bluuebunny/crossref_metadata_2025 huggingface dataset:
N17 Profile of ostomy patients treated at a referral hospital for inflammatory bowel disease
Authors: Barros J , Herrerias G , Oliveira L , Baima J , Alencar R , Saad-Hossne R , Sassaki L
Published: January 2020

Background

As part of the surgical treatment of inflammatory bowel disease (IBD), sometimes is necessary the intestinal stoma. The aim of this study is to identify the profile of ostomy patients treated at a referral public hospital in IBD in Brazil.

Methods

This is a descriptive study with a quantitative approach. The sample consisted of all patients who underwent stoma surgery at a referral public hospital in IBD in Brazil. The inclusion criteria were: to have a medical diagnosis of Crohn’s Disease (CD) or Ulcerative Colitis (UC) and to have or have had intestinal stoma. Data collection was performed through the analysis of patient records.

Results

The number of patients attending the outpatient clinic is approximately 200 with UC and 150 with DC. The sample consisted of 33 patients, the majority of male gender (51.52%), age between 22 to 77 years (44.55 ± 15.10), literate (93.94%), self-declared white (84.85%), coming from the state of São Paulo (96.97%), smokers (6.06%), alcoholics (3.03%), married (63.64%) and the number of children ranged from 01 to 10. Regarding the characteristics related to IBD, 15 (45.45%) were diagnosed with CD, 6 (40%) were fistulising ileocolonic type and 18 (54.55%) were diagnosed with UC and most with pancolitis (88.89%). The average time of illness was 14.2 years. Among the causes of the stoma, the most frequent were perforating acute abdomen (n = 5, 15.15%), severe acute colitis (n = 4, 12.12%), obstructive acute abdomen (n = 4, 12.12%), toxic megacolon. (n = 3, 9.09%) and neoplasia (n = 2, 6.06%). Regarding the character of the surgery, 10 (30.30%) were urgency and emergency and 11 (33.33%) elective. Only 5 (15.15%) surgeries performed the previous demarcation of the stoma. Regarding the types of stoma, 4 (12.12%) had temporary colostomy and 3 (9.09%) permanent, 16 (48.48%) had temporary ileostomy and 3 (9.09%) permanent. The average time of stoma was 3.19 years. 2 (6.06%) colostomised and 9 (27.27%) ileostomised reversed the stoma. 2 (6.06%) patients refused intestinal reconstruction.

Conclusion

The study results showed us that IBD with more severe extension and behaviour can result in intestinal ostomy, either temporary or permanent. The characterisation of ostomised patients is necessary for the identification of nursing needs to be highlighted, such as the previous demarcation of the stoma.
N21 Self-management and healthcare utilisation of 16–21 year olds with inflammatory bowel disease (IBD) attending one Irish hospital
Authors: Forry M , Milewska M , Lardner C , Lukose T , Godwin N , Boland K , Patchett S , O’Toole A
Published: January 2020

Background

IBD is an umbrella term used to describe Crohn’s disease and ulcerative colitis, both characterised as lifelong relapsing remitting diseases (O’Connor et al., 2013). Hope et al (2012) reported a significant increase in the incidence of childhood IBD in Ireland over a relatively short period of time.

The aim of this research study was to assess the self-management and healthcare utilisation skills of adolescents and young adults (AYA) (aged 16–21 years) with (IBD).

Methods

Service users aged from 16 to 21 attending the IBD service were asked to complete the Transition Readiness Assessment Questionnaire (TRAQ). Divided into five domains, 20 questions related to: managing medications, appointment keeping, tracking health issues, talking with providers and managing daily activities.

Results

31 completed questionnaires were returned via stamped addressed envelope provided. Seventeen patients were diagnosed in a paediatric hospital and 14 were diagnosed in adult hospital services. Seventy-five per cent of respondents manage their own medications, 50% take responsibility for appointment keeping and 51% keep track of their health issues. Eighty-nine per cent talk to health care providers independently and 81% manage daily activities independently. Further analysis showed that females had significantly higher health tracking scores compared with males p = 0.04. Overall, 65% of all female users provided positive feedback regarding this domain. In male group this score reached only 40%. The biggest discrepancy was noted in relation to query concerning the list of questions before doctor`s visit. Almost 70% of females replied positively to this question, while only 28% of male patients provided positive answer. There was no significant difference in scores from those diagnosed in paediatric setting vs. those diagnosed in adult hospital services.

Conclusion

Some aspects of the appointment keeping as well as health tracking issues (especially in male group) were identified as domains that need further improvement. Ongoing education will be provided to patients attending the service with training focused on increasing awareness of the users in the most lacking domains.
N22 Nurse led therapeutic drug monitoring (TDM) of Infliximab in IBD
Authors: Gleeson S , Sugrue K , Buckley M , McCarthy J
Published: January 2020

Background

Therapeutic drug monitoring (TDM) is the clinical practice of measuring serum drug concentrations to guide clinical decision making. Achieving therapeutic drug concentrations has been associated with clinical, endoscopic and histological outcomes in IBD. The use of TDM offers a more personalised treatment approach and is associated with sustained clinical remission. Proactive TDM was introduced to the Mercy University Hospital in 2014 for all patients on biologics.

Methods

One hundred patients receiving biologic infusion (Infliximab) were evaluated post induction (week 12) for therapeutic drug trough concentration and for clinical response. Serum samples were taken from all IBD patients at week 12. Biologic response assessment forms were complete for all patients to assess symptom improvement.

