Inflammation Score Research Articles

The association between systemic inflammation markers and the risk of incident dilated cardiomyopathy: a prospective study of 351,148 participants

Background The role of systemic inflammation in the development and progression of cardiovascular diseases has been attractive, but its association with incident dilated cardiomyopathy (DCM) is rarely investigated. This study aimed to systematically investigate the association between various inflammatory markers and DCM incidence. Methods The data were derived from the UK Biobank database. Systemic inflammation markers in this study encompassed peripheral immune cell counts and their ratios and the low-grade inflammation score (INFLA-score). The Cox proportional hazards regression, restricted cubic splines model, and segmented regression were adopted to assess the association between systemic inflammation markers and DCM incidence. Additionally, the subgroup Cox analysis stratified across sex was also performed. Results A total of 351,148 participants were enrolled in this study, and 377 subjects developed DCM during a mean follow-up of 12.21 years. The positive association between C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and CRP-to-lymphocyte ratio (CLR) and DCM incident risk was found (CRP: HR = 1.190, P = 0.001; NLR: HR = 1.315, P = 0.033; CLR: HR = 1.206, P < 0.001), while the lymphocyte-to-monocyte ratio (LMR) was negatively associated with DCM incident risk (HR = 0.756; P = 0.033). Furthermore, the increased risk of DCM incidence was significantly and nonlinearly correlated with the reduction of platelet count (HR = 0.543; P = 0.002). In the subgroup analysis, sex-specific inflammation markers related to DCM development were noticed. Conclusions The study has underlined that multiple inflammation markers were significantly associated with the risk of incident DCM, which would provide evidence for the aetiological study of DCM.

Hypothermic machine perfusion in uterus transplantation in a porcine model: A proof of concept and the first results in graft preservation.

Graft optimization is a necessity in order to develop uterus transplantation from brain-dead donors, as a complement to living donors, as these grafts are rare and the last organs retrieved in multiple organ donation. The aim of this study was to assess the feasibility and interest of hypothermic machine perfusion (HMP) in uterus transplantation using a porcine model; secondary outcomes were the evaluation of the graft's tolerance to a prolonged cold ischaemia time and to find new biomarkers of uterus viability. Fifteen uterus allotransplantations were performed in a porcine model, after 18 h of cold ischaemia, divided in three groups: Static cold storage in a HTK solution, HMP (with the VitaSmart (™) machine Bridge to Life Ltd.) with a UW-MP solution, and static cold storage in a UW solution. The main outcome was macroscopic: uterine arteries pulsatility, recoloration, and bleeding at the cut. Secondary outcomes were histological analyses (Zitkute and inflammation scores), caspase3 immunohistochemistry and plasmatic dosage of biomarkers. 14/15 allotransplantations were performed according to the protocol and met the criteria of macroscopic vitality. Grafts treated with HMP (MP did not show significantly more tissue) damage than the recipient's uterus, contrary to grafts in static cold storage, independently of the solution used. This difference disappeared one and 3 h after uterus transplantation. Plasma dosages before and after uterus transplantation did not allow to identify a new biomarker of uterus viability. HMP is feasible in a porcine model, without inflicting damage on the grafts during cold ischaemia time. Grafts exposed to HMP seemed to better endure reperfusion phenomena, but this advantage did not last over time.

The methyl-CpG binding domain 2 regulates peptidylarginine deiminase 4 expression and promotes neutrophil extracellular trap formation via the Janus kinase 2 signaling pathway in experimental severe asthma

