bluuebunny/crossref_metadata_2025 huggingface dataset:
OP07 Psychosocial factors are associated with risk of flare in IBD; results from the PREdiCCt study
Authors: Derikx L , Cotronei C , Gros B , Plevris N , Elford A , Blackwell J , Gaya D , Constantine-Cook N , Lees C ,   PREdiCCt Study Group
Published: January 2025

Background

Patients with IBD suffer a high prevalence of psychological disorders. The impact of psychosocial factors on the risk of a disease flare is unknown. We aimed to assess associations between psychosocial factors and disease flare.

Methods

The PREdiCCt study is the largest prospective study of the causes of IBD flare. 2629 patients in clinical remission were recruited from 47 UK sites and followed up for 24 months. At study entry, patients completed questionnaires evaluating anxiety (HADS-A), depression (HADS-D), sleep quality (PSQI), physical activity (GPAQ) and somatization (PHQ15). We investigated associations between psychosocial factors and risk of clinical flare (patient-reported from IBD-Control 8 score) and hard flare (clinical flare and CRP >5 mg/L or faecal calprotectin (FC) >250 mcg/g and change in treatment). Survival analyses with Cox frailty models were performed, separately for Crohn’s disease (CD) and UC/IBDU, adjusting for baseline FC, sex, index of multiple deprivation, hospital site + age.

Results

We included 1641 patients [CD=830, UC/IBDU=811] who had a complete dataset for analysis (Table 1). Clinical flares were reported by 595 patients [CD=280, UC/IBDU=315], with an overall two-year flare rate of 36%. Hard flares were recorded for 219 patients [CD=99, UC/IBDU=120; two-year flare rate: 13%].

UC patients with higher depression scores had an increased risk of both clinical [elevated HADS-D scores of 8-10: aHR 1.72 (95%CI 1.21-2.43, p=0.002)] and hard flare [aHR 2.50 (p<0.001); Figure 1]. Anxiety was associated with an increased risk of clinical flare [elevated HADS-A scores of 11-21: UC/IBDU: aHR 1.46 (1.08-1.99, p=0.01); CD: aHR 1.86 (1.38-2.52, p<0.001)]. In addition, IBD patients with higher somatization scores were at increased risk for clinical flare [CD: aHR 3.86 (2.33-6.40, p<0.001); UC/IBDU: aHR 1.96 (1.25-3.07, p=0.003)], with a borderline effect for hard flare only in CD [aHR 2.34 (1.02-5.38, p=0.05)]. Significant associations were found between sleep deprivation and clinical flare risk in CD [aHR 1.58 (1.22-2.04, p<0.001)]. UC/IBDU patients who did not meet WHO-recommended exercise levels were at increased risk of hard flare [aHR 1.55 (1.03-2.32, p=0.03)].

Conclusion

In this large prospective IBD cohort study we demonstrated a significant burden of several psychosocial factors. Anxiety, depression, somatization, and sleep disturbances were associated with an increased clinical flare risk. Depression and lack of exercise were associated with an increased hard flare risk in UC patients. These findings emphasize the need for a holistic IBD treatment approach.

Table 1: baseline characteristics

Figure 1: Clinical flare risk (left) and hard flare risk (right adjusted for site [fixed effect], sex, IMD, FC + age)
OP13 Higher neoplasia detection rate and lower number of targeted biopsies associated with virtual chromoendoscopy in IBD surveillance: a real-world, multicentre UK study
Authors: Radia C , King A , Harlow C , Yeo J H , Hickey A , Wyatt N , Michael E , Gerard P , Colwill M , Patel C , Patel K , Speight A , Harrow P , Kandiah K , Samaan M , Kent A J , Pavlidis P
Published: January 2025

Background

Dye chromoendoscopy (DCE) with targeted biopsies has traditionally been considered the gold standard for optimal detection of dysplasia in the context of inflammatory bowel disease (IBD) surveillance. Randomised trials have challenged this with both virtual chromoendoscopy (VCE) and high-definition white light endoscopy (WLE) appearing to have comparable yield. This multicentre UK study aims to test the hypothesis that neoplasia detection rate (NDR) in IBD surveillance as part of routine clinical care is not affected by the modality used.

Methods

IBD surveillance colonoscopy procedures for patients with ulcerative colitis (UC) and colonic Crohn’s disease (CD) performed in five UK centres between 2018 and 2024 were reviewed. For procedures with polypectomy or missing data, median withdrawal times for each modality from non-polypectomy cases were imputed. Significant variables in a univariate analysis were included in a logistic regression model to adjust NDR in the three modalities.

Results

A total of 2,673 IBD surveillance colonoscopies in 2,050 patients were included: 1,275 (48%) WLE, 1,032 (38%) DCE, 366 (14%) VCE. Disease breakdown included 74% UC and 26% CD, and 25% of patients had concomitant primary sclerosing cholangitis. The majority (67%) were performed by endoscopists with expertise in IBD surveillance. Median (IQR) withdrawal time in minutes without polypectomy was DCE: 17 (13, 22), VCE: 14 (12, 20), WLE: 11 (8, 14). Neoplasia was detected in 305 (11%) procedures. The NDR (95% CI) were VCE: 19% (15.3, 23.6), DCE: 12% (9.9, 13.9) and WLE: 9% (7.5, 10.7), p<0.001 (figure 1A).

In a univariate analysis, 8 variables were significantly associated with NDR. A logistic regression model including these variables (figure 2) showed that VCE significantly increased dysplasia detection (p<0.001). Older age, previous dysplasia, and longer withdrawal time also significantly increased NDR (p<0.001), with active disease having the opposite effect (p=0.035). Adjustment for these variables did not change modality related NDR substantially (figure 1B). A higher number of targeted biopsies per procedure were taken with DCE 0.52 (SD 1.68) compared to VCE 0.33 (SD 1.59) or WLE 0.13 (SD0.78), p <0.001. However, this did not improve dysplasia yield within these biopsies: DCE 3.2%, VCE 5.7%, WLE 5.0%, (p=0.248).

Conclusion

In this study of IBD surveillance in routine clinical practice VCE has higher NDR than DCE and WLE. DCE was associated with more targeted biopsies without greater dysplasia detection.
OP14 The United European Gastroenterology green paper—climate change and gastroenterology
Authors: Duijvestein M , Sidhu R , Zimmermann K , Carrington E V , Hann A , Sousa P , Touw H R , van Hooft J E , Müller M
Published: January 2025

Background

The 2024 Lancet Countdown highlights the urgent need for aligned structural and sustained changes to avoid the most severe global health impacts. According to the latest Emissions Gap Report from 2024 by the UN Environment Programme, the continuation of current policies would lead to 3.1°C of global warming. Climate change exacerbates extreme weather, food insecurity, and disease prevalence, thereby affecting human health, medical practice, and healthcare stability. Physicians increasingly encounter these effects in daily patient care, with alterations in the gut microbiome, air pollution, heatwaves, and shifts in infectious disease patterns affecting gastrointestinal and hepatic health.

Methods

The United European Gastroenterology (UEG) conducted a comprehensive literature review to assess the climate change associated health hazards and outcomes in gastroenterology as well as the environmental impact of gastroenterology practices. Additionally, the review aimed to identify research gaps and barriers to the implementation of eco-friendly practices in gastroenterology.

Results

Climate change and healthcare exist in a bidirectional feedback loop: healthcare: emissions, waste and resource consumption from the healthcare sector amplify climate change, which subsequently increases the incidence of GI and liver diseases, heat-related illnesses, zoonoses, vector-borne diseases, and malnutrition. The healthcare sector contributes to 4.4% of global carbon emissions, with gastroenterology procedures, particularly endoscopy as the third highest generator with 3.09 kg of waste per day per bed. The "5 Rs of Greener Gastroenterology" framework—reduce, reuse, recycle, rethink, and research—offer a pathway towards reducing the environmental footprint of gastroenterology. These include minimizing unnecessary procedures, advocating for the Planetary Health Diet, and integrating eco-friendly practices such as telemedicine, digitalization, and sustainability-focused education and research. Promoting roles such as "eco-gastroenterologists," "eco-endoscopists", “eco-intensivist” and "eco-surgeons" is essential to advancing sustainable healthcare on both personal and institutional levels.

Conclusion

The United European Gastroenterology Green Paper aims to raise awareness and outline key principles that the GI workforce can adopt to tackle the climate crisis together. To facilitate adoption and transformation into clinical practice, UEG has developed a toolkit for stakeholders to promote such concepts and provide possible solutions at any structural level. This is a call to joint action between national und specialist gastroenterology societies.
OP15 ECCO Topical Review on Pouch Disorders
Authors: Kayal M , Bislenghi G , Adamina M , Ardalan Z , Avallaneda N , de Buck van Overstraeten A , Duijvestein M , Estevinho M M , Furfaro F , Hart A , Holubar S , Lobaton T , Ollech J , Vavricka S , Ferrante M
Published: January 2025

Background

Pouch disorders are common and may present with symptoms of increased stool frequency, urgency, incontinence, pelvic cramping, and perianal drainage, leading to poor sleep, fatigue, and disability. This topical review provides expert consensus recommendations for the diagnosis and management of the most common inflammatory, functional, structural and neoplastic pouch disorders.

Methods

An open-call for participation was made to all ECCO members. Four working groups were formed each focusing on a specific category of pouch disorders. Each group member performed a comprehensive literature review for their assigned disorder using appropriate key words and drafted summary texts. Sections were reviewed and integrated into a single manuscript by MK, GB, and MF.

Results

Symptoms that arise and persist immediately following pouch construction may indicate surgical issues, while those that gradually develop after a prolonged period of wellness may suggest inflammatory or functional disorders. Symptoms of increased stool frequency, abdominal cramping, and urgency are suggestive of an inflammatory disorder, and a short trial of oral antibiotics may confirm the most likely diagnosis of pouchitis, though a pouchoscopy is preferable to exclude other causes. In case of persistent or recurrent symptoms of pouchitis, additional evaluation via stool studies, pouchoscopy and cross-sectional imaging should be considered to rule out chronic antibiotic-dependent or –refractory pouchitis, or Crohn’s-like disease of the pouch. Symptoms of chronic pelvic pain, intermittent obstruction, and incomplete evacuation suggest a structural disorder. Evaluation with pouchography, MR defaecography, pouchoscopy and examination under anaesthesia should be performed to evaluate for pouch prolapse or volvulus, afferent or efferent limb syndrome, anastomotic leakage, strictures or fistulae. Symptoms of incomplete evacuation, incontinence, and pelvic pain that occur in the absence of an inflammatory or structural abnormality point to a functional disorder. Assessment with anorectal manometry, balloon expulsion tests, and defaecography should be conducted to evaluate pelvic floor dynamics and rule out pelvic floor dyssynergia or irritable pouch syndrome.

Conclusion

A multidisciplinary approach is essential for the diagnosis and management of most pouch disorders. Centres with a specialized pouch care team are often best equipped to manage these complex cases, providing the expertise necessary for accurate diagnosis and tailored interventions.
OP21 MIF-CD74 signaling promotes intestinal LTi-like ILC3s activation and gut fibrosis via upregulating pSTAT3
Authors: Zhao Y , Tu Y , Yang Q , Zhang Y , Zou D
Published: January 2025

Background

Intestinal fibrosis is a common complication of inflammatory bowel disease, and its core pathogenesis is fibroblast activation and massive extracellular matrix (ECM) deposition. In recent years, innate lymphoid cells (ILCs) have been shown to be an important source of fibroblast activation signals in fibrotic diseases. This study aims to explore the heterogeneity of ILC3 (the main ILC subgroup in the human intestine) in the intestinal fibrosis and the mechanism of its interaction with stromal cells.

Methods

The intestinal fibrosis model was constructed with ILC3 deficiency mice (Rorc knock out) treated with chronic DSS/TNBS. Flow cytometry was performed to detect the proportion of ILC3 subsets and cytokine expression level. ILC3 were sorted out for transcriptome sequencing and co-culture experiment with primary intestinal fibroblasts.

Results

In chronic DSS/TNBS models, the colon CCR6+ILC3 significantly expanded (p<0.05), and the expression of cytokine IL-22 was upregulated (p<0.05). ILC3 deficiency mice showed lower degree of intestinal fibrosis, including decrease in collagen involvement area (p<0.05) and decrease in ECM-related genes expression(p<0.05). After adoptively transferred of CCR6+ILC3, the severity of intestinal fibrosis in mice increases again. Flow cytometry revealed that CCR6+ILC3 was the main source of IL-22 in the mouse colon. CCR6+ILC3 cells were then sorted by flow cytometry, and co-cultured with mouse intestinal fibroblasts in vitro. Results shown that CCR6+ILC3 can activate fibroblasts. The expression level of α-SMA protein was significantly upregulated (p<0.05). Cell migration ability was also improved in the scratch experiment (p<0.05). Blocking IL-22 could inhibit the effects above. Transcriptome sequencing analysis of sorted ILC3 revealed a significant upregulation in signaling pathways related to cell activation, proliferation and adhesion, with CD74 existing in all of them. Flow cytometry confirmed the expression of CD74 on ILC3 for the first time, which specifically present on CCR6+ILC3 within RORγt+ cells. Cell stimulation experiments in vitro showed that macrophage migration inhibitory factor (MIF)-CD74 signal upregulated IL-22 level of ILC3 cells and was associated with increased phosphorylation of STAT3 signaling pathway. And MIF, the CD74 ligand, significantly increased in both mouse intestinal fibrosis models and stenosis tissue samples from CD patients (p<0.05).

Conclusion

CCR6+ILC3 is enriched in the intestinal fibrotic microenvironment and can continuously promote disease progression by activating fibroblasts through IL-22. CCR6+ILC3 can sense the pathogenic inflammatory factor MIF in chronic colitis through CD74, and increase IL-22 expression by promote STAT3 phosphorylation.
OP22 NR1D1 Deficiency Induces CD47 Upregulation Impairing Macrophage Efferocytosis and Exacerbating Intestinal Inflammation in Ulcerative Colitis
Authors: Chen Y , Liangru Z
Published: January 2025

Background

Ulcerative colitis (UC) is marked by excessive apoptosis of colonic epithelial cells, driven by intrinsic epithelial defects and impaired macrophage efferocytosis. Inefficient clearance of apoptotic cells perpetuates inflammation and obstructs tissue resolution. NR1D1, a nuclear receptor involved in cellular homeostasis and inflammation, has been implicated in immune regulation, but its role in UC pathogenesis, particularly in macrophage efferocytosis, remains poorly understood.

Methods

A clinical cohort of 300 individuals (200 UC patients and 100 healthy controls) was analyzed to assess the relationship between NR1D1 expression and disease severity, using the Mayo score as a measure of clinical progression. In parallel, dextran sulfate sodium (DSS) was used to induce acute colitis in wild-type and NR1D1-knockout mice. Proteomic profiling was employed to elucidate the effects of NR1D1 deficiency on intestinal inflammation. Mechanistic insights into NR1D1 regulation of CD47 expression were obtained using CUT&Tag, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays in colonic epithelial cells from UC patients and healthy controls. The impact of NR1D1 deficiency on macrophage efferocytosis was explored in vitro using co-cultures of macrophages and organoids. Therapeutic potential was evaluated by administering a hydrogel loaded with SR9009, an NR1D1 agonist, to DSS-treated mice, followed by single-cell RNA sequencing (scRNA-seq) to assess cellular and molecular changes.

Results

NR1D1 expression was significantly reduced in UC patients and inversely correlated with disease severity, as reflected by the Mayo score. Proteomic analysis in DSS-treated mice confirmed that NR1D1 deficiency aggravated intestinal inflammation. CUT&Tag and ChIP assays identified CD47 as a direct transcriptional target negatively regulated by NR1D1. Loss of NR1D1 led to elevated CD47 expression in epithelial cells, which impaired macrophage efferocytosis and disrupted the resolution of inflammation. Administration of SR9009 via a hydrogel delivery system restored NR1D1 activity, reduced CD47 expression, and improved efferocytosis. scRNA-seq of colonic tissues from treated mice revealed a shift toward anti-inflammatory cellular states, with enhanced macrophage functionality and improved epithelial integrity.

Conclusion

NR1D1 deficiency exacerbates epithelial apoptosis and inflammation in UC by upregulating CD47, thereby impairing macrophage efferocytosis. Restoring NR1D1 activity with SR9009 ameliorates inflammation and promotes resolution through improved apoptotic cell clearance. Targeting the NR1D1-CD47 axis represents a promising therapeutic strategy for UC.
OP29 Young Researcher Award: Breaking New Ground in IBD Research: Organoid Models as the Vanguard for Personalized Therapies
Authors: Verstockt B
Published: January 2025

Background

Organoid technology has emerged as a pivotal tool in IBD research, offering unparalleled insights into disease mechanisms, mechanisms-of-action, and host-microbiota interactions. Advances in these models enable the establishment of co-cultures in dynamic and IBD-specific intestinal environments.

Methods

Intestinal crypts from biopsies of IBD patients were isolated, adult stem cells expanded into 3D organoids and differentiated to reflect epithelial subtypes. To enable easy basolateral and apical access, organoid-derived epithelial cells were cultured in Transwells. For enhanced physiological relevance, organoids were integrated into gut-on-a-chip platforms featuring microfluidic flow and peristalsis, and prolonged co-cultures with stimuli and cell types of interest. Advanced imaging techniques, including high-resolution microscopy, were used to evaluate epithelial dynamics, barrier integrity, and inflammatory responses. These models were utilized to test therapeutic compounds and assess personalized responses based on patient-specific profiles (Figure 1).

Results

Organoid-based models replicated key features of IBD pathology, including inflammation-induced epithelial dysfunction and barrier loss. Imaging provided critical insights into cell-cell interactions and mucus expression under inflammatory conditions and therapeutic interventions. Barrier integrity was rigorously assessed using transepithelial electrical resistance in Transwells, confirming functional disruptions associated with inflammation or ER-stress. Transcriptomic analyses revealed patient- and disease-specific responses to cytokines, microbial metabolites, and environmental stressors, demonstrating the relevance for personalized therapeutic strategies. Early gut-on-a-chip experiments validated the integration of intact (Papp) organoid-derived epithelial monolayers with stromal components and dynamic flow.

Conclusion

The convergence of organoid technology and gut-on-a-chip systems heralds a new era in IBD translational research. These platforms provide complementary strengths, enabling researchers to tailor models to specific investigative needs. Gut-on-a-chip models integrate organoid-derived epithelial layers with stromal, vascular, and/or immune components under dynamic flow conditions, offering unparalleled insight into the spatial and functional complexities of the gut environment. Together, these systems support personalized exploration of disease pathways and (preclinical) therapeutic efficacy, bridging the gap between in vitro modeling and clinical application. This convergence establishes a versatile foundation for precision medicine, addressing individual variability and driving transformative advances in patient care.
OP35 Low remission recapture after ustekinumab dose optimization in Crohn’s disease: results of the randomized placebo-controlled double-blind REScUE study.
Authors: Bossuyt MD PhD P , Rahier J F , Baert F , Louis E , Macken E , Lobaton T , Busschaert J , Peeters H , Dewint P , Franchimont D , Dutré J , Willandt B , Claessens C , Dewit O , Ferrante M , Vermeire S
Published: January 2025

Background

In Crohn’s disease (CD), an exposure-response relationship exists for ustekinumab, with higher serum levels associated with better outcomes. Although several retrospective and observational studies demonstrate dose-escalation of ustekinumab can be effective in case of secondary loss of response (LOR), prospective placebo-controlled data are lacking. The aim of the REScUE study (NCT04245215) was to investigate the effect of 2 different re-induction regimens with ustekinumab on clinical, endoscopic, biological and pharmacological outcomes in patients with CD.

Methods

This Belgian multicentre prospective double-blind randomized placebo-controlled trial included adult patients with CD treated with ustekinumab who presented with secondary LOR to ustekinumab after documented primary response. Secondary LOR was defined by PRO-2 (AP> 1 AND SF> 3) and confirmed by either an elevated biomarker (CRP >5 mg/L or faecal calprotectin >250 µg/mg) or endoscopic signs of inflammation. All patients received a single IV re-induction with ustekinumab (≈6mg/kg) and were then randomized 1:1 to blinded maintenance ustekinumab 90 mg SC Q4W (intervention) or 90 mg SC Q8W (control) for 48 weeks. Primary endpoint was proportion of patients with steroid-free clinical remission (definition in fig 1) at week 48, with missing data were handled using non-responder imputation.

Results

In total, 132 patients were screened, and 108 patients were included: 67% female, median [IQR] age 41 [32-54] year, median disease duration 14 [7-22] years. Prior anti-TNF exposure was reported in 92% of patients, while ustekinumab was the first-line advanced treatment in 7% of patients. The primary endpoint of steroid-free clinical remission at week 48 was achieved by 9/54 (17%) patients in the q4w regimen vs 8/54 (16%) in the q8w regimen (p=0.96) (fig 1). Endoscopic remission (SES-CD <3) was achieved in 5/54 (10%) vs 3/54 (6%) (p=0.52), endoscopic response (≥50% decrease in SES-CD from baseline) was achieved in 11/54 (22%) vs 6/54 (12%) (p=0.23) and 0.52biomarker remission was achieved in 20/54 (38%) vs 13/54 (26%) (p=0.19) in the q4w regimen vs the q8w regimen, respectively. Time to first clinical remission was similar between groups (fig 2). Association with ustekinumab serum levels will be reported. No new safety signals were observed.

Conclusion

In patients with CD experiencing secondary LOR to ustekinumab, dose optimization with a single IV re-induction followed by intensified maintenance dosing (90 mg SC q4W) was not superior to a single IV re-induction followed by conventional maintenance dosing (90 mg SC q8W) in achieving steroid-free clinical remission. The secondary endpoints were numerically higher but not significant in the intensified regimen.
DOP010 Optimizing the switch from escalated intravenous to subcutaneous infliximab: a population pharmacokinetics–pharmacodynamics study
Authors: Wang Z , Ferrante M , Vermeire S , Dreesen E
Published: January 2025

Background

The standard subcutaneous (SC) infliximab (IFX) of 120 mg bi-weekly (Q2W) has shown non-inferior pharmacokinetics (PK) and comparable efficacy to the intravenous (IV) IFX of 5 mg/kg Q8W in clinical trials. However, it remains unclear whether patients on escalated IV dosing regimens can transition to standard SC dosing without losing therapeutic response. This study aims to elucidate the dose–exposure–response relationship during IV-to-SC switching of IFX in patients with Crohn’s disease (CD) and ulcerative colitis (UC) through population pharmacokinetics–pharmacodynamics (popPK–PD) modelling and simulation.

Methods

Data were collected from healthy volunteers in two single-dose Phase I studies ([1]; NCT03446976) and patients with IBD in a two-part Phase I study (NCT02883452). In patients with IBD, frequent PK sampling was conducted during switching from 5 mg/kg IV IFX to Q2W SC IFX injections of 120/180/240 mg in Part 1 and 120/240 mg in Part 2. Faecal calprotectin (FC) was measured in patients at baseline, week (w)2, w6, and Q8W thereafter until w54. Endoscopic remission (ER) was assessed at screening, w22/30, and w54. We performed popPK–PD modelling and simulation (n=1000) using NONMEM to evaluate post-switch FC time courses and probabilities of ER.

Results

A total of 253 healthy volunteers and 179 patients (101 CD, 78 UC) contributed 7351 IFX and 1201 FC concentrations. IFX clearance increased with decreasing serum albumin, increasing body weight, and presence of neutralizing antibodies. FC levels decreased when overall IFX exposure (not just IFX trough concentrations) increased. Lower FC at w14 were associated with increased probabilities of ER in patients with UC, but not CD.

Simulations showed that the standard IV-to-SC switch at w6 of IFX therapy further decreases FC and results in a significantly higher probability of ER at w22/30 (54% if no switch vs 63% if switch) (Figure 1). Simulations also showed that patients on escalated Q6W/Q8W IV maintenance regimens can switch to 120 mg Q2W SC infliximab without FC increasing (Figure 2A). Patients on Q4W IV infliximab require SC dose escalation to either 120 mg QW or 240 mg Q2W to avoid an increase in FC (Figure 2B).

Conclusion

Infliximab trough concentrations are only a surrogate for therapeutic response, with overall infliximab exposure being the true driver. Therefore, the higher trough concentrations on standard SC dosing are needed to compensate for the lower SC peak concentrations. Standard SC dosing is superior to standard IV IFX dosing as evidenced by lower FC and higher ER rates (in patients with UC). Patients on Q6W and Q8W IV regimens can switch to standard SC IFX without an increase in FC.

References

[1] Westhovens R et al., [P0387] Poster presented at UEGW 2017.
DOP014 Efficacy and safety up to 3 years of risankizumab maintenance treatment in patients with moderately to severely active ulcerative colitis: interim results from phase 3 COMMAND open-label extension study
Authors: Atreya R , Louis E , Loftus Jr. E V , Rubin D T , Dubinsky M , Hisamatsu T , Kalabic J , Mendez P , Chen S , Shah S , Morisset P , Duan W R , Panaccione R
Published: January 2025

Background

Risankizumab (RZB), a high-affinity humanised IgG1 monoclonal antibody targeting interleukin-23 p19, has shown sustained efficacy and an acceptable safety profile for patients (pts) with ulcerative colitis (UC).1 This interim analysis reports efficacy data at week (wk) 0 and wk 96, as well as safety data of the COMMAND (NCT03398135) open-label extension (OLE).

Methods

The COMMAND OLE enrolled pts who completed 52-wks maintenance dosing in the COMMAND substudies or entered directly from the induction study.1 All pts received RZB180 subcutaneous (SC) starting at OLE wk 0, except pts who had prior rescue therapy (single RZB 1200 mg intravenous [IV] dose then RZB360 Q8w) who continued RZB360 in the OLE. The OLE was not designed to compare RZB180 and RZB360 groups. The data cut-off date for this interim analysis was as of June 30, 2024. Efficacy endpoints assessed were clinical remission (CR) per AMS, clinical response per AMS, endoscopic improvement, endoscopic remission, and corticosteroid-free CR per Partial AMS up to wk 96. Data are reported as observed prior to RZB rescue therapy during OLE. The safety analysis also includes pts who directly entered the OLE from induction; presented as events/100 pt years (E/100 PY).

Results

Of the pts who entered the OLE (RZB180, N = 701; RZB360, N = 302), approximately 40% of pts had the opportunity to reach OLE wk 96 as of the cut-off date. At OLE wk 0 and 96, a similar proportion of patients in the RZB180 group achieved clinical and endoscopic outcomes (Figure 1A). In the RZB360 group, the percent of pts achieving clinical and endoscopic endpoints increased from OLE wk 0 through OLE wk 96 (Figure 1B). Similar rates of serious AEs, severe AEs, and AEs leading to discontinuation of study drug were reported in the RZB180 group and the RZB360 group with no new safety risks identified (Table 1).

Conclusion

In this interim analysis of the OLE, a sustained benefit was observed with long-term RZB treatment up to 96 wks. The long-term safety profile for RZB remains consistent and supports the long-term use.

References

1. Louis E et al. JAMA 2024;332(11):881-897
DOP015 Consistency and Quality of Inflammatory Bowel Disease care in Australasia; Towards Benchmarking, Crohn’s Colitis Cure Data Insight’s Program
Authors: Su W K , McNamara J , Wilson W , Wark G , Lynch K , Su H , Forbes A , Lawrance I , An Y K , Dutt S , Brett L , Walker G , Andrews J M , Connor S J , Ghaly S
Published: January 2025

Background

Inflammatory bowel disease (IBD) is a global health issue with Australia (AUS) and New Zealand (NZ) having amongst the highest prevalence rates worldwide. Our study examined the quality, safety, and consistency of care amongst ten Australasian centres.

Methods

Crohn’s Colitis Care (CCCare) is a cloud-based IBD-specific electronic medical record (EMR) used in Australasia. Deidentified data prospectively entered by clinicians and consumers during routine clinical practice were retrospectively analysed. Key performance indicators (KPI) were compared across two time periods, baseline (1st October 2021 to 30thSeptember 2022) and follow up periods (1st October 2023 to 30th September 2024). Centres with over 100 people with IBD with an assessment during the last 14-month period were included.

Results

At the end of the follow up period, 6794 people with IBD were included, 55.8% (n=3790) with Crohn’s Disease, 41.3% (n=2808) with Ulcerative Colitis and 2.9% (n=196) with IBD-Unclassified. There was an even gender distribution with 49.0% (n=3329) male, 48.2% (n=3276) female and 2.8% (n=189) did not have gender documented. The median age was 42 years (IQR 32 – 57) with a median disease duration of 11.3 years (IQR 5.6 – 19.7). The majority of people resided in AUS (71.2%, n=4834) and 28.8% (n=1960) in NZ.

Across the two study periods, the proportion of people receiving an advanced therapy remained stable (53.2% vs 52.9%, p=0.76), however the number of people on dose escalated (DE) therapy increased (25.1% vs 28.5%, p < 0.001). In parallel, steroid use decreased; 12.4% vs 10.5%, p < 0.01. There was a reduction in the rate of hospital admissions (4.1% vs 2.6%, < 0.001) and surgeries (3.6% vs 1.6%, p < 0.001). There were no differences in the rates of endoscopic (53.1% vs 54.7%, p=0.34) and radiologic remission (41.0% vs 43.0%, p=0.49).

There was a significant reduction in the completion of healthcare maintenance across all sites with a fall in overall covid vaccination (36.9% vs 29.8%, p<0.001), influenza vaccination (20.1% vs 5.0%, p<0.001) and skin care checks (12.0% vs 4.0%, p<0.001). There was no significant difference in the proportion of people currently smoking (10.5% vs10.9%, p=0.54).

Conclusion

Observed clinical improvements, including reduced steroid use, admissions, and surgeries, coincided with increased DE therapy, reflecting a shift toward tailored healthcare. Post-pandemic reduction in healthcare maintenance likely reflects provider and consumer fatigue. Implementing a value-based IBD management approach with continuous KPI monitoring via digital tools like CCCare is essential for optimizing outcomes, highlighting trends, and identifying areas for improvement in healthcare delivery.
DOP017 Infliximab induction fails to reach targets in Perianal Fistulizing Crohn’s Disease: first results from the ATLANTIC study
Authors: Mulders L , Anjie S I , Chevallot-Beroux M , Loeff F , Mathot R A , D'Haens G R , Gecse K B
Published: January 2025

Background

In perianal fistulizing Crohn’s Disease (PFCD), higher serum concentrations of infliximab (IFX) have been associated with better outcomes. In clinical practice, the majority of PFCD patients receive dose intensification. However, the pharmacokinetics of IFX treatment in PFCD has not been described specifically. We hypothesized that patients with PFCD have altered IFX pharmacokinetics, compared to Crohn’s disease patients without perianal fistulizing disease (CD).

Methods

Patients with CD and PFCD starting standard dose intravenous IFX (5 mg/kg at week 0,2,6, thereafter every 8 weeks) were enrolled. Pre-infusion samples were collected from the second infusion (week 2) until 26 weeks to measure IFX trough level (TL), and anti-drug antibodies if IFX TL was below 1.0 μg/mL (radioimmunoassay). Target TL during induction were 20 μg/mL at week 2, 15 μg/mL at week 6, and at week 14 10 μg/mL for PFCD and 5.0 μg/mL for CD patients. Statistical analysis included unpaired T-tests and Mann-Whitney U tests for numerical differences, and chi-square tests (X²) for differences in proportions.

Results

A total of 149 patients were included (63 PFCD, 86 CD), and a total of 761 serum samples were analyzed. Patient demographics, including age, disease duration and treatment characteristics were largely comparable between groups, only luminal disease activity and use of concomitant immunomodulators were higher in CD patients (see Table 1).

During induction, target IFX TL were achieved in significantly lower proportion of PFCD compared to CD patients (43% vs. 57%, p=0.038). At week 14, median serum IFX concentrations were significantly lower in PFCD patients (2.8 μg/mL, IQR 1.0-5.4) compared to CD patients (4.8 μg/mL, IQR 2.0–6.6) (p = 0.014) (Figure 1). At week 14, target IFX TL in PFCD patients were achieved in only 9% (5/57) and 46% (36/78) of CD patients (p<0.0001).

Anti-drug antibodies were detected in 16% (10/63) of PFCD patients and 12% (10/86) of CD patients (p=0.169) after a median of 20 weeks (IQR 9-28), which were transient in 35% (7/20) of patients during follow-up.

