bluuebunny/crossref_metadata_2025_split huggingface dataset:
OP03 Highly stable epigenome-wide peripheral blood DNA methylation signatures accurately predict endoscopic response to adalimumab, vedolizumab and ustekinumab in Crohn’s disease patients: The EPIC-CD study
Authors: Joustra V , Li Yim A , Hageman I , Levin E , Noble A , Chapman T , McGregor C , Adams A , Satsangi J , de Jonge W , Henneman P , D’Haens G 
Published: January 2023

Abstract

Background
Despite the proven efficacy of biological treatments in Crohn’s disease (CD), many patients fail to respond or lose response over time. Therefore, predictive biomarkers for treatment efficacy would be of extreme value. Previous epigenome-wide association studies associated differential DNA methylation with CD-specific phenotypes, suggesting a potential use in classification and prediction of response to treatment.

Methods
We prospectively collected and measured longitudinal peripheral blood DNA methylation profiles of 184 adult CD patients prior to (T1) and after a median of 28 weeks (T2) following biological treatment with Adalimumab (ADA), Vedolizumab (VEDO) or Ustekinumab (USTE) in a discovery (n=88) and independently collected internal validation cohort (n=96) using the Illumina EPIC BeadChip array. Response (R) was defined as the combination of endoscopic response (≥50% reduction in SES-CD score) and steroid-free clinical response (≥3 point drop in HBI or HBI ≤4 AND no systemic steroids) and/or biochemical response (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin or a CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Biomarker identification and classification analyses were performed using stability selection gradient boosting on samples taken at T1 whereas samples taken at T2 and intraclass correlation (ICC) data were used to assess long-term stability of our identified CpG loci1.

Results
A total of 58 ADA-patients (NR=29, NNR=29), 64 VEDO-patients (NR=36, NNR=28) and 62 USTE-patients (NR=30, NNR=32) were included. Prior to treatment, at T1, we identified distinct panels of 100 ADA-, 22 VEDO- and 68 USTE-associated CpG loci that, in combination, predict clinical- and endoscopic response with high accuracy (AUC ADA=0.73, VEDO=0.89 and USTE=0.94) upon validation. Notably, for these CpG loci, methylation levels did not significantly differ between T1 and T2, implicating stability during both induction and maintenance treatment, irrespective of inflammatory status and therapeutic intervention. In addition, the majority of these CpG loci (&gt;60%) demonstrated long-term hyper stability (ICC-values ≥0.90). Furthermore, genes annotated to the CpGs of interest suggest drug specific involvement in TNF-signaling, endothelial cell-cell adhesion, integrin dependent T-cell homing, the innate immune system and Th17/Treg differentiation, corroborating to the mode of action of each drug.

Conclusion
Here, we report on 3 validated panels of highly stable, epigenetic biomarkers that predict clinical and endoscopic response in CD patients treated with ADA, VEDO or USTE. Additional external- and clinical validation as part of EPIC-CD and the OMICROHN clinical trial are currently ongoing.
OP09 Long-term Colectomy rates of Ulcerative Colitis over 40-year of Different Therapeutic eras – Results from a Western Hungarian Population-based Inception Cohort between 1977–2020
Authors: Lakatos PhD P L , Gonczi L , Lakatos L , Golovics P A , Pandur T , David G , Erdelyi Z , Szita I 
Published: January 2023

Abstract

Background
Few population-based studies have investigated the long-term colectomy rates of ulcerative colitis (UC). The present study is a continuation of the Veszprem IBD population based cohort with a follow-up of the incidence and disease course for over 40 years. We aimed to assess the colectomy rates over 40 years of different therapeutic eras in a prospective population-based inception cohort from Veszprem Province, Western Hungary.

Methods
Patient inclusion lasted between January1,1977 and December31, 2018. Patient follow-up ended December 31,2020. Both in-hospital and outpatient records were collected and comprehensively reviewed at diagnosis and during clinical follow-up. Disease extension was evaluated based on the Montreal classification. Colectomy rates and disease course were examined in three different eras based on the time of UC diagnosis; cohort-A(1977-1995),cohort-B(1996-2008), and cohort C(2009-2018).

