Introduction

Inflammatory bowel disease (IBD) is a complex disease characterized by the dysregulation of host immunity. A key feature is the intestinal activation of T cells with cytotoxic activity and pro-inflammatory cytokine release. Therefore, targeting these pro-inflammatory T cells is a reasonable therapeutic approach. CCR9 is the main activator of gut tropism in the lymphocytes and a promoter of their migration into the lamina propria.
SBR3 is a best-in-class anti-CCR9 monoclonal antibody that effectively depletes CD4⁺ CCR9⁺ T cells in intestinal biopsies and peripheral blood of Crohn’s Disease (CD) and Ulcerative Colitis (UC) patients, which leads to a marked reduction in pro-inflammatory cytokines and restoration of immune homeostasis.
The main objective of this study is to evaluate the translational efficacy of SRB3 in depleting CD4⁺CCR9⁺ T cells in intestinal explants from patients with UC and CD, and to assess its correlation with clinical parameters such as fecal calprotectin levels and current treatments.

Aims & Methods

Intestinal biopsies were collected in routine colonoscopies with inflammatory activity (defined as a Mayo Endoscopic Score <1 in ulcerative colitis and presence of ulcers in CD) from a cohort of IBD patients that included both naïve individuals and those previously treated with biologics, including TNF inhibitors (adalimumab, infliximab) and IL-12/23 antagonists (ustekinumab). Gut explants were cultured and treated ex vivo with SRB3. The frequency of CD4⁺CCR9⁺ T cells and cytokine levels were measured by flow cytometry and multiplex immunoassays. Clinical and demographic parameters from the patient cohort, including smoking habits, type of disease, Montreal Classification, and fecal calprotectin levels (μg/g), were reviewed to evaluate correlations with SRB3 response.

Results

SRB3 efficiently depleted CD4⁺ CCR9⁺ T cells in both naïve patients and those treated with biologic therapies, including anti-TNF agents and IL-12/23 antagonists, indicating robust activity across diverse treatment backgrounds.
Importantly, higher levels of fecal calprotectin showed a statistically significant correlation (p = 0.032) with the extent of CCR9⁺ cell depletion following SRB3 treatment. Given that elevated calprotectin levels are commonly associated with active disease or acute inflammatory flares, this finding suggests that SRB3 is particularly effective in patients with moderate-severe inflammatory activity.

Conclusion

These findings support the broad therapeutic potential of SRB3 in IBD patients, demonstrating efficacy not only in bio-exposed patients but also in those with active disease, where higher calprotectin levels correlate with stronger depletion levels.

Disclosure

Dr. Barreiro and Dr. Conde are both collaborators in a project funded by SunRock Biopharma.

Introduction

Crohn’s Disease (CD), a subtype of Inflammatory Bowel Disease (IBD), is believed to arise from complex interactions between gut microbes, environment, and genetics. A significant proportion of patients develop fistulae, but unclear aetiopathogenesis impacts treatment outcomes, quality of life, and healthcare costs. Chronic granulomatous disease (CGD) is a monogenic condition caused by pathogenic variants in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complexes which can present as CD-like colitis, abscesses, and immunodeficiency. Given CD’s genetic and phenotypic similarities with CGD, we hypothesised that NADPH oxidases may contribute to CD phenotypes, specifically in relation to fistulating disease behaviour.

Aims & Methods

This study explores the role of genetic variation in NADPH oxidases in CD patients (Southampton IBD cohort) using a per-patient, per-gene deleteriousness score (GenePy) to determine whether CD fistulating disease behaviour can be predicted and establish any potential epistatic interactions between genetic variation of subunits of the NAPDH oxidase complexes relevant to CD. Key NADPH oxidase protein-coding genes involved in CD were identified via literature review. Protein-protein interaction databases were used to collate a comprehensive network of potentially implicated genes. To determine subgroups of patients with differing genetic variation in the NAPDH oxidase genes we employed a principal component analysis (PCA), followed by hierarchical clustering of patients using GenePy scores, with optimal cluster numbers determined by silhouette scores. Cluster enrichment for fistulating disease was explored using Fisher’s exact test. To identify genes driving separation between CD patients we assessed differences in GenePy scores for the top PCA gene drivers between fistulating and non-fistulating subgroups using a Mann-Whitney U-test. Mutational profile characterisation include potential gene-gene interactions were evaluated via Spearman correlations. Multiple test correction was applied.

Results

Twenty-nine protein-coding genes were analysed. Clustering patients by GenePy scores for these genes after PCA resulted in distinct clusters, but no significant association between fistulating phenotype and cluster assignments was observed. However, significant differences between the GenePy scores of the top 5% of fistulating and non-fistulating groups were found for NOX3 (p = 0.016) and DUOX2 (p = 0.001), with fistulating patients having lower GenePy score for these genes, indicating these genes may drive a proportion of inflammatory CD behaviour.
Four gene pairs were significantly correlated (Table 1), indicating potential epistasis within NADPH oxidase complexes for patients with CD. High deleteriousness scores in multiple genes within a complex may indicate oligogenic contribution to a disease phenotype within individuals.

