Introduction

Intestinal barrier integrity is emerging as a key therapeutic target in inflammatory bowel disease (IBD). Advanced endoscopic imaging techniques, including ultra-high magnification endocytoscopy (ECS) and probe-based confocal laser endomicroscopy (pCLE), enable real-time, in vivo structural and functional intestinal barrier assessment. Raman Spectroscopy (RS) can add a molecular dimension through vibrational fingerprinting of barrier-associated metabolites in biological samples.¹

Aims & Methods

This study explores the potential of RS integration with advanced endoscopy to characterise the intestinal barriers in IBD, targeting on tryptophan-derived metabolites and carbohydrates. A total of 46 IBD patients [25 Crohn’s disease (CD) and 21 ulcerative colitis (UC)] and 7 healthy controls (HC) undergoing endoscopic assessment or surveillance were prospectively enrolled from two academic centres. ECS or pCLE were used to evaluate epithelial and vascular barrier integrity. Barrier healing was defined as ECS score ≤ 1 or pCLE score ≤ 4, with preserved villi/crypt architecture, normal vasculature, and also absence of fluorescein leakage for pCLE. Advanced endoscopy-guided biopsies were collected from representative bowel segments. Mucosal healing (MH) was assessed by experienced pathologists using Nancy’s Histological Index ≤1. Epithelial (Claudin-2 and ZO-1) and vascular (PV-1 and CD-31) barrier markers were analysed through confocal microscopy, and their expression was automatically quantified using QuPath. Micro-RS was applied to tissue samples and matched sera to measure key tryptophan metabolites (kynurenine, indolepropionic acid, and melatonin) and carbohydrates.^2,3 Six-month major adverse outcomes (MAOs) were recorded. Group differences in Raman spectra were analysed with the Mann-Whitney test; correlations were assessed via Pearson’s test.

Results

Among patients undergoing ECS, barrier healing was observed in 10/22 (45%) colonic and 6/9 (67%) ileal cases. pCLE-based assessment revealed healing features in 5/16 (31%) colonic and 2/15 (13%) ileal evaluations. Raman spectral analysis showed a significant (p<0.05) reduction in tryptophan metabolites and carbohydrate-associated peaks in IBD tissues and sera compared to HC, especially in inflamed patients. When stratified by advanced endoscopy-identified barrier integrity, tryptophan metabolites -known barrier modulators-, and carbohydrates -likely reflecting mucin barrier layer- were markedly reduced (p<0.05) in patients with impaired barrier function. Notably, tryptophan derivatives positively correlated with Claudin-2 and ZO-1 in UC (r>0.4), and with PV-1 in CD (r>0.5). Similarly, carbohydrates correlated positively with Claudin-2 in UC (r=0.4) and negatively with CD-31 in CD (r=-0.4). Lower levels of indolepropionic acid and carbohydrates correlated with worse short-term MAOs (r<-0.4).

Conclusion

The integration of RS with advanced endoscopic images offers a novel, multi-layered approach to assess intestinal barrier integrity in IBD. RS can identify novel non-invasive biomarkers of mucosal and barrier healing, with potential real time applications for monitoring disease activity and predicting therapeutic outcome. Tryptophan metabolites may serve as a predictive biomarker of barrier healing paving the way toward personalised, barrier-targeted therapies.

References

1 Smith SCL, Banbury C, Zardo D, et al. PLoS One 2021; 16: e0252210.
2 Michaudel C, Danne C, Agus A, et al. Gut 2023; 72: 1296–307.
3 Arras W, Breugelmans T, Oosterlinck B, et al. J Crohns Colitis 2025; 19.

Introduction

Janus kinase inhibitors (JAKi) exhibit distinct performance characteristics versus monoclonal antibody (mABs) biological agents in the management of ulcerative colitis (UC). There is a lack of direct comparative effectiveness data of JAKi small molecules versus mABs in the real world.

Aims & Methods

In the absence of direct head-to-head comparisons, we determined the persistence of tofacitinib (TOF) versus vedolizumab and tumour necrosis factor inhibitor (TNFi) mABs in advanced therapy (AT)-naïve and AT-exposed real-world UC subjects from a population-based prospective registry.

The Persistence Australian National IBD Cohort (PANIC5) registry collected AT prescribing data for the entire Australian population up until Dec 2021. In Australia, all advanced therapies for IBD are prescribed without a hierarchical order in subjects with moderate-severe UC refractory to conventional therapies, irrespective of occupation and insurance status. Treatment is provided indefinitely in those that enter into clinical remission. Non-persistence was defined as failure to continue AT prescriptions for >6-months. Propensity score matching (PSM) statistically controlled for baseline selection biases. Kaplan-Meier survival curves were generated for AT persistence and compared using the log-rank test. Cox proportional hazards regression models were employed to calculate hazard ratios (HR) and 95% confidence intervals (CI). P<0.05 was deemed statistically significant (SPSS, USA).