Results

Thirty-five per cent of patients had sub therapeutic trough levels at week 12. They subsequently received 3 increased doses of 10mgs/kg and levels were rechecked. Of these 90% achieved therapeutic levels after the dose escalation. 65% of patients had therapeutic levels at week 12. There was a correlation between therapeutic trough levels and patient reported improvement of clinical symptoms in 85% of respondents.

Conclusion

TDM in our unit facilitates appropriate dose 100 patients receiving biologic infusion (Infliximab) were evaluated post induction (week 12) for therapeutic drug trough concentration and for clinical response. Serum samples were taken from all IBD patients at week 12. Biologic response assessment forms were complete for all patients to assess symptom improvement.
N24 Prioritised adolescent healthcare transition readiness factors by Canadian inflammatory bowel disease nurses
Authors: Rohatinsky N , Risling T , Kumaran M , Hellsten L A
Published: January 2020

Background

Canada has over 270,000 individuals living with inflammatory bowel disease (IBD). Over 7000 children and adolescents have been diagnosed and these numbers are continuing to increase. Due to the chronic, life long nature of IBD, more adolescents are transitioning from paediatric to adult healthcare environments than ever before. There is great need to ensure that adolescents are properly supported through this transitional period to ensure that their health outcomes are maximised. IBD nurses are integral members of the transition team; however, their perspectives on priority transition readiness factors are limited. Therefore, the purpose of this study was for Canadian IBD nurses to prioritise healthcare transition readiness assessment factors.

Methods

An anonymous survey was created and distributed to IBD nurses across Canada. Nine transition topic categories with several transition statements within each category were identified based on a previous scoping review and expert opinion. Nurses were asked to rank the top three statements under each category.

Results

Fifty-six Canadian IBD nurses participated in the survey. The highest priority statement that was most frequently identified as the top selection under each transition topic category is listed below.

Conclusion

IBD nurses identified key transition readiness factors that will ultimately allow young adults to self-manage their IBD; promote successful transition into adult care; and allow for positive health outcomes.
N29 Application of the AREA model to a standard care plan for patients with inflammatory bowel disease
Authors: Mateos Hernandez M I
Published: January 2020

Background

The clinical characteristics of the inflammatory bowel disease (IBD), its psychosocial/occupational impact and the increase in its incidence and prevalence, justify the proliferation of Multidisciplinary Care Units (with reference nurses for patients). The standardisation of care and the recording of the performance of the professionals that integrate them are necessary to give continuity to the care, to value the role of each of them in these, to reduce the variability in clinical practice and the collection of data that allow decision-making at the management and research assistance level. All of the above plus the existence in our country of legal regulations that define and regulate the records of mandatory existence and completion in the medical records, of our patients has made us set ourselves as a general objective: Develop a standard nursing care plan for the care of patients with IBD.

Methods

A literature review of the literature published in the last 10 years in the Medline, Cocharane, Cinahl and Cuiden databases is carried out. The search criteria establish the existence of the words ‘Care plan’ ‘nursing care’ and ‘nursing diagnoses’, all of them combined with IBD. Natural words bounded by the limits determined in the inclusion criteria. The needs model of Virginia Henderson (Institutional model) is used for the assessment and for the diagnosis, objectives and planning of nursing interventions the taxonomies NANDA, NOC, and NIC (NNN). Finally, in order to achieve a realistic and applicable plan of care taking into account, criteria of average hospital stay per process, and average time of outpatient care, we apply the AREA model (Analysis of Current State Outcomes) of Pesut1.

Results

The assessment highlights the altered needs: food, disposal, safety mobility, self-realisation, values and communication beliefs. In relation to the diagnoses, we classify them into clinical, psychosocial and secondary to the treatment, discriminating those written as diagnosed by nurses and therefore resolved or minimised autonomously by the nurses from whom they should be considered as collaborative problems.

Normality characteristics are defined by protocol.

Conclusion

The model favours a broad and comprehensive view of the situation, leading to the selection of the diagnosis (or more than three) that allows the holistic approach to be effective and efficient. It would allow us to know the prevalence and incidence of diagnoses and agree on objectives and activities to establish comparison patterns.
N30 Experience of living with intestinal failure: a systematic review of qualitative studies
Authors: Czuber-Dochan W , Liu Q , Roberts D , Smith P , Norton C
Published: January 2020

Background

Intestinal failure (IF) affects about 2000 people with Crohn’s disease (CD) in the UK. It is a result of the most severe phenotype of CD where an individual can no longer obtain sufficient nutrients from their gut to sustain life without supplementation in the form of parenteral nutrition (PN) or fluids intravenously and most have a stoma. Many cannot tolerate any food and very little drink by mouth. Such individuals usually need a permanent central venous catheter and must have an infusion of PN overnight, all or most nights in the week, often for 10–12 h at the time. Complications such as infection or thrombosis of the central line are a constant risk. This treatment must often continue for life. This systematic review aimed to explore the experience of people living with IF and the impact of the condition on their daily lives.

Methods

The following databases were searched in July 2019: MEDLINE, PubMed, PsychINFO, Web of Science and Global Health Scopus. Search terms included ‘intestinal failure’, ‘short bowel syndrome’, ‘quality of life’ (QoL) and terms relating to psychosocial functioning. English language articles were retrieved and screened by one reviewer at title and abstract, ratified by a second reviewer. The resulting articles selected at abstract were screened at full text by 3 reviewers.

