bluuebunny/crossref_metadata_2025 huggingface dataset:
P106 Single-cell transcriptomic analysis reveals insights into the mechanism of action of Granulocyte-monocyte apheresis
Authors: Kioroglou D , Cabriada J L , Martinez Marigorta U , Rodriguez-Lago I
Published: January 2024

Background

Granulocyte-monocyte apheresis (GMA) is a non-pharmacological treatment approved for the management of ulcerative colitis (UC), particularly steroid-dependent cases. The exact mechanism of action and immunological changes associated with GMA remain undescribed. Gene expression analysis at the single-cell level (through scRNA-Seq) has emerged as a key tool of choice to characterize drug response at the molecular level. We used scRNA-Seq to characterize the transcriptomic effects and immune cell population alterations in GMA.

Methods

We generated scRNA-Seq from peripheral blood mononuclear cells (PBMC) of two ulcerative colitis (UC) patients undergoing GMA treatment. We compared the gene expression profile before and after 5 sessions of GMA treatment. The analytical pipeline included quality control and classical filtering steps, cell-type annotation, differential gene expression analysis and pathway enrichment profiling.

Results

We report three main results. First, we observed significant reductions of cell types directly affected by GMA treatment in UC patients. This includes classical CD14+ monocytes and Natural killers, which are central components of the innate system. Of note, we observed a remarkable increase in Double-negative T cells (dnT) after 5 sessions of GMA treatment, suggesting potential expansion of protective populations involved in decreased inflammation. Second, we observe a variety of genes and regulatory pathways altered by GMA treatment. In total, we detect 86 differentially expressed genes (DEGs), which overall are biased towards downregulation (63%). Of note, we detected dnT-s exhibiting upregulation of NEFL that is associated with the MAPK cascade and downregulation of genes related to immune response and signaling pathways. Finally, the effects of GMA treatment extend beyond the above mentioned populations, with particular alterations in CD4+ T cell populations such as CD4+ central memory and CD4+ Naive (7 and 13 DEGs, respectively).

Conclusion

For the first time, we generated single-cell transcriptomic profiles to characterize the effects of GMA treatment in peripheral blood of UC patients. Our preliminary analysis detects important alterations in the gene regulation and cell type composition in samples obtained after 5 sessions of GMA. Through expansion of this dataset to include more time points and profiles for more individuals, we will discuss the longitudinal changes and molecular mechanisms involved in response to GMA treatment.
P114 Role of NLRX1 Agonist NX-13 in Reducing Visceral Hypersensitivity in Preclinical Gastrointestinal Inflammation
Authors: Verstockt B , Vermeire S , Peyrin-Biroulet L , Yarur A , Panaccione R , Mosig R , Cataldi F , Danese S
Published: January 2024

Background

NLRX1 activation reduces inflammation by decreasing oxidative stress and altering cellular metabolism within multiple cell types implicated in ulcerative colitis (UC). Colitis animal models demonstrated reduced disease severity and a phase 1b clinical trial showed signs of rapid symptom and endoscopic improvement in patients with active UC.1, 2 Abdominal pain driven by visceral hypersensitivity may persist in patients even after inflammation has resolved, negatively affecting their quality of life.3, 4 Therapeutic agents which address inflammation, epithelial healing, and visceral hypersensitivity concurrently may provide greater symptomatic relief and improved quality of life as many patients, even in remission, still complain of abdominal pain. We here describe the effects of oral NX-13 in a rat model of visceral hypersensitivity.

Methods

Rats (n=8) were dosed daily for a period of 3 days with NX-13 or vehicle. Under anesthesia, electrodes were positioned to monitor oblique abdominal muscle contraction and a colonic balloon catheter was inserted intra-anally. Visceral pain was assessed at baseline and 3 h post lipopolysaccharide injection (1 mg/kg subcutaneous) through measuring of visceromotor response (VMR) via electromyogram (EMG) recording and visual assessment of abdominal withdrawal reflex (AWR). Data are represented as median (IQR) and statistical significance determined by non-parametric Mann-Whitney U test.

Results

Compared to the vehicle control, oral NX-13 delayed the onset of muscle contraction in response to colonic distension in LPS-treated rats. Further, NX-13 treated rats experienced reduced contraction intensity and reduced sustained abdominal muscle contraction period compared to the vehicle control. Specifically, NX-13 decreased the number of AWR during colonic expansion compared to the control group (p=0.01, Fig1A). Moreover, NX-13 desensitized the VMR response by numerically increasing the minimum volume of the colonic distension balloon required to induce significant VMR. The mean minimum volume of water injected required to induce significant VMR increased 23%, from 650 μL in the vehicle group to 800 μL in the NX-13 treated rats (p=0.16, Fig1B). Lastly, NX-13 visually reduced the maximum abdominal EMG amplitude during colonic distention (p=0.19, Fig1C).

Conclusion

Adequate management of persistent pain in IBD patients with or without active bowel inflammation remains an unmet need in the treatment of IBD. The potential for NX-13 to specifically reduce visceral hypersensitivity and abdominal pain will be evaluated further in the ongoing phase 2 human NEXUS trial in patients with UC.

