bluuebunny/crossref_metadata_2025 huggingface dataset:
P013 A single cell approach reveals immune cell dynamics in Inflammatory Bowel Disease (IBD) and highlights association of CD8 intraepithelial lymphocytes (IELs) with response to vedolizumab treatment
Authors: Paraskevopoulou M , Mayer L , Krueger A , Pattekar A , Ramos A , Fulton M , Wai Lau C , Chau L , Ren Y , Tondon R , Al Garawi A , Bittinger K , Fogt F , Yajnik V , Lee H , Lewis J , Wu G , Bewtra M , Tomov V , Juarez J
Published: January 2022

Background

Dysregulated immunity in the gut is central to the pathogenesis of inflammatory bowel disease (IBD) and its contribution to patient responses following biologic treatment is poorly understood. Single cell protein- and sequencing-based analyses have provided unprecedented understanding of cell heterogeneity and function in IBD. In this study, recent cytometry by time of flight (CyTOF) and single cell transcriptomics technology advancements have been leveraged to characterize the intestinal mucosa of IBD patients treated with vedolizumab.

Methods

Single cell RNA sequencing from IBD mucosa biopsies were analysed to derive cell molecular signatures and deconvolute bulk transcriptomic datasets of UC patients treated with biologics. Cellular abundance differences in response to therapy were in-silico validated in both vedolizumab and anti-TNF treated patients. CyTOF analysis of intestinal biopsies from 24 UC patients and 29 healthy controls (HC) was applied to complement transcriptomic findings and further understand T cell dysregulation in disease activity and treatment response. CyTOF panels were focused on T cell polarization, memory differentiation, effector function and homing. Mucosal microbiota analysis by 16S rRNA gene sequencing was employed and correlated with patient/host cellular dynamics.

Results

Deconvolution analysis of UC bulk transcriptomic data with single cell molecular signatures from mucosa biopsied samples (Smillie et al.) revealed decreased abundance of CD8 IELs along with increased activated T cells, inflammatory/activated stromal cells in non-responders to both vedolizumab and anti-TNF therapy compared with responders and HC. CyTOF analysis of intestinal biopsies from patients responding or not responding to biologic treatment confirms cellular alterations at the protein level. Specifically, in patients that respond to vedolizumab, we observed greater levels of immune cells with CD8 IEL phenotype (CD8+ CD69+ CD103+) similar to HC. In contrast, in non-responder patients we observed lower levels of these cells but higher abundances of CD8+ Tc17 and CD4+ Th17 cells. In non-responders, Tregs were also elevated compared with responders and HC. Assessment of mucosal biopsies with 16S rRNA gene analysis also revealed microbial metabolic pathways supportive of CD8 IEL development associated with elevated CD8 IELs in vedolizumab treatment responders.

Conclusion

This multi-modal and deep molecular phenotyping approach revealed CD8 IELs to be associated with healthy intestinal tissue and treatment response to vedolizumab. These findings suggest that CD8 IELs may be beneficial for supporting and restoring tissue homeostasis.
P019 GS-1069518 is a potent and selective small molecule α4β7 inhibitor
Authors: Wang Y , Zhou J , Chang C , Roedder S , Bonne-Annee S , Marchand B , Hung K , Currie K , Clarke A
Published: January 2022

Background

The interaction between the adhesion molecule MAdCAM-1 and the α4β7 integrin heterodimer enables the trafficking of gut-antigen specific lymphocytes to the small and large intestines and to gut-associated lymphoid tissues. The role of the α4β7 integrin in the pathophysiology of IBD has been clinically demonstrated, and targeted therapeutics have been shown to mitigate inflammation and mucosal damage mediated by α4β7+ lymphocytes. The purpose of this study was to determine the potency and selectivity of the small molecule α4β7 inhibitor GS-1069518.

Methods

The selectivity of GS-1069518 and relevant reference molecules was determined using in vitro cell capture assays with natural integrin ligands and by measuring receptor occupancy in human and cynomolgus monkey whole blood. The number of RPMI-8866 cells binding to MAdCAM-1-coated surfaces (a natural α4β7 ligand) and Jurkat cells binding to VCAM-1-coated surfaces (a natural α4β1 ligand) were quantified with high content imaging. Receptor occupancy on CD3+CD4+CD45RO+β7+ (human) or CD3+CD4+CD45RA-β7+ (cynomolgus monkey) and CD3+CD4+CD45RO+α4+β1+β7- (human) or CD3+CD4+CD45RA-α4+β1+β7- (cynomolgus monkey) memory T cells was measured by flow cytometry with fluorescent probes that detect occupancy in the ligand-binding sites.

Results

In a MAdCAM-1 cell capture assay, the EC50 of GS-1069518 was 0.034 nM, with 71-fold and >10,000-fold selectivity over α4β1 and αLβ2, respectively. In α4β7 receptor occupancy assays the EC50 of GS-1069518 was 0.36 nM in human whole blood and 0.4 nM in cynomolgus monkey whole blood. GS-1069518 was 482-fold selective for α4β7 over α4β1 in human whole blood and 119-fold selective for α4β7 in cynomolgus monkey blood.

Conclusion

GS-1069518 is a highly potent and selective small molecule inhibitor of the α4β7-MAdCAM-1 ligand binding interaction.
P026 Inflammatory bowel disease does not preclude the presence of environmental enteropathy in Zambian adults
Authors: Hodges P , Mulenga C , Banda R , Kelly P
Published: January 2022

Background

Although data is scarce, inflammatory bowel disease (IBD) seems to be increasing in incidence in newly industrialised countries.(1) The environmental factors driving this change are not entirely clear, although it seems likely that changing diet and improving hygiene and sanitation are involved. In China, incidence of IBD is positively associated with gross domestic product.(2)

Environmental enteropathy (EE) is a lesion of the small bowel with villous blunting, chronic inflammation and increased gut permeability seen in people living in insanitary conditions in resource-limited settings. We set out to examine whether EE would be present in patients with IBD in Zambia, as these individuals are likely to come from higher socioeconomic strata hence would be expected to live in more sanitised environments. Here we report preliminary data.

