bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP18 Brain structural correlates of fatigue in active and quiescent Crohn’s Disease
Authors: Thomann A , Schmitgen M , Szabo K , Ebert M , Reindl W , Wolf C 
Published: January 2023

Abstract

Background
Fatigue is a common and debilitating symptom in IBD, affecting the majority of patients with active disease. While impaired energy metabolism may contribute to the development of fatigue during active phases of the disease, the high prevalence of fatigue in remitted IBD is less comprehensible. The underlying mechanisms of fatigue are poorly understood, but a disturbance along the microbiota-gut-brain-axis seems likely. This study examined brain structural correlates of fatigue in patients with Crohn’s Disease (CD) in an active (aCD) or quiescent (qCD) state and healthy controls (HC).

Methods
Patients with CD (n=45; aCD=22, qCD=23) and HC (n=35) underwent structural MRI at 3T and completed a questionnaire (WEIMuS) to assess somatic (sFat) and cognitive fatigue (cFat). Whole-brain grey matter volume (GMV) was analysed using CAT12 in SPM12. We calculated group differences between HC and CD as well as CD subgroups and extracted raw values of anatomical regions with significant differences between the groups (at p&lt;.005; k=173) for subsequent correlation analyses with sFat and cFat (Spearman’s ρ).

Results
Patients had significantly higher mean fatigue scores than HC (both sFat and cFat, p&lt;0.001). Patients with aCD had higher mean fatigue scores than qCD, but differences between groups were not significant (p&gt;0.2). Differences in GMV between CD (aCD+qCD) and HC were detected in frontal, temporal, parietal, and occipital cortex, as well as in the putamen and cerebellum (all p&lt;.005). Across the patient group, GMV in the majority of the above mentioned regions was negatively correlated with sFat and cFat (Fig. 1). Subgroup analysis revealed a negative correlation between sFat and GMV in inferior frontal gyrus in aCD, while several other regions were negatively associated with both sFat and cFat in qCD (all p&lt;.05). No positive correlations between GMV and fatigue were observed.

Conclusion
This study suggests a brain structural involvement in fatigue symptoms in CD. While fatigue is more common in active CD, the symptom correlation with GMV in this study was more widespread in patients with quiescent disease. The results indicate possible differences in the development and/or processing of fatigue in different disease states and may reflect disturbed brain-gut-interactions in quiescent CD with fatigue. These findings can help to increase our understanding of fatigue in CD and indicate that different therapeutic approaches targeting fatigue in CD may need to be considered depending on the state of disease activity.
DOP22 Antibiotic Use as a Risk Factor for Inflammatory Bowel Disease Across the Ages: A Population-Based Cohort Study
Authors: Faye A , Allin K , Iversen A , Agrawal M , Faith J , Colombel J F , Jess T 
Published: January 2023

Abstract

Background
There is an increasing incidence of inflammatory bowel disease (IBD) for which environmental factors are suspected. Antibiotics have been associated with development of IBD in earlier generations, but their influence on IBD risk across the ages is uncertain. We assessed the changing impact of antibiotic exposure, including dose response, timing, and antibiotic class, on the risk of IBD in all individuals ≥10 years-old.

Methods
Using Denmark nationwide registries, a population-based cohort of residents ≥10 years-of-age was established between 2000 and 2018. Incidence rate ratios (IRRs) for IBD following antibiotic exposure were calculated using Poisson regression, with adjustment for concomitant PPI, antiviral and antifungal use.

Results
There were a total of 6,104,245 individuals, resulting in 87,112,328 person-years of follow-up, 36,017 new cases of ulcerative colitis (UC) and 16,881 new cases of Crohn’s disease (CD). Antibiotic exposure was associated with an increased risk of IBD as compared with no antibiotic exposure for all age groups, though was greatest among individuals aged 40-60 years-old and ≥ 60 years-old (10-40 years-old, IRR 1.28, 95%CI 1.25-1.32; age 40-60 years-old, IRR 1.48, 95%CI 1.43-1.54; age ≥ 60 years-old, IRR 1.47, 95%CI 1.42-1.53). When assessing the number of antibiotic courses received, each subsequent course added additional risk, leading to a positive dose response relationship for all age groups: increase in IRR per antibiotic course was 1.11 (95% CI 1.10-1.12), 1.15 (95% CI 1.14-1.16), and 1.14 (95% CI 1.13-1.15) for individuals aged 10-40 years, 40-60 years, and ≥60 years, with similar results seen for both UC and CD. The highest risk of developing IBD was observed 1-2 years after antibiotic exposure, and after use of antibiotic classes often prescribed to treat gastrointestinal pathogens. Nitrofurantoin, which has minimal impact on the intestinal microbiome, was not associated with risk of IBD across all age groups (age 10-40 years IRR 1.11, 95%CI 0.88-1.38; age 40-60 years IRR 1.22 (95%CI 0.95-1.53); age ≥60 years IRR 0.93, 95%CI 0.79-1.07).