Results

A total of 9,671 consecutive UC patients were recruited (53% male, 23,348 patient-years of follow up). The cohort comprised 14,772 treatment lines: 6,044 infliximab (IFX), 1,981 adalimumab (ADA), 5,467 vedolizumab (VED), 750 golimumab (GOL) and 530 tofacitinib (TOF). TOF exhibited superior persistence versus IFX (HR: 1.88, 95%CI: 1.34-2.63, P<0.001), ADA (HR: 2.10, 95%CI: 1.49-2.94, P<0.001) and GOL (HR: 2.20, 95%CI: 1.55-3.11, P<0.001) but not versus VED (HR: 1.28, 95%CI: 0.92-1.80, P=0.14). Following PSM, TOF was not significantly higher in persistence compared to mABs among AT-naïve subjects (all P>0.05). However, TOF showed superior persistence compared to all mABs among AT-exposed (all P<0.001). The persistence of TOF (P=0.77) did not significantly decline moving from AT-naive- to AT-exposed treatment status, unlike for TNFi (-8 months) and VED (-19 months, both P<0.001). PSM-multivariate Cox regression showed predictors of higher persistence to be use of TOF, AT-naïve status, use of immunomodulator. Rankings of persistence of ATs are presented for AT-naïve- and AT-exposed UC subjects (Table).

Conclusion

This is the first real-world study comparing treatment effectiveness using a national universal insurance persistence dataset. It found that tofacitinib had significantly greater persistence than biological agents in patients with ulcerative colitis who had previously received advanced therapy. Unlike monoclonal antibodies, tofacitinib did not show a decline in persistence after exposure to advanced therapy. Given these findings, JAK inhibitors like tofacitinib should be strongly considered for patients switching advanced therapies in ulcerative colitis.

Disclosure

RL advisory board: AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences, Takeda; research grants: Joanna Tiddy USYD, McCusker Charitable Foundation, Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer, MRFF

Introduction

Artificial intelligence tools for endoscopic assessment of Ulcerative Colitis remain limited due to suboptimal agreement with expert readers and reliance on small, inconsistently labeled datasets. We developed a novel computer vision model (DovaVision) trained on a large-scale, expert-annotated video dataset to assess UC activity using detailed frame-level features.

Aims & Methods

DovaVision was pre-trained using DINOv2 self-supervised learning on 845 colonoscopies and millions of GI images, then significantly refined using annotations collected via a proprietary platform. 15 IBD central readers (CRs) scored video frames for five UC features (vascular pattern, bleeding, ulcers/erosions, friability, erythema) across multiple severity levels. Annotators underwent standardized onboarding to ensure high inter-rater reliability. The model comprises two vision transformer architectures: a Quality Control (QC) module to exclude low-quality/non-diagnostic frames, and a Scoring module that outputs feature-specific severity grades. Model outputs include burned-in heatmaps (for mapping of disease activity to specific timepoints) and structured JavaScript Object Notation (JSON) files.

Results

A total of 83.8 million frames from 200 colonoscopy videos were labeled by 3 expert CRs across 7 categories per video, yielding 16.9 million merged labels by majority vote. Inter-rater agreement on modified Mayo Endoscopic Score (MES) showed strong reliability (ICC = 0.86; QWK = 0.88). On a 31-video validation set from 3 separate data sources, DovaVision showed equivalency with the gold standard of CR consensus (2+1 majority vote), achieving a QWK of 0.904 and ICC of 0.907. In comparison, the pool of 3x CRs assigned/video on this same set showed ICC of 0.905. On friability assessment—a challenging feature-- DovaVision showed 90% agreement and 0.811 ICC when compared to gold standard (3x CR majority vote), while the agreement for 3 CRs per video was only 0.447 ICC on the same set. The average model inference time was short at 3.5 minutes per video. The model also outputs continuous “frame-by-frame” level information on the sub-score characteristics. The model is an entire data processing pipeline deployed on a cloud architecture with an API for secure authentication, bulk data upload, and secure results storage/retrieval.

Conclusion

DovaVision is a validated AI-based model for automated grading of UC severity on endoscopy. Its high concordance with expert readers, detailed feature-level (sub-score characteristics) analysis, and rapid inference support real-world integration into clinical and research workflows. Although further validation with additional datasets is required.

Disclosure

Dr. Michael Byrne is the Chairman, Founder and CMO at Dova Health Intelligence

Introduction

Tyrosine kinase 2 (TYK2) inhibitors block signaling downstream of multiple pro-inflammatory cytokines involved in immune-mediated inflammatory diseases, including inflammatory bowel disease, and may have an improved safety profile relative to Janus kinase inhibitors. Phase 2 studies of the highly selective and potent TYK2 inhibitor zasocitinib in Crohn’s disease (CD; NCT06233461) and ulcerative colitis (UC; NCT06254950) are ongoing.^1,2 Here, we describe the design of a combined open-label extension trial (NCT06764615), which will include patients from both parent trials who are responsive to treatment.

