Introduction

Hepatobiliary disorders are recognised extraintestinal manifestations in inflammatory bowel disease (IBD). Up to 30% of patients exhibit abnormal liver function tests and 5% will develop chronic liver disease (1). IBD-associated liver diseases (IBDALD), comprising primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH) and AIH/PSC overlap syndrome carry significant morbidity through progressive hepatobiliary damage and increased cancer risk. Early recognition is challenging due to non-specific biochemical derangement and heterogeneous presentation. No validated stratification tools exist for prospective risk identification. This study investigated whether routinely collected biomarkers convey predictive value for IBDALD, leveraging large-language model (LLM) refined phenotyping.

Aims & Methods

We analysed 1,571 paediatric and adult-onset IBD patients recruited to the “Genetics of IBD” study (Southampton, UK; 2010–). IBDALD cases were identified through LLM-assisted (Llama 3.1-70B-Instruct) structuring of 32,041 free-text imaging and histopathology reports, followed by clinician verification (2). Participants diagnosed with IBDALD prior to IBD were excluded from further analysis. Examined biomarkers included ALT, ALT and ESR (n=335,605 datapoints for the examined cohort). For each biomarker, patient-level medians were calculated from all available results within ±6 months of IBD diagnosis. A 1:4 individual matched case-control design was applied (matched on age at IBD diagnosis, gender, and IBD subtype) in R. Conditional logistic regression models assessed associations between IBDALD and biomarker values, treated as both continuous (patient-level medians) and binary – normal versus abnormal - (age- and sex-adjusted lab range flags) variables. Longitudinal biomarker trajectories were explored using LOESS and linear mixed-effects models.

Results

Thirty-five cases of IBDALD were identified (27 post-IBD diagnosis). Median follow-up duration was 11.5 (0.5–59.5) years and median 4.5 years (0.4–39.1) from IBD diagnosis to liver disease onset. In whole cohort analyses, ALT, ALP, and ESR were significantly elevated in IBDALD at diagnosis of IBD (p < 0.01). In matched case-control models, higher median ALT (OR = 1.04 per U/L increase, 95% CI: 1.01–1.07, p = 0.012), ALP (OR = 1.01, 95% CI: 1.00–1.02, p = 0.014), and ESR (OR = 1.05, 95% CI: 1.00–1.09, p = 0.034) were each associated with IBDALD. In a combined model including all three biomarkers, none retained statistical significance. When analysed as binary (normal/abnormal) variables, ALT and ALP remained significantly associated with IBDALD (ALT: OR = 5.10, 95% CI: 1.57–16.59, p<0.01; ALP: OR = 15.33, 95% CI: 1.87–125.77, p<0.05). ESR did not reach significance (OR = 3.71, 95% CI: 0.75-18.32 p=0.107). Longitudinal modelling supported distinct ALT and ALP trajectories in the IBDALD group and distinct trends over time were visualised for ALT, ALP and ESR in LOESS scatterplots.

Conclusion

These data suggest that routinely measured biomarkers may carry early predictive signals for IBD-associated liver disease, identifiable at the time of IBD diagnosis. The use of LLM-assisted phenotyping enabled high-fidelity case definition within real-world data. These findings should be interpreted cautiously given the rarity of IBDALD and potential overfitting in multivariable models. Future prospective studies are warranted to validate predictive models and support integration into IBD care pathways.

References

1. Scott JA, Mysko C, Purssell H, et al. Investigation of abnormal liver blood tests in patients with inflammatory bowel disease. Frontline Gastroenterology 2024;15:516-522.
2. Kadhim A, Green Z, Nazari I, et al. Application of Generative Artificial Intelligence to Utilise Unstructured Clinical Data for Acceleration of Inflammatory Bowel Disease Research. Article in PrePrint medRxiv 2025.03.07.25323569; doi: https://doi.org/10.1101/2025.03.07.25323569

Disclosure

JJA is a SAB member for Orchard Therapeutics.

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

IIn Crohn’s disease, chronic inflammation drives fibroblast activation, excessive collagen deposition, and creeping fat expansion, all contributing to fibrostenotic strictures. We examined serum markers related to collagen formation, macrophage and neutrophil activation, and NETosis, exploring their associations with stricturing Crohn’s disease in a treatment-naïve IBD inception cohort.

