bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP18 UCEIS is associated with PRO2, partial Mayo and SCCAI remission in UC: Final results from a prospective study
Authors: Golovics P , Gonczi L , Reinglas J , Verdon C , Pundir S , Afif W , Wild G , Bitton A , Bessissow T , Lakatos P L 
Published: May 2021

Abstract

Background
Optimal management of patients with ulcerative colitis (UC) requires the accurate assessment of disease activity. Endoscopic evaluation is considered the gold standard approach, but it is invasive. We aimed to determine the operating characteristics of the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), to quantify the cut off most closely correlated with clinical remission or activity and determine agreement with the Mayo endoscopic subscore (MES), Baron score, clinical scores and biomarkers.

Methods
171 patients were included prospectively and consecutively (age: 49 (IQR: 38–61) years, duration 12 (4–19)years, 79 females (46.2%), 57.3% extensive disease, 42.7% on biologicals) at the time of the colonoscopy. Ulcerative Colitis Endoscopic Index of Severity (UCEIS) Mayo endoscopic subscore (MES), Baron scores were calculated, as well as the 2 item patient reported outcome (PRO), partial MAYO, Simple Clinical Colitis Activity Index (SCCAI). C reactive Protein (CRP) and fecal calprotectin (FCAL) was available in 83 and 45.6% of patients. 17.0% had clinical flare, treatment was escalated in 14.6% of patients. Sensitivity, specificity, PPV and NPV values were calculated, ROC analysis and K-statistics were performed.

Results
UCEIS was strongly associated to PRO2 SF (AUC:0.863), RBS (AUC:0.924), PRO2 combined (AUC:0.898), partial MAYO (AUC:0.945) and SCCAI (AUC:0.901) remission in a ROC analysis. A UCEIS of ≤3 was identified as the best cut-off to identify RBS subscore of 0, or total PRO2 remission (RBS 0 and SF ≤1), partial MAYO (≤2) and SCCAI (≤2.5) remission, while a UCEIS≥4 identified active disease frequently needing change in medical therapy.

A moderate agreement was found between UCEIS &lt;4 and MES 0 (K=0.471) or Baron 0 (K=0.414)/Baron 0–1 (K=0.353). Correlation between FCAL and UCEIS (coeff:0.701, p&lt;0.0001) was strong, while modest only with CRP (coeff:0.248, p=0.01).

Conclusion
UCEIS was strongly associated with clinical remission defined as PRO2, SF, RBS, partial Mayo or SCCAI with best agreement with RBS and partial Mayo remission. A UCEIS of ≤3 was identified as a cut-off for quiescent disease, while a UCEIS≥4 identified active disease, which can support clinical decision-making based on endoscopic findings. Agreement between UCEIS and FCAL was strong, while agreement with UCEIS and MES/Baron scores was moderate.
DOP27 The fibre fermentative capacity of the gut microbiota is diminished in children with Crohn’s Disease and it is independent of disease activity or treatment with exclusive enteral nutrition
Authors: Gkikas K , Logan M , Milling S , Ijaz U Z , Hansen R , Russell R K , Gerasimidis K 
Published: May 2021

Abstract

Background
Induction of clinical remission with exclusive enteral nutrition (EEN), has been associated with accompanying changes in the concentration of short chain fatty acids (SCFA) (a biomarker of fibre fermentation) in faeces of children with Crohn’s disease (CD) 1. Here, we assessed the fibre fermentative capacity of the gut microbiota of children with active CD in vitro, before, during and after EEN and compared with healthy children.

Methods
44 faecal samples from 14 children (female, n=7, age, median [Q1, Q3]: 14.1 [11.1, 15.1] years) with active CD were collected before, during (4 weeks) and at the end of EEN (8 weeks) and after food reintroduction (median [Q1, Q3]: 21 [16, 31] days post-EEN). All children had achieved clinical remission at the end of EEN (weighted Paediatric Crohn’s Disease Activity Index &lt;12.5). A single faecal sample was collected from 11 healthy children (female, n=4, age, median [Q1, Q3]: 12.4 [9.6, 13.0] years). 24-hour in vitro batch fermentations were performed using 4 fibre substrates (pectin, high-resistant maize starch, wheat bran and a mixture of the three). Net production of SCFA was measured with gas chromatography.

