bluuebunny/crossref_metadata_2025_split 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

Abstract

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&lt;0.001) and 38/78 patients (48.7%) - anti-TNF (OR 5.29, 95%CI 2.39-11.71, p&lt;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&lt;0.001) and 27/49 (55.1%) with anti TNF (OR 12.03, 95%CI 2.99-48.47, p&lt;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

Abstract

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

Abstract

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 &lt; 0.001; Figure 1). Normal C-reactive protein and fecal calprotectin (FC) &lt;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 &lt; 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

Abstract

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 &gt;0 and a Global Histologic Disease Activity Score &gt;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

Abstract

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

Abstract

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

Abstract

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

Abstract

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.