Conclusion
Our results demonstrate a positive dose response, highlighting the strong association between antibiotic exposure and the development IBD, particularly among adults forty years and older. This risk was highest in the years immediately following antibiotic use, persisted across antibiotic classes impacting the gastrointestinal microbiome, and was associated with the development of both UC and CD. Thus, antibiotic stewardship may be important not only to limit the development of multidrug resistant organisms, but also to reduce the risk of IBD, particularly among older adults.
DOP23 Decrements in quality of life associated with symptoms of Inflammatory Bowel Disease: results from the UK IBD-BOOST survey
Authors: Roukas C , Miller L , Hamborg T , Gordeev V , Lindsay J , Norton C , Mihaylova B 
Published: January 2023

Abstract

Background
Inflammatory Bowel Disease (IBD) affects about 7 million people worldwide. People with active disease often experience symptoms of abdominal pain, fatigue and incontinence which may persist even in remission. We assess the impact of these symptoms, and the further contribution of anxiety and depression, on health-related quality of life (QoL) of people with IBD.

Methods
In the IBD-BOOST survey, over 12,500 people with IBD in the UK were approached across outpatient clinics, the IBD-BioResource participants and the Crohn’s and Colitis UK charity membership; 8486 self-completed surveys were returned. Participants’ QoL was measured using the EQ-5D-5L questionnaire, a generic health-related QoL instrument. Patients’ QoL, ranging from 1 (perfect health) to -0.594 (worst health) was calculated using UK value set. Our approach involved three pre-specified stages of linear regression model development to assess the effects of symptoms on QoL. At stage 1 the model included IBD type, IBD activity score, IBD control score, socio-demographic characteristics and co-morbidities. At stage 2, the three key IBD symptoms: pain, fatigue and bowel incontinence were added. At stage 3, anxiety and depression were also included.

Results
Table 1 presents selected characteristics of the 8486 IBD-BOOST survey participants (mean age 50 years, 58% women, 49% Crohn’s disease). The EQ-5D-5L questionnaire was completed by 8114 (96%) participants reporting problems across QoL domains (Figure 1: 30% problems with mobility, 13% with self-care, 43% with usual activities, 60% pain/discomfort and 50% anxiety/depression). The mean QoL was 0.76 (SD 0.22).
Health-related QoL was substantially reduced in respondents reporting higher IBD activity or worse IBD control (Table 2; stage 1). These associations weakened substantially following adjustment for the key IBD symptoms of pain, fatigue and bowel incontinence for which strong and graded associations with higher symptom severity associated with lower QoL were observed (Table 2; stage 2). The further inclusion of adjustments for anxiety and depression only moderately weakened previous associations and strong and graded associations between more severe anxiety or depression and lower QoL were also observed (Table 3; stage 3). Being male, obese, unemployed/retired, or having physical or mental health comorbidity were associated with lower QoL, and being in a relationship with higher QoL (results not shown).

Conclusion
We report graded associations between symptoms of pain, fatigue, bowel incontinence, anxiety and depression and QoL in IBD. These estimates could inform assessments of interventions to improve IBD management.
DOP26 Burden of perianal disease and perianal surgery in Crohn’s disease over different therapeutic eras – a population-based study from western Hungary between 1977–2020, data from the Veszprem county cohort
Authors: Gonczi L , Lakatos L , Golovics P A , Pandur T , David G , Erdelyi Z , Szita I , Lakatos P L 
Published: January 2023

Abstract

Background
Few population-based studies have investigated rates and management of perianal disease and long-term perianal surgery rates in Crohn’s disease (CD). The present study is a continuation of the Veszprem IBD population based cohort with a follow-up osince 1977. Our aim was to analyze the long-term rates of perianal surgical procedures over different therapeutic eras in a prospective population-based database from Veszprem Province, including incident CD patients.