Results
Compared to healthy children, the total production of SCFA was significantly lower in children with CD, for all 4 fibre substrates, and regardless of the study timepoint (Figure 1). Net production of SCFA remained unchanged during EEN and at food reintroduction, and for all fibre substrates (Figure 1). No significant association with levels of faecal calprotectin was observed at any of the timepoints. Acetate production was significantly lower in children with CD compared to healthy children for all fibre substrates except for resistant maize starch (Figure 1). Likewise, except for pectin, production of butyrate was significantly lower in children with CD than healthy controls (Figure 1). Production of propionate did not significantly differ between any of the groups.

Legend: Production of SCFA after 24-hour in vitro fermentation of faecal samples from CD and healthy children. Asterisks indicate significant differences. A: before EEN, B: 4-week EEN, C: End of EEN, D: Food reintroduction, HC: Healthy children

Conclusion
Fibre fermentative capacity is independent of disease activity in patients with CD and remains lower compared to healthy controls. It might be unlikely that the mechanism of action of EEN is mediated by modulation of fibre fermenting bacteria.

Reference
1. Gerasimidis K, Bertz M, Hanske L, Junick J, Biskou O, Aguilera M, et al. Decline in presumptively protective gut bacterial species and metabolites are paradoxically associated with disease improvement in pediatric Crohn’s disease during enteral nutrition. Inflamm Bowel Dis. 2014;20(5):861–71.
DOP36 Non-invasive assessment of postoperative disease recurrence in Crohn’s Disease: A multicenter, prospective cohort study
Authors: Furfaro F , Zilli A , Craviotto V , Aratari A , Bezzio C , Gilardi D , D’Amico F , Saibeni S , Papi C , Peyrin-Biroulet L , Fiorino G , Danese S , Allocca M 
Published: May 2021

Abstract

Background
Prevention of postoperative recurrence is a critical goal in Crohn’s disease (CD) management.
Currently, postsurgical CD management and treatment are based on endoscopic monitoring performed within the first year after surgery. However, colonoscopy (CS) is an invasive and expensive procedure, unpleasant to patients. A non-invasive and patient friendly approach is required.

Methods
Consecutive CD patients who underwent ileo-cecal resection from July 2017 to January 2020 were prospectively enrolled in three Italian Centers and performed CS and bowel ultrasound (US) after six months from the surgery, in a blinded fashion. The patients also underwent complete clinical assessment and blood and stool samples were obtained for C-reactive protein (CRP), and fecal calprotectin (FC) measurements. The disease was considered clinically active if the Harvey–Bradshaw Index (HBI) was higher than 4. Uni- and multivariable analyses were used to assess the correlation between non-invasive parameters, including bowel US findings and FC values and endoscopic recurrence, defined by a Rutgeerts’s score (RS) &gt; 2. Sensitivity, specificity, accuracy, PPV and NPV of bowel US parameters alone and in combination with FC in assessing endoscopic recurrence were calculated.

Results
Seventy patients were enrolled, 45 patients (64%) had an endoscopic recurrence (RS &gt; 2) at 6 months. Thirteen out of 45 (29%) were symptomatic (HBI &gt; 4). Bowel wall thickness (BWT), bowel wall flow (BWF, presence of vascular signals at color Doppler), the presence of mesenteric hypertrophy, the presence of limph-nodes and FC values significantly correlated with the endoscopic recurrence (p &lt; 0.005). Independent predictors for endoscopic recurrence were BWT (for 1-mm increase: OR 2.63; 95% CI 1.136.12; p= 0.024), presence of lymph-nodes (OR 23.24; 95% CI 1.85291.15; p= 0.014) and FC &gt; 50 µg/g (OR 11.86; 95% CI 2.60–54.09; p= 0.001). Sensitivity, specificity, accuracy, PPV and NPV of bowel US and/or FC are showed in Table 1.
Table 1: Diagnostic accuracy of Bowel US and/or FC compared to CS in assessing endoscopic activity (CI 95%): per-patient analysis

