bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP08 A novel multiomic approach to unravel the mechanisms of action of biologics and tofacitinib in Inflammatory Bowel Disease
Authors: Baldan-Martin M , Azkargorta M , Aransay A M , Gil-Redondo R , Moreno-Indias I , Iloro I , Soleto I , Orejudo M , Ramírez C , Lucendo A J , Rodríguez Gutiérrez C , Gutiérrez A , Martín Arranz E , Bujanda L , Rodríguez-Lago I , Riestra S , Iglesias-Flores E , Bermejo F , Van Domselaar M , García M J , Fernández Salazar L , De Prado Á , Calvet X , Torrealba L , Bastón Rey I , Pallarés H , Ber Y , Carnerero E L , Casanova M J , Millet Ó , Elortza F , Mato J M , Tinahones F J , Chaparro M , Gisbert J P 
Published: January 2024

Abstract

Background
Inflammatory bowel diseases (IBD), which includes Crohn´s disease (CD) and ulcerative colitis (UC), are complex and heterogeneous diseases characterized by a multifactorial etiology. IBD prevalence is increasing worldwide. The availability of diverse treatments with different mechanisms of action have revolutionized the ability to achieve clinical remission and endoscopic healing. The aim of this study was to achieve a deeper understanding of the mechanism of action and response to different IBD treatments using a multiomic approach.

Methods
We analysed the metabolome of serum and urine, metagenome of stool samples and transcriptome and proteome of mucosal biopsies from 53 patients with moderate-to-severe CD and 50 UC patients initiating biologic therapy (anti-TNF, ustekinumab or vedolizumab) or tofacitinib. Patients were assessed at 14 weeks for endoscopic remission and were categorized into responders or non-responders. The methodologies employed in this study were RNA-seq analysis, liquid chromatography-mass spectrometry, nuclear magnetic resonance, and 16S rRNA gene sequencing.

Results
The multiomic analyses revealed substantial alterations in the transcriptome, proteome, metabolome and metagenome of both responders and non-responders IBD patients before and after treatment (14 weeks) to different biologics and tofacitinib (Table 1). Gene enrichment analysis showed notewhorthy differences in all study comparisons, except for patients with CD and UC who did respond to anti-TNF and tofacitinib. Functional enrichment analysis of differentially expressed proteins indicated several processes that could be potentially involved in the mechanisms of action of different treatments. More differences were observed in lipoproteins than in serum and urine metabolites in the different study comparisons. Finally, metagenomic findings indicated changes in the composition of gut bacteria communities among CD patients treated with ustekinumab and UC patients treated with tofacitinib (responders vs non-responders at 14 weeks) (Figure 1).

Conclusion
The present study provides novel insights into the mechanisms of action of different IBD treatments from a multiomic approach. Nonetheless, multiomic data integration and validation studies are needed to confirm these findings within a more extensive and independent cohort of patients.
DOP13 Effect of 8 weeks of combined aerobic and resistance exercise on quality of life, muscle strength, aerobic capacity, and disease activity in patients with Inflammatory Bowel Disease; a parallel group randomized clinical trial
Authors: Mirmoosavi S , Alborzi Avanaki F , Javaherian M , Tabatabaei B 
Published: January 2024

Abstract

Background
Sarcopenia is prevalent in patients with IBD (inflammatory bowel disease). This study aimed to assess the effects of an 8-weeks combined aerobic and resistance training program on the quality of life, disease activity, muscle strength, and aerobic capacity in patients with IBD. (Registration ID: NCT05455762)

Methods
This study was a single-blind parallel-group randomized clinical trial. Inclusion criteria were patients 18 to 65 years old with a confirmed diagnosis of IBD. Exclusion criteria: active malignancy, consumption of systemic corticosteroids, and patients with moderate to severe physical activity more than 150 minutes/week. Patients were allocated to each group by block randomization with a 1:1 ratio. The intervention consisted of walking sessions on even days and six resistance exercises on odd days. The primary outcome was the patients' quality of life, measured by the Persian version of the ibdq-9 questionnaire. secondary outcomes included disease severity, muscle strength, 6-minute walk test, and 30-second sit-to-stand test. We measured muscle strength by a handheld dynamometer.

