BACKGROUND AND AIMS:Interactions between fibroblasts and monocytes have emerged as a contributing factor in inflammatory bowel disease (IBD) pathogenesis and therapy resistance, owing to the ability of both cell types to participate in tissue inflammation and repair. We have previously shown that the tumor necrosis factor superfamily member TWEAK (TNFSF12) can induce an ulcerative colitis (UC)-like inflammatory profile in colonic fibroblasts in vitro, in turn promoting monocyte adhesion and activation. However, the mechanisms underlying fibroblast-monocyte communication and its dysregulation in ulcerative colitis are incompletely understood. METHODS:Here we use co-culture models, human biopsies from UC patients and healthy donors, and public single-cell transcriptomics to characterize the mechanisms underlying fibroblast-mediated monocyte activation. RESULTS:We show that TWEAK-treated inflammatory fibroblasts induce a transcriptional program that resembles early monocyte/macrophage intermediates in UC and is enriched for genes associated with resistance to anti-TNF (TREM1, OSM, IL1B) and susceptibility to IBD (NOD2, ATG16L1). We find that conditioned media from TWEAK-treated fibroblasts causes a sustained activation of STAT3 phosphorylation in monocytes, and that inhibition of the NF-κB inducing kinase (NIK) impairs the ability of inflammatory fibroblasts to activate STAT3 phosphorylation in monocytes, resulting in reduced expression of inflammatory mediators. Using tissues from UC patients, we show that the expansion of CD90+/PDPN+ inflammatory fibroblasts and increased FN14 in UC correlates with the accumulation of TWEAK+ myeloid cells in the colonic mucosa, and that these fibroblasts co-localize with infiltrating monocytes in sites of active inflammation. CONCLUSION:Together, our findings suggest that the TWEAK/NF-κB/STAT3 axis represents an attractive target to tune inflammatory stroma/monocyte crosstalk.

Screen-detected colorectal cancers (CRCs) represent an increasing proportion of diagnoses as population screening is expanded. They are associated with improved prognosis compared to non-screening cases even when adjusted for stage. We aimed to evaluate the histopathological features and impact on survival of faecal immunochemical test (FIT)–based screen-detected CRCs with comparison to a cohort of non-screening cases. We analysed a database of screen-detected CRCs (n = 191) in our institution since screening began in 2012 with comparison to a cohort of non-screening cases (2019–2020, n = 358). Histopathological reports were reviewed for prognostic factors such as lymphovascular invasion (LVI), perineural invasion (PNI) and tumour budding. The patient record was reviewed for survival analysis. Screen-detected CRCs were associated with an earlier stage of diagnosis (p = 0.002) and had lower rates of serosal involvement (T4) (20

This is the second of two articles presenting the European Crohn's and Colitis Organisation [ECCO] evidence‑based consensus guidelines on the management of adult patients with ulcerative colitis [UC]. The first article covers the medical management of UC, including acute severe colitis. The present article addresses the surgical management of medically refractory UC, including the general surgical approach and perioperative optimisation, surgical strategies and techniques, and recommended levels of centre expertise and surgical specialisation. Together, these two articles aim to inform shared decision‑making and to guide clinicians and healthcare professionals involved in the care of patients with UC, drawing on the best available evidence.

