Introduction

20-25% of ulcerative colitis (UC) patients will experience at least one episode of acute severe colitis (ASUC). Up to 20% of non-responders to medical treatment will require surgery during the index episode. For approximately one third of the patients, ASUC is the first manifestation of the disease, presenting unique challenges.

Aims & Methods

A single-center, retrospective, cohort study. We included adult patients hospitalized in our gastroenterology department with ASUC. We aim to compare the clinical outcomes between patients with new-onset and established UC.

Results

62 (33.5%) patients had new-onset UC, while 123 (66.5%) had established UC. No significant differences were found in demographic and baseline clinical characteristics of the two groups. Patients with new-onset UC experienced longer hospitalizations (19 ± 22 vs. 12 ± 11 days, P = 0.002), longer delay until receiving rescue therapy [11 days (IQR 6) vs. 6 days (IQR 8), (P = 0.014)] and more severe bacterial infections (16% vs. 4%, P = 0.005) compared with patients with established UC. Histological features of chronicity, including architectural distortion, were more frequently observed in patients with established disease. We found no significant differences in steroid response (P = 0.719), need for rescue therapy (P = 0.522), response to rescue therapy (P = 0.234), colectomy (P = 0.655), mortality (P = 0.516) and hospital readmission (P = 0.929) between groups. After one year, colectomy or death occurred in 13.5% of patients. Independent predictors of adverse outcomes included active smoking, extensive colitis, the need for rescue therapy, and severe bacterial infections — but not new-onset disease.

Conclusion

Major clinical outcomes were similar between patients with new onset and established ASUC. These findings support the efficacy of standardized, protocol-driven management in mitigating risks across both groups.

References

Ordás I, Eckmann L, Talamini M, Baumgart DC, Sandborn WJ. Ulcerative colitis. Lancet. 2012;380(9853):1606-1619. doi:10.1016/S0140-6736(12)60150-0
Hindryckx P, Jairath V, D’Haens G. Acute severe ulcerative colitis: from pathophysiology to clinical management. Nat Rev Gastroenterol Hepatol. 2016;13(11):654–664. doi: 10.1038/nrgastro.2016.116
Dhaliwal J, Tertigas D, Carman N, et al. Outcomes Following Acute Severe Colitis at Initial Presentation: A Multi-centre, Prospective, Paediatric Cohort Study. J Crohns Colitis. 2024;18(2):233-245. doi:10.1093/ecco-jcc/jjad143
Spinelli A, Bonovas S, Burisch J, et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Surgical Treatment. J Crohns Colitis. 2022;16(2):179-189. doi:10.1093/ecco-jcc/jjab177

Introduction

Ulcerative colitis (UC) is a chronic, relapsing-remitting inflammatory bowel disease (IBD) with increasing global prevalence. The FDA has emphasized the importance of histologic endpoints in clinical trials, noting mucosal healing claims should be supported by more than just endoscopic findings. However, there are many challenges to achieving a standardized assessment of histologic disease activity in a UC clinical trial, including: the heterogeneity in the collection of mucosal biopsies (number, location) from study to study, a lack of fully validated histology scoring systems and an absence of community standards for definitions of histologic improvement or histologic remission.

Aims & Methods

This work was conducted by the FNIH Biomarkers Consortium Mucosal Healing in UC Project, a collaborative initiative involving academic institutions, pharmaceutical companies, patient advocacy organizations, and regulatory agencies to foster consensus, encourage adoption of findings, and support regulatory decision-making.
Aim 1: McBride et al. analyzed 994 biopsies from UC colectomy specimens to determine optimal biopsy sampling strategies for histologic grading.
Aim 2: A prospective study enrolled 153 UC patients to compare targeted versus non-targeted biopsy strategies across four colonic segments, assessing both endoscopic and histologic remission.
Aim 3: Data from three clinical trials (NCT02840721, NCT02958865, NCT02065622) and four independent datasets were compiled, yielding 9,652 whole slide images (WSIs) were used to train two AI tools:
• AIM-HI UC: Multiple instance learning models for predicting Geboes Score (GS) subgrades directly from H&E-stained WSIs.
• IBD Explore: A suite of convolutional neural networks (CNNs) for segmentation and classification of histologic features, including tissue types, crypt architecture, and cells. Performance was evaluated using a held-out test set (N=578 WSIs) and inter-pathologist agreement metrics.

