bluuebunny/crossref_metadata_2025 huggingface dataset:
The healing myocardium mobilizes a distinct B-cell subset through a CXCL13-CXCR5-dependent mechanism
Authors: Heinrichs Margarete , Ashour DiyaaElDin , Siegel Johanna , Büchner Lotte , Wedekind Georg , Heinze Katrin G , Arampatzi Panagiota , Saliba Antoine-Emmanuel , Cochain Clement , Hofmann Ulrich , Frantz Stefan , Campos Ramos Gustavo
Published: May 2021

Aims

Recent studies have revealed that B cells and antibodies can influence inflammation and remodelling following a myocardial infarction (MI) and culminating in heart failure—but the mechanisms underlying these observations remain elusive. We therefore conducted in mice a deep phenotyping of the post-MI B-cell responses in infarcted hearts and mediastinal lymph nodes, which drain the myocardium. Thereby, we sought to dissect the mechanisms controlling B-cell mobilization and activity in situ.

Methods and results

Histological, flow cytometry, and single-cell RNA-sequencing (scRNA-seq) analyses revealed a rapid accumulation of diverse B-cell subsets in infarcted murine hearts, paralleled by mild clonal expansion of germinal centre B cells in the mediastinal lymph nodes. The repertoire of cardiac B cells was largely polyclonal and showed no sign of antigen-driven clonal expansion. Instead, it included a distinct subset exclusively found in the heart, herein termed ‘heart-associated B cells’ (hB) that expressed high levels of Cd69 as an activation marker, C-C-chemokine receptor type 7 (Ccr7), CXC-chemokine receptor type 5 (Cxcr5), and transforming growth factor beta 1 (Tgfb1). This distinct signature was not shared with any other cell population in the healing myocardium. Moreover, we detected a myocardial gradient of CXC-motif chemokine ligand 13 (CXCL13, the ligand of CXCR5) on Days 1 and 5 post-MI. When compared with wild-type controls, mice treated with a neutralizing CXCL13-specific antibody as well as CXCR5-deficient mice showed reduced post-MI infiltration of B cells and reduced local Tgfb1 expression but no differences in contractile function nor myocardial morphology were observed between groups.

Conclusion

Our study reveals that polyclonal B cells showing no sign of antigen-specificity readily infiltrate the heart after MI via the CXCL13-CXCR5 axis and contribute to local TGF-ß1 production. The local B-cell responses are paralleled by mild antigen-driven germinal centre reactions in the mediastinal lymph nodes that might ultimately lead to the production of specific antibodies.
DOP26 The relationship between vedolizumab therapeutic drug monitoring, biomarkers of inflammation, and clinical outcomes in Inflammatory Bowel Disease in the real-world setting
Authors: Afif W , Marshall J K , Kaidanovich-Beilin O , Ward R , Seow C
Published: May 2021

Background

Despite widespread use of therapeutic drug monitoring to guide anti-TNF biologic prescribing in IBD, its role for other biologic classes remains unclear. The present study aimed to assess the relationship between early vedolizumab trough concentrations (VTC) and real-world outcomes in inflammatory bowel disease (IBD).

Methods

Individuals with IBD enrolled in the Takeda Canada Patient Support Program were assessed at regular intervals from 2018–2020. VTC, albumin, faecal calprotectin (FC), C-reactive protein (CRP), and disease scores were collected from Crohn’s disease (CD; Harvey-Bradshaw Index, HBI) and ulcerative colitis (UC; Partial Mayo scores, PMS) patients. The relationship between post-induction (Week 6) VTC, baseline albumin, and Week 30 remission as defined by CRP (<5mg/L), FC (<250µg/g), or disease scores (HBI <5; PMS <3) was assessed.

Results

Week 6 VTC levels were higher in IBD patients who achieved Week 30 CRP remission compared with those who did not (n=248, p=0.0004). The Week 6 VTC cut-off that best predicted CRP remission for all IBD patients was 39.65µg/mL (AUROC: 0.61, 95% CI: 0.54–0.69, p<0.001), with significance in both univariate (n=248; p<0.001) and multivariate (p=0.002) analyses. In disease-specific subgroups, optimal VTC cut-offs in CD and UC patients displayed this same relationship. UC patients with Week 6 VTC levels >39.65µg/mL had significantly longer treatment duration (n=115; HR: 0.29, 95% CI: 0.10–0.86); CD patients did not. Week 6 VTC levels were higher in IBD patients who achieved Week 30 FC remission compared with those who did not (n=170, p=0.003). The Week 6 VTC cut-off that best predicted Week 30 FC remission for all IBD patients was 41.9µg/mL (AUROC: 0.62, 95% CI: 0.54–0.7, p<0.0001), with significance in univariate (n=170; p=0.002) but not multivariate analyses. Baseline albumin levels in all IBD patients were independently associated with Week 30 FC remission by multivariate analyses (n=170, p=0.006). In disease-specific subgroups, optimal Week 6 VTC cut-offs and baseline albumin levels were associated with Week 30 FC remission in CD patients only. All IBD patients with Week 6 VTC levels >41.9µg/mL had longer treatment duration (n=170; HR: 0.31, 95% CI: 0.12–0.83). No relationships were found between Week 6 VTC and HBI or PMS disease scores.