Results
Of 72 patients screened 64 were eligible for the study. During the follow-up period, 13 patients, 8 from the exercise group and 5 from the control group, were excluded from the study. 51 patients, 28 females and 23 males, with a mean age of 34.9 ± 10.57 were analyzed. Two groups were matched in demographic and IBD-related characteristics. Unlike the control group, the exercise group showed a significant increase in overall quality of life (40.29 to 47.75, p=0.005), particularly in intestinal and systemic symptoms domains (p=0.01 and p=0.004). the inter-group analysis found no significantly higher mean difference in QOL scores between the exercise and control groups (p=0.053). The Partial Mayo score in patients with ulcerative colitis (UC) significantly decreased in the intervention group but not in the control group. The Harvey-Bradshaw index in Crohn patients didn’t change in either group. There were no exercise-related serious complications. The 6-minute walk test distance significantly increased in the exercise group but not in the control group. The 30-second sit-to-stand test didn’t significantly change in either group. Of muscles examined (hand grip, shoulder abductor, hip flexor, knee extensor, and elbow flexor) only knee extension strength increased in both groups.

Conclusion
Combined resistance and aerobic exercise in patients with IBD is safe and can significantly improve the quality of life and aerobic capacity. This regimen also improved clinical severity in patients with UC but not in Crohn’s. Muscle strength did not significantly improve when comparing the two groups, possibly due to the short duration of the intervention.
DOP23 The role of histology for the prediction of clinical relapse in Crohn’s Disease: A substudy of the STORI cohort
Authors: Reenaers Dr C , Enea D , Nachury M , Laharie D , Bouhnik Y , Fumery M , Gornet J M , Amiot A , Altwegg R , de Vos M , Marteau P , Bourreille A , Nancey S , Viennot S , Louis E , svrcek M 
Published: January 2024

Abstract

Background
Deep remission has become the target in the management of Crohn’s disease (CD). The role of histology in the management of CD has not yet been established. The aim of this work was to study the impact of histological inflammation on the risk of clinical relapse in patients with CD in clinical and endoscopic remission and to study the correlation between histology and endoscopic scores and biomarkers.

Methods
All patients included in STORI (1) were eligible for inclusion. Fecal calproptectin and colonoscopy with CDEIS calculation were performed at inclusion. Two biopsies, taken either from the most inflammed macroscopic area or from an area with previous inflammation in case of mucosal healing (MH) were prospectively performed. MH was defined by the absence of ulcers. Different histological scores were calculated by 2 independent pathologists: Robart, Geboes, modified Geboes, Nancy, and DCA-IBD scores. Histological remission was defined by Nancy=0 ; Geboes ≤2 ; modified Geboes of grade 0 ; Robarts ≤3, IBD-DCA of C≤1 and A=0. Clinical relapse was prospectively evaluated in the STORI trial as CDAI&gt;250 or CDAI between 150 and 250 with an increase of 70 points during 2 successive weeks compared to the inclusion visit.
(1) Louis E et al .Gastroenterology 2012

Results
Eighty biopsies (22 ileal and 58 colonic) were available from 76/115 patients included in STORI. Among the 45 patients with MH, 30 had colonic biopsies, 11 had ileal biopsies and 4 had biopsies in both locations. Among colonic biopsies 68% had histological remission according to Nancy and modified Geboes scores, 65% according to DCA-IBD and Geboes scores and 71% according to Robarts score. Among ileal biopsies 53% had histological remission according to Nancy score, 47% according to Modified Geboes, Geboes and DCA-IBD scores, and 67% according to the Robarts score. Thirty-five patients (46%) experienced a clinical relapse during the follow-up including 16/45 (36%) and 19/31 (61%) in the group with MH and without MH respectively. Histological characteristics and histological scores were not predictive of clinical relapse. In the total cohort (n=76), the CDEIS score was correlated to Nancy (p&lt;0,001, r=0,43), Geboes (p&lt;0,001, r=0,47) and Robarts (p&lt;0,001, r=0,45) scores. Fecal calprotectin was correlated to Nancy (p&lt;0,001, r=0,48), Geboes (p&lt;0,001, r=0,45) and Robarts (p&lt;0,001, r=0,46) scores. The histological scores of Nancy, Robarts and Geboes were highly correlated (p&lt;0,0001 ; r &gt; 0,9).