Results

Aim 1: Sampling 2–3 biopsies per colonic region most effectively captured histologic heterogeneity and improved grading reliability. Agreement across histologic indices increased with biopsy number, particularly after the second and third biopsies.
Aim 2: Rectal histologic remission was highly predictive of proximal colonic remission (93% endoscopic, 88% histologic concordance). Histologic scores showed high correlation between targeted and non-targeted biopsies (ρ = 0.80–0.86), especially in remission.
Aim 3: Most AIM-HI UC models outperformed individual pathologists in predicting GS subgrades. IBD Explore generated interpretable histologic features—such as epithelial-to-lamina propria ratio, crypt distortion, and lymphocyte density—supporting advanced spatial analysis beyond conventional scoring systems.

Conclusion

This consortium-based endeavor generated several key findings: 1) Up to 3 biopsy samples per region of interest are required to overcome microscopic heterogeneity and ensure accurate histological grading in active colitis; 2) Targeted and random biopsies provide comparable histologic information, supporting the use of random biopsies in future clinical trials and practice; 3) Rectal endoscopic and histologic remission are highly predictive of pancolonic remission in extensive UC, supporting assessment limited to rectum in stable disease. Development of a ML-based approach for predicting GS subgrades, combined with these sampling insights, has the potential to improve standardization and automation of GS histological assessment, enhancing measurement of histological treatment response and endpoints in clinical trials.

References

IBD Explore and AIM-HI UC are for Research Use Only. Not for use in diagnostic procedures
McBride, R. B., Suarez-Farinas, M., Ko, H. M., Chen, X., Liu, Q., & Harpaz, N. (2023). Density of Biopsy Sampling Required to Ensure Accurate Histological Assessment of Inflammation in Active Ulcerative Colitis. Inflammatory bowel diseases, 29(11), 1706–1712. https://doi.org/10.1093/ibd/izad063
Danese S, Klopocka M, Scherl EJ, et al. Anti-TL1A Antibody PF-06480605 Safety and Efficacy for Ulcerative Colitis: A Phase 2a Single-Arm Study. Clin Gastroenterol Hepatol. 2021;19(11):2324-2332.e6. doi:10.1016/j.cgh.2021.06.011
Sandborn WJ, Danese S, Leszczyszyn J, et al. Oral Ritlecitinib and Brepocitinib for Moderate-to-Severe Ulcerative Colitis: Results From a Randomized, Phase 2b Study. Clin Gastroenterol Hepatol. 2023;21(10):2616-2628.e7. doi:10.1016/j.cgh.2022.12.029
Panés J, Colombel JF, D'Haens GR, et al. Higher vs Standard Adalimumab Induction and Maintenance Dosing Regimens for Treatment of Ulcerative Colitis: SERENE UC Trial Results. Gastroenterology. 2022;162(7):1891-1910. doi:10.1053/j.gastro.2022.02.033

Disclosure

Disclosures of Primary Authors
Autumn Jones: None
Russell McBride: None
Stephen Laroux: holds shares of stock in AbbVie
Christina Jayson: PathAI stock holder
Noam Harpaz: has served as an advisory board member or consultant for Lilly, Inc., Abbvie Inc., Bristol Meyer Squibb, Inc., and PathAI, Inc.

All listed organizations are financially contributing partners and/or consulting partners of the Foundation for the National Institutes of Health Biomarkers Consortium project team.
PathAI employees, previous and current are PathAI stock holders.