bluuebunny/crossref_metadata_2025_split huggingface dataset:
OP40 Analysis of clinical features associated with favourable outcomes from ustekinumab treat-to-target strategy in Crohn’s Disease patients in the STARDUST trial
Authors: Danese S , Vermeire S , Dignass A , Panés J , D’Haens G , Magro F , Le Bars M , Nazar M , Lahaye M , Ni L , Bravatà I , Gaya D R , Peyrin-Biroulet L 
Published: May 2021

Abstract

Background
The 48-week (W) interventional STARDUST trial assessed whether a treat-to-target (T2T) strategy using ustekinumab (UST) may optimize Crohn’s disease (CD) outcomes; primary efficacy and safety data have been reported before.1 Here we assessed which patient (pt) subgroups may benefit from T2T vs standard of care (SoC) in achieving endoscopic response after 1 year of UST treatment.

Methods
Adult pts with moderate–severely active CD (CD activity index [CDAI] 220–450) and Simple Endoscopic Score in CD [SES-CD] ≥3) who failed conventional therapy and/or 1 biologic were included. Pts received iv, weight-based UST ~6 mg/kg at W0 (baseline [BL]); then SC UST 90 mg at W8. At W16, CDAI 70 responders were randomized (1:1) to T2T or SoC arms. Pts in the T2T arm were assigned to SC UST q12w or q8w based on 25% improvement in SES-CD score vs BL. From W16–48, UST dose was further intensified up to q4w if the following were not met: CDAI &lt;220 and ≥70-point improvement from BL, and C-reactive protein ≤10 mg/L or faecal calprotectin (FCal) ≤250 µg/g. Pts who failed treatment target despite UST q4w were discontinued. In the SoC arm, UST dose was assigned based on EU SmPC (q12w or q8w). We report the treatment effect for the primary endpoint (endoscopic response [≥50% improvement in SES-CD score vs BL] at W48), evaluated for subgroups of pts, based on demographics at BL. For each subgroup, the odds ratio (OR) and 95% confidence interval (CI) of T2T vs SoC were provided based on the logistic regression model that included treatment arm and stratification factors (prior exposure to biologics [none or 1] and SES-CD score [≤16, &gt; 16] at BL) as independent variables.

Results
Of 500 pts enrolled, 441 were randomized to T2T (n=220) or SoC (n=221); 79.1% and 87.3% completed W48. At W48, pts randomized to T2T were more likely to achieve endoscopic response compared to SoC (p&lt;0.05), if they had at BL: (i) longer disease duration (&gt;median [79.1 months]; OR 2.2; 95%CI 1.17–3.94); (ii) clinically moderate disease (CDAI ≤300; OR 1.7; 95%CI 1.03–2.76); (iii) normal FCal (≤250; OR 3.0; 95%CI 1.22–7.56), (iv) endoscopically active CD (SES-CD ≥4 for ileal or ≥6 for colonic and/or ileocolonic disease; OR 1.8; 95%CI 1.10–2.91); and (v) history or presence of strictures/fistula or occurrence of an intra-abdominal abscess (OR 2.3; 95%CI 1.06–5.01 and OR 3.5; 95%CI 1.07–11.19, respectively; Figure 1).

Conclusion
T2T was more effective than SoC (p&lt;0.05) in achieving endoscopic response after 1 year of UST treatment in certain subgroups including pts with higher endoscopic scores at BL and those with history/presence of bowel damage.

Reference
P008 Store-operated calcium entry controls immune cell function and activation in Inflammatory Bowel Disease
Authors: Letizia M , Kaufmann U , Gerbeth L , Sand A , Brunkhorst M , Wang Y , Böttcher C , Schlickeiser S , Fernández-Zapata M C , Kunkel D , Siegmund B , Feske S , Weidinger C 
Published: May 2021

Abstract

Background
Inflammatory bowel disease (IBD) comprises ulcerative colitis (UC) and Crohn’s disease (CD), both representing major clinical challenges in need of new treatment modalities to improve patient care. Store-operated calcium entry (SOCE) is the predominant calcium influx pathway in immune cells regulating many of their functional properties. Conditional knockout mice, in which SOCE signaling components are deleted in T cells, have revealed that SOCE is required for the induction of intestinal inflammation in mouse models of colitis. However, it is currently unknown whether the pharmacologic inhibition of SOCE is a suitable drug target in IBD and it remains elusive, which immune cell subsets are affected by the pharmaceutical blockade of SOCE. Therefore, we here aimed to investigate the effects of the SOCE inhibitor BTP-2 on the function and activation of lymphocytes isolated from IBD patients.

