Introduction

Histological assessment in Inflammatory Bowel Disease (IBD) is often required with endoscopic diagnoses to establish disease activity. This is evident in patients where histological healing is a major therapeutic goal and when endoscopic healing can also exhibit microscopic disease. IBD can manifest in numerous landmark features which are structural and inflammatory related. Histological activity is determined through erosion/ulceration, architectural changes in tissue morphology, mucin depletion and presence of varied inflammatory cells the colonic crypts, Muscularis Mucosae (MM) and Lamina Propria (LP). Histological scoring systems vary in complexity and methodology and subject to discrepancies in inter-rater consensus. Our model aims to provide accurate measurements of key histological features in Ulcerative Colitis (UC) used in scoring systems as both a decision support tool for improving pathologist scoring alignment and sensitive quantitative metrics of inflammatory cells to evaluate disease activity.

Aims & Methods

We developed an ensemble of convolutional neural networks to identify cell types, tissue foreground, crypts, MM, and haemorrhage in H&E images of IBD biopsy data. Models were trained with expert-labelled annotations comprising 34,289 image-annotation pairs (80% training, 20% validation) from in-house and publicly available data. Model accuracy was assessed with 6,464 held-out image-annotation pairs from 26 Whole Slide Images (WSIs) from all sites of the large intestine commonly sampled during endoscopic investigation, while ground truth annotations were reviewed by GI-trained pathologists to certify accuracy. We used geospatial methods to derive boundaries of the LP from other predicted domains, associate cells to delineated regions, measure architectural changes and derive spatially differentiated metrics of inflammatory burden in 66 patients with confirmed UC.

Results

The AI model spatially differentiates and segments cell types and tissue compartments. This produces metrics for inflammatory cell counts in regions of interest such as crypts, LP, and MM. Goblet cell segmentation within crypts allows for measurement of mucin depletion. This can be visualized for pathologists where each inflammatory cell type across the WSI is represented as density metrics. Automated quantification of inflammatory cells across AI-identified tissue domains throughout the bowels of UC patients revealed large intra- and inter-patient variability.

Conclusion

Our AI model can measure histological healing by detecting architectural change, inflammatory cell number, goblet cell reduction and erosions and ulceration. This allows for metrics and visual overlays to assist with pathologist reading and quantifying changes in mucosal biopsies in a clinical trial setting which requires extremely sensitive tools only AI can provide.

Disclosure

DW/AM/RL/PA/PW and CL are employees at Perspectum Ltd. EF and RG are consultants for Perspectum Ltd. All other co-authors have no conflicts of interest to declare relevant to this work.

Introduction

Immune checkpoint inhibitors (ICIs), a new class of immunotherapeutic agents, are the first-line treatment for many advanced epithelial cancers. Gastrointestinal irAEs, particularly diarrhea and colitis, affect approximately 40% of ICI-treated patients and often lead to therapy discontinuation.¹ High-dose corticosteroids represent the first-line treatment, but about one-third of patients show inadequate response and require second-line immunosuppressants such as Infliximab or Vedolizumab.² As the body of evidence about the role of gut microbiota in the pathogenesis of GI irAE grows, fecal microbiota transplantation (FMT) is emerging as a potential treatment for steroid- and biologic-refractory ICI-induced colitis.³ Although data are still preliminary, FMT represents a promising therapeutic strategy in this setting.

Aims & Methods

The aim of this study is to evaluate the safety and efficacy of FMT in patients referred to our Microbiome clinic for steroid- and biologic-refractory ICI-induced colitis. After clinical evaluation, patients were treated with FMT via colonoscopy from healthy donors. FMT was performed as already described, following international clinical guidelines.^4,5 Following the endoscopic procedure, patients were evaluated at 1, 4, 8, and 12 weeks. We collected data on: patient characteristics, cancer type, cancer treatment and its suspension, severity of diarrhea before FMT (graded via CTCAE)⁶, time in weeks from initiation of cancer therapy to onset of diarrhea, grade of diarrhea following treatment and resumption of ICI.

