bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP21 Role of P2X7 in intestinal fibrosis and inflammasome activation: Relevance in Crohn′s Disease
Authors: Lis-López L , Bauset C , Ortiz-Masia D , Gisbert-Ferrándiz L , Coll S , Calatayud S , Barrachina M D , Cosín-Roger J 
Published: May 2021

Abstract

Background
Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract whose etiology is unknown. CD is associated with complications such as fibrosis or fistula, which cannot be pharmacologically reversed, requiring repeated surgery. Although a profibrotic effect of the P2X7 receptor has been described in some scenarios such as lung, heart and liver, its role in intestinal fibrosis has not been analysed yet. Given the crosstalk between fibrosis and inflammasome, we aim to analyze the relevance of P2X7 in intestinal fibrosis and inflammasome activation.

Methods
Surgical intestinal resections of CD patients and healthy ileum of carcinoma patients were obtained. Murine chronic colitis was induced by 4 cycles of DSS in wild-type (WT) or P2X7-/- (KO) mice. HT29 cells were treated 24 hours with an inflammasome activator cocktail (LPS, TNF-α and IFN-γ) and the P2X7 antagonist A-80. Gene and protein expression of P2X7, inflammasome markers (NLRP3, ASC, CASPASE1, IL1β and IL18) and alternative inflammasome pathways (APIs) (NLRP1, NLRC4 and AIM2) were analysed by qPCR and Western Blot. The collagen layer was analysed by Sirius Red Staining. Results are expressed by mean±SEM. Statistical analysis was performed with one-way ANOVA and correlations were analysed with Spearman coefficient.

Results
In CD patients, the expression of P2X7 (2.97±0.50), Nlrp3 (2.53±0.41), Asc (5.61±0.76), Caspase1 (6.90±1.41), IL18 (4.17±0.89) and APIs Nlrp1 (3.07±0.40), Nlrc4 (6.99±1.19) is significantly increased vs non-IBD patients. Moreover, P2X7 expression positively and significantly correlates with the expression of the inflammasome markers NLRP3 (r=0.51), ASC (r=0.38), CASPASE1 (r=0.46), IL18 (r=0.36) and API such as NLRP1 (r=0.73), NRLC4 (r=0.67) and AIM2 (r=0.51) in CD patients (n≥45). The chronic murine model of DSS revealed that: a) KO-DSS showed more aggravated colitis with lower survival and greater weight loss compared with WT-DSS; b) the expression of NLRP3, IL18, IL1β and NLRP1 were significantly increased in KO-DSS (101.00±16.33, 3.28±1.49, 327.50±113.90, 4.92±1.00 respectively) vs WT-DSS; c) the thickness of the collagen layer in KO-DSS was increased vs WT-DSS. As expected, HT29 cells treated with the inflammasome cocktail increased protein expression of caspase-1 and the treatment with the P2X7 antagonist A-80 impaired the inflammasome activation since it significantly reduced the protein expression of caspase-1.

Conclusion
An increased expression of P2X7 receptor, the inflammasome and its APIs is detected in CD patients. Lack of P2X7 worsens chronic colitis associated with an increased activation of the inflammasome. Additional studies are needed in order to elucidate this dual role of P2X7 in intestinal fibrosis.
DOP38 An observational study to evaluate the burden of illness in patients with Crohn’s Disease with and without perianal fistulas in the USA
Authors: Jiang J , Cazzetta S E , Athavale A , Kuharic M , Fan T , Silber A , Vijay A , Hadker N , Sharpe E , Nazarey P P 
Published: May 2021

Abstract

Background
Crohn’s disease (CD) is a chronic inflammatory condition of the gastrointestinal tract that can lead to complications such as perianal fistulas (PAFs). This study compared disease burden, experiences and health-related quality of life between patients who have CD with PAFs (CPF) and those who have CD without PAFs (non-PAF CD).

