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Abstract：
We aimed to predict response to biologics in inflammatory bowel disease (IBD) using computerized image analysis of probe confocal laser endomicroscopy (pCLE) in vivo and assess the binding of fluorescent-labeled biologics ex vivo. Additionally, we investigated genes predictive of anti-tumor necrosis factor (TNF) response.
Twenty-nine patients (15 with Crohn\'s disease [CD], 14 with ulcerative colitis [UC]) underwent colonoscopy with pCLE before and 12 to 14 weeks after starting anti-TNF or anti-integrin α4β7 therapy. Biopsies were taken for fluorescein isothiocyanate-labeled infliximab and vedolizumab staining and gene expression analysis. Computer-aided quantitative image analysis of pCLE was performed. Differentially expressed genes predictive of response were determined and validated in a public cohort.
In vivo, vessel tortuosity, crypt morphology, and fluorescein leakage predicted response in UC (area under the receiver-operating characteristic curve [AUROC], 0.93; accuracy 85%, positive predictive value [PPV] 89%; negative predictive value [NPV] 75%) and CD (AUROC, 0.79; accuracy 80%; PPV 75%; NPV 83%) patients. Ex vivo, increased binding of labeled biologic at baseline predicted response in UC (UC) (AUROC, 83%; accuracy 77%; PPV 89%; NPV 50%) but not in Crohn\'s disease (AUROC 58%). A total of 325 differentially expressed genes distinguished responders from nonresponders, 86 of which fell within the most enriched pathways. A panel including ACTN1, CXCL6, LAMA4, EMILIN1, CRIP2, CXCL13, and MAPKAPK2 showed good prediction of anti-TNF response (AUROC >0.7).
Higher mucosal binding of the drug target is associated with response to therapy in UC. In vivo, mucosal and microvascular changes detected by pCLE are associated with response to biologics in inflammatory bowel disease. Anti-TNF-responsive UC patients have a less inflamed and fibrotic state pretreatment. Chemotactic pathways involving CXCL6 or CXCL13 may be novel targets for therapy in nonresponders.
Twenty-nine patients (15 with Crohn\'s disease [CD], 14 with ulcerative colitis [UC]) underwent colonoscopy with pCLE before and 12 to 14 weeks after starting anti-TNF or anti-integrin α4β7 therapy. Biopsies were taken for fluorescein isothiocyanate-labeled infliximab and vedolizumab staining and gene expression analysis. Computer-aided quantitative image analysis of pCLE was performed. Differentially expressed genes predictive of response were determined and validated in a public cohort.
In vivo, vessel tortuosity, crypt morphology, and fluorescein leakage predicted response in UC (area under the receiver-operating characteristic curve [AUROC], 0.93; accuracy 85%, positive predictive value [PPV] 89%; negative predictive value [NPV] 75%) and CD (AUROC, 0.79; accuracy 80%; PPV 75%; NPV 83%) patients. Ex vivo, increased binding of labeled biologic at baseline predicted response in UC (UC) (AUROC, 83%; accuracy 77%; PPV 89%; NPV 50%) but not in Crohn\'s disease (AUROC 58%). A total of 325 differentially expressed genes distinguished responders from nonresponders, 86 of which fell within the most enriched pathways. A panel including ACTN1, CXCL6, LAMA4, EMILIN1, CRIP2, CXCL13, and MAPKAPK2 showed good prediction of anti-TNF response (AUROC >0.7).
Higher mucosal binding of the drug target is associated with response to therapy in UC. In vivo, mucosal and microvascular changes detected by pCLE are associated with response to biologics in inflammatory bowel disease. Anti-TNF-responsive UC patients have a less inflamed and fibrotic state pretreatment. Chemotactic pathways involving CXCL6 or CXCL13 may be novel targets for therapy in nonresponders.
摘要：
背景：我们的目的是使用体内探针共聚焦激光显微内镜（pCLE）的计算机图像分析来预测炎症性肠病（IBD）对生物制剂的反应，并评估体外荧光标记的生物制剂的结合。此外,我们研究了预测抗肿瘤坏死因子（TNF）反应的基因。
方法：29例患者（15例克罗恩病[CD]，14患有溃疡性结肠炎[UC]）在开始抗TNF或抗整合素α4β7治疗之前和12至14周后接受了pCLE的结肠镜检查。进行异硫氰酸荧光素标记的英夫利昔单抗和维多珠单抗染色和基因表达分析。进行pCLE的计算机辅助定量图像分析。在公共队列中确定并验证了预测反应的差异表达基因。
结果：体内，血管弯曲，隐窝形态,和荧光素泄漏预测UC的响应（接收器工作特性曲线下面积[AUROC]，0.93;准确率85%,阳性预测值[PPV]89%；阴性预测值[NPV]75%)和CD(AUROC，0.79；准确率80%；PPV75%；NPV83%）患者。离体,在UC（UC）的基线预测反应时，标记的生物制剂的结合增加（AUROC，83％；准确性77％；PPV89％；NPV50％），但不包括克罗恩病（AUROC58％）。共有325个差异表达基因区分应答者和非应答者，其中86个属于最富集的途径。包括ACTN1、CXCL6、LAMA4、EMILIN1、CRIP2、CXCL13和MAPKAPK2的一组显示抗TNF应答的良好预测(AUROC>0.7)。
结论：在UC中，较高的粘膜结合性与治疗反应相关。在体内,pCLE检测到的粘膜和微血管变化与炎症性肠病对生物制剂的反应相关.抗TNF反应性UC患者的炎症和纤维化状态预处理较少。涉及CXCL6或CXCL13的趋化途径可能是无应答者治疗的新靶点。
方法：29例患者（15例克罗恩病[CD]，14患有溃疡性结肠炎[UC]）在开始抗TNF或抗整合素α4β7治疗之前和12至14周后接受了pCLE的结肠镜检查。进行异硫氰酸荧光素标记的英夫利昔单抗和维多珠单抗染色和基因表达分析。进行pCLE的计算机辅助定量图像分析。在公共队列中确定并验证了预测反应的差异表达基因。
结果：体内，血管弯曲，隐窝形态,和荧光素泄漏预测UC的响应（接收器工作特性曲线下面积[AUROC]，0.93;准确率85%,阳性预测值[PPV]89%；阴性预测值[NPV]75%)和CD(AUROC，0.79；准确率80%；PPV75%；NPV83%）患者。离体,在UC（UC）的基线预测反应时，标记的生物制剂的结合增加（AUROC，83％；准确性77％；PPV89％；NPV50％），但不包括克罗恩病（AUROC58％）。共有325个差异表达基因区分应答者和非应答者，其中86个属于最富集的途径。包括ACTN1、CXCL6、LAMA4、EMILIN1、CRIP2、CXCL13和MAPKAPK2的一组显示抗TNF应答的良好预测(AUROC>0.7)。
结论：在UC中，较高的粘膜结合性与治疗反应相关。在体内,pCLE检测到的粘膜和微血管变化与炎症性肠病对生物制剂的反应相关.抗TNF反应性UC患者的炎症和纤维化状态预处理较少。涉及CXCL6或CXCL13的趋化途径可能是无应答者治疗的新靶点。