Methods

IBD cases were recruited at time of diagnosis or follow-up. Two groups of controls were recruited: individuals of higher socioeconomic status attending the GI clinic for investigation of symptoms of dyspepsia who had normal upper GI endoscopy were recruited to control group A, and healthy individuals from Misisi compound where studies on EE have been conducted over the past two decades to control group B (low socioeconomic status). All participants gave informed consent and underwent upper GI endoscopy and collection of duodenal biopsies. Haematoxylin- and eosin-stained sections of paraffin-embedded formalin-fixed biopsies were imaged on an Olympus VS120 scanning microscope then assessed for villous height, crypt depth, and epithelial surface area. Demographic information was collected via questionnaire.

Results

Biopsies were collected from 13 cases, 7 controls in group A and 10 controls in group B. Demographics are shown in Table 1. Cases and controls in group A had a higher number of rooms in the house than controls in group B but there was no significant difference in other environmental factors. Other than crypt depth, which was greater in controls from the lower socioeconomic group, there was no significant difference in morphometric parameters between IBD cases and controls (Table 2). The most severe enteropathy is seen in the biopsy from control group B (Figure 1c) which is made up of participants recruited a socioeconomically deprived district of Lusaka.

Figure 1

Conclusion

EE can coexist alongside IBD, suggesting that immunological drivers of these conditions are not distinct, and do not support the hygiene hypothesis. There is evidence of some degree of EE in small bowel biopsies from all cases and controls. Normal villous height to crypt depth ratio is likely to be between 3 and 5 (3) whereas medians for villous height:crypt depth in all groups in this study were less than 2.
P044 Enteric dopaminergic pathways in mouse and human intestinal inflammation
Authors: Cerantola S , Faggin S , Caputi V , Cortese V , Bosi A , Banfi D , Rambaldo A , Porzionato A , Giaroni C , Savarino E V , Giron M C
Published: January 2022

Background

Changes in dopamine beta-hydroxylase (DBH) and anomalies in dopaminergic machinery have been shown in inflammatory bowel disease (IBD) patients and related animal models. Thus, we aimed to evaluate the dopaminergic pathways in IBD patients as well as in a mouse model of dextran sodium sulphate (DSS)-induced ileitis.

Methods

Colon biopsies (CB) obtained from healthy volunteers (N=3) and matched-IBD patients (N=3), were used to evaluate DBH immunoreactivity by confocal microscopy. Male C57/Bl6 (8±2 weeks old; N=16 mice) received 1.5% DSS in drinking water for 5 days, then switched to regular drinking water for 3 days. Inflammatory cytokines (IL-1β, TNFα, IL-6) were measured to assess ileitis severity. Changes in ileal muscle tension were isometrically recorded following 30 μM dopamine or 30 μM SKF38393 (a dopamine receptor 1 (D1R) agonist) or 30 μM bromocriptine (a D2R agonist). Immunofluorescence distribution of Iba1 (a macrophage specific marker), D1R, DBH and dopamine transporter (DAT) were determined in longitudinal muscle-myenteric plexus whole-mount preparations (LMMPs) by confocal microscopy. D1R and D2R mRNA transcripts were evaluated by qRT-PCR.

Results

CB from IBD patients and LMMPs from DSS mice showed a significant increase of DBH immunoreactivity compared to healthy patients and sham mice (+25% [p<0.01], +20% [p<0.01], respectively). DSS treatment caused a significant increase of DAT and D1R immunoreactivity as well as D1R mRNA levels (+27% [p<0.05], +24% [p<0.05], +6-fold [p<0.05], respectively), accompanied by a significant reduction of dopamine-mediated relaxation (-27% [p<0.01]). SKF38393 determined a marked inhibitory response in ileal preparations from DSS mice compared to sham mice (+73% [p<0.01]), suggesting that dopamine responses are mainly mediated through D1R. A 2-fold increase of resident Iba1+ macrophages was observed in the myenteric plexus of DSS mice associated with a 2.9- and 1.5-fold enhancement of IL-6 and IL-1β mRNA levels, respectively.

Conclusion

Human colitis and mouse ileitis affect dopamine machinery in the enteric nervous system. Experimentally induced ileitis impairs dopaminergic neurotransmission altering D1R-mediated responses. These findings provide novel information on the involvement of dopaminergic pathways in IBD.
P045 TIGIT expression differentiates regulatory from inflammatory Th1* gut-homing effector CD4+ T cells in inflammatory bowel disease patients
Authors: Heredia M , Costes L M M , Tindemans I , Aardoom M A , Klomberg R C W , Kemos P , Joosse M E , van Haaften D H , Tuk B , Ruemmele F , Croft N M , Escher J C , de Ridder L , Samsom J N
Published: January 2022

Background

Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by intestinal infiltration of pathogenic effector CD4+ T cells. The defects driving loss of T-cell regulation vary between patients and remain undefined. Previously, we have shown that in human intestine, 20–40% of effector (CD62LnegCD4+) T cells express TIGIT (T cell immunoglobulin and ITIM domain), an inhibitory receptor modulating dendritic cell and T-cell function. TIGIT expression is enriched in circulating gut-homing CD38+ effector T cells in healthy controls while in a subgroup of IBD patients with active intestinal inflammation, frequencies of inhibitory TIGIT+CD38+ effector T cells are decreased and associated with earlier relapse of disease. Here we hypothesized that gut-homing effector T cells lacking TIGIT (TIGITneg) are pathogenic mediators of intestinal inflammation in IBD and assessed whether patients with low frequencies have a distinctive disease immunotype.

