bluuebunny/crossref_metadata_2025 huggingface dataset:
DOP008 High clinical and endoscopic remission rate with Vedolizumab in early CD patients: the 2nd interim analysis from a prospective multicenter interventional Study (EARLY CD)
Authors: Liu J , Guo H , Li Y , Zhu L , Jia Y , Zhang H , Zhang H , Huang Q , Gao X , Cao Q
Published: January 2025

Background

Early treatment with advanced therapy prior to the development of complications such as stricture and fistula, is associated with better disease prognosis in patients (pts) with Crohn’s disease (CD). This study (EARLY CD) aims to evaluate the efficacy and safety of Vedolizumab (VDZ) as first line therapy in pts with early CD.

Methods

EARLY CD is a prospective, single-arm, multicenter, interventional study (ChiCTR2200063233). Target enrollment was 172 pts and all pts will receive up to 50 weeks of VDZ treatment with dose optimization (additional dose at week 10 if no clinical response, and switch to Q4W if secondary loss of response at maintenance). Main inclusion criteria for early CD are disease duration less than 18 months, no previous use of immunosuppressive agents and advanced treatment, no complications such as fistula or stricture (except for inactive perianal fistula). Primary endpoint was clinical and endoscopic remission at week 52, together with several secondary endpoints including clinical and endoscopic response, transmural healing assessed by MRE, and improvements in both PRO and QoL. This second interim analysis was conducted when all 172 enrollments were completed.

Results

172 pts were recruited with a median follow-up of 7.1 months (IQR 3.3-11.7). Mean age was 30.9 years, 73.8% were male. Mean CDAI score at baseline was 245.97 and SES-CD score was 9.7 (table). Clinical and endoscopic remission rates reached 83.8% and 48.7% at week 14, with further increase to 92.1% and 71.1% at week 52 (figure). Early clinical improvement was observed, with both abdominal pain score (APS) and loose stool frequency score (LSFS) started to decline from week 1, APS decreased by 50.6% (from 44.9 to 22.2), LSFS decreased by 56.1% (from 32.5 to 14.26). From week 1 to week 52, IBDQ improved from 157.8 to 185.9, self-rated health status EQ visual analogue scale increased from 72.3 to 85.4, and self-reported fatigue score assessed by FACIT improved from 38.1 to 43.9. Twenty pts have completed MRE evaluation both at baseline and week 52, with MaRIA score showing a decline from 23.9 to 20.3. Adverse events occurred among 20 pts (11.6%), including exacerbation of perianal disease that required surgical drainage (n=6), arthralgia (n=4), infection (n=7), GI bleeding (n=1), acute appendicitis (n=1), and elevated transaminase (n=1).

Conclusion

This is the first study worldwide to prospectively evaluate the efficacy of VDZ as first-line therapy among bio-naïve pts with early CD. Interim analysis showed promising results including high clinical and endoscopic remission rates through week 52, together with early PRO response and improvement in quality of life.
DOP011 Colectomy rates of newly diagnosed Finnish Ulcerative Colitis patients are decreasing
Authors: Kontola K , Oksanen P , Huhtala H , Helavirta I , Ilus T
Published: January 2025

Background

The effect of biological medication on colectomies is still unclear. Our aim was to determine colectomy risk in newly diagnosed Finnish ulcerative colitis (UC) patients and compare the risk of prebiological and biological era.

Methods

We used the registry of Social Insurance Institution of Finland to find newly diagnosed UC patients. Data on colectomies were collected from the Finnish Institute for Health and Welfare. Patients were stratified according to the UC diagnosis year and the availability of biological medication in Finland to three groups: 2000-2005 (prebiological), 2006-2012 (only infliximab available) and 2013-2020 (multiple advanced therapies available). We defined the subgroups as paediatric (aged <20), adults (aged 20-59), and the elderly (aged ≥60).

Results

We identified 32,108 UC patients and 2,195 colectomies performed on them. The 1-, 5- and 10-year cumulative colectomy risks were 1.0%, 4.7% and 7.3%, respectively. Throughout the study period, the risks were declining with the incidence rate ratio (IRR) 0.98 (p=0.009) in 1-year, IRR 0.97 (p<0.001) in 5-year and IRR 0.97 (p<0.001) in 10-year colectomy risk. Colectomy rates were lower in advanced therapy era (IRR 0.76 (p = 0.048) in 1-year and IRR 0.70 (p <0.001) in 5-year risk) and the 10-year risk also in infliximab era (IRR 0.87 (p = 0.010)) . The paediatric population had lower risk of surgery in advanced therapy era (IRR 0.33 (p =0.021) in 1 and 0.43 (p <0.001) in 5 years) , whereas the risk of the elderly stayed constant (IRR 1.33 (p =0.400) in 1 and IRR 1.12 (p =0.553) in 5 years postdiagnosis).

Conclusion

The risk of colectomy among newly diagnosed UC patients has decreased along the 21st century. This could be due to the use of advanced therapy options and more active treatment strategies.
DOP013 Risk of immune mediated inﬂammatory diseases associated with anti-TNFs and ustekinumab in Crohn’s disease: a nationwide population-based cohort study
Authors: Kirchgesner MD- PhD J , Giboin C , Curmin R , Tubach F
Published: January 2025

Background

Biologics have been variously associated with an increased risk of paradoxical immune mediated inﬂammatory diseases (IMIDs) in patients with Crohn’s disease (CD). While this risk has been assessed in cohort studies for tumor necrosis factor inhibitors (anti-TNF), only case reports have reported the paradoxical occurrence of IMIDs in patients treated with ustekinumab. The aim of this study was to assess the risk of an incident second IMID in patients with CD treated with anti-TNF and ustekinumab.