Results
Data of 1,370 incident UC patients were analyzed (male/female: 702/668; median age at diagnosis: 37 years(y) [IQR: 26-51]), with a median of 17y (IQR 9-24) follow-up. Table 1. The overall colectomy rate was 76/1,370 patients during the total follow-up. The proportion of extensive colitis at diagnosis increased over time (24.2% / 24.3% / 34.9% in cohorts A/B/C; p=0.001). Overall immunosuppressive therapy exposure was increasing in the cohorts (11.3% / 20.9% / 34.4%; p&lt;0.001), as well as the probability of biological therapy initiation within 5 years of diagnosis (0.0±0% / 3.3±0.7% / 13.9±1.8%; pLogRank&lt;0.001). Figure 1. There was no significant difference in the cumulative probability of proximal disease progression from proctitis (E1) to left-sided colitis/extensive colitis (E2/E3) or from left-sided colitis (E2) to extensive colitis (E3) over time in cohorts A, B, and C (Long-rank=0.482). Figure 2. The cumulative probability of colectomy in the total population was 4.1±0.6% after 10 years, 6.3±0.8% after 20 years, and 8.8±1.2% after 30 years. There were no statistically significant differences in the cumulative probability of colectomies between cohorts A/B/C: 1.7±0.7% / 2.2±0.6% / 3.7±1.0% after 5 years; 3.5±1.0% / 3.9±0.8% / 4.5±1.2% after 10 years; and 6.9±1.4% / 5.3±1.0% (cohorts A/B) after 20 years [pLogRank=0.447]. Figure 3. Extensive disease (HR 2.3;95%CI 21.60-3.37) and continuous uncontrolled disease activity (HR 6.89;95%CI 4.15-11.46) were independent predictors for colectomy. Table 2.

Conclusion
No differences in proximal disease progression and colectomy rates have been observed in the incident UC patients over 40 years despite increasing use of immunomodulators and biological therapies.
OP25 Prevalence of IBD in the Netherlands: development and validation of machine learning models for administrative data
Authors: Van Linschoten R , van Leeuwen N , Hazelzet J A , van der Woude C J , van Noord D , West R L 
Published: January 2023

Abstract

Background
Treatment of IBD has improved with the introduction of biologics and small molecules, yet this has come with a considerable increase in healthcare costs. Due to the increasing cost burden, reliable nationwide epidemiological data on the prevalence of IBD is necessary to inform health policy makers, especially as the prevalence of IBD is forecasted to double between 2010 and 2030. We aimed to develop a model for identifying prevalent IBD cases in administrative data and to determine prevalence of IBD in the Netherlands.

Methods
Data on hospital care came from the Dutch National Hospital Care Basic Registration (Landelijke Basisregistratie Ziekenhuiszorg). This database contains data on all hospital admissions (since 1991), outpatient clinic visits (since 2017), and dispensations of biologics and small molecules (since 2015) of all hospitals in the Netherlands. Data on pathology reports were retrieved from the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA), this database contains coded pathology reports of all Dutch hospitals since 1991. These datasets were combined with a reference cohort with a verified IBD diagnosis (yes/no) and demographics for all patients. Models were trained to optimise the F-score and evaluated using five-times repeated ten-fold cross-validation. The best performing model from cross-validation was applied to assess IBD prevalence in the Netherlands.

Results
The reference cohort consisted of 10,155 patients, of which 3,381 were diagnosed with IBD. All models performed well in the cross-validation procedure, with F-scores of 0.870 and higher. The use of more flexible models led to improved performance, with gradient boosted trees performing best in the cross-validation procedure (Table 1). When applying the gradient boosted trees model to the general population, a prevalence of 691 per 100,000 was found for IBD in the Netherlands on 31-12-2020. Cases are unevenly distributed throughout the Netherlands (Figure 1), with the highest incidence in the south (Middle Limburg: 936 per 100,000 inhabitants) and the lowest in the northwest (Amsterdam: 545).

Conclusion
Prevalent IBD cases can be identified from administrative data using a gradient boosted trees model. Using this model, we have shown that prevalence of IBD in the Netherlands is increasing. However, while prior studies have predicted a growth in prevalence of 50% over the last 10 years, we found that IBD prevalence has only increased by 12% in that time range. The lower increase in prevalence may be predictive of a transition to the fourth epidemiological stage of IBD, aptly named Prevalence Equilibrium.
DOP09 Eosinophils exert a pro-inflammatory role in a chronic DSS colitis model without an impact on fibrosis
Authors: Jacobs I , Deleu S , Cremer J , De Hertogh G , Vermeire S , Breynaert C , Vanuytsel T , Verstockt B 
Published: January 2023

Abstract

Background
Eosinophils might play a pro-inflammatory role in inflammatory bowel disease (IBD). However, the role of eosinophils in intestinal fibrosis remains poorly understood, although a pro-fibrotic function has been hypothesized based on data outside the gastrointestinal tract. Therefore, we aimed to unravel the role of eosinophils in chronic intestinal inflammation and fibrosis and to explore eosinophil depletion as a potential therapeutic target.

