Clinical, imaging, and endoscopic outcomes of children newly diagnosed with Crohn's disease

项目摘要/摘要 儿童克罗恩病(CD)的治疗目标已从临床改善或缓解转变为 回结肠镜下的内窥镜愈合(EH)和磁共振肠镜下的跨壁愈合(TH) (MRE)。这种转变的发生是因为完全痊愈的患者(CH、TH和EH)体验更低 随后住院、治疗升级或手术的比率高于仅患有EH或无法治愈的患者。我们 假设特定的治疗前临床、放射学、基因组和微生物因素以及获得 靶向抗肿瘤坏死因子生物暴露的比例将与主要终点CH和主要次要终点相关联 开始抗肿瘤坏死因子治疗52周后，EH和TH的终点。我们将在一项前瞻性队列研究中检验这一假设。 在570名新诊断的儿童CD患者中，他们在6个月内开始接受抗肿瘤坏死因子药物治疗 几个月的诊断。我们将在治疗药物的指导下进行个性化的抗肿瘤坏死因子生物治疗 使用我们开发的一种新的剂量算法进行监测(TDM)。 目标1.评估假设的关联并探索CH和基线之间的新关联 临床和放射学严重程度的测量。我们假设治疗前的营养状况， 抗肿瘤坏死因子开始治疗52周后，抗菌血清和MRE结果将与CH相关。正式 将进行假设测试，以确认一组预先指定的衡量标准的预测能力 Logistic回归模型。我们还将对通过机器识别的新预报器进行探索性分析 学习方法，在调整已确定的主要预测因素后，评估它们与CH的关系。 目的2.评估推测的相关性，并探索CH与基线宿主和 微生物基因组和代谢因素。我们假设治疗前的基因表达特征 微生物因素将与第一年的CH有关。我们将描述寄主的基因类型，纵向 微生物分类和代谢组特征，以及回肠和结肠宿主表观基因组和转录组 在开始抗肿瘤坏死因子治疗后52周。 目的3.采用k重交叉验证法确定第一年慢性肝炎的最优预测模型。 我们假设，包括宿主基因签名和微生物的模型将改善对CH的预测 而不仅仅是基于临床和影像因素。该模型将包括重要的临床和成像 来自AIM 1和基线宿主和微生物特征子集的预测因子被发现有可能 目标2中的解释。 冲击力。拟议的初始队列研究CAMEO将是独一无二的，它将提供一个强大的、新颖的平台 研究有助于儿童CD治愈的因素，然后立即转化为临床 实践，以及指导未来针对患者的微生物区系和宿主免疫反应的治疗 用目前的方法不太可能实现治愈。

Project Summary/Abstract Therapeutic goals in pediatric Crohn’s Disease (CD) have shifted from clinical improvement or remission to endoscopic healing (EH) by ileocolonoscopy and transmural healing (TH) by magnetic resonance enterography (MRE). This shift happened because patients who achieve complete healing (CH, TH and EH) experience lower rates of subsequent hospitalization, therapy escalation, or surgery than those with EH alone or no healing. We hypothesize that specific pre-treatment clinical, radiologic, genomic, and microbial factors along with attainment of targeted anti-TNF biologic exposure will be associated with the primary endpoint, CH, and the major secondary endpoints, EH and TH, 52 weeks after anti-TNF start.. We will test this hypothesis in a prospective cohort study of 570 newly diagnosed pediatric-onset CD subjects who initiate treatment with anti-TNF medication within 6 months of diagnosis. We will administer personalized anti-TNF biologic therapy guided by therapeutic drug monitoring (TDM) using a novel dosing algorithm which we developed. Aim 1. Evaluate putative associations and explore novel associations between CH and baseline measures of clinical and radiologic severity. We hypothesize that pre-treatment nutritional status, antimicrobial serologies, and MRE findings will be associated with CH 52 weeks after anti-TNF start. Formal hypothesis tests will be carried out to confirm the predictive power of a set of pre-specified measures using a logistic regression model. We will also conduct exploratory analyses of novel predictors, identified via machine learning methods, to assess their relationship with CH after adjusting for the confirmed primary predictors. Aim 2. Evaluate putative associations and explore novel associations between CH and baseline host and microbial genomic and metabolic factors. We hypothesize that pre-treatment gene expression signatures and microbial factors will be associated with year 1 CH. We will characterize the host genotype, longitudinal microbial taxonomic and metabolomic profiles, and ileal and colon host epigenome and transcriptome at baseline and at 52 weeks after anti-TNF start. Aim 3. Use a k-fold cross-validation procedure to determine the optimal predictive model of year 1 CH. We hypothesize that a model which includes host gene signatures and microbes will improve prediction of CH beyond one based on clinical and imaging factors alone. The model will include significant clinical and imaging predictors from Aim 1 and the subset of baseline host and microbial characteristics found to be potentially explanatory in Aim 2. Impact. The proposed inception cohort study, CAMEO, will be unique in providing a robust, novel platform to study factors that contribute to healing in pediatric CD that can then be immediately translated into clinical practice, as well as guiding future therapies targeting the microbiota and host immune responses in patients unlikely to achieve healing with current approaches.