Methods

We identified individuals with CD and no other IMIDs switching after a first anti-TNF to either a second anti-TNF or ustekinumab based on the French administrative healthcare databases 2008-2022. The primary outcome was the occurrence of a second IMID, including inflammatory rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and polymyalgia rheumatica), skin diseases (psoriasis, hidradenitis suppurativa, and vitiligo), neurologic diseases (multiple sclerosis, myasthenia gravis), thyroiditis, connective tissue diseases, and vasculitis. Follow-up started from treatment switch until occurrence of a second IMID, treatment withdrawal, or December 31, 2022. A lag period of 3 months was considered to minimize protopathic bias. Hazard ratios for the risk of second IMID were calculated, following 1:1 propensity score (PS) weighting, in order to control for confounders including demographics, previous and baseline IBD disease activity, co-treatment exposure, and comorbidities.

Results

Among 13,994 CD patients included, 10,712 (76.5%) and 3,282 (23.5%) patients were exposed to a second anti-TNF and ustekinumab, respectively. The overall proportion of women was 59.6%. Mean age at cohort entry was 38.0 (SD, 13.8) and 41.6 years (SD, 14.8) in the anti-TNF and ustekinumab groups, respectively. The median follow-up was 5.7 years (IQR, 3.3-9.1). Overall, 578 incident second IMID occurred (incidence rates: 23.2 per 1000 PY, person-years), mainly consisting in psoriasis (350, 60.6%) and ankylosing spondylitis (117, 20.2%). The cumulative incidence of second IMID after 10 years of follow-up was 9.85% (confidence interval 95% [8.84-10.85]). All covariates included in the PS model were balanced with an absolute standardized difference lower than 0.1. The risk of second IMID was lower in patients exposed to ustekinumab compared to those exposed to a second anti-TNF (HR=0.63 CI 95%[0.48-0.81], p-value<0.001).

Conclusion

Based on a population-based and propensity score weighted cohort of 13,994 CD patients, exposure to ustekinumab was associated with a lower risk of second IMID compared to anti-TNF.
DOP018 Etrasimod for the treatment of Ulcerative Colitis: Up to 4 years of safety data from the global clinical programme
Authors: Vermeire S , Rubin D T , Regueiro M D , Takeuchi K , Walsh A , Kotze P G , Charabaty A , Goetsch M , Lazin K , Wu J , Tsamos G , Segovia M , Branquinho D , Danese S
Published: January 2025

Background

Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). The long-term safety, tolerability and efficacy of etrasimod are being evaluated in an ongoing open-label extension (OLE) study.1 We report an updated cumulative safety analysis from the etrasimod UC clinical programme with a maximum of 4 years of exposure.

Methods

Patients who received etrasimod in completed phase 2 (OASIS; OASIS OLE), phase 3 (ELEVATE UC 52; ELEVATE UC 12) and ongoing ELEVATE UC OLE (data cutoff 30 Aug 2023) and ES101002 OLE (data snapshot 30 Aug 2022) studies were included. Treatment-emergent adverse event (TEAE) frequency and exposure-adjusted incidence rates (IRs) per 1 patient-year (PY) were analysed.

Results

A total of 1196 patients received ≥1 dose of etrasimod 1 mg or 2 mg once daily with a mean (standard deviation) exposure of 70.66 (54.36) weeks, and 1619.5 PYs of total exposure. Demographics and baseline characteristics are reported in Table 1. Most TEAEs were nonserious and rarely led to discontinuation. The IRs of TEAEs of interest were generally low (Table 2). Serious infections and herpes zoster infections were infrequently reported (all IR ≤0.02). Three patients experienced four nonserious events of macular oedema (0.3%, IR <0.01), including one event leading to discontinuation that resolved. One patient experienced two nonserious events of cystoid macular oedema (<0.1%; IR <0.01) that resolved. Malignancies were uncommon and included five patients with serious events (0.4%), two patients with squamous cell carcinomas and one with basal cell carcinoma. Eleven patients (0.9%) had alanine aminotransferase (ALT) levels >3 times the upper limit of normal (ULN) at two consecutive post-baseline visits. Notably, no patients exhibited >3× ULN in either ALT or aspartate aminotransferase and >2× ULN in total bilirubin (laboratory criteria for Hy’s law). TEAEs leading to death were reported in three patients (all deemed unrelated to treatment). No serious adverse events of hypertension or bradycardia were reported. No events of second-degree Mobitz type 2 atrioventricular (AV) block or third-degree AV block occurred.

Conclusion

Etrasimod remains well tolerated in patients with moderately to severely active UC, with a favourable safety profile that has not changed with longer-term treatment exposure for up to 4 years.

References

1. Vermeire S et al. J Crohns Colitis 2023; 17: i619–i620.

Pfizer’s generative artificial intelligence tool MAIA was used to assist production of the abstract first draft. Authors reviewed/edited and take responsibility for the content.
DOP022 Shared and Distinct Features of the Gut Microbiome in Immune-mediated Inflammatory Diseases: Initial Analysis from the INTEGRATE Cohort Study
Authors: Kim H S , Kim J E , Nam B , Oh S J , Kim B H , Park S K , Lee S W , Jo S , Lee J Y , Bae J W , Lee Y A , Park D I , Kim T H , Lee C K
Published: January 2025

Background

Inflammatory bowel disease (IBD) and ankylosing spondylitis (AS) share overlapping pathophysiological mechanisms as immune-mediated inflammatory diseases. While gut microbial dysbiosis has been implicated in both conditions, the shared and distinct features of the oral-gut microbiome axis remain poorly understood. This study aims to characterize the oral and gut microbial signatures and their relationship with environmental factors in IBD and AS to identify common pathogenic pathways and disease-specific patterns.

