bluuebunny/crossref_metadata_2025 huggingface dataset:
DOP12 Validation of radiomics features on MR enterography characterizing inflammation and fibrosis in stricturing Crohn’s disease
Authors: Sleiman J , Chirra P , Gandhi N , Gordon I O , Viswanath S , Rieder F ,   Stenosis Therapy and Anti-Fibrotic Research (STAR) Consortium
Published: January 2023

Background

MR enterography (MRE) accurately detects Crohn’s disease (CD) strictures, yet its ability to differentiate inflammatory from fibrostenotic components within a CD stricture is limited. Artificial intelligence in cross sectional imaging, termed radiomics, is a quantitative image extraction analysis technology creating an opportunity to enhance characterization of strictures on routine MRE exams. We present a study on machine-reader evaluation of MRE to distinguish inflammation and fibrosis in CD strictures via quantitative radiomic features and compare radiomics performance to central radiologist scoring of MRE.

Methods

In this retrospective single center study 51 patients (n=34 for discovery; n=17 for validation) had confirmed stricturing CD (using CONSTRICT criteria) on MRE. Surgical histopathology scoring of specimens within 15 weeks of MRE exam (range 0-100, scores ≥70 =severe) was used as the reference standard for both inflammation and fibrosis. An expert abdominal radiologist blinded to clinical and histopathologic results provided a global visual analog scale (VAS, 0-100) assessment of stricture inflammation and fibrosis. 2164 3D radiomic features were extracted from the stricture regions on MRE, from which the most relevant feature subsets were identified via cross-validated machine learning analysis in the discovery cohort for differentiating between severe vs mild inflammation and fibrosis. Radiomic features and VAS scores were evaluated against pathology-defined inflammation and fibrosis in the validation cohort.

Results

Clinical variables including sex, age, Montreal classification and stricture type across discovery and validation groups can be found in Table 1. The median time from MRE to surgical resection was 7.1 90-15) weeks. 43% of strictures in the overall cohort were classified as severe for inflammation and 43% had severe fibrosis. Two distinct sets of radiomic features capturing textural heterogeneity (patterns, local entropy) within strictures were significantly associated with severe inflammation or severe fibrosis (p<0.01). For inflammation, AUC for discovery and validation were 0.69 and 0.67, respectively (Figure 1). For fibrosis, AUC for discovery and validation were 0.83 and 0.77, respectively (Figure 2). The radiologist VAS had an AUC of 0.71 for identifying inflammation and AUC 0.46 for identifying fibrosis. Combining radiomic features and radiologist VAS had no significant impact on predictor performance.

Conclusion

Radiomic analysis may support the identification of fibrosis, but not inflammation in stricturing CD compared to radiological visual assessment. This tool may offer a novel way to stratify patients for future anti-fibrotic therapies.
DOP13 Plasma metabolite fingerprint could discriminate inflammatory bowel disease patients from healthy subjects
Authors: Farkas K , Endre G , Bacsur P , Resál T , Kocsmárszky-Koósz V , Tömösi F , Tóth E , Rutka M , Bálint A , Fábián A , Bor R , Szepes Z , Goretity Á , Thibodeau I , Molnár T
Published: January 2023

Background

Inflammatory bowel diseases (IBD, Crohn’s disease [CD], ulcerative colitis [UC]) are chronic immune-mediated systemic diseases with unknown aetiology. In the past few years, experimental studies revealed associations of human serum and plasma metabolites’ with IBD with a possible discriminative power between IBD and healthy subjects. Our study focused on the utility of plasma metabolome profiling as a diagnostic marker in patients with different phenotypes.

Methods

IBD patients were enrolled in a double-centre prospective cohort study. Large number of healthy subjects were included to reduce methodological bias. Blood samples were obtained at baseline and stored at –20°C and plasma metabolites were measured by high performance liquid chromatography coupled with tandem-mass spectrometry (HPLC-MS/MS). Logistic regression, minimum redundancy maximal relevance (mRMR), principal component analysis (PCA), and linear discriminant analysis (LDA) were used to calculate discriminative power.