Up to 75% of CD patients require surgery during disease course, and post-operative recurrence (POR) occurs in up to 70% patients within 1 year. Early, accurate and frequent monitoring is therefore critical for optimal management. Intestinal ultrasound (IUS) has emerged as a safe and widely available tool to assess CD activity. Bowel wall thickness (BWT) is a key feature that correlates with the presence of endoscopic recurrence. However, IUS interpretation is often burdened by subjectivity and high interobserver variability, underscoring the need for standardised, objective assessment tools. Artificial intelligence (AI) offers an opportunity to enhance precise and reproducible IUS-based disease evaluation. We aimed to develop a novel computer-aided model for automated quantitative measurement of BWT across different intestinal segments. IUS videos from CD patients enrolled in the international, multicentre PROSPER study (NCT06505304) were included. 70 high-quality frames from 22 videos were manually and randomly extracted. Additional 12 frames were extracted to develop the computer-aided system to detect bowel wall layers from the cross section of bowel wall. Regions of interest (ileum, anastomosis, and colon) were identified and bowel wall layers were manually segmented as ground truth. Drawing a line across the bowel wall (from lumen to serosa) was required as input. After extracting the grey-level intensity from the frames along this line, the intensity profile was smoothed to reduce noise. Layers’ boundaries were automatically identified by detecting most relevant peaks and valleys in the grey-level intensity profile. Considering the sequence and echogenicity of layers, the thickness of each layer was computed, enabling accurate estimation of overall BWT (Figure 1). The diagnostic performance was evaluated by correlating computer-derived measurements with experts manual assessment. Table 1 details model performance. A very high correlation (r 0.98; mean absolute error 3.8 pixels, mean percentual error 8.63%) was identified between the manual and the automated estimation of BWT. Excellent performance was confirmed in assessed intestinal tracts: r 0.97 in the neo-terminal ileum, r 0.98 in the anastomosis and r 0.97 in the colon proximal to the anastomosis. Our semi-automated method accurately measure BWT through reliable layer stratification and demonstrates excellent concordance with manual assessment. This approach offers a promising avenue for fully automated identification and quantification of bowel wall layers on IUS. Further refinement and integration of additional sonographic features will enhance standardization and clinical utility in POR monitoring. Conflict of interest: Iacucci, Marietta: No conflict of interest Dr. Zammarchi, Irene: No conflict of interest Verstockt, Bram: No conflict of interest Allocca, Mariangela: Personal Fees: consulting fees from Nikkiso Europe, Mundipharma, Janssen, Abbvie, Pfizer, Ferring, Galapagos, Sandoz, Lilly and Alfasigma Bezzio, Cristina: Personal Fees: I received consulting/advisory board/lecture fees from Alfa Sigma, AbbVie, Celltrion, Eli Lilly, Ferring, Gilead, Johnson & Johnson MSD, Pfizer and Takeda Banai Eran, Hagar: No conflict of interest Castiglione, Fabiana: Honoraria from: Takeda, AbbVie, Celltrion, Johnsson Johnsson, Cadigroup, Sandoz, Pfizer, Lilly, Lionhealth, Nestlè Cannatelli, Rosanna: No conflict Dal Buono, Arianna: speaker’s fees from AbbVie, Alphasigma, Ferring, Lilly, Janssen, and Celltrion Doherty, Glen: No conflict of interest Furfaro, Federica: Grant: IG-IBD Personal Fees: Pfizer, Biogen, J&J, Abbvie, Amgen, Janssen Lepore, Federica: No conflict of interest Lo Bello, Antonio: No conflict of interest Lu, Cathy: No conflict of interest Maconi, Giovanni: No conflict of interest Nardone, Olga Maria: No conflict of interest O’grady, John: No conflict of interest Piazza O Sed, Nicole: No conflict of interest Ricci, Chiara: No conflict of interest Ghosh, Subrata: No conflict of interest Naranjo, Valery: No conflict of interest Grisan, Enrico: No conflict of interest

BACKGROUND AND AIMS:The British Society of Gastroenterology recommend use of structured transition programs to improve control of chronic gastrointestinal disease in adolescents. We sought to determine the impact of attending a structured transition program on engagement of patients with inflammatory bowel disease (IBD) services and disease outcomes. METHODS:We performed a retrospective multicenter study of patients with IBD prior to and post-transfer to adult services. Patients were grouped into those who attended a structured transition program and those who received standard care, transferred with a referral letter. RESULTS:A total of 282 patients were included: 155 patients in our structured transition program cohort and 127 patients in the standard care cohort. Patients who took part in a structured transition program had significantly better engagement with adult IBD services with significantly lower rates of nonattendance at outpatient clinics 1-year post-transfer (12.3% vs 27.2%, P = .002) and significantly lower rates of disengagement with services (4.2% vs 13.1%, P = .015). There were no significant differences seen in rates of biologic failure, need for steroid/surgery or median fecal calprotectin levels between either group. Attending a structured transition program was the only factor that positively impacted engagement with IBD services in a multivariate analysis (OR 4.08, confidence interval 1.41-11.91, P = .01). CONCLUSION:Structured transition programs in IBD can improve engagement of patients with IBD services with significantly lower rates of disengagement with IBD services seen in our study. Large prospective studies are needed in this field to further investigate this and the impact of these programs on disease outcomes.