Methods

The INTEGRATE study is a nationwide prospective observational study in Korea targeting recruitment of 1,100 IBD patients, 700 AS patients, and 2,244 healthy controls over five years (Table 1). Systematic collection includes clinical data and biological samples (saliva, stool, blood, intestinal tissues) for multi-omics analyses. Microbial characterization employs full-length 16S rRNA gene sequencing and shotgun metagenomics for saliva and stool samples, complemented by metabolomic analyses of saliva, stool, and plasma. This initial analysis includes gut microbiome data from 254 IBD patients, 156 AS patients, and 194 healthy controls.

Results

Alpha diversity analysis revealed a gradient pattern, with IBD patients showing lowest gut microbiome diversity, AS patients intermediate, and healthy controls highest (p<1.0e-12 for all indices, Fig. 1). In IBD patients, alpha diversity significantly correlated with disease activity indices (Harvey-Bradshaw Index score in Crohn's disease, total Mayo score in ulcerative colitis) and inflammatory markers (CRP, r=-0.13, p=0.042). Blood urea nitrogen levels showed positive correlation with alpha diversity in both IBD (r=0.21, p=0.00062) and AS cohorts (r=0.20, p=0.015). Beta diversity analysis demonstrated distinct clustering patterns (UniFrac distance), with AS patients positioned intermediately between IBD patients and healthy controls (Healthy vs IBD: R²=0.0502, Healthy vs AS: R²=0.0148, IBD vs AS: R²=0.0198; all p=0.001). Species-level analysis through full-length 16S rRNA sequencing identified specific taxa (Clostridium bolteae, Blautia hansenii) significantly enriched in both IBD and AS patients compared to controls.

Conclusion

Our initial analysis demonstrates distinct gut microbiome signatures across IMIDs, with a clear diversity gradient and shared taxonomic features between IBD and AS. These findings, coupled with specific clinical correlations, provide a foundation for understanding common pathogenic pathways. Ongoing multi-omics analyses and quantitative microbiome profiling will further elucidate the role of the oral-gut microbiome axis in these IMIDs, potentially identifying novel microbial biomarkers for precision medicine.
DOP023 Bifidobacterium-candida warfare in the gut of patients with ulcerative colitis
Authors: Jangi S , McDermott L , Shum A , Stiff K , perera L , Friedman S , Kumamoto C
Published: January 2025

Background

C. albicans is identified more frequently in the gut of patients with active ulcerative colitis (UC), and may drive inflammation through activation of specific fungal receptors in the intestine. Pathogenic expansion of C. albicans in UC may occur due to loss of specific protective bacterial strains. Prior work has suggested that Bifidobacterium species may antagonize Candida species. However, relationships of Bifidobacterium species with Candida species in patients with UC are not known, and whether Bifidobacterium may mechanistically suppress C. albicans growth is unclear.

Methods

We utilized data from the Study of a Prospective Adult Research Cohort with IBD to interrogate relationships between fungal and bacterial species during varying inflammatory phases of UC. Relative abundances of fungal and bacterial taxa was obtained from 18 internal transcribed spacer sequences and shotgun sequences. Spearman’s correlations between fungal and bacterial relative abundance were performed. To further assess observed bacterial-fungal correlations in vitro, cell-free supernatants from lab-derived and patient-derived strains were utilized to assess their suppressive ability in competitive assays.

Results

We found that C. albicans is increased in active UC vs during remission (q-val <0.05). Across all patients, 15 unique Bifidobacterium species were identified, including B. adolescentis, B. longum, and B. bifidum [Fig 1A]. The relative abundance of fecal B. adolescentis was negatively associated with C. albicans abundance in UC (p<0.05) [1B]. Multiple strains of B. adolescentis were detected [1C], although these strains did not demonstrate significant genetic variability when compared to a reference marker [1D]. We further observed that cell-free supernatants from lab-derived strains of both Bifidobacterium adolescentis (ATCC 15703) and Bifidobacterium bifidum (ATCC 29521) were able to inhibit C. albicans (ATCC 18804) growth [2CD], while cell-free supernatants from control species Blautia producta (ATCC 27340) only showed partial inhibition of C. albicans [2B]. Using donated fecal samples from 7 patients with active UC, we were able to isolate in culture 11 separate isolates of Bifidobacterium strains (confirmed by MALDI-TOF), and 1 isolate of Candida species, with inhibitory assays between patient derived strains ongoing.

