bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP15 Transmural healing with vedolizumab in patients with active Crohn’s disease
Authors: Rimola J , Colombel J F , Bressler B , Adsul S , Siegelman J , Cole P E , Lindner D , Danese S 
Published: January 2020

Abstract

Background
VERSIFY, an open-label phase 3b study of vedolizumab (NCT02425111; EudraCT 2014-003509-13), demonstrated endoscopic mucosal healing in patients with Crohn’s disease (CD).1 An exploratory analysis of a subset of these patients who underwent magnetic resonance enterography (MREn) also demonstrated healing.1 Further exploratory analysis of MREn imaging features of transmurality in patients treated with vedolizumab is reported herein.

Methods
In VERSIFY, patients treated with intravenous vedolizumab (300 mg) on Day 1, Weeks 2 and 6, and then every 8 weeks for 26 or 52 weeks were imaged at screening, Week 26, and Week 52, with images assessed centrally.1 All patients with disease detectable by MREn at screening (≥1 ileocolonic segment with a segmental magnetic resonance index of activity [MaRIA] score ≥7) who completed 26 or 52 weeks of treatment and had evaluable segments at all MREn timepoints were included in this analysis. Ileocolonic segments with a MaRIA score ≥7 at baseline were evaluated for improvement of oedema and bowel wall thickness. Further exploratory assessment of mesenteric fluid and lymph nodes are ongoing.

Results
Week 26 analyses included 27 patients with a total of 83 ileocolonic segments; Week 52 analyses included 13 patients with a total of 38 segments. Week 26 and Week 52 patient populations had baseline mean (standard deviation [SD]) simplified endoscopic activity scores for CD (SES-CD) of 15.7 (7.7) and 16.5 (7.8) and Crohn’s disease activity index (CDAI) scores of 301 (61) and 297 (79), respectively. The proportion of segments with oedema or wall thickness &gt;3 mm decreased from baseline to Week 26 and to Week 52 (Figure 1). All segments evaluated had wall thickness &gt;3 mm at baseline. The proportion of patients with oedema or wall thickness &gt;3 mm in ≥1 evaluated segment decreased from baseline to Week 26 and/or Week 52 (Figure 2). In the Week 26 population, 2/27 (7.4%) patients had no oedema with wall thickness &lt;3 mm at Week 26 in segments that had MaRIA ≥7 at baseline. In the Week 52 population, 1/13 (7.7%) patients at Week 26 and 3/13 (23.1%) at Week 52 had no oedema with wall thickness &lt;3 mm in segments that had MaRIA ≥7 at baseline.

Conclusion
Vedolizumab treatment of patients with CD reduced the number of ileocolonic segments with transmural inflammation (oedema, wall thickness &gt;3 mm) as detected by MREn and the overall number of patients with transmural inflammation from baseline at treatment Weeks 26 and 52. This exploratory analysis contributes to the understanding of transmural disease processes in CD and the impact of vedolizumab on components of transmural inflammation in CD.

Reference
DOP17 Identification of biomarkers and mechanistic insight for upadacitinib in ulcerative colitis: Analysis of serum inflammatory mediators in the phase 2b U-ACHIEVE study
Authors: Vermeire S , Guay H , Verstockt B , Fann J , Cheng J , Hong F , Lee W J , Lacerda A , Zhou W , Danese S 
Published: January 2020

Abstract

Background
The U-ACHIEVE trial evaluated upadacitinib (UPA), an oral JAK1 selective inhibitor, in patients with moderately to severely active ulcerative colitis (UC). Patient-reported and endoscopic outcomes improved after UPA treatment. This analysis used pharmacodynamic profiling to link changes in serum biomarkers to changes in UC disease activity, and to assess the UPA mechanism of action in UC.

Methods
U-ACHIEVE (NCT02819635) was a randomised, double-blind, placebo (PBO)-controlled phase 2b clinical trial. Adults with an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants, or biologic therapies were randomised to receive 7.5, 15, 30, or 45 mg UPA once daily or PBO for 8 weeks (weeks). Serum samples (baseline [BL], weeks 2, 4, and 8) were analysed by OLINK® inflammation panel (92 proteins) and by Singulex immunoassay for interleukin-1b (IL-1b), IL-17A, IL-17F, and IL-22. Protein-level changes were analysed by a mixed-effect model; BL protein level was adjusted as a covariate; treatment group, time point, and their interaction were included as fixed effects. Spearman rank-correlation coefficients were used to determine the relationship between changes of serum biomarker levels and improvements in adapted Mayo scores and endoscopic subscores. Multiplicity adjusted P values were calculated using 1000 runs of random permutations.