Objective The prognosis for severe asthma is poor, and the current treatment options are limited. The methyl-CpG binding domain protein 2 (MBD2) participates in neutrophil-mediated severe asthma through epigenetic regulation. Neutrophil extracellular traps (NETs) play a critical role in the pathogenesis of severe asthma. This study aims to detect if MBD2 can reduce NETs formation and the potential mechanism in severe asthma. Methods A severe asthma model was established in C57BL/6 wild-type mice exposure to house dust mite (HDM), ovalbumin (OVA), and lipopolysaccharide (LPS). Enzyme-linked immunosorbent assay was used to measure the concentrations of IL-4, IL-17A, and IFN-γ in lung tissues. Flow cytometry was employed to determine the percentages of Th2, Th17, and Treg cells in lung tissues. Quantitative real-time polymerase chain reaction was utilized to assess the mRNA expression levels of MBD2, JAK2, and PAD4. Western blotting and immunofluorescence were conducted to detect the protein of MBD2, JAK2, PAD4, and CitH3. HL-60 cells were differentiated into neutrophil-like cells by culturing in a medium containing dimethyl sulfoxide and then stimulated with LPS. KCC-07, Ruxolitinib, and Cl-amidine were used to inhibit the expressions of MBD2, JAK2, and PAD4, respectively. Results Severe asthma mice were characterized by pulmonary neutrophilic inflammation and increased formation of neutrophil extracellular traps (NETs). The expression of MBD2, JAK2, and PAD4 was elevated in severe asthma mice. Inhibiting the expression of MBD2, JAK2, and PAD4 reduced NETs formation and decreased airway inflammation scores, total cell counts and neutrophil counts in BALF, and percentage of Th2 and Th17 cell in lung tissues, whereas increasing Treg cell counts. In both severe asthma mice and HL-60-differentiated neutrophil-like cells in vitro, inhibiting MBD2 reduced the mRNA and protein expression of JAK2 and PAD4, and inhibiting JAK2 reduced the expression of PAD4 mRNA and protein. Conclusion MBD2 regulates PAD4 expression through the JAK2 signaling pathway to promote NETs formation in mice with severe asthma. Further bench-based and bedside-based studies targeting the MBD2, PAD4, and JAK2 signaling pathways will help open new avenues for drug development of severe asthma.

Predictive strength of inflammatory scores for in-hospital mortality in infective endocarditis.

Inflammatory markers have been proposed as prognostic tools for predicting in-hospital mortality in infective endocarditis (IE). Nonetheless, it is unclear whether these markers provide additional prognostic value over established indicators. This study compared nine different inflammation scores to assess their effectiveness in enhancing the prediction of in-hospital mortality. Patients with IE diagnosed between 2017 and 2023 at two cardiology centers in Istanbul were included in this study. Pre-treatment inflammatory markers were obtained from the hospital electronic database system. In-hospital mortality prognostication was assessed using Cox proportional hazards models. Atotal of 122 patients who were diagnosed with IE were included in the analysis. Overall, 38patients died during the hospital stay. The patients were categorized into two groups based on their mortality status. The prognostic nutritional index (PNI), platelet-to-lymphocyte ratio (PLR), and modified Glasgow prognostic score (mGPS) were identified as statistically significant predictors of in-hospital mortality. Based on the results of Cox regression analysis, the PNI (hazard ratio [HR]: 0.921, 95%confidence interval [CI]: 0.853-0.994, p = 0.035) emerged as the only independent predictor of in-hospital mortality of IE patients. Nine inflammatory scores were evaluated in this study. The PNI, PLR, and mGPS were statistically significant predictors of in-hospital mortality in patients with IE. The PNI was identified as the optimal score.

Effect of rapamycin-eluting stents on in-stent restenosis and early inflammatory response in coronary artery narrowing animal models

Objectiveit was to evaluate the efficacy and safety of rapamycin-eluting stents at different doses in the treatment of coronary artery narrowing in miniature pigs.Methodsa total of 20 miniature pigs were randomly assigned into four groups: S1 group (low-dose rapamycin-coated stent, 55 µg/mm2), S2 group (medium-dose rapamycin-coated stent, 120 µg/mm2), S3 group (high-dose rapamycin-coated stent, 415 µg/mm2), and D0 group (bare metal stent). The stent size was 3.0 mm × 18 mm, with an over-expansion ratio of 1.1. Each group consisted of five pigs. Stent implantation was followed by euthanasia and tissue collection after 1 month. Vascular measurements, inflammatory response scores, cardiovascular injury scores, endothelialization scores, liver and kidney function indices, and myocardial injury markers were compared among the groups.Resultsthe neointimal thickness in the S2 and S3 groups was significantly lower than that in the S1 and D0 groups (S1 group: 24.08 ± 3.95, S2 group: 1.86 ± 0.28, S3 group: 2.72 ± 0.74, D0 group: 22.85 ± 3.15, P < 0.05). The residual lumen area in the S2 and S3 groups was significantly larger than that in the S1 and D0 groups (S1 group: 2.73 ± 0.51, S2 group: 4.25 ± 0.78, S3 group: 3.91 ± 0.73, D0 group: 2.91 ± 0.44, P < 0.05). The neointimal area in the S2 and S3 groups was significantly smaller than that in the S1 and D0 groups (S1 group: 3.44 ± 0.84, S2 group: 1.78 ± 0.25, S3 group: 2.07 ± 0.41, D0 group: 3.43 ± 0.72, P < 0.05). The degree of lumen narrowing in the S2 and S3 groups was significantly lower than that in the S1 and D0 groups (S1 group: 44.25 ± 3.66%, S2 group: 14.19 ± 2.01%, S3 group: 15.29 ± 2.45%, D0 group: 21.79 ± 3.51%, P < 0.05). The inflammation scores of coronary artery walls in the S2 and S3 groups of miniature pigs were markedly lower than those in the S1 and D0 groups (P < 0.05). The cardiovascular injury scores (P = 0.072) and endothelialization scores (P = 0.085) differed slightly among the four groups (P > 0.05). Post-operative liver function indicators (alanine transaminase, aspartate transaminase), kidney function indicators (blood urea nitrogen, serum creatinine), and myocardial injury markers (creatine kinase, creatine kinase-MB) also showed neglectable differences among the four groups (P > 0.05).Conclusionmedium and high doses of rapamycin-eluting stents effectively inhibit neointimal hyperplasia and local vascular inflammatory response in miniature pigs without causing damage to liver and kidney functions or myocardial cells. These stents demonstrate high efficacy and safety. Rapamycin-coated coronary stents, as an effective treatment for coronary artery stenosis, may achieve further improvement in therapeutic efficacy through optimization of drug dosage and stent design.

P0554 Machine Learning-Based Interpretation of Unstructured Radiology Reports for Objective Scoring of Inflammation and Stenosis in IBD: A Nationwide Study From the epi-IIRN

Abstract Background Systematic interpretation and quantification of inflammation and stenosis in inflammatory Bowel Disease (IBD) from radiology reports of CT and MR enterography exams are challenging due to their unstructured nature, often leading to variability and reduced reproducibility. This study leverages data from the epi-IIRN nationwide cohort to develop and evaluate machine-learning-based scores for inflammation and stenosis derived from these unstructured radiology reports. Methods We identified radiology reports for IBD-diagnosed patients within the nationwide epi-IIRN cohort, which encompasses data from Israel’s four HMOs, covering 98% of the population. Using our in-house HSMP-BERT natural language processing (NLP) platform, we extracted radiological indicators related to inflammation, stenosis, and location, including wall thickening, enhancement, lumen narrowing, and dilation across specified regions: jejunum, ileum, caecum, colon, sigmoid, and rectum. We developed and evaluated a machine-learning model to predict both categorical (no, mild, and moderate or severe) and VAS (0-100) scores of global inflammation and stenosis, using physician-based scoring as the reference standard. A 5-fold cross-validation experimental setup was applied to assess model performance. Evaluation metrics included accuracy, F1 score, Cohen’s kappa, AUC, PPV, and NPV for categorical scores, and RMSE, r2 and MAE for VAS-like scores. Results The dataset included 9658 reports from 7389 patients with a mean age of 36.4±17.6 years, of whom 49% were male. In the annotated subset (500 reports), inflammation severity was distributed as approximately 37% no, 34% mild, and 29% moderate or severe, while stenosis severity was distributed as 72% no, 15% mild, and 13% moderate or severe. Table 1 summarizes key metrics for inflammation and stenosis, including accuracy, PPV, NPV, F1, and Cohen’s kappa for categorical scores, and RMSE, r2, and MAPE for VAS-like scores, averaged over 5 folds with mean [95% CI]. Main results showed strong performance for both inflammation and stenosis predictions: for inflammation, mean accuracy/F1/kappa/AUC/NPV/PPV/r2/RMSE/MAE were 0.786/0.782/0.676/0.914/0.897/0.775/0.629/13.57/8.571, and for stenosis these values reached 0.912/0.906/0.793/0.955/0.959/0.837/0.760/8.431/3.270. Figure 1 illustrates the joint distribution of predicted versus ground truth VAS-like scores, with both axes spanning the full range of 0 to 100 as defined by physician-based scoring. Conclusion This study demonstrates the feasibility of machine-learning models for mass scoring of inflammation and stenosis from unstructured radiology reports of IBD patients, enabling reliable mass tagging of CTE and MRE as well as determining disease phenotype in large populations.

