Development of a tissue-based risk prediction model combining histology and barrier biomarkers for clinical relapse in ulcerative colitis with endoscopic healing.

BACKGROUND

Although endoscopic remission is a primary therapeutic target in ulcerative colitis (UC), a meaningful proportion of patients with endoscopic healing still experience clinical relapse (CR). Histologic activity and epithelial barrier dysfunction may help explain this residual risk.

OBJECTIVES

To develop and internally assess an exploratory tissue-based risk prediction model combining histologic activity with epithelial barrier and immunoregulatory markers for relapse risk stratification in UC patients with endoscopic healing.

DESIGN

Multicenter prospective observational cohort study with internal model assessment.

METHODS

Consecutive UC patients with confirmed endoscopic remission (Mayo Endoscopic Subscore 0 or 1) were followed for 12 months. Baseline colonic biopsies were assessed using the Nancy Histological Index (NHI) and immunohistochemical quantification of vitamin D receptor (VDR), Claudin-2, and mucin-2 (MUC-2). A prespecified four-marker logistic regression model was developed using these tissue-based predictors. Model performance was described by receiver operating characteristic analysis, calibration assessment, 1000-sample bootstrap internal validation, and exploratory therapeutic subgroup analyses.

RESULTS

Among 145 patients, 36 (24.8%) experienced CR within 12 months. In the final four-marker model, higher Claudin-2 and NHI were associated with increased relapse risk, whereas higher VDR and MUC-2 expression were protective. The model showed high apparent discrimination in the development cohort (area under the curve (AUC) = 0.968, 95% confidence interval: 0.943-0.992). Bootstrap internal validation yielded an optimism-corrected AUC of 0.957, Brier score of 0.075, calibration intercept of -0.067, and calibration slope of 0.827. A data-derived Youden cut-off of 0.379 classified 39 patients as higher risk, of whom 32 relapsed, and 106 patients as lower risk, of whom 4 relapsed. These estimates reflect internal model performance and should be interpreted cautiously because of the limited number of events and absence of external validation.

CONCLUSION

A tissue-based model integrating Claudin-2, VDR, MUC-2, and NHI may help identify UC patients with different relapse risks despite endoscopic healing. These findings are exploratory and hypothesis-generating, and external validation with standardized biomarker quantification is required before clinical implementation.