Results
Paired BL and week 8 serum samples were available from 114 patients (PBO, n = 17; UPA 7.5 mg, n = 21; UPA 15 mg, n = 21; UPA 30 mg, n = 29; UPA 45 mg, n = 26). UPA treatment reduced expression of pro-inflammatory mediators associated with immune cell migration, type I/II IFN responses, T-cell responses, macrophage and dendritic cell activity and increased expression of biomarkers associated with haematopoiesis, neuroprotection and mucosal repair in a dose-dependent manner. Improvements in adapted Mayo score, endoscopic subscore, and stool frequency correlated with increases in CX3CL1, DNER and FLt3L (p &lt; 0.05 for all). Endoscopic improvements correlated with reductions in OSM, and improvements in fatigue correlated with increases in CCL25 and NT-3. There was a substantial overlap in biomarkers modulated by UPA in patients with UC and Crohn’s disease (Figure).

Conclusion
UPA modulated expression of serum pro-inflammatory mediators found in pathways associated with the pathogenesis of UC, including immune cell migration, type I/II IFN responses, T-cell responses, macrophage and dendritic cell activity, haematopoiesis, neuroprotection, and mucosal repair. Consistent correlations were observed between changes in biomarker expression and improvements in disease activity and symptoms of UC.
DOP19 Real-world healthcare resource utilisation among patients with inflammatory bowel disease administered vedolizumab for 6 months
Authors: Cohen B , Chang H , Jason Rogers J R , Garg S , Lawrence D , Fasihuddin F , Lissoos T , Atreja A 
Published: January 2020

Abstract

Background
Inflammatory bowel disease (IBD) is associated with high healthcare resource utilisation. Vedolizumab (VDZ) is a gut-selective monoclonal antibody that binds the α4β7 integrin and is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD). We investigated real-world healthcare resource utilisation for these patients in the 6 months after initiating VDZ treatment.

Methods
This retrospective, non-interventional, cohort study examined healthcare resource utilisation for adults with IBD treated with VDZ at Mt Sinai Medical Center (New York, NY) between June 1, 2014, and May 31, 2019. IBD-related healthcare resource utilisation (emergency room [ER] visits, hospitalisations, procedures, corticosteroids) and VDZ treatment patterns (induction, persistence, adherence) were assessed for 6 months after first VDZ infusion. Discontinuation was defined as a ≥90-day gap between infusions or stopping VDZ treatment &lt;6 months after the first infusion. Patients who had ≥90-day gaps were not counted as discontinuing if they experienced clinical benefit that continued beyond the 6-month period.

Results
880 patients treated with VDZ were assessed. Mean age was 39.6 years; 51.6% of patients were female. 369 (41.9%) and 504 (57.3%) patients were diagnosed with CD and UC, respectively. 81.4% of patients received 3 VDZ induction doses by Day 98; 69.0% received 4 doses by Day 120. The rates of ER visits, hospitalisations and elective surgical or urgent hospitalisations and procedures among VDZ-treated patients were &lt;1 per 100 pt–months. Steroids (oral or IV) were prescribed to 42.2% of patients during the 6-month period. In the 2 months after their last infusion, 81.6% of patients who received ≥3 VDZ doses were steroid-free. Timing of the last infusion was variable. Overall VDZ persistence was 68.0% (65.0% and 70.2% for CD and UC, respectively; Figure). Most patients (67.2%) had ≥80% of days covered in a 180-day period

Conclusion
At a tertiary IBD centre, VDZ was associated with low healthcare resource utilisation during the first 6 months of treatment. More than two-thirds of patients persisted with treatment, with most being steroid-free at last follow-up.
DOP25 Medication use and comorbidities among elderly when compared with younger patients with inflammatory bowel disease in the TARGET-IBD cohort
Authors: Barnes E , Hanson J , Regueiro M , Saha S , Sands B E , Rubin D , Dubinsky M , Siegel C , Gazis D , Crawford J , Long M 
Published: January 2020

Abstract

Background
When compared with younger patients, much less is known regarding inflammatory bowel disease (IBD)-related medications in the elderly (&gt;65 years) patients. This analysis uses a large cohort of patients with IBD to describe the distribution of patient characteristics and patterns of medication use.