Results

Plasma metabolome profile of 26 IBD (13 UC and 12 CD) patients and 168 HC participants were analyzed, and 388 metabolites were measured. 33 and 58% of CD patients and 31 and 39% of UC patients had clinical and endoscopic activity based on clinical (mean pMayo: 2.8±3.4, CDAI: 56±62) and endoscopic (mean PanMayo: 7.4±13.3 and SES-CD: 7.3±8.2) indices. Low plasma level of cysteine (CV=-0.36; p<0.01), triglycerides (CV=-0.19; p<0.01) and hexosylceramide (HexCer(d18:1/23:0); CV=-0.18; p<0.01), while high level of arginine (CV=0.3; p<0.24), hexosylceramide (HexCer(d18:2/23:0); CV=0.2; p=0.02), glutamate (CV=0.19; p<0.01) and lactate (CV=0.16; p=0.01) were significantly associated with IBD. According to mRMR analysis, cysteine (p<0.001), triglyceride (p<0.01), and HexCer(d16:1/22:0); (p<0.001) ranked highest in terms of feature importance (discriminative power). Based on the 16 metabolites considered to be of the highest discriminative power, the healthy and the IBD groups were well separated (PC1=18.2%, PC2=14.7%; Figure 1.).

Conclusion

Based on our results, plasma metabolite levels may help to discriminate IBD and healthy subjects. Integrative analysis of different biological samples may potentially predict IBD and could promote achieving personalized medicine. Further sample collections and analysis within this study can reveal discriminative metabolite fingerprints among IBD subtypes and correlations with activity as well.
DOP14 Identification and validation of a lipidomic signature as a novel diagnostic biomarker of paediatric Inflammatory Bowel Disease
Authors: Salihovic S , Nyström N , Bache-Wiig Mathisen C , Andersen S , Olbjørn C , Perminow G , Opheim R , Detlie T E , Huppertz-Hauss G , Bazov I , Kruse R , Lindqvist C M , Hedin C R H , Carlson M , Öhman L , Magnusson M , Keita Å V , Söderholm J D , D’Amato M , Orešič M , Repsilber D , Hyötyläinen T , Hoivik M L , Halfvarson J
Published: January 2023

Background

Improved diagnostic biomarkers are an unmet clinical need for paediatric inflammatory bowel disease (IBD). We therefore aimed to identify a diagnostic lipidomic signature of IBD in blood.

Methods

We performed a non-targeted liquid chromatography-time of flight mass spectrometry-based lipidomics (UPLC-QTOFMS) analysis of plasma samples from 211 treatment-naïve children with suspected IBD (Table 1). Discovery cohort: the Uppsala Children’s Hospital cohort (n=94); Validation cohort: children from the population-based IBSEN III inception cohort (n=117). All children underwent diagnostic workup for IBD in accordance with the ESPGHAN/Porto criteria. Multivariable and supervised machine learning were used to identify a diagnostic lipidomic signature and its performance was compared to clinically established biomarkers i.e., high sensitivity C-reactive protein (hsCRP) and faecal Calprotectin.

Results

The discovery cohort comprised of 58 children with IBD and 36 symptomatic controls without any discernible evidence of IBD. In the validation cohort, the corresponding numbers were 80 and 37. In a multivariable analysis, using regularized regression and discovery cohort data, a lipidomic signature comprising 30 lipid species was identified as influential in distinguishing IBD from symptomatic controls (Figure 1). Further, while examining both individual lipidomic species and lipidomic signatures in the discovery cohort, the highest diagnostic accuracy was observed for a short lipidomic signature comprising of only two lipid species, LacCer(d18:1/16:0) and PC(18:0p/22:6). When applied to the validation cohort, the short signature improved the diagnostic prediction of paediatric IBD (AUC=0.87 [95%CI 0.79-0.95]) compared to high-sensitivity C-reactive protein (hsCRP) alone (AUC=0.73 [95%CI 0.63-0.82]), P-value=0.0004. Adding hsCRP to the diagnostic model did not improve its performance (AUC=0.86) (Figure 2). Only 77 (66%) children from the validation cohort provided a stool sample, and among these children, the diagnostic capacity of the short lipidomic signature (AUC=0.88 95%CI 0.80-0.95) and faecal Calprotectin (AUC=0.93 95%CI 0.87-0.99) did not differ (P-value=0.22).

Conclusion

This study has identified and validated a diagnostic lipidomic signature of pediatric IBD that was superior to hsCRP and did not differ from faecal Calprotectin. This signature could be developed into an accessible and scalable blood test for paediatric IBD, particularly among patients unwilling to provide stool samples.
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

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<.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<0.001). Patients with aCD had higher mean fatigue scores than qCD, but differences between groups were not significant (p>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<.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<.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

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

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

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

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

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

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 < 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 < 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<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

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 <2), and mucosal healing (endoscopy subscore of ≤1 point and Geboes index score <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.
DOP44 Tofacitinib versus corticosteroids for induction of remission in moderately active ulcerative colitis (ORCHID): A prospective randomized open-label pilot study
Authors: Singh A , Midha V , Mahajan R , Kaur K , Singh D , Sood A
Published: January 2023

Background

The exact positioning of tofacitinib in the therapeutic algorithm is still unclear. We evaluated the efficacy of tofacitinib in comparison to corticosteroids for induction of remission in patients with moderately active UC.

