Prognostic Biomarkers to Identify Patients Likely to Develop Severe Crohn's Disease: a Systematic Review.

BACKGROUND:Identification of biomarkers that predict severe Crohn's disease is an urgent unmet research need, but existing research is piecemeal and haphazard.OBJECTIVE:To identify biomarkers that are potentially able to predict the development of subsequent severe Crohn's disease.DESIGN:This was a prognostic systematic review with meta-analysis reserved for those potential predictors with sufficient existing research (defined as five or more primary studies).DATA SOURCES:PubMed and EMBASE searched from inception to 1 January 2016, updated to 1 January 2018.REVIEW METHODS:Eligible studies were studies that compared biomarkers in patients who did or did not subsequently develop severe Crohn's disease. We excluded biomarkers that had insufficient research evidence. A clinician and two statisticians independently extracted data relating to predictors, severe disease definitions, event numbers and outcomes, including odds/hazard ratios. We assessed risk of bias. We searched for associations with subsequent severe disease rather than precise estimates of strength. A random-effects meta-analysis was performed separately for odds ratios.RESULTS:In total, 29,950 abstracts yielded just 71 individual studies, reporting 56 non-overlapping cohorts. Five clinical biomarkers (Montreal behaviour, age, disease duration, disease location and smoking), two serological biomarkers (anti-Saccharomyces cerevisiae antibodies and anti-flagellin antibodies) and one genetic biomarker (nucleotide-binding oligomerisation domain-containing protein 2) displayed statistically significant prognostic potential. Overall, the strongest association with subsequent severe disease was identified for Montreal B2 and B3 categories (odds ratio 4.09 and 6.25, respectively).LIMITATIONS:Definitions of severe disease varied widely, and some studies confounded diagnosis and prognosis. Risk of bias was rated as 'high' in 92% of studies overall. Some biomarkers that are used regularly in daily practice, for example C-reactive protein, were studied too infrequently for meta-analysis.CONCLUSIONS:Research for individual biomarkers to predict severe Crohn's disease is scant, heterogeneous and at a high risk of bias. Despite a large amount of potential research, we encountered relatively few biomarkers with data sufficient for meta-analysis, identifying only eight biomarkers with potential predictive capability.FUTURE WORK:We will use existing data sets to develop and then validate a predictive model based on the potential predictors identified by this systematic review. Contingent on the outcome of that research, a prospective external validation may prove clinically desirable.STUDY REGISTRATION:This study is registered as PROSPERO CRD42016029363.FUNDING:This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 45. See the NIHR Journals Library website for further project information.