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In the Pursuit of Methotrexate Treatment Response Biomarker in Juvenile Idiopathic Arthritis—Are We Getting Closer to Personalised Medicine?

  • Pediatric Rheumatology (S Ozen, Section Editor)
  • Published:
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Abstract

Purpose of Review

Methotrexate (MTX) is the most widely used disease-modifying antirheumatic drug (DMARD) in paediatric rheumatology and the mainstay in the therapy of juvenile idiopathic arthritis (JIA). Despite its common use, about 30% of children fail to respond to this medicine that results in potentially irreversible joint damage.

Recent Findings

No clinical biomarker that would predict the outcome of MTX therapy exists. Results of several studies focused on gene polymorphisms and outcome of this DMARD therapy have been published, but no reliable genetic marker useful to tailor the therapy has been discovered so far. The results of the first genome-wide association study in this field have recently revealed new genetic candidates from outside the metabolic pathway of MTX that may be associated with the efficacy of treatment.

Summary

However promising, those outcomes need validation in independent prospective cohorts before we can claim that clinically useful biomarker predicting MTX treatment response is discovered.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Fragoulakis V, Mitropoulou C, Williams M, Patrinos G (2015) Economic evaluation in genomic medicine. Academic Press, p. 27–34

  2. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31:390–2.

    PubMed  Google Scholar 

  3. Giannini EH, Brewer EJ, Kuzmina N, Shaikov A, Maximov A, et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A. – U.S.R.R. double-blind, placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and The Cooperative Children’s Study Group. N Engl J Med. 1992;326(16):1043–9.

    Article  CAS  PubMed  Google Scholar 

  4. Weinblatt ME. Methotrexate in rheumatoid arthritis: a quarter century of development. Trans Am Clin Climatol Assoc. 2013;124:16–25.

    PubMed  PubMed Central  Google Scholar 

  5. Pastore S, Stocco G, Favretto D, De Ludicibus S, Taddio A. Genetic determinants for methotrexate response in juvenile idiopathic arthritis. Front Pharmacol. 2015. doi:10.3389/fphar.2015.00052.

    PubMed  PubMed Central  Google Scholar 

  6. Joshi P, Dhaneshwar SS. An update on disease modifying antirheumatic drugs. Inflamm Allergy Drug Targets. 2014;13:249–61.

    Article  CAS  PubMed  Google Scholar 

  7. Morgan SL, Baggott JE. Folate supplementation during methotrexate therapy for rheumatoid arthritis. Clin Exp Rheumatol. 2010;28:102–9.

    Google Scholar 

  8. Dervieux T, Kremer J, Lein DO, Capps R, Barham R. Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglumate levels in patients with rheumatoid arthritis. Pharmacogenetics. 2004;14(11):733–9.

  9. •• Cobb J, Cule E, Moncrieffe H, Hinks A, Ursu S, et al. Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases. Pharmacogenomics J. 2015;14(4):356–64. This is the first study on this topic performed by genome-wide association study method. What is more, the results show the correlation between the polymorphism of genes from outside of MTX metabolic pathway and its efficacy.

    Article  Google Scholar 

  10. Hinks A, Moncrieffe H, Martin P, Ursu S, Lal S, et al. Association of the 5-aminoimidazole-4-carboxamide ribonucleotide transformylase gene with response to methotrexate in juvenile idiopathic arthritis. Ann Rheum Dis. 2011;70:1395–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pastore S, Stocco G, Moressa V, Zandona L, Favretto D, et al. 5-Aminoimidazole-4-carboxamide ribonucleotide-transformylase and inosine-triphosphatate-pyrophosphatase genes variants predict remission rate during methotrexate therapy in patients with juvenile idiopathic arthritis. Rheumatol Int. 2015;35:619–27.

