bluuebunny/crossref_metadata_2025 huggingface dataset:
DOP047 Effectiveness of second-and-third line biologics in perianal Crohn’s disease (pCD) – a multicenter propensity score-matched study
Authors: Shani U , State M , Mateescu R B , Davidoiu A M , Negreanu L , Silva I , Magro F , Plevris N , Roblin X , Castellet-Farrús S , Gonzalez Lama Y , Wang S , Abad C , Imperatore N , Lukas M , Vojtechova G , Ukashi O , Nancey S , Savarino E , Stawczyk-Eder K , Eder P , Toskas A , Kamperidis N , Arebi N , Farkas B , Farkas K , Pipek B , Falt P , Karmiris K , Nikolaou P , Krznaric Z , Brinar M , van Lierop L , Barreiro-de Acosta M , Zaborowska M , Zagorowicz E , Pugliese D , Cuccia G , Truyens M , Kopylov U
Published: January 2025

Background

Perianal involvement affects approximately 20-30% of Crohn’s Disease patients, significantly impairing their quality of life. Anti-tumor necrosis factor-α inhibitors (anti-TNFs) are still the established biological treatment for perianal Crohn's disease (pCD). However, relapse and non-response are frequent and evidence regarding the effectiveness of 2nd- and 3rd-line biologics is limited. This study aims to compare the efficacy of 2nd- and 3rd-line biologics in patients with pCD who have previously failed 1st-line anti-TNF therapy.

Methods

A retrospective multicenter study of adult pCD patients who failed 1st line anti-TNF therapy. The primary outcome was defined as clinical perianal response based on physician assessment. The main secondary outcome was radiological perianal response, based on magnetic resonance imaging (MRI) or transrectal ultrasound (TRUS). Additional secondary outcomes were clinical perianal remission and radiological perianal healing. Propensity-score matching (PSM) used to address baseline clinic-demographics differences between treatments.

Results

486 patients with pCD were included. Of them, 333/486 patients (68.5%) in 2nd-line and 216/263 patients (82.1%) in 3rd-line treatment-groups were matched by PSM. Figure 1 illustrates patient inclusion in the study, stratified by active versus inactive disease status and 2nd-line versus 3rd-line treatment, along with the respective rates of primary outcome achievement. 62/78 (79.5%) patients with active pCD who were treated with ustekinumab (UST) as 2nd-line biologic met the primary outcome, compared to 46/78 patients (58.9%) with VDZ (OR 4.47, 95%CI 1.94-10.28, p<0.001) and 38/78 patients (48.7%) - anti-TNF (OR 5.29, 95%CI 2.39-11.71, p<0.001). 38/49 patients (77.6%) with active pCD who were treated with UST as 3rd line met the primary outcome, compared to 29/49 patients (59.2%) with VDZ (OR 9.96, 95%CI 2.6-38.4, p<0.001) and 27/49 (55.1%) with anti TNF (OR 12.03, 95%CI 2.99-48.47, p<0.001). Patients who were treated with UST as 3rd-line biologic had higher rates of radiological response and healing than patients who were treated with VDZ (OR of 3.28 95%CI 1.07-10.07, p=0.038) and anti-TNF (OR of 2.80 95%CI 0.95-8.21, p=0.061).

Conclusion

Clinical perianal outcomes in patients with active perianal Crohn’s disease were more frequently achieved with ustekinumab following the failure of 1st-line anti-TNFs.
DOP048 Efficacy and safety of dose de-escalation from 50 mg to 25 mg QD of obefazimod maintenance treatment: Analysis of a subset of patients with moderately to severely active ulcerative colitis (UC) who have completed 2 years with 25mg QD
Authors: Danese S , Sands B E , Dulai P S , Peyrin-Biroulet L , Dubinsky M , Tilg H , Siegmund B , Hisamatsu T , Shan K , Ploncard P , Jacobstein D , Cataldi F , Rabbat C , Vermeire S
Published: January 2025

Background

Obefazimod is an investigational, oral, once-daily (QD), small molecule that enhances expression of microRNA-124 and is currently in phase 3 clinical trials for the treatment of patients with UC [1]. Obefazimod demonstrated efficacy and safety at Week 8 in two double-blind, placebo-controlled induction trials and ensuing open-label maintenance (OLM) studies [2, 3]. In a subsequent OLM study utilizing a lower dose, interim analysis indicated efficacy in patients with varying exposure lengths. Here, we report efficacy and safety in a subset of patients that completed both week 48 (W48) and week 96 (W96) endoscopies.

Methods

Patients with UC who received obefazimod 50mg QD for approximately four years in the Phase 2a OLM study and approximately two years in the Phase 2b OLM study, provided they met eligibility criteria (Mayo Endoscopic subscore = 0 or 1), were enrolled in a subsequent OLM study utilizing a reduced dose of 25mg QD for up to an additional 54 months. This interim analysis reports findings among the subset of patients who had completed W48 and W96 with all components of the modified Mayo score (MMS) available at the cutoff date (11SEP2024).

Results

As of the cutoff date, there were 73 patients who have all 3 components of the MMS available at baseline (ie, last before the first dose of 25mg QD), W48 and W96, with a mean age of 44.2 years; 37% were female, and mean UC disease duration of 10.6 years at the entry to this OLM study. At baseline of this OLM study, prior to dose de-escalation, 92% (67/73) of patients were in symptomatic remission. Following dose de-escalation, the proportion of patients achieving symptomatic remission was maintained at or above 92% for all quarterly study visits through W96. Similarly, median fecal calprotectin (FCP) levels were below 70 µg/g at each visit from baseline through W96 (min-max: 50.5-69.0 µg/g) (Figure 1). No new safety findings were identified over these 96 weeks.

