bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP64 Utilising genomics to predict outcomes and delineate novel subgroups in inflammatory bowel disease
Authors: Ashton J , Cheng G , Stafford I , Beattie R M , Ennis S 
Published: January 2023

Abstract

Background
The rise of ‘big data’ in inflammatory bowel disease (IBD) presents an opportunity to improve understanding of pathogenesis and unpick the molecular complexity of this heterogenous condition. Personalisation of IBD management relies on predicting outcomes, response to therapy and prevention of complications. Here, we present results outlining subgrouping of patients and outcome prediction using multiomic/clinical data.

Methods
Using whole exome sequencing from 1100 patients in the Southampton IBD cohort, including 650 paediatric cases, we have performed iterative studies focused on 1) Impact of genomic variation across the NOD-signaling pathway measured by perturbation of transcription across multiple genes, 2) Development of NOD2 as a genomic biomarker of stricturing Crohn’s disease (CD), 3) Utilising machine learning and genomic data to develop disease classification models. These data utilise GenePy, a tool developed in house that summarises genomic variation to give a per individual, per gene deleteriousness metric.

Results
Within the NOD-signaling pathway patients harbouring deleterious variation in NOD2 had reduced NOD2 expression and increased NFKBIA expression, reflecting reduced NFKB signaling, figure 1A. We report deleterious variation in several key complexes including NOD2-RIPK2 and TAK1-TAB, resulted in reduced transcription of NFKB activators and alternative inflammatory pathway activation, figure 1C-D.

Utilising genomic data we constructed a NOD2 prediction model for stricturing disease in Crohn’s disease; 56.7% of patients in the ‘high-risk group’ had stricturing behaviour, whilst in the low-risk group only 21.4% had strictures. Addition of terminal ileal (TI) disease to the NOD2 risk groups significantly improved prediction, figure 2A. Using survival modelling, high-risk group paediatric patients presenting with TI disease had a HR of 4.89 (P = 2.3×10-5) compared with the low-risk group patients without TI disease, figure 2B.

Finally, we used supervised machine learning of genomic data to classify patients with CD or ulcerative colitis. We employed different gene lists and assessed how accurately we could assign patients to their diagnosis. An autoimmune gene panel produced the best model (AUROC 0.68), compared to an IBD panel (AUCROC 0.61). NOD2 was the most discriminating gene in all the gene panels.

Conclusion
These iterative projects demonstrate the utility of integrating genomic and clinical data to improve the subtyping of patients with IBD and provide disease prediction models. Future work will include analyses of additional inflammatory pathways and targeting different clinical outcomes. We hope clinical translation of these findings will be a step-change in precision medicine for IBD.
DOP74 Artificial Intelligence Quantifying Endoscopic Severity of Ulcerative Colitis in Gradation Scale
Authors: Takabayashi K , Kobayashi T , Matsuoka K , G Levesque B , Kawamura T , Tanaka K , Kadota T , Bise R , Uchida S , Kanai T , Ogata H 
Published: January 2023

Abstract

Background
The existing endoscopic scores for Ulcerative Colitis (UC) such as the Mayo Endoscopic Subscore (MES) and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) are objectively categorize the severity of the disease based on presence or absence of endoscopic findings. Therefore, they may not reflect the range of clinical severity within each category. But, Inflammatory bowel disease expert endoscopists do not only categorize the severity, but rather diagnose the overall impression of degree of inflammation. Therefore, the purpose of this study was to develop an AI that can accurately represent the complexed assessment of endoscopic severity of UC by expert endoscopists, similarly to Visual Analogue Scale (VAS).

Methods
To enable the AI to perform continuous evaluations of inflammation in line with the strategy used by IBD expert endoscopists, we did not utilize scores determined from images using MES or UCEIS for physician data. Rather, we incorporated data for the relationships identified by IBD expert endoscopists who compared the severity of paired images. This study was conducted using a method that incorporates data on relationships identified by comparing the severity of paired images created from 59595 endoscopic images by an IBD expert endoscopist into a Ranking- Convolutional Neural Network, and then the severity was then expressed on a scale called UC Endoscopic Gradation Scale (UCEGS) rather than a score. Using 4,000 images for which the MES had been assessed beforehand by an IBD expert endoscopist, correlation coefficients were calculated to ensure that there were no inconsistencies in assessments of severity made using results of this novel AI diagnosed UCEGS and the current MES score. The correlation coefficients of the means of the UCEGS results for the 50 test images evaluated by the five IBD expert endoscopists and the novel AI were also calculated.

