Introduction

Ulcerative colitis (UC) is a chronic inflammatory bowel disease where accurate assessment of disease activity is essential for effective patient management. Endoscopy is the gold standard for evaluating mucosal inflammation, but non-invasive alternatives, such as transabdominal ultrasound (TAUS), are garnering interest.

Aims & Methods

This study aimed to evaluate the sensitivity of rectal wall thickness measurements using TAUS in assessing disease activity in ulcerative colitis, and to identify an ideal cut-off threshold by comparing results with endoscopic and histological findings.
In a prospective, observational study, we enrolled consecutive patients with UC who were referred to our tertiary center from May 2024 to April 2025. Eligibility required a scheduled TAUS within 30 days of a staging colonoscopy, without intervening therapy adjustments. Exclusion criteria included technically inadequate TAUS readings (e.g., due to anatomical variations or excessive gas interposition) and minor-aged patients. Each patient underwent TAUS performed by a single, experienced operator. A second experienced operator blind assessments were recorded to evaluate inter-observer variability. Rectal wall thickness was measured and compared with clinical, laboratory (CRP, fecal calprotectin), and endoscopic (MAYO score) indicators of disease activity. Histological status (active/inactive) and additional clinical data, including disease duration, extent, and therapy, were recorded.

Results

A total of 74 patients were analyzed, of whom 51.4% were female, with a median age of 55 years (IQR: 42–68). The majority presented with left-sided colitis (Montreal E2, 62.2%), followed by extensive colitis (E3, 25.7%) and proctitis (E1, 12.1%). The median disease duration was 12 years (IQR 5–23). Patients with an endoscopic MAYO score of 0 or 1 had a median rectal wall thickness of 4.95 mm (IQR 4.5–5.88), while those with a score of 2 or 3 had a median of 6.15 mm (IQR 5.3–6.7; p=0.003). Receiver Operating Characteristic (ROC) analysis for TAUS rectal wall thickness showed good discriminatory ability for endoscopic activity (cut-off: 5.55 mm, AUC 0.725, 95CI 0.597-0.853, Se 0.80, Sp 0.71), comparable to fecal calprotectin (cut-off: 277 µg/g, AUC 0.717, 95CI 0.589-0.845, Se 0.70, Sp 0.66; p=0.256) and superior to CRP (cut-off: 1 mg/L, AUC 0.511, 95CI 0.357-0.664, Se 0.50, Sp 0.50; p<0.0001). For histological activity, TAUS again performed well (cut-off: 5.55 mm, AUC 0.794, 95CI 0.682-0.906, Se 0.76, Sp 0.80), closely matching fecal calprotectin (cut-off 302, AUC 0.744, 95CI 0.627-0.861, Se 0.69, Sp 0.73; p=0.425) and outperforming CRP (cut-off 1.5, AUC: 0.631, 95CI 0.497-0.765, Se 0.62, Sp 0.63; p<0.0001). Inter-observer agreement for TAUS rectal wall thickness was excellent, with an intraclass correlation coefficient of 0.923 (p<0.0001), underscoring the reproducibility of this non-invasive method.

Conclusion

TAUS measurement of rectal wall thickness demonstrates promising sensitivity and reproducibility in detecting mucosal and histological activity in UC, aligning closely with established markers such as fecal calprotectin. A cut-off value of 5.55 mm showed good discriminatory performance in this cohort, suggesting potential utility as a non-invasive marker of disease activity..Given its non-invasive nature, low cost, and strong inter-observer agreement, TAUS is a valuable adjunct for routine UC monitoring. Combined with clinical and biochemical data, it may reduce the need for repeated endoscopy, minimizing patient burden, healthcare costs, and environmental impact.

Introduction

Metabolic dysfunction-associated steatohepatitis (MASH) is often associated with metabolic disorders such as obesity, metabolic syndrome, and/or diabetes. FGF21 analogs are promising therapies for MASH due to their direct anti-fibrotic effects as well as additional hepatic and extrahepatic benefits. Pegozafermin (PGZ), an FGF21 analog, was evaluated for safety and efficacy in a Phase 2b trial (ENLIVEN) with either weekly (QW) or every two-week (Q2W) dosing versus matching placebo in MASH patients with biopsy-proven F2/F3 fibrosis. Primary histology endpoints and non-invasive tests (NITs) were assessed at week 24, followed by additional NIT evaluation at the end of a 24-week blinded extension for a total of 48 weeks.