Conclusion

Bifidobacterium adolescentis is negatively associated with C. albicans in fecal samples from UC patients. Both B. adolescentis and B. bifidum strains completely suppress C. albicans growth in vitro. Bifidobacterium species may provide colonization resistance against C. albicans in the UC gut. Loss of Bifidobacterium strains may allow for C. albicans expansion which may contribute to inflammation and relapse.
DOP029 SPP1 in colitis-associated colon cancer
Authors: Manna S , Sehn M , Cardoso da Silva D , Liu X , Wiese J J , Heldt C , Siegmund B , Hummel M , Schumann M
Published: January 2025

Background

Colitis-associated carcinoma (CAC) is a major complication that arises in patients with a long-standing ulcerative colitis (UC) and Crohn’s disease (CD). Albeit numerous studies report mutational landscape of CAC, its transcriptomic landscape is poorly understood. Thus, to interrogate the tumour ecology & mechanisms behind CAC development, we adopted a muti-modal approach utilizing FFPE tissues from human CAC patients and colon organoids. We leveraged immunology bulk gene expression and spatial gene expression to derive a robust gene signature of CAC at a single cell resolution.

Methods

To comprehensively profile the CAC immune microenvironment, we created a comprehensive dataset (Nanostring) covering relevant clinical FFPE samples encompassing 40 patients suffering from either IBD or CAC, alongside inflammation-free healthy controls (10 patients/group). We observed a robust upregulation of the SPP1 (Secreted Phosphoprotein 1) gene encoding osteopontin (OPN) in CAC. Subsequently, we extended our methodology to spatially resolved transcriptomics (Xenium) using 5μm FFPE sections from CAC & UC patients (3 patients/group). This provided insights into the spatial and single cell expression of SPP1 and its target receptors at a subcellular resolution. Furthermore, we mapped the ligand-receptor pairs onto cell types to uncover SPP1 signalling in CAC. These findings were validated at a protein level by whole FFPE section confocal microscopy.

Results

Immunology gene expression (Nanostring) dataset revealed a strong upregulation of SPP1 gene encoding OPN in CAC as compared to UC and CD. Spatially resolved transcriptomics (Xenium) unveiled the spatial heterogeneity of SPP1 expression in CAC, that is primarily arising from CD68+ CD163+ macrophages in CAC (Fig 1B), validated through OPN/CD68 immunostainings. Ligand-receptor (LR) analysis revealed a distinct LR pairing focusing on SPP1, that is secreted (outgoing signal) macrophages to T cells (as incoming signal) via upregulated integrin and CD44-receptors (Fig 1D/E). Furthermore, CAC tumour cells surrounding the SPP1+ macrophages exhibited a distinct gene expression signature associated with T cell exclusion and immunosuppression in CAC (Fig 1C/FG).

Conclusion

We identified a CAC specific upregulation of SPP1 at both RNA and protein levels, expressed by CD68+ CD163+ macrophages. Mutually exclusive spatial location of SPP1/OPN+ macrophages and CD8+ T cells suggests a crucial indirect role of SPP1/OPN in mediating an immunosuppressive tumour microenvironment. We further uncovered CAC specific, single cell gene expression signature that has the potential to identify pre-malignant stages of CAC.
DOP062 Quantitative histologic features of the inflammatory microenvironment using digital pathology prior to adalimumab treatment allows prediction of response in patients with Ulcerative Colitis.
Authors: Shamshoian J , Najdawi F , Degryse S , Jayson C , Brosnan-Cashman J , Kolahi K , Shrotre A , Guay H , Laroux F S
Published: January 2025

Background

Ulcerative Colitis (UC) is a chronic, immune-mediated disease. Despite the advent of anti-inflammatory biologics, the degree of response to therapy is unpredictable and achievement of deeper responses is limited to a minority of patients, rendering the choice of therapy complex and empiric. Quantitative histologic features of the inflammatory microenvironment in UC has potential to inform treatment selection. To address this hypothesis, we compared such features derived from machine-learning (ML) models with endoscopic response status (Mayo endoscopic score; MES<2) in patients with UC treated with adalimumab (ADA).

Methods

A retrospective analysis of a subset of patients with UC from phase III clinical trial of ADA (NCT02065622) was performed. A suite of ML models, collectively known as IBD ExploreTM (PathAI, Boston1) previously trained to quantify tissue regions (e.g., epithelium) and cells (e.g., lymphocytes) were deployed on hematoxylin and eosin (H&E)-stained whole slide images (WSI; N=343) of rectum and sigmoid biopsies at ADA baseline (week 0). Human interpretable features (HIFs) were extracted from each WSI and correlated with end-of-maintenance (week 52) region-level endoscopic response status using univariate logistic regression. Multivariable logistic regression predictive models were also developed on a subset of the data (277 WSIs) using 5-fold cross validation. Biopsies from each subject were placed in a single split to minimize data leakage. Predictive accuracy was assessed on a held-out test dataset (66 WSIs).

Results

Of the model-derived HIFs assessed at baseline (N=657), 70 were associated (p<0.05) with end-of-maintenance region level MES response status after Benjamini-Hochberg (BH) false discovery rate correction. Examples of HIFs associated with end-of-maintenance MES response and their associated odds ratio are shown in Table 1. A model predicting region-specific end-of-maintenance endoscopic response (L2 penalized, class balance weighted) achieved a sensitivity and specificity of 0.64 and 0.61, respectively, on WSIs not seen during predictive model development.

Conclusion

ML-derived baseline histologic features were associated with response to ADA in patients with UC. Features capturing the co-localization of neutrophils to the epithelium-lamina propria junction had the strongest association to end-of-maintenance region MES response. ML-derived quantitative histology features have the potential to guide therapeutic decisions in UC that leverage mechanistic rationale derived from histology, contributing to precision medicine in immunology.