Conclusion
Combined use of bowel US and FC is accurate in assessing endoscopic recurrence at 6 months in CD patients and represent a valid alternative to endoscopic assessment after surgery
DOP59 Evaluation of the efficacy of tofacitinib as maintenance therapy in patients with Ulcerative Colitis stratified by OCTAVE Sustain baseline endoscopic subscore
Authors: Lee S D , Allegretti J R , Steinwurz F , Connelly S B , Lawendy N , Paulissen J , Gecse K B 
Published: May 2021

Abstract

Background
Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib in patients (pts) with UC were evaluated in two 8-week, Phase 3 induction studies (OCTAVE Induction 1&2), a 52-week, Phase 3 maintenance study (OCTAVE Sustain), and an open-label, long-term extension study. Here, we evaluate tofacitinib efficacy in OCTAVE Sustain (NCT01458574) by baseline Mayo endoscopic subscore (ES).

Methods
Pts with an OCTAVE Sustain baseline ES of 0 or 1 were included. Proportion of pts achieving efficacy endpoints at Week 52 of OCTAVE Sustain (responders from OCTAVE Induction 1&2; tofacitinib 5 or 10 mg twice daily [BID] or placebo [PBO]) was evaluated in relation to OCTAVE Sustain baseline ES. Using logistic regression, the difference in treatment effect (tofacitinib vs PBO) between baseline ES (0 vs 1) for each efficacy endpoint was assessed. Cox proportional hazards regression was used to model the difference in treatment effect between baseline ES (0 vs 1) for time to treatment failure and loss of response.

Results
At Week 52 of OCTAVE Sustain, a numerically higher proportion of pts with a baseline ES of 0 achieved remission and endoscopic improvement vs pts with a baseline ES of 1, regardless of tofacitinib dose (Table). Logistic regression analyses showed a larger treatment effect of tofacitinib 5 mg BID at Week 52 in pts with a baseline ES of 0 vs 1 (p=0.0306) for clinical response (Table). Treatment effect of tofacitinib 10 mg BID was not significantly different between baseline ES 0 vs 1 for any endpoint (Table).
In tofacitinib 5 mg BID-treated pts, Cox proportional hazards regression showed difference in risk vs PBO to be larger in pts with a baseline ES of 0 vs 1 for treatment failure (p=0.0231) and loss of response (p=0.0209); corresponding differences for 10 mg BID-treated pts were not significant (p=0.9239 and p=0.9613, respectively).

Conclusion
In general, at Week 52 of OCTAVE Sustain, a higher proportion of tofacitinib-treated pts achieved endpoints with a baseline ES of 0 vs 1. Based on proportions, the treatment effect of tofacitinib 5 mg BID was more evident in pts with a baseline ES of 0 vs 1. This difference in treatment effect related to baseline ES was not observed with tofacitinib 10 mg BID. Baseline ES may be an important factor in predicting outcomes, and suggests that aiming for a deeper remission after induction may allow successful maintenance with tofacitinib 5 mg BID. These analyses were post hoc and limited by the small sample sizes.
OP12 Blood proteins related to immunoregulation or cellular junctions reveal distinct biological profiles associated with the risk of short-term versus mid/long-term relapse in Crohn’s Disease patients stopping infliximab
Authors: Pierre N , Huynh-Thu V A , Allez M , Bouhnik Y , Laharie D , Bourreille A , Colombel J F , Meuwis M A , Louis E 
Published: May 2021

Abstract

Background
In Crohn’s disease (CD), biologics can induce mucosal healing and stable remission. After reaching this target, treatment de-escalation could be considered but the risk of relapse needs to be estimated. Current biomarkers used to predict relapse (C-reactive protein: CRP, faecal calprotectin) offer a limited prognostic capacity. Furthermore, they only monitor inflammation while we recently highlighted various and distinct pathological processes associated with the risk of short-term (&lt;6 months) and mid/long-term (&gt;6 months) relapse in CD patients stopping infliximab. Herein, the aim of our study was to further characterise this distinction.