Conclusion

Post-induction VTC predicts remission by CRP in individuals with CD and UC but not remission by FC or clinical disease indices. Baseline albumin is independently associated with FC remission. Further research is warranted to better understand these relationships, and to develop multivariable predictive tools that combine baseline biomarkers with early vedolizumab pharmacokinetics.
DOP48 Use of biologic therapies with different mechanisms of action (MOA) in the first-line (1L) treatment of Crohn’s Disease (CD) in the U.S
Authors: Huang Z , Ba Y , Kamble P , Wang S
Published: May 2021

Background

Anti-cytokine biologics (anti-TNF agents, anti-IL-12/23 agent) and gut-selective anti-lymphocyte trafficking agent (MAdCAM α4β7 blocker) are available treatment options for patients (pts) with moderate-to-severe CD. There are limited data on treatment persistence of these different MOA as 1L biologic treatment of CD in real-world setting.

Methods

This retrospective study used the Truven Health MarketScan administrative claims database to assess treatment patterns in a large U.S. insured population. Biologic naïve adult CD pts (CD diagnosed by using ICD 9 and 10 codes) who initiated (date of initiation defined as index date) 1L biologic treatment (adalimumab [ADA], infliximab [IFX], vedolizumab [VDZ] or ustekinumab [UST] between 09/2016 and 09/2019) with ≥6 months of continuous health benefits enrolment post biologics initiation were included. Treatment persistence was defined as time to index drug discontinuation with a pre-defined gap or switch to other biologic drugs.

Results

Overall, 2648 ADA, 1446 IFX, 474 VDZ, and 415 UST treated CD pts were identified. The mean age was highest for VDZ pts (45.5 y), followed by UST (42.2 y), ADA (40.1 y) and IFX (38.8 y). The use of corticosteroid in 12 months prior to 1L biologics was highest for ADA pts (74.3%), then UST (68.2%), VDZ (65.2%), and IFX (64.9%). Disease duration (time from the first observed CD diagnosis to 1L biologics initiation date) ≤ 2 yrs was found lowest in VDZ pts (48.1%), then UST (54.7%), ADA (59.6%), and IFX (67.6%). Fistulising condition in 12 months before 1L biologics was highest in IFX pts (11.9%), then UST (9.4%), ADA (7.7%), and VDZ (5.3%). Continuation on 1L biologics was highest in VDZ pts (59.1%), followed by IFX (58.0%), UST (57.6%), and ADA (50.8%). Treatment discontinuation was highest in UST pts (35.7%), then ADA (35.4%), VDZ (30.2%), and IFX (28.2%). Switch to 2L biologics was highest in IFX pts (13.9%), then ADA (13.8%), VDZ (10.8%) and UST (6.8%). Median treatment persistence was highest for VDZ pts (842 days), followed by IFX (770 days), UST (566 days) and ADA (507 days). VDZ pts showed higher treatment persistence than ADA pts (log-rank p-value=0.005) or UST pts (p=0.14). IFX pts had higher persistence than ADA pts (p<0.0001) or UST pts (p=0.07). The adjusted hazard ratio of treatment discontinuation, with VDZ as the reference group, was highest for ADA (1.36, p<0.0001), then UST (1.27, p=0.023) and IFX (1.07, p=0.45).

Conclusion

In biologic naïve CD pts, real-world evidence shows that VDZ is associated with longer treatment persistence when compared with any of the currently approved anti-cytokine biologics. With >2 years of treatment persistence, VDZ and IFX were significantly superior to both ADA and UST.
DOP76 No durable impact of COVID-19 on disease activity and microbiome composition in patients with IBD
Authors: Funez-dePagnier G , Lima S , Duenas-Bianchi L , Lai D , Ahmed W , Battat R , Scherl E , Lukin D , Longman R
Published: May 2021

Background

Although patients with inflammatory bowel disease (IBD) reported an increased frequency of gastrointestinal (GI) symptoms following infection, the durable impact of COVID-19 on underlying IBD is not well defined.

Methods

In 118 IBD patients with COVID-19, clinical and endoscopic IBD activity, laboratory markers (ESR, CRP, hemoglobin (Hb), fecal calprotectin(FCP)), and medication utilization was assessed up to 6 months post-infection and compared to during infection or up to 6 months prior to infection. Active disease was defined by a Harvey Bradshaw Index > 4, Mayo Score ≥2, SES-CD ≥2, Mayo endoscopic score ≥1. 16S rRNA analysis was used to evaluate microbiome composition in a subset of 12 patients before and after COVID-19.

Results

Although upper respiratory (86.6%) and new GI symptoms (39.1%) were common in patients with IBD, there was no significant change in IBD clinical disease activity (Pre vs. Post-COVID-19 HBI: 4.7 vs. 4.9; partial Mayo: 3.0 vs. 2.1), endoscopic evaluation (Pre vs. Post-COVID-19 SES-CD: 7.2 vs. 8.9, Mayo endoscopic score: 1.5 vs. 1.7), or laboratory markers (Pre vs. Post-COVID-19 CRP: 1.2 vs. 1.3; ESR: 25 vs. 26; Hb 12.8 vs. 13.2; FCP: 388 vs. 250) up to 7 months post-COVID-19 compared to the 6 months prior to infection (Table 1). Overall active disease was present in 60% of the cohort prior to COVID-19 and 55% and 59% during and post-COVID-19, respectively. More subjects (8.5%) reported a delay in medical therapy during COVID-19, but there were no differences in the need for corticosteroids, a change in medical therapy, or IBD-related surgery or hospitalization during or post-COVID-19 compared to the prior 6 months. Microbiome composition stratified by underlying IBD disease activity, but did not show significant change post-COVID-19 (Figure 1).