References

1IBD Explore is for research use only. Not for use in diagnostic procedures.
DOP065 SRB1: a Best-in-Class CCR9 depleting antibody that restores immune homeostasis in IBD patients
Authors: Arosa García L , Bastón-Rey I , Ferreiro-Iglesias R , Porto M , Nieto L , Domínguez-Muñoz J E , Roca-Lema D , Álvarez-Coiradas E , Garrido P , Simón L , Barreiro-de Acosta M , Conde Aranda J
Published: January 2025

Background

Inflammatory bowel disease (IBD) is a complex disease characterized by the dysregulation of multiple factors, including host immunity. The intestinal activation of T cells showing cytotoxic activity and pro-inflammatory cytokine production is one of the key factors in its pathology. Therefore, targeting pro-inflammatory leukocytes from the circulation and in the inflammatory site is a reasonable therapeutic goal. CCR9 is the main activator of gut-tropism in the lymphocytes and responsible for the activation of migratory responses in lymphocytes into the lamina propria.

SBR1 is a humanized IgG1 anti-CCR9 mAb showing high-affinity and specific binding towards CCR9+ cells. Displaying effector functions such as Antibody-Dependent Cellular Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP), SRB1 shows specific depletion of infiltrating and circulating CCR9+ cells in vivo and restores the immune homeostasis in patient samples of Crohn’s Disease and Ulcerative Colitis.

Methods

Matching blood and 5 mm gut explants were obtained from IBD patients, then they were cultured for 16h with SRB1 and subsequently, CCR9+ cells were characterized by flow cytometry. The culture supernatants from these explants as well as blood samples from the same patients were analyzed for pro-inflammatory cytokine production by Multiplex cytokine immune assay. Finally, in non-human primates (Macaca fascicularis) CCR9 cell depletion was determined by flow cytometric assays at doses of 8, 15 y 25 mg/kg.

Results

We showed that CCR9 is highly expressed in intestine samples from IBD patients, especially in T cells, but also in other cell types including dendritic cells, macrophages and neutrophils. Treatment with SRB1 was able to effectively deplete CCR9+ cells, specifically T CD4+ CCR9+ and CCR9+ memory T cells from blood and intestinal samples from IBD patients. This depletion also reduced the pro-inflammatory cytokine levels in the culture media. Finally, SRB1 also showed efficacy depleting CCR9 in non-human primates (Macaca fascicularis) at different doses without showing any secondary adverse effects. All these data suggest a potential therapeutic potential of the antibody in the pathogenesis of IBD patients.

Conclusion

SRB1 delivers potent blood and tissue depletion of CCR9 expressing cells ex vivo and in vivo and restores the immune homeostasis in patients’ samples of Crohn’s Disease and Ulcerative Colitis. These data demonstrate the therapeutic potential of SRB1 (anti-CCR9 mAb) a novel therapeutic approach for Inflammatory Bowel Diseases including CD and UC.
DOP071 Distinctive pathogenic memory T cell and neutrophil responses at diagnosis identify CD patients who develop severe therapy resistant disease
Authors: Calado B , Smits W , Heredia M , Barendregt D , Grillmaier M , Tuk B , Hulleman-van Haaften D H , van Berkel L A , Klomberg R C W , Camman A , Vuijk S , Escher J C , de Ridder L , Pascutti M F , Samsom J N
Published: January 2025

Background

CD4+ memory T cells (Tm) drive chronicity of inflammation in Crohn’s disease (CD). Variability in response to treatments specifically targeting Tmem hamper disease management. Recently, we have established that a subgroup of pediatric CD patients with high frequencies of circulating gut-homing IFN-g-secreting ex-Th17/Th1* TIGITneg Tmem at time of diagnosis develop a severe disease course. Specifically, they fail to reach remission within 6 months or lose remission within 1 year, despite anti-TNF treatment. As neutrophils are key targets of Tmem function, we hypothesized that pathogenic gut-homing IFN-g-secreting ex-Th17/Th1* TIGITneg Tmem alter intrinsic neutrophil transcriptional programming at an early stage, before the cells enter the tissue, associating with therapy resistant intestinal disease.

Methods

We analyzed clinically well-characterized therapy-naive pediatric CD patients (n=33) and IBD-negative controls (IBDneg;n=15) from the PIBD-SETQ cohort at time of diagnosis; performed bulk RNA-seq of purified circulating neutrophils, bulk RNAseq of intestinal biopsies, multiparameter flow cytometry of circulating immune cells and plasma proteomics using Proximity Extension Assay technology.

Results

At diagnosis, CD neutrophils differentially expressed 263 genes (DEGs) compared to IBDneg neutrophils. CD neutrophil transcriptomes were enriched for pathways related to neutrophil activation, granule biology, and IFN signaling. Hierarchical clustering of CD patients on the basis of the 263 DEGs identified two patient clusters: cluster_1 with a neutrophil transcriptional pattern similar to IBDneg, and cluster_2 with a pronounced enrichment in IFN and TNF signaling and complement genes. In line with our hypothesis, neutrophil cluster_2 patients had higher frequencies of circulating gut-homing IFN-g-secreting ex-Th17/Th1* TIGITneg Tm, reduced frequencies of inhibitory Tm and higher plasma concentrations IFN-g pathway-associated proteins including IFN-γ, CDCP1, and CXCL9 compared to cluster_1 patients.

Crucially, lesional colonic biopsies of neutrophil cluster_2 patients were transcriptionally distinct from cluster_1 with a signature of increased IFN-g signaling, extracellular matrix re-organization and Fc-receptor expression but did not differ in the number of infiltrating neutrophils/mm2 or histological disease activity.