1Leber et al. J Immunol 203(12)

2Peyrin-Biroulet et al. JCC (17)Supp

3Abreu et al. JCC (14)Supp

4Wils et al. J Clin Med 11(15)
P117 Transglutaminase 2 is elevated in Crohn’s disease associated strictures and exerts profibrotic activities in myofibroblasts and experimental intestinal fibrosis
Authors: Chandra J , Czarnecki D , Mukherjee P K , Mao R , Bergin M , Huang L , Johnson T , West G , Kessler S , Fiocchi C , De La Motte C , Rieder F
Published: January 2024

Background

Intestinal fibrosis is a significant clinical problem in Inflammatory bowel disease (IBD). This may lead to intestinal strictures induced by excessive accumulation of extracellular matrix (ECM) produced by human intestinal myofibroblasts (HIMF). Transglutaminase (TG)2 covalently cross-links ECM-associated proteins, increases ECM stiffness and has direct pro-fibrotic effects. We investigated the role of TG2 in intestinal fibrosis in human tissues, HIMF and transgenic mouse models.

Methods

TG2 was detected in human tissues from Crohn’s disease (CD) strictures (CDs; n=10), CD non-strictured (CDns; n=20), ulcerative colitis (UC; n=10) and non-IBD controls (NL; n=14) by immunofluorescence (IF), qPCR, in-situ hybridization (ISH), and biotinylated cadaverin incorporation (BCI). Relative contribution of TG2 was measured by BCI using a TG2-selective blocking antibody (TAb). The cellular source of TG2 was evaluated by IF. HIMF ECM production was measured using a novel ECM deposition assay and TG2-inhibitors. HIMF were exposed to anti-TG2 antibody or isotype control and bulk RNA-sequencing (RNAseq) analysis was performed. Tamoxifen-inducible global Cre/TG2 floxed conditional KO (cKO) mice were used in the DSS and TNBS fibrosis models.

Results

Total TG activity was increased in CDs and UC vs. NL in the submucosa (SM) and muscularis propria (MP; P≤ 0.04). Strikingly 90-99% of TG activity were attributable to TG2 in all groups. TG2 activity correlated with fibrosis scores (P≤0.02), but not inflammation scores. TG2 amount was elevated in CDs patients vs. NL in qPCR and ISH (P≤0.05). IF revealed HIMF as the major source of TG2 in the intestine as indicated by colocalization with alpha-SMA. HIMF, invitro, produced 82–97% of active TG2. Inhibition of TG2 by cell-permeable inhibitor or Tab reduced fibronectin (FN) and collagen (COL)1 and 3 deposition by HIMF. RNAseq showed TAb-treated cells expressed 432 downregulated and 402 upregulated genes. Functional enrichment analysis showed pathways associated with fibroblast activation/proliferation, ECM, and fibrosis-associated signaling (e.g. AKT) pathways to be downregulated in TAb-treated HIMF. Associated genes included nuclear protein (NUPR1) and sphingolipid signaling pathway proteins (SMPD1 and CTSD), which may be potential targets for TG2-mediated activity in HIMF. Deletion of TGM2 prior to inducing murine DSS or TNBS experimental fibrosis did not lead to any difference in inflammation, but decreased fibrosis (picrosirius red intensity, COL1/FN expression, wall thickness) in TG2 cKO mice vs. wild type (P≤0.05).

Conclusion

TG2 is involved in inflammation-independent progression of intestinal fibrosis and may represent a future anti-fibrotic target.
P126 Differential granulocyte populations as therapeutic targets in fistula
Authors: Becker M , Koelink P , Buskens C , Wildenberg M
Published: January 2024

Background

Despite the recent increase in therapeutic options in IBD care, treatment of perianal disease and in particular fistula remains highly challenging. Specific targeted medical therapy is not currently available, and a majority of patients fails to respond to surgical intervention. In contrast, cryptoglandular fistula show much higher response rates with closure in up to 80-90% of patients. Interestingly, the most present cell type in fistula, the granulocyte, is also the least studied due to their fragile nature. To fill this void, we evaluated granulocytes in perianal fistula and those present in the blood.

Methods

Curettage material of 18 fistula (Crohn n=15 and cryptoglandular n=5) was obtained and processed by mass cytometry. Two additional samples were obtained (1 Crohn, 1 cryptoglandular) together with matching blood samples and assessed by single cell RNASeq.

Results

As expected, granulocytes formed the majority of all cells in all fistula (mean 64%). Cryptoglandular fistula displayed significantly more granulocytes than Crohn’s related fistula. Single cell analysis showed 4 subsets: Subset 1 was the main subset in blood, and expressed high levels of LAMTOR4. Interestingly, although found both in blood and fistula, abundance was much higher in blood (80 vs 10%) and signaling cascades differed. In blood, activity was associated with degranulation, IL8 activity and migration. In fistula, a very strong IFNa/b signature was present. Subset 2 expressed high MMP9, and showed degranulating activity. Subsets 3 and 4 were almost exclusively found in the fistula tracts, and were defined by expression of PI3 and LRG1 respectively. Pathway analysis showed the PI3+ population to have strong cytokine signaling but little degranulating or migratory activity. Conversely, the LRG1+ population showed little cytokine activity, but stronger degranulating activity and integrin signaling. The two populations also expressed distinctive chemokine receptors, with PI3+ cells expressing high levels of CXCR4, while LRG1+ express CXC1 and CXCR2, suggesting differntial recruiment and potential modulation. In that light, it is interesting to note the proportion of PI3+ and LRG1+ cells differed between patients, with the majority of Crohn derived cells being PI3+ while the cryptoglandular fistula mainly contained LRG1+ cells.

