Predicting disease flare and treatment response in inflammatory bowel disease

预测炎症性肠病的疾病发作和治疗反应

• 批准号: MR/X023656/1
• 负责人: Charles Lees
• 金额: $ 75.89万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX023656%2F1
• 关键词: Predicting; disease; flare; treatment; response

BACKGROUND: Crohn's disease and ulcerative colitis are the common forms of inflammatory bowel disease (IBD) affecting up to 1 in 100 people in the Western world, with someof the highest prevalence rates in the UK (approx. 1.0%). Incidence rates are increasing sharply in the previously undeveloped world driven by a Western lifestyle. IBD typicallymanifests in adolescence / early adulthood with disturbed bowel function, a robust inflammatory response, systemic upset, psycho-social disturbance and substantial health-economic burden. Recent years have seen massive biotech / pharma investment in IBD with multiple different drug modalities now approved for use. However, remission rates arehitting a ceiling at 1 year of 30-40%, and no reliable biomarkers exist to aid with drug positioning. Management of IBD is further complicated by our inability to prognosticate ontreatment response or disease progression.IBD develops in genetically susceptible individuals when there is a dysregulated mucosal immune response to a gut microbiota altered by Western diet and other environmental stimuli. A decade of gene discovery has yielded >250 susceptibility loci and multiple druggable targets. But it has not provided meaningful insights into disease phenotype ornatural history. Having made substantial contributions to the UK and International IBD Genetics consortia, I have seen both the success of large sample sizes and the limitations ofretrospective data capture in this highly complex and heterogenous disease. More recently, whilst working as a full-time NHS gastroenterologist, I have developed a programme ofwork to facilitate prospective biological and clinical data capture, both cost-effectively and at scale (recruiting 120-150 patients pcm). I now plan to expand this work to address aseries of questions of fundamental importance to improving the outcomes of people with IBD.RESEARCH QUESTIONS:1. What aspects of disease phenotype, diet, lifestyle, genetics and the gut microbiota contribute to a) disease flare, b) disease progression & c) treatment response in IBD?2. How can we stratify patients based on disease biology and risk of progression?3. Based on this, how can we intervene to improve outcomes?4. Can we identify signals in samples taken before the development of IBD and intervene to prevent disease development in at risk individuals?RECENT WORK: I have established the PREdiCCt study and the Lothian IBD Registry. PREdiCCt has recruited 2629 patients with Crohn's disease and UC in clinical remission, and performed a deep dive into clinical, dietary, lifestyle, microbial and genetic factors at baseline. Patients have been followed up for a minimum of 24 months, with 60% followed for >48 months.PLANNED WORK: The PREdiCCt cohort will be analysed in detail to ascertain what aspects of habitual diet, the environment, microbiome and genetics are associated with and predict disease flare. We will performed an analysis of diet and microbiome interactions in a group of approximately 800 participants who have 4 day weighed food diaries completed. Psychosocial and quality of life parameters - collected longitudinally via monthly questionnaires will be analysed, including resilience.The Lothian IBD registry has been enriched with calprotectin data - a robust measure of gut inflammation in faecal samples - collected, and analysed using the same assay, over a 15 year period. Mathematical modelling will assign patients to different classes dependent on their calprotectin trajectories. These data will inform a dynamic clinical decision support tool to enable patients and clinicians to predict outcomes.OUTREACH: My goal is to improve the outcomes for people living with IBD. I want to build community globally and provide people with the tools for hope. I am doing this through multiple distributed media networks to provide a dynamic two-way knowledge interchange with all key stakeholders.

背景：克罗恩病和溃疡性结肠炎是炎症性肠病 (IBD) 的常见形式，在西方世界，每 100 人中就有 1 人患有克罗恩病，其中英国的患病率最高（约 1.0%）。在西方生活方式的推动下，以前不发达的世界的发病率急剧上升。 IBD 通常表现为青春期/成年早期，伴有肠道功能紊乱、强烈的炎症反应、全身不适、社会心理障碍和沉重的健康经济负担。近年来，IBD 领域出现了大量生物技术/制药投资，多种不同的药物模式现已获批使用。然而，1 年缓解率达到 30-40% 的上限，并且不存在可靠的生物标志物来帮助药物定位。由于我们无法预测治疗反应或疾病进展，IBD 的管理变得更加复杂。当对西方饮食和其他环境刺激改变的肠道微生物群产生失调的粘膜免疫反应时，IBD 在遗传易感个体中发生。十年的基因发现已经产生了超过 250 个易感位点和多个可药物靶标。但它并没有为疾病表型或自然史提供有意义的见解。我为英国和国际 IBD 遗传学联盟做出了重大贡献，在这种高度复杂和异质的疾病中，我看到了大样本量的成功和回顾性数据采集的局限性。最近，在担任全职 NHS 胃肠病学家的同时，我制定了一项工作计划，以促进前瞻性生物和临床数据采集，既经济有效又大规模（招募 120-150 名患者 pcm）。我现在计划扩大这项工作，以解决一系列对于改善 IBD 患者的治疗结果至关重要的问题。研究问题：1。疾病表型、饮食、生活方式、遗传学和肠道微生物群的哪些方面会影响 IBD 的 a) 疾病发作、b) 疾病进展和 c) 治疗反应？2.我们如何根据疾病生物学和进展风险对患者进行分层？3.基于此，我们如何进行干预以改善结果？4．我们能否识别 IBD 发生前采集的样本中的信号，并进行干预以预防高危个体疾病的发生？ 近期工作：我已经建立了 PREdiCCt 研究和 Lothian IBD 登记处。 PREdiCCt 招募了 2629 名临床缓解的克罗恩病和 UC 患者，并在基线时深入研究了临床、饮食、生活方式、微生物和遗传因素。患者接受了至少 24 个月的随访，其中 60% 的患者随访时间超过 48 个月。 计划工作：将详细分析 PREdiCCt 队列，以确定习惯饮食、环境、微生物组和遗传学的哪些方面与疾病发作相关并预测疾病发作。我们将对一组大约 800 名参与者进行饮食和微生物组相互作用的分析，这些参与者已完成 4 天的称重食物日记。将分析通过每月问卷调查纵向收集的心理社会和生活质量参数，包括恢复力。Lothian IBD 登记处已丰富了钙卫蛋白数据（粪便样本中肠道炎症的有力衡量指标），并使用相同的测定法在 15 年的时间里进行收集和分析。数学模型将根据患者的钙卫蛋白轨迹将患者分配到不同的类别。这些数据将为动态临床决策支持工具提供信息，使患者和临床医生能够预测结果。拓展：我的目标是改善 IBD 患者的结果。我想在全球范围内建立社区，并为人们提供充满希望的工具。我通过多个分布式媒体网络来实现这一点，以便与所有关键利益相关者提供动态的双向知识交换。