Results

Eight papers, based on 7 studies, were included with a total of 97 participants: 36 male, 61 female. The age range of adults was 28–83. One study was conducted in children, with age range of 7–17. In 5 studies, all participants were on HPN. In 2 studies, 4/6 and 7/10 participants were on HPN respectively. There was one overarching theme: ‘Complications and challenges of living with IF’, with three specific themes that reflect the patients’ experience: (1) ‘Eating for survival’ encompasses the perpetual need to eat in order to make up for the large quantities of nutrients lost due to malabsorption (2) ‘Life with HPN: nutritional safety net at a price’ describes relief from the pressure to eat for survival but with drawbacks such as restrictions on social activities and risk of catheter line infections. (3) ‘Benefits and pitfalls of having a stoma’ relates to benefits of having a stoma, such as reduced frequency of toilet visits, and the accompanying inconvenience of leaks, high output and negative body image.

Conclusion

Living with IF has many challenges. Patients struggle with retaining enough nutrients and the physical and technical difficulties with having HPN and/or a stoma. The psychosocial well-being in these patients is affected by these challenges, as a result. Overall, QoL is poor and currently very little is being done to improve this.
DOP65 Mirikizumab regulates genes involved in anti-TNF resistance and ulcerative colitis disease activity
Authors: Steere B , Schmitz J , Powell N , Higgs R , Gottlieb K , Liu Y , Jia B , Tuttle J L , Sandborn W J , Sands B E , Krishnan V
Published: January 2020

Background

Mirikizumab (miri), a p19-directed IL-23 antibody, demonstrated efficacy and was well-tolerated in a phase 2 randomised clinical trial in patients with moderate-to-severe UC (NCT02589665). This abstract explores gene expression changes in colonic tissue from study patients and their association with clinical outcomes.

Methods

Patients were randomised 1:1:1:1 to receive intravenous placebo (PBO, N = 63), miri 50 mg (N = 63) or 200 mg (N = 62) with the possibility of exposure-based dose increases, or fixed miri 600 mg (N = 61) every 4 weeks for 12 weeks. Patient biopsies were collected at baseline (BL) and Week 12, and differential gene expression was measured using an Affymetrix HTA2.0 exon-format microarray workflow. Genes were represented by their largest groups of highly correlated exons. Weeks 0 and 12 data were compared in all treatment groups to produce differential expression values (DEVs). Mean fold changes in DEVs between PBO and each dose group were calculated in a mixed-effect model. A threshold of false discovery rate-adjusted p-value ≤ 0.05 was applied to the significance of the fold change values, and a filter of an absolute value for the fold changes of ≥0.5 log2 units was applied.

Results

The greatest improvement in clinical outcomes at Week 12 was observed in the 200 mg miri group1; likewise, the greatest PBO-adjusted change from BL in transcripts was observed in this group. Transcripts correlating with key UC disease activity indices at BL, including modified Mayo score (MMS), ulcerative colitis Endoscopic Index of Severity (UCEIS), Geboes score, and Robarts Histopathology Index (RHI), included MMP1, MMP3, S100A8, IL1B, and UGT2A3, with the highest correlations occurring with the histopathologic indices (Figure 1). Miri treatment modulated the expression of transcriptional modules predicted to be enriched in cell profiles identified as key drivers of UC2 (Table 1, columns 1–2) as well as genes determined to be associated with UC by genome-wide association studies (GWAS; Table 1, column 3). Moreover, miri treatment affected transcripts involved in resistance to anti-TNF treatments (Table 1, column 4). A number of the genes in these categories were among those most affected by miri treatment (Table 1, columns 5–6).

Conclusion

This is the first large-scale gene expression study of diseased tissue from UC patients treated with anti-IL23p19 therapy. It is the first study to show how anti-IL23p19 therapy modulates biological pathways involved in resistance to anti-TNFs. These results are consistent with the demonstrated efficacy of miri in patients in whom TNF antagonists have failed.

References
DOP70 High-dimensional analysis reveals a novel signature for IL-17 producing CD8 T cells in inflammatory bowel disease
Authors: Globig A M , Otto-Mora P , Hipp A , Heeg M , Schwacha H , Tomov V , Thimme R , Hasselblatt P , Bengsch B
Published: January 2020

Background

The pathogenesis of IBD has previously mainly been associated with a dysregulation of CD4 T-cell responses, and active disease is linked to induction of pathogenic IL-17 producing T helper cells. Importantly, CD8 T cells can also produce IL-17 and demonstrate a significant increase in active IBD. However, it remains unclear whether this is due to conventional or unconventional T-cell responses and whether these CD8 responses could play a role as novel biomarkers or therapeutic targets of active IBD.

Methods

We isolated lymphocytes from the peripheral blood and intestinal tissue of IBD patients (n = 56) and performed a detailed analysis of CD8 T-cell phenotype and function using high-parametric flow cytometry and mass cytometry in combination with algorithm-aided bioinformatic analysis.

Results

We observe a significant increase in IL-17 production by CD8 T cells in active IBD, primarily produced by conventional CD8 T cells. Unconventional T-cell subsets (e.g. MAIT cells, γδ T cells and NKT cells) represented only ~30% (peripheral blood) or ~25% (intestinal tissue) of IL-17 producing CD8 T cells (Tc17). The mass cytometric analysis identified Tc17 cells as a distinct cell population within the intestinal CD8 T-cell compartment that can be further subdivided into 3 subsets which share expression of phenotypic markers such as CD6, CD39, CD69 and PD1 and a low expression of CD27. This novel signature was validated in a separate cohort of IBD patients. Moreover, at initial IBD diagnosis, the IL-17 signature is associated with flare-free survival in a retrospective cohort analysis based on published transcriptome data.

