Predicting disease flare and treatment response in inflammatory bowel disease

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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.