Conclusion

In a patient population treated for 2-4 years in OLM studies with 50mg QD, a high percentage of patients who were compliant with the two annual endoscopy visits maintained efficacy measures for two additional years on a reduced dose of 25mg QD. FCP levels below 70 µg/g are generally associated with mucosal healing or remission. Safety was consistent with prior studies, with no new findings. These data further support the long-term efficacy and safety of a lower obefazimod maintenance dose.

References

1. Vermeire S, et al. J Crohns Colitis 2023

2. Vermeire S, et al. Gastroenterology 2021

3. Vermeire S, et al. The Lancet Gastroenterol & Hepatol 2022.
DOP051 Upadacitinib for induction of remission in pediatric Ulcerative Colitis: An international multicenter study
Authors: Yerushalmy-Feler A , Spencer E A , Dolinger M T , Suskind D L , Mitrova K , Hradsky O , Conrad M A , Kelsen J R , Uhlig H H , Tzivinikos C , Ancona S , Wlazlo M , Hackl L , Shouval D S , Bramuzzo M , Urlep D , Olbjorn C , D'Arcangelo G , Pujol-Muncunill G , Yogev D , Kang B , Gasparetto M , Rungø C , Kolho K L , Hojsak I , Norsa L , Rinawi F , Sansotta N , Magen Rimon R , Granot M , Scarallo L , Trindade E , Velasco Rodríguez-Belvís M , Turner D , Cohen S
Published: January 2025

Background

Data on upadacitinib therapy in children with ulcerative colitis (UC) or unclassified inflammatory bowel disease (IBD-U) are scarce. We aimed to evaluate the effectiveness and safety of upadacitinib as an induction therapy in pediatric UC or IBD-U.

Methods

In this multicenter retrospective study, children treated with upadacitinib for induction of remission of active UC or IBD-U from 30 centers worldwide were enrolled. Demographic, clinical and laboratory data as well as adverse events (AEs) were recorded at week 8 post induction.

Results

One hundred children were included (90 UC and 10 IBD-U, median age 15.6 [interquartile range 13.3–17.1] years). Ninety-eight were previously treated with biologic therapies, and 76 were treated with ≥2 biologics. At the end of the 8-week induction period, clinical response, clinical remission, and corticosteroid-free clinical remission (CFR) were observed in 84%, 62%, and 56% of the children, respectively. The median pediatric ulcerative colitis activity index (PUCAI) decreased from 45 [33-60] to 0 [0-20] at week 8 (p < 0.001; Figure 1). Normal C-reactive protein and fecal calprotectin (FC) <150 mcg/g were achieved in 75% and 50%, respectively. The median FC level declined from 1645 [628-2263] mcg/g at baseline to 140 [33-669] mcg/g at week 8 (p < 0.001) (Figure 1).Combined CFR and FC remission was observed in 18/46 (39%) children with available data at 8 weeks. AEs were recorded in 37 children, including one serious AE of an appendiceal neuroendocrine tumor. The most frequent AEs were hyperlipidemia (n=13), acne (n=12), and infections (n=10, five of whom with herpes viruses).

Conclusion

In this largest and first multicenter study on a cohort of children with UC treated with upadacitinib, upadacitinib was an effective induction therapy for refractory pediatric UC and IBD-U. Efficacy should be weighed against the potential risks of AEs.
DOP054 Early Histologic Response and Remission are Associated With Objective Control of Inflammation After One Year of Treatment With Mirikizumab in Moderately-to-Severely Active Crohn’s Disease
Authors: Magro F , Jairath V , De Hertogh G , Feagan B , Harpaz N , Hisamatsu T , D’Haens G , Pai R , Yu G , Tao Luo W , Protic M , Hon E , Moses R , Escobar R , Reinisch W
Published: January 2025

Background

Histologic inflammation persists in up to 1/4 of patients with Crohn’s disease (CD) despite endoscopic mucosal healing. Histologic and combined endoscopic-histologic endpoints are evolving measures of treatment efficacy in CD; however, the impact of histologic healing on long-term outcomes and disease progression is unknown. Week (W) 52 data comparing mirikizumab (Miri) vs placebo (PBO) in the randomized, double-blind, placebo- and active-controlled, treat-through Phase 3 VIVID-1 trial in patients with moderately-to-severely active CD (NCT03926130) were reported previously.1

Methods

The main objective was to evaluate the association of W12 histologic response and W12 histologic remission with W52 clinical and endoscopic outcomes in VIVID-1. Two biopsy specimens from each of 5 intestinal segments (1 ileal and 4 colonic) were obtained from the edge of the ulcers, or the most inflamed mucosa from randomized patients at screening, W12, and W52. All analyses were post hoc and among patients with active histologic disease (defined as a Robarts Histopathology Index >0 and a Global Histologic Disease Activity Score >0) at baseline.

Results

At W12, treatment with Miri resulted in statistically significantly higher rates of achieving histologic response and histologic remission vs. PBO (Figure). At W12, 62.1% of patients had agreement (k=0.27 [fair]) between histologic response and endoscopic response, with a greater percentage achieving histologic over endoscopic response (59.0% vs. 38.8%)*. Significantly greater proportions of patients who achieved histologic response at W12 also achieved histologic response, histologic remission, endoscopic response, endoscopic remission, combined CDAI (Crohn’s Disease Activity Index) remission and endoscopic response, and normalisation of faecal calprotectin levels ≤250 µg/g and ≤150 µg/g at W52 (Table). Similar associations were observed between W12 histologic remission and W52 outcomes.

Conclusion

Histologic response seems to be an early objective sign of anti-inflammatory response and was significantly associated with one-year endoscopic and histologic outcomes, as well as biomarker normalisation.