Conclusion

Our data indicate that conventional IL-17 producing CD8 T cells are a very distinct cell population that is linked to IBD activity. The identification of a novel IL-17 CD8 signature may help guide treatment decisions as a biomarker and for immunotherapeutic approaches.
DOP72 Safety, tolerability and efficacy of anti-TL1A antibody PF-06480605 in treatment of ulcerative colitis: The open-label, multicentre, Phase 2a TUSCANY study
Authors: Danese S , Klopocka M , Scherl E J , Romatowski J , Allegretti J R , Peeva E , Vincent M S , Schoenbeck U , Xi L , Ye Z , Hassan-Zahraee M , Rath N , Li G , Neelakantan S , Banfield C , Lepsy C , Chandra D , Hung K E
Published: January 2020

Background

Widespread disruption of the mucosal immune system is central to the pathogenesis of ulcerative colitis (UC). One component, tumour necrosis factor (TNF) α-like ligand 1A (TL1A), is upregulated at the site of active disease in UC. Treatment of preclinical rodent models with anti-TL1A antibodies decreases disease activity, highlighting their therapeutic potential for UC. PF-06480605 is a first-in-class fully human immunoglobulin G1 monoclonal antibody targeting TL1A.

Methods

The Phase 2a, open-label, multicentre, single-arm TUSCANY study (NCT02840721) evaluated the safety, tolerability and efficacy of PF-06480605 in treatment of moderate to severe UC. Participants received 500 mg intravenous (IV) PF-06480605 every 2 weeks (Q2W) for a total of 7 doses, with a 14-week follow-up period. Primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and endoscopic improvement (EI) (Mayo endoscopic subscore [centrally read] of ≤1 without friability) at Week 14, respectively. Secondary efficacy endpoints included remission (total Mayo score ≤2, with no individual subscore >1) and endoscopic remission (Mayo endoscopic subscore = 0) at Week 14. Transcriptomic profiling on intestinal biopsies was performed.

Results

Of the 50 participants who received PF-06480605, 42 completed the study. The majority were male (56.0%) and white (96.0%), with a mean age of 40.0 years and prior experience of anti-TNF inhibitors (72.0%). Pancolitis (48.0%) and left-sided colitis (32.0%) were the most common forms of UC at baseline. There were 109 TEAEs, of which 18 were treatment-related. Aside from worsening UC, the most common TEAE by system organ class was arthralgia, which occurred in 6 participants, and 1 was treatment-related. Treatment-emergent serious adverse events were reported in 3 participants, and considered treatment-related in 1 participant (Table 1). No malignancies or deaths were reported. At Week 14, statistically significant EI was observed in 38.2% of participants (Table 2). The proportions of participants achieving remission and endoscopic remission at Week 14 were 24.0% and 10.0%, respectively. Transcriptomic analyses demonstrated normalisation towards a non-inflamed transcriptome in participants with EI.

Conclusion

PF-06480605 exhibited an acceptable safety and tolerability profile and statistically significant EI in participants with moderate to severe UC. These results warrant further evaluation in subsequent studies.
DOP73 Efficacy and safety of escalation to tofacitinib 10 mg BID for patients with UC following loss of response on 5 mg BID maintenance therapy: Results from OCTAVE open-label, long-term extension study
Authors: Sands B E , Moss A C , Armuzzi A , Marshall J K , Lindsay J O , Sandborn W J , Danese S , Zeroncio M , Modesto I , Salese L , Lawendy N , Zhang H , Su C
Published: January 2020

Background

Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib have been demonstrated in patients with moderate to severe UC in three Phase 3 studies (OCTAVE Induction 1 and 2 [NCT01465763; NCT01458951]; OCTAVE Sustain [NCT01458574]) [1]. Here, we present updated efficacy and safety data of tofacitinib dose escalation in patients with UC participating in an ongoing, open-label, long-term extension (OLE) study (OCTAVE Open, NCT01470612) [2].

Methods

We present updated data from the dose-escalation subpopulation of the OLE study (as of May 2019; database not locked) comprising patients who achieved clinical response (CR) following 8 weeks of tofacitinib 10 mg twice daily (BID) induction therapy, entered OCTAVE Sustain receiving tofacitinib 5 mg BID, experienced treatment failure between Week 8 and Week 52, and subsequently entered OCTAVE Open with escalation to tofacitinib 10 mg BID. Treatment failure was defined as an increase of ≥3 points from maintenance study baseline total Mayo score, plus an increase of ≥1 point in both rectal bleeding subscore and centrally read endoscopic subscore (ES), and an absolute ES of ≥2 after ≥8 weeks of maintenance therapy. CR, mucosal healing (MH) and remission (R) were evaluated at Months 2, 12, 24 and 36 of OCTAVE Open (non-responder imputation and last observation carried forward [NRI-LOCF] and observed data). Safety was evaluated throughout the study.

Results

Of 944 patients enrolled in the OLE study, the dose escalation subpopulation comprised 59 patients. In these patients, CR, MH and R rates 36 months after dose escalation were, respectively, 40.7%, 39.0% and 30.5% for NRI-LOCF and 95.2%, 86.4% and 66.7% for observed data (Table). Of these 59 patients, 29 had prior tumour necrosis factor inhibitor (TNFi) failure; in these patients, CR, MH and R rates at Month 36 were, respectively, 51.7%, 51.7% and 41.4% for NRI-LOCF, and 100.0%, 92,3% and 75.0% for observed data. Incidence rates for safety events and pt-years’ exposure are reported in the table.