Methods
Patient inclusion was between January 1, 1977 and December 31, 2018; follow-up ended December 31, 2020. Both in-hospital and outpatient records were collected. Perianal surgical procedure was defined as any perianal surgical procedure including fistulotomy, abscess drainage or seton placement. Surgery rates were examined in three different eras based on time of diagnosis: cohort-A, 1977-1995; cohort-B, 1996-2008; and cohort-C, 2009-2018.

Results
Data of 946 incident CD patients were analyzed (male/female: 496/450; median age at diagnosis: 28 years(y) [IQR: 22-40]). Median follow-up time for the entire cohort was 15 years (IQR: 9-21). Table 1. Perianal disease at diagnosis was present in 17.4% (n=165) of the total cohort, and in 24.7%/ 18.5%/ 13.2% in cohorts A/B/C, respectively. By the end of follow-up, an additional 9.3% (n=88) of the total cohort developed perianal disease. Cumulative immunosuppressive and biologic therapy exposure increased by time in cohorts A/B/C (Table 2 and Figure 1), and biologic use was higher in patients with perianal disease compared to the overall population.Figure 2. The overall rate of perianal surgical procedures was 44.7% (113/253) in patients with perianal disease during the total follow-up. The cumulative probability of perianal surgical procedure in patients with perianal disease was 28.3±2.9% after 10 years, 41.0±3.5% after 20 years, and 64.1±5.1% after 30 years. No statistically significant differences have been observed in the cumulative probability of perianal intervention between cohorts A/B/C: 24.2±5.4%/ 19.9±3.5%/ 29.4±5.8% after 5 years; 33.9±6.0%/ 23.6±3.8%/ 31.7±6.1% after 10 years; [LogRank=0.594]. Figure 3. Cox-regression multivariate analysis showed that stenosing or penetrating disease (B2/B3) behavior (HR 1.81; 95%CI 1.19-2.75; p=0.005) was independent predictor of perianal surgical procedure. Table 3.

Conclusion
The burden of perianal disease and perianal surgical interventions was high in this cohort. Patients with perianal CD had higher exposure to biologicals. No difference was observed in perianal surgical intervention rates despite the increasing use of immunosuppressives and biologicals over time, however these procedures may partly represent a medical decision and the complex management of perianal disease.
DOP29 Single cell analysis of Crohn’s disease fistula; comparison of different locations
Authors: Becker drs. M , Koelink P , Bemelman W , Buskens C , Wildenberg M 
Published: January 2023

Abstract

Background
A common complication of Crohn’s disease(CD) are perianal fistulae, highly impacting the quality of life in these patients. The pathogenesis of these fistulas is incompletely understood. Treatment is often given based on knowledge of disease processes in the inflamed intestine itself, but whether the immune activity in the fistula tract is similar remains unknown. Full characterization of the intestinal mucosa versus the fistula tract itself may reveal immunological differences between the two, and generate leads for both development of new interventional options as well as allow better stratification of patients.

Methods
Matched biopsies were obtained from the rectal mucosa, the internal opening of the fistula and the tract itself. A total of 30 patients were included (20 CD; 10 non-IBD patients). Tissues were processed to cell suspensions and selected for live CD66b- cells. Single cell RNASeq analysis was performed using 10x Chromium. In total, 111.955 immune cells were annotated and used for analysis.

Results
T cells comprised the largest cluster of immune cells, which was subclustered into 19 clusters. Both the internal opening and the fistula tracts contained elevated proportions of effector memory and cycling T cells. Conversely, the rectum contained more central and tissue resident memory cells. T cells expressing IL-22, which were previously described in fistula were detected in considerable number in the rectum and internal opening, but were scarce in the fistula tract itself. These cells were clearly distinct from the IL17A producing subset, and IL17F expressing cells and mainly found in the fistula tracts. Only the tract contained a clear subset of CXCL13 expressing T cells, suggesting follicular helper T cells. Presence of these cells was strongly correlated to the presence of lymphoid inducer cells as well as IgG producing B cells rather than the IgA subset found in the rectum. Clusters of myeloid cells were largely derived from the fistula tracts. Subclustering into 10 clusters indicated a shift from anti-inflammatory to pro-inflammatory macrophages in the tracts compared to the rectal mucosa. Finally, a striking difference in NK cells subsets was observed, with significantly more CD56bright NK cells present in the rectal samples while the internal opening and the tracts were comparable.