*Observed data

References

1.Jairath V, et al. Presented at: UEGW 2024. OP131.
DOP070 Activated protein C mitigates thrombo-inflammatory CD4+ T cell activity present in Inflammatory Bowel Disease.
Authors: Leon G , Klavina P A , Rehill A M , Cooper S , Dominik A , Chomanahalli Basavarajappa S , O’Donnell J S , Hussey S , Walsh P T , Preston R J S
Published: January 2025

Background

IBD patients exhibit up to 6-fold increased risk of venous thromboembolism (VTE) compared to the general population, although the mechanistic basis for this increased risk is unknown. Pre-clinical studies suggest an important role for diminished protein C (PC) pathway activity in IBD pathophysiology.

Aims

To evaluate the procoagulant activity of colitogenic T cells and assess the impact of activated protein C (APC) signalling in regulating T cell immunothrombotic activity.

Methods

The pro-thrombotic potential of T cells was determined using bespoke T-cell-dependent calibrated automated thrombinography assays, flow cytometry and microscopy. Meta-transcriptomic and gene expression analysis were used to assess the dysregulated expression of coagulation-associated genes in IBD patient gut biopsies. To elucidate the potential anti-thromboinflammatory effect of APC on T cells, ex vivo functional assays were established using paediatric IBD patients or donor PBMC-derived T cells treated with APC variants.

Results

We identified the presence of tissue factor (TF)+CD4+CD3+ T cells in the colons of both colitogenic mice and paediatric IBD patients during active disease (Fig 1.A-E). TF is best known as the predominant cellular initiator of blood coagulation, and subsequent ex vivo functional studies revealed that pro-inflammatory CD4+ T cells upregulate TF expression in response to T cell receptor ligation, resulting in rapid TF-dependent plasma thrombin generation and clot formation. TF is typically expressed in an ‘encrypted’ state and requires decryption for optimal procoagulant activity. Notably, activated and inflammatory CD4+ T cells were found to express significantly increased levels of acid sphingomyelinase and protein disulfide isomerase, critical mediators for TF decryption, on their cell membrane compared to naïve T cells. To understand how this process might be regulated, we performed meta-transcriptomic and gene expression analysis of IBD patient gut biopsy tissue, identifying dysregulated expression of genes involved in the regulation of coagulation, including PC (PROC) and its receptor (EPCR; PROCR) in IBD patients (Fig 1.F), revealing an environment permissive to, but deficient in, PC pathway anti-inflammatory activity. Subsequent functional studies revealed that activated protein C (APC) anti-inflammatory signalling reduced colitogenic T cell generation and activity, potently impaired TF decryption and significantly reduced T cell-mediated thrombin generation and clot formation (Fig 1.G-K).

Conclusion

These data implicate activated T cell thrombogenicity in IBD and demonstrate a prominent role for APC signalling in regulating colitogenic T cell thrombo-inflammatory activity.
DOP077 EndoUC: an AI-assisted endoscopic Ulcerative Colitis activity grading application for deployment in clinical trials
Authors: Kusumam K , Mohankumar G , Favory X , Beaton A , Teare P , Lundin P , Eberhardson M , Sherlock S P , Marks D J B
Published: January 2025

Background

Manual scoring of ulcerative colitis (UC) disease activity from endoscopy videos using the Modified Mayo Score (mMS) by experts is known to have high inter-rater and intra-rater variability.1 In clinical trials, central reviewers review endoscopy videos and provide a single score for the entire video leading to a loss of transparency with no evidence of scoring rationale or segmental involvement. We developed an AI-assisted severity scoring application for clinical trials to address this challenge by intelligently highlighting video segments showing pathological information and providing a continuous scoring approach to severity grading.

Methods

Unlike previous approaches that rely heavily on large-scale, expensive, and restrictive frame-level expert labels, we developed our models on video-level grading available in typical clinical trial settings. We used data from the brazikumab clinical trial [NCT03616821], comprising 423 videos from 249 patients scored on the mMS scale. Our preprocessing module removes uninformative, low-quality frames and applies detection, tracking and alignment algorithms to identify regions of interest across frames. Our EndoUC model has 3 components: a pathology-enriched frame identification module (PEFIM), an aggregator, and a classifier.The PEFIM module identifies regions that characterise signs of UC, such as ulcers or erosions. The aggregator and classifier modules learn to combine the information at the video level. We focus on the clinical utility of the EndoUC model in two ways: (i) having task-specific classifiers focusing on clinical decision boundaries of UC and (ii) enhancing scoring granularity of UC severity prediction using ordinal regression.

Results

We developed an application to enable experts to review lengthy endoscopy footage in clinical trials efficiently. The app allows seamless navigation to key regions identified by the EndoUC and transparently reveals the basis of the AI model’s assessments. We conducted 5-fold cross-validation on the clinical trial data and evaluated the model on a held-out test set with 87 videos. The remission (mMS 0, 1 vs 2, 3) model performs with an AUC-ROC of 0.85, F1 of 0.87, normal/inactive and severe models with AUC-ROC of 0.81and 0.83 respectively. The continuous grading model has an MSE of 0.42 and MAE of 0.40.

Conclusion

We developed an AI-assisted reading tool for UC endoscopic severity assessment to help accelerate clinical trails through rapid evaluation of patient eligibility, detection of treatment response grounded by key region evidence, and potential for continuous grading of endoscopic changes.