Conclusion

COVID-19 showed no durable impact on clinical IBD disease activity or microbiome composition supporting guidelines for continued maintenance care.
N01 Does physical activity positively impact fatigue in individuals with Inflammatory Bowel Disease?
Authors: Farrell D , Bager P , Bredin F , Cairnes V , Forry M , Gilham E , Godwin N , Herdmangrant R , Ni Dhalaigh D , O’ Shea T , Sugrue K
Published: May 2021

Background

Patients with Inflammatory Bowel Disease (IBD) often experience the problematic and burdensome symptom of fatigue, both during periods of relapse and remission. The optimal management of fatigue in IBD is uncertain, however there is evidence suggesting that physical activity is likely to be a beneficial way of managing the symptom. The aim of this study is to explore the relationship between fatigue and objective measurements of both physical activity metrics and varying intensities of physical activity for individuals with IBD.

Methods

A multi-centred, European, cross-sectional, correlational study was employed. A consecutive sample of 187 patients with Crohn’s disease (59%) or ulcerative colitis (41%) were recruited from six IBD centres in the Republic of Ireland (42%), United Kingdom (40%) and Denmark (18%). Fatigue was measured using the IBD-Fatigue (IBD-F) scale, including both the level of fatigue (IBD-F, Section 1) and impact of fatigue (IBD-F, Section 2). Physical activity was objectively measured using scientifically validated triaxial accelerometers (ActiGraph wGT3X-BT) during seven consecutive days.

Results

A moderate level of fatigue (IBD-F Section 1 Md (IQR) = 10 (6 – 13)), predominantly intermittent in nature (72%) was reported by participants (57.4% female; 59% Crohn’s disease; 43% active disease). Participants self-reported sleeping an average of 8.7 hours over the seven nights. During the week, the intensity of activity was predominantly sedentary (Md 5 days, 22 hours, 20 minutes) or light (Md 19 hours, 35 minutes). The median moderate-to-vigorous intensity of physical activity per day was 32.2 minutes and step count over the week was 47052 steps. There was no evidence of a unique linear or non-linear relationship between each of the objective measurements of physical activity with IBD-related fatigue. This lack of evidence extended separately to patients in remission and to patients with active disease. These findings are in the context of a statistically significant moderately-strong relationship between disease activity (measured using both HBI and SCCAI) and level of fatigue for both patients of Crohn’s disease (rs = .327, p = .001, n = 96) and ulcerative colitis (rs = .353, p = .003, n = 71).

Conclusion

This large multi-centred study shows no association between objective measurements of physical activity and IBD-fatigue. These findings suggest that engaging or not engaging in physical activity has no differential impact on self-assessment of fatigue.
N12 A decade of waiting to know is not good enough! Experiences of women with vulval Crohn’s disease
Authors: Fourie S , Czuber-Dochan W , Jackson D , Norton C
Published: May 2021

Background

Vulval Crohn’s disease is a rare extra manifestation of inflammatory bowel disease, and there is no treatment consensus for it. Current evidence is mainly from case studies and includes only about 250 participants globally. We explored how vulval Crohn’s disease affects women’s sexual well-being, and aimed to understand what might be the specific experiences of sexuality in this group

Methods

Three participants from a phenomenological study exploring sexuality in inflammatory bowel disease have self-reported as diagnosed with vulval Crohn’s disease. Data collected from telephone interviews were analysed using thematic analysis.

Results

Women with vulval Crohn’s disease reported a severe disease course with devastating consequences on their sexuality, and suffered years of delay in their diagnosis. Their experiences were summarised in four main themes: Scarred by Crohn’s, Striving for normality, Waiting too long, and Who’s going to help? Sex posed extreme challenges imposed by the condition, and participants waited almost a decade to get a diagnosis, which negatively affected their trust in clinicians. In their effort to continue to enjoy a sexual life as normal as possible, they had feared for the future, as they felt healthcare professionals were unsure of who should help those living with vulval Crohn’s disease.

Conclusion

In spite of specialists having knowledge of vulval Crohn’s disease, participants experienced lengthy periods to get a diagnosis, with damaging consequences for their lives. Discussing sexual well-being in clinical settings may increase chances of early detection and avoid worsening symptoms.
N16 ‘Sex? Don’t even remember what that is …’ exploring IBD patient engagement with online forums regarding the topics of relationships and intimacy
Authors: Barnes H , Fourie S
Published: May 2021

Background

Online forums available to those living with Inflammatory Bowel Disease (IBD) are a platform enabling peer support. Some use online forums to discuss sensitive issues, such as the effect of chronic conditions on their intimate and sexual lives. This study explored the common topics regarding relationships and intimacy with IBD that are discussed on online forums.

Methods

This study collected anonymous data available from a public domain (online forum) and analysed it using Braun and Clarke’s thematic analysis. Data were collected from 15 threads discussing topics relating to IBD and relationships from 2008 to 2016. In total, it involved around 144 people engaged in group conversations on the topics. No subscription was needed to access the data, and all participants used pseudonyms.

Results

Two themes were developed from analysing online forum engagement on sensitive topics: Relationships and IBD and ‘ Sex? What’s that?’ . The most prevalent discussions were around broken-down relationships: ‘The guy I was dating when I was diagnosed broke up with me 6–8 months later, in large part because of how the disease was changing my life’. There were many concerns about the right time for disclosure of illness whilst dating: ‘I feel like 5 dates/one months was definitely the right time. It’s not first date material.’ Participants actively sought others’ intimate experiences for advice and found consolation in sharing common experiences, particularly regarding symptoms affecting sex:’ Intimacy and Crohn’s can be an awful combination’, or relationships: ‘I am dating two! My iPad and my UC! Neither snore, but both are very needy!’ Participants also expressed their findings of comfort from hearing others experiences online: ‘This thread gives us hope though that it is possible to be with someone with this disease’. Additionally, sexual minority groups can also feel that they have a platform where they can discuss sexuality without prejudice and easily access others of the same sexual orientation when asking for advice.

