Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, and Department of Rheumatology, Shizuoka Kousei Hospital, Shizuoka, Japan.
Drug Metab Pharmacokinet. 2013;28(2):164-8. doi: 10.2133/dmpk.dmpk-12-nt-038. Epub 2012 Sep 11.
Methotrexate (MTX) exhibits large inter-individual and inter-ethnic differences in the dose required for its anti-rheumatic effect. To maintain low disease activity, patients may require increased MTX doses or co-administration of biologic disease-modifying anti-rheumatic drugs (bDMARDs). The availability of a marker predicting the effect of MTX will make it possible to increase the MTX dose and prescribe bDMARDs to patients at an early stage. To establish individualized medication for rheumatoid arthritis (RA), we investigated genetic polymorphisms of the folate pathway in Japanese RA patients. Eighty-nine patients were treated with MTX alone (MTX group). MTX and bDMARDs were co-administered to 81 patients because of insufficient MTX efficacy (MTX + bDMARDs group); an equally stable therapeutic effect was achieved in both groups. Polymorphism analyses using bDMARD co-treatment as the objective variable revealed a significant association between age and the G80A polymorphism of the reduced folate carrier 1 gene (RFC1) as an explanatory variable. Compared to patients with the A allele, patients with the G allele may have less intracellular MTX uptake and, therefore, poor efficacy; a greater number of them were found to be bDMARD concomitant cases. The results of this study suggest that the RFC1 G80A polymorphism may be a useful marker for predicting MTX efficacy in Japanese patients with RA.
甲氨蝶呤（MTX）在抗风湿作用所需剂量方面存在个体间和种族间的巨大差异。为了维持低疾病活动度，患者可能需要增加 MTX 剂量或联合使用生物疾病修饰抗风湿药物（bDMARDs）。如果有一个可以预测 MTX 效果的标志物，就可以在早期为患者增加 MTX 剂量并开处方使用 bDMARDs。为了为类风湿关节炎（RA）建立个体化药物治疗，我们研究了日本 RA 患者叶酸途径的遗传多态性。89 名患者单独接受 MTX 治疗（MTX 组）。由于 MTX 疗效不足，81 名患者同时接受 MTX 和 bDMARD 治疗（MTX+bDMARDs 组）；两组均达到了同样稳定的治疗效果。使用 bDMARD 联合治疗作为因变量的多态性分析表明，年龄与还原叶酸载体 1 基因（RFC1）的 G80A 多态性之间存在显著关联，该多态性是一个解释变量。与携带 A 等位基因的患者相比，携带 G 等位基因的患者可能细胞内 MTX 摄取较少，因此疗效较差；发现他们中有更多人同时使用 bDMARD。这项研究的结果表明，RFC1 G80A 多态性可能是预测日本 RA 患者 MTX 疗效的有用标志物。