Conclusion
Cellular composition and activity of the immune cell compartment differs considerably between the rectum, the internal opening of the fistula and the tract. Subsequently, therapy targeted at processes involved in mucosal inflammation may not actually target the fistula itself, which may explain the low success rate in fistula resolution. Careful analysis of the fistula may help to identify targets useful in the treatment.
DOP36 Vedolizumab-treated IBD patients show an increased gut microbial diversity associated with a specific serum metabolic signature
Authors: Pisani L F , Crespi G , Mellai M , Flavio C , Annunziata M L , Manfredi M , Luca P , Porta C 
Published: January 2023

Abstract

Background
A role for gut microbes in IBD has been suspected since the early descriptions of potential infectious agents. IBD is clearly associated with intestinal dysbiosis, that is the imbalance in structures and functions of gut microbiota that disrupts host-microbe and immune homeostasis. Members of the commensal gut microbiota may play a role in etiopathogenesis of IBD. New therapies with diverse mechanisms of action inhibiting leukocyte trafficking or blocking inflammatory cytokines have revolutionized therapeutic approach. A less diverse microbiome, greater abundance of pro-inflammatory and depletion of species with protective mechanisms, such as short-chain fatty acid production, is associated with intestinal inflammation in IBD. Given that intestinal dysbiosis is a hallmark of IBD patients, we investigate the potential role of biologic drugs on both gut microbial and serum metabolomic in the restoration of microbial homeostasis.

Methods
In 2020-2021, 238 IBD patients (CD=145, UC=93) and 45 healthy controls of the North Italy were enrolled. To define the characteristics of metabolic profile of IBD patients, three different machine learning models based on serum metabolic signatures were developed and applied for the random forest analysis of anti-TNF or anti-integrin users. Stool sample from anti-integrin (N=18) or anti-TNF (N=19)-treated IBD patients was profiled by 16S rRNA gene sequencing, to identify putative associations between medication and microbial composition.

Results
In IBD patients untargeted metabolomics on serum samples confirmed that both most of the IBD patients (70% of anti-TNF and 100% of vedolizumab users) harbor a metabolic profile enriched of anti-inflammatory and antioxidant molecules. Noteworthy, vedolizumab-treated patients showed a higher microbial diversity than anti-TNF users along with an enrichment of both Bacteroidetes and Proteobacteria. Despite the prevalence of Firmicutes species (60,85-62,97%) in IBD patients, the Firmicutes/Bacteroidetes ratio of vedolizumab (2,9:1) is lower than anti-TNF (5,7:1) users, suggesting that anti-integrin-treated patients have an improved microbial composition.

Conclusion
The gut microbiome is a key determinant of initiation and propagation of luminal inflammation in IBD. We describe the microbial composition and structure from a large cohort of IBD patients with different biologic therapies, and their metabolomic profile. We found a correlation between an improvement of dysbiosis and a more anti-oxidant and anti-inflammatory metabolic profile in vedolizumab-treated patients. Further experimental studies are important to mechanistically determine how biologic drugs differentially influence gut microbiota and metabolomic and how this may impact IBD course.
DOP38 Upadacitinib Therapy Reduces Crohn’s Disease Symptoms Within the First Week of Induction Therapy
Authors: Colombel J F , Hisamatsu T , Bresso F , Thin L , Parra R , Ford S , Remple V , Lacerda A P , Hecht P , Mallick M , Garrison A , Regueiro M 
Published: January 2023

Abstract

Background
Upadacitinib (UPA), an oral, selective JAK inhibitor demonstrated superior efficacy for clinical remission compared with placebo (PBO) and an acceptable safety profile in patients with moderately to severely active Crohn’s disease (CD) in 2 phase 3 induction trials, U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836).1-2 There remains an unmet need for therapies that provide rapid symptom relief in ambulatory patients with moderate to severe CD experiencing disease flares. This sub-analysis evaluated the efficacy of UPA 45 mg once daily (UPA45) on early symptomatic improvement for the first 15 days of treatment, using pooled data from U-EXCEL and U-EXCEED.

Methods
U-EXCEL and U-EXCEED were multicentre, double-blind, PBO-controlled trials that enrolled patients who had average daily very soft or liquid stool frequency (SF) ≥4 and/or abdominal pain score (APS) ≥2 at baseline, plus a Simple Endoscopic Score for CD ≥6 (≥ 4 for patients with isolated ileal disease), excluding the narrowing component. Patients (n=1021) were randomized (2:1 ratio) to receive UPA45 (n=674) or PBO (n=347) for 12 weeks. First dose of study drug was administered on day 1. Improvement in daily symptoms of SF and APS, in addition to time to first achievement of daily SF/APS clinical remission were assessed.