Methods
A 3-cycles chronic dextran sodium sulphate (DSS) model was induced in 6-8-week-old C57BL/6 wild type mice. Mice received 3 DSS cycles (1.5% - 2.00% - 2.00%) in which 1 DSS cycle consisted of 1 week of DSS administration followed by 2 weeks of recovery. During the 3 cycles, and starting 3 days prior to colitis induction, anti-CCR3 antibody or isotype injections were given twice weekly to study the effect of the eosinophil depletion (total of 18 injections). The disease activity index (DAI; weight loss, stool consistency and presence of blood) was determined twice weekly. At sacrifice, colonic damage was scored macroscopically (presence of hyperaemia, adhesions and length and degree of colon affected by inflammation) and colonic single cells were isolated and fluorescently stained for flow cytometry. Eosinophils were thereby identified as CD45+ CD11b+ Siglec-F+ CD117- cells. Lastly, a histological active disease score was determined comprising of the sum of neutrophil infiltration, mononuclear cell infiltration, changes in mucosal architecture, goblet cell loss and epithelial defects (Creyns et al., 2019). Intestinal fibrosis was assessed via colon weight/length ratio, COL1A1 gene expression and collagen deposition with a Martius Scarlet Blue (MSB) staining and a colorimetric hydroxyproline assay.

Results
Blood and colonic eosinophil depletion via anti-CCR3 injections was confirmed via flow cytometry (figure 1). The DAI in the eosinophil depleted group was decreased compared to the isotype injected group (area under the curve 115.4 ± 29 vs 160.6 ± 28; p=0.02). A similar trend was seen in the macroscopic damage score (2.0 ± 1.3 vs 3.9 ± 2.1; p=0.08). Furthermore, a lower histological active disease score was found in the mice in which the eosinophils were depleted compared to the isotype injected mice (8.8 ± 0.8 vs 12.8 ± 1.5; p=0.002) (figure 2). Lastly, no differences in the parameters for fibrosis between the anti-CCR3 injected and isotype injected groups were observed (figure 3).

Conclusion
Eosinophil depletion via intraperitoneal anti-CCR3 injections resulted in partial protection from intestinal inflammation in chronic DSS, and could therefore be further explored as a potential therapeutic agent. In contrast, eosinophil depletion does not seem to have any anti-fibrotic effect
DOP16 Anti-integrin αvβ6 autoantibodies predate Ulcerative Colitis diagnosis by up to 10 years and are associated with adverse disease-related outcomes
Authors: Livanos A , Dunn A , Fischer J , Ungaro R C , Turpin W , Lee S H , Rui S , Del Valle D M , Jougon J J , Martinez-Delgado G , Riddle M S , Murray J A , Laird R M , Torres J , Agrawal M , Magee J S , Dervieux T , Gnjatic S , Sheppard D , Sands B E , Porter C K , Croitoru K , Petralia F , Colombel J F , Mehandru S ,   CCC-GEM Project Research Consortium and OSCCAR Consortium
Published: January 2023

Abstract

Background
Biomarkers for predicting the development of Ulcerative Colitis (UC) and disease-related complications are lacking. Anti-integrin αvβ6 IgG autoantibodies (anti-αvβ6) have been recently described in patients diagnosed with UC. Here, we sought to determine if anti-αvβ6 autoantibodies predate UC development and to study associations between anti-αvβ6 and disease outcomes in newly diagnosed UC patients.

Methods
In a unique pre-clinical IBD cohort from the PRoteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects (PREDICTS), anti-αvβ6 were measured in longitudinal pre-diagnosis serum samples from 82 subjects who later developed UC as well as in 82 matched subjects that did not develop IBD (HC). Sample A was at the time of UC diagnosis, Sample B was at a median of 2 years before Sample A, Sample C was at a median of 4 years before Sample A and Sample D was at a median of 10 years before Sample A. In a distinct, external validation cohort (the Crohn’s and Colitis Canada Genetics Environment Microbial (GEM) Project), we tested samples from 12 subjects who later developed UC and compared those with 49 matched subjects who remained asymptomatic. Further, anti-αvβ6 were measured in 2 incident IBD cohorts (COMPASS, n=55 and OSCCAR, n=104 UC subjects) and associations between anti-αvβ6 and adverse UC-outcomes were defined using Cox proportional-hazards model.