References

1.Daperno M, Comberlato M, Bossa F, et al. Inter-observer agreement in endoscopic scoring systems: Preliminary report of an ongoing study from the Italian Group for Inflammatory Bowel Disease (IG-IBD).Digestive and Liver Disease. 2014;46(11):969-973.
DOP081 The EXTENT Study (Calculating the LEmann indeX using inTEstiNal ulTrasound): Results from an international expert Delphi consensus
Authors: Palmela C , Torres J , Frias-Gomes C , Allocca M , Buisson A , Colombel J F , Maaser C , Novak K , Rimola J , Albshesh A , Bonifacio C , Krugliak Cleveland N , De Voogd F , Dollinger M , Furfaro F , Jauregui-Amezaga A , Karakan T , Kellar A , Kralj D , Lu C , Pruijt M , Rieder F , Roager Madsen G , Vizhi Nagarajan K , Sagami S , Scharitzer M , Stoker J , Taylor S A , Tews H , Vanslembrouck R , Vaughan R , Wilkens R , Verstockt B
Published: January 2025

Background

A primary objective in the management of Crohn's disease (CD) is the prevention of bowel tissue damage. The Lémann index (LI) characterizes structural bowel damage based on magnetic resonance enterography (MRE) or computed tomography enterography (CTE) and, for colonic CD, colonoscopy. Intestinal ultrasonography (IUS) provides a non-invasive imaging alternative, though its role in the LI assessment remains unexplored. This study aimed to establish a consensus on parameters and standardized acquisition for scoring small bowel and colonic damage using IUS in accordance with the LI.

Methods

Thirty international experts in IUS and/or MRE participated in a three-round Delphi process. Participants provided feedback and rated agreement with statements outlining IUS parameters and standardized acquisition in two virtual rounds. During the final in-person round, unresolved items were discussed and voted upon. Statements with at least 80% agreement were accepted.

Results

Twenty-two statements reached a consensus: 10 defined IUS parameters for stricturing and penetrating lesions for scoring LI-IUS, and 12 addressed optimal IUS cineloop acquisition for centralized review (Table 1). No consensus was reached regarding IUS equivalents for grade 1 stricturing lesions in the small bowel and colon.

Conclusion

Ultrasonographic equivalents for assessing small bowel and colonic damage in CD were derived to align with the validated LI criteria for MRE/CTE and colonoscopy. These statements mark the first phase of the EXTENT project, supporting the potential use of IUS in clinical practice and disease modification trials as an alternative tool for bowel damage assessment. The lack of consensus on grade 1 stricturing lesions suggests further exploration of IUS parameters is required.
DOP090 Serum metabolites predict endoscopic disease activity and clinical and endoscopic remission in Ulcerative Colitis
Authors: Welz L , Harris D , Schuchardt S , Tran F , Waschina S , Verstockt B , Vermeire S , Rosenstiel P , Schreiber S , Aden K
Published: January 2025

Background

In IBD, clinical symptoms often do not correlate with mucosal inflammation, generating an unmet need for non- or minimally invasive biomarkers of endoscopic disease activity. Furthermore, biomarkers predicting disease course and enabling early targeted therapy are lacking. We aimed to identify serum metabolites that distinguish healthy controls (HC) from UC patients, correlate with endoscopic disease activity and predict clinical and endoscopic remission in UC.

Methods

Serum was collected from HC (n=195) and UC patients in longitudinal (n=92) and cross-sectional cohorts (n=91; Kiel, Germany; discovery cohort). A longitudinal UC cohort (n=55; Leuven, Belgium) served as validation cohort. In longitudinal studies, serum was sampled in week (w) 0 and w14 before and after initiating advanced therapy. Endoscopic (eMayo≤1) and clinical remission (PRO2≤1) were assessed in w14. Metabolomics was conducted with the Biocrates MxP Quant 500 Kit. Statistical analysis was performed with linear mixed models, logistic and lasso regression, receiver operating curve (ROC) analysis and generalized estimating equation (GEE) (R version 4.4.1).

Results

Using linear mixed models, several serum metabolites predominantly related to amino and bile acid metabolism as well as triglycerides and sphingomyelins were significantly differentially abundant between HC and active UC (eMayo≥2, PRO2≥2). Among those, significantly increased beta-alanine, Hex2Cer(d18:1/16:0) (dihexosylceramide d18:1/16:0), glycocholic acid and hypoxanthine as well as significantly diminished tryptophan, taurine and histidine indicated endoscopically or clinically active compared to inactive UC (Fig. 1). To assess whether metabolites most robustly associated with active UC would better estimate endoscopic and clinical disease activity than C reactive protein (CRP), GEE and ROC analysis were employed. Indeed, combining beta-alanine, Hex2Cer(d18:1/16:0) and histidine with CRP augmented the area under the curve compared to CRP alone in the discovery and validation cohort. Lastly, combinations of metabolites selected via lasso regression (hypoxanthine, 1-methylhistidine, methionine, CRP, tryptophan, diglyceride 16:0_16:1 (DG(16:0_16:1)), triglyceride 18:0_34:3 (TG(18:0_34:3)) and triglyceride 16:0_30:2 (TG(16:0_30:2)) robustly predicted both clinical and endoscopic remission in w14 in the discovery and validation cohort (Fig. 2).

Conclusion

A combination of CRP with the serum metabolites beta-alanine, Hex2Cer(d18:1/16:0) and histidine detects active UC. Combining baseline CRP with hypoxanthine, 1-methylhistidine, methionine, tryptophan, DG(16:0_16:1), TG(18:0_34:3) and TG(16:0_30:2) predicts endoscopic and clinical remission in w14 with 90% probability.
DOP103 Optimization of Ustekinumab Treatment Induction Using a Pharmacokinetic Model in Inflammatory Bowel Disease Patients
Authors: Ramos Lopez L , Del Rosario-García B , Pérez-González F , Alonso-Abreu I , Carrillo-Palau M , Reygosa C , Medina-Chico J S , Medina-Heras S , Benítez-Zafra F , Morant-Domínguez A , Vera-Santana B , Ramos-Díaz R , Gutiérrez-Nicolás F , Hernández-Guerra M
Published: January 2025

Background

Therapeutic drug monitoring and pharmacokinetic modeling, implemented in the treatment of patients with inflammatory bowel disease (IBD), improve drug efficacy and reduce side effects. Recently, Ustekinumab (UST) levels associated with therapeutic targets have been established, principally during induction, highlighting the need for appropriate optimization of this phase to improve response to UST treatment.