Conclusion

Granulocytes form the main cellular component of fistula tracts in both Crohn and cryptoglandular fistula. Four different subsets of granulocytes could be identified, of which the two main subtypes in fistula tracts appear to differ significantly both in phenotype, activity and method of recruitment. This data may be a starting point for specific interventions in this highly abundant but often overlooked cell type.
P134 Characterization for the similarity assessment between proposed biosimilar SB17 and ustekinumab reference product using state-of-the-art analytical method
Authors: Yang S Y , Lee C , Hwang K , Lee J , Lee J , Hong J , Jung S
Published: January 2024

Background

SB17 is being developed as a proposed biosimilar to ustekinumab reference product (RP), a human monoclonal antibody (IgG1 kappa immunoglobulin) that binds to the common p40 subunit of cytokines interleukin (IL)-23 and IL-12. Binding to this subunit prevents interaction with their receptor, resulting in modulation the immune system responses which play a key role in the inflammatory disease. The objective of this study was to demonstrate structural, physicochemical, and biological similarity between ustekinumab RP and SB17 using various state-of-the-art analytical methods.

Methods

Comprehensive analytical characterization was conducted with side-by-side comparison of SB17 with the EU and US ustekinumab RP using various analytical methods. Comparisons included purity, product-related impurity, charge heterogeneity, primary structure, post-translational modification, higher order structure, quantity, Fab-related biological activities (potency and binding activity), and Fc-related biological activities.

Results

Based on the analytical similarity assessment, the structural, physicochemical, and biological characterization results demonstrated that SB17 is highly similar to the EU and US ustekinumab RP. In the structural aspects, it was confirmed that there is no clinically meaningful difference between post-translational modification profiles and higher order structures of SB17 compared to the ustekinumab RP. Product-related impurities in the form of aggregates were also confirmed to be similar. SB17 has a lower of acidic and basic peaks compared with ustekinumab RP, due to the difference in producing cell line. Ustekinumab RP is expressed in an Sp2/0 cell line, whereas SB17 is expressed in CHO cell line. However, the difference between SB17 and ustekinumab RP in the charge variants is not considered clinically meaningful since equivalent biological activity was observed. In case of mechanism of action (MoA)-related biological activities, SB17 is highly similar to the EU and US ustekinumab RP with respect to overall critical and non-critical quality attributes analyzed. Moreover, similarity or lack of activity in Fc-related biological activities was also confirmed. Based on these results, SB17 is expected to have highly similar safety and efficacy as compared to ustekinumab RP.

Conclusion

In summary, the overall analytical characterization and similarity assessment results show that SB17 is highly similar to the EU and US ustekinumab RP in terms of structural, physicochemical, biophysical, biological attributes.
P158 Expression of IL-19 and IL-24 in intestinal mucosa of inflammatory bowel disease: An immunohistochemical study
Authors: Toskas A , Milias S , Papamitsou T , Meditskou S , Dellis G , Sioga A
Published: January 2024

Background

Interleukins are considered as targets for future inflammatory bowel disease ( IBD) treatments. IL-19 and IL-24 are members of IL-10 family and through the JAK-STAT pathway induce proinflammatory cytokine production. A retrospective single center study was performed to study the IL-19 and IL-24 expression in 121 patients with moderate to severe IBD, before and after treatment with biologics.

Methods

A retrospective study of 121 patients with moderate to severe IBD was performed using immunochemistry between 1999 and 2017. This study included 72 patients with Crohn's disease (CD), 49 with Ulcerative Colitis (UC) and 20 healthy controls. The age, gender, disease extent, severity and treatment choice were recorded. Endoscopy reports before and after 12 months of treatment were retrieved. Intestinal biopsy samples were retrieved from the Histopathology Lab before and 1 year after treatment with biologics. A signed consent was received from all the patients involved and the study was approved by the Bioethics Committee of Aristotle University of Thessaloniki.

The histological specimen were stained for IL-19 and IL-24 before and one year after treatment with biologics. The results were analysed using SPSS for each of the IBD groups (CD, UC) and further to subgroups depending the biologic treatment they received, anti-Tumor Necrosis Factor alpha(anti-TNFa), Vedolizumab (VDZ), Ustekinumab (USK).

Results

A statistically significant increase was found in IL-19 and IL-24 patients in IBD patients versus healthy controls (P<0.05). On the biologics treated group and the anti-TNFa subgroup, there was statistically significant increase in IL-24 expression post treatment (P<0.01). In UC patients, the IL-24 expression was significantly increased after a successful treatment in relation with Mayo score ( P<0.01). On the CD group, a reverse statistically significant correlation was found between the pre-treatment IL-19 expression and the Harvey Bradshaw Index (H.B.I.) score reduction in the anti-TNFa and the VDZ subgroups (p<0.05).

Conclusion

A possibly proinflammatory role of IL-19 was found on the CD group. This can be used as a tool in the future to assess the disease activity and support the diagnosis as a diagnostic biomarker, as IL-19 was found normal in healthy controls. An anti-inflammatory role of IL-24 was found especially in the UC group and in relation with the activity index score post-treatment. This can be used potentially as a marker of response to treatment in active UC, assisting the clinical management. Further research is needed to delineate the exact role of these interleukins in intestinal inflammation.
P178 Changes in composition and structure of ileal mucus in Crohn’s disease patients compared to healthy controls
Authors: Kramer C , Rulff H , Kuppe A , Addante A , Fentker K , Ziegler J , Bischoff P , Gradzielski M , Mertins P , Mall M , Glauben R , Siegmund B
Published: January 2024

Background

Crohn’s disease (CD) is a chronic transmural disease that can affect any part of the gastrointestinal tract. Typically, the terminal ileum is impacted. The pathogenesis of this disease results from a complicated interaction of multiple factors, with the intestinal barrier playing a critical role. The intestinal barrier in the ileum is comprised of epithelial cells that are coated with a mucus layer. This barrier is permeable to nutrient absorption and microbiota. Detailed analyses of human ileal mucus are currently absent. Our study aimed to comprehend the function of mucus and the biophysical and biochemical stimuli that exist in the mucus layer during ileal inflammation, in contrast to the healthy state.

