bluuebunny/crossref_metadata_2025_split huggingface dataset:
P111 Efficacy of a novel long-acting lipidated interleukin-22, alone and in combination with anti-TNF treatment, in a murine chronic DSS colitis model
Authors: Van De Bunt M , D'Alessio S , Norrild J C , Kjølbye A L , Jorgensen R 
Published: January 2023

Abstract

Background
Most current treatments and new agents in clinical development for Inflammatory Bowel Disease focus on inhibition of excessive inflammation. However, to break the ceiling on current clinical remission rates, new approaches, for example targeting mucosal healing, are needed. The cytokine interleukin-22 (IL-22) plays a key role in epithelial healing and has early proof-of-concept as a potential drug class in a phase 1 trial in Ulcerative Colitis. Here we present results from a mouse model of colitis demonstrating the efficacy of IL-22 agonism and complementarity with existing immunomodulatory treatment options.

Methods
Eight-week-old female C57Bl/6N mice (n=56) were subjected to a DSS-induced model of colitis; mice were given 2% (weight/volume) DSS in the drinking water for three 7-day cycles followed by 7 days of regular drinking water. Mice were treated from day 18 until the end of study with either vehicle, lipidated IL-22, an anti-murine TNF antibody at a suboptimal dose, a combination of the lipidated IL-22 and anti-TNF, and, as positive control, anti-murine TNF at an optimal dose. Colitis severity was monitored during the study and at study end endoscopic scoring was performed. Colon length and weight were measured, and histological analysis on formalin-fixed paraffin sections performed by a blinded pathologist.

Results
At termination, all treatment groups showed reduced body weight loss and improved DAI scores compared to vehicle treated animals, which was significant for all but the suboptimal anti-TNF group. Combination treatment resulted in an additive treatment effect compared to single treatment alone, with mean DAI improving by 13% and 48% for the anti-TNF and IL-22 groups alone versus 68% in combination. Similar effects were observed for the endoscopic and histological scores. The compositive endoscopic score improved by 21% (anti-TNF) and 55% (IL-22) versus 66% for the combination, and histological scores 22% and 52% versus 66%. These combination results likely represent the maximum response that can be achieved in the model, since the improvements obtained are the same as those for the treatment positive control for the model (68% and 62% improvements in endoscopic and histological scores, respectively).

Conclusion
A novel long-acting lipidated IL-22, which acts on epithelial repair mechanisms, demonstrated strong and significant improvements on all measured parameters in a chronic DSS model of colitis. Combining the IL-22 mode-of-action with an immunomodulatory agent, exemplified by a murine anti-TNF antibody, demonstrated the complementarity of IL-22 agonism to existing treatment options. Clinical trials to assess safety and tolerability of lipidated IL-22 are expected to commence at the start of 2023.
P115 Trehalose modulates Dextran Sulfate Sodium-induced colitis by regulating macrophage polarization
Authors: Li Y , Law H K W 
Published: January 2023

Abstract

Background
Inflammatory bowel disease (IBD) is a collective term for chronic inflammatory diseases resulting from complex genetic susceptibility, microbial flora, and immune abnormality. Due to the complicated pathogenesis, therapies for IBD are largely limited to the treatment of symptoms. However, these existing drugs sometimes fail or lead to adverse effects in long-term therapies. The development of new drugs and new therapies for IBD are still the top priorities. Trehalose (TRE) is an autophagy inducer through an mTOR-independent pathway. Given its safe and protective nature, TRE has gained significant attention for the potential application in disease treatment. It is a natural product that may be used as a harmless autophagy regulator. In our research, we use the Dextran Sulfate Sodium (DSS)-induced IBD model to explore the therapeutic effects of trehalose on autophagy and inflammation in mice.

Methods
6-8 weeks old C57BL/6J male mice were used for experiments. Mice were given 2% DSS (MP Biomedicals) in autoclaved drinking water for 4 days to induce colitis, Then TRE (2 g/kg body weight, Sigma-Aldrich), rapamycin (1.25mg/kg body weight, MedChemExpress) or normal saline were intraperitoneally injected for 5 days. Mice were weighed daily, and stool consistency, diarrhea, or blood in the stools were monitored to calculate the disease activity index (DAI). At the end of the experiment, the colons were measured, opened longitudinally, and handled according to standard procedures. The tissue samples were collected for RNA, protein extraction, histology, and macrophage isolation respectively. Western Blot was used for autophagy analysis and flow cytometry was used for macrophage subtype and apoptosis analysis. Besides, Real-time quantitative PCR assay was used for examining the cytokine expression.