Objectives

To evaluate the effectiveness of proactive dose optimization of UST using pharmacokinetic modeling during induction (target concentration at week 8) in the treatment of IBD with UST.

Methods

A prospective comparative study was conducted on IBD patients initiating UST treatment, divided into two groups: standard induction protocol (initial intravenous UST dose adjusted to weight) or optimized induction protocol (following the initial weight-adjusted intravenous UST dose, UST levels were measured at 4 weeks and, using a pharmacokinetic model—including weight, height, and serum albumin levels—induction dosing was adjusted). UST plasma concentration was measured by FIA at 4 weeks in the optimized group and at 8 weeks from treatment initiation in all patients. Data on IBD and the clinical status of patients at UST treatment initiation were reviewed.

Results

A total of 88 patients were included: 72 in the standard protocol group (male 52.8%; Crohn's disease 59.2%; prior biologic use 95.8%; fecal calprotectin >150 g/kg 61.5%) and 16 in the optimized group (male 56.3%; Crohn's disease 68.8%; prior biologic use 93.88%; fecal calprotectin >150 g/kg 68.8%), with no significant differences in baseline characteristics between groups. The mean UST concentration at the end of induction (8 weeks) was significantly higher in patients with optimization via pharmacokinetic model compared to the standard protocol (15.4 [10.4-20.3] µg/ml vs 9.2 [7.7-10.7] µg/ml; p>0.0018) (Fig. A). In the optimized group, 6 patients (37.5%) received additional intravenous UST doses (3 patients received 1 dose and 3 patients received 2 doses before week 8). The percentage of patients achieving a UST concentration ≥ 6.6 µg/ml (linked to biochemical remission at weeks 12 and 24) and ≥ 9 µg/ml (associated with treatment durability ≥ 12 months) was significantly higher in the optimized group compared to those on the standard protocol (Figs. B and C).

Conclusion

Optimized UST treatment, through proactive dose adjustment based on pharmacokinetic modeling, achieves a target UST concentration during induction that should ensure treatment efficacy.
DOP106 Geographic disparities in Healthcare Utilisation in people with inflammatory bowel disease, Crohn’s Colitis Cure Data Insights Program
Authors: Su W K , Wilson W , Ng W , Su H , Forbes A , Walker G , Kim A , Giles E , Lawrance I , Dutt S , Brett L , An Y K , Lynch K , Connor S J , Andrews J M
Published: January 2025

Background

Inflammatory bowel disease (IBD) is a lifelong illness, increasing in prevalence, with Australia (AUS) and New Zealand (NZ) amongst the highest in the world. Long-term management poses significant economic burden on people with IBD and the healthcare system. We aim to describe the healthcare utilisation (HCU) across 18 sites using Crohn’s Colitis Care (CCCare) as their IBD electronic management record (EMR).

Methods

CCCare is a cloud based EMR used in Australasia. Data feed into a de-identified clinical quality registry (CQR), which was interrogated in September 2024 to examine HCU over a 12-month period (September 2023 to 2024). People under active care, with a clinical assessment during the last 14 months were included. Descriptive statistics and a negative binomial regression model were used to examine for possible relationships amongst disease and demographic characteristics.

Results

There were 7506 eligible people, with a median age of 42 years (IQR 31 – 56). There was an even gender distribution (49.0%, n=3679, male) and more than half had Crohn’s disease (CD) (55.8%, n=4187), 41.4% (n=3107) ulcerative colitis (UC), and 2.8% (n=212) IBD-Unclassified. The median disease duration was 10.7 years (IQR 5.1 – 19.2). Most resided in AUS (73.1%, n=5487) and 26.9% (n=2019) in NZ. The majority of people resided in a metropolitan area (75.2%, n=4973), with 26.9% (n=1643) in non-metropolitan areas. Patient demographics are presented in table 1.

Ambulatory HCU is presented in table 1. Over the past 12 months, there were 10,705 helpline contacts (1.4 pp) and 11,439 (1.5 pp) clinical assessments either in-person or via telehealth. There were notably fewer endoscopic (0.2 pp) and radiology (0.3 pp) events. People with UC received endoscopies at a higher rate, but radiological events at a lower rate than those with CD (both p<0.001). Helpline contacts were also less frequent from people with UC compared to those with CD (p<0.01). Those residing in NZ consistently show lower HCU than in AUS in all HCU measures (p<0.01). Residing in non-metropolitan area is associated with lower use rate of radiology (p<0.05) and clinical assessments (p<0.01), but higher rates of helpline contacts compared to those in metropolitan areas (p<0.001).

Conclusion

The disparity in HCU suggests unwarranted variation in care or disparities in resource allocation creating inequities in health outcomes and access to care. The significant difference in HCU between countries and regions requires further correlation with healthcare outcomes. Identifying the most cost-effective approach to care that also improves patient outcomes will ultimately optimise health outcomes and advance value-based healthcare models for IBD management.
DOP112 Inflammation-associated monocytes express ACOD1 to curtail inflammatory behaviour in IBD and experimental colitis
Authors: Jones G R , Drury B , Hegarty L , Alegbe T , Krzak M , Raine T , Byrne A , Anderson C , Ho G T , Bain C
Published: January 2025

Background

ACOD1 is the ubiquitous source of the anti-inflammatory metabolite itaconate. We hypothesised monocyte ACOD1 expression is an inhibitory pathway that limits intestinal inflammation.

Methods

We performed single-cell RNA sequencing of colonoscopic biopsies from >120 Crohn’s disease (CD) patients and healthy controls, with complementary analysis of DSS treated C57BL/6J (WT) mice, validated using flow cytometry in independent cohorts. Acod1–/– mice received 2% DSS in acute and recovery models, complemented by competitive bone marrow chimeric mice, anti-IFN / itaconate-derivate treatment and transgenic cell depletion models.

