Systemic Immune Signatures of Endoscopic-Histologic Discordance in Inflammatory Bowel Disease: A Pilot Study

Background: Endoscopic remission is a central therapeutic target in inflammatory bowel disease (IBD); however, histologic inflammation may persist despite apparent mucosal healing. The biological mechanisms underlying endoscopic-histologic discordance remain incompletely defined. We aimed to characterize systemic cytokine patterns associated with discordant disease. Methods: In this prospective cross-sectional study, 59 patients with IBD undergoing clinically indicated colonoscopy underwent concurrent endoscopic and histologic assessment. Endoscopic remission was defined as a Mayo endoscopic subscore ≤ 1 for ulcerative colitis and SES-CD ≤ 2 for Crohn's disease. Histologic healing was defined as a Geboes score < 2.0. Patients were classified into concordant remission, discordant disease (endoscopic remission with persistent histologic activity), and concordant active disease. Circulating interleukin (IL)-10, IL-23, and C-reactive protein (CRP) levels were compared across phenotypes using nonparametric methods. Associations with discordant disease were evaluated using Firth penalized logistic regression, and model discrimination was assessed using receiver operating characteristic (ROC) analysis with bootstrap internal validation. Results: Among 36 patients in endoscopic remission, 14 (38.9%) exhibited persistent histologic activity. Discordant patients demonstrated significantly lower IL-10 and higher IL-23 concentrations compared with concordant remission (both p < 0.001), whereas CRP did not differ significantly. Across phenotypes, IL-10 decreased progressively, while IL-23 increased stepwise (both p < 0.001). In multivariable analysis, lower IL-10 (OR 0.0014; 95% CI 0.000003-0.576; p = 0.032) and higher IL-23 (OR 16.94; 95% CI 1.90-151.32; p = 0.011) were independently associated with discordant disease. A model incorporating IL-10 and CRP demonstrated strong discrimination (AUC 0.925), with further improvement after inclusion of IL-23 (AUC 0.994), although these estimates should be interpreted with caution given the limited sample size. Conclusions: Endoscopic-histologic discordance is associated with a distinct systemic cytokine profile characterized by reduced IL-10 and elevated IL-23 levels, despite low CRP concentrations. These findings suggest incomplete restoration of immune regulatory balance and highlight the potential role of circulating cytokines, particularly IL-10, in identifying ongoing microscopic inflammation. These results are exploratory and hypothesis-generating and require validation in larger, prospective cohorts before clinical application.