Methods
This cross-sectional, observational study was conducted in three cohorts of US patients aged 18–89 years with self-reported physician-diagnosed CD: (1) non-PAF CD; (2) CPF without PAF-related surgery; and (3) CPF with PAF-related surgery. Data on medical and surgical interventions, CD-specific symptoms and Fecal Incontinence Quality of Life (FIQL) were collected via a web-enabled questionnaire. Statistical comparisons were assessed at the 0.05 level.

Results
The mean (standard deviation) age of patients in cohorts 1 (n = 300), 2 (n = 51) and 3 (n = 52) was 47 (16.4), 40 (12.2) and 39 (13.1) years, respectively. In patients with CPF (cohort 2 + 3), 59 (57%) reported multiple fistulas and 48 (47%) reported fistula recurrence/persistence. Compared with cohort 1 (non-PAF CD), more patients with CPF reported currently receiving biologic treatment or immunomodulators for CD (58% vs 43% and 23% vs 15%, respectively; both p = 0.01). More patients with CPF also reported undergoing ≥ 1 CD-related surgery and experiencing ≥ 1 failures of CD-related surgery (79% and 20%, respectively) versus cohort 1 (53% and 9%, respectively; both p &lt; 0.001). In cohort 3, 63% of patients had ≥ 3 PAF-related surgeries, and in those receiving seton placement (n = 37), 8% reported placement failure. Post-surgical/seton placement complications were common; the most frequently reported were worsening of pain and swelling around the anus (33%) and fever/infection (29%).
CD-specific symptom frequency and severity results indicated a high symptom burden across cohorts; fatigue was reported with the highest frequency and severity. Faecal incontinence (FI) and leakage-related symptoms affected greater proportions of patients in cohorts 2 and 3, often with greater severity and frequency, compared with cohort 1 (Fig.1). Across all cohorts, 58% of patients (cohort 1/2/3, n = 158/35/40) reported experiencing FI and completed the FIQL questionnaire: cohorts 2 and 3 reported lower (worse) FIQL scores across domains than cohort 1 (Fig.2).

Conclusion
The burden of illness in patients with CPF is substantial, with medical and surgical intervention rates, and symptom severity and frequency greater than for those with non-PAF CD. Higher disease burden, including FI, was noted in patients with CPF compared with the non-PAF CD cohort. An unmet need remains for improved management and outcomes of CPF.
Sponsor: Takeda Pharmaceuticals USA, Inc.
DOP45 Utilization and sustainability of biologics in CD - A nationwide study from the epi-IIRN
Authors: Atia O , Yogev D , Chagit F , Gili F , Orlanski-Meyer E , Magen Rimon R , Natan L , Shira G , Kariv R , Yisca L W , Gabay H , Nevo D , Matz E , Gorelik Y , Chowers Y , Iris D , Turner D 
Published: May 2021

Abstract

Background
Real-world studies demonstrate that ~33% of CD patients fail to respond to induction therapy with biologics. In this nationwide study we aimed to evaluate trends in biologics utilization and sustainability in CD during the last 15 years.

Methods
This study was performed on data from the four Israeli Health Maintenance Organizations, covering 98% of the population. Sustainability was defined as continuous treatment without IBD-related surgeries and at most one short steroid course. Sustainability was compared across different biologics utilizing a propensity score (PS) weighted analysis, estimated by generalized boosted modeling (GBM).