Methods

We enrolled 28 patients diagnosed with Crohn’s disease (CD) and 27 healthy individuals as part of our study. Mucus and biopsies from the terminal ileum were collected during a colonoscopy. The extent of clinical, endoscopic and histologic inflammation in the terminal ileum at the time of collection was evaluated using the Harvey-Bradshaw Index, Simple Endoscopic Score, and modified Naini and Cortina score. The disease trajectory and dietary behaviors of all patients and healthy controls were documented. Samples were processed following protocols for various analyses, including rheology, proteomics and scanning electron microscopy (SEM).

Results

Our study presents the first data on the rheology and viscoelastic properties, of human ileal mucus. Interestingly, we discovered notable variations in the viscoelastic properties of mucus in CD patients compared to healthy individuals. Furthermore, the mucus mesh size and structure differed in CD patients in comparison to healthy controls. The SEM pictures also displayed these quantitative changes. We further assessed clinical characteristics, encompassing duration of disease, and observed certain variations, although their significance is not yet statistically established.

A distinct profile was detected in CD patients compared to healthy controls using proteomic analysis. The ileal mucus of CD patients demonstrated elevated levels of ITGB2 and S100 proteins, which are involved in inflammatory pathways. Moreover, a correlation was found with histologic inflammation at the time of the collection.

Conclusion

In our study, significant changes in mucus composition and structure were found in the terminal ileum of CD patients, compared to healthy controls. This preliminary analysis provides a basis for further investigations to establish correlations between mucus composition and viscoelastic properties, and the subsequent effects on the underlying epithelial barrier.
P183 Therapeutic Effects of Curcumin and Ginsenoside Combination in a Animal Model of Radiation Proctitis
Authors: Kim S E , Kim M S , Lee R A , Yang S J , Lim H , Lee T Y , Woo S Y
Published: January 2024

Background

Although various preventive and therapeutic modalities have been proposed to manage radiation-induced proctitis, there are no universally accepted preventive measures for effective treatment. This study aimed to investigate using an animal model whether the combination of curcumin and ginsenoside could be an effective treatment or preventive agent for progressive rectal inflammation caused by radiation.

Methods

C57BL/6 mice were exposed to gamma irradiation at 27 Gy (3 Gy/min) in the lower abdominal (rectal) region, establishing an animal model with acute radiation proctitis. A combination hydrogel containing 5 mM curcumin and 1 mM ginsenoside Rh1 was prepared and administered into the inflammed rectum of the murine model. This administration was repeated every 2 to 3 days after radiation exposure for a total of 6 times. Two weeks after radiation exposure, the mice were sacrificed to obtain the irradiated tissue samples. The histological and molecular evaluations were performed using H&E staining, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis, Proliferating Cell Nuclear Antigen (PCNA) staining, immunohistochemistry, and qPCR.

Results

The murine group treated with the combination hydrogel of curcumin and ginsenoside showed significant restoration of the damaged rectal mucosa induced by radiation, including recovery of the mucosal layer and villi, mitigation of epithelial loss, and repair of crypt damage, compared to control group. Additionally, at the cellular level, a comparative analysis of apoptosis and proliferation within the tissues through TUNEL and PCNA staining demonstrated the combination hydrogel not only significantly inhibited cell death but also significantly increased cell proliferation. The gene expression of inflammatory cytokines in rectal tissue, including IL-6 and IFN-γ was significantly decreased in the treatment group. The infiltration of immune cells including T cells (CD4) and macrophages (CD68), which are important components in the pathogenesis of radiation proctitis, as shown by immunohistochemistry of tissue samples, was significantly reduced in the treatment group compared to the control group.

Conclusion

These promising results suggest that the combination of curcumin and ginsenosides has therapeutic potential for the management of radiation proctitis and provide valuable insights into new therapeutic strategies in clinical applications.
P185 Food avoidance and dietary restrictions in patients with Inflammatory Bowel Disease
Authors: Norman E , Hoque S
Published: January 2024

Background

Nutrition has a key role in IBD, more so in Crohn’s disease (CD) than ulcerative colitis (UC) and studies have shown that patients restrict or avoid certain dietary items; not necessarily due to medical advice. This could be detrimental to nutritional status by causing weight loss, disordered eating and nutritional deficiencies.

Methods

An online survey was carried out amongst IBD patients attending a teaching hospital in an urban area in the UK. Ten questions were asked and the survey was sent to 100 patients with their consent.

Results

The total survey response rate was 38%. Only 8% of patients had a long diagnosis due to diagnosis when a child, and although all restricted their diet still, this did not seem to show significance (p = 0.597). There was no significant difference between IBD type and whether the patient restricted their diet or not (p = 0.107). Notably, we did find that the most common reason for avoiding dietary items was patients ‘feel it helps symptoms’ (less so the ‘advised by clinician’ choice), however there was no significant difference between types of IBD and dietary exclusion reasons (p = 0.721). The most common dietary avoidances were spicy foods, followed by caffeine and fibre. There was a significant difference between CD and UC patients and the dietary groups they limited (p = 0.006), with there being a difference between CD and UC patients specifically for fibre (p = 0.027), for gluten/wheat (p = 0.0002) and for dairy (p = 0.077), however the latter did not reach significance. Of note, there is no difference in how long patients avoided dietary items, showing restriction is widespread irrespective of disease status (active or in remission).