Post-operative recurrence (POR) of Crohn’s disease (CD) remains a major challenge, affecting up to 80% of patients within 10 years after surgery. Conventional endoscopy struggles to distinguish early inflammatory recurrence from post-surgical ischaemic changes, delaying effective treatment. Virtual chromoendoscopy (VCE) offers precise visualisation of mucosal and vascular changes. The PROSPER study aims to develop and validate a novel endoscopic score integrating advanced imaging features to predict early POR in CD. This analysis is part of the international, multicentre, prospective PROSPER study (NCT06505304). Adult CD patients undergoing ileocolic resection were enrolled pre-operatively or within 3 months post-operatively and underwent endoscopic assessment at 3 or 6 months after surgery, guided by faecal calprotectin levels (cutoff 150 µg/g). Endoscopic videos were obtained using white-light and VCE modalities —TXI, RDI, and NBI with the Olympus (EVIS-X1) platform, and i-scan1 and OE mode 1–2 with the Pentax (INSPIRA) platform— following a standardised protocol. A three-round modified Delphi process defined the PROSPER domains: two in-person consensus meetings and an online survey (Qualtrics platform) where experts rated each feature. Consensus required >75% agreement. Seven core experts participated in both the first (10 videos) and second (15 videos) rounds, scoring the colon proximal to the anastomosis, the anastomotic region (including anastomotic line, ileal inlet, ileal body, and, when present, blind loops), and the neo-terminal ileum. All anastomotic configurations -end-to-end, end-to-side, side-to-end, side-to-side, and Kono-S- were assessed (Fig 1). Inter-rater agreement was evaluated using Fleiss’ κ, Gwet’s AC1/AC2, and ICC(2,k). Mucosal and vascular domains were selected, including erosions, superficial and deep ulcers, villi morphology, vessel dilatation, and bleeding (Tab 1). Agreement across both in-person rounds was moderate to substantial for features in the neo-terminal ileum and colon proximal to the anastomosis (AC1/AC2 = 0.61–0.78) and lower for the anastomotic region (fair to moderate), particularly for villi and erosions (AC2 ≈ 0.40–0.50). Ulcers and vascular patterns showed higher reproducibility (AC1 ≈ 0.70–0.80). Moderate agreement was observed for the anastomosis type (κ 0.51). The Delphi survey confirmed selected domains, with over 80% expert agreement on inclusion and weighting. The novel PROSPER score is a multimodal tool integrating advanced imaging for comprehensive assessment of the anastomosis, showing good inter-expert agreement across most domains. These results support its feasibility for detecting early POR. The next phase will involve real-life validation. Conflict of interest: Iacucci, Marietta: Grant: Pentax, Olympus, Eli lilly, Helmsley Personal Fees: Pentax, Pfitzer, Janssen, EliLilly, J&J Dr. Santacroce, Giovanni: No conflict of interest Zammarchi, Irene: No conflict of interest Nardone, Olga Maria: Advisory board fees from Eli Lilly, Nestlè, Janssen Speaker fees from AbbVie, Janssen, Eli Lilly, Ferring, Alfa Sigma, Recordati, Noòs, and Pfizer Cannatelli, Rosanna: No conflict of interest Doherty, Glen: Research or Education Grants (last 36 months):Abbvie, Pfizer, Janssen, Takeda, Tillotts, Celltrion, Abbott, Dr Falk, Amgen Speaker/Meeting Honoraria (Last 36 months):Abbvie, Dr Falk, Galapagos/Alfa Sigma, GSK Furfaro, Federica: Grant: IG-IBD Personal Fees: Pfizer, Biogen, J&J, Abbvie, Amgen, Janssen Gabbiadini, Roberto: No conflict of interest Lu, Cathy: Advisory board - Abbvie, JnJ, Takeda, Ferring, Merck, Celltrion, Pfizer Research Funding - Abbvie, JnJ Pugliano, Cecilia Lina: No conflict of interest Snir, Yifat: No conflict of interest Ghosh, Subrata: No conflict of interest Tontini, Gian Eugenio: • Speaker honoraria from Pentax (2022), Medtronic (2021), NTC Pharma (2021), Ferring (2024) • Consultant fees from NTC Pharma (2022, 2024), F. Hoffmann-La Roche Ltd (2022), Fujinon (2023), Invicro (2025). Bisschops, Raf: Grant: Pentax Europe, Medtronic, Norgine Personal Fees: Pentax Europe, Fujifilm, Norgine, Medtronic, Ipsen, Alfasigma, Viatris, Endostart, Falk Foundation Non-financial Support: Pentax Europe, Fujifilm, Boston Scientific, Olympus, Erbe, Norgine