Methods
PBMC and/or lamina propria lymphocytes (LPMC) were isolated from UC and CD patients undergoing colon resection. Cells were ex -vivo stimulated with PMA/Ionomycin in the presence or absence of increasing concentrations of BTP-2, fixed and stored at -80°C until acquisition by mass cytometry. LPMCs were stained using 37 lineage and functional markers targeting B, T, NK or myeloid cells and the resulting flow cytometry standard (FCS) files were analyzed by using cytobank and the R/Bioconductor 9 packages. Additionally, Ca2+ influx measurements were performed in order to assess the impact of SOCE inhibition on the calcium homeostasis of various immune cell subsets.

Results
Data on B, T, NK, and myeloid cells revealed that treatment with BTP-2 causes a dose-dependent inhibition of calcium influx, demonstrating that BTP-2 is a potent inhibitor of SOCE in human LPMCs and PBMCs. By applying mass cytometry, we investigated how the gradual pharmacologic inhibition of SOCE affects the activation and pro-inflammatory functions of various immune cell subsets obtained from colon specimens of patients with UC and CD, which were characterized by the accumulation of CD4+ effector T cells, IFNγ-producing CD8+ T cells and IL-17-producing innate lymphoid cells (ILCs) compared to non-inflamed specimens. Remarkably, inhibition of SOCE attenuated the production of cytokines including IL-2, IL-4, IL-6, IL-17, TNF-α and IFNγ by T cells and ILCs, reduced the activation of B cells and decreased the production of IFNγ by myeloid cells without affecting the viability of primary human epithelial cells.

Conclusion
Our data reveal for the first time that the cytokine production and the activation of several immune cell subtypes can be modulated by SOCE blockade in human intestinal inflammation, identifying SOCE as a novel therapeutic target in colitis.
P052 Comprehensive proteomic profiling of stool from UC and CD patients reveals expected and novel mucosal pathobiology, enabling identification of candidate non-invasive biomarkers to monitor mucosal disease activity
Authors: Harder B , Casavant E , McBride J , Park K T , Mathews W R , Anania V G , Lekkerkerker A 
Published: May 2021

Abstract

Background
Inflammatory bowel disease (IBD) is a multifactorial disorder characterized by chronic gastrointestinal (GI) inflammation. In clinical practice, physicians urgently need biomarkers to monitor changes in mucosal disease to manage treatment. Non-invasive tools such as fecal biomarkers could allow for frequent monitoring of mucosal disease activity and may reflect inflammation of the entire GI tract. Towards identification of novel non-invasive fecal biomarkers, we performed a comprehensive, unbiased, analysis of the human fecal proteome from ulcerative colitis (UC), Crohn’s disease (CD) patients, and healthy controls (HC), focusing on human secreted proteins using proteomic approaches.

Methods
Fecal extraction processes optimized for recovery of secreted proteins were applied to stool samples of mild to severe UC and CD patients and HCs, 20 samples per group. An unbiased survey of the human fecal proteome of the IBD and HC stool extracts was performed using both data-dependent acquisition and data-independent acquisition methods on QExactive HF and Fusion Lumos mass spectrometers. Data were analyzed in Spectronaut for peptide identification, followed by analysis in MS Stats for protein quantification. Fecal calprotectin (fCAL) levels were measured in these stool samples using the Buhlmann EK-CAL immunoassay kit to correlate fCAL levels to proteomic calprotectin (S100A8/S100A9 heterodimer).

Results
We identified and quantified 594 differentially expressed proteins in stool using proteomics, including known proteins perturbed in IBD pathobiology. Elevated levels of neutrophilic proteins, e.g. fCal, neutrophil elastase, lactoferrin and leucine-rich Α-2 glycoprotein 1 were detected as well as proteins linked to rectal bleeding and ulceration e.g. hemoglobin subunit alpha 1 and beta. Pancreatic enzymes, suggested to be associated with active disease, were also detected. Overall, UC and CD contained many proteins not detected in HC. Differential abundances were observed between UC and CD patients, possibly reflecting differences in mucosal pathophysiology. The abundance of proteomic calprotectin correlated highly with the fCAL levels as determined by immunoassay (Spearman rank order &gt; 0.9 for S100A8 and S100A9 to fCAL), validating the fecal proteomic approach to uncover known and novel proteins of IBD biology.