Aims & Methods

142 Serum samples from CD patients were analysed (IBSEN III population matched baseline and 1-year follow-up). The Montreal classification (luminal, fibrostenotic strictures, fistula) was applied to assess disease complications at the time of serum sampling, e.g. baseline biomarkers measurements were paired with baseline Montreal B assessment, and one-year followup biomarkers measurements were paired with one-year followup Montreal B assessment. The biomarkers C4M, C6M, C7M, PRO-C3, PRO-C4, PRO-C5, PRO-C6, PRO-C11, PRO-C16, PRO-C22, VICM, CTX-III, CPa9-HNE were measured in the serum samples at baseline (total n=142; luminal n=114; fibrostenotic n=23, fistula n=5) and 1-year follow-up (total n=142; luminal n=111; fibrostenotic n=24, fistula n=7). One-way-ANOVA with LSD correction was applied for statistical analysis.

Results

The PRO-C6 (p<0.001) and CPa9-HNE (p<0.05) biomarkers were significantly elevated in CD patients with fibrostenotic strictures compared to luminal CD patients at baseline, and PRO-C6 was continually elevated in serum after 1 year of follow-up in patients with fibrostenotic strictures (p<0.01). At baseline, C7M was demonstrated to be elevated in fistulizing CD patients compared to luminal and fibrostenotic CD patients (P<0.01). PRO-C5 (p<0.001) and PRO-C16 (p<0.01) were significantly elevated at 1-year follow-up in the CD patients with fibrostenotic strictures compared with luminal CD patients. None of the remaining biomarkers were associated with stenotic or fistulizing CD.

Conclusion

These encouraging biomarker data from the IBSEN III, especially PRO-C6, seem to be a promising biomarker for intestinal fibrosis, as PRO-C6 was demonstrated to be elevated at baseline and after 1 year follow-up. CPa9-HNE levels were highest in the fibrostenotic group, suggesting neutrophil activity and NETosis involvement in intestinal fibrogenesis. Elevated levels of C7M were associated with fistula in CD patients, suggesting that C7M is reflective of transmural inflammation. The biomarkers PRO-C5 and PRO-C16 are also relevant biomarkers of established intestinal fibrosis, as these were elevated after 1 year of follow-up. Collectively, these biomarker data highlight the importance of quantifying collagen protein fragments in serum as tools for assessing intestinal fibrosis in Crohn’s disease.

Disclosure

Full time employee at Nordic Bioscience A/S

Introduction

Chemotherapy-induced diarrhea (CID), a dose-limiting toxicity impairing treatment adherence and anticancer efficacy, lacks targeted prophylaxis. While short-acting glucagon-like peptide-2 (GLP-2) analog was approved for short bowel syndrome (SBS), the mucosal regenerative properties of GLP-2 suggest therapeutic potential for CID prevention. GLP-2 can also enhance the intestinal mucosal barrier and may provide a new treatment option for inflammatory bowel disease (IBD). In this study, we developed FT1, a long-acting GLP-2 analog engineered for sustained exposure, and reported first-in-human phase I trial data of FT1 in Chinese healthy adults.

Aims & Methods

This randomized, double-blind, placebo-controlled, single-center phase I study (NCT06610487) evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of FT1 to establish dosing rationale for the future CID trials. Single ascending dose (SAD: 0.05-0.4 mg/kg) and multiple ascending dose (MAD: 0.1-0.2 mg/kg, once weekly for 3 weeks) were administered subcutaneously. Participants were randomized 3:1 (SAD; except for 0.05 mg/kg: 2:1) or 4:1 (MAD) to receive FT1 or placebo. Plasma citrulline, a validated biomarker of enterocyte mass, served as the primary PD endpoint. Safety, PK, PD, and immunogenicity were assessed up to 28 days post-dose.