Results
Spearman's correlation coefficient between MES and AI-diagnosed UCEGS was approximately 0.89, indicating a strong positive correlation for the order of severity between the AI-diagnosed UCEGS and MES. Correlation coefficient between IBD expert endoscopists and the AI of the evaluation results were all higher than 0.95 (P&lt;0.01).

Conclusion
In this study, we developed a novel AI that does not rely on conventional scoring methods but instead aims to leverage the intelligence of IBD expert endoscopists when evaluating the disease status of UC. This AI quantifies inflammation as a gradient, allowing for an automated visualization of the expert endoscopist's assessment of mucosal inflammation.
DOP75 Video capsule endoscopy may detect active small bowel Crohn’s disease requiring change of treatment despite unremarkable ileo-colonic anastomosis
Authors: Thurm T , Zmora N , Hirsch A , Deutsch L , Maharshak N 
Published: January 2023

Abstract

Background
Previous studies have shown benefit in performing video capsule endoscopy (VCE) in Crohn’s disease (CD) diagnosis, especially in cases of an unremarkable ileo-colonoscopy, however data on the role of VCE in postsurgical follow-up of CD patients is lacking. We aimed to evaluate CD endoscopic activity in the small bowel (SB) of patients presenting with disease remission at the ileo-colonic anastomosis.

Methods
We retrospectively obtained data on patients with CD older than 18 years of age, who underwent ileo-colonoscopy between the dates 1/10/2012 through 31/09/2022. Patients in whom VCE was performed within 8 months of ileo-colonoscopy were eligible for analysis. Lewis and Rutgeerts scores were calculated based on VCE images and endoscopy reports, respectively. Disease remission was deemed as Rutgeerts score of i0-i1 at the ileo-colonic anastomosis, and Lewis score (LS) of&lt;135 on VCE.

Results
A total of 1,334 ileo-colonoscopies were performed in CD patients with ileo-colonic anastomoses during the study period, of whom 31 patients (male gender 58.06%; mean age 41.77±14.19 years) were referred to VCE within 8 months of ileo-colonoscopy, (median 124.81 days). Twenty patients exhibited endoscopic remission at the anastomosis, 3 of them failed passage of a patency capsule and 17 successfully completed VCE. Only 5 patients (29.4%) had a normal LS, while 12 (70.6%) exhibited an active SB disease (LS≥135, mean 791.3±1254.9). Patients with a discrepancy between the two scores, were characterized by a shorter disease duration (P=0.011) and showed a trend towards a shorter time since surgery (P=0.06). No correlation was found between SB disease activity and concurrent medical therapy (P=0.898). Treatment modification was applied in 7 patients (41.2%) and was associated with a higher LS (biserial correlation coefficient 0.51, P=0.037).

Conclusion
Endoscopic remission at the ileo-colonic anastomosis is not an accurate indicator for CD remission in the SB, especially in a new-onset disease and soon after the surgery. VCE has an added value to ileo-colonoscopy in postsurgical follow-up and treatment adjustment in patients with CD.
DOP82 Biological Treatment Cycles in Crohn’s Disease
Authors: Noor N , Sousa P , Bettenworth D , Gomollon F , Lobaton T , Bossuyt P , Casanova M J , Ding N , Dragoni G , Furfaro F , van Rheenen P , Chaparro M , Gisbert J , Louis E , Papamichael K 
Published: January 2023

Abstract

Background
There are now a growing number of licensed biological therapies for patients with Crohn’s disease (CD) but given the costs of long-term maintenance treatment, as well as some concerns about potential side effects, there has been increasing interest in elective biological treatment discontinuation in selected patients, after a period of sustained remission. Following discontinuation, in cases of relapse, limited but reassuring evidence has suggested that remission may often be regained by retreatment with the same biological agent. Therefore, a concept has emerged where cycles of biological therapy might be used. If this treatment strategy were applied in a subgroup of patients at low-risk of relapse, cycling might allow lower, overall drug exposure but still enable appropriate disease control. However, currently, there remains uncertainty about the benefit-risk balance for using cycles of biological treatment in patients with CD.

Methods
An expert panel was convened by the European Crohn’s and Colitis Organisation (ECCO) to review the published literature and agree a series of consensus practice positions (CPPs) on the topic of biological treatment cycles (biocycling). An open-call was announced to all ECCO members, following which 15 individuals were selected based on their expertise, and three subgroups were formed. The panel aimed to provide evidence-based guidance to support shared decision-making.

