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Clinical–pharmacogenetic predictive models for MTX discontinuation due to adverse events in rheumatoid arthritis

The Pharmacogenomics Journal volume 17, pages 412–418 (2017)Cite this article

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Abstract

We describe a novel approach to investigate and evaluate combined effect of a large number of clinical and pharmacogenetic factors on treatment outcome. We have used this approach to investigate predictors of methotrexate (MTX)-induced adverse events (AEs) leading to treatment discontinuation in rheumatoid arthritis (RA) patients. In total, 333 RA patients were genotyped for 34 polymorphisms in MTX transporters, folate and adenosine pathways. The effect of clinical and pharmacogenetic factors was assessed with penalized regression in the cause-specific Cox proportional hazards model. The predictive capacity was evaluated with the area under time-dependent receiver operating characteristic curve where cross-validation was applied. SLC19A1, ABCG2, ADORA3 and TYMS were associated with discontinuation because of AEs in clinical–pharmacogenetic model. Cross-validation showed that both clinical–pharmacogenetic model and nongenetic model had worthless predictive ability for MTX discontinuation because of AEs. These models could be further improved, either with additional polymorphisms or with epigenetic predictors.

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Acknowledgements

We acknowledge collaborators from the Department of Rheumatology, University Medical Centre Ljubljana, Slovenia: Žiga Rotar and Alojzija Hočevar for referring the patients and Saša Čučnik and Katja Lakota for the support with sample collection. This work was financially supported by The Slovenian Research Agency (ARRS Grant No. P1-0170).

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Authors and Affiliations

  1. Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

    B Jenko & V Dolzan

  2. Faculty of Medicine, Institute for Biostatistics and Medical Informatics, University of Ljubljana, Ljubljana, Slovenia

    L Lusa

  3. Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia

    M Tomsic & S Praprotnik

  4. Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

    M Tomsic & S Praprotnik

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  1. B Jenko
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Correspondence to V Dolzan.

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Jenko, B., Lusa, L., Tomsic, M. et al. Clinical–pharmacogenetic predictive models for MTX discontinuation due to adverse events in rheumatoid arthritis. Pharmacogenomics J 17, 412–418 (2017). https://doi.org/10.1038/tpj.2016.36

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  • DOI: https://doi.org/10.1038/tpj.2016.36

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