bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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&lt;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&lt;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

Abstract

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

Abstract

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

Abstract

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&lt;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 &gt;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

Abstract

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

Abstract

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&lt;0.0001) (Figure 1b). Rapid progressors were older at CD diagnosis (median age 25 years [21–38] vs 19 years [15–24], p&lt;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&lt;0.0001) and underwent surgery for disease progression earlier (median 2 years [1.1–4.3] vs 10 years [6.9–13.4], p&lt;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&lt;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

Abstract

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

Abstract

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&lt;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.