Methods

In the Rotterdam PIBD-SETQuality cohort of newly diagnosed pediatric IBD patients (CD: n=50; UC: n=25), patients with suspicion of IBD but negative diagnosis (n=17) and age-matched healthy controls (HC: n=22), we monitored TIGIT+ and TIGITnegCD38+ effector T cells in peripheral blood, collected plasma at diagnosis and during therapy and phenotyped intestinal T cells.

Results

At diagnosis, 50% of CD patients had strongly reduced frequencies of inhibitory TIGIT+CD38+ effector T cells compared to UC patients and HC. CD patients with reduced frequencies of inhibitory TIGIT+CD38+ effector T cells had higher plasma IFN-γ concentrations and 53% of them experienced a disease relapse by 1 year versus 25% for CD patients with normal TIGIT+CD38+effector frequencies. In keeping with our hypothesis that TIGITneg gut-homing effector T cells are pathogenic, absence of TIGIT expression identified CD38+ effector T cells enriched in recent proliferation and having high expression of chemokine receptors associated with inflammatory non-classical T helper-1 IFNγ highIL-17Alow producing (Th1*) cells. Moreover, intestinal TIGITnegCD4+ T cells of CD patients contained higher frequencies of IFNγ and IL-17A producing cells than TIGIT+CD4+ T cells. In order to identify the factors that drive differentiation of the pathogenic Th1* cells, inhibitory TIGIT+CD38+ effector T cells from HC were exposed to an array of IBD-associated cytokines in vitro. Only IL-12p70, a known driver of IFNγ, could convert inhibitory TIGIT+CD38+ effector T cells into their TIGITneg proinflammatory counterpart.

Conclusion

We identify TIGITneg gut-homing effector T cells, enriched in Th1* cells, as potential drivers of intestinal inflammation in a subgroup of CD, but not UC patients, with a more severe disease course.
P061 Circulating inflammatory protein and cellular profiles at time of diagnosis classify inflammatory bowel disease patients according to their underlying immune response and clinical disease course
Authors: Heredia M , Charrout M , Klomberg R C W , Aardoom M A , Jongsma M M E , Kemos P , van Haaften D H , Tuk B , van Berkel L A , Bley Folly B , Mahfouz A , Reinders M J T , Ruemmele F , Croft N , Escher J C , de Ridder L , Samsom J N
Published: January 2022

Background

Chronicity of inflammatory bowel disease (IBD) is driven by reactivation of inflammatory memory CD4+ T helper (Th) cells which activate an inflammatory cascade involving innate immune cells and structural intestinal tissue cells. Because of disease heterogeneity, novel treatment strategies tailored to more precisely target the patient’s individual immune defect are required to prevent disease reactivation. We hypothesize that analysis of changes in circulating inflammatory protein abundance combined with phenotyping of circulating Th cells allow to dissect underlying immune pathogenesis and aim to stratify pediatric IBD patients accordingly.

Methods

We performed plasma analysis of 92 inflammatory proteins in a cohort of pediatric IBD patients (CD: n=62; UC/IBD-U: n=20), patients with suspicion of IBD but negative diagnosis (n=13) and age-matched healthy controls (HC: n=30). Peripheral blood was obtained at diagnosis and after induction treatment (t=10–14 weeks). Plasma protein concentrations were assessed with Olink Proximity Extension Assay technology® and Th cells were analyzed with flow cytometry.

Results

Thirty-six plasma proteins discriminated pediatric IBD patients from HC. CD and UC/IBD-U patients shared increased abundance of 17 proteins amongst which interleukin-6 and oncostatin-M. Increased abundance of the Th1 cytokine interferon-γ was strictly associated with CD while Th17-associated interleukin-17A was significantly more abundant in UC/IBD-U. Hierarchical clustering of plasma protein profiles discriminated 2 clusters of UC patients with different clinical disease activity and disease extent. In CD, three patient clusters were identified. CD#3 patients had lower clinical disease activity, lower C-reactive protein and higher blood albumin concentrations, while clusters CD#1 and CD#2 had comparable clinical parameters. CD#1 patients had higher abundance of 14 proteins associated with neutrophil function and interferon-γ signaling while CD#2 patients had a marked increase in frequencies of activated (HLA-DR+) memory Th cells. The three CD clusters responded differently to therapy with CD#1 patients exhibiting more modulated proteins and greater fold changes, CD#2 patients showing intermediate modulation and CD#3 patients exhibiting only a few changes.

Conclusion

Combined plasma immune protein and circulating Th cell profiling combined with in depth clinical monitoring discriminates subgroups of pediatric IBD patients during active disease which differ in their response to induction therapy.

Abbreviations: CD: Crohn’s disease; UC: ulcerative colitis; IBD-U: IBD-unclassified.
P073 Eosinophil depletion partially protects from colonic inflammation, but increases colonic collagen deposition in a DSS colitis model
Authors: Jacobs I , Deleu S , Cremer J , Guedelha Sabino J , Ferrante M , Vermeire S , Breynaert C , Verstockt B , Vanuytsel T
Published: January 2022

Background

The role of eosinophils in intestinal inflammation and fibrosis in inflammatory bowel disease (IBD) is largely unknown. Therefore, we assessed the functional role of eosinophils in a chronic murine model of colitis and associated fibrosis via anti-CCR3 mediated eosinophil depletion.