Results
16,936 patients were diagnosed with CD in Israel since 2005 (2,932 [17%] pediatric-onset, 14,004 [83%] adult-onset), of whom 5,804 (34%) were ever treated with biologics (1,659 [57%] pediatric-onset, 4,145 adults [30%], OR 3.1 [95%CI 2.9–3.4]) with a median of 6.4 years follow up (IQR 3.4–9.9). Infliximab was the most common first-line treatment in children (58%, p&lt;0.001), while adalimumab was the most common in adults (63%, p&lt;0.001). However, in recent years there was an increase in adalimumab and vedolizumab utilization in parallel with a decrease in infliximab (Figure). The rate of initiating biologics in the first year of diagnosis increased from 20% among all biologics users during 2005–2010 through 36% during 2011–2014 and 74% since 2015 (p&lt;0.001). The use of combination therapy with immunomodulators is becoming less common in last years and decreased in infliximab from 38% until 2010 to 21% in 2018 (P&lt;0.001) and in adalimumab from 22% to 7%, respectively (p&lt;0.001). The sustainability rate in those treated with infliximab was 65% at one year from initiation of biologics, and 46% and 42% at three and five years, thereafter; compared to 72%, 61% and 57% with adalimumab and 84% and 80% after one and two years in vedolizumab. The rate of primary non-response was 21% with infliximab, 17% with adalimumab and 12% with vedolizumab.
Sustainability was associated with male sex (HR 0.9 [95%CI 0.8–0.95]) and earlier initiation of biologics (HR 0.92 [95%CI 0.9–0.95]). In the PS-adjusted model the sustainability of both infliximab (HR 0.7 [95%CI 0.6–0.8]) and vedolizumab (HR 0.8 [95%CI 0.7–0.95]) were lower than adalimumab. Compared with monotherapy, combination therapy did not change significantly the sustainability rate of all three biologics (adalimumab: HR 1.3 [95%CI 0.8–2.1], infliximab: HR 1.2 [95%CI 0.7–1.9], and vedolizumab: HR 0.8 [95%CI 0.5–1.3]).

Conclusion
Biologics are being increasingly used in CD and earlier during the disease course, but most patients do not sustain treatment at five years. Sustainability rate was higher with adalimumab compared with either infliximab or vedolizumab
DOP51 De-escalation of biological therapy in Inflammatory Bowel Disease patients following prior escalation
Authors: Thomas P , Smits L , Te Groen M , West R , Russel M , Jansen J , Römkens T , Hoentjen F 
Published: May 2021

Abstract

Background
There are limited data available on de-escalation of biological therapy after prior escalation in inflammatory bowel disease (IBD) patients. The aim of this study was to assess the frequency and success rate of de-escalation of biological therapy in IBD patients after prior dose escalation and evaluate which measures are used prior to de-escalation.

Methods
This multicentre, prospective, cohort study enrolled IBD patients treated with infliximab (IFX), adalimumab (ADA) or vedolizumab (VEDO) in whom therapy was de-escalated at least once after prior biological escalation. Objective disease measures for de-escalation were defined as faecal calprotectin ≤ 200 µg/g and/or therapeutic or supratherapeutic trough levels and/or radiologic or endoscopic remission. Successful de-escalation was defined as remaining on the same or lower biological dose for ≥6 months after de-escalation.

Results
In total, 206 IFX users, 85 ADA users and 55 VEDO users underwent therapy escalation. Of these, 34 (17%) patients on IFX, 18 (21%) patients on ADA and 8 (15%) patients on VEDO had received at least one subsequent de-escalation. De-escalation was successful in 91% of IFX patients, 89% of ADA patients and 100% of VEDO patients. The probability of remaining on the de-escalated regimen or further de-escalation after 1 year was 85% for IFX, 62% for ADA and 100% for VEDO. De-escalation based on objective disease measures was performed in 67% of all de-escalations. Objective de-escalations were successful in 98% versus 80% of subjective de-escalations.

Conclusion
De-escalation after biological escalation is successful in the majority of patients. Objective markers of remission increase the likelihood of successful de-escalation.
DOP88 Effect of risankizumab on patient-reported outcomes in patients with Crohn’s Disease who had an inadequate response or intolerance to conventional and/or biologic treatments: Results from phase 3 MOTIVATE and ADVANCE trials
Authors: Peyrin-Biroulet L , Louis E , Ghosh S , Lee S D , Griffith J , Wallace K , Berg S , Loftus E V 
Published: May 2021

Abstract

Background
Risankizumab (RZB), an IL-23 inhibitor, is being investigated for Crohn’s disease (CD). MOTIVATE (NCT03105128) and ADVANCE (NCT03104413) were two double-blind, randomised, placebo (PBO)-controlled phase 3 trials evaluating the efficacy and safety of RZB as induction therapy for CD after inadequate response or intolerance to biologic treatment, or conventional or biologic treatment. We investigated the effect of RZB on patient-reported outcomes (PROs) in these two trials.

