Systematic review and external validation of prediction models based on symptoms and biomarkers for identifying endoscopic activity in Crohn's disease

Abstract Background & Aims Endoscopic healing, an important target of treatment for Crohn’s Disease (CD), requires ileocolonoscopy, which is costly and burdensome. We investigated whether published non-invasive models (based on symptoms and biomarkers) to evaluate CD activity have sufficient accuracy to replace ileocolonoscopy. Methods We performed a systematic review of published non-invasive diagnostic models to evaluate CD activity that used endoscopic features of activity (endoscopic activity) or healing as the reference standard. We externally validated these models for the outcome endoscopic activity (CD endoscopic index of severity scores of 3 or more) using data from the TAILORIX study (346 ileocolonoscopies in 155 patients) and the Utrecht Activity Index (UAI) study (93 ileocolonoscopies in 82 patients). We calculated area under the receiver operating characteristic curves (AUCROCs) for the models using data from these studies, and compared the performance of these models against measurements of fecal calprotectin (FC) and C-reactive protein (CRP). Results We screened 5303 articles and identified 27 models (from 21 studies) for our analysis. Seven models could be externally validated; in the TAILORIX dataset, these models identified patients with endoscopic activity with AUROC values ranging from 0.61 (95% CI, 0.51–0.70) to 0.81 (95% CI, 0.76–0.86). In this dataset, the AUROC value for FC concentration was 0.79 (95% CI, 0.74–0.85) and the AUROC value for CRP level was 0.72 (95% CI, 0.66–0.77). The AUROC values for the validation in the UAI-dataset were similar. In the TAILORIX and/or UAI-dataset, 4 of the 7 models, as well as the FC and CRP assays, were able to identify patients with endoscopic activity with positive predictive values of 90% or more. Two of the 7 models (but not the FC or CRP values) identified patients without endoscopic activity with a negative predictive value (NPV) of 90% or more, leading to correct prediction of endoscopic healing in 3.2% to 11.3% of all patients. For example, applying the Herranz-Bachiller model (1 of 7 models) at a NPV of 92.1% and positive predictive value of 91.9% correctly identified 35.7% of all patients in whom ileocolonoscopy could be avoided for expected endoscopic activity or healing but incorrectly identified 3.2% of all patients. Most ileocolonoscopies (66.5% in TAILORIX and 72.6% in the UAI of all ileocolonoscopies) could correctly be avoided based on concentrations of FC of 100 μg/g or less and 250 μg/g or higher. However, using this range of FC concentrations to identify patients that don’t require ileocolonoscopy caused 18.7% of all patients in the TAILORIX cohort and 19.8% of all patients in the UAI cohort to incorrectly being predicted to have endoscopic activity or healing.. Conclusions In a systematic review and external validation of non-invasive models to identify patients with endoscopic activity of CD, we found only 2 of 7 models evaluated to have NPVs of 90% or more, however, only leading to correct predicted EH in a small proportion of patients. Ileocolonoscopy must therefore be used to evaluate CD mucosal disease activity and healing.