Title: Using medical imaging to improve disease phenotyping and prediction of adverse outcomes in Crohn's Disease
Funder: Department of Health and Social Care

Abstract: RESEARCH QUESTIONS: Do ultrasound (US) parameters accurately quantify Crohn's Disease (CD) activity and bowel damage? Does adding US parameters to existing clinical variables improve the prediction of disabling CD within 5yrs of new diagnosis? Do (a)morphological magnetic resonance imaging (MRI) parameters and (b)US parameters improve prediction of therapeutic response at 1yr in patients commencing anti-tumour necrosis factor treatment (anti-TNFs) for CD? STUDY DESIGN: 3 linked studies, synergistic with existing NIHR-funded multicentre cohorts. Study1: Development and validation of US activity and bowel damage scores. Development phase=retrospective analysis of US data collected from previous METRIC study (HTA11/23/01). Validation phase=multicentre prospective cohort study in 5 NHS hospitals. Study2: Prediction of disabling CD after new diagnosis. Extended follow-up of METRIC new diagnosis cohort (recruited at 8 NHS hospitals) to average 5yrs (min=4yrs). Development and internal validation of a multivariable prediction model incorporating US features with existing clinical predictors. Study3: Prediction of response to anti-TNF therapy after initiation. Addition of morphological MRI and US to a 110 patient subset of the MOTILITY study (EME14/201/16) recruited at 5 NHS hospitals. POPULATION: Study1: Patients presenting to hospital with either new CD diagnosis or acute relapse. Study2: Newly-diagnosed CD. Study3: Patients commencing anti-TNFs for active small bowel (SB) CD as standard care. INTERVENTIONS:Enteric US&MRI. US requires 4-6hr fast and 20min scan. MRI requires similar fasting, 1-1.5L oral contrast ingestion and 20-30min scan.ENDPOINTS/REFERENCE STANDARD: Study1: Histological score of CD activity (endoscopic-biopsy Acute Inflammatory Score=eAIS). Study2: Development of disabling CD (defined per Beaugerie[38]) Study3: Response or Remission (RoR) one year after anti-TNF treatment, defined using CD Simple Endoscopic Score (SES-CD) or validated MRI-based alternative with Patient-Reported Outcome Measures for those unable to have endoscopy. PRIMARY OUTCOMES: Study1: Predictive performance of US activity scores for eAIS. Study2: Comparative predictive ability of prognostic models incorporating US scores alongside clinical characteristics vs. models using clinical characteristics alone to predict disabling CD within 5yrs of new diagnosis. Study3: Comparative predictive performance of multivariable prognostic models incorporating changes in morphological MRI parameters vs. those using the inflammatory marker, C-reactive protein, to predict RoR to anti-TNFs at 1yr. KEY SECONDARY OUTCOMES: Study1: (a)Agreement between US and MRI bowel damage scores. (b)Inter- and intra-observer agreement for score calculation. Study2: (a)Identification of key individual US features for prediction of disabling CD. (b)Comparative predictive ability of US&MRI. Study3: Predictive ability of (a)diffusion-weighted MRI and (b)US activity scores for RoR to anti-TNFs at 1yr. ANALYSIS: Study1: Multivariable regression modeling:eAIS as the output variable, pre-specified US parameters associated with CD activity as inputs. Internal (bootstrap) and external (separate cohort) validation. Study2: Multivariable prognostic modeling to predict disabling CD using US scores and pre-specified clinical predictors. Study3: Multivariable prognostic modeling using logistic regression to predict RoR to anti-TNF therapy. Known clinical predictors pre-specified. All modeling conducted in accordance with TRIPOD guidance.SAMPLE SIZE:Study1=200; Study2=167; Study3=110. Each study has >10 events per variable for prognostic model development. Clinical predictors of disabling CD (Study 2) and response to anti-TNFs (Study3) are pre-specified, conserving statistical power for model evaluation (vs. variable selection).RECRUITMENT&DURATION: Study1: All clinical and imaging data already collated via METRIC. Study2: Participant recruitment and baseline scans already conducted; 5yr follow-up. Study3: 18month recruitment at 5 NHS sites, 12month follow-up. 1.22 patients/site/month target recruitment. Site selection and study duration informed by site audits, confirming feasibility. DISSEMINATION:Via peer-reviewed literature; conferences; to patients via PPI links.BENEFITS&EXPECTED IMPACTS: Reliable US indices of CD activity and bowel damage using a test that patients prefer. Early identification of those at high risk of aggressive disease, permitting triage for early intensive therapy. Rapid prediction of non-response to anti-TNFs, allowing early adjustment of therapeutic strategy.