Methods

This was a randomized, parallel-group active-controlled pilot study comparing the efficacy and safety of corticosteroids and tofacitinib in inducing remission in adults with moderately active UC (defined as total Mayo clinic score 6-9). Patients were randomly assigned to receive corticosteroids (prednisolone, starting 40 mg daily and tapered by 5 mg every week over 8 weeks) or tofacitinib (10 mg twice daily) for 8 weeks. The primary endpoint was composite remission (defined as total Mayo clinic score≤2, with an endoscopic subscore of 0 and fecal calprotectin<100 mcg/g) at 8 weeks. Clinical remission (defined as Mayo clinic score ≤2) and clinical response (defined as a decrease of 30% in the Mayo clinic score from baseline or more and 3 or more points, along with either a rectal bleeding subscore of 0 or 1 or a decrease in the rectal bleeding subscore of 1 point or more) at week 8 were also evaluated. Follow-up assessments for efficacy and safety were done at weeks 2, 4, and 8.

Results

Seventy-eight patients (mean age 37.78±13.94 years, 42[53.84%] males; 43 assigned to tofacitinib and 35 to corticosteroids group) were enrolled. At week 8, there was no significant difference in the proportion of patients achieving composite remission in the two treatment groups (7 of 43, 16.28% in the tofacitinib group versus 3 of 35, 8.57% in the corticosteroid group; p=0.31). Clinical remission at week 8 was achieved in 18 of 43(41.86%) patients receiving tofacitinib and 13 of 35 (37.14%) patients receiving corticosteroids (p=0.67). Clinical response was seen in 28 of 43(65.12%) and 25 of 35(71.42%) patients in the tofacitinib and corticosteroid groups, respectively(p=0.55). No difference was observed in the median number of days required to achieve symptomatic remission between the two groups (10[IQR 7-18.75] and 10[IQR 5-12.5] days for tofacitinib and corticosteroids, respectively;p=0.25). One patient in the tofacitinib and corticosteroid group discontinued treatment due to the development of pulmonary tuberculosis and pustular acne, respectively. Another patient receiving tofacitinib developed herpes zoster. No serious adverse events or major adverse cardiovascular events were observed.

Conclusion

In patients with moderately active ulcerative colitis, there is no difference between the efficacy and safety of tofacitinib and corticosteroids for induction of remission. Tofacitinib can be used as a first-line therapy for inducing remission in moderately active UC. (CTRI Registration number: CTRI/2021/10/037641)
DOP45 Predicting late responders to filgotinib in patients with moderately to severely active Ulcerative Colitis: A post hoc analysis of SELECTION and SELECTIONLTE
Authors: Matsuoka K , Löwenberg M , Fumery M , Takatori Y , Fujitani Y , Oortwijn A , Faes M , Jamoul C , Hibi T
Published: January 2023

Background

Filgotinib (FIL) is a once-daily, oral, Janus kinase 1 preferential inhibitor approved for the treatment of ulcerative colitis (UC) in Europe and Japan. Previous analyses of the SELECTION programme showed that, in patients with moderately to severely active UC, C-reactive protein, rectal bleeding and stool frequency at day 7 predicted response to FIL at week 10,1 and that patients who did not respond to FIL induction benefited from an additional 12 weeks of FIL 200 mg.2 This post hoc analysis was conducted to identify factors associated with late response to FIL.

Methods

The SELECTION programme comprises a phase 2b/3, randomized, double-blind, placebo (PBO)-controlled study (SELECTION; NCT02914522) and its open-label, long-term extension (SELECTIONLTE; NCT02914535). Adult patients aged 18–75 years were randomized to FIL 100 mg, FIL 200 mg or PBO once daily for 11 weeks in the induction study. This post hoc analysis only included patients receiving FIL 200 mg who did not have clinical remission or a Mayo Clinic Score (MCS) response at week 10 of induction and who subsequently entered SELECTIONLTE on FIL 200 mg. Patient characteristics at induction baseline and changes in surrogate markers of response from baseline to week 4 of induction were compared between patients who had observed partial MCS (pMCS) response (pMCS late responders) or observed non-response (pMCS non-responders) at week 12 of SELECTIONLTE using univariate and multivariate logistic regression models.