Results
In TRE-treated mice, the cessation of diarrhea and anal bleeding occurred earlier and hence the DAI scores decreased more rapidly when compared to the other groups. Correspondingly, the colons in TRE-treated mice shortened less than the saline treated control suggesting recovery from DSS-induced colitis. Even though no significant difference was observed in H&E staining and tissue scores for mice in different groups, significant difference in macrophage polarization and cytokine production was observed. DSS-induced intestinal CD86+ macrophages, whereas TRE treatment increased CD206+ macrophages and decreased the expression of pro-inflammatory cytokines, such as IL-6 and TNF-alpha.

Conclusion
Our results demonstrate that TRE decreases the symptoms of experimental colitis by regulating macrophage polarization, probably mediated by macrophage autophagy. These findings indicate the potential of TRE to be an adjuvant therapy for IBD.
P118 Induction of ETS1 and senescence associated secretory phenotype in human intestinal fibroblasts
Authors: Seco-Cervera M , Argilés-Alberola D , Bauset C , Lis-López L , Coll S , Cosín-Roger J , Ortiz-Masià D , Calatayud S , Barrachina M D 
Published: January 2023

Abstract

Background
Fibrosis is a complication commonly present in Crohn’s disease (CD) patients with a structuring (B2) or penetrating (B3) behaviour, with no available treatment. This process is characterized by an excessive extracellular matrix deposition, mainly associated with a dysregulated function of myofibroblasts. We analyse here, the expression of markers of senescence in human intestinal fibroblasts.

Methods
Human small intestinal fibroblasts (HSIF; P10760, Innoprot, Spain) were treated during 48h with 2µg/mL of DLL4, 20ng/ml of TNFα, 2ng/ml of IL-1β, 5ng/ml of TGFβ1, and 100ng/ml of. In some cases, fibroblasts were treated with 20nM of siRNA to ETS1 gene (siETS21) or negative control (NC). Gene expression profiles were analysed by RT-qPCR.

Results
Treatment of fibroblasts with IL-1β significantly increased the mRNA expression of a) different senescence-associated secretory phenotype (SASP) factors (IL-1α, IL-1β, IL-8, and Serpine1); b) a metalloprotease ADAM12 and the chitinase CHI3L1 and c) the transcription factor related to senescence ETS proto-oncogene 1 (ETS1), all compared with vehicle treatment. Treatment with PDGF significantly increased the mRNA expression of ADAM12, ETS1, PTEN and the transcription factor, E2F5, while it induced a non-significant increase in the expression of senescence markers such as P16, P21, P53 and MCL1. Treatment with TGFβ1 did not significantly alter the expression of markers reported above and it only significantly increased the expression of IGFBP3 gene, another SASP factor. Both DLL4 and TNFα failed to significantly modify the expression of any of the above markers. Finally, a cellular model of depletion of ETS1 showed that siETS1 fibroblasts in basal conditions exhibited decreased levels of IL-8 and BCL2.

Conclusion
In human primary intestinal fibroblasts, treatment with IL1b increased the expression of senescence associated secretory phenotype while treatment with PDGF increased the expression of markers involved in cell cycle arrest. The induction of ETS1 by both treatments and the involvement of this transcription factor regulating gene expression in basal conditions, suggest a relevant role for ETS1 in the activation of intestinal fibroblasts
P120 Development and validation of a dedicated score to assess transmural response and transmural healing in patients with Crohn’s disease : final results of the DEVISE-CD project
Authors: Buisson A , Junda J , Vignette J , Lecoq E , Bouguen G , Pereira B , Hordonneau C 
Published: January 2023

Abstract

Background
Transmural healing (TH) is associated with better outcomes that endoscopic remission in Crohn’s disease (CD) but is not yet considered as therapeutic target owing to the lack of validated and consensual definition.
In the DEVISE-CD project, we aimed to 1) build and validate a dedicated score to assess transmural response (TR) and TH in CD patients and 2) to confirm that these definitions of TR and TH are associated with improved outcomes.