Conclusion

IBD patients use online forums to discuss their intimate lives when looking for help from others experiencing a similar situation or looking for acceptance. This suggests patients may feel embarrassed talking about sex and may not see their health care professionals as the first port of call for questions about intimacy, highlighting the importance of online forums in seeking peer support for such topics. Further research is recommended to understand how patients might prefer to express their worries in an anonymous, safe environment.
OP07 Artificial intelligence surpasses gastrointestinal experts in the classification of endoscopic severity among Ulcerative Colitis
Authors: Lo B Z S , Liu Z , Bendtsen F , Igel C , Vind I , Burisch J
Published: May 2021

Background

Evaluation of endoscopic disease severity is a key component in the management of ulcerative colitis (UC) patients. However, endoscopic assessment suffers from substantial intra- and interobserver variation, up to 75 %, thereby limiting the reliability of individual assessments. Our aim was to develop an artificial intelligence (AI) model capable of distinguishing active from healed mucosa as well as to differentiate different levels of endoscopic disease activity.

Methods

1484 unique endoscopic images from 467 patients were extracted for classification. Two experts classified all images independent of each other according to the Mayo endoscopic subscore (MES). In case of disagreement, a third expert classified the images.

Different convolutional neural network architectures were implied in the development of the AI model. Five-fold cross-validation was employed to select the best model. Unseen test data were used for evaluation.

The final model was evaluated on its performance for distinguishing MES 0 from 1–3, MES 0–1 (i.e. mucosal healing) from 2–3, and distinguish between all MES.

The accuracy, sensitivity, specificity, positive and negative predictive value, and Cohen’s Kappa were used to evaluate the final models.

Results

Our final model achieved at the most difficult task (distinguishing between all 4 categories of MES) a mean accuracy of 0.82, mean AUC of 0.99, test accuracy of 0.84, a sensitivity of 0.88, and a specificity of 0.81 and a weighted Cohens Kappa of 0.83 (p<0.001 compared to the experts).

The results from the other tasks are shown in table 1.

Conclusion

We propose a new standardised way of evaluating endoscopic images from UC patients for both clinical and academic purposes. The proposed AI model demonstrated a very good capability of distinguishing between all 4 MES levels of activity. This will optimize and unify the evaluation of the disease severity measured by the Mayo endoscopic subscore across all centres and hospitals no matter the level of medical expertise.
OP10 Response to biologics in IBD patients assessed by Computerized image analysis of Probe Based Confocal Laser Endomicroscopy with molecular labeling and gene expression profiling
Authors: Iacucci M , Jeffery L , Acharjee A , Nardone O M , Smith S C , Labarile N , Zardo D , Cannatelli R , Shivaji U N , Ungar B , Buda A , Grisan E , Gkoutos G , Subrata G
Published: May 2021

Background

Biologics are being used increasingly in the treatment of Inflammatory Bowel Disease. However, up to 40% of patients do not respond to biologics. Therefore, methods to predict response are imperative. We aimed to identify novel genes and pathways predictive of anti-TNF response in patients with Ulcerative Colitis (UC) undergoing electronic chromoendoscopy and probe confocal laser endomicroscopy (pCLE). We further evaluated the ex-vivo binding of fluorescent labelled biologics as markers of response

Methods

26 UC patients starting anti-TNF therapy as standard of care were recruited. Pre-treatment colonoscopy, with electronic chromoendoscopy and pCLE (Cellvizio, Mauna Kea) by injecting intravenous fluorescein (2.5-5mls), was performed to assess disease activity. Targeted biopsies were taken for fluorescein isothiocyanate (FITC)-labelled infliximab staining and RNA extraction and gene expression analysis. Ex vivo labelling was evaluated by an automated analysis: after a first pre-processing step to remove biases, the labelled regions were identified using statistical multi-level thresholding, and evaluated as area and intensity. To assess response, the same endoscopic procedure was repeated at week 12–14 after anti-TNF. cDNA libraries were prepared using QIAseq UPX 3’Transcriptome reagents and sequenced. Normalised gene expressions were obtained through the CLC Genomics Workbench. Differentially expressed genes (DEGs) (FDR-corrected P-value<0.05) were determined using the Limma package and PLS-DA modelling performed to calculate their importance (VIP score). Functionally related genes were identified and classified using DAVID tools. Strongest indicators of response were predicted by Random Forest area under the curve (AUC) analysis in this cohort and a similar validation cohort

Results

At baseline increased binding of the labelled biologic was associated with a higher likelihood of response to treatment (AUROC81%, accuracy77%, PPV100%, NPV63%). 342 DEGs (75 up-regulated, 267 down-regulated) distinguished responders from non-responders, 76 fell within enriched pathways. Pathways related to inflammation, chemotaxis, TGF-beta signalling, extracellular matrix and carbohydrate metabolism were reduced and cell-cell adhesion increased in responders pre-treatment. Among the 37 genes with VIP>1, CRIP2, CXCL6,EMILIN1,GADD45B, LAMA4 and MAPKAPK2 were upregulated in non-responders pre-treatment and were good predictors of response (AUROC>0.7) in this cohort and validation cohort

Conclusion

A higher mucosal binding of the biologics before treatment was observed in anti-TNF responders. Responsive UC patients have a less inflamed and fibrotic state pre-treatment. Chemotactic pathways, involving CXCL6 may be novel targets to treat non-responders
P004 Critical paralog proteins has a cell-type specific rewiring role in Ulcerative Colitis associated signalling processes
Authors: Kornilova P , Potari-Gul L , Modos D , Madgwick M , Haerty W , Korcsmaros T
Published: May 2021

Background

Cell functions are regulated by signalling pathways that often cross-talk with each other. These cross-talks are usually cell-type specific and, as we showed earlier, often mediated by so called critical paralog proteins (proteins resulted due to gene duplication but then diverged both in terms of their regulation and their functions). As dysregulation of cell functions is a hallmark of chronic inflammatory diseases, including Ulcerative Colitis (UC), here we investigated the role of such critical paralog proteins in the regulation of some key functions, in UC-associated cell types.