Results
A total of 14 CPP consensus statements were developed following comprehensive review of the literature. The statements evaluated multiple different aspects of biological treatment discontinuation and cycling, including the risk of relapse after elective treatment discontinuation, predictors of likely relapse or remission, safety, patient preferences and pharmacoeconomic aspects. Discussion and a preliminary voting round took place, with subsequent revision of CPP statements and supporting text, followed by a further meeting with voting to agree on final statements.

Conclusion
With increasing focus on patient preferences, long-term safety and costs, elective biological treatment discontinuation may be considered for some patients with CD in remission. In cases of relapse, there have been reassuring findings on subsequent retreatment with the same biological agent. However, there is a need for more data to support routine elective treatment discontinuation and cycling in CD, especially for newer biological agents. In particular, randomised, controlled trials comparing biological cycling to current maintenance therapy strategies would be highly informative. Currently, discussions about biological treatment discontinuation and cycling should be individualised, to enable shared decision-making by patients with their clinicians.
DOP84 IBD-related hospitalization and surgery rates in biologic-naïve patients with IBD treated with vedolizumab versus other biologics: Results from a long-term, prospective, observational study
Authors: Sebastian S , Siegel C , Siegmund B , Zhou J , Jones S , Adsul S , Louis E 
Published: January 2023

Abstract

Background
Hospitalisations and surgeries are a major driver of health resource utilisation increasing disease burden on patients (pts) with ulcerative colitis (UC) and Crohn’s disease (CD). This analysis aimed to evaluate the number of hospitalisations and surgeries among pts with UC and CD initiating vedolizumab (VDZ) or other biologic treatment, as a marker for disease modification and health resource utilisation.

Methods
Secondary outcome data from a multicentre, observational, prospective, cohort post-authorisation safety study (PASS; NCT02674308) of biologic-naïve pts with UC or CD initiating VDZ or other biologic treatment were utilised. Pts received treatment under routine standard of care with clinical decisions at the discretion of treating physicians, and so treatment could be modified or changed without the need to withdraw from the study. Inflammatory bowel disease (IBD)-related hospitalisation rate and occurrences of IBD-related surgeries were assessed in pts initiating VDZ and other biologic. Time to first hospitalisation and surgery was also assessed.

Results
In total, 1149 pts with UC (556 initiating VDZ, 593 initiating other biologics) and 1338 pts with CD (312 initiating VDZ, 1026 other biologics) were included in this analysis. Baseline characteristics are displayed in Table 1. VDZ-treated pts with UC had fewer IBD-related hospitalisations (12.9% vs 25.0%; risk ratio [RR] 0.52 [95% CI 0.40, 0.67]) and IBD-related surgeries (4.3% vs 10.1%; RR 0.43 [0.27, 0.68]) than those treated with other biologics (Table 2). With regard to surgical procedures, VDZ-treated pts with UC had fewer total colectomies (RR 0.40 [0.20, 0.80]), colectomy (RR 0.32 [0.13, 0.79]) and other IBD-related surgeries (RR 0.37 [0.17, 0.78]). Among pts with CD, those treated with VDZ had fewer IBD-related hospitalisations (19.2% vs 26.4%; RR 0.73 [0.57, 0.93]) and IBD-related surgeries (7.1% vs 13.8%; RR 0.51 [0.33, 0.78]) than those treated with other biologics (Table 2). Pts with UC treated with VDZ had a longer time to event of first IBD-related hospitalisation and primary and secondary IBD-related surgery (in pts without history of IBD-related surgery at baseline) than pts treated with other biologics (Table 3).

Conclusion
In this large multinational, observational study, fewer biologic-naïve pts with UC or CD on VDZ treatment had hospitalisations and IBD-related surgeries than pts on other biologics. These real-world data suggest VDZ as a first line biologic treatment may contribute to modifying the course of IBD over time. Further research into the role of additional factors associated with differences in biologic treatments shown here is warranted.
DOP86 Subcutaneous infliximab (CT-P13 SC) as maintenance therapy for Crohn’s disease: A phase 3, randomised, placebo-controlled study (LIBERTY-CD).
Authors: Colombel J F , Hanauer S B , Sandborn W , Sands B E , Schreiber S , Danese S , Kierkus J , Kulynych R , Klopocka M , Lahat A , Gonciarz M , Osipenko M , Borzan V , Kowalski M , Saenko D , Sardinov R , Kim S , Bae Y , Lee S , Yang S , Lee J , Lee S J , Lee S G , Park G ,   CT-P13 SC 3.8
Published: January 2023

Abstract

Background
CT-P13 subcutaneous (SC) infliximab formulation showed comparable efficacy and safety with CT-P13 intravenous (IV) infliximab in inflammatory bowel disease (IBD)1 and rheumatoid arthritis2. This study aimed to demonstrate the superiority of CT-P13 SC over placebo as maintenance therapy after induction therapy of CT-P13 IV in patient with Crohn’s disease (CD).

