Predicting disease flare and treatment response in inflammatory bowel disease

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人受到影响，在英国是患病率最高的国家之一(约.1.0%)。在由西方生活方式驱动的以前不发达的世界，发病率正在急剧上升。典型的IBD表现在青春期/成年期早期，肠道功能紊乱，强烈的炎症反应，全身不适，心理社会障碍和沉重的健康经济负担。近年来，在IBD方面进行了大规模的生物技术/制药投资，目前已批准使用多种不同的药物形式。然而，缓解率正在达到一年30-40%的上限，而且没有可靠的生物标记物来帮助药物定位。由于我们无法预测治疗反应或疾病进展，IBD的管理进一步复杂化。当对被西方饮食和其他环境刺激改变的肠道微生物区系产生失调的黏膜免疫反应时，IBD在遗传易感个体中发生。十年的基因发现已经产生了250个易感基因位点和多个可用药靶点。但它并没有提供关于疾病表型或自然病史的有意义的见解。在为英国和国际IBD遗传学联合会做出重大贡献后，我既看到了大样本量的成功，也看到了在这种高度复杂和异质性疾病中回溯性数据采集的局限性。最近，在作为NHS全职胃肠病专家工作的同时，我开发了一个工作计划，以促进预期的生物和临床数据捕获，既有成本效益，也有规模(招募120-150名患者PCM)。我现在计划扩大这项工作，以解决一系列对改善IBD患者预后至关重要的问题。研究问题：1.疾病表型、饮食、生活方式、遗传学和肠道微生物区系的哪些方面有助于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.我们能否在IBD发生之前的样本中识别信号，并进行干预以预防高危人群的疾病发展？最近的工作：我建立了PreEdiCCt研究和Lothian IBD注册。PREdiCCT招募了2629名克罗恩病和UC临床缓解期患者，并在基线水平上对临床、饮食、生活方式、微生物和遗传因素进行了深入研究。患者至少被随访24个月，其中60%的患者被随访48个月。计划工作：将对PreEdiCCt队列进行详细分析，以确定习惯性饮食、环境、微生物群和遗传学的哪些方面与疾病暴发相关并预测疾病暴发。我们将对一组大约800名参与者的饮食和微生物群相互作用进行分析，他们完成了4天的称重食物日记。通过每月问卷纵向收集的心理社会和生活质量参数将被分析，包括恢复力。洛锡安IBD登记处已经用钙保护素数据丰富了--一种衡量粪便样本肠道炎症的可靠指标--收集了15年，并使用相同的分析方法进行了分析。数学建模将根据患者的钙保护素轨迹将患者划分为不同的类别。这些数据将成为一个动态的临床决策支持工具，使患者和临床医生能够预测结果。OUTREACH：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，为人们提供希望的工具。我正在通过多个分布式媒体网络进行这项工作，以便与所有关键利益攸关方进行动态的双向知识交流。

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.