Fibroblasts have emerged as inflammatory entities in ulcerative colitis (UC) and eosinophilic oesophagitis, positioning these cells as attractive therapeutic targets. Previous studies have shown that hydroxylase inhibitors elicit anti-inflammatory responses, but their effects on fibroblasts during inflammation remain unknown. Here we test the effects of hydroxylase inhibitors on TNFSF14/LIGHT-driven inflammation in intestinal and oesophageal fibroblasts. Human endoscopic biopsies were obtained from paired inflamed or non-inflamed areas of active UC patients. Primary human colonic and oesophageal fibroblasts from healthy donors were pre-treated with hydroxylase inhibitors and/or treated with LIGHT. Flow cytometry, qRT-PCR, enzyme-linked immunosorbent assays, immunoblotting, immunofluorescence and RNAseq were used. LIGHT induced inflammatory responses in intestinal fibroblasts predominantly via lymphotoxin β receptor (LTβR), which was more highly expressed than herpes virus entry mediator in UC biopsies and colonic fibroblasts. A comparative analysis of the response to LIGHT between colonic and oesophageal fibroblasts revealed unique transcriptional profiles and a shared inflammatory gene programme. Pretreatment with hydroxylase inhibitors had a selective inhibitory effect on the expression of several LIGHT-mediated inflammatory factors in colonic and oesophageal fibroblasts. Mechanistic studies revealed differential molecular targets as LIGHT-driven non-canonical nuclear factor-κB activity was targeted by hydroxylase inhibitors in oesophageal but unaffected in colonic fibroblasts. While dimethyloxalylglycine (DMOG) abrogated LIGHT-induced p38 phosphorylation in colonic fibroblasts, p38 inhibitors did not phenocopy the anti-inflammatory effects of DMOG. In summary, we established a previously unrecognised LIGHT/LTβR-driven inflammatory response in intestinal fibroblasts and characterised differential effects and pathways for LIGHT signalling in intestinal and oesophageal fibroblasts. We identified therapeutic effects of hydroxylase inhibitors via targeting of distinct pathways in these cells. KEY POINTS: LIGHT induces partially conserved inflammatory responses in colonic and oesophageal fibroblasts. Hydroxylase inhibitors selectively diminish LIGHT-mediated inflammation in both types of fibroblasts. Dimethyloxalylglycine reduces accumulation of the non-canonical nuclear factor-κB member p52 in oesophageal fibroblasts. The mechanism whereby hydroxylase inhibitors reduce LIGHT-mediated inflammation in colonic fibroblasts remains to be elucidated.

