高甲氨蝶呤三谷氨酸水平是亚洲印度类风湿关节炎患者不良反应的独立预测指标——一项初步研究

High Methotrexate Triglutamate Level Is an Independent Predictor of Adverse Effects in Asian Indian Rheumatoid Arthritis Patients-A Preliminary Study.

作者信息

Sandhu Amit, Dhir Varun, Bhatnagar Archana, Dhawan Veena, Kaur Jasbinder, Sood Ankita, Naidu Shankar, Ahmad Shabeer, Varma Neelam, Sharma Aman, Sharma Shefali

机构信息

*Department of Internal Medicine (Rheumatology Unit), Postgraduate Institute of Medical Education and Research; †Department of Biochemistry, Punjab University; ‡Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research; §Department of Biochemistry, Government Medical College and Hospital; and ¶Department of Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

出版信息

Ther Drug Monit. 2017 Apr;39(2):157-163. doi: 10.1097/FTD.0000000000000375.

DOI:10.1097/FTD.0000000000000375

PMID:28107255

Abstract

BACKGROUND

It is unclear whether erythrocyte methotrexate polyglutamate levels (MTX-glun) are associated with response or adverse effects to methotrexate in rheumatoid arthritis. This preliminary study evaluated their utility in Asian Indian patients over 24 weeks.

METHODS

Rheumatoid arthritis patients were started on oral methotrexate at a dose of 15 mg/wk, which was escalated to 25 mg by 12 weeks and continued till 24 weeks. Erythrocyte (RBC) MTX-glu1 to MTX-glu5 levels (nmol/L RBC) were determined at 4, 8, 16, and 24 weeks by using reverse-phase high-performance liquid chromatography. Area under the concentration curve (AUC) of MTX-glu1-5, MTX-glu3-5, and MTX-glu3 levels was compared between groups with regards to response and adverse effects.

RESULTS

This study included 117 patients with mean (SD) age of 42.7 (±11.9) years and disease duration of 2.0 (1.7) years. Mean (SD) RBC MTX-glu1-5 levels at 4, 8, 16, and 24 weeks were 93 (±29), 129 (±46), 143 (±49), and 159 (±65) nmol/L RBC; the highest individual polyglutamate was MTX-glu3 (40%). There was significant correlation between MTX-glu1-5 (r = 0.38, P < 0.001) and MTX-glu3 (r = 0.49, P < 0.001) with methotrexate dose. There was no significant difference of AUC MTX-glun between responders and nonresponders. However, AUC MTX-glu3 was significantly (P = 0.03) higher in patients with adverse effects. On logistic regression, AUC of MTX-glu3 [odds ratio = 1.004 (95% confidence interval 1.002-1.007)] and methotrexate dose at 24 weeks were independent predictors of adverse effects.

CONCLUSIONS

In this preliminary study, higher levels of RBC MTX-glu3 were found to be the independent predictors for adverse effects in rheumatoid arthritis patients.

摘要

背景

红细胞甲氨蝶呤多聚谷氨酸水平（MTX - glun）是否与类风湿关节炎患者对甲氨蝶呤的反应或不良反应相关尚不清楚。这项初步研究评估了其在24周内对亚洲印度患者的效用。

方法

类风湿关节炎患者开始口服甲氨蝶呤，剂量为15mg/周，12周时增至25mg，并持续至24周。在第4、8、16和24周时，采用反相高效液相色谱法测定红细胞（RBC）中MTX - glu1至MTX - glu5水平（nmol/L RBC）。比较MTX - glu1 - 5、MTX - glu3 - 5和MTX - glu3水平的浓度曲线下面积（AUC）在反应者和无反应者以及有不良反应和无不良反应者之间的差异。

结果

本研究纳入了117例患者，平均（标准差）年龄为42.7（±11.9）岁，病程为2.0（1.7）年。第4、8、16和24周时红细胞MTX - glu1 - 5水平的平均（标准差）分别为93（±29）、129（±46）、143（±49）和159（±65）nmol/L RBC；最高的单个多聚谷氨酸是MTX - glu3（40%）。MTX - glu1 - 5（r = 0.38，P < 0.001）和MTX - glu3（r = 0.49，P < 0.001）与甲氨蝶呤剂量之间存在显著相关性。反应者和无反应者之间MTX - glun的AUC无显著差异。然而，有不良反应的患者中MTX - glu3的AUC显著更高（P = 0.03）。经逻辑回归分析，MTX - glu3的AUC[比值比 = 1.004（95%置信区间1.002 - 1.007）]和24周时的甲氨蝶呤剂量是不良反应的独立预测因素。