Methods
Patients with moderately to severely active CD (CD activity index of 220–450, Simple Endoscopic Score for CD excluding the narrowing component ≥ 6 or ≥ 4 for isolated ileal disease, and average daily stool frequency ≥ 4 and/or average daily abdominal pain score ≥ 2) were randomised 1:1:1 (MOTIVATE; N=569) or 2:2:1 (ADVANCE; N=850) to intravenous RZB 600 mg, RZB 1200 mg or PBO at Weeks 0, 4 and 8. PROs assessed were Inflammatory Bowel Disease Questionnaire (IBDQ), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and 36-Item Short Form Health Survey (SF 36). Least-squares mean change from baseline to Week 4 and 12 were assessed for each PRO. Additionally, the proportion of patients achieving IBDQ remission (IBDQ total score ≥ 170 points) was evaluated. Comparisons between RZB dosage groups and PBO were based on Cochran-Mantel-Haenszel or chi-square/Fisher’s exact tests; missing data were reported using non-responder imputation.

Results
In the MOTIVATE (100% biologic inadequate responder [bio-IR]) and ADVANCE (57% bio-IR) trials, significant (P&lt;0.05) improvements in nearly all PROs evaluated were seen as early as Week 4 (Figures 1–4). At Week 12, significant improvements in all PROs were reported for both doses of RZB compared with PBO in both trials, except for the SF-36 Mental Component Summary score (RZB 1200 mg in MOTIVATE), which improved, but not significantly. In MOTIVATE, at Week 4 and 12, IBDQ remission was achieved by significantly (P&lt;0.05) more patients taking RZB (600 mg, 25.1%/38.3%; RZB 1200 mg, 31.9%/44.6%) than PBO (15.5%/26.8%). Results were similar in ADVANCE: RZB 600 mg 30.9%/44.5%, RZB 1200 mg 33.7%/51.5%, and PBO 18.4%/29.8% at weeks 4 and 12, respectively (P&lt;0.001 for both RZB groups compared to PBO).

Conclusion
Patients with active CD and an inadequate response to conventional or biologic treatment who received RZB (600 mg or 1200 mg) induction therapy reported significant improvements in disease-specific (IBDQ) and general health-related PROs (FACIT and SF-36) compared with PBO, with improvements seen as early as Week 4.
Funding statement: Study was funded by AbbVie.
Acknowledgement: Medical writing support was provided by Joann Hettasch of Fishawack Facilitate Ltd, and was funded by AbbVie.
N04 Being an IBD Clinical Nurse Specialist in the UK National Health Service: Challenges, Stressors and Coping Mechanisms
Authors: Dibley L , Kemp K , Duncan J , Mason I , Lisa Y 
Published: May 2021

Abstract

Background
Inflammatory Bowel Disease Clinical Nurse Specialists (IBD-CNSs) provide essential therapeutic and emotional support services to patients with often complex disease. The ever-increasing role expectations, treatment modalities and rising patient population places significant demands on IBD-CNSs (Stansfield, 2019), many of whom enter the role soon after qualifying. Posts in the UK-based RCN IBD Nurse Facebook© page suggest stress is high amongst members. Sustaining IBD-CNSs wellbeing is essential for ensuring sustainability of services. Our aim was to explore experiences of being an IBD-CNS in the UK, in order to inform the wider dialogue around workforce and the wellbeing of specialist nurses.

Methods
This hermeneutic phenomenological study used purposive sampling with maximum variation to recruit Band 6–8 IBD-CNSs who currently, or until recently, worked in NHS Trusts across the UK. Data were collected between July and September 2020, via online or telephone interviews. Focussing on personal perceptions, participants were invited to ‘Tell me what it means to be an IBD-CNS’ with follow-up prompts and probes as needed. Diekelmann et al’s (1989) team analysis method was used.

Results
Twenty-five IBD-CNSs participated [92% Female; Band 6 (n=3), Band 7 (n=10), Band 8 (n=13); 0.5–19 (mean 5.8) years in post; ex-NHS (n=4)]. Two constitutive patterns: ‘Giving and receiving support’, and ‘Developing potential’ were revealed, informed by relational themes addressing patients’ needs, service design/delivery challenges, workload, professional development opportunities, and peer support. Junior IBD-CNSs worried more about workload and learning the role, whilst senior nurses often struggled with the shift towards management responsibilities which they were expected to take on often without any managerial skills or training. The IBD-CNS role was often poorly understood by senior service managers, whose level of support varied widely. Some participants had techniques to mitigate against stressors, but there were also limited professional development opportunities especially in senior roles.

Conclusion
IBD-CNSs are committed to patients, despite an often-burdensome workload. Structural, institutional, and hierarchical issues undermine confidence. Many IBD-CNSs are stressed by mixed messages of delivering an excellent service yet being criticised/under-appreciated by the system. Robust senior support structures lead to better experiences for IBD-CNSs. This work contributes to the UK and global data evidencing the need to pursue strategies which promote wellbeing of all specialist nurses.
N08 Construction of an explanatory model for quality of life in outpatients with ulcerative colitis
Authors: Takahashi M , Nunotani M , Aoyama N 
Published: May 2021

Abstract

Background
Previous studies have reported explanatory models of health-related quality of life (HRQoL) in patients with Crohn disease or inflammatory bowel disease. However, no model for HRQoL has been developed that is specialised for patients with ulcerative colitis (UC). In this study, we aimed to develop and evaluate a predictive explanatory model for HRQoL among outpatients with UC in Japan.

Methods
We conducted a cross-sectional survey between December 2019 and July 2020 at a clinic in Japan. HRQoL was evaluated using the 32-item Inflammatory Bowel Disease Questionnaire (IBDQ-32). We extracted explanatory variables of HRQoL, including disease activity, psychological symptoms, and social support, from previous studies and created an explanatory model based on the conceptual model of Wilson & Cleary (1995). The relationship between explanatory variables and the IBDQ-32 total score was examined using the Spearman’s rank correlation coefficient, Mann–Whitney test, or Kruskal–Wallis test. We conducted multiple regression analysis and path analysis to examine the effect of explanatory variables on IBDQ-32 total score.

Results
We included a total of 203 patients with UC. Variables that were significantly associated with the IBDQ-32 total score were partial Mayo Score, presence or absence of treatment side effects, Hospital Anxiety and Depression Scale (HADS) score, and having/not having an adviser when patients were severely ill-conditioned. HADS had the largest negative effect on IBDQ-32 total score (β = −0.474), followed by partial Mayo Score (β = −0.408), presence/absence of treatment side effects (β = −0.116), having/not having an adviser when patients were ill-conditioned (β = 0.081). Having an adviser or not when ill-conditioned had an indirect effect on patients’ IBDQ-32 total score via HADS (β = −0.111). We verified the final model, which included IBDQ-32 total score and the above four explanatory variables (adjusted R² = 0.501, GFI = 0.996, AGFI = 0.970, CFI = 1.000, RMSEA = 0.010, AIC = 28.043).

