青少年特发性关节炎患者细胞内甲氨蝶呤多聚谷氨酸盐的分析：给药途径对细胞内甲氨蝶呤多聚谷氨酸盐浓度变异性的影响

Analysis of intracellular methotrexate polyglutamates in patients with juvenile idiopathic arthritis: effect of route of administration on variability in intracellular methotrexate polyglutamate concentrations.

作者信息

Becker Mara L, van Haandel Leon, Gaedigk Roger, Lasky Andrew, Hoeltzel Mark, Stobaugh John, Leeder J Steven

机构信息

Children's Mercy Hospital, Kansas City, Missouri, USA.

出版信息

Arthritis Rheum. 2010 Jun;62(6):1803-12. doi: 10.1002/art.27434.

DOI:10.1002/art.27434

PMID:20191581

Abstract

OBJECTIVE

Intracellular methotrexate (MTX) polyglutamates (MTXGlu) have been shown to be potentially useful biomarkers of clinical response in adult patients with rheumatoid arthritis. The present study was undertaken to measure intracellular MTXGlu concentrations in a cohort of patients with juvenile idiopathic arthritis (JIA) to determine the predictors of MTXGlu variability in these patients.

METHODS

Blood samples were obtained from patients with JIA who were being treated with a stable dose of MTX for >or=3 months. Clinical data were collected by chart review. Concentrations of MTXGlu(1-7) in red blood cell lysates were quantitated using an innovative ion-pairing chromatography procedure, with detection by mass spectrometry.

RESULTS

Patients with JIA from a single center (n = 99; mean +/- SD age 117.8 +/- 56.5 months, 69 female) were included in the analysis. The mean +/- SD dose of MTX was 0.51 +/- 0.25 mg/kg per week, with a median treatment duration of 18 months (interquartile range 3-156 months). MTX was administered subcutaneously in 66 patients (67%). Fifty-six patients (57%) had active arthritis at the time of the clinic visit. Total intracellular MTXGlu (MTXGlu(TOT)) concentrations varied 40-fold, with a mean +/- SD total concentration of 85.8 +/- 48.4 nmoles/liter. Concentrations of each MTXGlu subtype (MTXGlu(1-7)) were measured individually and as a percentage of MTXGlu(TOT) in each patient. MTXGlu(3) was the most prominent subtype identified, comprising 42% of MTXGlu(TOT), and the interindividual variability in the concentration of MTXGlu(3) was the most highly correlated with that of MTXGlu(TOT) (r = 0.96). The route of MTX administration was significantly associated with MTXGlu(1-5) subtypes; higher concentrations of MTXGlu(1 + 2) were observed in patients receiving oral doses of MTX, whereas higher concentrations of MTXGlu(3-5) were observed in patients receiving subcutaneous doses of MTX (P < 0.0001).

CONCLUSION

In this cohort of patients with JIA, the MTXGlu(TOT) concentration varied 40-fold. Individual MTXGlu metabolites (MTXGlu(1-7)), which have, until now, not been previously reported in patients with JIA, were detected. The route of MTX administration contributed to the variability in concentrations of MTXGlu(1-5).

摘要

目的

细胞内甲氨蝶呤（MTX）多聚谷氨酸盐（MTXGlu）已被证明可能是成年类风湿关节炎患者临床反应的有用生物标志物。本研究旨在测量一组幼年特发性关节炎（JIA）患者的细胞内MTXGlu浓度，以确定这些患者MTXGlu变异性的预测因素。

方法

从接受稳定剂量MTX治疗≥3个月的JIA患者中采集血样。通过查阅病历收集临床数据。使用创新的离子对色谱法对红细胞裂解物中MTXGlu(1 - 7)的浓度进行定量，并通过质谱检测。

结果

分析纳入了来自单一中心的JIA患者（n = 99；平均±标准差年龄117.8±56.5个月，69名女性）。MTX的平均±标准差剂量为每周0.51±0.25 mg/kg，中位治疗持续时间为18个月（四分位间距3 - 156个月）。66例患者（67%）皮下注射MTX。56例患者（57%）在门诊就诊时患有活动性关节炎。细胞内MTXGlu总浓度（MTXGlu(TOT)）变化40倍，平均±标准差总浓度为85.8±48.4纳摩尔/升。分别测量每个MTXGlu亚型（MTXGlu(1 - 7)）的浓度，并将其作为每个患者MTXGlu(TOT)的百分比。MTXGlu(3)是鉴定出的最主要亚型，占MTXGlu(TOT)的42%，MTXGlu(3)浓度的个体间变异性与MTXGlu(TOT)的变异性相关性最高（r = 0.96）。MTX给药途径与MTXGlu(1 - 5)亚型显著相关；口服MTX的患者中观察到MTXGlu(1 + 2)浓度较高，而皮下注射MTX的患者中观察到MTXGlu(3 - 5)浓度较高（P < 0.0001）。