Methods

6-8-week-old C57BL/6 RAG-/- mice received three cycles of dextran sodium sulphate (DSS) (1.75% - 2.25% - 2.25%) each interspersed with 14 days of recovery. Twice weekly, anti-CCR3 antibody (n=8), isotype (n=8) or saline injections (n=8) were given intraperitoneally. At the same timepoints, the disease activity index (DAI; mouse weight, stool consistency and presence of blood) was determined. At sacrifice, colonic damage was scored macroscopically (presence of hyperaemia, adhesions and length and degree of colon affected by inflammation). Colonic single cells were isolated and stained for flow cytometry, where eosinophils were characterized as CD45+ CD11b+ Siglec-F+ CD117- cells. Intestinal fibrosis was scored via colon weight/length, collagen deposition (using a colorimetric hydroxyproline assay) and COL1A1 expression by PCR.

Results

Anti-CCR3 mediated eosinophil depletion resulted in decreased disease activity compared to the other DSS treated groups injected with saline or isotype, determined by the area under the curve of the DAI (74.6±18.4 vs. 127.5±42.9 and 136.9±33.6, p=0.01 and p=0.0008 respectively) (figure 1). The macroscopic damage score also suggested eosinophil depleted mice to be partially protected from colonic inflammation compared to the saline and isotype injected mice that received DSS (1.1±1.0 vs. 2.1±1.2 and 3.0±0.7, p=0.09 and p=0.001 respectively) (figure 1). Colon weight/length and hydroxyproline assay showed a trend towards increased fibrosis in the anti-CCR3 injected group compared to saline (p=0.03 and 0.07, respectively) but not isotype (p=0.3 and 0.1, respectively) injected groups (figure 2). However, COL1A1 expression levels were significantly increased in the eosinophil depleted mice compared to the saline and isotype injected mice receiving DSS (43.2±11.4 vs. 23.3±8.7 and 30.1±11.0, p=0.002 and 0.04 respectively) (figure 2), indicating increased collagen deposition.

Conclusion

Eosinophil depletion via intraperitoneal anti-CCR3 injections resulted in partial protection against colonic inflammation, but was associated with increased collagen production. Caution is therefore needed when designing therapeutic interventions targeting eosinophils.
P082 The profibrogenic role of neutrophil extracellular traps in stenotic Crohn’s disease: a new antifibrotic target?
Authors: Dragoni G , Ke B J , Verstockt B , Abdurahiman S , Innocenti T , Giudici F , De Hertogh G , Milla M , Bagnoli S , Picariello L , Galli A , Matteoli G , Vermeire S
Published: January 2022

Background

Neutrophil extracellular traps (NETs) are structures constituted of DNA filaments and protein granules, extruded by neutrophils after various insults, such as chronic inflammation. Their formation is dependent on the citrullination of histone H3 (H3cit) in the nucleus by peptidylarginine deiminase 4 (PAD4). The pathogenic effect of NETs in Crohn’s disease (CD) has been poorly addressed so far. Recently, a profibrogenic role of NETs has been proposed in the lung.

The aim of the present study was to assess whether NETs may trigger the fibrotic process in patients with CD.

Methods

Multiplex immunofluorescence (M-IF) for PAD4, myeloperoxidase, neutrophil elastase, H3cit, vimentin and alpha-SMA were performed in unaffected, inflamed and fibrotic ileum of patients operated for stricturing CD. From the same patients, primary intestinal fibroblasts (PIF) were cultured from unaffected ileum.

NETs were obtained from healthy volunteers’ neutrophils, incubated with 50 nM phorbol myristate acetate for 3.5 hours. Subconfluent PIF were stimulated in vitro with NETs for 6 hours and RNA extracted for sequencing (RNAseq). Cell culture medium was collected for soluble collagen analysis, using SIRCOL®. Experiments were replicated in 5 patients.

CCD-18Co cell line was used to test the migratory activity of fibroblasts with a scratch test and to confirm the expression of profibrogenic proteins, such as fibroblast activation protein (FAP) and collagen 3A1.

M-IF was interpreted using computational analysis. Statistics was performed with Kruskal-Wallis Test for collagen quantification, with p < 0.05. For RNAseq, Poisson distribution and DESeq2 were used, with significance set at Q < 0.05; the resulting gene list was then analysed with ClueGo® software.

Results

M-IF showed that NETs were primarily found in inflamed areas, with clusters of these traps located close to intestinal myofibroblasts in the deeper submucosa layer (Figure 1).

The gene ontology of RNAseq (Figure 2) showed significant upregulation of profibrogenic pathways of TGFB1/SMAD and p38/MAPK in the group of PIF co-cultured with NETs.

NETs stimulation determined a higher release of collagen in the medium (p = 0.003), and an increase in the protein expression of FAP and collagen 3A1 in PIF. Accordingly, NETs profibrotic effect resulted also in a slower migratory ability of activated fibroblasts.

Conclusion

Our data show that NETs are produced during active inflammation of CD and their colocalisation with intestinal myofibroblasts suggests that they may represent an early trigger of fibroblast activation. Clinically, the inhibition of PAD4 might result in both contrasting inflammation and fibrogenesis. An in vivo chronic model of colitis on PAD4-KO mice is ongoing to confirm these findings.
P098 Mucosal Microbiota Composition Predicts Infliximab Response in Inflammatory Bowel Diseases
Authors: Gazouli M , Dovrolis N , Kolios G
Published: January 2022

Background

The inflammatory bowel disease (iBD) etiology remain elusive and both genetic and environmental factors have been implicated in the establishment of systemic inflammatory reactions that typify IBD. A basic, modifiable environmental factor is the gut microbiota and dysbiosis seems to be a key factor in IBD pathogenesis. Nowadays, it is well known that anti-TNF therapy significantly improves the rates of remission in patients with inflammatory bowel disease (IBD), however, there is a subgroup of patients who do not respond to treatment. The aim of the present study is to profile changes in the mucosal gut microbiome before and after anti-TNF therapy and investigate its possibility to predict patient response at baseline.

