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Pharmacogenomics. 2019 Jan 10. doi: 10.2217/pgs-2018-0144. [Epub ahead of print]

Validation of a clinical pharmacogenetic model to predict methotrexate nonresponse in rheumatoid arthritis patients.

Author information

1
Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
2
Leiden Network for Personalised Therapeutics (LNPT), Leiden, The Netherlands.
3
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
4
Department of Rheumatology, Erasmus Medical Center, Rotterdam, The Netherlands.
5
Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.

Abstract

AIM:

To study the performance of a clinical pharmacogenetic model for the prediction of nonresponse in rheumatoid arthritis (RA) patients treated with methotrexate (MTX) in combination with other synthetic or biologic disease-modifying anti-rheumatic drugs . This prediction model includes gender, smoking status, rheumatoid factor positivity and four genetic variants in AMPD1 (rs17602729), ATIC (rs2372536), ITPA (rs1127354) and MTHFD1 (rs17850560).

METHODS:

 A total of 314 RA patients from three Dutch studies were retrospectively included. Eligible patients were adults diagnosed with RA and had a treatment duration with MTX and follow-up for at least two study evaluation visits. Prediction model risk scores at the first and second evaluation were calculated and compared with the actual nonresponse (disease activity score >2.4). Regression and receiver operating characteristic curve analyses of the prediction model were performed. Also, the sensitivity, specificity and the positive and negative predictive values (PPV and NPV) were determined.

RESULTS:

The receiver operating characteristic area under the curve was 75% at first and 70% after second evaluation. At the second evaluation, prediction nonresponse had a sensitivity of 67% (CI: 54-78%), specificity of 69% (CI: 60-77%), PPV of 52% (CI: 45-60%) and NPV of 80% (CI: 73-85%).

CONCLUSIONS:

This study demonstrates that the clinical pharmacogenetic model has an inadequate performance for the prediction of nonresponse to MTX in RA patients treated with combination therapies.

KEYWORDS:

effectiveness of therapy; methotrexate; pharmacogenetic models; prediction model; rheumatoid arthritis

PMID:
30628539
DOI:
10.2217/pgs-2018-0144

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