Methods
TARGET-IBD is a longitudinal cohort of patients with IBD receiving usual care at community and academic practices in the US. Patients with IBD enrolled between July 2017 and May 2019 were included in this analysis. The prevalence of medication use by drug class at the time of enrolment among patients with both ulcerative colitis (UC) and Crohn’s disease (CD) was estimated. Age was stratified into the following categories: &lt;30, 30–49, 50–65 and &gt;65 years. Proportions and means of patient characteristics were compared using tests of association. The odds of biologic use at enrolment was modelled as was the 95% CI by patient characteristics using logistics regression.

Results
681 patients with UC and 979 patients with CD were included in the analysis. At enrolment, mesalamine was the most common medication used among patients with CD &gt;65 years (34%) and among patients with UC across all age categories (58%–77%, Table 1). The use of mesalamine generally increased with advancing age. Patients with CD &gt;65 years were more than twice as likely to be users of mesalamine at enrolment than patients &lt;30 years (p &lt; 0.0001). Among patients with either disease type, anti-tumour necrosis factor α (anti-TNF) use decreased in patients &gt;65 years compared with patients &lt;30 years. Thiopurine use did not vary across age categories. Among patients &gt;65 at enrolment, use of a 5-ASA derivative, anti-TNF, steroid, or thiopurine did not differ by established and newly diagnosed patients. There was no association between age, type of IBD, insurance, gender, race or cardiovascular disease and the odds of biologic use in patients &gt;65 years (Figure 1).

Conclusion
Elderly patients with IBD, whether those with new diagnoses or individuals with the longstanding disease make up a substantial portion of the IBD population. Given that elderly patients demonstrate significant differences in medication use patterns compared with younger patients with IBD, studies of efficacy and adverse events specific to this population are warranted.
DOP34 Transplantation of human intestine into the mouse: A novel platform for study of inflammatory enterocutaneous fistulas
Authors: Bruckner R S , Nissim-Eliraz E , Marsiano N , Nir E , Shemesh H , Leutenegger M , Gottier C , Lang S , Spalinger M R , Leibl S , Rogler G , Yagel S , Scharl M , Shpigel N Y 
Published: January 2020

Abstract

Background
In Crohn’s disease patients, enteric and perianal fistulas represent a severe and medically challenging comorbidity that affects a broad number of patients. Enteric fistulas do not develop in animal models of colitis what prevents in vivo experiments so far. Based on our preliminary data, we proposed transplantation of the human foetal gut into mice as a novel platform for studying inflammatory enterocutaneous fistulas.

Methods
Human foetal gut segments were transplanted subcutaneously into mature SCID mice, where they grew and fully developed over the course of several months. We first analysed the resident immune cells and inflammatory response elicited by systemic lipopolysaccharide in normal, fully developed human gut xenografts. Thereafter, we used immunostaining to analyse fully developed xenografts that spontaneously developed entero-cutaneous fistulas.

Results
We found a broad number of resident human innate and adaptive immune cells in gut xenografts during steady-state and inflammation. The expression of human IL-8, IL-1β, IL-6, TNF-α, A20, and IkBα was significantly elevated in response to LPS, with no change in IL-10 gene expression. Approximately 17% [19/110] of fully developed subcutaneous human gut xenografts spontaneously developed enterocutaneous fistulas, revealing striking histopathological similarities with CD fistula specimens. Immunohistochemical analyses of fistulating xenografts revealed transmural lymphocytic enteritis associated with a massive expansion of resident human CD4+ lymphocytes and their migration into the intraepithelial compartment. Regionally, mucosal epithelial cells assumed spindle-shaped mesenchymal morphology and formed fistulous tracts towards chronic non-healing wounds in the host mouse skin overlying the transplants.

Conclusions
Inflammation and fistulas developed in human gut xenografts lacking IL-10 gene response. This novel model system will enable systematic studies of the inflamed and fistulating human gut in live animals.
DOP40 Does levels of concerns and expectations predict IBD disease status?
Authors: Pittet V 
Published: January 2020

Abstract

Background
Patient-reported disease perceptions may influence disease management thus health outcomes. Previous studies showed that concerns and expectations are numerous in IBD patients. Such perceptions may be indicative of overall well-being, thus of individual quality of life. We aimed at assessing if quality of life and its perceptions may predict clinical disease status in IBD patients.

Methods
We conducted a cross-sectional study on adult patients included in the Swiss IBD cohort study (SIBDCS). We sent patients a questionnaire on concerns and expectations, including a question on frequency and severity of their symptoms. We retrieved data on demographics, clinical parameters, treatments, and psychosomatics data from the SIBDCS databases. We built a binary outcome for disease status (clinical remission / active disease). Predictors associated with disease status were assessed through a series of classification models (K-nearest neighbours (KNN), decision trees, random forest and logistic regression). ROC curves were used to compare models predictive performance. We used a confusion matrix to visualise classification results.