Conclusion

Our survey indicates that food avoidance is commonplace among IBD patients, and the common foods avoided are spicy foods, caffeine and fibre, more so with CD than UC. These appear self-induced without medical advice, and this could have a detrimental impact on nutritional status. This is important information which merits further studies, perhaps with a larger sample size.
P208 Personalized Machine Learning Algorithm to Predict Ulcerative Colitis Disease Activity from Wearable Data
Authors: Saleh A , Abraham B
Published: January 2024

Background

Due to its ease of use and ability to determine complex information, wearables have been gaining popularity over the last decade. Smart rings such as OuraTM present the ability to track metrics such as sleep quality, resting heart rate, body temperature, and daily activity. This is not only useful for the predicting disease activity in inflammatory bowel disease (IBD), but also to understand behavior changes that can be associated with disease activity. This study aimed to evaluate potential use for wearable data in IBD management.

Methods

Daily OuraTM ring data of a patient with ulcerative colitis (UC) was collected from OuraTM ring application programming interface from 2019 to 2023. Days were classified as “active disease” or “remission” based on patient symptoms, colonoscopies, and fecal calprotectin levels. Data was collected on the patient’s sleep metrics, activity levels, and daily vitals. Variables with >50% null values were not included in model training. A univariate analysis was conducted to determine features that correlated with flaring periods (p-value <0.3) [ABPM1] [AS2] to be included in model training. An XGBoost classifier was selected with the target variable being flare status. Boosting parameters were then hypertuned to optimize model performance. After hypertuning and kfold cross-validation, the model’s mean accuracy, mean logarithmic loss, and AUC was reported. Further analysis was conducted comparing remission, active disease and pre-diagnosis data.

Results

963 days were collected. 444 days were determined to be “flare” based on reported symptoms, 4 fecal calprotectin levels, 2 colonoscopies, and 1 intestinal ultrasound confirming disease activity. Remission was determined by no reported symptoms, 2 normal fecal calprotectin levels and a normal intestinal ultrasound. Generally, worse sleep quality, increased resting heart rate, increased respiratory rate, and deviations in activity levels were positively associated with disease activity. After model training with XGBoost classifier and 10-fold stratified cross-validation, the mean accuracy was 0.92 ± 0.08, mean logarithmic loss of 0.134 ± 0.11, and a mean AUC was 0.94 ± 0.02. The patient’s mean biometric values such as heart rate and respiratory appeared to recover to pre-diagnosis levels with the exception of heart rate.

Conclusion

Data from the OuraTM ring demonstrated the potential application of wearables in IBD management in a single patient with UC. The high accuracy and AUC of our XGBoost model demonstrates how individualized wearable data can be used to predict IBD flares. Prospective studies with multiple patients could be useful to consider wearables as an additional adjunct disease monitoring device in IBD.
P212 Evaluation of the accuracy of MR-Enterography and CT-Enterography in the preoperative measurement of small bowel segments affected by Crohn's Disease: a single center experience
Authors: Sacchetti F , Larosa L , Minordi L M , Balzano D , Caprino P , Pastena D , Pugliese D , Scaldaferri F , Sofo L
Published: January 2024

Background

The surgical treatment of Crohn's Disease (CD) must deal with heterogeneous intra-operative scenarios, multiple disease locations and the risk of short bowel syndrome related to repeated surgery. A precise preoperative assessment of the exact extension of the disease is essential to avoid extensive surgeries and to plan the best strategy.

The aim of our study is to evaluate the accuracy of the pre-operative radiological assessment for predicting the intra-operative measurement of the affected bowel.

Methods

Consecutive patients underwent either first or repeated surgeries for ileocecal or ileal CD from November 2017 to April 2023 with an available preoperative radiological assessment trough (at most 3 months before) MR-Enterography (MR-E) or CT-Enterography (CT-E) were retrospectively included. Radiological examinations were performed according to standard protocols and each of them was independently reviewed by two experienced radiologists and the length of pathological small bowel segments were measured using a vessel analysis software. Radiological measurements were compared, using Pearson correlation coefficient, with those acquired by a single surgeon intra-operatively on the still vascularized pathologic small bowel segment.

Results

We included 81 patients (44% male), with a median age of 42 years [range 18-81], undergoing first (92%) or repeated surgery for fistulizing (34%) or stenosing CD.

The median length of radiological measurements was 27 cm [range 3-205] while the median length of intra-operative measurements was 30 cm [range 5-165].

Pearson correlation coefficient was used to analyze the variation between the measurements and there was a statistically significant positive correlation between radiological measurements and intra-operative in-vivo small bowel lenght (r2 = 0.962; p < 0.01).

Conclusion

MR-E and CT-E allow precise and accurate measurements of the extent and location of intestinal tracts involved by CD. Such information is extremely important to properly plan the surgical strategy and to be able to quantify the risk of short bowel syndrome in cases of extensive disease or repeated surgery.
P241 Systemic redox status associates with disease activity and clinical phenotypes in Inflammatory Bowel Disease
Authors: Geertsema S , Bourgonje A R , Gacesa R , Fagundes R R , Spekhorst L M , Hu S , Kannan A K , Ruane D , de Jong S , Jansen B H , Bulthuis M L C , Reinders-Luinge M , Weersma R K , van Goor H , Dijkstra G , Faber K N
Published: January 2024

Background

Oxidative stress is a key pathophysiological mechanism in inflammatory bowel diseases (IBD). Systemic levels of oxidative stress are reflected by reduced levels of free thiols (FT) in circulating proteins, especially those in albumin, which associates with disease activity in IBD. Yet, clinal value of circulating FT level as biomarkers of disease and therapy response remains largely unexplored. Here we investigated the association between plasma FT levels and clinical parameters, the plasma inflammatory proteome and medication use.