Results

We profile the monocyte / macrophage compartment in human IBD using single-cell RNA sequencing and identify a discrete population of intestinal CXCL9/10+ cells that accumulate in IBD, which we term inflammation associated monocytes (IAMs).

These can be identified by the expression of CD319, CD274 and CCRL2, and demonstrate specific expression of IBD susceptibility genes, including NOD2. By performing cross-species analysis in mice, we show an analogous population of IAMs accumulate during chemically induced colitis. Using transgenic fate mapping approaches, we show these cells likely derive from a discrete MDP-precursor in the bone marrow and are locally imprinted to produce heightened IL-1β and TNF in mouse and humans.

Importantly, we show that co-incident with a hyper-inflammatory phenotype, these same cells uniquely and specifically express aconitate decarboxylase (ACOD1) in response to local Toll-like receptor (TLR) and interferon (IFN) receptor signalling, to limit unrestricted cytokine production.

Conclusion

Thus, the intestinal environment after injury instructs both inflammation and recovery specifically within a transitioning population of monocytes that are absent in health. Reduced itaconate production from IAMs in CD may predispose to chronic inflammation and disease progression.
DOP114 LDN-071, the novel amino acid-based PAI-1 inhibitor, significantly reduces the severity of acute and chronic inflammation in colitis models
Authors: Jójárt B , Csákány-Papp N , Laub H , Vasas B , Barta B , Szabó V , Kajári L , Bagyánszki M , Farkas K , Mándity I , Heltovics G , Pallagi P , Maléth J ,   Epithelial Cell Signaling and Secretion Research Group
Published: January 2025

Background

Over recent decades, significant progress has been made in the pharmacological management of Inflammatory Bowel Diseases (IBD). However, the sustained efficacy of existing anti-inflammatory therapies remains suboptimal, highlighting the urgent need for novel treatments. Recent studies have implicated the coagulation pathway, particularly Plasminogen Activator Inhibitor 1 (PAI-1), as a crucial link between epithelium and inflammation in IBD. Genetic deletion of PAI-1 has been shown to reduce experimental colitis severity in mice. Based on these findings, we aimed to develop and evaluate novel PAI-1 inhibitors for IBD treatment.

Methods

Using the A3SMO® platform, we synthesized LDN-071, an amino acid-based PAI-1 inhibitor, and assessed its inhibitory potential and cytotoxicity in vitro. Acute and chronic colitis models were induced in mice using DSS, with 10 mg/bwkg LDN-071 administered orally. Body weight, spleen weight, and colon length were monitored, while colon histology was analysed. Cytokine expression was measured via ELISA and qRT-PCR, and collagen deposition was quantified using a hydroxyproline assay. Human colon organoid (HCO) and fibroblast (FB) cultures from IBD patients were used to evaluate LDN-071’s effects. Toxicity was assessed in vivo in mice.

Results

LDN-071 effectively inhibited PAI-1 in vitro without cytotoxicity (1µM–1mM). In DSS-treated mice, 10 mg/bwkg LDN-071 prevented body weight loss, bloody diarrhea, colon shortening, and spleen enlargement. Histological analysis showed that PAI-1 inhibition significantly reduced severe inflammation, ulceration, crypt structure loss, and goblet cell depletion in acute and chronic colitis models. Additionally, PAI-1 inhibition reduced mucosal TNF-α, IL-1β, and IL-6 expression during acute inflammation. In chronic colitis, LDN-071 decreased inflammation, epithelial erosion, and fibrosis while significantly lowering collagen deposition. Importantly, no toxicity was observed at 100 mg/bwkg LDN-071 for seven days. In vitro, LDN-071 reduced pro-inflammatory cytokine expression in HCOs from IBD patients and significantly decreased fibrosis-related gene expression in patient-derived FB cultures.

Conclusion

Our results showed that LDN-071, a novel amino acid-based inhibitor of PAI-1, significantly ameliorated the severity of acute and chronic colitis in mice. However, the LDN-071 reduced the expression of inflammation- and fibrosis-related genes and proteins in vitro human models. We propose that the inhibition of PAI-1 could be a potential novel therapeutic strategy in IBD.
DOP117 Innate lymphoid cells control colitis and intestinal fibrosis via cellular stress response in mice and human
Authors: Cao S , Ma K , Deepak P
Published: January 2025

Background

Group 2 innate lymphoid cells (ILC2s) are increased in peripheral blood and intestinal samples from IBD patients and mice with colitis. ILC2s are major producers of type 2 cytokines including IL-5 and IL-13 and growth factor AREG that induce goblet cell hyperplasia and mitigate acute inflammation in the gut. On the other hand, prolonged or uncontrolled ILC2 activation may contribute to chronic inflammation and tissue fibrosis, although the role of ILC2s in stricturing/fibrostenotic Crohn’s disease (CD) has been unknown. In this study, we investigated the function of IRE1a-XBP1 pathway, a regulatory hub of cellular stress response, in colitis and fibrosis in mice and CD patients.

Methods

We generated conditional knockout Ire1aflo/floxIl5-Cre (Ire1aΔIl5) and Rag-/-Ire1aΔIl5 mice with Ire1a deleted in ILC2s. Dextran sodium sulfate (DSS)-induced and T-cell transfer colitis models were used. Human peripheral ILC2s were collected for flow cytometry and ex vivo stimulations.