    Article  CAS  PubMed  Google Scholar 

  12. Schmeling H, Biber D, Heins S, Horneff G. Influence of methylenrtetrahydrofolate reductase polymorphisms on efficacy and toxicity of methotrexate in patients with juvenile idiopathic arthritis. J Rheumatol. 2005;32:1832–6.

    CAS  PubMed  Google Scholar 

  13. Moya P, Salazar J, Arranz MJ, Diaz-Torne C, del Rio E, et al. Methotrexate pharmacokinetic genetic variants are associated with outcome in rheumatoid arthritis patients. Pharmacogenomics. 2016;17(1):25–9.

  14. Becker ML, van Haandel L, Gaedigk R, Lasky A, Hoetzel M, et al. Analysis of intracellular methotrexate polyglumates in patients with juvenile idiopathic arthritis. Effect of route of administration on variability in intracellular methotrexate polyglumate concentration. Arthritis Rheum. 2010;62:1803–12.

    Article  CAS  PubMed  Google Scholar 

  15. Tukova J, Chladek J, Hroch M, Nemcova D, Hoza J, et al. 677TT genotype is associated with elevated risk of methotrexate (MTX) toxicity in juvenile idiopathic arthritis: treatment outcome, erythrocyte concentrations of MTX and folates and MTHFR polymorphisms. J Rheumatol. 2010;37:2180–6.

    Article  CAS  PubMed  Google Scholar 

  16. Yanagimachi M, Naruto T, Hara T, Kikuchi M, Hara R, et al. Influence of polymorphisms within the methotrexate pathway genes on the toxicity and efficacy of methotrexate in patients with juvenile idiopathic arthritis. Br J Clin Pharmacol. 2011;71(2):237–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schmeling H, Horneff G, Benseler SM, Fritzler MJ, et al. Pharmacogenetics: can genes determine treatment efficacy and safety in JIA? Nat Rev Rheumatol. 2014;10(11):682–90.

    Article  CAS  PubMed  Google Scholar 

  18. Hashkes PJ, Becker ML, Cabral DA, Laxer RM, Paller AS. Methotrexate: new uses for an old drug. J Pediatr. 2013;164:231–6.

    Article  PubMed  Google Scholar 

  19. 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. 2013;13(3):227–34.

  20. Chan ES, Cronstein BN. Methotrexate—how does it really work? Nat Rev Rheumatol. 2010;6:175–8.

  21. van de Ven R, Oerlemans R, van der Heijden JW, Scheffler GL, De Grunji TD, et al. ABC drug transporters and immunity: novel therapeutic targets in autoimmunity and cancer. J Leukoc Biol. 2009;86:1075–87.

  22. de Graf D, Sharma RC, Mechetner EB, Schimke RT, Roninson IB. P-glycoprotein confers methotrexate resistance in 3T6 cells with deficient carrier-mediated methotrexate uptake. Proc Natl Acad Sci. 1996;93:1238–42.

  23. Lang T, Hitzl M, Burk O, Mornhinweg E, Keil A, et al. Genetic polymorphisms in the multidrug resistance-associated protein 3 (ABCC3, MRP 3) gene and relationship to its mRNA and protein expression in human liver. Pharmacogenetics. 2004;14:155–64.

  24. Moncrieffe H, Hinks A, Ursu S, Kassoumeri L, Etheridge A, et al. Generation of novel pharmacogenomic candidates in the response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype. Pharmacogenet Genomics. 2010;20:665–76.

  25. de Rotte MC, Bulatovic M, Heijstek MW, Jansen G, Heil SG, et al. ABCB1 and ABCC3 gene polymorphisms are associated with first-year response to methotrexate in juvenile idiopathic arthritis. J Rheumatol. 2012;39(10):2032–40.

  26. Becker ML, Gaedick R, van Haandel L, Thomas B, Lasky A. The effect of genotype on methotrexate polyglumate variability in juvenile idiopathic arthritis and association with drug response. Arthritis Rheum. 2011;63(1):276–85.