Methods

Plasma samples from 1,028 patients with IBD (567 Crohn's disease [CD] and 461 ulcerative colitis [UC]), and 500 healthy controls (HCs) participating in the 1000IBD and LifeLines projects were profiled for free thiols (FT), uric acid, bilirubin and 92 inflammation-related proteins (Olink Inflammation panelÒ). All biomarkers were associated with clinical phenotypes using general linear models adjusting for age, sex, body mass index, smoking and medication use.

Results

Plasma FT levels were significantly lower in IBD compared to HCs (p<0.05) (Figure 1A), with patients with UC showing even lower levels than patients with CD (p<0.05). Patients with UC on induction therapy had lower FT levels compared to patients on maintenance therapy (p<0.05). Furthermore, FT levels of patients with IBD were strongly associated with systemic inflammation (C-reactive protein [CRP], p<0.05) (Figure 1B). In both patients withCD and UC, reduced FT levels were associated with elevated levels of inflammation-, apoptosis-, and growth factor-related proteins, including C-X-C motif chemokine 9 (CXCL9) (Figure 1C-D), CUB domain-containing protein 1 (CDCP1) and caspase-8 (CASP8), proteins previous associated with preclinical IBD1-3. Furthermore, specifically for patients with UC, reduced FT levels were associated with elevated eotaxin-1 (CCL11) (Figure 1C), monocyte chemotactic protein-1 (MCP-1), and several cytokine biomarkers like Interleukine-6 (IL6) and Interleukin-17A (IL17A).

Conclusion

Systemic FT levels associate with inflammatory disease activity and clinical therapy and may offer potential utility in clinical assessments. This study highlights the intricate involvement of oxidative stress in various inflammatory pathways and components, particularly in innate/adaptive immune balance, cell damage, and apoptosis. These findings contribute to a deeper understanding of the interplay between oxidative stress, inflammation, and IBD.

Funding: This study was supported by Janssen Research & Development LLC.

References:

1. Leibovitzh H, et al. Gut. 2023

2. Chen J, et al. JCC. 2023

3. Bergemalm D, et al. Gastroenterology, 2021
P253 Knowledge and acceptability of the Lémann Index to measure progressive intestinal damage in Crohn’s disease: results from an international cross-sectional survey
Authors: Wong C , Torres J , Burisch J , Ungaro R C , Colombel J F , Buisson A , Lambert J , Arebi N
Published: January 2024

Background

Chronic inflammation in Crohn’s disease (CD) predisposes to progressive structural bowel damage (SBD). The Lémann index (LI) is a prospectively validated tool that captures extent and severity of strictures, penetrating disease and surgery to generate a SBD score.1 It is earmarked as a potential outcome measurement tool for CD modification trials. Understanding perceived barriers and knowledge gaps is critical to its wider adoption.

Methods

We conducted a multinational, cross-sectional study (March to October 2023) to determine SBD and LI knowledge, and LI acceptability. An online survey link (REDCap) was distributed to clinicians by email through GI professional societies and snowball sampling. The questionnaire included 23 items, 5 sections (demographic, SBD knowledge, LI perception and knowledge, future LI adoption, and optional case) and responses (binary, 5-point Likert scale, 10-point visual analogue scale (VAS) and free-text) were captured on Excel.

Results

From 170 respondants: 82 (48%) were female; 142 (82.4%) from Europe, 13 North America (7.6%) and 13 Asia (7.6%). Most were IBD specialists (121; 71.2%), General Gastroenterologists (36; 21.2%), managing >40 CD patients per month (60; 35.3%). 88 (51.8%) questionnaires were incomplete (≥1 questions were unanswered). From completed responses, 99 (92.5%) knew about SBD, 97 (90.7%) rated it ‘’very’’ and ‘’fairly’’ important to measure SBD in clinical trials and 82 (76.6%) in clinical practice; 5 (4.7%) felt it was ‘’not important’’. Most agreed LI would improve long-term outcomes in CD (55; 55%) and show achievement of treatment targets (74; 74.7%). More (43; 42.6%) replied it was ‘’very difficult’’ or ‘’difficult’’ to complete the LI for each patient; 36 (36%) felt that it took ‘’significant’’ or ‘’a lot’’ of effort (Figure 1). Most (86; 80.4%) were untrained in calculating the LI; 73 (68.2%) felt it was ‘’very’’ and ‘’fairly’’ important to receive training. Most reported intestinal ultrasound instead of MR enterography to be important (VAS scores 8-10) for encouraging LI calculation in future clinical trials (53; 54.6%) and clinical practice (49; 52.7%) (Figure 2). Lack of time (80.2%), automated calculation methods (64.2%) and dedicated radiologist (50.6%) were the top 3 perceived barriers to wider adoption.

Conclusion

Most respondents had baseline knowledge of SBD and perceived the LI to be important in future long term CD research and clinical practice. Interventions to improve training and automation are needed to facilitate wider adoption of the LI.