Conclusion
Although correlated with endoscopy and biomarkers, histology was not predictive of clinical relapse in CD patients in clinical and endoscopic remission. These findings do not support the use of histology to predict clinical relapse in CD in clinical practice.
DOP27 Systemic antibody responses against gut microbiota flagellins implicate shared and divergent immune reactivity in Crohn's Disease and chronic fatigue syndrome
Authors: Bourgonje A R , Hörstke N V , Fehringer M , Innocenti G , Vogl T 
Published: January 2024

Abstract

Background
Patients with Crohn’s disease (CD) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) exhibit elevated antibody responses against gut microbiota flagellins. However, flagellin-specific antibody repertoires and functional roles in the diseases remain incompletely understood. Bacterial flagellins can be categorized into three types depending on their interaction with toll-like receptor 5 (TLR5): (1) "stimulator" and (2) "silent" flagellins, binding TLR5 through a conserved N-terminal motif, with only stimulators activating TLR5 due to a specific C-terminal domain; (3) "evader" flagellins of pathogens, which circumvent TLR5 activation via mutated N-terminal TLR5 binding motifs. Here we studied the characteristics, epitope binding, and sequence (dis)similarity of anti-flagellin antibody responses in CD and ME/CFS.

Methods
Since conventional antibody profiling methods like enzyme-linked immunosorbent assays [ELISAs] do not allow for large-scale measurements of antibody repertoires, we leveraged phage-display immunoprecipitation sequencing (PhIP-Seq) to characterize 344,000 rationally selected peptide antigens in 256 patients with CD, 40 patients with ME/CFS and in two equally sized groups of age- and sex-matched healthy controls from population-based cohorts in the Netherlands and U.K., respectively. Different sequence alignment strategies were employed to compare flagellin peptide structures with observed antibody-bound flagellin peptide reactivity.

Results
Both patients with CD and ME/CFS exhibited elevated antibody responses against distinct regions of flagellin peptides compared to healthy individuals (P&lt;0.001). N-terminal binding to Lachnospiraceae flagellins was comparable in both diseases, while C-terminal binding was more prevalent in CD. N-terminal antibody-bound flagellin sequences were similar across CD and ME/CFS, resembling ‘stimulator’ and ‘silent’ flagellins more than evaders. However, C-terminal antibody-bound flagellins showed higher resemblance to stimulator than to silent flagellins in CD, but not in ME/CFS. This group of antibody-bound flagellins was exclusively identified in a subset (10-20%) of patients with CD and characterized by its strong overrepresentation (exceeding 20-fold), underscoring its potential significance in distinguishing pathophysiologic subtypes of CD.

Conclusion
Antibody binding to the N-terminal domain of stimulator and silent flagellins may impact TLR5 activation in both CD and ME/CFS patients. Furthermore, elevated antibody binding to the C-terminal domain of stimulator flagellins in CD may explain pathophysiological differences between diseases. Our results highlight the diagnostic potential of these antibody responses and their impact on innate/adaptive immunity balance.
DOP32 CD226+TIGITneg expression identifies pathogenic inflammatory CD4+ memory T cells in severe Crohn’s Disease patients, opening up opportunities for patient-tailored treatment strategies
Authors: Barendregt D , Heredia M , Tindemans I , Klomberg R C W , Calado B , Hulleman-van Haaften D H , Tuk B , van Berkel L A , Escher J C , de Ridder L , Samsom J N 
Published: January 2024