Results

In total, 160 patients were included (102 [63.8%] pMCS late responders and 58 [36.3%] pMCS non-responders) (Table 1). In univariate analysis, prior use of biologics was not significantly associated with late response to FIL. Changes in surrogate markers of response showed that none were significantly associated with late response (Figure 1). In multivariate analysis of baseline characteristics, older age was positively associated with late response to FIL (odds ratio [OR]: 1.042, 95% confidence interval [CI]: 1.011–1.073, p = 0.007), while body mass index (BMI) < 18.5 kg/m2 (OR: 0.041, 95% CI: 0.003–0.519, p = 0.014) was negatively associated with late response.

Conclusion

In SELECTION programme participants, older age was positively associated with late response to FIL 200 mg and BMI < 18.5 kg/m2 was negatively associated with late response. These factors should be taken into account when monitoring patients on FIL with insufficient response at week 10. No other strong predictors were identified. The results of this analysis should be interpreted in the context of previous findings.1

1. Feagan B et al. United European Gastroenterol J 2022;10(S8):462–3

2. Vermeire S et al. United European Gastroenterol J 2021;9(S8):215–6
DOP53 Community types of the human gut virome are associated with endoscopic outcome in UC patients
Authors: Jansen D , Falony G , Vieira-Silva S , Simsek C , Marcelis T , Machiels K , Caenepeel C , Raes J , Severine V , Matthijnssens J
Published: January 2023

Background

Inflammatory bowel diseases (IBD) are a group of chronic inflammatory diseases of the gut. The pathophysiology is unknown; however, it is thought to result from an inappropriate immune reaction to the commensal gut microbiota. Community-typing is a common practice in bacteriome analysis allowing for the stratification of individuals based on their gut microbiome (eg., ‘enterotyping’). A viral counterpart of these enterotypes might allow stratification of individuals based on their gut virome. The aim of the present study is to investigate the existence of such viral community types and assess the impact of therapeutic outcome (and other covariates) on the gut virome in IBD patients.

Methods

Fecal samples were selected from 181 patients undergoing immunomodulatory therapy, and a baseline (pre-intervention) and a primary endpoint (post-intervention) have been collected for each patient. Viral metagenomics and deep sequencing were performed following viral enrichment with the NetoVIR protocol. Redundancy analysis and Dirichlet Multinomial Mixtures were applied to determine covariates of the virome composition and to condense the gut virota into viral community types, respectively.

Results

IBD patients were stratified based on unsupervised machine learning into two viral community types. Community type CA showed a low α-diversity and a high relative abundance of Caudoviricetes [non-CrAss] phages and was associated to the dysbiotic Bact2-enterotype. Community type CrM showed a high α-diversity and a high relative abundance of Caudoviricetes [CrAss] and Malgrandaviricetes phages. The gut virome variation was explained by several factors: patients’ individuality (75.8%), disease location (1.4%), age (0.5%) and faecal moisture (0.3%), with diagnosis not showing a non-redundant effect. Despite our expectations the choice of biological therapy did not show an association with the virome variation. During post-interventional analysis, endoscopic outcome (0.5%) was associated to gut virome variation as well. Remitting UC, but not CD, patients revealed a high percentage of community type CrM, a high Shannon diversity and a low phage lysogenic potential. Conversely, non-remitting UC, but not CD, patients revealed a high percentage of community type CA, a low Shannon diversity and a high lysogenic potential.

Conclusion

These findings suggest that viral community-typing allows for stratification of IBD patients based on their gut virome composition and might be a valuable tool to better understand IBD subtypes or as a potential future biomarker.
DOP60 Environmental risk factors for Inflammatory bowel disease: A large prospective case-control study in India
Authors: Banerjee R , Pal P , Prakash N , Mudigonda S , Joseph S , Patel R , Khalil M , Komawar A , Korikana S , Mekala D , Akki Y , Gaddam A , Valluri S
Published: January 2023

Background

Increasing urbanization and westernization of lifestyles have been implicated for the rising incidence of IBD in the developing world. However real world data is very limited. We planned a comprehensive assessment of environmental exposures in a large cohort of patients with and without IBD in India to identify key risk factors.

Methods

This study is a part of a wider epidemiologic colonoscopic screening program for detection of IBD on all symptomatic patients attending the hospital and specially conducted rural health camps. A detailed questionnaire based survey of environmental risk factors including diet, smoking, antibiotic use, hygiene status, microbial exposures, vaccination, water supply, rural/urban residence was conducted prior to colonoscopy. The risk factors were compared among the IBD and non IBD patients with normal colonoscopy. Univariate logistic regression was done initially adjusting for age and sex followed by multivariate analysis to estimate adjusted ORs (aOR) and 95% CIs.