Methods

In this study, we compared healthy and diseased (non-inflamed UC) conditions. Using network biology approaches combined with single-cell RNAseq data, we identified critical paralog groups in myofibroblasts, regulatory T cells and goblet cells that show cell and/or condition specificity in the process of autophagy, Notch and T-cell receptor signalling.

Results

We focused our analysis on the Notch pathway-related processes, in particular the EGLN paralogs (EGLN1-3). The EGLN enzymes are prolyl hydroxylases and EGLN1, EGLN3 can directly inhibit the HIF1A transcription factor, while HIF1A induces the expression of all the three EGLN gene upon hypoxia. This negative feedback loop tends to control the amount of EGLNs and the activation status of the HIF1A proteins, therefore maintaining an adequate hypoxia response. In the intestine, EGLN2 and EGLN3 are described as potential regulators of inflammation, and both are downregulated in UC patients. Importantly, we found that the expression of EGLN paralogs shows cell-type and condition specificity. While goblet cells express all three paralogs in both healthy and UC conditions, myofibroblasts express EGLN3 only in the healthy condition. As EGLN3 is responsible for tight junction integrity, and it can regulate hypoxia response, the lack of EGLN3 in UC could contribute to the disrupted epithelial barrier function and dysregulation of myofibroblasts. Accordingly, in mice, depletion of Egln3 causes an increased susceptibility to colitis.

Conclusion

We have developed a bioinformatic pipeline to reconstruct cell-type specific signalling networks to identify the key differences among critical regulators of the signalling flow (ie., critical paralog proteins) in UC-associated cell types and in comparison of healthy and non-inflamed UC conditions. We analysed the altered expression of paralog genes in signalling pathways in UC-associated cell-types, and demonstrated their role with the condition and cell-type specific expression of EGLN3.
P005 Cytokine mediated intercellular communication in inflammatory bowel disease
Authors: Thomas J P , Olbei M , Hautefort I , Modos D , Korcsmaros T
Published: May 2021

Background

During inflammatory bowel disease the mucosal immune system is altered. The mucosal immune cells are communicating through the various cytokines. Single cell and small volume RNA-seq and proteomics approaches make the investigation of cytokine networks plausible However the lack of specific resources make such efforts hard.

Methods

To address this need in this project, we built a cell-cell communication map, CytokineLink, which collates cytokine mediated intercellular interactions. CytokineLink collects the cytokine-cytokine receptor interactions from the OmniPath, immuneXpresso and immunoGlobe databases. We demonstrate the applicability of CytokineLink by presenting how cytokine feedback loops are built and altered during Ulcerative Colitis. We mapped single-cell RNA-seq expression data from inflamed and uninflamed Ulcerative Colitis biopsies to the interactions between cytokines and cytokine receptors, and then we compared the specific cytokine-mediated cell-cell interactions.

Results

Using our approach, we were able to point out major differences in cell-cell communication between inflamed and uninflamed conditions, and identify key cytokine changes. For example, the generally anti-inflammatory cytokine IL-10 is produced by regulatory T-cells in both conditions. However the IL-10 receptor positive cells are altered between the inflamed and uninflamed condition: dendritic cells and innate lymphocytes did not express the receptor in the sufficient amount. It suggests that not the cytokine level directly but the receptor level alterations are involved in ulcerative colitis. Also the chemokine CXCL12 was expressed by the inflammatory fibroblasts. This cytokine promotes the T-cell recruitment and through that inflammation.

Conclusion

With CytokineLink, researchers are capable to pinpoint the most important interactions in the changing mucosal immune system and propose novel therapeutic approaches. We are currently developing a website and easy to follow workflows to make CytokineLink available.
P062 Effects of exposure to steroids on the PredictSURE whole blood prognostic assay in Inflammatory Bowel Disease
Authors: Alsoud D , Verstockt S , Sabino J , Ferrante M , Noor N , Verstockt B , Vermeire S
Published: May 2021

Background

Accurately predicting disease course at diagnosis is critical to facilitate personalized therapy in inflammatory bowel disease (IBD). PredictSURE IBDTM is a whole blood qPCR assay that was developed to predict prognosis in newly diagnosed, treatment-naïve IBD patients – classifying them into IBDhi (high-risk) or IBDlo (low-risk). The current recommendation is that PredictSURE IBDTM should not be used in those who have commenced steroids. In this study, we aimed to determine the impact of steroid therapy on the performance of PredictSURE IBDTM.

Methods

Whole blood was serially taken from patients admitted with severe IBD requiring intravenous (IV) steroids (pre-steroid, day 3, day 5; n=10, cohort 1) and from patients receiving oral steroids as outpatients (pre-steroid, week 1, week 6; n=10, cohort 2). An independent cohort of 43 IBD patients, all within 3 months of diagnosis and on corticosteroid treatment (41 systemic and 2 topical, cohort 3) was recruited. RNA was extracted and analyzed with PredictSURE IBDTM (PredictImmune, UK). Patients were prospectively followed and treated according to routine clinical management by physicians blinded to the test results, and clinically stratified according to one of the original definitions used to construct and validate the test (need for step up to immunosuppressive or biological therapy or surgery).