Results

Our cohort included 7 patients with steroid- and biologic-refractory ICI-induced colitis (grade 1: n=0 ; grade 2: n=1 ; grade 3: 5=x; grade 4: n=1). Four patients were affected by renal cell carcinoma, 2 by melanoma, 1 by pulmonary cancer. All patients were treated with PD-1/PDL-1 inhibitors or CTLA-4 ( Nivolumab: n= 3; Nivolumab and Ipilimumab: n=2; Durvalumab: n= 1; Pembrolizumab: n= 1) and 6 patients interrupted ICI due to gastrointestinal irAEs. All patients received single FMT from healthy donors via colonoscopy. Following FMT, diarrhea improved to grade ≤ 1 in 6 patients (85%) at week 1, 4, 8, and 12 after the procedure, suggesting a sustained effect of microbiome modulation in the medium term. One patient died during follow-up for reasons other than ICI-colitis.

Conclusion

Our preliminary findings suggest that FMT may be a promising therapeutic strategy for refractory ICI-colitis. Further, larger and randomized studies are warranted to confirm our data.

References

1. Dougan M, Wang Y, Rubio-Tapia A, Lim JK. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review. Gastroenterology. 2021;160(4):1384-1393. doi:10.1053/j.gastro.2020.08.063
2. Haanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(12):1217-1238. doi:10.1016/j.annonc.2022.10.001
3. Wang Y, Wiesnoski DH, Helmink BA, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018;24(12):1804-1808. doi:10.1038/s41591-018-0238-9
4. Cammarota G, Ianiro G, Kelly CR, et al. International consensus conference on stool banking for faecal microbiota transplantation in clinical practice. Gut. 2019;68(12):2111-2121. doi:10.1136/gutjnl-2019-319548
5. Ianiro G, Rossi E, Thomas AM, et al. Faecal microbiota transplantation for the treatment of diarrhoea induced by tyrosine-kinase inhibitors in patients with metastatic renal cell carcinoma. Nat Commun. 2020;11(1):4333. doi:10.1038/s41467-020-18127-y
6. Freites-Martinez A, Santana N, Arias-Santiago S, Viera A. Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr. 2021;112(1):90-92. doi:10.1016/j.ad.2019.05.009

Disclosure

G.I. has received personal fees for acting as speaker for Biocodex, Danone, Sofar, Malesci, Metagenics and Tillotts Pharma, and for acting as consultant and/or advisor for Ferring Therapeutics, Giuliani, Malesci and Tillotts Pharma. A.G. reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, SinergieSrl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai. G.C. has received personal fees for acting as advisor for Ferring Therapeutics. All other authors have no conflicts of interest to disclose.

Introduction

The achievement of histological remission (HR) is a key treatment goal in ulcerative colitis (UC), as it is suggestive of better disease management and predicts response to therapy.
The absence of neutrophils in epithelium and lamina is crucial to define HR. However, the role of neutrophil number and localisation remains unclear. We aimed to develop a novel artificial intelligence (AI)-driven system to automate neutrophil detection, localisation, and quantification, supporting assessment of HR and enable the prediction of response to therapy.

Aims & Methods

We developed an AI-driven system by integrating two deep learning models to (1) segment whole slide images (WSIs) into epithelium, crypts and lamina propria and to (2) detect and quantify neutrophils. Outputs from these models were combined to compute neutrophil densities in the lamina propria, epithelium, and overall tissue. The optimal neutrophil density cut-offs to assess disease activity (Geboes score >2B.0) in UC patients were identified in the AMAC phase 2 Mirikizumab trial, and subsequently validated in the multicentre prospective PICaSSO cohort study. Cut-offs to determine treatment response at weeks 12 and 52 (histological improvement [HI; Geboes score ≤3.1] and histological remission [HR; Geboes score ≤2B.0]), were also evaluated.

