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在优化克罗恩病英夫利昔单抗治疗失败时,不同检测方法检测药物和抗药物抗体的临床意义:一项随机对照试验的事后分析。

Clinical implications of measuring drug and anti-drug antibodies by different assays when optimizing infliximab treatment failure in Crohn's disease: post hoc analysis of a randomized controlled trial.

机构信息

Department of Gastroenterology, Herlev Hospital, Herlev, Denmark.

Institute for Inflammation Research, Rigshospitalet, Copenhagen, Denmark.

出版信息

Am J Gastroenterol. 2014 Jul;109(7):1055-64. doi: 10.1038/ajg.2014.106. Epub 2014 May 6.

Abstract

OBJECTIVES

Cost-effective guidance of therapeutic strategy in Crohn's disease patients with secondary infliximab (IFX) treatment failure may be achieved by serum IFX and anti-IFX antibody (Ab) measurements by radioimmunoassay (RIA). This study investigated implications of using other techniques for this purpose.

METHODS

This is a post hoc analysis of randomized clinical trial including 66 Crohn's disease patients with IFX failure in whom IFX and anti-IFX Ab measurements by RIA had been used for therapeutic guidance. Samples were additionally assessed by enzyme-linked immunosorbent assay (ELISA), homogeneous mobility shift assay (HMSA), and functional cell-based reporter gene assay (RGA).

RESULTS

IFX detection was comparable between assays (82% RIA, 76% ELISA, 88% HMSA, and 74% RGA), and it correlated significantly (Pearson's r=0.91-0.97, P<0.0001). However, IFX concentrations varied systematically between all pair of assays except RIA-RGA. Anti-IFX Ab detection was variable (27% RIA, 9% ELISA, 33% HMSA, and 11% RGA), but correlated significantly (Pearson's r=0.77-0.96; P<0.0001). Anti-IFX Abs detected by RIA and HMSA were often from sera without drug-neutralizing activity (RGA). Assays agreed on classification of underlying mechanism for treatment failure in most cases (79-94%). The majority (74-88%) failed IFX owing to pharmacodynamic problems, or had noninflammatory pathophysiology for symptoms resembling relapse. Applied threshold for therapeutic vs. subtherapeutic IFX level influenced classifications. The four different assays did not differ in terms of the ability to predict response to interventions defined by the algorithm.

CONCLUSIONS

Despite variable analytical properties, common assays result in similar classifications and interventions in patients with IFX treatment failure, and with comparable clinical outcomes. Implications are, however, profound for the minority classified differently.

摘要

目的

通过放射免疫分析(RIA)检测血清中的英夫利昔单抗(IFX)和抗 IFX 抗体(Ab),可以为 IFX 治疗失败的克罗恩病患者提供经济有效的治疗策略指导。本研究旨在探讨其他技术在此目的中的应用意义。

方法

本研究是一项事后分析,纳入了 66 例 IFX 治疗失败的克罗恩病患者的随机临床试验,这些患者接受了 RIA 检测 IFX 和抗 IFX Ab,以指导治疗。另外还使用酶联免疫吸附试验(ELISA)、均相迁移率分析(HMSA)和基于功能性细胞的报告基因分析(RGA)对样本进行了评估。

结果

不同检测方法之间 IFX 的检测结果相当(82%的 RIA、76%的 ELISA、88%的 HMSA 和 74%的 RGA),且相关性显著(Pearson's r=0.91-0.97,P<0.0001)。然而,除了 RIA-RGA 之外,所有配对检测方法之间的 IFX 浓度均存在系统差异。抗 IFX Ab 的检测结果存在差异(27%的 RIA、9%的 ELISA、33%的 HMSA 和 11%的 RGA),但相关性显著(Pearson's r=0.77-0.96;P<0.0001)。RIA 和 HMSA 检测到的抗 IFX Ab 通常来自于无药物中和活性的血清(RGA)。在大多数情况下,检测方法在确定治疗失败的潜在机制方面具有较高的一致性(79-94%)。大多数患者(74-88%)因药效学问题而对 IFX 治疗失败,或存在与复发症状相似的非炎症性病理生理学。治疗与亚治疗性 IFX 水平的应用阈值会影响分类。四种不同的检测方法在预测算法定义的干预措施的反应能力方面没有差异。

结论

尽管分析特性存在差异,但在 IFX 治疗失败的患者中,常用检测方法的分类和干预结果相似,且临床结局相当。然而,对于被分类不同的少数患者,其影响是深远的。

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