P0205 Fecal host transcriptomics accurately assesses endoscopic inflammatory activity in patients with inflammatory bowel diseases

Abstract Background The intestinal mucosa regenerates every few days, and cells are continuously shed into the gut lumen. These cells, primarily epithelial and immune cells, have recently been shown to remain viable after shedding and hold critical information for assessing bowel pathology. Analysis of endoscopic washes of luminal material during colonoscopies suggests that the human transcriptome in fecal material accurately reflects degree of histologic inflammation in patients with inflammatory bowel diseases (IBD). We aimed to define whether transcriptomic analysis of stool samples can reflect degree of intestinal inflammation in patients with IBD. Methods Bulk RNA sequencing was performed on stool samples to obtain fecal human transcriptomes from 82 IBD patients, as well as from healthy controls. Each sample received an inflammation score derived from a group of pro-inflammatory transcripts. Inflammatory score was compared to fecal calprotectin as well as endoscopic evaluation. Results The quality of human RNA isolated from fecal content was high, with a median of 2,218 human genes detected per sample. The correlation between fecal calprotectin protein levels and mRNA expression was high (r=0.75). An inflammatory score was generated based on a group of differentially expressed genes. The inflammatory score provided high sensitivity and specificity (both 90%) in predicting endoscopic inflammatory activity when compared to colonoscopic findings. Conclusion Fecal shed cell transcriptomics provided a novel non-invasive tool to measure inflammatory activity at the endoscopic level in patients with IBD. Ongoing studies will address whether this technology can assist in defining degree and location of inflammation, as well as predict response to different therapies.

P1019 Role of Oncostatin M (Osm)-Osmr signaling in colonic inflammation and host defense during citrobacter rodentium infection

Abstract Background Elevated Oncostatin M (OSM) and its receptor (OSMR) are linked to the pathology of inflammatory bowel disease (IBD), particularly in severe, treatment-refractory cases. While anti-OSM therapies hold potential for IBD management, their impact on susceptibility to acute enteric infections remains unclear. This study aims to clarify the role of Osm-Osmr signaling in the context of Citrobacter rodentium infection, a murine model mimicking acute colonic inflammation. Methods Temporal studies were conducted on C57BL/6J mice infected with C. rodentium, assessing gene expression, bacterial load, and immune dynamics at days 3, 7, 14, and 21 post-infection. Histological analysis and flow cytometry were performed to evaluate inflammation and immune infiltration. Additionally, Osm knockout (KO) and Osmr conditional KO mice were utilized to investigate the role of OSM signaling in pathogen control and immune responses. Results Colonic expression of Osm and Osmr peaked at day 14, concurrent with increased levels of Il-22, IFN-g, and antimicrobial peptides (Reg3b, Reg3g), indicating robust immune activation and epithelial repair. ELISA confirmed elevated OSM protein levels. Histology at day 14 revealed severe colonic inflammation, with high Osm/Osmr expression correlating with inflammation scores (p &amp;lt; 0.0001). Flow cytometry showed increased CD45⁺ immune cells, including neutrophils, monocytes, and memory T cells. Notably, OSM signaling was dispensable for bacterial clearance, as Osm knockout mice displayed comparable bacterial loads to wild-type controls despite similar inflammatory responses, suggesting that OSM’s role may be more focused on modulating inflammation and tissue repair rather than direct pathogen control. Conclusion Osm-Osmr signaling plays a key role in modulating inflammation and epithelial repair during C. rodentium infection. The coordinated upregulation of OSM and OSMR enhances immune responses and supports epithelial integrity, highlighting potential therapeutic implications for IBD. Further research is needed to assess the impact of anti-OSM therapies on balancing inflammation control and host defense against infections.