Approximately 50-75% of patients with Crohn’s disease (CD) require surgery during disease course, yet post-operative recurrence (POR) may occur in 70% of patients within the first year (1). Early detection is crucial for guiding timely treatment and improving long-term outcomes. Intestinal ultrasound (IUS) is a safe, cost-effective, and patient-friendly non-invasive tool for assessing and monitoring CD activity (2). However, evaluation of POR, particularly at anastomotic site, remains challenging. While validated IUS scoring systems enable the assessment of CD activity (3), no scores are currently available to standardize POR assessment. We aimed to develop the first IUS score to predict POR in CD: the PROSPER-IUS score. CD patients enrolled in the international, multicenter PROSPER study (NCT06505304) who underwent IUS at 3 and 6 months following ileocolic resection were included. Key IUS features relevant to POR were identified through a Delphi process during two in-person consensus meetings (Figure 1). Ten expert IBD-IUS readers independently scored 10 standardised videos evaluating selected features at neoterminal ileum, anastomotic site, colon, and, when present, blind loop. Interrater agreement for each feature was assessed using intraclass correlation coefficients (ICC) and Gwet’s AC1/AC2. Features to be included in the final PROSPER score were selected through an anonymised online survey. Consensus was defined as ≥ 75% agreement among participants. Overall, assessment of bowel wall thickness (BWT) and submucosal thickness demonstrated good agreement (ICC 0.7 and 0.62, respectively). Agreement for BWT at anastomosis was moderate (ICC 0.53), while it was good for the neoterminal ileum (ICC 0.61) and very good for ascending colon (ICC 0.93). Evaluation of bowel wall stratification and vascularization achieved excellent agreement across all segments. Assessment of ileal motility, inflammatory mesenteric fat (iFAT), and lymph nodes reached moderate-to-substantial agreement (AC1 0.57, 0.6 and 0.66, respectively). Finally, presence of fistulas, abscesses, spiculates and free fluid showed excellent agreement (Table). Following the online survey, most features achieved a score >80% for inclusion in the final score, except for submucosal thickness, ileal motility, and free fluid. The novel PROSPER IUS score demonstrated good to excellent interobserver agreement across most evaluated domains, supporting its reliability for assessing POR in CD. A multicenter prospective validation study is currently underway, benchmarking the score against clinical biomarkers, endoscopic findings, and patient outcomes. These findings highlight its strong potential for future adoption in clinical practice and clinical trials. References: 1. Bernstein CN, Loftus E V, Ng SC, Lakatos PL, Moum B. Hospitalisations and surgery in Crohn’s disease. Gut. 2012 Apr;61(4):622–9. 2. Kucharzik T, Taylor S, Allocca M, Burisch J, Ellul P, Iacucci M, et al. ECCO-ESGAR-ESP-IBUS Guideline on Diagnostics and Monitoring of Patients with Inflammatory Bowel Disease: Part 1. J Crohns Colitis. 2025 Jul 3;19(7). 3. Yanai H, Feakins R, Allocca M, Burisch J, Ellul P, Iacucci M, et al. ECCO-ESGAR-ESP-IBUS Guideline on Diagnostics and Monitoring of Patients with Inflammatory Bowel Disease: Part 2. J Crohns Colitis. 2025 Jul 3;19(7). Conflict of interest: Verstockt, Bram: Research support from AbbVie, Biora Therapeutics, Celltrion, Landos, Pfizer, Sanofi, Sossei Heptares/Nxera and Takeda. Speaker’s fees from Abbvie, Agomab, Alfasigma, Biogen, Bristol Myers Squibb, Celltrion, Eli Lily, Falk, Ferring, Galapagos, Materia Prima, Johnson and Johnson, Pfizer, Sandoz, Takeda, Tillots Pharma, Truvion and Viatris. Consultancy fees from Abbvie, Alfasigma, Alimentiv, Anaptys Bio, Applied Strategic, Astrazeneca, Atheneum, BenevolentAI, Biora Therapeutics, Boxer Capital, Bristol Myers Squibb, Domain Therapeutics, Eli Lily, Galapagos, Guidepont, Landos, Merck, Mirador Therapeutics, Mylan, Nxera, Inotrem, Ipsos, Johnson and Johnson, Pfizer, Sandoz, Sanofi, Santa Ana Bio, Sapphire Therapeutics, Sosei Heptares, Takeda, Tillots Pharma and Viatris. Stock options Vagustim and Thethis Pharma. Dr. Zammarchi, Irene: No conflict of interest Allocca, Mariangela: No conflict of interest Bezzio, Cristina: No conflict of interest Banai Eran, Hagar: No conflict of interest Castiglione, Fabiana: Honoraria from: Takeda, AbbVie, Celltrion, Johnsson Johnsson, Cadigroup, Sandoz, Pfizer, Lilly, Lionhealth, Nestlè Cannatelli, Rosanna: No conflict Dal Buono, Arianna: speaker’s fees from AbbVie, Alphasigma, Ferring, Lilly, Janssen, and Celltrion Doherty, Glen: No conflict of interest Furfaro, Federica: Grant: IG-IBD Personal Fees: Pfizer, Biogen,J & J, Abbvie, Amgen, Janssen Lepore, Federica: No conflict of interest Lu, Cathy: Advisory board - Abbvie, JnJ, Takeda, Ferring, Merck, Celltrion, Pfizer Research Funding - Abbvie, JnJ Maconi, Giovanni: Personal Fees: Abbvie, Arena Pharmaceuticals, Alfa-Wasserman, Fresenius-Kabi, Gilead, Janssen Cilag, Roche Non-financial Support: Takeda, Abbvie, Alfa-Wasserman Nardone, Olga Maria: Advisory board fees from Eli Lilly, Nestlè, Janssen Speaker fees from AbbVie, Janssen, Eli Lilly, Ferring, Alfa Sigma, Recordati, Noòs, and Pfizer O’grady, John: No conflict of interest Piazza O Sed, Nicole: No conflict of interest Ricci, Chiara: No conflict of interest Ghosh, Subrata: None None None Iacucci, Marietta: Grant: Pentax, Olympus, Eli lilly,Helmsley Personal Fees: Pentax, Pfitzer, Janssen, EliLilly, J & J