Results
Anti-αvβ6 were significantly higher in the PREDICTS cohort among individuals who developed UC compared to HC up to 10 years prior to diagnosis (Figure 1A). The anti-αvβ6 seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 timepoints. Additionally, the predictive performance of anti-αvβ6 autoantibodies as assessed via area under the receiver operator curves (AUROC) with 10-fold cross validation was at least 0.8 up to 10 years before diagnosis (Figure 1B). Elevated levels of anti-αvβ6 in pre-clinical UC samples were further validated in the GEM cohort (Figure 1C). Finally, high anti-αvβ6 were associated with a composite of adverse UC-outcomes including hospitalization, disease extension, colectomy, systemic steroid use and/or escalation to biologic therapy in both incident cohorts (Figure 1D).

Conclusion
Anti-integrin αvβ6 autoantibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.
DOP20 The impact of early life antibiotics on the occurrence of paediatric inflammatory bowel disease - a nationwide study from 1995 – 2018
Authors: Jawad A , Jansson S , Malham M , Wewer V ,   Copenhagen Center for Inflammatory Bowel Disease in Children- Adolescents and Adult
Published: January 2023

Abstract

Background
Early–life antibiotic exposure has been associated with a decreased richness of the microbiome, which is associated with the development of inflammatory bowel disease (IBD). The aim of this study was to assess the risk of developing paediatric-onset IBD (pIBD) after being exposed to systemic antibiotics during the first five years of life.

Methods
We identified all patients &lt; 18 years old diagnosed with pIBD in Denmark between 1995-2018 in the National Patient Registry. Data on antibiotic prescriptions during first five years of life were retrieved from the National Prescription Register. PIBD patients were matched with up to ten healthy controls. Risk estimates were presented by Hazard ratios (HR).

Results
We identified 1,808 patients with pIBD (989 Crohn’s disease [CD]/819 ulcerative colitis [UC]) and 17,234 matched controls. An increased risk of developing pIBD was associated with prescription of antibiotics during first five years (HR = 1.32 [95%CI: 1.2-1.5], p= &lt;0.0001), and risk was further increased if the patient had ≥ 4 antibiotic prescriptions compared to no antibiotic prescription (HR = 1.43 [95%CI: 1.2-1.6], p= &lt;0.0001). Prescription of broad-spectrum antibiotics increased the risk of pIBD compared to prescription of only narrow-spectrum antibiotics (HR: 1.19, [95%CI 1.0-1.4], p=0.04). When stratified by IBD subtypes, only CD was significantly associated with exposure to antibiotics (HR = 1.43 [95%CI: 1.2-1.7], p=0.0003).

Conclusion
In this nationwide registry-based study, we found that antibiotic exposure during first five years of life, was associated with an increased risk of pIBD. Repeated antibiotic exposures increased risk estimates.
DOP89 Impact of biologics on the risk of early postoperative complications in Crohn’s disease: a French nationwide study
Authors: Fumery M , Nancey S , Nachury M , Allez M , Rouillon C , Boureille A , Altwegg R , Serrero M , Vuitton L , Bouguen G , Abitbol V , Boualit M , Biron A , Panis Y , Laharie D , Amiot A , Simon M , Caillo L , Hébuterne X , Vidon M , Benezech A , Elgharabawy Y , Peyrin-biroulet L ,   GETAID
Published: January 2023

Abstract

Background
While the effect of anti-TNFs on postoperative outcomes in patients with Crohn’s disease (CD) has been widely studied, the impact of vedolizumab and ustekinumab on the risk of postoperative complications remains poorly known.

Methods
All consecutive patients who underwent intestinal resection for CD between July 2014 and April 2022 within 22 French centers were included in a retrospective cohort. The risk of early post-operative complications (≤30days) in patients exposed to biologics was compared to patients not exposed by logistic regression and propensity score-matched analysis adjusted for age, previous intestinal resection, corticosteroids or immunosuppressants exposure, disease activity, presence of abscess, urgent surgery and initial stoma (preoperative contra-indication to anastomosis).