Results

In cohorts 1 and 2, both oral and intravenous steroids affected the PredictSURE IBDTM result: misclassification as IBDlo occurred in 5/8 IBDhi patients receiving oral, and 5/7 IBDhi patients receiving IV, steroids. In 60% this change was detectable early (within 1 week of oral steroids and 3 days of IV steroids). Steroids did not affect the classification of IBDlo patients. Consistently, the prognostic accuracy was limited in patients already receiving steroids (cohort 3). After a median follow-up of 31.8 [IQR 18.7 - 42.1] months, 35 (81%) patients required step-up therapy. PredictSure IBDTM correctly classified only 23 (54%) patients with accuracy of 0.53 (sensitivity: 0.51, specificity: 0.63, positive likelihood ratio: 1.38, negative likelihood ratio: 0.77). Seventeen (80%) of the misclassifications were clinically high-risk patients who were predicted as IBDlo. Time to treatment escalation was similar between patients classified as IBDhi or IBDlo after starting steroid therapy (p= 0.47) (Figure 1).

Conclusion

The prognostic accuracy of PredictSURE IBDTM is limited if performed after steroid therapy has begun, most likely because of the misclassification of high-risk patients as low risk. Therefore, the test should only be performed in patients with active disease who are not receiving steroid therapy, as currently recommended.
P086 Sphk2 deletion is involved in structural abnormalities and Th17 response but does not aggravate colon immune dysregulation and intestinal permeability in a stress-induced colonic inflammation
Authors: Martin-Hernández D , Robledo Montaña J , López-Gutiérrez I , González-Prieto M , González Bris Á , Ulecia-Morón C , MacDowell K , Tendilla-Beltrán H , Moreno B , Calleja-Rodríguez N , Rodríguez-Mascarenhas S , Caso J R , García-Bueno B , Marín-Jiménez I , Leza J C , Menchen Viso L A
Published: May 2021

Background

Colon immune dysregulation results in a chronic inflammatory response typical of IBD and mainly driven by T-cell response to microbial antigens. Interestingly, stress can trigger or modulate inflammation and even modify the clinical course of IBD. Sphingosine 1-phosphate (S1P) increase in tissues is involved in T-cell recruitment and different compounds acting on S1P signaling are currently under clinical trials to test their ability to impact IBD progression, including sphingosine kinase 2 (Sphk2) inhibitors.

Methods

Male C57BL/6NJ and Sphk2-/- mice were randomly assigned to 4 experimental groups: Control WT (n=5), Control Sphk2-/- (n=5), Stress WT (n=8), and Stress Sphk2-/- (n=8). A sub-chronic stress mixed model based on immobilization and ultrasound exposure for 2h during 4 days was used. A set of tissue and biochemical assays was performed to evaluate stress and immune responses, S1P pathways, and epithelial barrier integrity.

Results

Stress caused weight loss and corticosterone upregulation regardless of the genotype. S1P was increased in the colon of stressed mice due to a decrease in its degradation enzymes and Sphk2, leading to an immune dysregulation reflected by an upregulation of TLR4 pathway, an inhibition of anti-inflammatory mechanisms – 15-lipoxygenase, N-formyl-peptide receptor 2 and Liver X Receptor – a decrease in IgA+ and a decrease in IgM+ B-cells and plasmablasts, and a Th17 polarization. Sphk2 deletion did not affect inflammatory processes but could interfere with Th17 response. Moreover, Sphk2-/- mice showed lower expression levels of claudins 3, 4, 5, 7, and 8 that could be related to structural abnormalities relevant to IBD. Stress exposure also decreased some of these claudins and increased intestinal permeability, but a synergistic effect between stress and genotype for permeability was not detected.

Conclusion

Sub-chronic stress induced colon S1P increase, immune dysregulation and increased intestinal permeability. Sphk2 deletion is involved in structural abnormalities and Th17 response but did not aggravate the inflammatory processes exerted by stress.
P102 Outcomes of coronavirus disease 2019 among patients with inflammatory bowel diseases and the influence of IBD-related medications– A Danish prospective population-based cohort study
Authors: Attauabi M , Poulsen A , Kajbæk Verner-Andersen M , Rosager Hansen M , Pedersen N , Pilegaard Prahm A , Berg Lødrup A , Haderselv K , Larsen L , Jess T , Glerup H , Molazahi A , Mathiassen Oppfeldt A , Dahlerup J F , Lodberg Hvas C , Neumann A , Wase A , Dam Jensen M , Nathan T , Jensen S , Theede K , Kiszka-Kanowitz M , Benedict Seidelin J , Burisch J
Published: May 2021

Background

Population-based data regarding outcomes of coronavirus disease 2019 (COVID-19) among patients with ulcerative colitis (UC) and Crohn’s disease (CD) are limited. Studies on the association of COVID-19 outcomes and immunomodulating therapies, are scarce. Therefore, we aimed to conduct a population-based study investigating the outcomes of COVID-19 among patients with UC and CD in Denmark.

Methods

The Danish COVID-19 IBD Database is an extensive population-based database that prospectively monitors the disease course of laboratory-confirmed COVID-19 among patients with UC and CD in Denmark. Severe COVID-19 was defined as COVID-19 necessitating intensive care unit admission, ventilator use, or death. Regression analysis was adjusted for age, sex, disease type, disease activity, cardiovascular disease, and corticosteroids.