In line with this distinctive immunotype, cluster_2 patients had higher clinical disease scores, higher endoscopic scores and lower rates of normal FCP remission at 1 year after diagnosis despite similar anti-TNF use compared to cluster_1 patients.

Conclusion

We define a subgroup of pediatric CD patients who have a distinctive pathogenic Tm-neutrophil immunotype at diagnosis and develop severe therapy resistant disease.
DOP086 Burden of depression and anxiety among patients with pediatric-onset Inflammatory Bowel Diseases: A nationwide study from the epi-IIRN
Authors: Soluiman M , Bloch-Priel S , Kopylov U , Schusheim G , Matz E , Ben-Tov A , Lev-Tzion R , Dotan I , Zacay G , Loewenberg Weisband Y , Turner D , Rinawi F
Published: January 2025

Background

Data regarding burden of depression and anxiety in pediatric-onset inflammatory bowel diseases (PIBD) are limited. We aimed to study the prevalence of depression and anxiety in a nationwide cohort of PIBD

Methods

Data were retrieved from the epi-IIRN, a nationwide cohort of the 4 Israeli Health Maintenance Organizations covering 98% of the population from 2005. We matched PIBD children to non-IBD controls for calculating time to depression/anxiety. Patients with depression/anxiety prior to IBD diagnosis were excluded. Poor disease course (PDC) was defined as IBD-related surgery, steroid-dependency, or need for more than one biologic class. A time-dependent Cox-proportional-hazard-ratio model was fit to examine predictors of the development of depression/anxiety over time. Inverse probability weights (IPW) were calculated to estimate the probability that an individual will develop depression at each time point within an individual follow up period

Results

In total, 4,960 PIBD cases were included [mean age 13.4±3.8 years; 3,304 (67%) with Crohn's disease (CD) and 1,656 (33%) ulcerative colitis (UC)], translating into 32,700 person-years of follow-up. These were individually matched to 4,806 non-IBD children. In a univariable Cox proportional regression model, PIBD was associated with overall anxiety/depression compared to controls (HR=1.9 95%CI 1.7-2.2). The probability of depression/anxiety was higher in PIBD patients vs controls at 3 (6% vs 2.5%) and 10 years (17.5% vs 10.2%; p<0.001, Figure 1). There were no differences in the probability of depression/anxiety between patients with UC and CD (HR=0.96 95%CI 0.81-1.1, p=0.62). In multivariable Cox proportional regression model in patients with CD; perianal disease [HR=1.5 (95%CI 1.3-2)], need for >1 biologic class, [HR=1.6 (95%CI 1.03-2.63)], and hospitalizations [HR=1.4 (95%CI 1.1-1.9)] were associated with developing anxiety/depression. Risk for anxiety/depression was lower among patients after CD related surgery compared with those who did not undergo surgery [HR 0.5 (95%CI 0.28-0.99)]. For patients with UC, steroid dependency was associated with anxiety/depression [HR 1.5, (95%CI 1.05-2.1)].

Figure 1 (Depression free survival probability)

Conclusion

Our study highlights the substantial burden of depression/anxiety in PIBD and identifies risk factors for these conditions. These findings emphasize the need for mental health monitoring and early intervention in this vulnerable population
DOP087 Characterization of a European population with recently diagnosed Crohn’s Disease: results from the prospective Crohn´s Disease Cohort (CROCO) Study
Authors: Vieujean S , Monin L , Revés J , Arebi N , Fabra A , Burisch J , Madsen G R , Buisson A , Bonnet-Dodel M , Cravo M , Duricova D , Ellul P , Kaimakliotis I , Sebastian S , Ordas I , Rodríguez-Lago I , Mocanu I , Hernandez V , Nachury M , Mathurin M F , Goldis A , Pedersen N , Conceição D , Barberio B , Guedes A , Ribeiro R , Ungaro R , Mary J Y , Bigot N , Lambert J , Colombel J F , Torres J
Published: January 2025

Background

Crohn’s disease (CD) is a chronic and progressive condition with a growing global prevalence, leading to potential bowel damage and disability. Data on the clinical presentation, outcomes, and treatment options in newly diagnosed CD patients in Europe in the current era are essential to guide physicians. The aim is describe the clinical characteristics of a contemporary European cohort of recently diagnosed CD patients.

Methods

The Crohn's Disease Cohort (CROCO) is an ongoing, multicenter, European prospective study of CD patients diagnosed within the last 12 months, aimed at tracking bowel damage progression and disability. This report presents the baseline characteristics at study inclusion.

Results

From August 2021 to October 2024, 399 patients (56% male, 46% current or former smokers) with a median age at diagnosis of 33.7 years (IQR 24.6; 49.2) were recruited across 18 centers. The median delay between symptom onset and diagnosis was 6.2 months (IQR 2; 15.4), and the median disease duration at inclusion was 3.8 months (IQR 1.6; 7.4). Ileal involvement (L1/L3) was reported in 85% of patients. Overall, 15% had perianal disease and 28% had extraintestinal manifestations, predominantly arthritis/arthralgia. Complicated disease behavior was observed in 32% of patients at diagnosis (stricturing: 17%; penetrating: 15%); 6% had undergone intestinal surgery, and 3% perianal surgery from diagnosis to inclusion. CD-related hospitalizations were reported by 22% of patients. Regarding treatments, 51% received steroids (28% systemic steroids), 17% 5-ASA, 1% immunosuppressants monotherapy, and 44% initiated biological therapy (168 anti-TNF, 8 anti-IL 12/23, and 6 anti-integrin, representing 42%, 2% and 2% of the cohort, respectively). A total of 31% were managed with a combination of biologic and immunosuppressant therapies. Disability assessment showed that 48% of patients reported no disability, 24% mild disability, and 28% moderate to severe disability.