Conclusion
We developed and qualified methods to perform fecal proteomics on IBD stool samples, enabling identification of known and novel proteins of mucosal UC and CD disease biology. In depth analysis of these proteomic datasets may reveal novel fecal biomarker candidates, targeted to reflect mucosal disease activity and potentially serve as non-invasive surrogates for endoscopy and help guide treatment in IBD patients.
P056 Crohn’s Disease associated fibrosis modulates the expression of collagen receptors
Authors: Coll S , Bauset C , Cosín-Roger J , Ortiz-Masià D , Gisbert-Ferrándiz L , Navarro-Vicente F , Barrachina D , Calatayud S 
Published: May 2021

Abstract

Background
Crohn’s Disease (CD) patients often develop stenotic complications as immunomodulatory treatments do not prevent the fibrogenic response in the affected tissues, where a dysregulated activation of stromal cells provokes an excessive deposition of extracellular matrix (ECM). Recent evidences support the notion that local cells can sense the consequent alterations in tissue structure and rigidity through receptors that respond to some ECM components, and this may perpetuate the fibrogenic process even in the absence of inflammation. We aim to analyse the relevance of these signalling pathways in the fibrotic process associated to CD.

Methods
We obtained fibrotic ileal tissues from CD patients and healthy ileal samples from colon carcinoma patients (control), and analysed the expression (RT-PCR, IHQ) of collagen receptors (integrins, discoidin domain receptors/DDR) and of markers for some stromal cells (fibroblasts, endothelial cells). The relationship between these sets of data was analysed by Pearson’s correlation and the results organized as a correlation matrix. The expression of collagen receptors was also analysed in endothelial cells (HUVEC) treated with TGFβ 2 (1ng/ml, 48h).

Results
Ileal samples from CD patients present a differential gene expression of collagen receptors (Fig 1), with increased levels of ITGA10, ITGA11 and DDR2, and reduced expression of DDR1. In CD tissues, the expression of ITGA11 and DDR1 showed a significant correlation, positive and negative respectively, with that of endothelial markers (Fig 2). These correlations do not occur in control tissues.

Integrin-α11 was detected in endothelial cells of submucosal vessels (IHQ). In HUVEC, TGFβ 2 increased the expression of ITGA11 (8.1±0.7 fold induction, p&lt;0.01) and reduced that of DDR1 (0.74±0.06 fold induction, p&lt;0.01), without affecting that of the other collagen receptors.

Conclusion
Intestinal tissues from CD patients affected by fibrosis present an altered pattern of expression of collagen receptors, which suggests a regulatory role of the ECM in the fibrotic response, while the correlation analysis and the changes induced by the fibrotic cytokine TGFβ in endothelial cells insinuates a particular relevance of these stromal cells in this process.
P058 Proteomic analysis-based discovery of a novel biomarker that differentiates intestinal Behçet’s disease from Crohn’s disease
Authors: Park J , Daeun J , Youn Wook C , Jae Hee C , Ji-Hwan R 
Published: May 2021

Abstract

Background
Intestinal Behçet’s disease (BD) and Crohn’s disease (CD) present similar manifestations, but there are no specific pathognomonic clinical, laboratory, or histological diagnostic tests to differentiate intestinal BD from CD. We used a proteomic approach to discover a novel diagnostic biomarker specific to intestinal BD.

Methods
The colon mucosa tissue samples were obtained using colonoscopy-guided biopsy of the affected bowel from patients with intestinal BD or CD at the Inflammatory Bowel Disease Clinic of Severance Hospital, Seoul, Korea. Peptides from seven intestinal BD and seven CD patients were extracted and labeled using tandem mass tag (TMT) reagents. The labeled peptides were identified and quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The differentially expressed proteins were further validated using immunohistochemical (IHC) analysis with tissue samples and an ELISA test with serum samples from 20 intestinal BD and 20 CD patients.

Results
A total of 3,266 proteins were identified using TMT/LC-MS/MS-based proteomic quantification, including 39 candidate proteins differentially expressed between intestinal BD and CD. Beta-2 glycoprotein 1 (APOH) and maltase-glucoamylase (MGAM) showed significantly higher intensity in the IHC staining of the intestinal BD tissues than that of CD tissues. Furthermore, the serum MGAM level was significantly higher in patients with intestinal BD than in patients with CD.