Results

13421 completed environmental risk questionnaire.1306 IBD(576 CD;730 UC) cases diagnosed.12115 with normal colonoscopy served as the controls.

In multivariate model, current smoking(aOR 5.66; 95% CI 4.41-7.26),ex-smoking (aOR 1.79;1.24-2.58), regular alcohol intake (aOR 1.82, 1.14-2.9), non-vegetarian diet(aOR 1.8; 1.48-2.23),daily bakery/fast food consumption(aOR 1.57; 1.31-1.88),soft drink consumption(> 2/week)(aOR 1.37,1.14-1.66), delivery by cesarean section (aOR 1.49, 95% CI 1.28-1.76), antibiotic use(<1 yr age) (aOR1.33;1.1-1.58), exposure to pets(aOR 1.68;1.39-2.03), Western toilets (aOR3.52, 2.56-3.58)and childhood infections (aOR 1.74; 1.45-2.028) increased risk of UC (Fig 1, 2). Increased risk of CD was seen with current smoking(aOR 6.16; 95% CI 4.68-8.11), ex-smoking(aOR2.15; 1.43-3.22),non-vegetarian diet (aOR 1.69;1.34-2.13), soft drink consumption(> 2/week)(aOR 1.84,1.51-2.24),daily bakery/fast food consumption(aOR 2.24;1.85-2.71), oral contraceptive pill use (aOR 3.79, 1.29-12.17) antibiotic use (<1 year age)(aOR 1.27; 1.04-1.54),exposure to pets(aOR 1.79; 1.45-2.2), caesarean section(aOR 1.48;1.23-1.77), Western toilets (aOR 2.98, 2.47-3.59), non-human milk exposure (<6 months age) (aOR 1.28, 1.03-1.6) and childhood infections(aOR 2.51; 2.1-3.04)(Fig 3, 4). Breastfeeding >6 months, daily fruit consumption and daily exercise were protective for both UC and CD (Fig1-4).Rural habitat was not protective for development of IBD both UC and CD.

Conclusion

This large prospective case control study of IBD risk factors in India identifies environmental triggers including childhood immunological, hygiene and dietary factors which modulate risk of IBD later in life.
DOP79 Alternative polygenic forms of Inflammatory Bowel Disease are not captured by current generations of polygenic risk scores
Authors: Mateos B , Gaite A , Rodríguez-Lago I , Marigorta U M
Published: January 2023

Background

Polygenic risk scores (PRSs) have emerged as a promising tool to ascertain individuals at high risk of developing IBD. However, the sensitivity of current PRSs is limited, and will likely remain so in the immediate future. The default expectation is that patients not captured by PRSs must be enriched for rare variants with strong effects and/or environmental risk factors. We set out to investigate an alternative scenario, namely that combinations of common variants in non-GWAS genes conform population of patients that are missed by large genetic studies for the main forms of the disease.

Methods

MAGMA was used to identify genes from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) GWAS. We selected a sort of monogenic IBD genes1 which were significant for IBD (pval ≈ 10-4) but do not overlap with polygenic IBD genes. These genes were compared using DESeq tool on two transcriptomic databases: RISK (Crohn’s disease (CD) onset vs non-IBD) and PROTECT (ulcerative colitis (UC) onset vs 52 weeks). A second DESeq analysis was performed between patients with high against low expression of these 13 genes. We explored these genes using in-silico predicted expression based on eQTL in 9 different tissues for UK Biobank (UKBB) population, comparing UKBB individuals according to disease and polygenic risk score status.

Results

The starting point based on MAGMA analysis led to the detection of 13 monogenic IBD genes which may partially participate in polygenic forms of the disease. The transcriptomic analyses, based on stratification according to the levels of these 13 genes, implied that these genes participate in regulatory programmes that are particularly heterogeneous and variable among cases. The detected differentially expressed genes are associated with immune processes and receptors, inflammation transporters, and digestive problems, as well as skin development, humoral response, extracellular matrix, and mitochondrial component. The TWAS-based estimation analyses hint that low-PRS patients are indeed enriched for common variants associated with higher pathogenic levels at the 13 selected genes.

Conclusion

Although polygenic risk scores may play a valuable role in patient management, our study hints at the presence of patients with common polygenic forms that are not captured by current genetic risk estimators.

1. Chrissy B. et al, 2022. Gastroenterology.