Reference

1. Pariente B, et al.Validation and Update of the Lémann Index to Measure Cumulative Structural Bowel Damage in Crohn's Disease.Gastroenterology.2021 Sep;161(3):853-864.e13.
P268 Artificial Intelligence and Panendoscopy – Automatic Detection of Pleomorphic Lesions in Multibrand Device-Assisted Enteroscopy
Authors: Araújo Martins M P , Mascarenhas M , Afonso J , Ribeiro T , Cardoso P , Mendes F , Cardoso H , Andrande P , Mascarenhas Saraiva M , Ferreira J , Lopes S , Macedo G
Published: January 2024

Background

Device-assisted enteroscopy (DAE) stands as the sole diagnostic and therapeutic procedure capable of thoroughly examining the entire gastrointestinal (GI) tract. Nevertheless, its diagnostic yield falls short in ensuring a cost-effective panendoscopy and there is still a significant interobserver variability during the procedure. Multi-layered convolutional neural networks (CNN) have proven beneficial in numerous medical applications, yet there is a noticeable gap in research regarding their implementation in DAE. The aim of this study is to develop and a validate a multidevice CNN for panendoscopic detection of pleomorphic lesions (vascular lesions, hematic residues, protruding lesions, ulcers and erosions) during DAE.

Methods

In a retrospective analysis of 338 DAE procedures conducted at two specialized centers, frames from 152 single-balloon enteroscopies (Fujifilm®), 172 double-balloon enteroscopies (Olympus®), and 14 motorized spiral enteroscopies (Olympus®) were used to construct and validate the CNN. The dataset, comprising 40,655 images, was divided into a training dataset (90% of images, n=36,599) and a validation dataset (10% of images, n=4,066). We conducted a 5-fold cross validation, during training dataset. Primary outcomes were sensitivity, specificity, accuracy, and area under the precision recall curve (AUC-PR).

Results

During the training dataset's 5-fold cross-validation, the model demonstrated a mean sensitivity of 88.7% (88.0 – 89.5%), specificity of 98.0% (97.8 – 98.1%), PPV of 92.6% (92.0 – 93.1%), PPN of 97.0% (96.8 – 97.2%), with a mean accuracy of 96.0% (95.8 – 96.2%). During validation dataset, the CNN presented 88.9% sensitivity, 98.9% specificity, 95.8% PPV, 97.1% NPV, 96.8% accuracy and AUC-PR of 0.97. The CNN processed 124 frames per second.

Conclusion

This is the first CNN that can detect pleomorphic lesions in a panendoscopic and multidevice scenario (containing the majority of DAE devices used in medical practice). The model accurately identified pleomorphic lesions throughout the GI tract, featuring a short processing frame rate that may allow its application in real-time clinical procedures. The development and application of these systems could amplify the indications and benefits of DAE, increasing its diagnostic yield and cost-effectiveness.
P270 Male Genitourinary Dysfunction after Primary and Reoperative Ileoanal Pouch Surgery
Authors: Hernandez Dominguez O , Prien C , Almarzooqi R , Sanchetti H , Lavryk O , Somovilla J , Liska D , Kanters A , Gorgun E , Steele S , Holubar S
Published: January 2024

Background

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the preferred surgical treatment for patients with IBD or FAP. As these diseases often manifest during adolescence or early adulthood, treatment effects on genitourinary function (GU) and sexual function are of paramount importance. However, the reoperative IPAA (R-IPAA) effects on male GU function and sexual function compared to primary IPAA (P-IPAA) are not known. Therefore, we conducted an observational survey to compare the long-term GU functionality of P-IPAA and R-IPAA long-term GU functionality male patients. We hypothesized that R-IPAA is associated with higher GU-dysfunction compared to R-IPAA.

Methods

All adult male patients who underwent IPAA at a single tertiary hospital between 1983 and 2022 were identified and demographics and clinical data were obtained from our prospectively maintained pouch registry. Patients were surveyed using validated questionnaires (Table 1). The primary outcome was composite survey scores. Patients were stratified into P-IPAA or R-IPAA groups; R-IPAA was defined as IPAA excision, reconstruction, or revision. Patients status-post prostatectomy were excluded.

Results

A total of 1,836 male patients were surveyed, and 457 (24.9%) submitted a response. After exclusion criteria, 339 responses were analyzed:296 (87.3%) P-IPAA and 38 (11.2%) R-IPAA, which included 22 redo IPAA, 9 excisions, and 7 revisions. In both groups, most patients had ulcerative colitis (89 vs. 90%). P-IPAA compared to R-IPAA had a similar age at surgery (40.8 vs. 42, p=0.59), similar age at survey (56.2 vs. 56.4, p=0.94), and a similar interval between surgery and survey (15.4 vs. 14.4, p=0.51). The P-IPAA group had less severe sexual dysfunction than the R-IPAA group (IBD-MSDS, 2.0 vs. 7.0, p=0.002). No significant difference was observed between P-IPAA and R-IPAA in erectile dysfunction (SHIM score 21 vs. 18.5, p=0.24), urinary tract symptoms (CLLS, 5.5 vs. 8.0, p=0.06), use of therapeutic aids for sexual activity (6 vs. 7, p=0.29), or orgasm ability (4 vs. 4, p=0.3). Patients with P-IPAA had a higher CGQoL (0.83 vs. 0.7, p=0.02). There were no differences between patients who had difficulty conceiving a child (4 vs. 7, p=0.5) and those who experienced infertility (3 vs. 1, p=0.43). In patients with fertility problems, no quality-of-life differences were observed between the groups (FertiQoL, 85.9 vs. 88.5, p=0.62).