Methods

Mucosal biopsy samples from IBD patients [14 Crohn’s disease patients (CD), 6 ulcerative colitis (UC) patients] and healthy controls (HC) were examined for differences in microbiota composition (16S rRNA gene sequencing) at baseline and upon completion of anti-TNF treatment, accordingly, via an in silico pipeline.

Results

Although no statistically significant differences at phylum level were noted, a relative reduction in Bacteroidetes and an increase in Actinobacteria, Fusobacteria and Chloroflexi were detected in IBD versus HC biopsies, however the microbiomes of UC, CD and HC display qualitative differences at the OTU level. At genus level, statistically significant differential abundance between the HC and IBD groups was observed. The genera Parabacteroides, Barnesiella, Butyricimonas, Ruminococcus_1, Ruminococcaceae_UCG013, Phascolarctobacterium, Ruminoclostridium_6, Paraprevotella as well as members of the Eubacterium_ruminantium group appear reduced in IBD, whereas Dialister abundance is increased. The genus Collinsella exhibits an induction during UC versus both HC and CD. Regarding anti-TNF treatment on the microbiome, Alpha-diversity is reduced after anti-TNF treatment. Beta-diversity indicates differences before and after treatment as well as between responders and non-responders. By using the biomarker discovery tool LEfSe, we identified microbial genera associated mainly with anti-TNF responders.

Conclusion

In the present study, we showed that the response to anti-TNF therapy is related to specific microbiota profiles in the gut mucosa. Correlation analysis between these parameters of response at baseline showed that the assessment of microbial taxa can further distinguish responders from non-responders.
P103 Identifying CES-1 positive myeloid cells with mass cytometry as a potential therapeutic target for Crohn’s disease
Authors: Hageman MD I , Elfiky A , Becker M , Joustra V , Buskens C , Li Yim A , Hakvoort T , Verhoeff J , Garcia Vallejo J , D’Haens G , Wildenberg M , De Jonge W
Published: January 2022

Background

Myeloid cells are key players in the sustained inflammatory process in Crohn’s disease (CD), and are therefore therapeutic targets. Human mononuclear myeloid cells express the cell selective expression of carboxylesterase 1 (CES-1). Esterase-sensitive motif (ESM) technology has been developed to specifically target ESM tagged small molecules on human mononuclear myeloid cells, based on their CES-1 expression, creating a larger therapeutic window with less side effects. This study investigates the presence of CES-1 expressing cells in PBMCs, intestinal biopsies and fistula cells of CD patients, highlighting the potential of ESM-technology in CD. This could benefit CD treatment in non-responsive patients or patients with a fistulizing phenotype.

Methods

Intestinal biopsies were collected from CD patients who underwent endoscopy. PBMCs were collected from CD patients who were receiving Vedolizumab (VDZ) treatment and categorized as responders or non-responders. Criteria for response was based on clinical (HBI ≤4) and biochemical (fecal calprotectine ≤250 µg/g) and/or endoscopic assessment (≥50% reduction in SES-CD score). Fistula tissue was of CD patients was obtained during surgery. CES1-positive cells were phenotyped by mass cytometry with a panel of 32-markers, including the myeloid markers CES-1, CD14, CD16, HLA-DR, CD11c, CD206.

Results

We demonstrated the presence of CD14+HLADR+CD11a+CD44+CD11b+ myeloid cells exclusively expressing CES-1 in intestinal biopsies of CD patients (n=7). CES-1 expression did not differ between inflamed and uninflamed tissue. In PBMCs of VDZ responders (n=5) and non-responders (n=6), we were able to identify different subsets of myeloid cells such as classical (CD14++CD16-), intermediate(CD14+CD16+) and non-classical (CD14-CD16++) monocytes, DCs and CD2+ DC precursors all demonstrating CES-1 expression. Percentage of CES-1 positive cells in inflamed PBMCs (or non-responders) was higher than in uninflamed PBMCs (responders) in all of the above-mentioned subsets. Furthermore, we demonstrated different myeloid populations within fistula cells (n=13) such as pDCs (CD123+CD68+HLA-DR+), DCs (CD11c+CD11b+HLA-DR+ CD44+), CD141+DCs (CD141+CD49d+HLA-DR+),Macrophage (CD14+CD11c+CD11b+HLA-DR+CD44+) and M2 Macrophages (CD14+CD163+CD206+CD11c+CD11b+HLA-DR+CD44+), all expressing CES-1.

Conclusion

We demonstrated specific CES-1 positive myeloid cells within intestinal biopsies, PBMCs of non-responsive patients, and fistulae samples of CD patients. Targeting CES-1+ with ESM-technology could provide new therapeutic targets for CD.
P119 Hereditary Colorectal Cancer Syndromes and Inflammatory Bowel Diseases: an ECCO CONFER Multicenter Case Series
Authors: Barberio B , Savarino E , Verstockt B , Fumery M , Pugliese D , Bertani L , Buda A , Dragoni G , Goren I , Laish I , Spinelli A , Teich N , Truyens M , Ellul P
Published: January 2022

Background

Hereditary colorectal cancer syndromes (HCCS) are rare polyposis or nonpolyposis syndromes with a higher risk of developing colorectal cancer (CRC). Coexisting inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), with HCCS is exceedingly rare and presumably increases the risk of early-onset colorectal cancer.

Methods

This was a multicenter case series performed as a part of the European Crohn’s and Colitis Organisation (ECCO) Collaborative Network of Exceptionally Rare case reports (CONFER) project.