Aims & Methods

Patients are eligible for the phase 2 parent studies in CD and UC if they are aged 18–75 years with moderately to severely active disease, and have inadequate or loss of response to, or intolerance of, ≥ 1 standard or advanced therapy. Patients who have failed treatment with ≥ 3 classes of advanced therapy are excluded. Patients are randomized to one of three (CD) or two (UC) doses of zasocitinib, or placebo, for a 12-week double-blind induction phase followed by a 40-week sponsor-open (CD) or open-label (UC) maintenance period. At the end of the parent trials, patients will be eligible for the combined open-label extension if they are clinical (CD) or symptomatic (UC) responders at Week 52, defined as: (1) CD: a ≥ 30% decrease in average daily very soft or liquid stools and/or a ≥ 30% decrease in average daily abdominal pain from baseline; and (2) UC: a ≥ 1-point and ≥ 30% decrease from baseline in partial modified Mayo score, and a ≥ 1-point decrease from baseline in rectal bleeding (RB) subscore or achievement of an absolute RB subscore of ≤ 1. All enrolled patients will receive the same dose of open-label, oral, once-daily zasocitinib for a maximum of 108 weeks, with study visits every 12 weeks, followed by a 4-week safety follow-up period. Data analysis will be descriptive, with no formal statistical comparisons performed.

Results

The primary objective of the study is to determine long-term safety and tolerability, assessed through the incidence of treatment-emergent adverse events or adverse events of special interest. Secondary endpoints will assess the long-term efficacy of zasocitinib, including clinical, symptomatic, or endoscopic response or remission by visit or at Weeks 48 and 108, according to indication, and effects on patient-reported outcomes, including fatigue, bowel urgency, abdominal pain, and disease-specific health-related quality of life.

Conclusion

This open-label extension trial will provide data on the long-term safety of zasocitinib, as well as durability of treatment response among patients with CD or UC who experience treatment benefit in the phase 2 parent studies.

References

1. Jairath V et al. UEG Journal 2024;12(S8):1033.
2. Peyrin-Biroulet L et al. UEG Journal 2024;12(S8):1041.

Disclosure

GP reports receiving personal payments, honoraria, or speaker fees from AbbVie, Allergan, BMS, Celltrion, Ferring, Galapagos, Janssen, Pfizer, Sorriso, Takeda, and Tillotts, travel grants or fellowships from AbbVie, Celltrion, Ferring, Janssen, Takeda, and Tillotts, and is a Director and shareholder in Ampersand Health. SGR, LZ, VAN, LA, FN, TF, LS, and NS are employees and shareholders of Takeda.

Introduction

The intestinal mucosa undergoes constant renewal, with epithelial and immune cells routinely shed into the gut lumen. Recent findings suggest that these shed cells remain viable and retain transcriptomic signatures relevant to bowel pathology. Analysis of luminal content obtained during colonoscopy indicates that Fecal Host Transcriptomes (FHT) mirror histologic inflammation in IBD. This study aimed to evaluate whether sequencing of stool samples can noninvasively reflect the presence of intestinal inflammation in patients with IBD, predict the location of inflammation within the bowel and distinguish between IBD type; Crohn’s Disease and Ulcerative Colitis.

Aims & Methods

Our aim was to investigate whether transcriptomic analysis of stool samples that are taken ambulatory or at home could reveal the inflammation signature of inflamed IBD patients.
Bulk RNA sequencing of stool samples from 71 IBD patients and healthy controls was used to generate FHTs. Each sample was paired with an endoscopic assessment and clinical data to capture a time-matched view of intestinal inflammation. Three random forest classifiers were trained to: (1) distinguish active inflammation from remission; (2) predict inflammation location in Crohn’s disease (colon vs. small intestine). and (3) classifier based on gene modules expression was used to differ between CD and UC in patients with active inflammation.

Results

Fecal RNA quality was high, with a median of 2,140 human genes detected per sample. The FHT test demonstrated robust performance across all tested applications. The first model, designed to distinguish active inflammation from remission (n = 71), achieved a sensitivity of 85% and a specificity of 92%. The second model, which predicted the location of inflammation in Crohn’s disease patients (n = 21), achieved 100% sensitivity and 100% specificity. The third model, aimed at differentiating Crohn’s Disease from Ulcerative Colitis (n = 35), reached a sensitivity of 83% and a specificity of 100%. These findings underscore the potential of FHTs as a non-invasive tool for comprehensive inflammation profiling in IBD.

Conclusion

Fecal shed cell transcriptomics offers a novel, non-invasive approach for assessing mucosal inflammation at the endoscopic level in IBD patients. This approach enables differentiation between disease activity states, anatomical localization of inflammation, and IBD subtype classification. Ongoing studies aim to evaluate its utility in grading inflammation severity and predicting therapeutic response.

References

Dan et al., CMGH 2023
Ungar et al., GUT 2022