Results

The study recruited 363 patients (UC: 223; CD: 140) from January 28th, 2020, to February 7th, 2021. A total of 36 (16.1%) and 18 (12.9%) patients with UC and CD, respectively, required a COVID-19 related hospitalization, while eight (3.6%) and three (2.1%) patients required intensive care treatment. Death due to COVID-19 was observed among eight (3.6%) and two (1.4%) patients, respectively. The association between these outcomes and IBD-related treatment is presented in Table 1. As shown, none of the IBD-related medications were associated with severe COVID-19 in univariate and adjusted analysis. However, systemic steroids were found to be associated with the risk of COVID-19 related hospital admission among patients with UC (adjusted odds ratio (aOR)=6.54 (95% CI 1.09-36.39)) and CD (aOR=5.45 (95% CI 2.07-12.24)).

Conclusion

This ongoing Danish population-based study on COVID-19 outcomes among patients with UC and CD demonstrated severe COVID-19 among only a minority of patients, which was not associated with IBD-related medications. However, use of systemic steroids were associated with COVID-19 necessitating hospital admission among patients with UC and CD.
P103 Minimal Clinically Important Difference (MCID) for the Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms (UC-PRO/SS) Tool
Authors: Pulley J , Galloway D , Oh Y , Devine J , Petrek H , Khavarian A , Matsui A
Published: May 2021

Background

The UC-PRO/SS tool developed by the IBD PRO Consortium is undergoing FDA Drug Development Tool qualification (COA DDT# 000040). Derivation of minimal clinically important difference (MCID) thresholds for improvement in bowel and functional signs and symptoms domain scores are presented here.

Methods

MCID estimates for bowel and functional domains were derived using anchor- and distribution-based approaches applied to data from three studies of Etrolizumab. Initial MCIDs were developed using Mayo Clinic Score (MCS) and Inflammatory Bowel Disease Questionnaire (IBDQ) response thresholds as anchors; Cronbach’s alpha SEM and Cohen’s moderate effect size statistics were calculated. MCIDs were then cross-validated internally and externally, i.e. within and across target populations, using clinical (modified and partial MCS) and patient-centered (IBDQ “general wellness” item 10 and EQ5D VAS) measures, to support generalizability. CDF plots with pooled data provide further empirical support.

Results

Study populations had mean ages of 39.2–40.5 years; were 54.5–58% male; 77.5–93.9% white; and had mean disease duration of 8.75–8.98 years. Six points was selected as the bowel domain threshold as change of this magnitude aligns with the anchor settings (5.89, 6.93, and 7.15 for IBDQ and 5.63, 6.12, and 7.63 for MCS) and exceeds measurement error as shown by distributional methods (Cronbach’s alpha SEM 2.071, 2.160, and 2.167, Cohen’s moderate effect size range 2.086, 2.135, and 2.191). A two-point threshold was similarly selected for the functional domain based on anchor settings (1.77, 1.98, and 2.53 for IBDQ and 1.56, 1.68, and 2.01 for MCS) and distributional methods (Cronbach’s alpha SEM 1.336,1.140, and 1.417, Cohen’s moderate effect size range 1.204, 1.270, and 1.309). External, cross-validation showed numerically robust differences (no overlapping CI’s) between the group achieving the MCID versus not across clinical and PRO variables for both domains. Magnitudes of change on IBDQ item 10 and EQ5D VAS variables scores exceeded the ½ SD for interpreting moderate levels of PRO score change. For the bowel domain, separation of CDF curves between responder groups showed cumulative percentages of approximately 60% and 70% based on IBDQ and MCS anchors, respectively, at the thresholds indicating change of a six-point magnitude. For the functional domain, separation between CDF curves at the 2-point threshold occurred at points indicating cumulative proportions of response greater than 50% using both anchors.

Conclusion

MCIDs of 6 and 2 points for the bowel and functional domains of the UC-PRO/SS are robustly defined and cross-validated, allowing interpretation of clinical improvement in symptoms among moderate to severe adult UC patients.
P114 Frequent work productivity and activity impairment in caregivers of children with inflammatory bowel disease: a project of the prospective PIBD-SETQuality inception cohort study
Authors: Klomberg R , Kemos P , Aardoom M , Rizopoulos D , Croft N , de Ridder L , Neyt M
Published: May 2021

Background

Paediatric inflammatory bowel disease (IBD) can disrupt daily lives of patients and their caregivers, who may be impaired in performing work or daily activities due to increased caretaking responsibilities, accompanying to frequent hospital visits and increased school absence of their children. However, literature on these impairments is sparse. The aims of this study were to longitudinally quantify this work and activity impairment and evaluate associated factors. Second, to assess the impact of these impairments on caregiver’s health-related quality of life (HRQoL).

Methods

Since January 2017, children with newly diagnosed IBD are included for the international prospective PIBD-SETQuality inception cohort study1. Patient and disease characteristics are collected at time of diagnosis, at three and twelve months. The impact of the child’s IBD on caregiver’s socioeconomic functioning and HRQoL (rate 1–10) is longitudinally evaluated by the Work Productivity and Activity Impairment (WPAI) and EQ-5D-5L questionnaire. Primary outcomes, including absenteeism (percentage work time missed), presenteeism (percentage impairment while working), work productivity loss (percentage overall work impairment) and activity impairment (percentage affected daily activities, such as householding or exercise), were evaluated using generalized estimating equations models.