Conclusion

For most patients who lost initial CR to tofacitinib 10 mg BID induction therapy while on tofacitinib 5 mg BID maintenance therapy, including those with prior TNFi failure, dose-escalation back to 10 mg BID recaptured CR by Month 2 and was generally maintained over 3 years. The safety profile with tofacitinib 10 mg BID in the dose-escalation subpopulation was generally consistent with that in the overall study population, although there was a numerically higher rate of herpes zoster. These analyses are limited by low pt numbers and the absence of a comparator arm.

References
DOP78 Intestinal surgery rates in ulcerative colitis and Crohn’s disease in the era of biologics: A Danish Nationwide Register Study from 2003 to 2016
Authors: Vadstrup K , Alulis S , Borsi A , Olsen J , Jørgensen T R , Munkholm P , Qvist N
Published: January 2020

Background

Biologic response modifiers (biologics) has been introduced as potent drugs for the treatment of Crohn’s disease (CD) and ulcerative colitis (UC). Whether this has resulted in a reduction in the need for surgical treatment is controversial. This study aims to explore the surgery rates of patients diagnosed with CD and UC between 2003 and 2015 and correlate to those treated with biologics or not in Denmark with a follow-up until 2016.

Methods

This national register study included patients diagnosed between 2003 and 2015 and followed up until 2016, identified in the Danish National Patient Registry (NPR). Biologic therapies available in (parts of) the study period were infliximab, adalimumab, vedolizumab and golimumab. Surgery rates were identified through three types: bowel resections (code KJFB), total colectomies (code KJFH) and resections and excisions of the rectum (code KJGB). The share of patients undergoing surgery or initiating and receiving biologic treatment in each year was analysed. Additionally, patients undergoing surgery were stratified to receiving biological treatment in a period before the surgery or not and the time to first surgery was investigated.

Results

Among 10,302 CD patients and 22,144 UC patients, 2,328 CD patients and 2,128 UC patients underwent intestinal resection. Numbers were driven by the two first surgery codes (97% for CD and 93% for UC), and >1 resection was observed in 20% of the CD cases and more in the UC cases (40%), as expected due to reoperations. In the same period, 2,939 and 2,504 patients were treated with biologics for CD and UC, respectively, with an increase observed over the years. The vast majority were treated with an anti-TNF-α biologic, as vedolizumab was not approved in Denmark before 2015. We observed similar surgery rates of patients receiving biologics compared with those not treated with biologics. However, the time period from diagnosis to first intestinal surgery was observed to be longer for the patients treated with biologics (Figure1).

Conclusion

The number of patients undergoing intestinal resections or initiating biologic treatments after diagnosis increased throughout the study period for the full population. The risk of intestinal resections was similar in the group of patients who received biologicals compared with the group who did not, but the treatment seemed to postpone surgery in both diseases.
DOP82 Macrophages in Crohn’s disease mesentery are predominantly inflammatory and produce calprotectin
Authors: Bloemendaal F M , Becker M , Koelink P J , van der Bilt J D , Bemelman W A , D’Haens G R A M , Buskens C J , Wildenberg M E
Published: January 2020

Background

Alterations in the mesentery of Crohn’s disease (CD) patients have long been described, although the functional importance of this tissue is less clear. Some studies hypothesise an anti-inflammatory role for enhanced mesentery, whereas others consider a more pathologic function, given its close proximity to the inflamed intestine. Better phenotypic and functional evaluation of the cells present in this tissue is warranted to improve our understanding of its role in disease. We have previously shown a disproportionate presence of macrophages in CD mesorectum. In this study, we aimed to better characterise the phenotype and function of the macrophages in the mesentery in CD.

Methods

We collected mesenteric specimens from Crohn’s disease, ulcerative colitis (UC) and non-inflammatory bowel disease (IBD) patients, undergoing surgical bowel resections. In IBD patients, mesentery was collected contiguous to the inflamed region of the intestine, in non-IBD patients, mesentery adjacent to the resection margin. Macrophages were sorted by flow cytometry as CD45+ CD66b-CD14+CD11b+ cells. Sorted cells were analysed by expression profiling and functional analysis.

Results

Macrophages were present in all analysed tissues. Within the population, a discriminating expression pattern for CD11b was present, dividing CD14+ macrophages in a CD11bhigh and a CD11bdim subset. Transcriptional profiling and gene set enrichment showed the CD11bhigh population to be consistent with IFN-induced pro-inflammatory macrophages, while the CD11bdim population was most consistent with IL4-induced regulatory macrophages. Among the top upregulated genes in CD11bhigh macrophages were S100A8 and S100A9, the two heterodimeric subunits for calprotectin. Flow cytometry confirmed higher expression of calprotectin in the CD11bhigh population also on the protein level. Functionally, CD11bdim macrophages showed higher phagocytic capacity, again consistent a role in tissue repair. Strikingly, the CD11bdim subset was diminished significantly in the mesentery of CD patients, with a near absence in some patients, while the profile in UC was comparable to non-IBD patients.