Lay abstract: Crohn's disease (CD) is a common, important condition that inflames the gastrointestinal (GI) tract, affecting 100,000 people in the UK. It most frequently involves the intestines (the small and large bowel). Left untreated, inflammation damages the bowel, sometimes causing severe complications (needing hospitalization or surgery) or, rarely, death.Treatment aims to improve patient symptoms and quality of life. Traditionally, this prioritised short-term symptom control, but we now know that treatment to suppress inflammation is very important for the longer-term, to prevent the bowel damage mentioned above. Ideally, this treatment would be given early, before bowel damage can occur. Powerful drugs called anti-TNFs are often used because they are very effective at healing the bowel. Unfortunately, they cannot be used for everyone, because of side-effects (sometimes serious), inconvenience for patients, and high cost. Patients and their doctors need more effective ways to tell, in advance, which patients are likely to develop severe diseaseand so would benefit from early anti-TNF treatment. Additionally, when patients start anti-TNFs, we need to pinpoint people in whom it will work, and those in whom it will be ineffective (so they can have different medication or surgery).To answer these two questions (who will develop severe disease? and who will have a good response to anti-TNFs?), this research will use medical imaging; ultrasound (US) and magnetic resonance imaging (MRI). The NIHR has already funded two studies, one for each of the questions above (METRIC-EF and MOTILITY, both co-led by the applicant with their mentors). However, these studies focus purely on MRI (and, for MOTILITY, only a particular kind of MRI scanning measuring how fast the bowel moves). During discussion with patients, it has become clear that we need more work on US, because 75% of patients prefer it. US is faster, less claustrophobic and less inconvenient than MRI. It is also far cheaper, benefitting the wider NHS. Studying US therefore complements the existing MRI-based research very neatly, and at relatively low cost, because setup costs of the MRI-based studies have already been secured. The proposal is split into three parts.In the first, we will analyse US scans in great detail to see if we can use the images to develop an activity score that accurately measures how much bowel inflammation is present. Then we will see if US can measure how much the bowel is damaged (bowel damage score). All of these US scans have already been performed in another study that has just completed. The results are on record, and we have patient permission to use them. After we have developed these activity and bowel damage scores, we will test their reliability by doing US with the scores in a separate group of patients. This step (external validation) means we will be confident that the scores will work for most patients.In the second part of the research, we will see if patients with severely abnormal US at diagnosis are more likely to develop worse CD 5 years later. To do this, we will take a group of 167 patients who had US at the time of diagnosis, and ask for permission to see what happened to them over the next 5 years. These patients have already been identified and scanned via the METRIC-EF study. We will analyse the US images using the scores developed in part 1, and see if worse scores at diagnosis predict future development of severe Crohn's (disabling CD) 5 years later. If so, we will suggest that patients with severely abnormal US at diagnosis may need earlier, more intensive treatment.The third part of the research will test if early changes to MRI and US after starting anti-TNF treatment can predict whether the treatment will work. We are already about to start a study (called MOTILITY) that will identify 156 patients due to start anti-TNFs for their standard care. In MOTILITY, patients will have a limited MRI scan (looking at bowel motion only) before treatment, and again after 20-28 weeks. The current proposal will use the existing infrastructure of MOTILITY to save costs, but will add advanced MRI scanning techniques (taking 10mins longer per scan) and a 15min US scan in 110 of the patients. After 1 year, we will analyse whether or not early changes to these advanced MRI and US scans were able to predict response to anti-TNF treatment at 1 year.Once the research is completed, the results will be publicized at research conferences and in medical journals, and to patients via patient representatives.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL