bluuebunny/crossref_metadata_2025 huggingface dataset:
OP20 The effects of upadacitinib on ulcerative colitis symptom resolution and fatigue normalization in patients with moderately to severely active ulcerative colitis: Phase 3 U-ACHIEVE and U-ACCOMPLISH results
Authors: D'Haens G , Tran J , Danese S , Rubin D T , Aoyama N , Lügering A , Klaff J , Xuan S , Ilo D , Sanchez Gonzalez Y , Panes J
Published: January 2023

Background

Abdominal pain (AP), bowel urgency (BU), stool frequency (SF), rectal bleeding (RB) and fatigue are debilitating symptoms that reduce quality of life in patients with ulcerative colitis (UC). Results from two Phase 3 induction trials and one maintenance trial (U-ACHIEVE [NCT02819635] and U-ACCOMPLISH [NCT03653026]) showed significant and clinically meaningful improvements in these symptoms following induction and maintenance treatment with upadacitinib (UPA) in patients with moderately to severely active UC. We evaluated the effects of 8-week UPA induction and 52-week UPA maintenance treatment on UC symptom resolution, defined as no BU, no AP, and symptomatic remission (no RB, SF≤1), and normalization of fatigue, defined as achievement of a Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT–F) score ≥ 40.1.

Methods

A total of 988 patients were randomized in the U-ACHIEVE and U-ACCOMPLISH induction studies to receive UPA 45 mg once daily (QD; n=660) or placebo (PBO) QD (n=328). Patients who achieved a clinical response after 8 weeks of induction (n=451) were enrolled in the U-ACHIEVE maintenance study and re-randomised 1:1:1 to UPA 15 mg QD (n=148), UPA 30 mg QD (n=154), or PBO QD (n=149). Symptom resolution was assessed at induction Weeks 0, 2, 4, 6, 8 and maintenance Weeks 0, 4, 8, 12, 20, 28, 36, 44, and 52. A more stringent assessment of symptom resolution and normalization of fatigue was conducted at Weeks 0, 2, and 8 of induction and Weeks 0 and 52 of maintenance.

Results

A higher percentage of patients achieved symptom resolution during induction treatment as early as Week 2 with UPA 45 mg vs PBO (11.1% vs 0.9%, p <0.001; Figure 1), and sustained through Week 8 (31.2% vs 7.9%, p<0.001). This difference was also observed during maintenance treatment among clinical responders starting at Week 8 with UPA (15 mg: 43.2%; 30 mg: 42.2% vs PBO: 30.2%, p<0.01 and p<0.05, respectively; Figure 2) and sustained through Week 52 (15 mg: 37.2%; 30 mg: 46.1% vs PBO: 12.8%, p<0.001 for both). Furthermore, the percentage of patients who achieved symptom resolution and fatigue normalization was greater with UPA vs PBO at Week 8 of induction (45 mg: 23.4% vs PBO: 6.7%, p <0.001; Figure 3) and Week 52 of maintenance (15 mg: 24.3%; 30 mg: 36.4% vs PBO: 12.1%, p<0.01 and p<0.001, respectively).

Conclusion

Patients with moderately to severely active UC were more likely to achieve symptom resolution and normalization of fatigue during induction treatment with UPA compared to PBO, and these benefits were sustained during maintenance therapy.
OP35 Efficacy and safety outcomes up to ~4 years of treatment with filgotinib 200 mg among patients with Ulcerative Colitis: Results from the SELECTIONLTE study
Authors: Feagan B G , Matsuoka K , Rogler G , Faes M , Oortwijn A , de Haas A , Rudolph C , Peyrin-Biroulet L
Published: January 2023

Background

Filgotinib (FIL) is a once-daily, oral, Janus kinase 1 preferential inhibitor approved for the treatment of ulcerative colitis (UC). FIL 200 mg (FIL200) was effective in inducing and maintaining clinical remission vs placebo (PBO) and well tolerated in patients with UC in the randomized, phase 2b/3 SELECTION trial (NCT02914522).1 The efficacy and safety of continued FIL200 therapy are being assessed in the continuing SELECTION long-term extension (LTE) study.

Methods

The SELECTION programme comprises SELECTION and the associated LTE study (SELECTIONLTE; NCT02914535). In SELECTION, adults with moderately to severely active UC received induction (IND) FIL200, FIL 100 mg (FIL100) or PBO once daily for 11 weeks. Patients in clinical remission or with a Mayo Clinic Score (MCS) response at week 10 (responders) could enter the 47-week Maintenance (MNT) Study. SELECTIONLTE enrolled patients who completed IND and MNT (completers), patients who were not responders at IND week 10 (non-responders), and patients with disease worsening during MNT. This interim analysis assessed the efficacy and safety of open-label FIL200 through LTE week 144 in completers and LTE week 192 in non-responders, respectively, representing a total of 3.9 years of treatment each (completers: 58 + 144 weeks; non-responders 10 + 192 weeks). The cut-off date was 24 February 2022. Continuous measures of partial MCS (pMCS) and proportions of patients achieving the minimal clinically important difference (MCID) in total IBDQ score (≥16-point increase vs baseline) were assessed without imputation (as observed). Safety was assessed by the exposure-adjusted incidence rate per 100 patient-years of exposure (PYE) for treatment-emergent adverse events (TEAEs) and TEAEs of interest.

Results

This analysis included 148 completers and 372 non-responders (IND FIL100, n=212; IND FIL200, n=160). Among completers, the reductions in mean pMCS in SELECTION over weeks 0–10 were maintained up to LTE week 144 (Figure 1). In non-responders, mean pMCS decreased from LTE baseline to week 192 (Figure 2). High proportions of completers (>90%) and non-responders (>60%) achieved the MCID in IBDQ score; proportions were maintained over time (Table 1). Safety events among all patients treated with open-label FIL200 in the LTE study (total PYE=2055.5) are reported in Table 2.

Conclusion: FIL200 was effective in maintaining symptomatic remission and health-related quality of life for up to ~4 years. No new safety signals were observed over ~4 years of treatment, and safety events were comparable with those seen in previous analyses.2

1. Feagan BG et al. Lancet 2021;397:2372–84.

2. Feagan BG et al. J Crohns Colitis 2022;16(Suppl1):i456–7.
DOP21 Disease activity patterns of paediatric Inflammatory Bowel Disease – A Danish nationwide cohort study 1996-2018
Authors: Wewer M D , Jansson S , Malham M , Burisch J , Wewer V
Published: January 2023

Background

Inflammatory bowel diseases (IBD) are heterogenous diseases in terms of their clinical presentation including frequency and severity of flares.

We aimed to describe disease activity (DA) patterns in a Danish nationwide cohort including all IBD patients diagnosed < 18 years of age between 1996 and 2018.

Methods

Paediatric patients diagnosed with Crohn’s disease (pCD) or ulcerative colitis (pUC) were identified from national registers (Danish Civil Registration System, National Patient Registry, Danish National Prescription Registry and Danish Pathology Data Bank). DA was assessed in both incident and prevalent pIBD patients and categorised as mild-moderate in case of a course of topical corticosteroids, oral budesonide, or topical 5-ASA. Episodes were categorised as severe if they involved hospitalization, surgery, oral corticosteroids or biological therapy.

DA patterns in incident patients were assessed for 5- and 10-year periods from diagnosis as follows:

The 5-year DA pattern: A) No years with DA. B) 1 or 2 years with at least one episode of DA in each year. C) 3 or 4 years with at least one episode of DA in each year. D) All 5 years with at least one yearly episode of DA.

The 10-year DA pattern: A) Decreasing: First 5 years with 2 or more years with DA; following 5 years with 2 years or less with DA. B) Increasing: First 5 years with less than 2 years with DA; following 5 years with 2 or more years with DA. C) Chronic continuous: First 10 years with at least 8 years with DA. D) Quiescent: First 10 years with one year or less with DA. E) Chronic intermittent: DA pattern that does not meet the criteria above.

Results

1,965 pCD and 1,838 pUC incident patients were included. At diagnosis severe DA was found in 87% in pCD and 80% in pUC, in addition to 6.1% of pUC patients who had a colectomy the first year. After 5 years of disease the annual proportion of pCD and pUC with no DA 70% and 61%. This remained constant after 10 years (pCD:72% and pUC: 64%). In pUC, 12% and 16% required colectomy 5 and 10 years after diagnosis.

In prevalent pCD (N=2,515) and pUC (N=2,428) the proportion with no DA each calendar year was stable (pCD: 59%-73% and pUC: 50%-60%, prior to 2010). The majority of both pCD and pUC patients experienced one or two years with at least one episode of DA within the first five years (pCD: 51%, pUC: 53%). During the first 10 years from diagnosis, the decreasing DA pattern was the most common in both pCD and pUC (43% and 47%, respectively) (Figure).

Conclusion

DA patterns in pIBD are characterised by a high proportion of severe activity initially with a decreasing pattern after 5 and 10 years follow-up. No change in the proportion of patients with no DA was seen despite the introduction of biologic therapy in the period.
DOP24 Early life exposures and risk for inflammatory bowel disease: a nested case-control study in Quebec, Canada
Authors: Fantodji C , Rousseau M C , Nicolau B , Madathil S , Benedetti A , Jantchou P
Published: January 2023

Background

Early childhood is an important period for the establishment of gut microbiota. Most early life risks or protective factors for inflammatory bowel disease are likely to act through an effect on the gut microbiota. The aim of this study was to estimate the associations between exposures in infancy (birth until 3 years of age) such as breastfeeding, antibiotic treatment, presence of domestic pets, and passive smoking, and the occurrence of inflammatory bowel diseases.

Methods

This case-control study was nested within the Quebec Birth Cohort on Immunity and Health. Cases and controls were identified among persons born in Quebec in 1970-1974 based on their health services from 1983 to 2014 using validated algorithms. All cases and randomly selected controls were invited to participate in a web or telephone questionnaire. Participation rates were 47% among controls (n=946), and respectively 52% (n=1212) and 55% (n=570) among cases of Crohn’s disease and ulcerative colitis. Logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI), separately for Crohn’s disease and ulcerative colitis. Each exposure was analyzed in a multiple regression model adjusted for relevant covariates identified with a directed acyclic graph.

Results

Adjusting for perinatal and sociodemographic characteristics, the risk for Crohn’s disease or ulcerative colitis did not differ in subjects who were exclusively breastfed compared to non-breastfed subjects. Partial breastfeeding (breastfeeding combined with infant formula) was not associated with Crohn’s disease (OR=1.03, 95% CI: 0.76-1.40), but an increase in the odds of ulcerative colitis (OR=1.40, 95% CI: 0.99-1.99) was observed as compared with no breastfeeding. Early introduction of solid foods was associated with higher odds of Crohn’s disease (introduction at 3-6 months compared with >6 months: OR=1.35; 95% CI: 1.05-1.78), but not of ulcerative colitis (OR=1.06; 95% CI: 0.77-1.46). Antibiotic use and the presence of domestic pets were not associated with either Crohn’s disease or ulcerative colitis. Passive smoking was associated with increased odds of Crohn’s disease (OR=1.23; 95% CI: 1.00-1.51), but not ulcerative colitis (OR=0.96; 95% CI: 0.75-1.22).

Conclusion

Differences were noticed in early childhood risk factors for Crohn’s disease and ulcerative colitis. Early introduction of solid foods and passive smoking increased the risk of Crohn’s disease, whereas there was a trend of increased risk of ulcerative colitis with partial as compared with no breastfeeding. The results for partial breastfeeding and early introduction of solid foods are novel and will require further investigation.
DOP32 Crohn’s disease stricture matrisome analysis reveals the anti-fibrotic activity of milk-fat globule-epidermal growth factor 8 (MFGE8)
Authors: Lin S , Wang J , Mukherjee P , Mao R , West G , Czarnecki D , Zhao S , Elias M , Nguyen Q T , Chandra J , Le T H N , Chen M H , Dejanovic D , Holubar S , Olman M , Southern B , Hu S , Gordon I O , Atabai K , Fiocchi C , Rieder F
Published: January 2023

Background

Intestinal fibrosis is considered an inevitable consequence of chronic inflammatory bowel disease (IBD), leading to stricture formation and need for surgery. During the process of fibrogenesis, extracellular matrix (ECM) components critically regulate the function of mesenchymal cells. We characterized the composition and function of the ECM in fibrostenosing Crohn’s disease (CD) and control tissues.

Methods

Decellularized full thickness intestinal tissue platforms were tested using three different protocols and ECM composition in different tissue phenotypes was explored by proteomics and validated by quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Primary human intestinal myofibroblasts (HIMF) treated with Milk Fat Globule-Epidermal growth factor 8 (MFGE8) were evaluated regarding mechanism of their anti-fibrotic response, and the action of MFGE8 was tested in experimental intestinal fibrosis.

Results

We established and validated an optimal decellularization protocol for intestinal IBD tissues. Matrisome analysis revealed elevated MFGE8 expression in CD strictured tissue (CDs), which was confirmed at the mRNA and protein levels. Treatment with MFGE8 inhibited ECM production in normal control (NL) HIMF but not CDs HIMF. Next generation sequencing (NGS) uncovered functionally relevant integrin-mediated signaling pathways, and blockade of integrin αvβ5 and focal adhesion kinase rendered HIMF non-responsive to MFGE8. MFGE8 prevented and reversed experimental intestinal fibrosis in vitro and in vivo.

Conclusion

MFGE8 displays anti-fibrotic effects, and its administration may represent a future therapeutic approach for prevention of IBD-induced intestinal strictures.
DOP34 Human MD2 deficiency - an inborn error of immunity predisposing to early onset Inflammatory Bowel Disease
Authors: Li Y , Yu Z , Schenk M , Lagovsky I , Illig D , Walz C , Rohlfs M , Conca R , Muise A , Snapper S , Uhlig H , Garty B , Klein C , Kotlarz D
Published: January 2023

Background

Pattern recognition receptors (PRRs) serve as a hub of immune responses to microbes in the gut and play a critical role in maintaining intestinal homeostasis. Toll-like receptor 4 (TLR4) represents an important PRR that can recognize the gram-negative bacterial cell wall component lipopolysaccharide (LPS). Upon binding to LPS, TLR4 forms a multimeric complex with the indispensable co-receptor myeloid differentiation protein 2 (MD2) facilitating selection of TLR4 as cargo for endocytosis and TLR4-mediated activation of downstream signalling. Despite the critical role of TLR4 in innate immunity, no patients with TLR4 or MD2 deficiency have yet been reported.

Methods

To investigate potential genetic causes for two related patients presenting with very early onset Inflammatory Bowel Disease (VEO-IBD) and/or pneumonia, we have performed whole exome sequencing (WES). To assess the functional consequences of the identified LY96 (encoding for MD2) variant, we generated a CRISPR/Cas9-mediated knockout (KO) of MD2 or knockin (KI) of the patient mutation in induced pluripotent stem cells (iPSCs) and studied TLR4-mediated signalling, cytokine responses, and bacterial handling in iPSC-derived macrophages.

Results

Genetic analysis identified a 3 bp homozygous in-frame deletion in the LY96 gene (NM_015364.5, c.347_349delCAA; p.Thr116del) in our index patients following an autosomal recessive inheritance pattern. Immunoblotting revealed an altered protein expression of overexpressed Flag-tagged mutant MD2 protein due to impaired N-linked glycosylation. Correspondingly, iPSC-derived MD2-deficient macrophages showed an impaired LPS-induced TLR4 endocytosis. As a functional consequence, we could detect reduced NF-κB and MAPK signalling (phosphorylation of NF-κB p65 subunit, ERK1/2, and p38 MAPK) and dysregulated inflammasome activation (IL-1b production and secretion) upon challenge with LPS. Gentamycin protection assays and live cell imaging suggested that MD2-deficient macrophages exhibit an impaired phagocytosis of microbial pathogens. In addition, macrophages with mutant MD2 showed decreased cytokine expression (e.g., IFNB, IL6, IL10, and TNF) in response to LPS or gram-negative bacteria (E. coli and Salmonella typhimurium) but not gram-positive bacteria (Listeria monocytogenes).

Conclusion

Human MD2 deficiency is an inborn error of immunity that may predispose to VEO-IBD associated with altered TLR4-mediated signalling, cytokine responses, and bacterial handling. The first description of patients with MD2 deficiency provides critical insights on human TLR4/MD2 biology and warrants caution on therapeutics strategies targeting TLR4 signalling.
DOP42 Efficacy of etrasimod on symptomatic relief in patients with ulcerative colitis: an analysis of the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials
Authors: Chaparro M , Armuzzi A , Irving P M , Allez M , Dubinsky M C , Sands B E , Goetsch M , Wang W , Shan K , Woolcott J , Bartolome L , Wosik K , Panaccione R
Published: January 2023

Background

Patient-reported outcomes such as stool frequency (SF) and rectal bleeding (RB) are important measures of ulcerative colitis (UC) activity and treatment effect. Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active UC. We evaluated RB and SF subscores to assess symptomatic relief in the ELEVATE UC phase 3 programme.

Methods

In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). ELEVATE UC 52 utilized a treat-through design comprising a 12-week induction period followed by a 40-week maintenance period. ELEVATE UC 12 comprised a 12-week induction period. A key secondary endpoint was the proportion of patients with symptomatic remission (SF =0 [or =1 with a ≥1-point decrease from baseline] and RB =0) at week 12 and at week 52. RB and SF subscores, achievement of symptomatic remission, complete symptomatic remission (SF =0 and RB =0), and symptomatic response (≥30% decrease from baseline in composite RB/SF subscores) were assessed at each visit. Achievement of symptomatic remission was also summarized by subgroups in patients with prior biologic/Janus kinase inhibitor (bio/JAKi) use (yes [1, >1], no) and baseline corticosteroid use (yes, no).

Results

More etrasimod- vs PBO-treated patients achieved symptomatic remission by week 2 in ELEVATE UC 52 (15.3% vs 8.9%; P=0.049) and week 4 in ELEVATE UC 12 (27.5% vs 16.1%; P=0.007). Symptomatic remission increased in etrasimod- vs PBO-treated patients at each time point through week 12 in both ELEVATE UC 52 (46.0% vs 21.5%; P<0.001) and ELEVATE UC 12 (46.8% vs 29.5%; P=0.001) and was maintained through week 52 in ELEVATE UC 52 (43.4% vs 18.5%; P<0.001) (Figure 1A). Achievement of symptomatic response (Figure 1B), and significant improvements in RB and SF subscores, began as early as week 2 or week 4 for etrasimod vs PBO in ELEVATE UC 12 and ELEVATE UC 52, respectively. A significant difference in complete symptomatic remission was achieved at week 4 in both studies (Figure 1C). Subgroup analyses of symptomatic remission suggested a trend towards greater benefit in patients who were bio/JAKi naïve and patients with 1 prior bio/JAKi (vs >1) (Figures 2A-C).

Conclusion

In this analysis, symptomatic relief was achieved by a greater proportion of patients treated with etrasimod vs PBO as early as week 2 and was sustained through week 52. At week 2, symptomatic response and improvements in RB and SF subscores were observed. The greatest benefits were seen in patients who had no prior exposure to bio/JAKi or 1 prior bio/JAKi therapy.
DOP47 Gut microbiome contributes to the development of immune checkpoint inhibitor-related colitis
Authors: Liu X , Tang H , Zhou Q , Zeng Y , Lu B , Chen M , Xu Y , Wang M , Li Y , Tan B , Qian J
Published: January 2023

Background

The gut microbiota is implicated in shaping immune checkpoint inhibitors (ICIs) efficacy, but relatively little is known about how the microbiota influences immune-related adverse events (irAEs). Our study aimed to explore the association and causal relationship between gut microbiome and immune checkpoint inhibitor-related colitis.

Methods

We collected faecal samples from 32 patients with advanced malignant tumor patients developing irAE after anti-PD-1 therapy from May 2020 to Aug 2021. Faecal samples were analyzed by 16s rDNA amplicon sequencing method on Illumina MiSeq (PE300) sequencing platform. We also performed faecal microbiota transplantation (FMT) for antibiotic-treated mice with samples from patients with colitic irAE and without irAE.

Results

We compared the microbiota between 8 colitic irAE and 24 non-colitic irAE patients. Principal coordinates analysis (PCoA) plot showed significant difference of microbiota composition by Adonis analysis (P=0.003) (Fig. 1A). LEfSe analysis detected a lower abundance of Bacteroidota and a higher abundance of Proteobacteria at the phylum level and a lower abundance of Bacteroides and Bifidobacterium and higher abundance of Enterococcus at the genus level in colitic irAE (Fig. 1B). The total abundance of major butyrate-producing bacteria was lower in colitic irAE compared with non-colitic irAE patients (P=0.018) (Fig. 1C). Functional prediction analyses revealed different abundances of environmental information processing, genetic information processing, and metabolic pathways between colitic and non-colitic irAE patients (Fig. 1D). By FMT experiments in mice, we sought to explore the causal relationship between microbiota immune-related colitis. After injection of anti-PD-1 and anti-CTLA-4, three of nine colitic-irAE-FMT mice developed fatal severe colitis, while all nine non-irAE-FMT mice survived without colitis (P=0.052). The three colitic mice showed more rapid weight loss and higher disease activity index (DAI) scores compared with other mice (Fig. 2A and B). The histological colitis score in the irAE-FMT-Sac. mouse (14 points) was higher than those in the non-irAE-FMT mice (3.89 ± 1.17 points) and colitic-irAE-FMT-survival mice (3.67 ± 1.03 points) (Fig. 2C). The mean IHC scores of irAE-FMT-Sac. mouse from high to low were CD8 3.8 ± 1.3 points, CD4 2.0 ± 1.9 points, and CD20 1.1 ± 1.3 points (Fig. 2D), which also supported the occurrence of immune-related colitis.

Figure 1. The gut microbiotas of patients with colitic and non-colitic type irAEs.

Figure 2. Comparison of colitis in colitic-irAE-FMT and non-irAE-FMT mice.

Conclusion

Gut microbiota might play important role in the development of immune-related colitis, possibly by modulating metabolic pathways.
DOP51 Mucosa-associated microbial signatures associate with objective response prior to the start of anti-TNFα but not vedolizumab or ustekinumab in Crohn’s disease patients
Authors: Hageman I , Joustra V , Zafeiropoulou K , Davids M , Hakvoort T , Probert F , Satsangi J , D’Haens G , De Jonge W
Published: January 2023

Background

Crohn’s disease (CD) is a complex immune-mediated disease of the gastrointestinal tract where the gut microbiome plays an important role. Current biological treatment options in CD include the anti-TNFα agents adalimumab (ADA) and infliximab (IFX), vedolizumab (VDZ), and ustekinumab (USTE). Finding biomarkers to predict therapy response is still a clinical unmet need, as the majority of CD patients fail to reach endoscopic remission within 1 year of treatment. While the majority of studies focus on fecal samples, mucosa-adherent bacterial signature could bring forth stable biomarkers. In this study, we sought to identify signatures of the adherent microbiome in intestinal biopsies aimed at differentiating responders (R) from non-responders (NR), prior to the start of biological treatment.

Methods

We prospectively collected paired ileal and colonic biopsies (stored snapfrozen in -80 ºC) from adult CD patients scheduled to start anti-TNFα (IFX and ADA), VDZ and USTE treatment during baseline endoscopies. After 6-12 months of follow-up, patients were classified as either R or NR based on endoscopic response (≥50% reduction in SES-CD score) in combination with steroid-free clinical response (≥3 point drop in HBI or HBI ≤4) and/or biochemical response (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin or a basal CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Microbiome composition of the biopsies was determined using 16S RNA gene V3V4 amplicon sequencing.

Results

For the anti-TNFα cohort, we included in total 36 CD patients (21R and 18 NR), for VDZ cohort a total of 44 patients (28 R and 16 NR) and for USTE cohort a total of 40 patients (20R and 20 NR).When comparing α-diversity and β-diversity between R and NR, we did not find significant differences in ileal and colonic samples at baseline for the VDZ and USTE cohorts. Notable, for the anti-TNFα cohort (table 1), we obtained significant differences when comparing α-diversity (p=0.028) and β-diversity between R and NR. We demonstrated differences between colonic R and NR in taxa abundance for ASVs associated with the phyla Bacteroidetes, Firmicutes, Fusobacteria, Proteobacteria (figure 1). Furthermore, ASVs associated with Firmicutes, Bacteroidetes, Actinobacteria are different in abundance between ileal R and NR (figure 2).

Figure 1: Differential taxa abundance colonic R vs NR anti-TNFα

Figure 2: Differential taxa abundance ileal R vs NR anti-TNFα

Figure 3: graphical summary

Conclusion

Here, we investigated the microbial signature of R and NR before the start of treatment of three separate cohorts and we demonstrated that the mucosa-associated microbiome differentiates R and NR to anti-TNFα therapy. Further analyses as part of the EPIC Pioneer study, are ongoing.
DOP52 The faecal bacterial and fungal microbiome of newly-diagnosed, treatment naïve children with Crohn’s disease and the modifying effects of exclusive enteral nutrition and re-introduction of habitual diet
Authors: Gerasimidis K , Nichols B , Papadopoulou R , Ijaz U , Rajendran R , Quince C , Russell R K , Hansen R , Ramage G
Published: January 2023

Background

The fungal community (mycobiome) and immunological responses to specific fungi have been implicated in Crohn’s disease (CD) pathogenesis and its phenotype. There is limited data on profiling the mycobiome in paediatric CD and how it changes during treatment

Methods

Fungal (ITS2) and bacterial (16S rRNA) microbiome analysis in faecal samples (n=124) from n=34 CD children before, during (30 and 60 days) and after exclusive enteral nutrition (EEN) at food reintroduction (within 60 days of EEN completion), and from 31 healthy controls were profiled. IgA and IgG anti-Saccharomyces cerevisiae antibodies (ASCA) analysis by enzyme-linked immunosorbent assay, in blood, was also carried out for CD patients prior to EEN initiation.

Results

The global mycobiome composition (β diversity) was different between CD and healthy children (R2=0.050; p=0.007) and presented lower Chao1 richness (mean 24.3 vs 33.0; p=0.005) for the CD cases; 13 fungal operational taxonomic units (OTUs) differed between the two groups. Similar signals were observed for the bacterial microbiome but the difference in global community structure (β diversity) was more profound than the fungal community (R2=0.094; p<0.001). Treatment with EEN induced drastic changes in mycobiome composition (β diversity), which were more profound and more variable than the effects observed for the bacterial community. Of the OTUs with abundance significantly lower in CD than healthy controls prior to EEN, one, belonging to S. cerevisiae, significantly decreased during EEN (compared with baseline; p<0.001 and p=0.086 at 30 and 60 days on EEN). Patients whose faecal calprotectin was low (<250 mg/kg) during food reintroduction had a lower mycobiome richness than those whose FC was raised (>250 mg/kg). 29 fungal OTUs were significantly different between these two groups in samples taken during food reintroduction, following EEN. Patients who were ASCA positive had a higher abundance of three OTUs of S. cerevisiae. In co-occurrence network analysis, Simplicillium chinense, presented significant more interactions with members of the bacterial community, particularly OTUs which changed during EEN. After participants had returned to their regular diets these microbial effects reversed and community structure moved towards that observed prior to EEN.

Conclusion

The mycobiome of children with CD present features of dysbiosis similar to the bacterial microbiome and improvement in disease condition during EEN is strongly associated with changes in its composition.
DOP59 What is the relationship between fatigue, pain and urgency in people with inflammatory bowel disease? Results of the IBD-BOOST survey in 8486 participants
Authors: Hart A , Miller L , Hamborg T , Stagg I , McGuinness S , Wileman V , Tzorovili E , Mihaylova B , Roukas C , Aziz Q , Czuber-Dochan W , Dibley L , Moss-Morris R , Pollok R , Saxena S , Winsor G , Norton C
Published: January 2023

Background

Fatigue, pain and faecal incontinence are common in people with IBD. However, little is known about co-existence of these multiple symptoms, how they inter-relate and whether people want help for these symptoms. In qualitative interviews, patients have reported that these symptoms are often ignored in clinical consultations, where the focus is on inflammation, but that they are very bothered by these symptoms, even when disease is apparently in remission. The aim of this study was to determine the presence and relationship between fatigue, pain and incontinence in people with inflammatory bowel disease, and desire for intervention for these symptoms.

Methods

A purpose-designed survey (online or postal), incorporating validated tools and demographic details, was sent to unselected UK clinic and UK IBD-BioResource adult patients. When the covid-19 pandemic halted clinic recruitment, additional self-selected UK recruits were solicited via social media. Using the validated PROMIS tools, the following definitions were used for presence of symptoms: fatigue: PROMIS fatigue T-score of 60 or more; pain: PROMIS pain intensity T-score of 60 or more; PROMIS bowel incontinence: raw score of 50 or more. Participants also reported disease activity using the relevant PRO-2 score, IBD-Control, anxiety (GAD-7), depression (PHQ-9) and quality of life (EQ-5D-5L) which will all be reported elsewhere.

Results

A total of 8486 useable responses were received (7716 online, 770 postal). 4176 reported Crohn’s disease, 4255 had ulcerative colitis or other form of IBD. There were 3281 men and 4883 women. Median age was 51 years (range 18 - 92). 2550 (30%) reported fatigue, 1766 (21%) pain and 4565 (54%) faecal incontinence according to the above definitions; 925 (10.9%) reported having all three symptoms. Demographics by symptom are shown in Table 1. Table 2 reports those participants indicating the presence of each symptom and each combination of symptoms. Table 3 shows a summary of self-defined severity and impact of symptoms (scoring scale 0-10 for both severity and impact of each symptom). Participants scored severity and impact a mean between 3.3 and 4.8, with a wide variation. 56% of all respondents (not just those with symptoms) “definitely” wanted help for fatigue; 42% wanted help for pain; 53% wanted help for incontinence. 29% reported “definitely” wanting help for all three symptoms (Table 4).

Conclusion

This study confirms that fatigue, pain and urgency are common in IBD and for the first time reports the co-existence and unmet need for help with these symptoms.
DOP61 Ethnic disparities in the management of Inflammatory Bowel Disease in Israel and impact on outcomes
Authors: Boaz E , Ledder O , Dagan A , Lujan R , Koslowsky B , Friss C , Greenfeld S , Kariv R , Loewenberg Weisband Y , Lederman N , Matz E , Dotan I , Yellinek S , Turner D
Published: January 2023

Background

In this nationwide study, we aimed to explore health services utilization, medical management, and disease outcomes of inflammatory bowel diseases (IBD) between Jews and Arabs, the two major ethnic groups in Israel.

Methods

We utilized a cohort including all patients diagnosed with IBD in Israel since 2005. The primary outcome was steroid-dependency, with secondary outcomes including use of biologics, time to surgery, and IBD-related admissions. Outcomes were controlled for possible inherent differences in disease course and phenotype.

Results

Of the 32,491 included patients, 18,252 (56%) had Crohn’s disease (CD) and 14,239 (44%) had ulcerative colitis (UC); 10% were Arabs and 90% were Jews. Jewish ethnicity was associated with lower rates of steroid-dependency compared to Arab ethnicity in both CD )HR=0.7 [95%CI 0.6-0.8]) and UC (HR=0.7 [95%CI 0.6-0.8]). In addition, Jewish ethnicity was associated with increased use of biologics during the first year from diagnosis in patients with CD (HR=1.3 [95%CI 1.1-1.6]) but not with UC. The risk of IBD-related surgery in CD at 3 and 5 years was higher in the Arab group at all time points (13% vs 10%, 16% vs 14%, respectively, p=0.005). Arabs had higher number of IBD-related hospitalizations than Jews (19% vs. 28% with two or more IBD-related hospitalizations at 5 years, p<0.001).

Conclusion

Arab ethnicity is associated with higher rate of hospitalizations, steroid-dependency and surgeries on one hand, and lower utilization of biologics on the other. The results should be considered by policy makers to improve access to medical care across all populations.
DOP63 Time Trends of Environmental and Socio-economical Factors in Patients with Inflammatory Bowel Disease over 40-year of Different Therapeutic Eras; results from a Population-based Cohort from Western Hungarian between 1977-2020, The Hygiene hypothesis revisited.
Authors: Wetwittayakhlang P , Gonczi L , Lakatos L , Golovics P , Pandur T , David G , Erdelyi Z , Szita I , Lakatos P L
Published: January 2023

Background

Data from population-based studies investigating the time trends in environmental and socio-economical factors associated with IBD is lacking. We aimed to assess time trends in environmental and socio-economical factors over 40 years of different therapeutic eras in patients with IBD from a prospective population-based inception cohort from Veszprem County, Western Hungary.

Methods

Patients from the incident IBD cohort were included between January 1,1977 and December 31,2020. Environmental and socio-economical factors, including an area of living, educational and type of employment, smoking status, appendectomy, and contraceptive drug use, were evaluated in three eras based on the different therapeutic strategies in IBD:cohort-A, 1977-1995 (pre-biologic/pre-immunomodulators era); cohort-B,1996-2008 (immunomodulator era); and cohort-C,2009-2020 (biological era).

Results

A total of 2,240 incident patients diagnosed with IBD were included [UC 61.2%, male 51.2%, the median age at diagnosis: 35 years (IQR 29-49)]. There was a significant increase in IBD incidence over time in both CD and UC1-2. A higher proportion of patients with active smoking in CD compared to UC, and the rates of smoking significantly decreased over time in CD; 60.2%, 49.9%, and 38.6% in cohorts A, B and C (p<0.001). In UC patients, the rates were lower and stable; 15.4%, 15.4%, and 14.5% in cohort A,B and C, respectively (p=0.981). The use of the contraceptive drug was more common in CD than UC, and the rates were stable; 23.7%,26.6%, and 23.7% in cohorts A, B and C (p=0.950). In UC patients, the appendectomy rates before diagnosis decreased over time; 6.4%, 5.5%, and 2.3% in cohorts A, B and C (p=0.013). No significant changes in the distribution of IBD population between geographic areas [municipal area: UC; 59.8%/64.8%/62.5% (p=0.309) vs. CD; 62.5%/62.0%/59.0% (p=0.636), in cohort A/B/C]. However, fewer percentages of IBD patients who achieved primary school as maximal education level (32.2%,21.9% and 11.7% in cohorts A,B, and C, p <0.001) as well as less physical work employment (53.4%,51.3%, and 42.3% in cohorts A,B and C, p=0.001) were observed in both UC and CD. (Reference 1.Gonczi L et al. Colitis. 2022 Sep 10:jjac132 Ref 2. Kurti Z et al. Crohns Colitis. 2022 Sep 19:jjac142)

Conclusion

This is one of the first long-term, prospective population-based cohorts investigating the time trends of socio-economical and environmental factors associated with IBD over 4 decades, including less primary school as maximal education level and less physical work employment. Results from this study highlight that the association between time trends of known environmental/socio-economic factors and IBD incidence is complex.
DOP64 Utilising genomics to predict outcomes and delineate novel subgroups in inflammatory bowel disease
Authors: Ashton J , Cheng G , Stafford I , Beattie R M , Ennis S
Published: January 2023

Background

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

Methods

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

Results

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

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

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

Conclusion

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

Background

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

Methods

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

Results

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

Conclusion

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

Background

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

Methods

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

Results

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

Conclusion

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

Background

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

Methods

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

Results

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

Conclusion

With increasing focus on patient preferences, long-term safety and costs, elective biological treatment discontinuation may be considered for some patients with CD in remission. In cases of relapse, there have been reassuring findings on subsequent retreatment with the same biological agent. However, there is a need for more data to support routine elective treatment discontinuation and cycling in CD, especially for newer biological agents. In particular, randomised, controlled trials comparing biological cycling to current maintenance therapy strategies would be highly informative. Currently, discussions about biological treatment discontinuation and cycling should be individualised, to enable shared decision-making by patients with their clinicians.