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  • Review Article
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Pharmacogenetics: can genes determine treatment efficacy and safety in JIA?

Nature Reviews Rheumatology volume 10, pages 682–690 (2014)Cite this article

Subjects

Key Points

  • A diagnosis of juvenile idiopathic arthritis (JIA) routinely results in many years of immunosuppressive therapy, administered daily or weekly as appropriate for the therapeutic agent

  • Validated and reliable clinical, biological or molecular markers that predict treatment efficacy and safety are currently lacking

  • Candidate-gene and genome-wide pharmacogenetic studies in JIA have identified single nucleotide polymorphisms (SNPs) and gene regions potentially associated with toxicity or response to methotrexate (MTX) and etanercept

  • Associations of SNPs and gene regions with the MTX and etanercept pathways have not been replicated or shown consistency

  • Studies in children provide the unique opportunity to understand ontogeny processes in addition to disease and treatment associations

  • Access to large, well-documented cohorts of patients with JIA and advanced molecular techniques might facilitate the identification of novel pathways and of patients likely to respond to a specific drug

Abstract

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood, with many children requiring immunomodulatory therapies for many years following diagnosis. A considerable proportion of children experience therapeutic inefficacy or substantial adverse effects, or both, but a lack of reliable clinical indicators and biomarkers to predict treatment response prevents optimization of existing therapies. The identification of valid candidate gene variants involved in the pathways of methotrexate and etanercept, the most commonly used medications in JIA, has seen little success to date. The limited success of these studies is possibly due to the presence of confounding variables in the study populations, the heterogeneity of outcome parameters used to determine treatment response and the small number of candidate gene variants analysed. The first genome-wide pharmacogenetic study in JIA has identified gene regions of particular biological interest, but these findings require validation. Moreover, epigenetic mechanisms as well as ontogeny processes might be additional factors influencing drug responses. Access to large, well-documented JIA cohorts and the rapid development of advanced genome analytics is ushering in a personalized approach to treatment. The discovery of new pharmacogenomic biomarkers and systems pathways can provide new drug targets and predictive tools for improved drug response and fewer adverse drug reactions in JIA.

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Figure 1: Factors influencing the pharmacology of methotrexate.
Figure 2: Pathways of methotrexate metabolism.

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Authors and Affiliations

  1. Alberta Children's Hospital Research Institute, University of Calgary, Heritage Medical Research Building, Room 293, 3330 Hospital Drive, NW, Calgary, T2N 4N1, AB, Canada

    Heinrike Schmeling & Susanne M. Benseler

  2. Department of Paediatrics, Centre of General Paediatrics and Neonatology, Asklepios Clinics, Arnold-Janssen Strasse 29, 537, Sankt Augustin, D-53757, Germany

    Gerd Horneff

  3. Cumming School of Medicine, Health Sciences Centre, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1, AB, Canada

    Marvin J. Fritzler

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  1. Heinrike Schmeling
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  2. Gerd Horneff
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  4. Marvin J. Fritzler
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Contributions

H.S. researched data and wrote the manuscript. H.S., G.H., S.M.B. and M.J.F. contributed substantially for the discussion of content and in reviewing/editing the manuscript before submission.

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Correspondence to Heinrike Schmeling.

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Competing interests

H.S. has received funding for industry-driven clinical trials, advisory board membership and honourara from AbbVie, Pfizer, Roche and UCB. G.H. has received funding and speaker fees from AbbVie, Pfizer, Novartis and Roche. S.B. and M.J.F. declare no competing interests.

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Schmeling, H., Horneff, G., Benseler, S. et al. Pharmacogenetics: can genes determine treatment efficacy and safety in JIA?. Nat Rev Rheumatol 10, 682–690 (2014). https://doi.org/10.1038/nrrheum.2014.140

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