Conclusion
Our proteomic analysis revealed that some proteins were differentially expressed in intestinal BD patients compared to CD patients. Differential MGAM expression in intestinal BD suggests its role as a potential novel diagnostic biomarker in the differentiation of intestinal BD from CD.
P060 A2B adenosine receptor deficiency ameliorates chronic murine Crohn’s-like-ileitis
Authors: O Connell L , Olli K , Wilkinson C , Collins C , Jedlicka P , Aherne C 
Published: May 2021

Abstract

Background
The A2B adenosine receptor (Adora2b) has been demonstrated to play an immunomodulatory and epithelial barrier protective role in acute murine colitis. A2B agonist treatment during acute murine colitis has been demonstrated to decrease colonic inflammation and damage suggesting targeting the A2B adenosine receptor may protect the intestinal barrier in acute intestinal inflammation. Crohn’s disease (CD) is associated with chronic inflammation and damage in the small intestine, most often the ileum. To date the role, if any, of the A2B adenosine receptor in the small intestine and in CD is unknown.

Methods
The TNFΔARE model of Crohn’s-like ileitis was used to investigate a possible role for A2B in small intestinal inflammation. TNFΔARE mice develop discontinuous, transmural inflammation in the distal ileum that progresses with age and is representative of the chronic inflammation observed in CD. Whole body A2B receptor deficient (Adora2b -/-) mice were crossed on to the TNFΔARE background to generate TNFΔARE mice deficient in the A2B adenosine receptor (Adora2b -/-/TNFΔARE+/-). Whole ileum was harvested from Adora2b -/-/TNFΔARE+/- and wildtype TNFΔARE mice for histological analysis during early (6–8 weeks), active (10–12 weeks) and chronic disease (&gt;20 weeks). Histological scoring was performed by a board-certified pathologist blinded to the study. Whole tissue was also harvested for digestion to perform live cell counts and cytokine analysis.

Results
Histological analysis revealed no significant difference between wildtype and Adora2b deficient TNFΔARE mice during early or active disease. However, during chronic disease Adora2b -/-/TNFΔARE+/- histological scores for active inflammation, chronic inflammation and degree of tissue damage were significantly reduced (approximately 25%) compared to wildtype TNFΔARE mice. This dramatic improvement in histological tissue health in mice with chronic disease was accompanied by an approximately 50% reduction in live cell counts in the ileum of Adora2b -/-/TNFΔARE+/- mice compared to wildtype TNFΔARE mice with a corresponding reduction in pro-inflammatory mediators CXCL1 and IL-1β

Conclusion
Our findings demonstrate that sustained loss of A2B receptor expression improves the outcome of chronic small intestinal inflammation. Previous studies demonstrate that A2B receptor expression promotes pro-fibrotic responses in chronic lung fibrosis. Our future studies will address the possible functional role of A2B in pro-fibrotic responses associated with chronic intestinal inflammation.
P094 Textbook outcome in Inflammatory Bowel Disease surgery
Authors: Burneikis D , Liska D , Lipman J , Valente M , Gorgun E , Kessler H , Hull T , Sklow B , Steele S , Lightner A , Holubar S 
Published: May 2021

Abstract

Background
Textbook outcome (TO) is a composite measure of quality representing the most ideal result that can be expected from a surgical encounter. TOs for hepatobiliary, bariatric and thoracic procedures have been described in the literature. The purpose of this study was to define and to benchmark the rates of TO for common procedures in patients with Inflammatory Bowel Disease (IBD).

Methods
The American College of Surgeons National Surgical Quality Improvement Project (NSQIP) participant user files (PUF) from 2011 to 2019 were examined. Adults undergoing surgery for Crohn’s disease or ulcerative colitis were included. Four index procedures were selected for the study using Current Procedural Terminology (CPT) codes: ileocolic resection (ICR), diverting loop ileostomy closure (DLIC), total abdominal colectomy (TAC), and ileal pouch construction (IPAA). Four criteria had to be satisfied completely to achieve TO: 1) no 30-day complications, 2) no unplanned return to operating room, 3) no 30-day readmission, and 4) length of hospital stay (LOS) less than or equal to a predetermined threshold for each procedure. The LOS thresholds were derived by surveying 12 colorectal surgeons at our institution about the ideal length of stay for each of index procedure. Relevant preoperative variables collected in the NSQIP PUF were analyzed with multivariable logistic regression to identify potential predictors of TO for each procedure.