P0433 Pouchitis described by the SES-CD score is more associated with the need for biologics initiation after IPAA than endoscopic subscore of PDAI

Abstract Background The ileal pouch-anal anastomosis (IPAA) is a well-established approach following proctocolectomy for ulcerative colitis (UC) or colorectal dysplasia. Although the functional results are good, many patients develop pouchitis. The pouchitis disease activity index (PDAI) is the most used tool to assess the inflammation of the pouch. However, the PDAI with endoscopic subscore of PDAI (ePDAI) is often not reliable or responsive (1, 2). The simplified endoscopic score for Crohn’s disease (SES-CD) has recently been proposed for this setting (3). In this retrospective study, we aim to describe the correlation between SES-CD score and several important clinical outcomes. Methods We performed a retrospective cohort study of patients who underwent IPAA surgery between March 2015 and February 2024 at out tertiary referral centre. According to internal hospital protocol, endoscopic and clinical examinations were performed at 1, 3, 6, and 12 months after IPAA for each patient. The ePDAI scores, demographics, comorbidities, laboratory tests and medication use were collected from the electronic medical records. Data was collected for the first year following IPAA surgery, and last known follow up. All pouchoscopies (n=497, 86.4% of total) with video- (83.5%) or photodocumentation (16.5 %) were reviewed by the same reviewer (JS) and additionally scored with SES-CD endoscopic score in the pouch body and afferent ileum. Descriptive and univariate analyses was performed. Kaplan-Meier curves were used to assess the impact of the ePDAI and SES CD scores for initiation of biologics. Pouchoscopies were classified as low-grade (ePDAI ≤ 1; SES CD ≤ 3) or high-grade inflammation (ePDAI &amp;gt; 1; SES CD &amp;gt; 3). Results The total cohort included 206 patients (46.1% female), of which 90.3% underwent IPAA surgery due to ulcerative colitis with a median follow up of 25 months after IPAA construction. Of those, 12.6% were receiving biologic therapy at the last follow up. There was linear corelation between ePDAI and SES-CD score (rho 0.69, p&amp;lt;0.001). For both scores, the patients with high-grade inflammation pouchoscopy at months 1 (p 0.0132 for ePDAI, p 0.0008 for SES-CD) and 6 (p 0.0001 for ePDAI, p 0.0007 for SES-CD) had a higher need for biologic therapy than patients with low-grade pouchoscopy. At month 3 and 12, only SES-CD was associated with higher need for biologic therapy (month 3: p 0.467 for ePDAI, p 0.042 for SES-CD; month 12: p 0.0571 for ePDAI and p 0.0387 for SES CD). Conclusion The SES-CD score may be an alternative to ePDAI for scoring of pouch inflammation. The pouch inflammation described by the SES-CD score is more associated with the need for biologics initiation in patients after IPAA than ePDAI. References (1)Jairath V, Feagan BG, Silverberg MS, et al. Mucosal healing with vedolizumab in patients with chronic pouchitis: EARNEST, a randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. Published online 2024. doi: 10.1016/j.cgh.2024.06.037 (2)Sedano R, Nguyen TM, Almradi A, et al. Disease activity indices for pouchitis: A systematic review. Inflamm Bowel Dis. 2022;28(4):622-638. doi:10.1093/ibd/izab124 (3)Barnes EL, Long MD, Raffals L, et al. Development of the endoscopic pouch score for assessment of inflammatory conditions of the pouch. Clin Gastroenterol Hepatol. 2023;21(6):1663-1666.e3. doi: 10.1016/j.cgh.2022.04.026

P0627 Pharmacokinetics, Pharmacodynamics, Safety, and Efficacy of Oral Resolvin E1-based Therapy in Inflammatory Bowel Disease (IBD): Translating Resolvin E1 Activation of BLT1 in Experimental Models to Healthy Volunteers