Results
A total of 1102 patients were included in the study (54% CD, 54% women, mean age: 48 years, disease duration: 15.7 years). Among those patients, 623 were classified as being in clinical remission and 479 in active disease. We used 771 cases for training and constructing models, and the remaining 331 cases to test the respective models. The KNN model with selected variables showed the best prediction accuracy (precision/recall of 0.72/0.76 for remission and 0.67/0.65 for active disease), Figure 1 and Figure 2. Selected variables that contributed the most to the model performance were the following: age, hematocrit level, SF-36 overall mental and physical quality of life (QoL), IBD-specific QoL, coping based on distraction, disease and treatments concerns and expectations, and the absence of abdominal pain.

Conclusion
Prediction accuracy of the model was good to moderate. We found the variables that were important to predict our outcome were highly related to quality of life or perception of quality of life (concerns and expectations).
DOP49 Quantitative proteomics analysis of macrophages from Crohn’s disease patients and infected with adherent-invasive Escherichia coli
Authors: Douadi C , Vazeille E , Chambon C , Hébraud M , Dodel M , Pereira B , Coban D , Buisson A , Barnich N 
Published: January 2020

Abstract

Background
Crohn’s disease (CD) is a disabling inflammatory bowel disease. Currently, the available treatments only alleviate the symptoms. The anti-TNFα represent the most efficient therapeutic class, but its mechanisms are poorly known. Experimental data have highlighted the role of intestinal macrophages in the pathogenesis of CD. These macrophages present a defect in the control of CD-associated adherent-invasive E. coli (AIEC) replication, which is linked to altered autophagy. The main aim of this study was to compare the proteomic profile of macrophages from CD patients with and without anti-TNFα treatment, to those from ulcerative colitis (UC) patients or healthy subjects, both at the basal state and after AIEC infection.

Methods
Peripheral blood monocyte-derived macrophages (MDM) were obtained from 44 CD patients including 22 with and 22 without anti-TNFα treatment, 22 UC patients and 22 healthy subjects. MDM was infected or not with AIEC LF82 reference strain. The numbers of intracellular bacteria were determined at 1h and 6h post-infection, using gentamicin protection assay. The ‘bottom-up’ proteomic analysis of macrophages after 6h of AIEC LF82 infection or not, was assessed by a mass spectrometer, using the label-free quantification.

Results
AIEC survival was reduced within MDM from CD patients with anti-TNFα treatment compared with those from CD without TNFα treatment (p = 0.0235). The proteomic analysis identified 1359 proteins, of which, 71 were differentially expressed between MDM at the basal state and infected by AIEC LF82 whatever the origin, 30 proteins were specific in CD patients with anti-TNFα treatment and 16 in CD patients without anti-TNFα treatment (fold change &gt;1.3). The bioinformatics analysis shows an impact of several pathways involved in cellular activation, immune process and lysosomal activity. Interestingly, CD macrophages expression levels of β3 integrin (ITGB3), glutathione peroxidase-1 (GPx-1) and peroxiredoxin 3 (PRDX3) are significantly correlated with AIEC survival at 6h post-infection and faecal calprotectin. The stratification of MDM from CD patients according to the level of faecal calprotectin highlighted that levels of calprotectin and α-L-Fucosidase 1 (FUCA-1) increased in a similar way, both at the basal state and after AIEC LF82 infection.

Conclusion
Our study highlighted that the anti-TNFα treatment limits bacteria replication and acts on macrophages function. For the first time, global proteomic analysis suggests that CD macrophages-AIEC interaction could be orchestrated by ITGB3, GPx-1, PRDX3 and FUCA-1. These proteins could represent potential therapeutic targets in CD patients that need to be further investigated.
DOP52 The phenotype of NOD-scid IL-2Rγnull mice reconstituted with peripheral blood mononuclear cells from patients with Crohn’s disease or ulcerative colitis reflects the respective disease
Authors: Unterweger A , Caesar J , Winkelmann P , Rüscher A , Seuß M , Breiteneicher S , Stallhofer J , Beigel F , Siebeck M , Gropp R 
Published: January 2020

Abstract

Background
Recently, we have developed a mouse model that relies on NOD-scid IL-2Rγnull (NSG) mice reconstituted with peripheral blood mononuclear cells (PBMC) derived from patients with ulcerative colitis (UC, NSG-UC). In this model, symptoms of UC are induced by rectal challenge with ethanol. The objective of the study was to adapt this model to Crohn’s disease and to compare the phenotypes of the NSG-UC and NSG-CD mouse models.