Conclusion
Psychological symptoms had the most direct effect on HRQoL in patients with UC and acted as a mediator in the relationship between social support and HRQoL. Nursing interventions to improve HRQoL in patients with UC should consider the effect of psychological symptoms and support when patients are severely ill-conditioned.
N09 Sexuality as lived incompleteness: exploring intimacy and sexuality experiences of people living with inflammatory bowel disease
Authors: Fourie S , Norton C , Jackson D , Czuber-Dochan W 
Published: May 2021

Abstract

Background
Sexual function in those living with Inflammatory Bowel Disease (IBD) is known to be affected by their condition, with impact on their psychosocial well-being. Little is known about the causality of low sexual functions scores and their contribution to low quality of life reports. The aim of this study was to explore how intimacy and sexuality is experienced in the context of IBD.

Methods
This was a phenomenological study guided by van Manen’s methodology. Data were collected from 43 participants from interviews and narrative accounts submitted via Google Forms. Reflection on four existential domains (body, relationships, space and time) and thematic analysis were used to interpret the data.

Results
Four themes were generated from data analysis: Otherness of the sick body, Interrupted connectedness, Missing out on life fullness and Fragmented openness. These led to the overarching theme Sexuality as lived incompleteness, which reflected the essence of the experiences described by participants. Their experiences were deeply embedded in everyday life, and the IBD posed an obstacle to intimacy and sexuality, negatively affecting their life, relationships, family planning and their social position, imposing limitations and isolation.

Conclusion
IBD has a significant impact on sexual well-being with negative effects on overall quality of life, which may be unknown to healthcare professionals, therefore remain unaddressed. A better understanding of the potential issues could help healthcare professionals identify and address concerns and worries related to sexual well-being, and approach them in a reflective, holistic manner in situations arising in practice.
P013 Potential Role of Epithelial Protein Disulphide Isomerases in Crohn’s Disease Fibrosis
Authors: Vieujean S , Hu S , Bequet E , Salée C , Massot C , Bletard N , Pierre N , Quesada Calvo F , Baiwir D , Mazzucchelli G , De Pauw E , Coimbra Marques C , Delvenne P , Edouard L , Meuwis M A 
Published: May 2021

Abstract

Background
Intestinal fibrosis is a common complication of Crohn’s disease (CD) characterized by an accumulation of fibroblasts differentiating into activated myofibroblasts secreting excessive extracellular matrix. In in-vitro experiments, this myofibroblastic differentiation is elicited by a whole series of factors among which transforming growth factor-β1 (TGF-β1) seems to play a key role. The potential role of the intestinal epithelium in this fibrotic process remains poorly defined.

Methods
We performed a pilot proteomic study comparing the proteome of surface epithelium isolated by laser-capture microdissection in normal and fibrotic zones of resected ileal CD strictures (13 zones collected in 5 patients). The pro-fibrotic role of selected epithelial proteins was investigated through in-vitro experiments using HT-29 epithelial cells and a CCD-18Co fibroblast to myofibroblast differentiation model.

Results
Proteomic study revealed an endoplasmic reticulum (ER) stress proteins increase in the epithelium of CD ileal fibrotic strictures, including Anterior gradient protein 2 homolog (AGR2), Protein disulphide isomerase A6 (PDIA6) and Endoplasmic reticulum resident protein 44 (ERP44) which are 3 protein disulphide isomerases. In HT-29 cells, tunicamycin-induced ER stress triggered AGR2, PDIA6, ERP44 as well as TGF-β1 intracellular expression and their secretion. Supernatant of these HT-29 cells, pre-conditioned by tunicamycin (Tm), led to a myofibroblastic differentiation when applied on CCD-18Co fibroblasts. The application of blocking agents for AGR2, PDIA6, ERP44 or TGF-β1 in the supernatant of these Tm-pre-conditioned HT-29 cells, attenuated the myofibroblastic differentiation induced by this supernatant, suggesting a pro-fibrotic role of these secreted epithelial proteins.

Conclusion
The development of CD fibrotic strictures may involve ER stress in epithelial cells, releasing a whole set of proteins into their environment, including AGR2, PDIA6, ERP44 as well as TGF-β1, which could exercise a pro-fibrotic role through a paracrine action.