Results

This report includes 26 patients with IBD (10 UC, 15 CD, and one with IBD unclassified (IBD-U)) and concomitant HCCS. Among these 26 patients (median age 33 years, IQR 20–44), 15 (57.7%) were males, 24 (92.3%) Caucasians and 2 (7.7%) of Arab origin. Among patients with UC, 4 (40%) had proctitis, 3 (30%) left-sided colitis and 3 (30%) an extensive disease; while, among patients with CD, 8 (53.3%) had ileal, 5 (33.3%) ileocolonic, 2 (13.3%) colonic disease. One of these patients had ileocolonic disease associated with upper disease location and six (40%) had an associated perianal disease. Many of patients with CD had a non-stricturing non-penetrating phenotype (53.3%, n=8), while 20.0% (n=3) and 26.7% (n=4) had a stricturing or penetrating phenotype, respectively. HCCS was diagnosed before the IBD diagnosis in 11 patients (42.3%), after diagnosis of IBD in 11 patients (42.3%) and concurrently in 4 patients (15.4%). Sixteen patients had Lynch syndrome, 7 had FAP, 2 had AFAP and one had MAP. The most frequent genetic mutations were those of APC (n=7) and MLH1 (n= 7). Thirteen patients were treated with immunomodulatory (IMM) therapy. During IMM therapy, only 5 patients developed drug-induced side-effects which did not require drug interruption. One patient treated with vedolizumab developed CRC, despite yearly colonoscopy surveillance, after 4 years of treatment. Overall, CRC developed in 38.5% of patients (n=10): in 5 patients (50%) after IBD diagnosis, in 4 (40%) patients before IBD diagnosis, and in 1 patient the 2 conditions were diagnosed simultaneously. Eighteen (69.2%) patients underwent colectomy or abdominal surgery: 9 patients due to CRC diagnosis, 7 patients preventively due to the underlying HCCS and 2 patients because of active IBD disease. On follow-up, one patient died due to CRC.

Conclusion

This case series describes the largest series to date of patients with IBD patients and HCCS, with special emphasis on the use of IMM in this population. The most frequent diagnosis of HCCS associated with IBD was Lynch syndrome. These data demonstrate the high malignancy rate and surgical intervention rate in this IBD cohort. The optimal medical approach still needs to be addressed.
P120 First year remission rates among patients with newly diagnosed Crohn’s disease: data from a real-world prospective inception cohort
Authors: Yanai H , Sharar Fischler T , Goren I , Ollech J , Snir Y , Broitman Y , Barkan R , Peffer-Gik T , Raykhel B , Kutukov L , Friedeberg A , Pauker M , Eran-Banai H , Avni-Biron I , Dotan I
Published: January 2022

Background

There are sparse data regarding the effectiveness of novel treatment strategies for newly diagnosed patients with Crohn’s disease (CD). Data from clinical trials demonstrate 30–40% remission rates after 1-year. We aim to assess remission rates among newly diagnosed patients with CD in a referral center.

Methods

A prospective observational cohort study of patients with newly diagnosed CD between 03/2018- 01/2021. Patients were scheduled for semi-annual visits for assessment, data collection, and education by an IBD-oriented gastroenterologist who determined a treatment plan, IBD nurse, and dietitian. Disease activity was determined by Crohn’s disease activity index (CDAI). Clinical remission (CR) at 1-year-period (9–18 months) was defined as: CDAI < 150, no active perianal disease, and steroid-free> 3 months. Biochemical remission: C-reactive protein (CRP)<1mg/dl, fecal calprotectin (FC)<150 ug/g and normal albumin levels. Endoscopic remission: SES-CD<3. Deep remission: composite of clinical, biochemical, and endoscopic remission. Predictors for clinical remission were assessed by multivariable logistic regression.

Results

Out of 110 enrollees, 77 completed 1-year period: 50.6% female, median age 27 years (22–38), median BMI 22 kg/m2 (20–25), 16.9% smokers. At diagnosis 72.7% had an inflammatory phenotype (B1), and 26% had complex perianal disease, 55.8% had moderate-severe CD (CDAI>220). During the first year after diagnosis 59.7% were treated with a biologic (58.5% anti-TNF, 1.3% ustekinumab, 3.9%>1 biologic), diagnosis-biologic interval 4.3 months (IQR:2.6–7.3), and 9.1% required surgery. At 1-year-period 63.6% achieved CR (comparable CR rates in patients recruited with mild-moderate vs moderate-severe CD:61.8% vs 65.1%, p= 0.814). Biochemical, endoscopic and deep remission rates: 51.9% (40/77), 44.4% (24/54), and 25.9% (14/54), respectively. Significant decrease in clinical and biochemical activity during follow up: median CDAI 233 (IQR:143–286) to 83 (IQR:29–150); median CRP 1.8 mg/dl (IQR:0.4–4.1) to 0.2 (IQR:0.1–1); median FC 714 ug/g (IQR:128–1538) to 114 (IQR:18–355); all p<0.001. Paired endoscopic data, available for 54 patients, demonstrated decrease in median SES-CD from 8 (IQR:5–11) to 3 (IQR:0–5), p<0.001. Short IBDQ score increased from a median of 43 (IQR:36–55) to 56 (IQR:42–61). B1/P0 phenotype and lower BMI at diagnosis were associated with higher probability to achieve CR (OR 3.37, 95% CI, 1.08–10.46; p=0.036, and 1.2, 95% CI, 1.37-1.05; p=0.06, respectively).