Methods
Serum abundance of 92 proteins were measured by proximity extension assay (immune response panel, Olink) at baseline of the STORI cohort (infliximab diScon-Tinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors, n=102). Association of markers with the risk of relapse was determined by univariable Cox model in stratified (relapse &lt;6 months or &gt;6 months) and non-stratified datasets. Study of protein characteristics and enrichment analyses were performed to find biological patterns differentiating short-term from mid/long-term relapsers. To evaluate the predictive capacity of markers, we combined them systematically by pairs (‘AND’ or ‘OR’ logical operators) and used log-rank statistics with false discovery rate (FDR) correction (Benjamini-Hochberg).

Results
The risk of mid/long-term relapse was associated with a decreased circulating level of anti-inflammatory effectors while the risk of short-term relapse was associated with an increased circulating level of pro-inflammatory effectors (Fig. 1A, 1B).
The risk associated with the downstream signalling of cytokine and pattern recognition receptors showed an opposite pattern in the short-term versus mid/long-term relapsers (Fig. 1D, 1E).
The risk of short-term relapse was characterised by a perturbed circulating level of proteins inducing tolerance and immunity in antigen presenting cells (Fig. 2A, 2B).
The risk of mid/long-term relapse was characterised by an increased circulating level of proteins promoting lymphocyte tolerance (Fig. 2D, 2E) and a decreased circulating level of cellular junction proteins (Fig. 3).
We found 1223 (short-term relapse dataset), 233 (mid/long-term relapse dataset) and 101 (non-stratified dataset) novel marker combinations with FDR&lt;0.05 and higher Z-scores than CRP and faecal calprotectin. The best combinations are showed in Fig. 4.

Conclusion
In CD patients stopping infliximab, blood proteins linked to immunoregulation or cellular junctions support the distinct profiles of short-term and mid/long-term relapsers. These proteins showed a capacity to predict the relapse.
P003 HDAC7 Controls Differentiation and Regeneration in the Intestinal Epithelium
Authors: Gerbeth L , Glauben R , Siegmund B 
Published: May 2021

Abstract

Background
The precise causes and drivers of inflammatory bowel disease (IBD) are still incompletely understood. In recent years, intensive research has shown that not only chronic activation of the immune compartment, but also the integrity of the epithelial barrier plays a central role in disease progression. Inhibitors of histone deacetylases (HDACs) are known for their anti-inflammatory effects and increasing evidence suggests them as promising therapeutics for chronic inflammatory conditions such as IBD. However, the roles of single HDACs in the intestinal epithelium, especially class II HDACs, are still scarcely investigated. In genome wide association studies, HDAC7 has been identified as a risk locus for the development of IBD. Here, we investigated the role of HDAC7 in the intestinal epithelium to evaluate its potential as a therapeutic target.

Methods
Intestinal epithelial organoids were derived from the ileum and colon of tamoxifen-inducible HDAC7 knockout mice. Hdac7 deletion of organoids was achieved in vitro by tamoxifen treatment over five consecutive days of culture. Morphological changes were monitored via microscopy and gene expression was analysed using qPCR. To examine barrier function, colon organoids were seeded as monolayers into filter inserts and transepithelial electrical resistance (TEER) was measured. Monolayer structure was verified using immunofluorescence.

Results
Hdac7 silencing in organoids of the small intestine caused a significant morphological shift to a spheroidal shape typical for an undifferentiated phenotype. Gene expression analysis revealed a dramatic downregulation of differentiation markers for all epithelial subtypes and an upregulation of stem cell markers. In colon organoids, undifferentiated HDAC7 knockout spheroids showed a significantly increased expression of goblet cell markers but displayed reduced enterocyte marker expression when subjected to differentiation medium. TEER build-up was consistently slower in colon organoid-derived monolayers after Hdac7 deletion but was higher after differentiation compared to wild type monolayers.

Conclusion
In the ileal epithelium, HDAC7 seems to play an important role in the differentiation process of all specialized epithelial subtypes while it appears to suppress mainly secretory lineages and promote differentiation into absorptive cells in the colon epithelium. These results suggest HDAC7 as an important regulator of intestinal differentiation and regeneration making it an interesting therapeutic target to treat inflammation-induced injuries in the gut.
P031 Class A1 scavenger receptor mediates macrophage polarization and apoptotic progression in a murine dextran sulfate sodium-induced colitis
Authors: Su J , Xie C , Hu Y , Huang Q , Shi H , Wang L , Ren J 
Published: May 2021

Abstract

Background
This study aimed to investigate the role of class A1 scavenger receptor (SR-A1) for regulating macrophage function and apoptotic pathway during intestinal inflammation of inflammatory bowel disease (IBD) in a DSS-induced murine colitis model.

