Prognostic biomarkers to identify patients likely to develop severe Crohn’s disease: a systematic review
Authors: Halligan Steve , Boone Darren , Archer Lucinda , Ahmad Tariq , Bloom Stuart , Rodriguez-Justo Manuel , Taylor Stuart A , Mallett Sue 
Published: July 2021

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.