Abstract Background Resolvin E1 (RvE1), an endogenous lipid mediator, shows efficacy in murine colitis models by modulating mucosal immunity and protecting epithelial barrier function. RvE1 and leukotriene B4 (LTB4) are both BLT1 receptor agonists but elicit distinct biological outcomes through biased agonism. LTB4, a pro-inflammatory lipid mediator, initiates and regulates inflammatory responses by stimulating recruitment and activation of immune cells. In contrast, RvE1 selectively engages BLT1 to promote immune homeostasis and repair. TP-317, a stabilized RvE1 molecule, is being investigated as oral therapy for inflammatory bowel disease (IBD). In a sub-chronic murine model of DSS colitis, oral TP-317 (4.0 mg/kg) significantly improved disease activity and histological scores for mucosal inflammation and crypt loss. GLP toxicology studies in rats and dogs support TP-317’s safety profile, with the highest RvE1 doses tested in both preclinical species determined to be the no observed adverse event levels (NOAEL). This Phase 1a clinical study describes the pharmacokinetics (PK), pharmacodynamics (PD) and safety profile of TP-317 given as an enteric-coated tablet to healthy volunteers. Methods Twenty-four subjects were randomized 3:1 to single oral doses of TP-317 at 10, 40 and 80 mg (n=8/group). Safety, tolerability and PK/PD were assessed using standard methods. Subjects receiving the 80 mg dose underwent frequent CBC testing to assess short-term fluctuations in circulating neutrophils. Results Oral TP-317 was well tolerated, producing peak plasma RvE1 concentrations exceeding the EC50 for BLT1 activation (~10 nM) by 1.2, 2.8, and 6.7 times at 10, 40, and 80 mg doses, respectively. The mean AUC of the 80 mg group met regulatory requirements when compared to NOAEL dose exposures in rats and dogs. All 80 mg subjects experienced transient neutropenia, with neutrophils dropping below 1500/mL near RvE1 peak, followed by complete recovery above normal within ~2 hours. A similar pattern was previously observed without safety concerns in healthy subjects receiving an RvE1 drug at 150 mg twice daily for 10 days. Conclusion TP-317 demonstrates good tolerability and achieves adequate systemic RvE1 levels to engage the BLT1 receptor, offering a novel agonist approach to the LTB4-BLT1 pathway. Transient neutropenia observed with TP-317, a known effect of BLT1 activation by LTB4 and RvE1, suggests target engagement in humans. Oral TP-317’s safety profile and unique pro-resolution, barrier-protective mechanism warrant further clinical studies in IBD patients.

P1276 Persistent Insomnia Ignites the Flames of Crohn's Disease by Elevating Systemic Inflammation

Abstract Background The association between insomnia and the risk of inflammatory bowel disease (IBD) remains inconclusive. We aim to investigate the association between insomnia and the risk of IBD, Crohn's disease (CD) and ulcerative colitis (UC), while further considering genetic vulnerability and inflammatory mediation. Methods This cohort study included 480,252 participants without IBD at baseline in the UK Biobank. The mean age of the population was 56.53 years old and 54.3% were female. Cox regression models examined the associations between insomnia and the incident of IBD, CD and UC. Polygenic risk score (PRS) for IBD, UC and CD was calculated. Subgroup and mediation analyses were conducted. Results A total of 480,252 participants were included. The mean age of the population was 56.53 years old and 54.3% were female. During a mean follow-up of 13.20 years, 3,219 incident IBD (1,005 CD and 2,207 UC) cases were documented. Compared to non-insomniacs, there was a significant increasing trend in the frequency of insomnia and the risk of incident IBD (P for trend=0.040) and CD (P for trend=0.003). Among individuals who usually have insomnia, the risk of CD incidence increased by 31% compared to those free of insomnia (hazard ratio [HR] 1.31; 95% confidence interval [CI]: 1.09-1.57; P=0.004), but no significant association was found between usually having insomnia and the risk of IBD (HR 1.10; 95% CI: 1.00-1.22; P=0.051) and UC (HR 1.03; 95% CI 0.91-1.16; P=0.678). Consistent results were observed in subgroup and sensitivity analyses. The connection between insomnia and CD was especially significant for participants with intermediate genetic susceptibility. High genetic risk individuals with usual insomnia were associated with a 2.51-fold increased risk of CD. The association between usually having insomnia and the risk of CD was partially mediated low-grade inflammation (INFLA) score by 6.36% (natural indirect effect [NIE] 1.018; 95% CI 1.013-1.023). Conclusion Insomnia exposure was associated with increased risk of CD but not UC. Further study is warranted to determine if modifying insomnia could mitigate CD risk.