Conclusion

Mesenteric macrophages contain two populations, CD11bhigh with a pro-inflammatory profile and CD11bdim with a regulatory profile. In the mesentery of CD patients, the CD11bdim population was strongly decreased, consistent with a pro-inflammatory role for this tissue.
P004 PN-943, an oral α4β7 integrin antagonist, inhibits MAdCAM1-mediated proliferation and cytokine release from CD4+ T cells independent of trafficking
Authors: CHENG L , Venkataraman S , Zhao L , Lee L , Tang T , Liu D , Mattheakis L
Published: January 2020

Background

PN-943, an oral gastrointestinal (GI) -restricted peptide antagonist of α4β7 integrin, is being developed for the treatment of inflammatory bowel disease (IBD). Blockade of α4β7 binding to mucosal addressin cell adhesion molecule-1 (MAdCAM1) is thought to treat IBD by preventing extravascular migration of blood T cells into the inflamed GI mucosa. Recent evidence suggests the involvement of other mechanisms. Saturation of circulating T-cell α4β7 by vedolizumab is not sufficient for optimal efficacy; and PTG-100, a PN-943 analogue, showed evidence of clinical and histological remission in ulcerative colitis patients at sub-saturating blood receptor occupancy (%RO). Here, we assessed the potential of a local GI-acting function of α4β7 by evaluating the ability of PN-943 to inhibit MAdCAM1-mediated CD4+ T-cell proliferation and cytokine production.

Methods

Primary CD4+ T cells were labelled fluorescently and incubated with plate-bound anti-CD3 alone or together with MAdCAM1 with or without inhibitors for three days. Phenotype, distribution of T-helper (Th) subsets and %RO analyses were conducted by flow cytometry. Supernatant cytokine levels were quantified by multiplex assays.

Results

MAdCAM1 combined with anti-CD3 markedly enhanced proliferation of CD4+ T cells compared with anti-CD3 alone (n = 7, 12–64%). Immune phenotyping revealed that proliferation occurred in both CD45RO- naïve and CD45RO+ memory T cells and was restricted to the β7+ population with successive cycles of proliferation showing increased β7 expression. Amongst the proliferated memory T cells, the percentage of the IFNγ-producing Th1 subset was higher than IL-17A-producing Th17 and IL-4-producing Th2 subsets. Multiplex profiling identified several cytokines, including but not limited to IL-6, IL-13, GM-CSF, and TNFα, whose release were promoted by MAdCAM1. PN-943 abolished MAdCAM1-mediated stimulation (n = 4, IC50 4.6 nM). The inhibitory effects were associated with lowered β7 expression indicative of internalisation by PN-943. Blockade was not observed with an inactive analogue indicating dependency on PN-943 binding to α4β7. Consistent with the requirement for a locally acting drug, 30 mg/kg oral dosing in mice demonstrated high exposure (n = 6, 39 nM) and occupancy of T-cell α4β7 (n = 6, 92%) in the GI compared within the blood.

Conclusion

The α4β7-MAdCAM1 interaction promoted β7+CD4+ T-cell proliferation and cytokine release, which may contribute to chronic inflammatory responses occurring in the diseased gut of IBD patients independent of T-cell trafficking. PN-943 inhibition of MAdCAM1-mediated signalling through α4β7 supports the potential therapeutic advantages for an oral GI-restricted approach, whereby PN-943 is delivered locally and directly blocks α4β7 function in the GI.
P005 Regulators of the guanylate cyclase pathway are potential novel markers of mucosal healing in IBD
Authors: Jeffery L E , Shivaji U N , Zardo D , Acharjee A , Nardone O M , Smith S C , Gkoutos G , Visweswariah S S , Ghosh S , Iacucci M
Published: January 2020

Background

Intestinal guanylate cyclase C (GC-C) present in epithelial cells has been shown to have a role in gut homeostasis. The downstream effects of activation of GC-C are due to production of cyclic-GMP. GC-C is encoded by the gene GUCY2C, mutations in which are implicated in Familial Diarrhoea Syndrome and noted as risk factors for Crohn’s disease. GUCY2C and its activator, GUCA2A have been shown to be downregulated in IBD. We hypothesised that regulation of this pathway might be important in remission and response to therapy.

Methods

Forty-four patients with IBD and 7 patients with polyps (controls) at University Hospitals Birmingham, UK were recruited under ethical consent. Relevant demographic and clinical data were extracted from the hospital EMR. All patients had disease activity recorded on endoscopic examination of mucosa and intestinal biopsies collected for analysis. Mucosal healing was defined as MES = 0 (UC) and SES-CD <6 (CD). Of 44 patients, 14 had matched baseline and 12-week post-biologic therapy assessment and had tissues collected. Intestinal biopsies were analysed by 3’RNA-sequencing using the Illumina Nextseq sequencer. FASTQ files were generated through BaseSpace and reads de-multiplexed, trimmed, aligned, and quantified using the GeneGlobe (Qiagen) workflow. Expression was compared between groups using either Wilcoxon tests or Kruskal–Wallis with Dunn post-hoc analysis as appropriate.

Results

Expression of Guanylate cyclase activators GUCA2A and GUCA2B in patients who showed mucosal healing was equivalent to controls, but GUCA2A was down-regulated in those with active disease (non-healing) (p = 0.006). The same pattern was observed for transcriptional regulators of GUCY2C, including HNF4A (p = 0.0248) and CDX2 (0.0062). Correspondingly, GUCY2C was reduced in non-healing mucosa, although the difference was not significant (Figure 1). In patients who responded to biologic therapy, both GUCA2A (p = 0.0234) and GUCA2B (p = 0.0117) were increased at follow-up but no change was observed for those who did not respond. Change in GUCY2C expression did not reach statistical significance in either group, although an increase was observed for a large proportion of responders.