Conclusion

In a cohort of patients with newly diagnosed CD treated by a multidisciplinary team, there were favorable 1-year outcomes; specifically, CR demonstrated in >60%.
P122 Low Risk of new dysplastic lesions during inflammatory bowel disease surveillance with dye-cromoendoscopy: a multicenter population-based retrospective study
Authors: Saiz Chumillas R M , Alba L , Gonzalez-Lama Y , Velayos B , Suarez P , Maroto-Martin C , Nuñez A , Hernandez L , Relea L , Fernandez-Salazar L , Sierra-Ausin M , Barrio J , Muñoz F , Arias L , Sicilia B
Published: January 2022

Background

The 21st century has witnessed advances in endoscopic surveillance technology such as high-definition imaging and virtual or dye-based chromoendoscopy, which have led to increased detection of dysplasia. It is unknown the rates of new dysplastic lesions or cancer progression with these techniques though it seems lower than previously described.

Methods

We developed a multicenter, population-based and retrospective cohort from 7 Spanish hospitals from the Group of Inflammatory bowel disease of Castilla Y Leon (GEICYL) including sequentially all patients with inflammatory bowel disease and colonic dysplastic lesions completely resected (R0) in surveillance with dye-based indigo carmine chromoendoscopy between January 2013 and December 2019, with a minimum endoscopic follow-up of 12 months. The aim was to evaluate the risk of developing more advanced metachronous neoplasia during follow-up, analysing possible associated risk factors.

Results

A total of 99 patients and 148 index lesions (145 low-grade dysplasias [LGD] and 3 high-grade dysplasias [HGD]) with a medium follow-up of 48.76 months (IQR: 36.34 – 67.15) were included. Patients and IBD baseline characteristics are reflected in table 1. During follow-up, 37 patients developed 97 new dysplastic lesions (92 LGD, 4 HGD and 1 CRC) and 1 patient developed multifocal invisible dysplasia (3 HGD). The overall incidence rate for new dysplastic lesions was 0.23 per 100 patient-year, 1.15 per 100 patients at 5 years and 2.29 per 100 patients at 10 years (Figure 1). Personal history of dysplasia was associated with higher risk of developing any grade of dysplasia during follow-up (p 0.025), meanwhile, left colon lesions was associated with a lower risk (p 0.043). 6 patients developed more advanced lesions (5 patients HGD and 1 CCR) with an incidence rate at year and 10 years of 1% and 14% respectively; LGD lesion >1cm was a risk factor for developing HGD or CRC (p 0.041), meanwhile LGD lesion < 1 cm was a protective factor (p 0.013) (table 2,3). 1/8 patients (13%) with HGD lesions developed CRC during follow-up. 3 patients were colectomized (2 by HGD and 1 by CRC). Neither mesalamine treatment or immunosuppressive or biological treatment were associated with a lower risk of dysplasia development.

Conclusion

Risk of dysplasia progression to advanced neoplasia and specifically risk of new neoplastic lesions after endoscopic resection of colitis-associated dysplasia are very low in our cohort with dye-chromoendoscopy. Personal history of dysplasia, as risk factor, and left colon location, as protective factor, were associated with new dysplastic lesions. Finally, size above 1 cm was the only risk factor for progression to advanced lesions.
P124 Views of patients with Inflammatory Bowel Disease on their care during COVID-19 pandemic
Authors: Klimova K , Ajaz I , Padilla Suarez C
Published: January 2022

Background

Patients with inflammatory bowel disease (IBD) have experienced changes to their usual management during the COVID-19 pandemic. We organised an anonymous survey to obtain their perspective on what impact COVID-19 had on their disease and care.

Methods

115 patients with IBD followed up in our clinics between August and October 2021 were sent a questionnaire with multiple choice questions as well as free comment sections which enabled patients to develop their answers in more detail. 53 patients returned the questionnaire until now.

Results

There were no statistically significant differences in descriptive characteristics – 52.8% patients were men, mean age was 53.1 years (range 18–85). 52.8% patients had Crohn’s disease. Overall, 38/53 were satisfied with services provided during the pandemic and similarly, 39/53 patients reported that they were happy or very happy with the use of virtual clinics. Overall, it was surprising that 56.6% patients felt that the pandemic had no impact on their disease. Nevertheless, 20.8% experienced delay in clinic appointments, 18.9% felt uncertainty about their diagnosis and 15.1% felt programmed investigations were postponed. 41 patients had a flare and 24/41 used our Helpline to obtain advice. Only one patient reported negative experience. In the free comment section, most messages were appraising the IBD team and Helpline as a useful way of keeping in touch and receiving advice. Patient 45 wrote: “I contact the team via email and am always responded to quickly.”

Most patients had positive views about virtual clinics, finding them easy and straightforward (31/53), with the advantage of not having to commute to hospital (28/53) and receiving good communication (26/53). 7/53 described virtual clinics as negative, rushed (8/53) and found it difficult to communicate (2/53). In the free comment section, many patients felt that “… there is no real substitute for a face-to-face consultation.” (patient 34) Nevertheless, in the future, 28.3% patients would like to continue with face-to-face appointments, 17.0% would be happy to continue with virtual clinics. The rest was happy with both options.

27/53 patients were able to have regular blood tests with their GP, the rest used hospital or associated services. 26/53 obtained their new medications directly from hospital, 7/53 were able to contact their GP. 18 patients did not require any new medications and continued with their regular prescription.

All patients have received vaccination against COVID-19.

Conclusion

Most of our patients were happy with the services provided during COVID-19 pandemic and felt that the pandemic had not had a significant impact on their disease.