Results

Up to February 2021, 436 children (247 Crohn’s disease (CD); 169 ulcerative colitis (UC)/IBD-unclassified (IBDU)) were eligible for analysis of the WPAI questionnaire. Mean employment rate at diagnosis was 81.0% (74.8% CD, 86.0% UC/IBD-U, p=0.050). At diagnosis, mean absenteeism, presenteeism, work productivity loss and activity impairment were 28.0%, 31.4%, 46.4% and 36.5% respectively (Figure 1A-D). Work productivity loss and activity impairment significantly decreased over time and were associated with disease activity, but not with IBD diagnosis or age at diagnosis (Figure 2A-B). Work productivity loss, but not activity impairment was negatively associated with HRQoL (β -0.067, p<0.01; β -0.027, p=0.387 respectively). Estimated costs related to absenteeism associated with the child’s disease were €8711 per patient during the first year after diagnosis.

Conclusion

Parents of children with IBD experience significant impairments in their work and daily activities. The impact is biggest at diagnosis, plateaus thereafter and is associated with disease activity. Work productivity impairment results in indirect costs and reduced HRQoL.

Reference

Figure 1

Figure 2
P117 Patient perceptions about causes of flare in IBD: results from the baseline dataset of the PREdiCCt study
Authors: Siakavellas S , Derikx L , Derr L , Williams L , Plevris N , Jenkinson P , Laura L , Constantine-Cooke N , Covil K , Murdoch L , Jones G R , Lees C
Published: May 2021

Background

Patient reported outcomes are important endpoints in IBD management, but patient perceptions of the causes of disease flare are unknown and thus may reveal novel areas for future study.

Methods

The PREdiCCt study (https://www.predicct.co.uk) is the largest prospective study of the causes of IBD flare. 2629 patients in clinical remission were recruited from 48 UK sites and followed for 2 years with detailed assessment of environmental and dietary factors via monthly questionnaires. 1946 (74%) patients completed the baseline questionnaires. We present here the results of the baseline questionnaire analysis of patient perceptions of disease flare, derived from a list of 17 putative causes from the literature and their own experience via free text input.

Results

In total 1,946 IBD patients [male=852, CD=1000; UC/IBDU=946, age 45.8±15.5 (mean±SD in years)] gave their opinion about factors initiating a flare. The commonest causes reported were stress (n=1359, 69.8%), dietary changes (n=911, 46.8%), alcohol use (n=385, 19.8%), sleep disturbances (n=331, 17%) and that their medication stopped working (n=308, 15.8%) (Figure 1). CD participants were more likely to identify dietary changes (50% vs 43%, p<0.001) and menstruation (16% vs 10% of female patients, p<0.001) as flare triggers than UC/IBDU participants, while UC/IBDU participants more frequently reported loss of response to medication as a trigger for flare (9% vs 5% for CD participants, p<0.001). CD patients with small bowel involvement were more likely to name dietary changes (61% vs 42%, p<0.001), travel (14% vs 9%, p=0.016) and smoking (4% vs 1%, p=0.04) as flare triggers. When compared by gender, the ranking of causes was identical but female participants were more likely to identify stress (77% vs 65%, p<0.001) and antibiotic use (12% vs 6%, p<0.001) as reasons for disease relapse compared to male participants.

Conclusion

Stress, dietary changes and alcohol use were identified as the main causes of flare by patients with dietary changes more frequently reported in CD (especially those with small bowel involvement). The impact of environmental and dietary factors in the development of flare is being further investigated with ongoing longitudinal data collection in the PREdiCCt Study.
P128 Depression, anxiety and stress among Inflammatory Bowel Disease patients during COVID-19: A UK cohort study
Authors: Luber R , Duff A , Pavlidis P , Honap S , Meade S , Ray S , Anderson S , Mawdsley J , Samaan M , Irving P
Published: May 2021

Background

Patients with chronic diseases, particularly those requiring immunosuppression, are thought to be at increased risk of poor mental health during the COVID-19 pandemic. However, few studies have assessed the mental health of such patients during the current or past pandemics.

We aimed to assess the incidence of depression, anxiety & stress in a cohort of inflammatory bowel disease (IBD) patients early during the COVID-19 pandemic, & explore for association with risk of severe COVID-19 based on British Society of Gastroenterology guidelines, & other factors.

Methods

A survey including the Patient Health Questionnaire-9, General Anxiety Disorder-7, & Perceived Stress Scale tools for depression, anxiety & stress, respectively, was administered to a cohort of IBD patients from a tertiary centre in London, United Kingdom, in June 2020.

Results

274 patients responded to the survey (57% response rate), including 54 low risk, 152 moderate risk, & 68 high risk for severe COVID-19. Moderate-severe depression was observed in 61 (22.5%), moderate-severe anxiety in 49 (18%), while 39 (14%) had both diagnoses (Table). Mean (SD) stress score was 16.2 (7.4). There was no association between degree of severe COVID-19 risk & psychological morbidity. Flare symptoms & fatigue were associated with worse psychological morbidity across all measures, while accessibility of information regarding COVID-19 risk & reducing that risk was protective for depression (OR 0.56 [0.33–0.94], p=0.03), anxiety (OR 0.62 [0.4–0.96], p=0.03), & stress (standardized β-coefficient -0.15 [-0.28--0.03], p=0.02) (Figure). 79 (30%) respondents were interested in receiving psychological support during the pandemic, while 200 (76%) expressed interest beyond the pandemic.

Conclusion

Depression, anxiety & stress among IBD patients during the pandemic are common, however their frequency is similar to pre-pandemic rates & general population levels reported during the same period. Ensuring easy access to personalized risk information with targeted psychological support may mitigate psychological burden as patients reintegrate into society & deal with future COVID-19 waves or variants.