Results

Table 1 shows the system diagnostic performance in assessing disease activity and predicting response to therapy at W12 and W52 in the Mirikizumab cohort.
303 WSIs from active UC patients from the multicentre, randomised, double-blind, parallel-arm, placebo-controlled phase 2 clinical trial of Mirikizumab were analysed. The model yielded a DICE SØrensen of 0.57 for segmentation, precision of 82.3% and recall of 77.0% for neutrophil detection. The system identified an overall optimal neutrophil density cut-off (cells/mm²) predictive of disease activity of >21.7.0 (>10.1 and >30.4 for epithelium and lamina propria, respectively), with an accuracy of 86% (85% and 85%, respectively). Further validation in the multicenter PICaSSO cohort yielded to similar results.
Moreover, the overall optimal cut-off to predict histological remission at W52 was <20.8 (<10.4 and <27.9 for epithelium and lamina propria, respectively), with an accuracy of 82.0% (81% and 80%, respectively).

Conclusion

Our novel AI-based system demonstrates strong potential as an automated tool to detect, localise, and quantify neutrophils to assess histological activity and predict response to therapy in a clinical trial UC cohort and real-world settings. This framework could be applied in clinical trials and routine clinical practice, offering objective guidance for personalised management in UC patients.

References

[1] Santacroce G, Meseguer P, Zammarchi I, et al. P406 A novel active learning-based digital pathology protocol annotation for histologic assessment in Ulcerative Colitis using PICaSSO Histologic Remission Index (PHRI). Journal of Crohn's and Colitis, Volume 18, Issue Supplement_1, January 2024, Pages i843–i844
[2] Graham S, Vu QD, Jahanifar M, et al. CoNIC Challenge: Pushing the frontiers of nuclear detection, segmentation, classification and counting. Med Image Anal. 2024;92:103047.

Disclosure

MI received research grants and consultant fees from Olympus, Pentax, Eli Lilly, and Janssen. All other authors declare no competing interests.

Introduction

Obefazimod (Obe) is an oral, once-daily (QD), small molecule which enhances expression of microRNA-124 and has been studied in two Phase 2 induction trials and subsequent open-label maintenance studies [1-3] in patients (pts) with moderately to severely active ulcerative colitis (UC). Here we report efficacy and safety of two Phase 3, 8-week, induction trials in adult pts with UC from ABTECT-1 [NCT05507203] and ABTECT-2 [NCT05507216].

Aims & Methods

The multicenter, randomized, double-blind, placebo-controlled ABTECT trials enrolled pts with moderate-to-severe UC (defined as modified Mayo score (MMS)≥ 5, with rectal bleeding sub-score (RBS) ≥ 1 and centrally read endoscopic score >2) who had inadequate response, loss of response, or intolerance to at least one prior therapy (with no upper limit), including corticosteroids, immunosuppressants, biologics, S1P receptor modulators and/or JAK inhibitors. Pts were randomized 2:1:1 to Obe 50 mg QD (Obe-50), Obe 25 mg QD (Obe-25) or placebo (PBO) for 8 weeks. The primary endpoint was clinical remission (per MMS) and secondary endpoints included clinical response, endoscopic improvement, symptomatic remission, and histo-endoscopic mucosal improvement (HEMI).