Objectives To evaluate the real-world technical performance, diagnostic yield and downstream endoscopy rates of colon capsule endoscopy (CCE) in Ireland and identify clinical factors associated with these outcomes. Methods This multicentre observational study analysed prospective data from the Irish Capsule Registry. Procedures from six centres between October 2023 and February 2026 were included. Outcomes included capsule transit, bowel cleansing adequacy, complete examination (complete transit with adequate cleansing), diagnostic yield and referral for lower gastrointestinal endoscopy. Multivariable logistic regression identified predictors of key outcomes. Results 920 CCE examinations were analysed (mean age 54.9±15.4 years; 61.4% female). Complete capsule transit was achieved in 81.1%, adequate bowel cleansing in 82.6% and complete examination in 70.1%. Clinically significant findings were detected in 38.7% of examinations, most commonly significant colonic polyps (≥3 polyps or any ≥6 mm). Lower gastrointestinal endoscopy was recommended in 38.0% of cases. Increasing age was independently associated with higher diagnostic yield (OR 1.01 per year, p=0.007), without affecting technical outcomes or endoscopy rates. Clinical indication influenced downstream endoscopy rates, highest in surveillance populations (50.4%) and lowest in inflammatory bowel disease assessment (22.2%). Incomplete examinations had substantially higher downstream endoscopy rates (56.2% vs 30.3%). Conclusions CCE demonstrated good technical performance and diagnostic yield in routine Irish practice, with downstream endoscopy rates consistent with a clinician-selected population. Outcomes varied by clinical indication, and older age was associated with higher diagnostic yield without adverse effects on performance. These findings emphasise patient selection, favouring lower-risk populations, while supporting use across age groups.

Background and study aims The National Gastrointestinal Endoscopy Quality Improvement (NEQI) Programme captures over 94% of endoscopic activity in the Republic of Ireland (ROI), accounting for > 120,000 colonoscopies per annum. The aim of this study was to assess temporal changes in colonoscopy Key Quality Indicators (KQIs) at a national level over a 5-year period among low-, intermediate-, and high-volume endoscopists. Methods A retrospective analysis of all NEQI colonoscopy episodes occurring between 2016 and 2022, collating colonoscopy KQIs (cecal intubation rate [CIR], comfort score [CS], polyp detection rate [PDR] and sedation use). Endoscopists with 5 consecutive years of activity were defined as low, intermediate, or high activity according to annual procedural volumes. Results Over 658,000 colonoscopies were completed by 1240 endoscopists. Workload is disproportionate, with 36% of endoscopists completing 66% of national colonoscopy volume. Low-, intermediate-, and high-activity endoscopists all demonstrated sustained improvements in KQI targets over the study period. Comparing experts (>= 300 colonoscopies/year) vs non-experts, KQI plateaus were demonstrated for PDR at < 150 colonoscopies per year (34.2% vs 29.6%, P = 0.002), CS at < 200 procedures per year (97.5% vs 94.9%, P < 0.001), and CIR at < 250 colonoscopies per year (94.5% vs 93.4%, P = 0.048). Conclusions This study represents the first published endoscopist-level NEQI data demonstrating ongoing KQI improvements for endoscopists at all activity levels. Sustaining this improvement and continuing to capture national endoscopic performance will remain a core role of the Irish NEQI program. Workforce imbalances and minimum annual volumes continue to represent challenges for national endoscopy programs.

Background/aimsACE2 is highly expressed in the gut and with known alterations in expression in IBD patients potentially linked to gut inflammation and fibrosis. In addition, little is known about the role of serum soluble ACE2 (sACE2) or its hypothetical role in SARS-CoV-2 binding. We sought to evaluate tissue and serum ACE2 profiles in IBD and healthy controls and evaluate alterations related to disease activity and medical therapy.MethodsCirculating sACE2 and intestinal tissue ACE2 was evaluated respectively in serum samples and endoscopic biopsies from patients with IBD and healthy controls in addition to murine DSS induced colitis.Results91 IBD (UC/n=41; CD n=50) and 55 controls were analyzed. Immunohistochemical ACE2 staining in controls was limited to brush border expression with markedly increased colonic ACE2 expression (and reduced ileal ACE2 expression) in IBD. This was not observed in the mouse model which demonstrated positive ileal ACE2 and negative colonic staining in healthy and DSS mice. Colonic ACE2 staining was further increased in Ulcerative Colitis in inflammation (% staining, 20(5-30) vs. 5(0-6.5), p<0.015) and in IBD patients receiving corticosteroids (% staining, 20(20-40) vs 10(0-20), p<0.052). Steroid use was associated with significantly lower sACE2 with a trend towards reduced sACE2 with biologic exposure.ConclusionWe observe significant increases in colonic ACE2 expression in IBD, especially with active colitis. Corticosteroids further modify the observed imbalance between tissue and serum ACE2 levels.