Aims & Methods

Patients were randomized to PGZ 15mg QW, 30mg QW, or 44mg Q2W or placebo for 24 weeks (histology-based primary endpoints). During the 24-week extension, most patients continued their assigned treatment with the exception of a subset of placebo patients who were re-randomized to receive PGZ 30mg QW. The full analysis set includes F2/F3 patients with NAFLD activity score (NAS) ≥4 at baseline (n=192).

Results

At 24-weeks, PGZ 30mg QW or 44mg Q2W led to statistically significant and clinical meaningful improvement in both primary histological endpoints (one stage of fibrosis improvement without worsening of MASH and MASH resolution without worsening of fibrosis) compared to placebo. Non-invasive testing at weeks 24 and 48 demonstrated that PGZ treatment was associated with robust and sustained reductions in liver fat content (MRI-PDFF), biomarkers of fibrosis (VCTE, ELF, PRO-C3) and liver injury (ALT, AST). PGZ also improved metabolic parameters such as lipids and HbA1c at both 24 and 48 weeks. PGZ was generally safe and well tolerated with the most common treatment emergent adverse events (TEAEs) being mild/moderate nausea and diarrhea. No deaths occurred; six early terminations for TEAEs including one drug-related serious AE occurred.

Conclusion

At 24 weeks, treatment with PGZ in MASH patients with F2/F3 fibrosis led to significant fibrosis regression and MASH resolution, which was corroborated by improvement across a variety of non-invasive tests including liver fat, inflammation, fibrosis, and metabolic markers. Benefits on NITs were sustained over the full 48-weeks of the study, with favorable safety and tolerability. PGZ is the first therapy to achieve fibrosis regression and MASH resolution with a Q2W dosing regimen. Phase 3 studies in noncirrhotic (ENLIGHTEN-Fibrosis) and cirrhotic (ENLIGHTEN-cirrhosis) patients are currently underway to confirm these results.

Disclosure

Jörn Schattenberg: Consultant: Akero, Alentis Therapeutics, Astra Zeneca, 89Bio, Boehringer Ingelheim, GSK, Ipsen, Inventiva Pharma, Madrigal, MSD, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Siemens Healthineers; Speaker: Gilead Sciences, Advanz, Echosens, MedPublico GmbH; Grants: Boehringer Ingelheim, Siemens Healthcare GmbH; Stock Options: AGED diagnostics, Hepta Bio
Arun J Sanyal: Consulting: Genefit, Gilead, Malinckrodt, Pfizer, Salix, Boehringer Ingelheim, Novartis, Bristol Meyers Squibb, Merck, Hemoshear, Lilly, Novo Nordisk, Terns, Albireo, Jannsen, Poxel, 89bio, Siemens, AstraZeneca, NGM Bio, Amgen, Regeneron, Genentech, Alnylam, Roche, Madrigal, Inventiva, Covance, Prosciento, HistoIndex, PathAI; Grants: Gilead, Malinckrodt, Boehringer Ingelheim, Novartis, Bristol Meyers Squibb, Merck, Lilly, Novo Nordisk, Fractyl, Madrigal, Inventiva; Stock holder: Exhalenz, GenFit, Hemoshear, Durect, Indalo, NorthSea, Tiziana, Rivus
Naim Alkhouri: Research funding: 89Bio, AbbVie/Allergan, Akero, Better Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Corcept, DSM, Galectin, Genentech, Genfit, Gilead, Hepagene, Healio, Intercept, Inventiva, Ionis, Madrigal, Merck, NGM, Noom, NorthSea, Novo Nordisk, Perspectum, Pfizer, Poxel, Viking, and Zydus; Speaker bureau: AbbVie/Allergan, Alexion, Echosens, Eisai, Exelixis, Gilead, Intercept, Perspectum, Salix, and Theratechnologies; Consultant: 89Bio, AbbVie/Allergan, Echosens, Fibronostics, Gilead, Intercept, Madrigal, Novo Nordisk, Perspectum, Pfizer, and Zydus.
Rohit Loomba: Consultant: Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Boston Pharmaceuticals, Bristol-Meyers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89bio, Terns Pharmaceuticals and Viking Therapeutics; Grants: Arrowhead Pharmacetuicals, AstraZeneca, Boegringer-Ingelheim, Bristol-Meyers Squibb, Eli Lilly, Galectin Therapeutics, Galmeed Pharmaceuticals, Gilead, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sonic Incytes and Terns Pharmaceuticals; Stockholder: Co-founder LipoNexus, Inc
Mildred D Gottwald, Shibao Feng, Germaine D Agollah, Cynthia L Hartsfield, Hank Mansbach, Maya Margalit: 89bio employee and stock holder