Results
Among the 1201 patients included, respectively 491 (41%), 76 (6.3%) and 57 (4.7%) were exposed to anti-TNFs, ustekinumab, or vedolizumab within six months before surgery. A total of 317 (26.4%) patients had at least one complication of which 123 (38%) were considered as severe (DINDO III/IV). New surgery was necessary in 69 (5.7%) patients and secondary stoma in 23 (1.9%). Three deaths were observed (0.25%). The rates of overall complications in patients not exposed to biologics, exposed to anti-TNFs, ustekinumab or vedolizumab were respectively 26.1%, 25.1%, 34.7% and 29.8%. The risks of intra-abdominal infectious complications in these four groups were respectively 13.5%, 11.1%, 13.3% and 8.8%. In multivariate analysis, age [OR, 1.02 (1.01-1.04); p=0.004], disease activity [OR, 8.36 (1.79 – 149); p=0.037], the presence of an abscess [OR, 2.01 (1.25-3.20); p=0.004] and initial stoma [OR, 1.70 (1.10 –2.61); p=0.016] were significantly associated with intra-abdominal infectious complications. Conversely, preoperative enteral nutrition [OR, 0.12 (0.01 -0.59); p=0.040] was associated with a reduction in this risk. Exposure to anti-TNFs [OR, 0.80 (0.51-1.24); p=0.31], ustekinumab [OR, 1.17 (0.39-3.51); p=0.78] and vedolizumab [OR, 1.28 (0.32-5.17); p=0.72] within the 3 months before surgery were not associated with the risk of intra-abdominal infectious complications. Similar results were observed in patients exposed to these treatments in the month before surgery.

Conclusion
In this large cohort, a quarter of patients operated on for CD presented an early postoperative complication and 10% a severe complication. Preoperative exposure to anti-TNFs, vedolizumab or ustekinumab was not associated with an increased risk of early postoperative complications. Preoperative enteral nutrition was associated with a reduced risk of intra-abdominal infectious complication.
P175 Burden of Inflammatory Bowel Disease in Mexico: RISE-MX, a Multi-center, Retrospective, 3-Year Data Study
Authors: Yamamoto-Furusho J K , Martinez-Vazquez M , Miranda-Cordero R , Bosques.Padilla F ,   RISE-MX Study Group
Published: January 2023

Abstract

Background
The incidence and prevalence of inflammatory bowel disease (IBD) has increased significantly in the last decade in Mexico. This work describes the burden of disease in terms of healthcare resources utilization and costs (direct and indirect) related to the management of patients (pts) diagnosed with moderate/severe ulcerative colitis (UC) and Crohn’s disease (CD), over 3 years.

Methods
This multicenter, retrospective, non-interventional study enrolled 335 IBD pts. Upon written consent for eligible pts, data regarding disease activity, treatment patterns and burden of disease were collected (Fig 1). Direct costs calculation was obtained by a micro-cost analysis and cross-sectional indirect costs (human capital/income) by proportional hours of absence/productivity, based on Work Productivity and Activity Impairment score. Unitary costs were taken from institutional data: Groups Related to the Diagnosis (GRD-IMSS) 2017 updated with the INEGI explosion factor in the middle of the year 2022 and IMSS Unit Costs 2022, the price of the drugs used was from the Annual Acquisitions, Leasing and Services Program updated to September 2022. Direct costs were obtained by multiplying resource use with relevant unit costs. Unit costs for each resource items were collected in Mexican reliable administrative databases or other sources. All data were descriptively analyzed.

Results
There were 335 pts enrolled and 326 eligible. 95 (29.1%) had CD and 231 (70.9%) had UC. In the CD group, 52 pts had remission/mild activity and 43 had moderate/severe activity. A total of 26.3% (25/95) disease–related hospitalizations were reported in CD pts and 15.6% (36/231) for UC pts. The mean of hospitalization duration was 11.7 days for pts with moderate/severe CD and 8.5 days for pts with moderate/severe UC. The absenteeism in CD pts was 19.9% for moderate/severe and 17.3% for remission/mild activity, while in UC pts was 9.8% for moderate/severe and 10.6% for remission/mild activity. Considering comorbidities, extraintestinal manifestations, previous treatments, medical appointments, hospitalizations and other medical procedures, the annual direct costs per-patient impact in CD was US$19,026 (moderate/severe) and US$12,126 (remission/mild). Furthermore, in pts with UC, the cost was US$11,516 (moderate/severe) and US$8,952 (remission/mild). The indirect costs represent US$1,191 for CD and US$376 for UC (Fig 1F).

Conclusion
The disability rate of CD is 25% [20-34%], this study reports 18.4%. CD was associated with higher rates of hospitalization and increase in cost of health care resources, compared to UC patients.