Results

Currently available analyzed data (n=50) revealed:
1. PK: FT1 exhibited dose-proportional exposure (C_max/ AUC_0-inf) across SAD doses (0.05-0.4 mg/kg). Median T_max was 24 h with prolonged t_1/2 = 67.6-69.1 h. MAD regimens showed moderate accumulation (1.42- 1.73-fold post-3rd dose).
2. PD: Citrulline elevation was dose- and regimen-dependent. SAD 0.4 mg/kg achieved maximal change in plasma citrulline (ΔE_max) = 3,340 ng/mL (baseline: 5,125 ng/mL) at 8.5 days post-dose. After weekly administration of FT1, the citrulline level was further enhanced. MAD 0.2 mg/kg induced 33% greater ΔE_max vs MAD 0.1 mg/kg (4,512 vs 3,390 ng/mL; both post-3rd dose), exceeding SAD 0.4 mg/kg response.
3. Safety: All adverse events were Grade 1-2 (CTCAE v5.0) with no dose-limiting toxicities or immunogenicity signals.

Conclusion

FT1 demonstrated favorable safety and linear PK up to 0.4 mg/kg (SAD) and 0.2 mg/kg weekly×3 (MAD) in healthy participants. The 0.2 mg/kg MAD regimen achieved superior enterotrophic effects (citrulline ΔE_max) versus lower doses while maintaining tolerability, supporting it as a priority candidate for further clinical evaluation in patients with once-weekly dosing.

References

1. McQuade RM, et al. Chemotherapy-induced constipation and diarrhea: pathophysiology, current and emerging treatments. Front. Pharmacol. 2016, 7:414.
2. Barzał J, et al. Plasma citrulline level as a biomarker for cancer therapy-induced small bowel mucosal damage. Acta Biochim Pol. 2014; 61(4):615-31

Disclosure

Chengyong Tang, Mingxue Zhu, and Lei Wan have no conflicts of interest that are directly relevant to the content of this article. Kai Fan, Qing Chen, and Yanmin Bai are Chongqing Peg-Bio Biopharm Co., Ltd employees.

Introduction

Epithelial injury is a hallmark of chronic mucosal damage in Crohn’s disease (CD), which can lead to fibrostenotic strictures. Type VII collagen, a critical component of the epithelial basement membrane, forms U-shaped anchoring fibrils that link the basement membrane to the interstitial matrix by binding fibrillar collagen. Genetic mutations in the COL7A1 gene, which encodes type VII collagen, are known to impair fibril formation and reduce tissue tensile strength, resulting in epithelial dysfunction, as seen in disorders such as dystrophic epidermolysis bullosa. This highlights the essential structural role of type VII collagen in maintaining matrix stability. In CD, the importance of this protein is underscored by the presence of autoantibodies targeting type VII collagen in up to 50% of patients with CD. Loss of tissue integrity, because of loss of the interaction between the basement and interstitial matrix, leads to tissue dysfunction and fibrosis.

Aims & Methods

We investigated C7M, a biomarker of type VII collagen degradation, to assess its specificity for intestinal mucosal damage. We analyzed serum samples from CD patients enrolled in a prospective cohort study. The cohort included 62 CD patients undergoing surgical resection for fibrostenotic strictures and 49 patients with luminal disease receiving treatment adjustments without surgery. Serum was collected at baseline, post-operative day 1 (POD1), and one-month post-resection. C7M levels were quantified using a competitive ELISA.

Results

At baseline, C7M levels were significantly elevated in fibrostenotic CD patients (median: 9.79ng/mL) compared to those with luminal CD patients (median: 6.03ng/mL) (p<0.01, AUC: 0.69). In the resected group, C7M levels rose sharply on POD1 (p<0.0001, AUC: 0.81), suggesting acute release in response to surgical injury. By one-month post-surgery, C7M levels had returned to baseline, closely resembling those observed in luminal CD patients (p<0.0001, AUC: 0.80). C7M also demonstrated mild-moderate correlations to biochemical markers of inflammation, including CRP (rho=0.62, p<0.0001), hemoglobin (rho=-0.28, p=0.0024), thrombocytes (rho=0.24, p=0.0105), albumin (rho=-0.52, p<0.0001), and fecal calprotectin (rho=0.25, p=0.019).

Conclusion

C7M was elevated in fibrostenotic CD patients relative to luminal CD, indicating its potential as a biomarker of more severe or complex mucosal pathology. The pronounced but transient increase following surgery, with normalization within one month, further supports C7M as a dynamic marker of intestinal epithelial damage. These findings suggest C7M may serve as a novel, disease-specific biomarker for assessing mucosal integrity and inflammatory burden in CD.

Disclosure

Full time employee at Nordic Bioscience