Genetic and clinical prediction models for the efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis: a multicenter cohort study

Autor: Akira Onishi, Akio Morinobu, Yuko Uemura, M. Takahashi, Goh Tsuji, M. Nishida, Shunichi Kumagai, Kenta Misaki, Shigeo Kamitsuji, Saori Hatachi, Takashi Nakazawa, Keisuke Nishimura, Mizuho Kawate, Yuichiro Yoshida, Yumiko Nobuhara, Toshiharu Saito, Masaki Kobayashi
Rok vydání: 2019
Předmět:
Zdroj: The Pharmacogenomics Journal. 20:433-442
ISSN: 1473-1150
1470-269X
DOI: 10.1038/s41397-019-0134-9
Popis: The objective of the study is to develop genetic and clinical prediction models for the efficacy and hepatotoxicity of methotrexate (MTX) in patients with rheumatoid arthritis (RA). Among RA patients treated with MTX, 1966 polymorphisms of 246 enzymes/transporters relevant to pharmacokinetics and pharmacodynamics were measured by the Drug Metabolism Enzymes and Transporters (DMET) microarray and direct sequencing, and clinical variables at baseline were collected. For efficacy, response criteria of the European League Against Rheumatism were used to classify patients as responders or non-responders. Hepatotoxicity was defined as elevations of aspartate aminotransferase or alanine aminotransferase ≥1.5 times the reference range upper limit. Among 166 patients, a genetic prediction model for efficacy using seven polymorphisms showed the area under the receiver operating characteristic curve (AUC) was 0.822, with 74.3% sensitivity and 76.8% specificity. A combined genetic and clinical model indicated the AUC was 0.844, with 81.5% sensitivity and 76.9% specificity. By incorporating clinical variables into the genetic model, the overall category-free net reclassification improvement (NRI) was 0.663 (P
Databáze: OpenAIRE
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