红细胞甲氨蝶呤-多聚谷氨酸水平与类风湿关节炎患者甲氨蝶呤疗效及肝毒性的关联：一项为期76周的前瞻性研究。

Association of erythrocyte methotrexate-polyglutamate levels with the efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis: a 76-week prospective study.

作者信息

Takahashi Chihiro, Kaneko Yuko, Okano Yutaka, Taguchi Hiroaki, Oshima Hisaji, Izumi Keisuke, Yamaoka Kunihiro, Takeuchi Tsutomu

机构信息

Division of Rheumatology, Department of Internal Medicine , Keio University School of Medicine , Tokyo , Japan.

Department of Internal Medicine and Center for Arthritis and Rheumatic Disease , Kawasaki Municipal Kawasaki Hospital , Kawasaki , Japan.

出版信息

RMD Open. 2017 Jan 3;3(1):e000363. doi: 10.1136/rmdopen-2016-000363. eCollection 2017.

DOI:10.1136/rmdopen-2016-000363

PMID:28123781

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5237762/

Abstract

OBJECTIVE

To assess the utility of erythrocyte methotrexate-polyglutamate (MTX-PG) concentrations in determining the safety and efficacy of MTX in patients with rheumatoid arthritis (RA).

METHODS

79 MTX-naïve patients with RA were enrolled in this prospective 76-week cohort study. MTX was initiated, and a predefined dose-escalation protocol was followed. Erythrocyte MTX-PG concentrations were measured using liquid chromatography. The associations of MTX-PG concentrations with disease activity and adverse events were analysed.

RESULTS

Dose escalation of MTX resulted in increased MTX-PG concentrations and a decrease in the mean Disease Activity Score in 28 joints (DAS28). A significant association was observed between total MTX-PG concentrations and ΔDAS28 at week 12 (β=-0.013, p=0.003) and at week 24 (β=-0.014, p=0.003). The maximum MTX-PG levels were significantly higher in patients presenting with elevated transaminases (≥100 IU/L) than in those without (146 vs 106 nmol/L, p=0.009). Receiver operating characteristic curve analysis revealed that a total MTX-PG concentrations of 83 nmol/L at week 12 was the threshold for a DAS28 improvement of ≥1.2 at week 24, and 105 nmol/L was the threshold for transaminases of ≥50 IU/L and 131 nmol/L for transaminases of ≥100 IU/L. MTX-PG concentrations were strongly influenced by body mass index and a serum albumin level.

CONCLUSIONS

MTX-PG concentrations are a useful biomarker in MTX therapy, in terms of efficacy and safety.

摘要

目的

评估红细胞甲氨蝶呤-多聚谷氨酸（MTX-PG）浓度在确定类风湿关节炎（RA）患者甲氨蝶呤（MTX）安全性和有效性方面的作用。

方法

79例初治的RA患者纳入了这项为期76周的前瞻性队列研究。开始使用MTX，并遵循预先定义的剂量递增方案。采用液相色谱法测量红细胞MTX-PG浓度。分析MTX-PG浓度与疾病活动度及不良事件之间的关联。

结果

MTX剂量递增导致MTX-PG浓度升高，28个关节的疾病活动评分（DAS28）均值降低。在第12周（β=-0.013，p=0.003）和第24周（β=-0.014，p=0.003）时，观察到总MTX-PG浓度与ΔDAS28之间存在显著关联。转氨酶升高（≥100 IU/L）的患者的最大MTX-PG水平显著高于未升高的患者（146对106 nmol/L，p=0.009）。受试者工作特征曲线分析显示，第12周时总MTX-PG浓度为83 nmol/L是第24周时DAS28改善≥1.2的阈值，105 nmol/L是转氨酶≥50 IU/L的阈值，131 nmol/L是转氨酶≥100 IU/L的阈值。MTX-PG浓度受体重指数和血清白蛋白水平的强烈影响。