Methods
DEVISE-CD project included 3 parts: a monocenter cohort of development (N = 274 patients), a monocenter validation cohort (N = 224 patients) and a prospective multicenter validation study (N = 64 patients). Inclusion criteria are given in Figure 1.

Results
In the development cohort, persistence of edema after treatment (HR = 4.78[1.74-13.13], p=0.002), contrast enhancement (HR=4.13[1.50-11.36], p=0.006), diffusion-weighted hyperintensity (HR=6.97 [2.50-19.41], p&lt; 0.001), bowel thickening (HR = 3.73 [1.61- 8.66], p = 0.002), ulcers (HR = 1.90[1.21- 2.97], p=0.005), fat wrapping (HR=1.87 [1.22-2.87], p=0.004) and enlarged lymph nodes (HR=2.31 [1.48-3.63], p &lt; 0.001) were associated with increased risk of bowel damage progression, contrary to the extent of the lesions. The study of collinearity/coexistence of these different lesions showed that edema, bowel thickening, contrast enhancement, and diffusion-weighted hyperintensity coexisted in &gt; 95% of the cases, giving the same information. The bowel thickness (quantitative value) had the best sensitivity to change (mean difference standard = 0.30). C-score was obtained from a multivariable analysis of factors associated to bowel damage progression (Figure 2).

TH (C-score &lt; 0.5), TR50 (&gt; 50%-decrease of C-score in all active segments) or TR25 (&gt;25%-decrease) were associated with a reduced risk of bowel damage progression in the development cohort (HR=0.28[0.13-0.63], p=0.002; HR=0.30[0.15-0.63], p=0.001; HR=0.37[0.19-0.71], p=0.003, respectively) and in validation cohort (HR=0.15[0.04 -0.53], p=0.003; HR=0.36[0.14-0.88], p=0.025; HR=0.46[0.23-0.94], p=0.034; respectively).
In the multicenter study, TH, TR50 and TR25 rates were 28.3%, 41.3%, and 47.8%, respectively, after 12 weeks of anti-TNF and were associated with remission at W52(CDAI &lt; 150, faecal calprotectin &lt; 250 μg/g and no steroid) (OR = 4.6[1.3–15.6], p=0.016; OR=6.9[1.8–26.0], p=0.008; OR=6.0[1.6–22.3], p=0.008; respectively).

Conclusion
The C-score is a validated, reliable and easy-to-use tool that could be implemented in daily practice and clinical trials to assess therapeutic efficacy using news targets such as TH, TR50 and TR25.
P131 Is stress associated with subclinical inflammation in Ulcerative Colitis? A population-based cross-sectional cohort study in southeastern Sweden
Authors: Borghede M , Marsal J , Faresjö T , Hjortswang H 
Published: January 2023

Abstract

Background
Ulcerative colitis (UC) is an immune-mediated chronic inflammatory bowel disease with a relapsing course. Whether perceived stress affects the disease activity remains debated. This study aimed to investigate if clinical and subclinical disease activity, perceived stress, and hair cortisol concentration (HCC) are associated.

Methods
We performed a population-based cross-sectional cohort study with 200 randomly selected adult patients with UC living in the catchment area of Linköping University Hospital in southeastern Sweden. Demographic and disease-related data, bowel symptoms registration, the 14-item Perceived Stress Scale (PSS), the Short Health Scale (SHS), the Inflammatory Bowel Disease Questionnaire (IBDQ), fecal calprotectin (FC), CRP, and hair samples for hair cortisol concentration (HCC) were gathered. HCC has proven a reliable marker of long-term stress, with one centimeter of scalp hair accounting for approximately 4–6 weeks of stress level. A PRO2 score was calculated. Clinical remission was defined as a PRO2 score of zero.