Conclusion

In this prospective European cohort of newly diagnosed CD patients, nearly one-third had a complicated disease phenotype and moderate to severe disability, despite a relatively short diagnostic delay. While steroid use remains common, early initiation of biological therapy in 44% of patients reflects a shift in CD management strategies.
DOP088 Speed of disease progression as hallmark of Crohn’s Disease Severity: The rapid and slow progressors.
Authors: Vuckovic C , Cremer A , Minsart C , Amininejad L , Bottieau J , Franchimont D , Liefferinckx C
Published: January 2025

Background

The natural course of Crohn's Disease (CD) can involve the development of intra-abdominal strictures and fistulae (Montreal B2 and B3 phenotypes, respectively). Yet, the speed of disease progression to these phenotypes may differ among patients. This study retrospectively analyses a large cohort of CD patients with luminal phenotype at diagnosis (Montreal B1) and evaluates the speed of disease progression to B2/B3 phenotypes, in a tertiary centre in Belgium.

Methods

A total of 1,262 IBD patients were screened from the 3000+ inflammatory bowel diseases (IBD) patient’s clinics. Among the 516 CD patients diagnosed after 1999 and meeting the inclusion criteria, 372 presented with a B1 phenotype at diagnosis. Of these, 108 patients progressed to B2/B3 phenotypes during follow-up (FU) and were analysed. Demographics, dynamic disease characteristics and treatment adaptations were collected. Patients were stratified into rapid progressors (within 5 years) and slow progressors (beyond 5 years), based on the median progression time in our cohort of 108 patients (median 5 years [1.8-9.9], Figure 1a). Statistical analyses were performed using Prism.

Results

Of the 108 patients progressing to B2/B3 phenotypes, 56 (52%) were rapid progressors (median time 1.8 years [0.8–3.5]) and 52 (48%) were slow progressors (median time 10 years [7.0–12.6]; p<0.0001) (Figure 1b). Rapid progressors were older at CD diagnosis (median age 25 years [21–38] vs 19 years [15–24], p<0.0001), as paediatric CD was more prevalent in slow progressors (33% vs 5%, p=0.0003). Although both groups required biologics and surgeries in similar proportions, rapid progressors started biologics earlier (median 1.3 years [0.3–3.1] vs 5.6 years [2.7–8.9], p<0.0001) and underwent surgery for disease progression earlier (median 2 years [1.1–4.3] vs 10 years [6.9–13.4], p<0.0001). All surgeries occurred after B2/B3 progression and slow progressors underwent surgery later after initiating biologics (median 6.7 year [2–9.5] vs 1.2 year [0.3–2.7], p<0.0001 – Figure 1d).

Conclusion

CD patients with initial B1 phenotype progressing to B2/B3 phenotypes can be classified as rapid and slow progressors based on their speed of progression to these phenotypes. Rapid progressors demonstrate a more aggressive disease course, with earlier biologics initiation and need for surgery. The description of disease progression may uncover a new dynamic disease phenotype of disease severity that is often overlooked or lacking in the current reported cohort and population-based studies. Stratification by the speed of progression may better define patients with severe disease, potentially guiding tailored therapeutic strategies.
DOP096 Durability of TNF inhibitors in Crohn’s disease patients does not change with prior use of non-TNF agents
Authors: Wong A , Gore E , Cohen E , Aronskyy I , Ungaro R , Bhattacharya A
Published: January 2025

Background

In patients with Crohn’s disease (CD), biologic therapies, particularly tumor necrosis factor inhibitors (TNFi) are one of the mainstays of treatment. However, there is limited literature on whether exposure to non-TNFi biologics affects subsequent clinical response to TNFi. This study compared the effectiveness and response rates to TNFi in biologic-naive CD patients versus in those with prior exposure to non-TNFi.

Methods

This was a retrospective cohort study performed at an academic tertiary care institution. A composite primary outcome was used to assess for treatment failure or disease-related complications within 12 months of TNFi initiation. Components of the primary outcome included discontinuation of the TNFi, new steroid initiation, disease-related emergency department visits, disease-related hospitalizations, and disease-related surgeries. Additional secondary outcomes included physician global assessments and evidence of endoscopic healing.

Results

This review included 273 adult CD patients (244 biologic-naive, 29 biologic-exposed) newly initiated on a TNFi between 2016 and 2023. Baseline demographics were largely similar between both groups. There was no significant difference in composite outcome (rates of treatment failure or disease-related complications) between biologic-naive and biologic-exposed patients within 12 months (p=0.511) [Figure A]. Rates of new steroid initiation within 12 months were higher in biologic-exposed versus biologic-naive patients (OR 3.67 [1.35-9.39]; p=0.008). All other primary outcome components and secondary outcomes did not differ significantly between the groups (Table 1; Figure B).