Results

1272 pts were randomized and treated in ABTECT-1 (636) and ABTECT-2 (636). In both trials, baseline demographics and disease characteristics were similar between groups; 45.3% and 49.3% of pts had inadequate response to 1 or more advanced therapies. A significantly higher proportion of pts receiving Obe-50 (ABTECT-1:21.7%, ABTECT-2: 19.8%) versus PBO (2.5% and 6.3%) achieved clinical remission (Obe-50-PBO difference: ABTECT-1: 19.3%, p<0.0001; ABTECT-2: 13.4%, p=0.0001) and met all key secondary endpoints in both trials. A significantly higher proportion of pts receiving Obe-25 versus PBO achieved clinical remission (Obe-25-PBO difference: 21.4%, p<0.0001) and met all key secondary endpoints in ABTECT-1. In a pooled analysis, both Obe-50 and Obe-25 met all primary and secondary endpoints with nominal significance (p<0.0001) (Table). The overall rate of serious adverse events and treatment emergent adverse events (TEAEs) leading to study drug discontinuation for pts treated with Obe were similar to PBO. Proportions of pts who reported at least one TEAE in ABTECT-1 were 59.4%, 46.9%, and 53.2% for Obe-50, Obe-25, and PBO, respectively. For ABTECT2, TEAEs occurred in 61.0%, 50.9%, and 48.4% for Obe-50, Obe-25, and PBO, respectively. The most frequent TEAE was headache (Obe-50: 20.8-25.8%; Obe-25: 14.5-15.6%; PBO: 5.7). The headaches were mild, transient, short in duration and not a barrier to treat as evidenced by a low discontinuation rate of 0-1.6%. No signal was observed for serious, severe, or opportunistic infections or malignancies.

Table: 8-week induction efficacy of obefazimod in ABTECT-1 and ABTECT-2 Phase 3 studies, and pooled ABTECT-1 and ABTECT-2^‡

Conclusion

In both ABTECT induction trials, primary and secondary endpoints were met; obe treatment led to statistically significant improvements in clinical, endoscopic, symptomatic and combined endoscopic-histologic endpoints at week 8. Obe was well tolerated with no new safety signals identified.

References

1. Vermeire S, et al. J Crohns Colitis. 2023; 17: 1689-1697
2. Vermeire S, et al. The Lancet Gastroenterology & Hepatology. 2022; 7: 1024-1035.
3. Vermeire S, et al. J Crohns Colitis. 2025 ; 19 : jjaf074

Disclosure

Authors reports following potential conflicts of interest:
BES: Abbvie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Fzata, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Kaleido, Kallyope, Lilly, Merck & Co., Microba, Microbiotica, Mitsubishi Tanabe, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, OSE Immunotherapeutics, Janssen, Palisade Bio, Pfizer, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Therapeutics, Spyre Therapeutics, Takeda, Target RWE,Teva, TLL Pharmaceutical, Tr1X, Trex Bio, Union Therapeutics, Ventyx Biosciences.
SV: AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, Zealand Pharma.
LPB: Abbvie, Abivax, Adacyte, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, BMS, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, Ysopia.
SD: AbbVie, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim.
PSD: Abbvie, Abivax, Adiso, Alimentiv, Bristol Meyer Squibb, Celltrion, Genentech, Geneoscopy, Janssen, Pfizer, Takeda.
MD: Abbvie, Abivax, Arena Pharmaceuticals, Astra Zeneca, Boehringer Ingelheim International GmbH, Bristol-Meyer Squibb, Eli Lilly and Company, F. Hoffmann-La Roche Ltd, Genentech Inc, Gilead, Janssen Pharmaceuticals, Merck, Pfizer Inc, Prometheus Biosciences, Takeda Pharmaceuticals.
HT: Abbvie, Abivax, Dr Falk Pharma, ferring, Galapagos, Microbiotica, MSD, Pfizer, Takeda.
BS: AbbVie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Dr. Falk Pharma, Eli Lilly, Endpoint Health, Falk, Galapagos, Gilead, Janssen, Landos, Materia Prima, PredictImmune, Pfizer, and Takeda; AlfaSigma, CED Service GmbH, MSD, Ferring, Galapagos, Tr1x bio
TH: Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., Boston Scientific Corporation, Kissei Pharmaceutical Co. Ltd, Janssen Pharmaceutical K.K., Pfizer Inc., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, Abivax.
XT: Celltrion, AbbVie, Johnson & Johnson, Lilly, Takeda, Alpha Sigma, Dr. Falk, Abivax, Biogen, Fresenius Kabi, MSD, Pfizer, Tillotts, and Thabor Therapeutics.
RA: AbbVie, Abivax, AstraZeneca, Bristol-Myers Squibb, Celltrion Healthcare, Galapagos, Johnson&Johnson, Lilly, MSD, Pfizer, and Takeda Pharma
US: AbbVie, Abivax, Amgen, Galapagos, Janssen, Eli Lilly, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Gilead Sciences, Pfizer, Roche,Takeda Pharmaceuticals
AA: AbbVie, Abivax, AG Pharma, Alfa Sigma, Astra Zeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Eli-Lilly, Enthera, Ferring, Galapagos, Gilead, Giuliani, Janssen, Lionhealth, MSD, Nestlé, Novartis, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sanofi, Sandoz, Takeda, Teva Pharmaceuticals, Tillots Pharma
FB: AbbVie, Amgen, Eurogenerics, J&J, Arena Pharmaceuticals, Celltrion, Ferring, Galapagos, Janssen, Merck Sharp & Dohme, Pfizer Inc, Takeda, Celgene, Fresenius Kabi, Sandoz
DTR: Abbvie, Abivax SA, Altrubio, Athos Therapeutics, Inc, Bristol-Myers Squibb, Celltrion, Connect BioPharma, Eli Lilly & Co., Genentech (Roche) Inc., Iterative Health, Janssen Pharmaceuticals, Johnson & Johnson, Merck & Co., Odyssey Therapeutics, Pfizer, Sanofi, Spyre, Takeda Pharmaceuticals, Vedanta Biosciences, and Ventyx.