Introduction

Up to 40% of patients with acute severe ulcerative colitis (ASUC) do not respond to infliximab (IFX)(1) presumably due to insufficient drug exposure (1, 2). We investigated whether personalised IFX induction using predefined serum concentrations was superior to standard dosing.

Aims & Methods

In this prospective, multi-centre trial, adult IFX-naive steroid-refractory ASUC patients were randomised 1:1 to standard (SD) or personalised IFX dosing (PD). After an initial 5 mg/kg IFX infusion, SD was 5 mg/kg IFX at week 2 and 6. In PD, additional 5 mg/kg IFX infusions were administered guided by a Bayesian pharmacokinetic algorithm (iDose™) aiming at IFX serum concentrations >28 ug/mL day 0-28 and >15 ug/mL day 29-42 (3). The primary composite endpoint was clinical and endoscopic response at day 42 (Lichtiger score <10 and ≥3 points drop and UCEIS ≥2 points drop from baseline). Video-endoscopies were performed at baseline, day 42 and 182 and scored by 2 expert readers (XR) with adjudication by a third XR and post hoc also by the DovaVision UC AI tool (AI-R)(4). Key secondary endpoints were day 42 clinical response, day 42 endoscopic response, day 182 clinical remission (Lichtiger ≤3), day 182 endoscopic remission (UCEIS ≤1 on all components), and safety.

Results

48 patients were randomised (23 PD/25 SD) and 31 completed the 26-week study (19 PD/12 SD). Patient characteristics were comparable. Median cumulative IFX dose until day 42 was 18.41 mg/kg [1.77, 20.27] for PD vs 13.79 mg/kg [10.38, 14.82] for SD. The primary composite endpoint at day 42 was not met with XR (57% in PD vs 44% in SD; p=0.564). However, AI-R showed a significantly higher composite response rate in PD (74% in PD vs 32% in SD; p=0.0047). PD showed higher day 42 clinical response vs SD (91% vs 64%; p=0.039). Day 42 endoscopic response was observed in 57% in PD vs 44% in SD (p=0.564) with XR and 74% in PD vs 32% in SD with AI-R (p=0.0047). The proportion of patients in clinical and endoscopic remission at day 182 was higher in PD than in SD (65% vs 36%; p=0.082). Day 182 endoscopic remission with AI-R was higher in PD (52% in PD and 20% in SD; p=0.0337). SAEs occurred in 9% of patients on PD vs 20% of patients on SD. Following an interim analysis, the trial was discontinued based on futility.

Table 1. Baseline characteristics

Conclusion

Personalised IFX dosing was superior to standard dosing in ASUC when endoscopies were read by AI. This is the first IBD study where the primary endpoint, missed by expert assessment, was overturned and met by AI assessment instead. This demonstrates the potential of AI to fundamentally improve clinical trial methodology.

References

1. Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2010;59(1):49-54.
2. Papamichael K, Van Stappen T, Vande Casteele N, Gils A, Billiet T, Tops S, et al. Infliximab Concentration Thresholds During Induction Therapy Are Associated With Short-term Mucosal Healing in Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol. 2016;14(4):543-9.
3. Ungar B, Mazor Y, Weisshof R, Yanai H, Ron Y, Goren I, et al. Induction infliximab levels among patients with acute severe ulcerative colitis compared with patients with moderately severe ulcerative colitis. Aliment Pharmacol Ther. 2016;43(12):1293-9.
4. Byrne M, Requa J, Panaccione R, Panes J, Bressler B, East JE, et al. Development and Validation of a novel AI-based computer vision solution for Ulcerative Colitis severity scoring on video for real world using high-volume expert-annotated video frames. United European Gastroenterol J. 2025 Oct.

Disclosure

This project received grant support from Pfizer Inc. and research support from Baysient LLC, Buhlmann Laboratories and Dova Health Intelligence.