Conclusion

NADPH oxidase genes, and epistatic interactions between them, may modify the risk of fistulating CD and drive disease phenotype in a proportion of patients.

Disclosure

JJA is a scientific advisory board member for Orchard Therapeutics

Introduction

Inflammatory bowel disease (IBD) is a group of chronic inflammatory diseases of the gastrointestinal tract and about 50% of patients develop liver function disorders of different severity in their course. There is unknown cause directly leading to the symptoms of liver damage, one of the suggested causes is impaired mucosal barrier and the associated increased intestinal permeability to bacterial and nutritional antigens and toxins.

Aims & Methods

The aim of the study was to assess the effect of the severity and location of inflammatory lesions in the gastrointestinal tract in the course of IBD on intestinal mucosal barrier disorders and the occurrence of symptoms of liver damage. To assess the degree of mucosal barrier impairment, the intestinal and liver fatty acid-binding proteins (I-FABP and L-FABP) concentrations were assessed, which are sensitive markers of mucosal damage and to assess the degree of liver damage, the fibroblast growth factor (FGF-19) concentrations assessment and laboratory and imaging results. For IBD severity evaluation, the clinical activity scoring indexes and serum tumour necrosis factor alpha (TNF-alpha) concentrations were assessed.
There were 20 children with Ulcerative Colitis (UC, 12 boys, 8 girls, mean age: 16.0 yrs, range: 7.5 – 18) and 20 with Crohn's Disease (CD, 10 boys, 10 girls, mean age: 14.8 yrs, range: 6.3 – 18) and 20 healthy controls enrolled into the study. Serum I-FABP, L-FABP, FGF-19 and TNF-alpha concentrations were assessed at the baseline, before the treatment and after 2 weeks of treatment, using ELISA immunoassays. Statistical analysis was performed with Statistica 13.0 software (TIBCO Software, USA) using Mann-Whitney U test, Wilcoxon signed rank test and Spearman’s correlation rank test.

Results

We found significantly elevated serum I-FABP in active UC group when compared to active CD group and controls (p<0.05), while in inactive UC group and inactive CD group they were comparable to controls (p=NS).
Moreover, serum L-FAPB was significantly increased in active UC group when compared to active CD group and controls (p<0,05) and in inactive UC group when compared to inactive CD group and controls (p<0,05).
When we assessed serum FGF-19 concentrations, we found them significantly increased both in active UC and active CD when comparable to controls (p<0,05) and in inactive UC group when compared to inactive CD group and controls (p<0.05). Additionally, serum FGF-19 concentrations were related to the stage of liver impairment in UC patients.

Conclusion

Increased serum concentrations of I-FABP and L-FABP may be associated to impaired mucosal barrier in IBD. Nevertheless, impaired mucosal barrier may be connected to increased penetration of bacterial and nutritional antigens and toxins and secondary may be related to liver damage. Furthermore, increased serum FGF-19 concentration may be associated with liver damage in the course of IBD in children.

Introduction

Disability is a multidimensional concept encompassing physical, psychological, and social limitations that can significantly burden individuals living with inflammatory bowel disease (IBD). However, as disability is shaped by various factors—including cultural, social, and healthcare-related influences that can differ between countries—its prevalence and characteristics may vary globally.

Aims & Methods

We aimed to meta-analyse global data on prevalence of moderate-to-severe disability (MSD) to explore differences in disability prevalence and characteristics by country, IBD subtype, disease activity. MEDLINE EMBASE, EMBASE Classic (from inception to 1^st December 2024) to identify cross-sectional and case-control studies reporting the prevalence of MSD based on validated tools (IBD–Disk and IBD-Disability Index) in adult patients (≥18 years) with confirmed IBD. Data were extracted, and pooled prevalence (PP), odds ratios (OR), and 95% confidence intervals (CIs) were calculated.

Results

The search strategy generated 3089 citations. From these, 160 individual articles appeared to be relevant to the study question and 17 fulfilled the eligibility criteria, containing 8225 patients with IBD recruited from 11 different countries. The pooled prevalence of MSD in patients with IBD was 29.6% (95% CI 22.6-37.1%; I²=98.0%, p<0.01), with no evidence of funnel plot asymmetry (Egger test, p=0.10). The lowest pooled prevalence of MSD was 7.0% in one Dutch study from the Netherlands, and the highest 51% and 52% in two studies from China and Italy, respectively. The pooled prevalence of MSD was higher in patients with IBD with active disease (56.9%, 95% CI 20.3-89.7%, I² = 93.0%, p<0.01) compared with those with inactive disease (27.0%, 95% CI 3.3-62.0%, I² = 93.0%, p<0.01). Based on three studies that reported MSD prevalence in both active and inactive disease, active IBD increased the odds of MSD more than threefold (odds ratio 3.13, 95% CI 1.74-5.64).

