Abstract Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease. While endoscopy is the gold standard for assessing activity, its invasiveness limits routine application. Fecal calprotectin (FC) offers a non-invasive alternative, but validated cut-offs for endoscopic activity, disease extent, and acute severe UC (ASUC) are lacking. This study aims to establish validated FC cut-offs using internal and external cohorts and to explore their relationship with disease extent and ASUC Methods This multicenter study consecutively enrolled 330 UC patients from five centers, dividing them into a 270-patient internal training cohort and a 60-patient external validation cohort. FC’s performance in differentiating endoscopic activity (Mayo subscore) was evaluated via ROC analysis. Exploratory analyses employed ordinal logistic regression to link FC with disease extent (Montreal E1/E2/E3) and the Mann-Whitney U test to compare FC levels between severe activity and ASUC patients, both within the internal cohort. Results In the internal training cohort, FC demonstrated excellent diagnostic performance in differentiating endoscopic activity grades. For detecting clinically significant endoscopic activity (Mayo endoscopic subscore ≥1), the AUC was 0.957 (95% CI: 0.931–0.983). A set of FC cut-offs was established: 97.5 μg/g for distinguishing remission from activity (sensitivity 90.1%, specificity 100%), 309.5 μg/g for distinguishing mild from moderate-to-severe activity (sensitivity 86.3%, specificity 91.7%), and 938 μg/g for distinguishing moderate from severe activity (sensitivity 88%, specificity 74.1%). These cut-offs showed consistent diagnostic performance in both the internal and external validation cohorts. Exploratory analyses revealed no independent correlation between FC levels and disease extent after adjusting for endoscopic activity (P 0.05). Notably, the FC assay’s upper detection limit (1800 μg/g) impacted its discriminatory performance. The AUC for differentiating moderate from severe activity decreased to 0.841 (95% CI: 0.789–0.894). Furthermore, FC could not effectively distinguish ASUC from non-ASUC severe patients median FC: 1800 μg/g vs. 1800 μg/g, P = 0.0638. Conclusion This study establishes and validates a set of FC cut-off values for stratifying endoscopic activity in UC, supporting its role as a valuable non-invasive alternative to endoscopy. However, FC was not associated with disease extent, and its utility in distinguishing ASUC and precisely differentiating moderate from severe activity was limited, partly due to the assay’s upper detection limit. In these specific scenarios, integrating FC with other clinical indicators is recommended References: 1. Le Berre C, Honap S, Peyrin-Biroulet L. Ulcerative colitis. Lancet. Aug 12 2023;402(10401):571-584. doi:10.1016/s0140-6736(23)00966-2 2. Jukic A, Bakiri L, Wagner EF, Tilg H, Adolph TE. Calprotectin: from biomarker to biological function. Gut. Oct 2021;70(10):1978-1988. doi:10.1136/gutjnl-2021-324855 Conflict of interest: He, Jindan: No conflict of interest Liang, Jie: No conflict of interest
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