Results
174 patients participated in the study (45.1% females). The median age was 52.0 years (IQR 40.0–65.0) and the median disease duration was 13.0 years (IQR 6.0–24.0). The median PSS score was 21.0 (IQR 16.0–27.0). 124 patients had a PRO2 score of zero. Patients in clinical remission had a significantly lower PSS score (median 21.0 (IQR 15.0–27.0)) compared to those with PRO2≥1 (median 24.0 (IQR 17.5–27.5)) (p&lt;0.01). Patients experiencing more perceived stress (PSS score&gt;21.0) had an impaired quality of life as measured with the SHS (p&lt;0.01) and the IBDQ (p&lt;0.01) compared with patients with lower PSS scores. The median FC was 43.1 µg/g, CRP 1.5 mg/l and HCC 24.7 pg/mg. HCC was lower in patients with clinically active disease (median 21.9 pg/mg) compared with patients in clinical remission (median 26.0 pg/mg) (p&lt;0.05). No significant differences in FC, CRP or HCC were detected comparing patients with high versus low PSS scores. Neither was a correlation between HCC and FC or CRP observed.

Conclusion
Bowel symptoms contribute to the feeling of being stressed. Perceived stress is associated with impaired QoL. Among patients in clinical remission, no association between subclinical inflammation (FC), and perceived stress or long-term stress (HCC) was observed. The issue of whether perceived stress may cause or augment intestinal inflammation, or vice versa, requires further investigation.
P140 Costs of home-monitoring by telemedicine versus standard care management of Inflammatory Bowel Disease – a Danish register-based five-year follow-up study
Authors: Al-Sheikh M , Olsen J , Spangaard M , Egedesø P , Peters-Lehm C , Fjordside E , Bennedsen M , Burisch J , Munkholm P 
Published: January 2023

Abstract

Background
The increasing incidence of Inflammatory bowel diseases (IBD) with subsequent increasing use of costly biological treatments such as well as the need for tight control of IBD places a significant economic direct and indirect cost burden on health care systems. Thus, eCare Constant-Care APP, home-monitoring of Patient Reported Outcome (PROs-SCCAI/HB-I, quality of life QoL, Disability index WEB-DI) and calprotectin (POCT-Point of Care Test) was introduced at North Zealand Hospital (NOH) in Denmark in 2015.
The aim of this study was to assess long-term cost effectiveness of remote telemedicine services (eCare) compared to standard care (sCare) for IBD patients during 5 years follow-up.

Methods
A retrospective register-based study was carried out among patients with ulcerative colitis (UC) or Crohn’s disease (CD) continuously included in the telemedicine service Constant Care (CC) in 2015-2020. Direct and indirect healthcare costs over a 5-year period were obtained from Danish registers and compared to a control group of IBD patients from all five regions in Denmark who were 1:5 matched on year of birth, gender, education, income, disease, use of biologics, duration of disease and Charlson Comorbidity index. The IBD patients (cases and controls) were identified in the National Patient Register (NPR) via registered ICD-10 diagnosis codes. Direct and indirect costs were estimated on a yearly basis from two years before inclusion in CC (i.e., the index year) and five years after using a linear regression model.

Results
A total of 572 IBD patients were included in the study. Average annual costs of IBD-related outpatient visits were significantly (P&lt;.005) higher among patients enrolled in CC compared to controls before and after index date whereas costs of hospital admissions were non-significant (ns). However, a slight decrease was observed in year 2 and 5 from index year (ns). The total direct costs were higher among CC patients compared to controls in the year prior to enrollment in CC and the five years after (Figure 1) primarily driven by the costs of outpatient visits.
Significantly (P&lt;.05) fewer CC patients were on early retirement compared to controls and CC patients received less public transfer payments compared to controls (ns).

Conclusion
Telemedicine care was associated with higher cost than standard care. One potential confounder is inefficient out-patient registration in NRP which highlights the need for continuous validation of clinical registration approaches in Denmark. A prospective RCT is warranted in future.
P151 Assessing comprehensive remission for Ulcerative Colitis in clinical practice: International consensus recommendations
Authors: Schreiber S W , Danese S , Dignass A , Domènech E , Fantini M , Ferrante M , Halfvarson J , Hart A , Magro F , Lees C , Leone S , Pierik M , Field P , Schofield H , Peyrin-Biroulet L 
Published: January 2023

Abstract

Background
Real-world treatment of ulcerative colitis (UC) requires a patient-centric, holistic definition of ‘comprehensive remission' that goes beyond standard regulatory definitions. In an international initiative, we reviewed aspects of UC that affect patients and attempted to achieve consensus on which aspects should be considered in a definition of ‘comprehensive remission’, using a modified Delphi process. This initiative summarized expert consensus recommendations on aspects of UC that are important to patients and that affect their lives, how to measure and score these aspects, and objective markers of mucosal inflammation that are relevant to evaluate in remission, such as endoscopic and histological activity and inflammatory biomarkers.

