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，苏格兰的患病率最高(&gt；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。IBD通常表现在青春期/成年期早期，肠道功能紊乱，强烈的炎症反应，全身不适，心理社会障碍和严重的健康经济负担。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，缓解率正在触及一年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。当肠道微生物区系被西方饮食和其他环境刺激改变时，IBD在遗传易感个体中发生黏膜免疫反应失调。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，我制定了一个工作计划，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，我们如何干预以改善结果？4.我们能否利用颠覆性数字医疗技术来大规模收集研究数据，为患者开发症状和闪光跟踪设备工作进展：我已经建立了PREdiCCT研究(www.predicct.co.uk)，旨在确定IBD疾病闪光的原因。PREdiCCT正在招募3100名IBD患者(10月3日1041人)。患者在临床缓解期被招募，进行生物标志物分层(CRP和粪便钙保护素)，并随访到疾病发作。基线数据通过以下方式收集：1.电子病历提取；2.Oshi患者APP(专业、生活方式和环境)；3.4天称重的食物日记；4.第四天的粪便收集；5.全血样分析；和6.桑格研究所的全基因组(WGS)和代谢组测序。Oshi应用程序(作为PREdiCCt数据收集工具开发)然后收集定期患者报告的结果(q100万)。计划工作：PreEdiCCt队列将巩固并扩展到24个月以上，包括饮食、生活方式、心理和炎症参数的纵向采样，以及每月3次的大便采样以进行钙保护素和微生物组测序。它将扩大到包括更多来自英国的患者；在北美，Oshi消费者应用程序的用户将直接成为招募的目标。这将显著增强研究的统计能力，并提供对创新症状跟踪工具的验证。然后，将通过招募患者在他们的IBD开始新的治疗之前建立PREdiCCT活动队列，并遵循治疗反应/无反应。将在一个小组中进行详细的分子表型实验。在这个过程中，我将成为一名全职的学术胃肠病专家，领导这项工作和英国的IBD。

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 some of the highest prevalence rates in Scotland (>1.0%). Incidence rates are increasing sharply in the previously undeveloped world driven by a Western lifestyle. IBD typically manifests 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 are hitting 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 on treatment 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 or natural 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 of retrospective data capture in this highly complex and heterogenous disease. More recently, whilst working as a full-time NHS gastroenterologist, I have developed a programme of work 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 a series 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 utilise disruptive digital healthcare technology to collect research data at scale, develop symptom and flare tracking devices for patientsRECENT WORK: I have established the PREdiCCt study (www.predicct.co.uk) which aims to establish the cause of disease flare in IBD. PREdiCCt is recruiting 3100 people with IBD (n=1041 on 03.10.18). Patients are recruited in clinical remission, with biomarker stratification (CRP & faecal calprotectin) and followed to disease flare. Baseline data is collected via 1. EMR extract; 2. Oshi patient app (PROs, lifestyle & environment); 3. 4-day weighed food diary; 4. stool collection on day 4; 5. a full blood panel; & 6. whole-genome (WGS) & metabolomic sequencing at Sanger Institute. The Oshi app (developed as the PREdiCCt data collection tool) then collects regular patient reported outcomes (q1m). PLANNED WORK: The PREdiCCt cohort will be consolidated and extended beyond 24 months and incorporate longitudinal sampling of dietary, lifestyle, psychological and inflammatory parameters with 3 monthly stool sampling for calprotectin and microbiome sequencing. It will be expanded to include additional patients from the UK; in N America users of the Oshi consumer App will be directly targeted for recruitment. This will significantly enhance the statistical power of the study and provide validation of innovative symptom tracking tools. The PREdiCCt-ACTIVE cohort will then be established by recruiting patients before they start a new treatment for their IBD, and followed to treatment response / non-response. A detailed molecular phenotyping experiment will be performed in a sub-group. In the process I will become a full-time academic gastroenterologist to lead this work and IBD in the UK.