Conclusion

During induction, standard infliximab dosing results in lower TL in PFCD, compared to CD. The previously suggested target IFX concentration at week 14 is only reached in a fraction of PFCD patients. This may contribute to a prolonged disease burden and may necessitate alternative dosing strategies in PFCD.
DOP019 Reduced Gut Microbial Amino Acid Auxotrophies and Enhanced Tryptophan Degradation in Inflammatory Bowel Disease
Authors: Waschina S , Harris D , Starke S , Homeister L , Schuchardt S , Tran F , Verstockt B , Ananthakrishnan A , Vermeire S , Rosenstiel P , Schreiber S , Aden K
Published: January 2025

Background

Microbial amino acid auxotrophies, the inability of certain gut bacteria to synthesise essential amino acids, are important microbiome features contributing to gut microbial diversity and stability.1 Their relationship with inflammatory bowel disease (IBD), including Ulcerative Colitis (UC) and Crohn’s Disease (CD), remains poorly understood.

Methods

Stool and serum samples were collected from healthy controls (HC, n=190) and IBD patients from two longitudinal biologic therapy exposure (Baseline, Week 14) cohorts in Kiel, Germany (nUC=26, nCD=29) and Leuven, Belgium (nUC=63). Additional stool metagenomes from a Boston, US cohort (nUC=49, nCD=65) were included. Stool DNA underwent shotgun metagenomic sequencing. Metagenomic data were processed with the ATLAS workflow for metagenome-assembled genomes (MAGs) inference and quantification. Serum metabolomes were analysed using the Biocrates MxP Quant 500 Kit. Microbial auxotrophies and amino acid degradation pathways were predicted using genome-scale metabolic modelling.2

Results

Amino acid auxotrophies were prevalent in the human gut microbiome, with Tryptophan (Trp) auxotrophies being the most common. Patients with IBD showed reduced auxotrophies compared to HC, with CRP levels correlating with more pronounced reductions in Trp auxotrophies. Metagenomic profiling revealed a distinct enrichment of amino acid degradation genes in IBD, particularly for Trp-degrading enzymes such as Tryptophan decarboxylase and Tryptophan transaminase. These changes correlated with specific serum metabolites, particularly aromatic compounds, indicating a strong interconnection between microbial and host amino acid metabolism.

Conclusion

Altered microbial metabolism in IBD is characterised by reduced Trp auxotrophies and increased Trp degradation. This suggests a microbial imbalance where Trp degraders outcompete auxotrophic genotypes, potentially contributing to IBD pathology. Understanding the shifts in amino acid requirements and degradation by the gut microbiome provides new insights into microbiome-host co-metabolism in IBD and may inform future therapeutic strategies targeting nutrient essentialities of gut microorganisms.

References

1. Starke S, Harris DMM, Zimmermann J, Schuchardt S, Oumari M, Frank D, Bang C, Rosenstiel P, Schreiber S, Frey N, Franke A, Aden K, Waschina S. Amino acid auxotrophies in human gut bacteria are linked to higher microbiome diversity and long-term stability. The ISME Journal. 2023;17(12):2370-2380. doi:10.1038/s41396-023-01537-3

2. Zimmermann J, Kaleta C, Waschina S. gapseq: informed prediction of bacterial metabolic pathways and reconstruction of accurate metabolic models. Genome Biol. 2021;22(1). doi:10.1186/s13059-021-02295-1
DOP021 Appendectomy regulates intestinal flora-bile acid axis inhibits macrophage lipid metabolism and improves Ulcerative Colitis
Authors: Chu F , Hailong C
Published: January 2025

Background

The specific role of the appendix as both an immune organ and a reservoir for gut microbiota in inflammatory bowel disease (IBD) remains elusive. Recent clinical studies have demonstrated that appendectomy can alleviate refractory ulcerative colitis and reduce the rate of colon surgical resection in patients. However, the underlying mechanisms are still unclear. This study aims to comprehensively explore the precise regulatory mechanisms of appendectomy in the process of colonic inflammation.

Methods

Appendectomy was performed on C57BL/6 mice followed by induction of dextran sulfate sodium (DSS)-induced colitis. Changes in colon length, body weight, and other parameters were evaluated.Quantitative real-time polymerase chain reaction (qPCR), western blot, and immunofluorescence staining were employed to assess production of pro-inflammatory cytokines and the level of colonic mucosal barrier markers. Public databases were utilized for bioinformatics analysis. Transcriptomic, 16S rRNA, and metabolomic sequencing were conducted.

Results

Appendectomy increased colon length, body weight, and enhanced mucosal barrier integrity in mice with colitis, indicating alleviation of colitis. 16S rRNA sequencing indicated significant differences in microbial taxa such as Mucispirillum, Bacleroides, Clostridium_sensu_stricto_1, Romboutsia genus, Turcicibacter. Metabolomics analysis suggested that secondary bile acids accumulation. Both tanscriptome sequencing and metabolomics analysis enriched in lipid metabolism.

Conclusion

This study highlights the critical role of' appendectomy in regulating gut microbiota and lipid metabolism, and its contribution to the remission of UC. Appendectomy may hold promise as a therapeutic approach for mitigating colonic inflammation and improving disease outcomes in patients with UC.