Introduction

The cause of Crohn’s Disease (CD) remains unclear; however evidence suggests that dietary factors play a key role. With a rising incidence and no definitive cure, identifying modifiable risk factors is critical in preventing CD development. We aimed to study the association between fermentable dietary fibre intake and the future development of CD in an at-risk population.

Aims & Methods

Participants were recruited as part of the Crohn’s and Colitis Canada GEM study, a prospective cohort study of healthy first-degree relatives of patients with CD. At enrolment, a validated food frequency questionnaire was administered. Pectin, β-glucan, inulin, fructooligosaccharides (FOS), and arabinoxylan intake were quantified, and values energy-adjusted. Survival analysis was used to test the association between intake of fibre subtypes and risk of CD development. Generalized estimating equation tested the association between fibre intake and baseline impaired intestinal permeability (fractional urinary excretion of lactulose to mannitol ratio (LMR) >0.025); subclinical gut inflammation (faecal calprotectin (FCP) >250 μg/g); and faecal microbiome composition via 16s rRNA sequencing.

Results

76 of the 2,659 participants developed CD with a median follow-up of 8.9 years (IQR=5.7-12.3). Median age at recruitment was 17 years (IQR=12-25). 47% were male. Higher intake of inulin (HR = 0.78; 95% CI=0.61–0.99; p=0.04) and β-glucan (HR = 0.78; 95% CI=0.61–0.99; p=0.04) were associated with a reduced risk of CD development. No fibre subtype was associated with a higher risk of CD development. Lower intake of pectin, inulin, FOS and β-glucan was associated with impaired intestinal permeability (0.005<p<0.04). Lower inulin intake was associated with high FCP levels (p = 0.046). Higher pectin intake was associated with increased alpha diversity of faecal microbiome (p = 0.028). Higher inulin, FOS and pectin intake was associated with a shift in microbial taxa previously shown to be protective against CD onset in the GEM cohort; a reduction in Ruminococcus torques and an increase in NK4A214 group (phylum Firmicutes) presence (3.25×10⁻¹⁰<q<0.04).

Conclusion

This study demonstrates that dietary intake of fermentable fibre subtypes is associated with a reduced risk of CD development as well as with pleiotropic changes in CD risk biomarkers including microbiome, intestinal permeability, and subclinical inflammation. This suggests that the potential benefit of fermentable fibres on CD risk may involve changes in barrier function, and microbiome composition and function. Targeted interventions based on these findings could prove effective in preventing the onset of CD.