Methods
Moderately to severely active CD patients with Crohn’s disease activity index (CDAI) score 220 to 450 and simplified endoscopic activity score for Crohn’s disease (SES-CD) of ≥6 points for ileal-colonic CD or ≥4 points including ulcer score from at least 1 segment for ileal CD or colonic CD were enrolled LIBERTY-CD study (NCT03945019) and treated with open-label CT-P13 IV 5 mg/kg at Weeks 0, 2 and 6 as induction therapy. At Week 10, patients who had a clinical response were randomised (2:1) to receive either CT-P13 SC 120 mg (CT-P13 SC) or placebo every 2 weeks up to Week 54. At Week 54, clinical remission and endoscopic response were assessed as co-primary endpoints. Clinical response, clinical remission (alternative definition), endoscopic remission, and corticosteroid-free remission were assessed at Week 54 as key secondary endpoint. Safety was evaluated up to Week 54.

Results
A total of 396 patients were enrolled and 343 patients (86.6%) were randomised (231 in CT-P13 SC arm and 112 in placebo arm) at Week 10. At Week 54, the clinical remission rate was greater in CT-P13 SC arm than placebo arm (62.3% and 32.1% respectively, with P &lt;0.0001). The endoscopic response rate was also greater in CT-P13 arm than placebo arm (51.1% and 17.9% respectively, with P &lt;0.0001). CT-P13 SC also had significantly greater efficacy on key secondary endpoints results compared to placebo arm (Table 1). Safety profiles were generally comparable between CT-P13 SC and placebo arms, but a single death was reported during the maintenance phase (Table 2).

Conclusion
CT-P13 SC was more effective than placebo in clinical remission, endoscopic response, clinical response, clinical remission (alternative definition), endoscopic remission, and corticosteroid-free remission at Week 54. No new safety concerns were found during treatment of CT-P13 SC. These results demonstrate that maintenance therapy with CT-P13 SC provides both a robust clinical benefit and the convenience of SC administration to moderately to severely active CD patients.
[1] Schreiber et al., 2021. Gastroenterology 2021;160:2340–23
[2] Westhovens et al., 2020. Rheumatology 2020;00:1
DOP87 The Anti-TL1A Antibody PRA023 Demonstrated Proof-of-Concept in Crohn’s Disease: Phase 2a APOLLO-CD Study Results
Authors: Feagan B G , Sands B , Siegel C A , Dubinsky M , Longman R , Sabinho J , Laurent O , Luo A , Lu J D , Nguyen D , Towfic F , DuVall A , Woyranowski M , Al Kharrat H , McGovern D P B 
Published: January 2023

Abstract

Background
Tumor necrosis factor-like cytokine 1A (TL1A) is an upstream regulator of pro-inflammatory cytokines and fibrosis signals. PRA023 is an anti-TL1A monoclonal antibody in development for multiple inflammatory/fibrotic diseases with a precision medicine approach. This Phase 2a multi-center, open-label study aimed to assess the efficacy and safety of PRA023 as induction treatment in adults with moderately to severely active Crohn’s Disease (CD).

Methods
Key eligibility criteria included Crohn’s disease activity index ≥220 and ≤450 with centrally read [with adjudication] Simple Endoscopic Score (SES)-CD score of ≥6 (≥4 isolated ileal disease) and a history of insufficient/loss of response and/or intolerance to conventional and/or approved biologic therapies (≤4 biologic agents from ≤3 classes). Eligible patients were treated with intravenous PRA023 1000mg on Day 1, 500mg at Weeks 2, 6, and 10. The primary endpoint was endoscopic response (reduction in SES-CD score of ≥50%) at Week 12. Study design utilized historical placebo control rate estimates as a benchmark. Exploratory endpoints include efficacy assessment in a subpopulation identified by a genetics-based companion diagnostic test (CDx).