Methods
NSG mice were reconstituted with PBMC from UC (n = 4) or CD (n = 3) patients. Mice were separated into two groups: unchallenged control and ethanol challenged mice. Readout were clinical-, colon and histological scores, analysis of frequencies of subgroups of human T cells, monocytes and B cells isolated from spleen and colon by flow cytometry, and the expression levels of the inflammatory markers TGFß, CRP, MCP-3, and IL-6 in the colon or serum by Luminex analysis.

Results
The pathological phenotype was markedly different in NSG-UC mice as compared with NSG-CD mice. Firstly, histological analysis revealed that NSG-UC mice exhibited more of a pro-inflammatory phenotype as indicated by a severe influx of inflammatory cells, oedema, crypt loss, crypt abscesses and epithelial hyperplasia. In contrast, NSG-CD mice displayed crypt loss and goblet cell atrophy and pronounced fibrosis indicating ongoing wound healing processes.

These observations were corroborated by frequencies of splenic and colonic leucocytes. Antigen experienced CD4+ T (CD45RO+) cells and switched B cells (CD19+ CD27+ IgD-) were significantly increased in NSG-UC mice, whereas significantly higher levels of experienced CD8+ T cells and M1 (CD64+), M2 (CD163+) CD14+ monocytes and unswitched B cells (CD19+ CD27+ IgD+) indicated a monocyte driven inflammation in NSG-CD mice.

This observation was also reflected in the colon of mice. Inflammation in UC was characterised by increased frequencies of neutrophils, activated CD4+ T cells (CD69+) and increased levels of CRP and MCP-3, whereas NSG-CD mice were signified by increased frequencies of M2 and M1 monocytes and of TGFß levels. In contrast to NSG-CD mice, NSG-UC mice also displayed higher serum levels of IL-6. Secondly, the impact of ethanol was more pronounced in the NSG-UC mice. In NSG-CD mice, the challenge did not evoke significant differences as compared with unchallenged control mice.

Conclusion
The comparison of pathological phenotypes of the NSG-UC and NSG-CD mouse models revealed differences, some of which reflect the respective human disease. The NSG-UC and NSG-CD mouse models may constitute powerful tools to get a better understanding of the different inflammatory processes in UC and CD.
DOP53 PTPN2 and TiO2 in the pathogenesis of inflammatory bowel disease
Authors: Conde J , Schwarzfischer M , Katkeviciute E , Häfliger J , Niechcial A , Brillant N , Atrott K , Bäbler K , Scharl M 
Published: January 2020

Abstract

Background
Inflammatory bowel disease (IBD) is caused by a complex interaction among genetic, immunological, bacterial and environmental factors. In this scenario, protein tyrosine phosphatase non-receptor type-2 (PTPN2) has been recognised as a risk factor for the development of IBD and functional studies revealed a major role for this protein in the development of experimental colitis through the regulation of the inflammasome, among other processes. In the same way, a potential relationship between diet components and IBD was suggested. In fact, it was reported that the food additive titanium dioxide (TiO2) was able to induce inflammasome activation in vitro and increase colitis severity in vivo. These observations led us to hypothesise a putative relationship between PTPN2 and TiO2 that could explain the effects of this microparticle in the pathogenesis of bowel inflammation.

Methods
DSS colitis model was performed in mice lacking PTPN2 in myeloid cells and their wild-type littermates, treated or not with titanium dioxide. After that, histology studies, flow cytometry, expression analysis, ELISA and barrier function experiments were performed. Also, bone marrow-derived macrophages (BMDMs) were used for in vitro studies.

Results
Titanium dioxide was able to exacerbate DSS-induced colitis, especially in mice lacking PTPN2 in myeloid cells. Flow cytometry analysis of the lamina propria revealed significant changes in different immune cell populations such as macrophages. In vitro experiments using BMDMs revealed that TiO2 induced the activation of the inflammasome. Also, this microparticle down-regulated the expression of the anti-inflammatory cytokine IL-10 and these effects were mainly mediated by JNK and ERK kinases.

Conclusions
The food additive titanium dioxide seems to play a negative role in colitis development by affecting the production of pro- and anti-inflammatory mediators in macrophages. This study reveals a new mechanism by which a certain component of the diet modulates intestinal inflammation.