Results

Mouse intestinal ILC2s express high level of Ire1a. The number of ILC2s increased in colon, small intestine (SI), and esophagus of Ire1aΔIl5 mice with elevated proliferation marker Ki67. Additionally, SI and colonic Ire1aΔIl5 ILC2s produced more IL-5, IL-13, and AREG after ex vivo stimulation with IL-33 or IL-25. Consistently, selective IRE1 inhibitor 4u8C enhanced production of IL-13, while selective IRE1 activator IXA4 suppressed IL-13 in sort-purified human ILC2s ex vivo (Figure 1). Bulk RNA-seq of SI Ire1aΔIl5 ILC2s showed reduced Rxrg and elevated fatty acid transport by pathway analysis, which may lead to the increased proliferation and cytokine production in Ire1aΔIl5 ILC2s. Upon DSS challenge, Ire1aΔIl5 mice exhibited milder signs of disease including weight loss, clinical scores as well as colon shortening and histology, which was accompanied by elevations in ILC2-derived cytokines and AREG as well as heightened goblet cell differentiation and mucin production. In contrast, upon adoptive T-cell transfer, Rag-/-Ire1aΔIl5 mice developed worsened chronic colitis and intestinal fibrosis, which was reversed by intraperitoneal injection of neutralizing antibody against IL-13 or AREG. Furthermore, CD patients with intestinal strictures expressed higher level of IL-13 in ILC2s in the blood (Figure 2).

Conclusion

IRE1a-XBP1 constrains cytokine production by intestinal ILC2s during inflammation. IRE1a deficiency in ILC2s protected against acute colitis with heightened type 2 cytokines and AREG; while loss of IRE1a exacerbated chronic colitis and fibrosis. The presence of CD strictures was associated with elevated IL-13 in peripheral ILC2s . We identified IRE1a and ILC2s as potential biomarkers and therapeutic targets for stricturing CD.
DOP123 Linking microbial genes to mucosal metabolites uncovers host-microbial interactions during 5-ASA therapy for ulcerative colitis
Authors: Jiang L , Guo M , Ruan G , Zhou R , Cao Y , Bai X , Yang H
Published: January 2025

Background

The severity of ulcerative colitis (UC) depends on the state of the colon mucosa, where achieving mucosal remission markedly improves patient prognosis and quality of life. The study aimed to characterize essential mucosal metabolites and microbial gene involved in UC remission, and to elucidate the mechanisms by which specific metabolites regulate intestinal homeostasis.

Methods

An integrated metagenomic and metabolomic analysis was conducted to elucidate the correlation between disease-associated microbes and host mucosal metabolites. Participants included non-UC controls and individuals with UC, comprising the responding group (UCR) and ineffective group (UCA) in 5-ASA treatment. The differential metabolite was further investigated using a DSS-induced colitis mouse model, followed by in vitro experiments to explore the mechanisms.

Results

The levels of mucosal secondary bile acids were found to have a significant negative association with intestinal inflammation during 5-ASA treatment. Integrated analysis of metagenomics and metabolomics revealed that host mucosal bile acid metabolites were negatively associated with the bile acid synthesis-related genes cbh in microbial genomes. Administration of the secondary bile acid mitigated mucosal inflammation in a colitis model by decreasing the proportion of Th17 and pathogenic Th17 cells. This secondary bile acid functions as an immunomodulatory metabolite, suppressing glycolysis in Th17-polarizing T cells to inhibit the Th17 cell response and modulating the gut microbiota.

Conclusion

These findings suggest that alterations in microbiome-metabolome interactions are critical for maintaining mucosal homeostasis during UC remission. The specific bile acid acts as an immunomodulatory metabolite, and may represent a potential therapeutic strategy for UC.

References

1.Lloyd-Price J, Arze C, Ananthakrishnan AN, et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 2019;569:655-662.

2.Dang EV, Barbi J, Yang HY, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 2011;146:772-84.

3.Png CW, Linden SK, Gilshenan KS, et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol 2010;105:2420-8.
DOP125 CD11b−CD27− NK subsets account for NK-cell dysfunction in patients with inflammatory bowel disease
Authors: Zhang Y , Hong G
Published: January 2025

Background

Natural killer (NK) cells play a crucial role in the dynamic interaction between innate and adaptive immune responses but their function is dysregulated in patients with inflammatory bowel disease (IBD)[1-4]. The mechanism that contributes to NK-cell dysregulation in IBD requires further elucidation.

Methods

Using flow cytometry staining, we precisely characterized the frequency, phenotype and function of NK subsets distinguished by CD27 and CD11b in 61 treatment-naive patients with active IBD (including 34 with Crohn’ s disease (CD) and 27 with ulcerative colitis (UC)), as compared to 30 healthy volunteers.

Results

We observed a significantly increased proportion of the peripheral CD11b-CD27- (double-negative, or DN) NK subsets in IBD patients. Notably, these relatively expanded DN NK subsets exhibited an inactive and immature phenotype. Functional analysis, conducted by stimulating and assessing the expression of CD107a and interferon-gamma (IFN-γ), revealed that the DN NK subsets had poor cytotoxic capacity and a deficient potential to produce IFN-γ. In addition, the percentages of DN NK subsets expressing CD107a and IFN-γ were positively correlated with NK degranulation and cytokine production, respectively. Interestingly, we also found that the frequency of DN NK subsets seemed to correlate with the plasma levels of IL-17A. High levels of IL-17A constrain the proliferation and maturation of NK cells in vitro. In some IBD patients who achieved clinical remission after receiving biological agent therapy, the percentage of DN NK subsets decreased accordingly.

Conclusion

The increased proportion of DN NK subsets may account for NK-cell dysfunction in IBD patients, potentially associated with elevated plasma levels of IL-17A. These alterations in NK cell subsets may contribute to defective killing and thus the secondary infections and increased risk of cancer observed in IBD patients.

References

1. Zaiatz Bittencourt V, Jones F, Tosetto M, Doherty GA, Ryan EJ. Dysregulation of Metabolic Pathways in Circulating Natural Killer Cells Isolated from Inflammatory Bowel Disease Patients. J Crohns Colitis. 2021;15(8):1316-1325.

2. Samarani S, Sagala P, Jantchou P, et al. Phenotypic and Functional Changes in Peripheral Blood Natural Killer Cells in Crohn Disease Patients. Mediators Inflamm. 2020;2020:6401969.