Interactions between fibroblasts and monocytes have emerged as a contributing factor in IBD pathogenesis and therapy resistance, owing to the ability of both cell types to participate in tissue inflammation and repair. We have previously shown that the TNF superfamily factor TWEAK (TNFSF12) can induce a UC-like inflammatory profile in colonic fibroblasts in vitro , in turn promoting monocyte adhesion and activation. However, the mechanisms underlying fibroblast-monocyte communication and its dysregulation in colitis are incompletely understood. Here we use co-culture models, human biopsies from ulcerative colitis (UC) patients and healthy donors, and public single-cell transcriptomics to characterise the mechanisms underlying fibroblast-mediated monocyte activation. We show that TWEAK-treated inflammatory fibroblasts induce a transcriptional programme that resembles early monocyte/macrophage intermediates in UC and is enriched for genes associated with resistance to anti-TNF ( TREM1, OSM, IL1B ) and susceptibility to IBD (NOD2, ATG16L1 ). We find that conditioned media from TWEAK-treated fibroblast causes a sustained activation of STAT3 phosphorylation in monocytes, and that inhibition of the NF-κB Inducing Kinase (NIK) impairs the ability of inflammatory fibroblasts to activate STAT3 phosphorylation in monocytes, resulting in reduced expression of inflammatory mediators. Using tissues from UC patients, we show that the expansion of CD90 + /PDPN + inflammatory fibroblasts in UC correlates with the accumulation of TWEAK + myeloid cells in the colonic mucosa, and that these fibroblasts co-localise with infiltrating monocytes in sites of active inflammation. Together, our findings suggest that the TWEAK/NF-κB/STAT3 axis represents an attractive target to tune inflammatory stroma/monocyte crosstalk.

Abstract Background Filgotinib (FIL), a once-daily, oral Janus kinase 1 preferential inhibitor, was approved for the treatment of Ulcerative Colitis (UC) following the phase 2b/3, randomized SELECTION clinical trial.1 Real-world data on the effectiveness and safety of FIL are needed to complement the results of clinical trials for applicability in daily clinical practice. Methods GALOCEAN (NCT05817942) is a European, multicenter, prospective, observational study that will recruit ~600 adults with UC receiving FIL in clinical care. In this interim analysis, we report data for up to 24 weeks. Effectiveness outcomes were the Mayo Clinic Score (MCS), the partial MCS (pMCS) and the two-item patient-reported outcome (PRO2) score, as well as Short Inflammatory Bowel Disease Questionnaire (SIBDQ), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) and Urgency Numerical Rating Scale (NRS) scores. Safety assessments included treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESIs). Data were analyzed for the overall patient group, and for those receiving FIL without baseline concomitant therapies (FIL−ct) or FIL with baseline concomitant therapies (FIL+ct; including conventional therapies, biologics and synthetic targeted small molecules). Results As of June 2024, 277 patients had been enrolled in GALOCEAN. Of these, 223 had available baseline data; 139 and 83 completed 10 and 24 weeks of treatment, respectively. At baseline, 53% of patients (118/223) received FIL−ct and 47% (105/223) received FIL+ct, of whom 92.4% (97/105) received aminosalicylates. Baseline characteristics are shown in Table 1. MCS, pMCS, PRO2, SIBDQ, FACIT-Fatigue and Urgency NRS data are shown in Table 2. At week 24, remission was achieved by 30% of patients (FIL−ct, 29%; FIL+ct, 31%) for the MCS, 47% (FIL−ct, 47%; FIL+ct, 47%) for the pMCS and 50% (FIL−ct, 44%; FIL+ct, 55%) for the PRO2 score. At week 24, minimal clinically important differences (MCIDs) were achieved by 66% of patients (FIL−ct, 75%; FIL+ct, 58%) for the SIBDQ score, 64% (FIL−ct, 72%; FIL+ct, 57%) for the FACIT-Fatigue score and 43% (FIL−ct, 50%; FIL+ct, 36%) for the Urgency NRS score. Overall, 30% of patients (FIL−ct, 25%; FIL+ct, 36%) had ≥1 TEAE and 6% (6% in each subgroup) had ≥1 AESI. Conclusion This study highlights the overall effectiveness and safety profile of filgotinib up to 24 weeks in a real-world cohort, both when used alone or with concomitant therapy. The safety profiles were consistent with previous data. The GALOCEAN study is ongoing. References 1.Feagan BG et al. Lancet 2021;397:2372–84.