Methods
The Delphi consensus panel comprised 10 physicians with expertise in UC and one patient advocate, and two additional physicians chaired the process. To inform the Delphi statements, we asked 18 patients about their experiences of living with UC in remission, asked panel members about their experience of treating patients and systematically reviewed associations between outcome measures in UC. Panel members voted on a 6-point Likert scale in three rounds of anonymous voting, the final round of which was preceded by a live discussion. Consensus was met if ≥ 67% of the panel agreed with the statement (4–6 on the 6-point Likert scale). Statements not meeting consensus in voting rounds 1 and 2 were revised and any not meeting consensus by the end of voting round 3 were discarded (Figure 1).

Results
The panel agreed that a definition of comprehensive remission should include aspects of UC that are currently measured in clinical trials (blood in stools, stool frequency, disease-related quality of life [QoL], endoscopic remission, histological inflammatory activity, inflammatory biomarkers and discontinuation of corticosteroids), but also additional patient-reported symptoms should be added. These were bowel urgency, abdominal pain, extra-intestinal manifestations, fatigue and sleep disturbance (Table 1). Suggestions for how the severity could be measured and thresholds for remission were agreed for each aspect, with the exception of extra-intestinal manifestations. Disease activity evaluated using ultrasound was voted as important to consider but was not recommended to be included in a measure of comprehensive remission at this stage.

Conclusion
We used a robust methodology to reach agreement and provide recommendations on the aspects of UC that can be used to define comprehensive remission and assessed in clinical practice. We plan to develop this as a combined measure which may also have applicability in clinical trials.
P157 Serial daily recording of patient-reported outcomes (PRO2) might predict treatment change in the patients with Ulcerative Colitis.
Authors: Tsuchiya K , Nagahori M , Hanazawa R , Sasaki M , Sato H , Hirakawa A , Anzai T , Takahashi K , Kobayashi Y , Hibiya S , Takenaka K , Watanabe M 
Published: January 2023

Abstract

Background
Patient-reported outcome (PRO2) score composed solely of the stool frequency and bleeding components from partial Mayo (pMayo) score are used for the evaluation of clinical symptom in the patients with Ulcerative Colitis (UC). Although pMayo and PRO2 score also perform as well as the full Mayo score to identify the disease activity and clinical response, it is unclear whether serial daily PRO2 score are relevant in clinical practice. Moreover, its clinical significance for long-term outcome has not been established. The aim of this study istherefore to clarify the relationship between daily PRO2 records using a smart device application and prognosis.

Methods
This study was approved by the ethics committee in Tokyo Medical and Dental University (TMDU). The application was originally developed by the cooperation with TMDU and Hitachi ltd. Patients with UC input their symptoms by themselves in accordance with PRO2 once a day using the application on their smart device. The alert for their symptom exacerbation is set according to our logic. Patient's condition including alert status is confirmed by the doctor once a week using doctor’s PC. Medical information such as therapeutics and blood examination, was extracted from the electronic medical chart in the hospital. The application data was combined with medical information on a daily basis. We defined a start or change of the treatment with prednisone or biologics as treatment change for the outcome of this study. The difference of PRO2 score before the date of treatment change is calculated for each patient and the odds ratio (OR) and AUC of the ROC curve are estimated by univariate logistic regression analysis.

Results
From July 2020 to March 2022, 183 UC patients participated in this study. Mean age was 46.6 years. Male to female ratio was 81:102. Mean observation period was 346 days. The number of the patients with alert of symptom exacerbation averaged 5.79/week. There were 27 patients with treatment change during the period. PRO2 score in the patients with treatment change was significantly increased compared with the patients with no change in treatment. The OR [95%CI] of the PRO2 change from 90 days to 5 days before treatment change was 7.708 [2.713-21.902], the AUC [95%CI] was 0.872 [0.772-0.973], the OR [95%CI] of the PRO2 change from 10 days to 5 days was 3.309 [1.601-6. 841] and AUC [95%CI] was 0.679 [0.569-0.789].

Conclusion
PRO2 variation over 90 days was highly reliable for predicting treatment change. Further analysis will clarify the clinical significance of serial daily PRO2 score recording.