Analysis of Intracellular Methotrexate Polyglutamates in Patients With Juvenile Idiopathic Arthritis Effect of Route of Administration on Variability in Intracellular Methotrexate Polyglutamate Concentrations
Analysis of Intracellular Methotrexate Polyglutamates in Patients With Juvenile Idiopathic Arthritis Effect of Route of Administration on Variability in Intracellular Methotrexate Polyglutamate Concentrations
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DOI：
10.1002/art.27434
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发表时间：
2010-06-01
影响因子：
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通讯作者：
Leeder, J. Steven
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文献类型：
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作者：
Becker, Mara L.;van Haandel, Leon;Leeder, J. Steven
目标。细胞内氨甲喋呤(MTX)多谷氨酸(MTXGlu)已被证明是成人类风湿关节炎患者临床反应的潜在有用生物标志物。本研究旨在检测幼年特发性关节炎(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。血液样本取自正在接受稳定剂量的MTX治疗3个月的JIA患者。临床资料采用图表复习的方法收集。红细胞裂解产物中MTXGlu(1-7)的浓度通过一种创新的离子对层析方法进行定量，并通过质谱仪进行检测。来自单一中心的JIA患者(n=99；平均+/-SD年龄117.8+/-56.5月，女性69例)纳入分析。MTX的平均+/-SD剂量为0.51+/-0.25 mg/kg/周，中位疗程为18个月(四分位数间隔3-156个月)。66例(67%)患者皮下注射甲氨蝶呤。56名患者(57%)在就诊时有活动性关节炎。细胞内总MTXGlu(MTXGlu(Tot))浓度变化40倍，平均+/-SD总浓度为85.8+/-48.4nmoles/L。分别测量每个患者的MTXGlu亚型(MTXGlu1-7)的浓度，并以MTXGlu(TOT)的百分比表示。MTXGlu(3)是最显著的亚型，占MTXGlu(Tot)的42%，且MTXGlu(Tot)与MTXGlu(Tot)的个体间变异最大(r=0.96)。MTX的给药途径与MTXGlu(1-5)亚型显著相关，口服MTX的患者MTXGlu(1+2)浓度较高，而皮下注射MTX的患者MTXGlu(3-5)浓度较高(P<；0.0001)。在这组JIA患者中，MTXGlu(TOT)浓度变化40倍。单独的MTXGlu代谢物(MTXGlu(1-7))被检测到，到目前为止，在JIA患者中还没有报道。MTX给药途径导致了MTXGlu(1-5)浓度的变化。
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 >= 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 (MTXGlu1-7) 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 MTXGlu3 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).