Abstract Background Ustekinumab (UST) is an anti-IL12/23 monoclonal antibody approved for use in psoriasis and inflammatory bowel disease (IBD). HLA-C*06 allele carriage has been associated with higher rates of response to UST in psoriasis patient populations.1 The association between HLA-C*06 carriage and UST response in IBD has not been previously evaluated. We aimed to further explore HLA-C*06 carriage as a pharmacogenetic marker as a response to UST therapy in IBD patients. Methods A multi-centre retrospective study of IBD patients treated with UST in Ireland was performed. Baseline demographics of the cohort were collected. HLA-C*06 genotypes were generated by imputation from whole genome sequence using HIBAG. UST therapy persistence, was considered a proxy for treatment response, and was expressed as time to discontinuation of UST therapy. The primary endpoint was UST therapy persistence segregated by HLA-C*06 allele genotype. Statistical analysis was performed using survival analysis and multivariate cox logistic regression with effect of covariates on outcome expressed as odds ratios (OR). Results 143 IBD patients were identified and included in the study population. In this population, 32 patients (22%) carried at least one HLA-C*06 allele. There was no significant difference in median time to UST therapy discontinuation comparing HLA-C*06 carriers to non-carriers at 700-days follow-up, p=0.32 [Figure 1]. In a multivariate regression neither HLA-C*06 allele carriage (OR 1.2, p=0.5), male gender (OR 1.2, p=0.6), CD phenotype (OR 1.6, p=0.44), nor concomitant immunomodulator use (OR 1.1, p=0.8) were independently associated with time to UST therapy discontinuation. Conclusion HLA-C*06 allele carriage is not associated with increased UST therapy persistence in IBD. Larger studies of UST therapy outcome in IBD patients with characterised HLA-C*06 genotype are required to confirm this finding. References 1.Talamonti M, Galluzzo M, Chimenti S, Costanzo A. HLA-C*06 and response to ustekinumab in Caucasian patients with psoriasis: Outcome and long-term follow-up. J Am Acad Dermatol. 2016;74(2):374-5.

Hidradenitis suppurativa (HS) is associated with inflammatory bowel disease (IBD). Using healthcare databases, an estimated 2.1

Background and Aims: Colorectal cancer (CRC) is the second most deadly cancer globally. The rapidly rising incidence rate of CRC, coupled with increased diagnoses in individuals <50 years, indicates that early detection of CRC, and those at an increased risk of CRC development, is paramount to improve the survival rates of these patients. Here, we profile caspase-4 expression across 2 distinct CRC development pathways, sporadic CRC (sCRC) and inflammatory bowel disease-associated CRC (IBD-CRC), to examine its utility as a novel biomarker for CRC risk and diagnosis. Methods: Tissue samples from patients with CRC, colonic polyps, IBD-CRC, and sCRC were assessed by immunohistochemistry for caspase-4 expression in epithelial and stromal compartments. RNAseq expression data for caspase-4 in CRC and normal tissue samples were mined from online databases. Results: Epithelial caspase-4 expression is selectively elevated in CRC tumor tissue compared to adjacent normal tissue, where it is not expressed. In the sCRC pathway, caspase-4 is expressed in the epithelial and stromal tissue of all histological subtypes of colonic polyps, with a significant increase in epithelial expression from low-grade dysplasia to high-grade dysplasia progression. For the IBD-CRC pathway, caspase-4 epithelial expression was specifically upregulated in dysplastic and neoplastic tissue of IBD-CRC but was not expressed in normal or inflamed tissue. Conclusion: This study demonstrates that epithelial caspase-4 is selectively expressed in colon tissue during the development of dysplasia. As such, epithelial caspase-4 represents a promising novel tissue biomarker for CRC risk and diagnosis.