. Jt Bone Spine. 2015;82:94–9.

    Article  CAS  Google Scholar 

  26. 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. 2006;124:521–6.

    CAS  PubMed  Google Scholar 

  27. Wessels JAM, De Vries-Bouwstra JK, Heijmans BT, Slagboom PE, Goekoop-Ruiterman YPM, Allaart CF, 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. 2006;54:1087–95.

    Article  CAS  PubMed  Google Scholar 

  28. 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. 2009;27:499–502.

    CAS  PubMed  Google Scholar 

  29. 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. 2006;54:3095–103.

    Article  CAS  PubMed  Google Scholar 

  30. Dervieux T, Wessels JaMM, van der Straaten T, Penrod N, Moore JH, Guchelaar H-J, et al. Gene–gene interactions in folate and adenosine biosynthesis pathways affect methotrexate efficacy and tolerability in rheumatoid arthritis. Pharmacogenet Genomics. 2009;19:935–44.

    Article  CAS  PubMed  Google Scholar 

  31. Lima A, Bernardes M, Azevedo R, Medeiros R, Seabra V. Pharmacogenomics of methotrexate membrane transport pathway: can clinical response to methotrexate in rheumatoid arthritis be predicted? Int J Mol Sci. 2015;16:13760–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Negi S, Kumar A, Thelma BK, Juyal RC. Association of Cullin1 haplotype variants with rheumatoid arthritis and response to methotrexate. Pharmacogenet Genomics. 2011;21:590–3.

    Article  CAS  PubMed  Google Scholar 

  33. Majorczyk E, Pawlik A, Gendosz D, Kuśnierczyk P. Presence of the full-length KIR2DS4 gene reduces the chance of rheumatoid arthritis patients to respond to methotrexate treatment. BMC Musculoskelet Disord. 2014;15:256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dalrymple JM, Stamp LK, O’Donnell JL, Chapman PT, Zhang M, Barclay ML. Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 2008;58:3299–308.

    Article  CAS  PubMed  Google Scholar 

  35. Eektimmerman F, Swen JJ, Böhringer S, Huizinga TW, Kooloos WM, Allaart CF, et al. Pathway analysis to identify genetic variants associated with efficacy of adalimumab in rheumatoid arthritis. Pharmacogenomics. 2017;18:945–53.

    Article  CAS  PubMed  Google Scholar 

  36. Muralidharan N, Mariaselvam CM, Jain VK, Gulati R, Negi VS. ATIC 347C>G gene polymorphism may be associated with methotrexate-induced adverse events in south Indian Tamil rheumatoid arthritis. Pharmacogenomics. 2016;17:241–8.

    Article  CAS  PubMed  Google Scholar 

  37. Hayashi H, Tazoe Y, Tsuboi S, Horino M, Morishita M, Arai T, et al. A single nucleotide polymorphism of reduced folate carrier 1 predicts methotrexate efficacy in Japanese patients with rheumatoid arthritis. Drug Metab Pharmacokinet. 2013;28:164–8.

    Article  CAS  PubMed  Google Scholar 

  38. Salazar J, Moya P, Altés A, Díaz-Torné C, Casademont J, Cerdà-Gabaroi D, et al. Polymorphisms in genes involved in the mechanism of action of methotrexate: are they associated with outcome in rheumatoid arthritis patients? Pharmacogenomics. 2014;15:1079–90.

    Article  CAS  PubMed  Google Scholar 

  39. Sharma S, Das M, Kumar A, Marwaha V, Shankar S, Aneja R, et al. Interaction of genes from influx-metabolism-efflux pathway and their influence on methotrexate efficacy in rheumatoid arthritis patients among Indians. Pharmacogenet Genomics. 2008;18:1041–9.

    Article  CAS  PubMed  Google Scholar 

  40. Kooloos WM, Wessels JA, van der Straaten T, Allaart CF, Huizinga TW, Guchelaar H-J. Functional polymorphisms and methotrexate treatment outcome in recent-onset rheumatoid arthritis. Pharmacogenomics. 2010;11:163–75.

    Article  CAS  PubMed  Google Scholar 

  41. 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. 2007;7:404–7.

    Article  CAS  PubMed  Google Scholar 

  42. Muralidharan N, Mariaselvam CM, Mithun CB, Negi VS. Reduced folate carrier-1 80G>A gene polymorphism is not associated with methotrexate treatment response in South Indian Tamils with rheumatoid arthritis. Clin Rheumatol. 2016;35:879–85.

    Article  PubMed  Google Scholar 

  43. Moya P, Salazar J, Arranz MJ, Díaz-Torné C, del Río E, Casademont J, et al. Methotrexate pharmacokinetic genetic variants are associated with outcome in rheumatoid arthritis patients. Pharmacogenomics. 2016;17:25–9.

    Article  CAS  PubMed  Google Scholar 

  44. Chatzikyriakidou A, Georgiou I, Voulgari PV, Papadopoulos CG, Tzavaras T, Drosos AA. Transcription regulatory polymorphism -43T>C in the 5′-flanking region of SLC19A1 gene could affect rheumatoid arthritis patient response to methotrexate therapy. Rheumatol Int. 2007;27:1057–61.

    Article  CAS  PubMed  Google Scholar 

  45. van der Straaten R, Wessels JA, de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Allaart CF, Bogaartz J, et al. Exploratory analysis of four polymorphisms in human GGH and FPGS genes and their effect in methotrexate-treated rheumatoid arthritis patients. Pharmacogenomics. 2007;8:141–50.

    Article  PubMed  Google Scholar 

  46. Wessels JAM, Van Der Kooij SM, Le Cessie S, Kievit W, Barerra P, Allaart CF, et al. A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis. Arthritis Rheum. 2007;56:1765–75.

    Article  CAS  PubMed  Google Scholar 

  47. Milic V, Jekic B, Lukovic L, Bunjevacki V, Milasin J, Novakovic I, et al. Association of dihydrofolate reductase (DHFR) -317AA genotype with poor response to methotrexate in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2012;30:178–83.

    PubMed  Google Scholar 

  48. Soukup T, Dosedel M, Pavek P, Nekvindova J, Barvik I, Bubancova I, et al. The impact of C677T and A1298C MTHFR polymorphisms on methotrexate therapeutic response in East Bohemian region rheumatoid arthritis patients. Rheumatol Int. 2015;35:1149–61.

    Article  CAS  PubMed  Google Scholar 

  49. Kung TN, Dennis J, Ma Y, Xie G, Bykerk V, Pope J, et al. RFC1 80G>A is a genetic determinant of methotrexate efficacy in rheumatoid arthritis: a human genome epidemiologic review and meta-analysis of observational studies. Arthritis Rheumatol. 2014;66:1111–20.

    Article  CAS  PubMed  Google Scholar 

  50. Li X, Hu M, Li W, Gu L, Chen M, Ding H, et al. The association between reduced folate carrier-1 gene 80G/A polymorphism and methotrexate efficacy or methotrexate related-toxicity in rheumatoid arthritis: A meta-analysis. Int Immunopharmacol. 2016;38:8–15.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are particularly grateful for the assistance for search terms given by Jan Schoones of the Walaeus library (LUMC).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Henk-Jan Guchelaar.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eektimmerman, F., Swen, J.J., Madhar, M.B. et al. Predictive genetic biomarkers for the efficacy of methotrexate in rheumatoid arthritis: a systematic review. Pharmacogenomics J 20, 159–168 (2020). https://doi.org/10.1038/s41397-019-0098-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41397-019-0098-9

Search

Quick links