References

1. Agrawal M, Allin KH, Mehandru S, Faith J, Jess T, Colombel JF. The appendix and ulcerative colitis - an unsolved connection. Nat Rev Gastroenterol Hepatol. 2023;20(9):615-624. doi:10.1038/s41575-023-00774-3

2. Arjomand Fard N, Armstrong H, Perry T, Wine E. Appendix and Ulcerative Colitis: a Key to Explaining the Pathogenesis and Directing Novel Therapies?. Inflamm Bowel Dis. 2023;29(1):151-160. doi:10.1093/ibd/izac106

3. Parian A, Limketkai B, Koh J, et al. Appendectomy does not decrease the risk of future colectomy in UC: results from a large cohort and meta-analysis. Gut. 2017;66(8):1390-1397. doi:10.1136/gutjnl-2016-311550

4. Elmahdi R, Jess T, Andersena NN. Appendectomy in Your First-degree Relative Protects You Against UC. J Crohns Colitis. 2019;13(12):1585. doi:10.1093/ecco-jcc/jjz089
DOP024 Transport of pks+ E. coli derived genotoxin colibactin from bacteria into host cell
Authors: Schloderer J , Neurath M , Günther C
Published: January 2025

Background

Colorectal cancer (CRC) is among the most prevalent cancer worldwide with a rapidly increasing frequency. Many studies have highlighted a close association between CRC, inflammatory bowel diseases (IBD), and alterations in gut microbial composition. Among these, particular attention has been drawn to B2 serotype Escherichia coli and other pks-positive Enterobacteriaceae. These bacteria carry a genetic island encoding a multi-enzyme assembly line responsible for the non-ribosomal synthesis of colibactin, a peptide-polyketide hybrid molecule that acts as a potent genotoxin. Colibactin alkylates double-stranded DNA, causing inter-strand crosslinks, double-strand breaks (DSB), and a specific mutational signature commonly found in CRC. Despite the growing knowledge about colibactin synthesis and its mode of action, the mechanism by which it is delivered from bacteria to the host epithelium remains unclear. Here, we hypothesize a small-particle carriage system to overcome the instability of colibactin and the physical obstacle posed by the mucus layer.

Methods

Conditioned media (CM) from pks+ and isogenic pks- bacteria were harvested, filtered, and ultracentrifuged to isolate distinct fractions, including vesicle and soluble portions. These fractions were tested for their ability to induce DNA DSBs in patient-derived colon organoids, which were detected by γH2AX staining. To more closely match in vivo exposure conditions, we created apical-out converted organoids in addition to classical basal-out growth. This approach allowed us to simulate and compare exposure to surfaces accessible before and only after the loss of barrier integrity, a typical hallmark of IBD.

Results

Our experiments demonstrated that basal application of bacterial isolates caused increased signs of cellular stress and genetic damage, independent of colibactin. In apical-out organoids, several fractions of the cell-free bacterial supernatant, but only those derived from pks+ E. coli, were able to reliably induce double-strand breaks.

Conclusion

Even though the genotoxic effect following CM treatment was substantially less pronounced than in co-culture experiments, our results suggest that the transfer of colibactin between bacteria and epithelium might not depend exclusively on direct physical contact, as suspected by other studies. The data support the presence of a mid-distance carriage system that is not limited by the size of bacteria and can therefore cross the intestinal barrier. Beyond that, we demonstrated that intestinal organoids are overall more susceptible to immunological stress by bacterial components when exposed at their basal surface, which indicates a significant bias in studies relying solely on classical organoid culture as an experimental system.
DOP025 Subjects sharing bacterial amplicon sequence variants exhibit differences in their IgA and IgG coating of gut bacteria, with enrichment of IgG binding for bacteria typically found in the oral cavity
Authors: Levhar N , Hadar R , Braun T , Efroni G , Ben-Horin S , Amir A , Haberman Y
Published: January 2025

Background

IgA is the predominant antibody in the gut, coating a larger proportion of intestinal bacteria. IgG is found in lower concentrations but tends to increase with gut inflammation. We aimed to characterize IgA- and IgG-coated gut microbial compositions in healthy controls and evaluate coating variations of shared bacteria across individuals.

Methods

We established a protocol for isolating IgA- and IgG-bound fecal bacteria, using magnetic streptavidin beads coated with biotin anti-human IgA or IgG (Fig. 1A). The initial stool, as well as the negative (unbound) and positive (IgG- or IgA-bound bacteria) fractions, were analyzed by 16S rRNA sequencing. For differential abundance, a non-parametric, permutation-based rank mean test was applied (dsFDR<0.25).

Results

Fecal samples from 13 healthy subjects (Mean age 40.6 years, 54% males) were simultaneously incubated with anti-human IgA- or IgG- coated beads. Within-sample variability was quantified using three different fecal aliquots per subject, and several controls were included throughout the process. Paired differential abundance between the positive and the negative IgA fractions identified 46 amplicon sequence variants (ASVs) bacteria significantly higher in the positive fraction (IgA bound) and 44 ASVs significantly higher in the negative fraction. To better characterize the bound and unbound ASVs, we calculated term enrichment f-scores using the dbBact knowledge base (PMID: 37326027). This indicated enrichment of bacteria consistently reported as IgA-bound in previous publications, implicating the validity of our separation of Ig-bound bacteria (Fig. 1B). Similar analysis for the IgG-bound bacteria, identified 58 and 49 differentially abundant ASVs in the positive and negative fractions, respectively, with significant enrichment of bacteria previously noted to show IgA-coating and of salivary/oral bacteria among IgG-bound bacteria (Fig. 1C). Using the Ig-coating index (ICI; PMID: 25171403) of each `shared` ASV (detected in more than two subjects), we noted large inter-individual variance among the controls, with 42.4% ASVs showing significant inter-individual variance in IgA-coating (FDR<0.1; Fig. 2A) and 30.3% ASVs with significant inter-individual variance in IgG-coating (FDR<0.1; Fig. 2B).

Conclusion

Healthy subjects show variations in the immunoglobulin coating of bacteria, even among shared ASVs, indicating a personalized immune-bacterial repertoire. However, it is still unclear if this variation contributes to the gut microbiome composition variations seen between subjects. In addition, we observed preferential enrichment for immunoglobulin coating of bacteria typically found in the oral cavity.