Conclusion

Primary-IPAA was associated with increased sexual function and overall higher global quality of life compared to R-IPAA. No difference in erectile function, LUTS, and the need for therapeutic aids for sexual function, orgasm ability, or fertility were observed.
P296 Preclinical protein signatures in blood predict Crohn's disease and Ulcerative colitis several years before the diagnosis
Authors: Grännö O , Salomon B , Lindqvist C M , Hedin C R H , Carlson M , Dannenberg K , Andersson E , Söderholm J D , Keita Å V , Öhman L , Magnusson M K , D’Amato M , Eriksson C , Hultdin J , Kruse R , Cao Y , Repsilber D , Bergemalm D , Grip O , Karling P , Halfvarson J
Published: January 2024

Background

We aimed to identify protein signatures predictive of a future diagnosis of inflammatory bowel disease (IBD).

Methods

We conducted a case-control study, nested within large population-based cohorts with biorepositories. Samples were obtained from individuals who later in life were diagnosed with IBD (preclinical cases) and compared with age and sex-matched individuals who remained free from IBD during follow-up (controls). Using proximity extension assays (Olink, Uppsala), we measured 176 proteins. We applied regularized logistic regression to identify protein signatures of preclinical disease in serum from the discovery cohort (n=312). Their performance was validated in an external preclinical cohort (n=222). The biological relevance of identified proteins was further assessed in an inception cohort (n=144). Finally, we used an IBD twin cohort (n=327) to examine the impact of genetic and shared environmental factors on identified proteins.

Results

We identified 34 proteins associated with preclinical Crohn’s disease (CD) in the discovery cohort (Pfalse discovery rate <0.10), with 9 confirmed in the validation cohort (Pfalse discovery rate <0.05). For preclinical ulcerative colitis (UC), 45 proteins were identified and 12 validated (Fig. 1A-B). In the discovery cohort, a signature of 29 proteins differentiated preclinical CD cases from controls with an AUC of 0.85 (Fig. 1G). Its performance was confirmed when applied to the preclinical validation cohort (AUC=0.84, Fig. 1H). Moreover, the signature had excellent capacity to differentiate newly diagnosed CD from healthy controls in the inception cohort (AUC = 0.99, Fig. 1I). The preclinical UC signature had a significant, but albeit lower, predictive capacity in the discovery (AUC=0.77), validation (AUC=0.67) and inception cohort (AUC=0.90, Fig. 1G-I).15 of 17 proteins associated with preclinical IBD demonstrated significantly higher intra-pair correlation coefficients in healthy monozygotic- compared to dizygotic twin pairs, indicating an influence from genetic factors on the regulation of these protein markers. The preclinical signature for CD demonstrated an AUC of 0.87 when comparing twins with preclinical CD (n=10) to matched external healthy twins. However, its predictive capacity was lower when comparing preclinical CD twins with their healthy twin siblings (AUC=0.58), i.e., when accounting for genetic and shared environmental factors. The difference in AUC estimates in the twin cohort was not significant (P=0.07).

Conclusion

We identified protein signatures for predicting clinical onset of CD and UC, validated across independent cohorts. Specifically for CD, the preclinical signature offers significant potential for early detection.
P299 Ulcerative Colitis Severity Assessment through Abdominal Ultrasonography: A Diagnostic Accuracy Meta-analysis
Authors: Elhadi M , Faraj H , Ala K
Published: January 2024

Background

Ulcerative colitis, a prevalent form of inflammatory bowel disease, necessitates a precise evaluation of disease severity. While effective, traditional diagnostic methods like colonoscopy are invasive and uncomfortable for patients. Abdominal ultrasonography offers a non-invasive alternative for this assessment, but its differential accuracy in evaluating disease severity in the right and left colon is not fully explored.This study aims to assess the diagnostic accuracy of abdominal ultrasonography in determining the severity of ulcerative colitis, focusing on its performance in the right and left colon.

Methods

A systematic review was conducted in PubMed, EMBASE, and the Cochrane Library, targeting studies up to June 2023. The selection criteria included studies that used abdominal ultrasonography for ulcerative colitis severity assessment, compared against histopathology or combined clinical, endoscopic, and radiological findings. Data analysis was performed using R software (version 4.0.3) with the mada package. This analysis focused on calculating sensitivity, specificity, diagnostic odds ratio, and positive and negative Likelihood Ratios for both the right and left colon, each with a 95% Confidence Interval.

Results

The search identified 5 studies with a total of 383 ulcerative colitis patients. In the right colon, the pooled sensitivity was 73.7% (95% CI, 57.6-85.2%, I2=0%), and specificity was 99.5% (95% CI, 1.6-100%, I2=0%). The diagnostic odds ratio was extremely high at 560.1 (95% CI, 0.04-6966551), with a positive Likelihood Ratio of 148.14 (95% CI, 0.01-1713586.1) and a negative Likelihood Ratio of 0.26 (95% CI, 0.15-0.45). In the left colon, sensitivity was higher at 93.7% (95% CI, 87.2-97%, I2=49.1%) with a specificity of 73.3% (95% CI, 41.8-91.3%, I2=70.9%). The diagnostic odds ratio for the left colon was 40.96 (95% CI, 8.67-193.62), with a positive Likelihood Ratio of 3.51 (95% CI, 1.31-9.42) and a negative Likelihood Ratio of 0.08 (95% CI, 0.04-0.19).

Conclusion

Abdominal ultrasonography shows promising results in assessing disease severity in ulcerative colitis, particularly in the left colon. The high specificity in the right colon is notable, but the wide confidence intervals suggest caution in interpretation, likely due to the small sample sizes and study variability. The left colon's more consistent and reliable performance indicates its suitability for routine clinical use in this region. This study highlights the need for further research with larger patient cohorts and standardized methodologies to solidify these findings and optimize ultrasonography’s role in ulcerative colitis management.