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 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.