(Note: this project is ongoing and will continue in November 21).
P126 The predictive value of the modified Rutgeerts score at index endoscopy after primary ileocolic resection in patients with Crohn’s disease for the risk of re-resection and severe endoscopic inflammation after long-term follow-up
Authors: Bak M , van Ruler O , Bodelier A , Dijkstra G , Romberg-Camps M , de Boer N , Hoentjen F , Stassen L , van der Meulen – de Jong A , West R , van der Woude C J , de Vries A
Published: January 2022

Background

The modified Rutgeerts score (mRS) differentiates i2 into lesions confined to the anastomosis (i2a) vs. ileal lesions (i2b), and is considered appropriate to assess postoperative recurrence in Crohn’s disease (CD) patients. This study aimed to assess the predictive value of mRS at index endoscopy after primary ileocolic resection for the risk of re-resection and severe endoscopic inflammation after long-term follow-up. In addition, we aimed to predict the association of i2a and i2b for both outcomes.

Methods

Data of CD patients who underwent a ICR, between 2000 – 2019, were retrospectively collected from a national, multicenter database. Patients were eligible for inclusion if ≥1 postoperative endoscopy assessed with the mRS was available. Primary outcome was re-resection per mRS (i0-i4) at index (i.e. first postoperative) endoscopy. Secondary outcome was severe endoscopic inflammation (defined as i3-i4) for a subset of patients (mRS i0-i2b). Rates for both outcomes were compared in subgroups (i0-i1, i2a-i2b, i3-i4) by Kaplan-Meier analyses. Multivariable analysis was conducted to identify risk factors for both outcomes.

Results

In total, 638 patients were included. Index endoscopy was performed at median 8.5 months (IQR: 5.9 – 22.8) after ICR(Table 1), with a mRS of i0(30.4%), i1(17.7%), i2a(15.8%), i2b(19.6%), i3(9.6%) and i4(6.9%). After a mean follow up of 6.5 years (SD: 4.7), re-resection rate (Figure 1) was 7.2% for patients with a mRS of i0, 6.2%(i1), 14.9%(i2a), 18.4%(i2b), 22.9%(i3) and 47.7%(i4). Re-resection rates in the subgroups were significantly higher in the group with a mRS i2a-i2b (16.8%) vs. i0-i1 (6.8%) (log-rank test, p<0.001) and in i3-i4 (33.3%) vs. i2a-i2b (16.8%)(log-rank test, p=0.006). Follow-up endoscopy was performed in 54.0% of the patients with mRS i0-i2b at median interval of 20.4 months (IQR: 10.9 – 37.7). Progression to severe endoscopic recurrence was observed in 19.8% of patients with i0, 33.9%(i1), 25.4%(i2a) and 33.8%(i2b) (Figure 2), but no significant difference was observed between subgroups i0-i1 vs. i2a-i2b (respectively 24.7% vs. 30.2%)(log-rank test, p=0.134). In multivariable analysis, anastomotic lesions (i2a) are not statistically significant associated with re-resection and progression to i3-i4 (Table 2).

Conclusion

After primary ICR, the ascending order of the mRS corresponds with an increasing long-term risk of re-resection. In multivariable analysis, anastomotic lesions (i2a) are not significantly associated with the risk of re-resection and progression to severe endoscopic inflammation, in contrast to i2b lesions. The influence of therapeutic decisions on these associations requires further investigation.
P138 Psychometric validation and interpretation of a patient-reported outcomes instrument to assess bowel urgency among adults with moderate to severe Ulcerative Colitis
Authors: Dubinsky M C , Delbecque L , Lewis J , Hunter T , Shan M
Published: January 2022

Background

Urgency, the sudden or immediate need for a bowel movement, is one of the most bothersome symptoms experienced by Ulcerative Colitis (UC) patients. We aimed to evaluate the psychometric properties of the Urgency Numeric Rating Scale (UNRS), inform the clinically meaningful within-patient change (MWPC) threshold and determine the UNRS threshold associated with clinical, endoscopic and histologic remission.

Methods

In this study, the UNRS was collected daily through an electronic diary that measures the severity of the urgency to have a bowel movement in the past 24 hours using an 11-point NRS ranging from 0 (no urgency) to 10 (worst possible urgency). A weekly score was calculated for a 7-day period by averaging the observed entries if 4 or more observations are available. Item performance, reliability, validity, responsiveness, and score interpretation were assessed at baseline (BL) and week 12 in moderate-severe patients with UC enrolled in a multicenter, randomized, placebo-controlled Phase 3 study.

Results

The full distribution of responses was provided by patients at BL and Week 12, with no floor or ceiling effects. Test-retest reliability was strong, with intra-class correlation coefficients ranging 0.76–0.89. As expected, moderate to high correlations were seen between the UNRS and health-related quality of life measures, patient ratings of UC severity, disease change, stool frequency and rectal bleeding (establishing convergent validity), while low correlations were seen with endoscopy and histology measures (establishing discriminant validity) (Table 1). As predicted, statistically higher UNRS scores were found in patients with more severe UC compared to those with less severe UC, providing evidence of known groups validity. Findings also indicated the UNRS is responsive to changes over time. Anchor-based analyses suggested that a 3-point score reduction from BL to week 12 constitutes a MWPC (Figure 1). A UNRS score of 0, 1, or 2 best reflected urgency severity level when patients were in clinical (YI=0.36), histologic (YI=0.27), or endoscopic remission (YI=0.27) (Table 2). A UNRS score of 0 or 1 may be a more conservative endpoint to define patients with no to minimal urgency.

Conclusion

The UNRS is a valid and reliable patient-reported measure of urgency in adults with UC. A 3-point improvement is a MWPC threshold. A UNRS score of 0 or 1 is a conservative threshold that reflects clinical, endoscopic and histologic remission. These findings provide strong evidence supporting that the UNRS is appropriate for inclusion as an endpoint in clinical trials to evaluate UC treatments efficacy.