Results
Patients treated with UPA45 experienced a significant improvement in daily symptoms compared with PBO-treated patients, simultaneously achieving SF &lt; 3 and APS ≤ 1 beginning at day 3 (9.6% UPA vs. 5.8% PBO) (P≤0.05, Figure 1A). Difference from PBO was maintained through day 15 (P≤0.05), except for day 4 (P=0.0518). Similar results were found when evaluating each symptom separately, with a higher proportion of patients who received UPA45 achieving either SF &lt; 3, beginning at day 5 (31.6% UPA vs. 23.1% PBO, Figure 1B). UPA-treat patients attained significance for APS ≤ 1 beginning at day 6 (49.1% UPA vs. 39.3% PBO, Figure 1C), compared with patients that received PBO. Differences from PBO were sustained through day 15 for either symptom (P≤0.01 for both endpoints). A greater proportion of patients receiving UPA45 also demonstrated at least a 60% decrease in SF by day 5, compared to PBO, which was maintained through day 15 (P≤0.01, Figure 1D). Patients treated with UPA45 achieved daily SF/APS clinical remission significantly earlier than PBO-treated patients (median time to clinical remission: 13 days UPA45 vs 32 days PBO; P&lt;0.0001, Figure 2).

Conclusion
Patients who received UPA 45 mg once daily significantly improved daily symptoms of diarrhea or abdominal pain within the first week of treatment and achieved daily clinical remission faster than PBO-treated patients, providing rapid symptom relief.
DOP39 Endoscopic, histologic, and combined outcomes with reinitiation of ozanimod after temporary discontinuation: 2-year interim analysis of the True North open-label extension study
Authors: Vermeire S , Dignass A , Colombel J F , Jain A , Canavan J B , Wu H , Lawlor G , Osterman M T , Rubin D T , Regueiro M 
Published: January 2023

Abstract

Background
Mucosal healing, evaluated by a combination of endoscopic and histologic examinations, is a desired outcome in ulcerative colitis (UC), but few long-term or open-label extension (OLE) studies of UC treatments have assessed these outcomes. In the phase 3 True North (TN) study, ozanimod 0.92 mg once daily demonstrated efficacy and safety for up to 52 weeks in patients with moderately to severely active UC. The current analysis evaluated long-term endoscopic and histologic endpoints in patients who reinitiated ozanimod after experiencing disease relapse when rerandomised to placebo during the TN maintenance period (MP).

Methods
Responders to ozanimod 10-week induction therapy were rerandomised 1:1 to ozanimod (n=230) or placebo (n=227); this OLE interim analysis (data cutoff: 10 January 2022, the point at which the OLE Week 94 disposition is available for patients) included all patients who relapsed on placebo during the MP and reinitiated ozanimod in the OLE. Endpoints included percentages of patients with endoscopic improvement (endoscopic subscore of ≤1 point), histologic remission (Geboes index score &lt;2), and mucosal healing (endoscopy subscore of ≤1 point and Geboes index score &lt;2) at OLE Weeks 46 and 94. Data were evaluated as observed case (OC) and nonresponder imputation (NRI) analyses.

Results
Seventy-seven (34%) patients rerandomised to placebo experienced a disease relapse in the TN MP. Median time to relapse was 12.7 weeks. At data cutoff, all 77 patients had either completed OLE Week 94 (51.9%) or discontinued treatment. At OLE Week 46, endoscopic improvement, histologic remission, and mucosal healing were achieved by 50%, 56%, and 42% of patients, respectively (OC analysis). Proportions with these endpoints further increased to 60%, 68%, and 48%, respectively, by OLE Week 94. Per NRI analysis, endoscopic improvement, histologic remission, and mucosal healing at OLE Weeks 46 and 94 were observed in 30% and 27%, 31% and 25%, and 23% and 17% of patients, respectively (Figure). Furthermore, 52% of patients with endoscopic improvement at OLE Week 46, 58% of patients with histologic remission at OLE Week 46, and 44% of patients with mucosal healing at OLE Week 46 continued to sustain the respective endpoints at OLE Week 94 with another year of ozanimod treatment.

Conclusion
In patients who experienced disease relapse after rerandomisation to placebo, reinitiation of ozanimod was associated with recapture of response and long-term endoscopic and histologic benefits, including histologic remission and mucosal healing. These data suggest that patients who experience disease relapse when ozanimod is temporarily discontinued may benefit from resumption of ozanimod treatment.