Conclusion

Our findings suggest that regulation of the Guanylate Cyclase pathway may be involved in the restoration of a stable mucosa in IBD and that expression of its regulators may be used to indicate response to treatment.
P009 The innate cytokines IL-1α and TNF-α induce the expression of Oncostatin M and its type II receptor in human colonic subepithelial myofibroblasts
Authors: Filidou E , Kokkotis G , Tarapatzi G , Boulkou M , Arvanitidis K , Drygiannakis I , Valatas V , Koutroubakis I , Vradelis S , Kolios G , Bamias G
Published: January 2020

Background

Oncostatin M (OSM), a cytokine of the IL-6 family, has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Specifically, OSM and its receptor, OSMR, are elevated in inflamed colonic regions of IBD patients; in addition, high OSM expression at baseline has been associated with failure to respond to anti-TNF. OSMR expression localised in stromal cells of the intestinal lamina propria. Our aim was to investigate the expression of OSM and its receptors subunits, OSMR, LIFR and gp-130 in primary subepithelial myofibroblasts (SEMFs) and test whether this expression is regulated by the innate cytokines, IL-1α and TNF-α.

Methods

Primary SEMFs were isolated from endoscopically-obtained colonic biopsies from healthy controls, set to culture and stimulated with 5ng/ml IL-1α and/or 50ng/ml TNF-α for 6 h. Total RNA was extracted and the mRNA transcripts for OSM, OSMR, LIFR and gp-130 were measured by reverse transcription-quantitative (RT-q) PCR.

Results

Unstimulated SEMFs had a basal expression of both OSM and its receptors subunits. IL-1α or TNF-α stimulations did not alter LIFR expression, but they induced a statistically significant upregulation of OSM, OSMR and gp-130. Specifically, the expression of OSM in SEMFs was significantly upregulated after stimulation with IL-1α alone or in combination with TNF-α (IL-1α: 11.48-fold increase, 8.29–26.05; IL-1α+TNF-α: 13.42-fold, 11.32–17.16; p < 0.0001). Regarding the OSMR and gp-130 subunits [which form the type II receptor of OSM], OSMR mRNA was induced by TNF-α alone or in combination with IL-1α (TNF-α: 1.75-fold, 1.27–2.02, p < 0.01; IL-1α+TNF-α: 2.06-fold, 1.83–2.34, p < 0.0001), whereas gp-130 mRNA expression was increased under all stimulatory conditions (IL-1α: 1.94-fold, 1.46–2.07; TNF-α: 1.81-fold, 1.46–2.25; IL-1α+TNF-α: 1.59-fold, 1.31–2.51; p < 0.01 for all comparisons).

Conclusion

Our results show that OSM and OSMR are expressed on primary human SEMFs and that they are upregulated under stimulation with innate pro-inflammatory cytokines. These data further support a potential role of this system of inflammatory mediators in the pathogenesis of intestinal inflammation.
P011 Dysbiosis and Goblet cells depletion triggers early intestinal barrier dysfunction that precedes gut inflammation in IL-10 deficient mice (IL-10−/−)
Authors: López Cauce B , Puerto M , García J J , Miranda-Bautista J , Vaquero J , Bañares R , Menchén L
Published: January 2020

Background

Interleukin-10 deficient mouse (IL-10−/−) is a widely used model of spontaneous ileocolitis that resembles human inflammatory bowel disease (IBD); intestinal barrier dysfunction is an early pathophysiological event, but its underlying mechanisms are still unknown. The objective of this work is to study the natural history of ileocolitis in IL-10−/−, and unravel the influence of intestinal barrier dysfunction and dysbiosis in the development of overt inflammation.

Methods

Wild-type (WT) and IL-10−/− mice were followed until sacrifice at 3, 5, 10, 20, 57 and 70 weeks of life. Bodyweight, colonic weight/length ratio and in vivo intestinal permeability (measured by rectal administration of FITC-dextran) were registered. After the sacrifice, the colon was harvested and the evaluation of the expression of inflammatory (interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), inducible nitric synthase (iNOS) and cyclooxygenase-2 (COX-2) and epithelial permeability (ZO-1, E-cadherin, Occludin, Claudins 2 and 7, and Reticulon-4B (RTN-4B) markers was performed by qPCR; expression of mucin-2 (MUC-2) and molecules involved in goblet cell maturation such as interleukin-18 (IL-18) and WAP Four-Disulphide Core Domain 2 (WFDC2), as well as the endoplasmic reticulum stress marker X-box-binding protein (Xbp)-1) by qPCR were also analysed. We also used colon slices for histologic evaluation with haematoxylin-eosin and alcian blue stainings. The microbiota composition was studied by sequencing of the V3-V4 regions of ribosomal 16S from faecal samples of all these mice.

Results

Compared with WT, IL-10−/− mice showed lower weight gain at all ages and a higher colonic weight/length ratio and histological evidence of inflammation at weeks 20 and 57. iNOS and IL-1b gene expression in the colon were significantly higher in IL-10−/− mice at weeks 10 and 20, respectively. Nevertheless, increased intestinal permeability was observed from week 10; the number of goblet cells and expression of MUC-2, IL-18, WFDC2 and XBP-1 were significantly lower in knockout mice from week 10. Moreover, dysbiosis in IL-10−/− mice began at week 5, increasing at 10 and showing the lowest diversity and appearance of pathogenic families at 20 weeks of age.

Conclusion

Dysbiosis and goblet cell depletion in the colon of IL-10−/− mice are associated with early intestinal barrier dysfunction, and precede overt gut inflammation in this animal model of IBD.
P012 α4β7 Receptor occupancy by vedolizumab at trough time-point occurs at the membranal level and is not associated with endoscopic healing in inflammatory bowel disease patients
Authors: Ungar B , Ben-Shatach Z , Haj-Natour O , Yavzori M , Fudim E , Picard O , Coscas D , Lahat A , Lidar M , Eliakim R , Kopylov U , Ben-Horin S
Published: January 2020

Background

Previous studies have shown inconclusive associations between vedolizumab trough levels and therapy outcomes. A near-complete occupancy of blood and intestinal α4β7 was exerted by vedolizumab through a wide-range of drug levels, regardless of clinical outcomes. However, these observations were not conducted specifically at the time of trough drug levels, did not include α4β7 highly expressing eosinophils and did not establish whether occupancy is in fact due to fully internalised VDZ- α4β7 complex in the target T-cell.