3. Yadav PK, Chen C, Liu Z. Potential role of NK cells in the pathogenesis of inflammatory bowel disease. J Biomed Biotechnol. 2011;2011:348530.

4. Giacomelli R, Passacantando A, Frieri G, et al. Circulating soluble factor-inhibiting natural killer (NK) activity of fresh peripheral blood mononuclear cells (PBMC) from inflammatory bowel disease (IBD) patients. Clin Exp Immunol. 1999;115(1):72-77.
DOP126 Circulating neutrophils exhibit distinct transcriptional and maturity changes in CD and UC that relate to pathogenic Th1/17 CD4+ memory T cell responses
Authors: Pascutti M F , Calado B , Smits W K , Tuk B , Hulleman-van Haaften D H , van Berkel L A , Barendregt D M H , Heredia M , Klomberg R C W , Camman A E , . Escher J C , de Ridder L , Samsom J N
Published: January 2025

Background

Neutrophils are key players in intestinal damage in Crohn’s disease (CD) and ulcerative colitis (UC) but their immunological role in disease heterogeneity is largely overlooked. In both diseases, mature circulating neutrophils enter the intestinal tissue to clear invading bacteria but cause irreversible tissue damage. However, neutrophil function can be altered by pathogenic Th1/17 CD4+ memory T cell (Tm) responses even before the cells enter the tissue. We hypothesize that altered neutrophil function differs between, and within, CD and UC and that interpatient differences in pathogenic Tm responses change transcriptional profiles in circulating neutrophils, impacting their function in the inflamed mucosa.

Methods

We analyzed clinically well-characterized therapy-naive pediatric CD (n=33) and UC (n=12) patients and IBD-negative controls (IBDneg; n=11) from the PIBD-SETQ cohort and performed RNAseq on purified circulating neutrophils, neutrophil flow cytometry and plasma proteomics using Proximity Extension Assay technology.

Results

Comparison of gene expression profiles at diagnosis revealed 263 differentially expressed genes (DEG) in neutrophils from CD vs IBDneg, and 421 DEG in UC vs IBDneg, with 137 genes common to both comparisons and 137 DEG in CD vs UC. CD and UC neutrophil transcriptomes were enriched for granule biology pathways (MMP8, S100A8/9), while IFN-related pathways were only present in CD neutrophils. As granule proteins are expressed in neutrophils during maturation in bone marrow but not in circulation, we assessed the maturity of circulating neutrophils by flow cytometry. Neutrophils from UC, but not CD patients had phenotypic features of immaturity (lower surface expression of CD10, CD16 and CXCR2). As predicted, neutrophil gene expression profiles showed high interpatient heterogeneity within CD and UC. Within both CD and UC, hierarchical clustering on the basis of neutrophil DEG identified two patient clusters. In UC1 patients, neutrophils had higher expression of genes for granule proteins which related to higher plasma concentrations of IL-17A, CCL20 and MMP10 compared to UC2. In CD2 patients, neutrophils had increased gene expression for IFN-signaling and extracellular matrix re-organization relating to higher plasma IFNg, CDCP1 and CXCL9 compared to CD1.

Conclusion

We demonstrate that at time of diagnosis circulating neutrophils have acquired changes in transcriptional and maturity profiles that differ between and within CD and UC. In individual patients, transcriptomic changes correlate to pathogenic Th1/17 CD4+ Tm profiles. These changes may functionally alter neutrophil-mediated bacterial clearance and tissue damage in the inflamed mucosa and help decipher disease pathogenesis in individual patients.
DOP128 Spatial transcriptomic analysis reveals evolutionary dynamics in colitis-associated colorectal cancer
Authors: Kim Y , Lee Y , Lee M , Yoon D K , Baek J , Hwang S W , Lee J L , Park S H , Yang D H , Kim J , Yang S K , Han B , Song K , Yoon Y S , Ye B D , Lee H S
Published: January 2025

Background

Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease, particularly ulcerative colitis. Despite its clinical significance, the spatiotemporal dynamics of neoplastic progression in CAC remain poorly understood. This study aimed to elucidate the evolutionary trajectory of CAC using spatial transcriptomics.

Methods

We employed spatial transcriptomics to analyze four tissue samples from three patients with ulcerative colitis at various stages of neoplastic progression. Whole-slide spatial transcriptomics RNA sequencing was performed, enabling simultaneous analysis of gene expression and tissue architecture. Integrated spatial transcriptomic data revealed recurring epithelial programs along the progression of copy number alteration.

Results

Our analysis using copy number variation (CNV) score and Hematoxylin and Eosin (H&E) staining image revealed progressive changes in gene expression patterns as tissue transitioned from non-tumor to pre-tumor and finally to tumor states. This progression was quantified using beta coefficient values, allowing us to track gradual alterations in gene expression across the disease continuum. We identified a core set of 48 genes that exhibited consistent changes across all four analyzed samples. Among these, 40 genes showed a progressive decrease in expression, while eight genes, including CLDN1, E2F1, and RECQL4, demonstrated a gradual increase in expression as the tissue advanced towards a tumorous state. These upregulated genes pointed to potential oncogenic drivers or compensatory mechanisms activated during tumor development. Pathway analysis of the 48 genes revealed enrichment in key cellular processes, including p53 signaling, transcriptional regulation by E2F factors, and role of PKR in interferon induction and antiviral response. Upstream Regulator analysis revealed YAP1 and TGFB1 as the most significant regulators, highlighting the importance of transcriptional control and growth factor signaling in CAC development.

Conclusion

This study provides unprecedented insights into the spatiotemporal dynamics of CAC progression. By leveraging spatial transcriptomics, we have mapped the evolutionary trajectory of CAC at high resolution, revealing key molecular events and spatial features associated with disease progression. These findings not only enhance our understanding of CAC pathogenesis but also highlight potential targets for early intervention and personalized treatment strategies.