    Article  CAS  PubMed  Google Scholar 

  27. Hawwa AF, AlBawab A, Rooney M, Wedderburn LR, Beresford MW, et al. Methotrexate polyglumates as a potential marker of adherence to long-term therapy in children with juvenile idiopathic arthritis and juvenile dermatomyositis: and observational, cross-sectional study. Arthritis Res Ther. 2015. doi:10.1186/s13075-015-0814-z.

    PubMed  PubMed Central  Google Scholar 

  28. Dervieux T, Furst D, Lein DO, Capps R, Smith K, Walsh M, et al. Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum. 2004;50:2766–74.

    Article  CAS  PubMed  Google Scholar 

  29. Albers HM, Wessels JA, van der Straaten RJ, Brinkman DM, Suijlekom-Smit LW, et al. Time to treatment as an important factor for the response to methotrexate in juvenile idiopathic arthritis. Arthritis Rheumatol. 2009;61:46–51.

    Article  CAS  Google Scholar 

  30. Bulatovic M, Hejistek MW, Van Dijkhuizen EH, Wulffraat NM, et al. Prediction of clinical non-response to methotrexate treatment in juvenile idiopathic arthritis. Ann Rheum Dis. 2012;71:1484–9.

    Article  CAS  PubMed  Google Scholar 

  31. Scheuern A, Fischer N, McDonald J, Brunner H, Johannes-Peter H, et al. Mutations in MTHFR gene are not associated with methotrexate intolerance in patients with juvenile idiopathic arthritis. Pediatr Rheumatol. 2016. doi:10.1186/s12969-016-0071-y.

    Google Scholar 

  32. Bulatovic M, Heijstek MW, Verkaaik M, van Dijkhulzen EH, Armbrust W, et al. High prevalence of methotrexate intolerance in juvenile idiopathic arthritis. Development and validation of methotrexate intolerance severity score. Arthritis Rheum. 2011;63:2007–13.

    Article  CAS  PubMed  Google Scholar 

  33. Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42:1118–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. El-Hini SH, Mohamed FI, Hassan AA, Ali F, Mahmoud A. Visfatin and adiponectin as novel markers for evaluation of metabolic disturbance in recently diagnosed rheumatoid arthritis patients. Rheumatol Int. 2013;33:2283–9.

    Article  CAS  PubMed  Google Scholar 

  35. Funk RS, Singh R, Pramann L, Gigliotti N, Islam S. Nicotinamide phosphoribosyltransferase attenuates methotrexate response in juvenile idiopathic arthritis and in vitro. Clin Transl Sci. 2016;9:149–57.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was funded by the grant no. 503/8-000-01/503-81-002 from Medical University of Lodz, Poland.

Authors’ Contributions

JR contributed substantially to the design, performance and reporting of the work. ES contributed to the study for important intellectual content and was involved in the drafting of the manuscript and article’s revising.

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Authors and Affiliations

  1. Department of Pediatric Rheumatology, Medical University of Lodz, Sporna 36/50, 91-738, Lodz, Poland

    Justyna Roszkiewicz & Elzbieta Smolewska

Authors
  1. Justyna Roszkiewicz
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  2. Elzbieta Smolewska
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Corresponding author

Correspondence to Elzbieta Smolewska.

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The authors declare their full consent for the article publication.

Availability of Data and Material

A systematic literature search was performed in PubMed Library. The search included phrases “methotrexate”, “juvenile idiopathic arthritis” and “gene polymorphism”. Three hundred thirty articles were found, dating from 1992 to 2016. Thirty-eight of them were referred to while preparing this article.

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Pediatric Rheumatology

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Roszkiewicz, J., Smolewska, E. In the Pursuit of Methotrexate Treatment Response Biomarker in Juvenile Idiopathic Arthritis—Are We Getting Closer to Personalised Medicine?. Curr Rheumatol Rep 19, 19 (2017). https://doi.org/10.1007/s11926-017-0646-8

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