Methods
A murine colitis model was established by feeding with 5% dextran sulfate sodium (DSS). Treatment groups were injected intravenously with SR-A1 antibody (100ug/kg), and control groups were injected with the vehicle only. Inflammatory activity and histological changes were evaluated on Day 8, and the percentage of macrophage markers in lamina propria mononuclear cells (LPMC) was measured by flow cytometer. The apoptosis and proliferation of intestinal epithelial cells were detected by TUNEL and Ki67 staining, and the expressions of related signaling pathway protein were determined with western blot.

Results
Treatment group showed a preventive effect on colitis symptoms and fewer inflammatory cell infiltrates compared with control group. After SR-A1 antibody treatment, flow cytometry of LPMC indicated that the percentage of F4/80+CD206+ Macrophages was elevated, while the percentage of F4/80+CD11c+ Macrophages was not obviously changed. Immunohistochemistry revealed that TUNEL-positive cells were significantly downregulated and Ki67- positive cells were upregulated in colonic mucosa of treatment group. In addition, the expressions of TLR4, MyD88 and NF-kB proteins in colonic mucosa were decreased after SR-A1 antibody injection.

Conclusion
Treatment with SR-A1 antibody could ameliorate macrophage-associated inflammatory response and epithelial cell apoptosis in a murine colitis model, which suggested that SR-A1 was a negative regulator of M2 polarization in IBD. SR-A1 mediated its effect by synergizing with TLR4/ MyD88 / NF-kB signaling pathway. Our research identified SR-A1 as a potential therapeutic target in IBD.
P043 Succinate receptor (SUCNR1) mediates leukocyte-endothelial cell interactions induced by TNFa
Authors: Coll S , Bauset C , Cosín-Roger J , Ortiz-Masià D , Gisbert-Ferrándiz L , Barrachina D , Calatayud S 
Published: May 2021

Abstract

Background
The Krebs cycle metabolite succinate contributes to inflammatory conditions like arthritis and colitis by activating its receptor SUCNR1. We aimed to analyze whether the succinate-SUCNR1 pathway contributes to the leukocyte-endothelial cell interactions that initiate the inflammatory response.

Methods
We evaluated leukocyte rolling and adhesion by intravital microscopy in cremaster venules of wild-type (WT) and Sucrn1−/− mice treated, 4h before, with succinate (1 Mm, intraescrotally), combined or not with the common pro-inflammatory cytokine TNFα (500 ng/mice, i.p.), or with their vehicles. We analyzed the activity of the NF-κB signaling pathway in endothelial cells (HUVEC) treated (4h) with succinate (0.5–1 mM) ± TNFα (20ng/ml), by detecting this transcription factor, its inhibitor iκBα, and their phosphorylated forms, by western blot. Results are expressed as mean±SEM (N≥6) and analyzed by ANOVA + Newman-Keuls test.

Results
In WT mice, succinate tended to induce leukocyte rolling and adhesion, and amplified the effects of TNFα on rolling. SUCNR1-deficient mice failed to increase leukocyte rolling in response to these treatments while showed an attenuated response to the effect of TNFα on leukocyte adhesion (Figure 1). Succinate treatment intensified the activation of the NF-κB pathway in HUVEC treated with TNFα, as shown by the increased IκBα phosphorylation, which allows its degradation, the reduced total IκBα, and the increased NF-κB/IκBα ratio (Figure 2).

Conclusion
Our results suggest that the endogenous release of succinate and the consequent stimulation of the SUCNR1 mediates the leukocyte-endothelial cell interactions induced by TNFα, and this pro-inflammatory activity may be related with an increased activation of the NF-κB signaling pathway in endothelial cells. Thus, the accumulation of succinate observed in various inflammatory diseases probably contributes to the initiation of the inflammatory focus by promoting the accumulation of leukocytes.

Bibliography