Results
Of the 55 patients in the full analysis data set, 53 (96.4%) completed the 12-week Induction Period. The patient population was notable for the high rate of prior biologic exposure (70.9%) and a mean (SD) disease duration of 10.3 (9.3) years (Table 1). A significantly greater proportion of patients receiving PRA023 achieved endoscopic response (26% PRA023 vs. 12% historical placebo estimate, p=0.002) and clinical remission (CDAI &lt; 150 points; 49% PRA023 vs 16% historical placebo estimate, p&lt; 0.001). Efficacy was observed in biologic-exposed patients (33% endoscopic response and 38.5% clinical remission) while concurrent steroid or immunosuppressant use did not impact efficacy. Significant reductions from baseline in C-reactive protein and fecal calprotectin were observed at all timepoints (Figure 1). Although the pre-specified CDx algorithm provided only limited additional benefit in clinical responses, an alternative CD-specific algorithm (not based on clinical trial data) using the same genetic markers demonstrated enhanced performance across both clinical (12/21 [57%] remission) and endoscopic (9/20 [45%] response) outcomes. No serious/severe AEs were deemed as study drug-related.

Conclusion
This Phase 2a study demonstrated robust proof-of-concept for PRA023’s efficacy in moderately to severely active CD with favorable tolerability. Patient selection using prespecified genetic markers showed promising results. Placebo-controlled clinical trials will be conducted to confirm these findings.
DOP90 The association of endoscopic and histologic endpoints with faecal calprotectin and C-reactive protein in patients with moderately to severely active ulcerative colitis treated with mirikizumab
Authors: Panaccione R , Sapin C , Chan-Diehl F W , Moses R E , Siegmund B , Walsh A , Kobayashi T , Parambir D S , Travis S 
Published: January 2023

Abstract

Background
Mirikizumab [(miri), a p19-directed IL-23 antibody] has been shown to be effective in patients with moderately to severely active ulcerative colitis (UC) in Phase 3, randomised, double-blind, placebo-controlled trials (LUCENT-1 NCT03518086; LUCENT-2 NCT03524092).1 Given the importance of understanding treat-to-target strategies, the relationship between improved histologic and endoscopic endpoints and improvement of the inflammatory biomarkers faecal calprotectin (fCal) and C-reactive protein (CRP) was studied within miri-treated patients enrolled in the programme.

Methods
This analysis focused on miri-treated patients (n=868) from the induction study receiving intravenous (IV) every 4 weeks (Q4W) until week (W)12 and miri induction responders at week W12, who were rerandomised for the maintenance period, receiving subcutaneous miri (n=365) Q4W up to W52. The relationship between achieving histologic-endoscopic mucosal improvement (HEMI), histologic-endoscopic mucosal remission (HEMR) (definitions in Tables) and improvement of fCal (≤250µg/g) and CRP (≤6mg/L) levels at W12 and W52 was explored using Fisher’s exact tests.

Results
At W12, a significantly higher percentage of miri-treated patients achieving HEMI (n=235/868) had normalised fCal and CRP values (76.2% and 88.5%), compared to miri-treated patients who did not achieve HEMI (n=633/868) (21.8% and 72.7%, both p&lt;0.001; Table 1). Similarly, a higher proportion of patients achieving HEMR (n=193/868) had normalised fCal and CRP values (79.3% and 89.6%), compared to those who did not achieve HEMR (n=675/868) (24.3% and 73.3%, both p&lt;0.001; Table 1).
At W52, a significantly higher percentage of the miri induction responder patients rerandomised to miri achieving HEMI (174/365) had normalised fCal and CRP values (74.1% and 87.9%), compared to patients not achieving HEMI (191/365) (32.5% and 61.3%; both p&lt;0.001). Similarly, at W52, a higher proportion of patients achieving HEMR (n=158/365) had normalised fCal and CRP values (76.6% and 88.0%), versus patients not achieving HEMR (n=207/365) (33.8% and 63.3%; both p&lt;0.001, Table 2).

Conclusion
At both W12 and W52, patients treated with miri who achieved HEMI or HEMR showed statistically significant improvements in fCal and CRP levels. This suggests that CRP and fCal may be useful markers of histology and endoscopy outcomes after induction and maintenance with miri.
1.Magro et al., MP245 Efficacy of mirikizumab in resolving active histologic inflammation in Ulcerative Colitis in Lucent-1 induction and Lucent-2 maintenance trials (2022), UEG Week Moderated Posters. United European Gastroenterol J, 10: 185-472.