Abstract

Background
CD4+ memory T cells (Tmem) drive chronicity of inflammation in Crohn’s disease (CD) and ulcerative colitis (UC). Treatments specifically targeting T cells effectively induce disease remission. However, due to disease heterogeneity and possibly variation in the Tmem response, not all patients achieve or maintain remission. As such, strategies are needed to identify and monitor the therapeutic target, i.e. the inflammatory Tmem response, in individual patients. Monitoring has been hampered by the large variety in both protective regulatory and pathogenic inflammatory Tmem phenotypes, thus, common denominators need to be identified to distinguish all inflammatory from all regulatory intestinal Tmem populations in individual patients. We have shown that the coinhibitory receptor T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is a common denominator identifying regulatory gut-homing Tmem. TIGIT shares its ligands with the costimulatory receptor CD226. While TIGIT ligation inhibits Tmem responses, CD226 engagement enhances Tmem activity. We hypothesize that TIGIT and CD226 differentiate the protective regulatory from the pathogenic inflammatory intestinal Tmem in individual IBD patients.

Methods
We studied CD38+CD62Lneg gut-homing Tmem in blood of therapy-naive pediatric IBD patients (CD n=59; UC n=32; IBD negative controls (IBDneg) n=24).

Results
In a subgroup of CD, but not UC patients, frequencies of regulatory TIGIT+ gut-homing Tmem at diagnosis were strongly reduced compared to IBDneg. Of these CD patients with low TIGIT frequencies, a significantly higher proportion had severe disease, defined as failing to achieve remission after 6 months or having a disease relapse within 1 year, compared to CD with normal TIGIT frequencies. As TIGIT is a common denominator for regulatory cells, we hypothesized that gut-homing Tmem without TIGIT (TIGITneg) contained inflammatory Tmem. Indeed, in CD, the TIGITneg Tmem population contained increased frequencies of pathogenic IFNg+IL-17+-double-producing cells compared to IBDneg. As TIGIT and CD226 frequencies inversely correlated (R=-0.78, p=4.8e-05) in CD patients, we assessed whether additional monitoring of CD226 could be used to more precisely identify and monitor inflammatory Tmem in CD. As anticipated, TIGITnegCD226+ gut-homing Tmem frequencies significantly increased in CD patients compared to UC patients and IBDneg. TIGITnegCD226+ Tmem were more proliferative and more activated compared to IBDneg, indicating increased inflammatory function.

Conclusion
These data establish that TIGIT and CD226 can be used to enumerate and differentiate the protective regulatory from the pathogenic inflammatory gut-homing Tmem in individual IBD patients, and to identify patients with severe disease.
DOP49 Guselkumab improves health-related quality of life as measured by PROMIS-29 in patients with moderately to severely active Ulcerative Colitis: Phase 3 QUASAR induction study
Authors: Panés J , Dignass A , Lichtenstein G , Huang K H , Germinaro M , Houck N , Han C , Miao Y , Zhang H , Abu Farsakh N , Patel B , Owczarek D , Hisamatsu T , Sands B , Bressler B 
Published: January 2024

Abstract

Background
Patients (pts) with ulcerative colitis (UC) suffer from symptoms that impair health-related quality of life (HRQoL). The Phase 3 QUASAR induction study (NCT04033445) evaluated the efficacy and safety of guselkumab (GUS), an IL-23 p19 subunit antagonist, in pts with moderately to severely active UC who had demonstrated inadequate response, loss of response, or intolerance to conventional and/or advanced therapies (ie, tumor necrosis factor-alpha antagonists, integrin receptor antagonists, and/or Janus kinase inhibitors). Here we report the effect of GUS IV induction on HRQoL at Week (Wk) 12 as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS)-29.

Methods
Pts were randomized 3:2 to receive GUS 200 mg IV or placebo (PBO) IV at Wks 0/4/8. PROMIS-29 consists of 7 domains (anxiety, depression, fatigue, pain interference, sleep disturbance, physical function, and social participation) and a pain intensity numeric rating scale (NRS, range 0-10). The raw score of each domain was converted into a standardized T-score based on a general population mean of 50 and standard deviation (SD) of 10. Higher scores indicate better outcomes for physical function and social participation and worse outcomes for all other domains. The physical component summary (PCS) and mental component summary (MCS) scores were calculated based on the domain T-scores for physical and mental HRQoL, with higher scores representing better outcomes. Minimum clinically meaningful improvement was defined as a ≥3-point improvement in the pain intensity NRS score, a ≥5-point (one-half SD of the population) improvement in each domain, and a ≥5-point improvement in the PCS/MCS scores. More stringent thresholds (eg, ≥7- or ≥9-point improvements) were also examined and will be presented.