Conclusion

The global prevalence of MSD in the IBD population is 29.6%, and even higher among patients with active disease. These findings underscore the value of incorporating disability assessment into both clinical decision-making and routine therapeutic response —especially in the context of disease modification trials.

Introduction

Older adults with ulcerative colitis (UC) have greater morbidity than younger adults, yet there is paucity of data on the management and outcomes of those who present with acute severe ulcerative colitis (ASUC) in this patient population. This study aims to investigate differences in the management and outcomes between older and younger patients hospitalised with ASUC.

Aims & Methods

We conducted a retrospective study on all ASUC presentations to a Quaternary Sydney hospital over a 10-year period. A modified True-love Witts’ Criteria was used to identify ASUC as ≥6 bloody bowel motions daily and presence of at least one systemic feature, including heart rate >90 bpm, temperature >37.8°C, haemoglobin <105 g/L, and C-reactive protein (CRP) ≥30 mg/L. Older patients who presented with ASUC was defined as those ≥65 years old at time of presentation. Data collected on management included rates of rescue therapy, colectomy and TPN requirement. Data collected on outcomes included hospital length of stay and rates of ICU admission, 30- and 90-day readmission, and 30- and 90-day mortality.

Results

A total of 172 presentations met criteria for ASUC. Of these presentations, 148 patients (86.1%) were <65 years old and 24 patients (13.9%) were ≥65 years old. Median age at presentation in older adults was 73.6 years old and in younger adults was 32.0 years old. Older adults had similar rates of need for rescue therapy (37.5% vs 35.1%, p=0.08), colectomy (12.5% vs 9.5%, p=0,64) and TPN (12.5% vs 10.1%, p=0.73), as their younger counterparts. Older adults (n=6, 25.0%) had significantly higher rates of ICU admission (p<0.01) compared to those <65 years old (n=3, 2.0%). Older adults also had significantly higher 30- and 90-day mortality rates (n=3, p<0.01). There was no mortality observed in adults <65 years old. There was no significant difference in 30- and 90-day readmission rates between older adults and those <65 years old at time of ASUC presentation. Table 1 compares management and outcomes in adults <65 years old and ≥65 years old who presented with ASUC.

Table 1. Comparison of management and outcomes in adults <65 years old and ≥65 years old who presented with ASUC

Conclusion

Despite similar rates of need for rescue therapy and colectomy, older patients who present with ASUC are more likely to have poorer outcomes, with increased requirement of ICU admission and higher mortality rates compared to patients <65 years old. The higher morbidity and mortality observed in our study in older adults who present with ASUC highlights the need for further research to optimise care pathways and improve outcomes in this patient population.

Introduction

Patients with ulcerative colitis (UC) are at increased risk of developing colorectal cancer (CRC), and this is assumed to be due to chronic inflammation of the colorectal mucosa.

Aims & Methods

To identify risk factors for the development of dysplasia or CRC in patients with UC. Retrospective observational cohort study. Clinical data and colonoscopy findings were collected from medical records. A 1:2 Propensity Score Matching (PSM) was performed to balance covariates adjusting for disease extension, age, gender, smoking habit and disease duration. An Andersen-Gill model was used to account for multiple colonoscopies per patient and time-varying risk of dysplasia or CRC, allowing for recurrent events and intra-individual correlation.

Results

A total of 571 UC patients were identified, median age at diagnosis was 39.5 (27.3-54.2), and 304 (53.2%) were men. At diagnosis, 147 (25.7%) had proctitis, 203 (35.6%) left side colitis and 191 (33.5%) extensive colitis. During a median follow-up of 7.1 years (IQR 3.7– 13.3), 51 patients (9.8%) developed dysplasia/CRC. This was more frequent in males (72.9% vs. 27.1%, p=0.004) and in older patients [48.1 years (36.7–60.2) vs. 38.5 years (26.5–53.8), p=0.004].
After PSM adjustment, 123 patients were included, 41 of whom had dysplasia/CRC, with a total of 381 colonoscopies over a follow-up period of 14.6 years (IQR 8.0–22.4). Macroscopic inflammatory activity was present in 283 (74.3%) colonoscopies and microscopic involvement in 5 (1.3%). Older age at diagnosis (aHR 1.03, 95% CI 1.04–1.10, p<0.001) and higher degree of macroscopic inflammation (aHR 1.44, 95% CI 1.02–2.03, p=0.041) were associated with an increased risk of dysplasia/CRC development; advance therapy, family history of CRC, disease extension and microscopic inflammation were not associated with an increased risk.

Table 1. Baseline characteristics of the complete cohort and after Propensity Matching Score.

Conclusion

Older age at diagnosis and the presence of macroscopic involvement on successive colonoscopies are associated with an increased risk of developing dysplasia or CRC in patients with UC.

Disclosure

Beatriz Gros has worked as an advisor for Abbvie, Pfizer, Alphasigma and Roche and has served as an speaker for Abbvie, Pfizer, Alphasigma, Roche, Janssen, Takeda and Gilead.