Conclusion

These results suggest that prior exposure to non-TNFi does not affect rates of TNFi treatment failure or disease-related complications in CD. Clinical decision-making surrounding inflammatory bowel disease therapies should be individualized for each patient.
DOP124 Fecal content from IBD patients causes more severe epithelial damage than fecal content from healthy donors, which can be moderated by supplementation of metabolites cocktail
Authors: Abbas-Egbariya H , Elwahidi L , Braun T , Granot M , Krauthammer A , Loberman-Nachum N , Weiss B , Leichtmann-Bardoogo Y , Maoz B , Denson L , Gal-Mor O , VanDussen K , Amir A , Haberman Ziv Y
Published: January 2025

Background

Inflammatory bowel disease (IBD) pathogenesis involves the gut epithelia. However, no specific epithelial interventions exist, and models that capture epithelial and human gut variations for pre-clinical screening of therapies are limited

Methods

Monolayered organoides, derived from human rectal mucosal biopsies, were incubated with fecal samples from Crohn's disease (CD), ulcerative colitis (UC), and healthy control. Organoid viability was quantified by ATP levels and validated by live microscopy imaging. Fecal metabolites were measured using a semi-targeted library of 550 predefined metabolites. Gut bacteria were characterized using 16Sseq.

Results

Fecal samples were processed by separating the supernatant, heat-killing (HK) the bacteria, and rejoining the samples (Fig. 1A). We generated three pools per group (CD p#1-3, UC p#1-3, controls p#1-3). Each fecal p#1 (CD, UC, and controls) was a mix of ten subjects, and fecal pools p#2-3 were each a mix of five other independent subjects. An additional saliva/oral pool was processed similarly as an independent bacterial/metabolite source. Microbial characterization shows the overall variations of the original and pooled samples, with separation between IBD and control samples (Fig. 1B). We then inculcated the oral or fecal contents pools with differentiated colonoid and compared epithelial viability to untreated organoids and to those exposed to inflammatory triggers. Fecal content from UC and CD patients significantly reduced colonoid viability and ATP metabolism compared to healthy controls (p<0.001, Fig. 1C-D). This effect was mediated mainly by the fecal supernatant that also includes the metabolites, rather than the HK fraction (Fig. 1E). Live microscopy confirmed cell clumping already after 3 hours with the IBD fecal material (Fig. 1F). Characterizing metabolite levels in the joined and supernatant pools and correlating them with disease state (IBD vs. controls) and the colonoids viability outcomes highlighted several metabolites higher in controls and linked with improved viability (Fig. 2A-B). Notably, supplementing these identified metabolites with the fecal content pools, UC p#3 and CD p#2 improved epithelial viability (Fig. 2C-D). Lower metabolite supplementation mediated the improvement of the CD pool, but only higher concentrations resulted in improvement of the UC pools. Similarly, microscopy showed improvement in cell clumping when the IBD pools were supplemented with the prioritized metabolites (Fig. 2E).

Conclusion

Fecal content from IBD patients was associated with significantly reduced organoid viability and ATP metabolism compared to fecal content from controls, which improved, in part, with supplementation with prioritized metabolites.
DOP127 A novel epithelial junction gene associated with very early onset IBD: a mechanistic study using patient organoids and transgenic mouse models
Authors: Ma K , Deepak P , Ciorba M , Cao S
Published: January 2025

Background

Very early onset inflammatory bowel disease (VEO-IBD) is often associated with a severe disease course and unique characteristics including underlying monogenic etiologies in some cases. In this study, we mechanistically defined the function of CGNL1, an epithelial junctional protein gene whose pathogenic variants may contribute to VEO-IBD.

Methods

Whole exome sequencing (WES) was performed on the affected patient and all first-degree relatives. Intestinal epithelial organoids (IEOs) were generated from the patient’s mucosal biopsies and were characterized by microscopy, whole-mount immunostaining, transcriptomics and transmission electron microscopy (TEM). In addition, we generated a new Cgnl1-/- mice for dextran-sodium sulfate (DSS)-induced colitis and infection by Citrobacter rodentium which directly compromises intestinal epithelium. Integrated analysis was performed to determine CGNL1 expression in single-cell datasets.

Results

In this patient with VEO-IBD who required early total colectomy with pouch formation, coexistent primary sclerosing cholangitis (PSC) and celiac disease, WES identified two rare, novel, pathogenic variants in the CGNL1 gene. Both pathogenic variants were also present in the patient’s younger sister, who has a similar history including fulminant UC and PSC-autoimmune hepatitis overlap syndrome. Furthermore, multiple relatives of the patient suffer from IBD and other inflammatory conditions including celiac disease, eosinophilic esophagitis, and type-1 diabetes. The RNA and protein levels of CGNL1 were diminished in the patient’s intestinal epithelium compared to that of healthy individuals and other IBD patients. The patient’s IEOs from pouch body and pre-pouch ileum formed smaller 3D spheroids with altered cell composition and significantly impaired barrier function compared to those from normal controls (Figure 1). TEM demonstrated disrupted tight junctions and adherens junctions in the patient’s IEOs. Similarly, impaired junctional complexes in intestinal epithelial cells and elevated intestinal permeability were present in Cgnl1-/- mice, which also showed increased susceptibility to DSS-induced colitis (Figure 2) and C. rodentium infection. Single-cell analysis revealed diminished expression of CGNL1 in intestinal and hepatic epithelial cells from patients with IBD or PSC, respectively.

Conclusion

The pathogenic CGNL1 variants may contribute to VEO-IBD and other inflammatory GI disease by disrupting gut barrier integrity. This study expands our understanding of epithelial barrier impairment in the pathogenesis of VEO-IBD and suggests the intestinal epithelium as a therapeutic target for some IBD patients.