Results
Among the primary analysis population, baseline mean PROMIS-29 domain scores were similar between treatment groups, with functional domain scores &lt;50 and symptom domain scores &gt;50, indicating impaired HRQoL (Table). GUS-treated pts achieved a greater mean change from baseline at Wk 12 in each domain T-score, the pain intensity NRS score, and the PCS/MCS than PBO-treated pts. Additionally, the percentage of pts achieving minimum clinically meaningful improvement at Wk 12 was greater for GUS vs PBO in each domain, the pain intensity NRS score, and the PCS/MCS scores (Figure).

Conclusion
Pts with moderately to severely active UC treated with GUS IV induction experienced broad and clinically meaningful improvements in HRQoL as measured by the PROMIS-29 at Wk 12.
DOP50 PINPOINT: The epidemiology of paediatric-onset Inflammatory Bowel Disease in the United Kingdom – a prospective, national, cohort study
Authors: Henderson P , Dobson L 
Published: January 2024

Abstract

Background
Paediatric inflammatory bowel disease (PIBD) incidence and prevalence is increasing worldwide. Robust epidemiology can inform new aetiological hypothesis, inform healthcare provision and improve patient outcomes. The last prospective United Kingdom (UK) PIBD incidence study was performed in 1999 (5.2/100,000/yr); we aimed to update this incidence data and to provide a robust prevalence figure for PIBD prospectively across the UK.

Methods
Robust site selection identified all units in the UK providing endoscopy services for paediatric patients. Patients were included if they were diagnosed with Crohn’s disease (CD), ulcerative colitis (UC) or IBD-unclassified (IBD-U) less than 16yrs of age while a permanent UK resident. A custom-built spreadsheet was used to record basic demographics prospectively from June 2021 – December 2022 (18 months). A point prevalence study on 28th February 2023 was also performed capturing all patients under 16yrs of age living in the UK. A subset of patients was approached to provide consent for future clinical note review, data linkage and future contact (the PINPOINT cohort). Multiple data points were triangulated to avoid duplicate records. Data was securely collated electronically by the IBD Registry (www.ibdregistry.org.uk) and basic descriptive statistics performed in R v4.1.3. Publicly available population data was used to calculate rates.

Results
All 34 selected sites prospectively recorded cases; all were diagnosed by ileocolonoscopy. During the study 2,243 new diagnoses were recorded (1,050 patients [47%] also consented to join the PINPOINT cohort). UK PIBD incidence was 12.1/100,000/yr (England/Wales 11.7/100,000/yr, Northern Ireland 12.7/100,000/yr, Scotland 17.2/1000,000/yr). CD (56%) was more prevalent than UC (33%) and IBDU (11%). Median age at diagnosis was 12.9yrs (IQR 10.6-14.5). There was a male preponderance (62%) with CD, IBDU and UC having male to female ratios of 1.8, 1.7 and 1.4 respectively. With regard to ethnicity 72% of patients identified as white; those of other ethnicities were diagnosed younger (12.1yrs vs 13.0yrs; p&lt;0.001) and had a higher incidence of UC (38.5% vs 30.3%; p=0.003). Regarding prevalence, 6,116 patients aged less than 16 years were identified as living with IBD on 28th February 2023 giving a UK prevalence of 49.6/100,000 (England/Wales 48.7/100,000, Northern Ireland 53.3/100,000, Scotland 58.6/1000,000).

Conclusion
There has been over a two-fold rise in PIBD incidence across all regions of the UK since 1999 with the first accurate prevalence figure mirroring this rise. Further detailed analysis of epidemiological trends using these data and the PINPOINT cohort are merited to drive improved care for this growing group of patients with high healthcare needs.