Results
The study included 15,261 distinct surgical encounters containing 6,862 ICR, 1,149 DLIC, 3,835 TAC and 3,415 IPAA. The survey mean ideal LOS for each procedure was 3 days for ICR, 2 days for DLIC, 4 days for TAC, and 4 days for IPAA. Using the above definition, TO was achieved in 29% of ICR, 20% of DLIC, 46% of TAC, and 35% of IPAA. The rate of achieving TO increased over time for all four procedures studied (Figure 1). Multivariable logistic regression identified several unique positive and negative predictors of achieving TO. For ICR, male sex and ASA class 4 were significant negative predictors of TO (OR 0.73 [0.66–0.82] and 0.23 [0.07–0.86] respectively); while for TAC, older age and presence of wound infection [DL3] made TO less likely (OR 0.51 [0.35–0.75] and 0.45 [0.23–0.88] respectively); for IPAA, laparoscopic approach made TO much more likely [DL4] (OR 2.0; [1.62–2.46]). We identified no statistically significant predictors of TO for DLIC. Satisfying the LOS threshold was the greatest determinant of achieving TO for all four procedures studied.

Conclusion
In this study, we present the rates of TO for the four most common IBD operations as captured in NSQIP. TO has the advantage of being easy to interpret and can be followed over time to benchmark individual and institutional performance.
P121 The study of the hypercoagulable state in Crohn disease: Results of a prospective comparative study
Authors: Serghini M , Ben Youssef H , Laabidi A , Ben Mustapha N , Hafi M , Fekih M , Boubaker J 
Published: May 2021

Abstract

Background
The risk of thrombosis is increased in Crohn disease (CD). Abnormalities in hemostasis during CD have been evaluated in several studies but the results remain controversial. The thrombin generation assay (TGA) provides an overall assessment of hemostasis compared to traditional tests. The purpose of this work was to study the hypercoagulable state in patients with CD through TGA and to correlate it with the clinical and biological status of the disease.

Methods
This was a prospective comparative study, collating 50 patients diagnosed with CD and compared to 50 matched controls according with age and sex, between May 2016 and January 2020. TGA was effectuated in both groups. Data related to CD were collected. Parameters of lag time (min), time to peak (min), peak (nM), endogenous thrombin potential (ETP in nM.min) and velocity index (VI in nM/min) were analyzed. Laboratory parameters of inflammation, factor VIII and anti-coagulant factors were evaluated in patients.

Results
Median age of patients was 44.02 years (29 men and 21 women). The proportion of patients in remission was 66%. The mean levels of FVIII (285.1±175.2 vs 133.8±41.9; p=0.001), ProteinC (117±22.8 vs 103.2±13.6; p=0.003) and Antithrombin (97.1±16.9 vs 80.65±13.2; p=0.001) were significantly higher in patients with CD compared to controls. No significant difference was found for the rates of ProteinS. Thrombin generation was faster in patients with CD compared to controls (IV: 163.9±41.9 vs 138.2±67.4; p=0.04) and in cases of fistulizing or stenosing phenotype compared to the inflammatory phenotype. Thrombin generation was higher in patients: hospitalized compared to those seen as outpatients (ETP: 1515±406.6 vs 1248.2 + 380.8; p=0.05), treated with corticosteroids (ETP=1718.7 + 126.9) compared to the rest of the patients (p=0.03), with CRP&gt; 6 mg/L compared to those with normal CRP (ETP= 1515 + 384.8 vs 1245 + 348.2) (p=0.02) and with hyperfibrinogenemia level compared to those with normal fibrinogen (Peak = 351.6±74.1 vs 294.9 ±64.4) (p= 0.03). A significant positive correlation was noted between the parameters of TGT, CRP and fibrinogen. ETP value was significantly correlated with CRP (r=0.45; p=0.001) and fibrinogen (r=0.35; p=0.02). This allowed us to determine two biological scores correlating ETP and CRP (ETP=1384 + 2.9 x CRP), as well as fibrinogen level (ETP=1060.7 + 130.5 x Fibrinogen)

Conclusion
Thrombin generation appears to be more accelerated in patients with CD than in controls. This hypercoagulability is associated with hospitalization, stenosing and fistulizing phenotypes, elevated CRP and fibrinogen and corticosteroid therapy. The determination of ETP from CRP and fibrinogen would be a valuable tool for assessing the state of coagulability in these patients.