Methods

Peripheral blood (PB) and intestinal lamina propria (LP) were collected from IBD patients undergoing lower endoscopies on the day of vedolizumab infusion (trough time-point). Clinical and endoscopic scores were prospectively recorded. FACS analysis was performed using fluorescent conjugated-vedolizumab to investigate α4β7 occupancy on effector-memory T cells (CD3+CD45RO+ cells) and on eosinophils (CD49d+CD294+) in PB. Using a newly-developed dissociation assay, we also assessed the degree of membrane-bound VDZ-mediated blocked- α4β7.

Results

Forty-five IBD patients (16, 35% Crohn’s patients, 18, 40% in endoscopic remission) underwent clinical and endoscopic assessment just before their scheduled vedolizumab infusions. The median percentage of free α4β7 receptors at trough was 1.3% (IQR 0.5–3.7%) for PB T cells and 7.2% (IQR 3.6–23.4%) for LP T cells. No statistically significant difference was detected in α4β7 receptor saturation between patients with and without mucosal healing, both for PB (free α4β7 receptors: median 0.5%, 1.46%, IQR 0.3–1.4%, 0.9–3.5% respectively, p = 0.15) and for LP (free α4β7 receptors, median: 11.5%, 7%, IQR 3.5–24.2%, 5.8–20.9%, p = 0.88). Similarly, almost complete α4β7 receptor saturation at trough was detected among PB eosinophils (1.5% free α4β7 receptors, IQR 0.9–2.6%). Upon dissociation assay, a significant number of membrane-bound α4β7 receptors became detectable both on PB and LP T cells, with medians of 31% (IQR 24–41%), 22.2% (IQR 15–31%) respectively, and also for eosinophils, with a median of 83% (IQR 67–89%). When compared with values before dissociation, the proportion of unbound receptors was considerably lower (p < 0.001 for all analyses, respectively).

Conclusion

Even at trough, almost complete α4β7 receptor saturation is reached, both for PB and LP T cells, as well as for PB eosinophils, regardless of endoscopic activity status. This receptor occupancy is unrelated to receptor-internalisation and reflects a complete and continuous antigen-binding at the membranal level.
P017 C86/CD16 macrophages accumulate in the mucosa of B3 patients and could mediate EMT in Crohn’s disease
Authors: Boronat-Muñoz A , Cejudo-Garces A , Lledo-Gil P , Cosín-Roger J , Coll S , Navarro-Vicente F , Alos R , Calatayud S , Barrachina M D , Ortiz-Masiá D
Published: January 2020

Background

Macrophages contribute to fibrosis through the release of different mediators and the pattern of secretion may vary according to their phenotype.

Methods

The aim of the present study is to analyse the pattern of expression of macrophages, of EMT-related genes and cytokines in surgical resections from Crohn’s disease (CD, n = 43) patients which were categorised according to Montreal classification (B2 or B3); unaffected mucosa of patients with ileocecal cancer was used as control (n = 20). mRNA was isolated from intestinal samples and the expression of macrophage, EMT markers and cytokines were analysed by RT-PCR. PBMCS were isolated from healthy donors and treated during 5 days with secretomes, from control, B2 or B3 surgical resections; the mRNA expression of macrophage markers was determined by RT-PCR. U937 cells were differentiated to macrophages and then treated with IFNγ (20 ng/ml) for 4 days, the mRNA expression of macrophages markers were determined by RT-PCR. Results are expressed as mean ± SEM (n ≥ 5). Statistical analysis was performed by ANOVA + Newman–Keuls or t-test. Correlations between data were analysed using Pearson’s correlation coefficient (*p < 0.05).

Results

The expression of CD16 and CD86 was significantly higher in intestinal samples from B3 CD patients (7.2 ± 1.1 and 7.7 ± 1.3, respectively) than in controls (1.4 ± 0.2 and 2.5 ± 0.4, respectively) or B2 CD patients (4.8 ± 0.9 and 4.5 ± 0.6, respectively). The mRNA expression of CD16 and CD86 were significantly higher in PBMCS treated with B3-secretomes than in those treated with B2- or control secretomes. The expression of CD16 and CD86 significantly correlated with FSP1 (r = 0.74, p = 0.002* and r = 0.66, p = 0.003*, respectively), VIMENTIN (r = 0.60, p = 0.02* and r = 0.82, p = 0.001*, respectively), SNAIL1 (r = 0.61, p < 0.01* r = 0.52, p = 0.04*, respectively), IL4 (r = 0.63, p = 0.01* and r = 0.60, p = 0.02*, respectively) and IFNγ (r = 0.56, p = 0.001* and r = 0.58, p = 0.01*, respectively) in intestinal tissue from the fistulising CD group. U937 cells treated with IFNγ increased significantly the mRNA expression of CD16 (1.94 ± 0.24* vs. vehicle) and CD86 (1.60 ± 0.17* vs. vehicle).

Conclusion

A macrophage phenotype expressing CD86/CD16 may act as a source of EMT mediators in intestinal tissue from CD patients with a penetrating (B3) behaviour. IFNγ could be responsible for the increase in the number of CD86/CD16 macrophages in the B3 behaviour.