P0077 Identification of symbiote candidates for pouchitis in patients with ulcerative colitis

Abstract Background Ulcerative colitis (UC) has been recognized as a life-long inflammatory disease. Although several novel treatments for UC has been developed, medication-uncontrollable UC patients require the surgical treatment. The surgical operation could improve the quality of life of the patients, but requires intensive medical following, because more than 40% develop to pouchitis. We have explored the symbiote candidates for Ileoanal pouch through comprehensive microbiome and metabolome analysis to prove the mechanism of pouchitis. Methods The fecal samples in patients with or without pouchitis were collected. 16S rRNA amplicon meta-analysis and metabolome analysis for 170 patients were performed. Results The alfa diversity in microbiome was significantly decreased with developing pouchitis. Several bacterial genera which include Lachnospiraceae, Bifidobacteriaceae, Prevotellaceae, Clostridiaceae, Ruminococcaceae, and Veillonellaceae were statistically reduced in correlation with inflammatory clinical score and were shown having significant relation with protective metabolites. In addition, the extent of decrease in these candidates was strikingly prominent in medication-refractory pouchitis. Additionally, some pouchitis revealed the increasing of Enterobacteriaceae, unclassified Lactobacillas, or Propionibacteriaceae. Conclusion Thus, our data show these bacterial taxa as symbiote candidates and could be attractive targets for maintenance of Ileal pouch in UC.

P1048 Vedolizumab in Indian patients with Inflammatory Bowel Disease: Final results from a prospective, multicentre, open-label, phase 4 study

Abstract Background India has rising prevalence of Inflammatory Bowel Disease (IBD), with an estimated 1.4 million cases reported in 2010.¹ Vedolizumab (VDZ) has demonstrated safety and effectiveness internationally as an alternative for achieving clinical response and remission. 2,3 There is limited data on VDZ’s efficacy and safety for Indian patients. This study provides the first focused evaluation of VDZ in this population. Methods In this prospective, multicenter, open-label phase IV study (NCT04804540), patients aged 18–65 with moderate to severe ulcerative colitis (UC) or Crohn’s disease (CD) unresponsive to corticosteroids, immunomodulators or anti-TNF agents received VDZ 300 mg intravenously at weeks 0, 2, and 6 (induction) and at weeks 14, 22, 30, 38, and 46 (maintenance). Patients had diagnosis of moderate to severe active UC or CD with a Full Mayo Score of 6-12 for UC and Harvey Bradshaw Index (HBI) of ≥8 for CD at the time of enrollment. Clinical remission was defined as Simple Clinical Colitis Activity (SCCAI) ≤2 for UC or HBI ≤4 for CD, while clinical response was defined as an SCCAI decrease of ≥3 or physician assessed response for UC and HBI decrease of ≥3 for CD. The primary objective analyzed the safety of VDZ in Indian UC or CD patients, with a secondary objective of assessing efficacy. The final analysis included data up to Week 46 or patient discontinuation. Results Of 215 patients screened, 150 were enrolled (102 with UC: median age 39 years; 48 with CD: median age 31 years). The median treatment duration was 325 days for UC and 323 for CD. AEs affected 83 patients (55.3%), with mild AEs in 72 (48%). TEAEs occurred in 52 (51%) patients with UC and 29 (60.4%) with CD, while SAEs occurred in 8 (5.3%) patients, with 2 treatment- related. Additionally, 5 patients (3.3%) had at least 1 ADR, and 4 (2.7%) had AESI. Reported ADR/AESI cases included one patient each with pulmonary tuberculosis, tuberculous pleurisy, rectal adenocarcinoma, and hypertension. Anaemia was most common TEAE, and small intestinal obstruction was most frequent SAE. No AE related deaths occurred(Table 1). Overall clinical response rates were 60.7% at Week 14, 65.3% at Week 30, and 72% at Week 46. Remission rates were 42% at Week 14, 44% at Week 30, and 53.3% at Week 46(Fig 1). Mucosal healing was observed in 27/150 (18%) patients at week 46. Quality of life scores showed improvements across both UC and CD groups, with median Short Inflammatory Bowel Disease Questionnaire score increases noted from baseline of 5 at week 14 to 13 at week 46 in both groups. Conclusion This study demonstrates that vedolizumab has a good safety profile in Indian patients with moderate-to-severe UC and CD, offering well-tolerated option for achieving clinical response and remission.

P0814 Transmural healing in Crohn’s disease: Real-world insights from the SUNRISE study on vedolizumab using intestinal ultrasonography

Abstract Background The use of patient-centric monitoring modalities for assessing therapies, such as vedolizumab (VDZ), are of growing interest to optimize disease outcomes in patients (pts) with Crohn’s disease (CD). Transmural healing is an emerging outcome assessed by intestinal ultrasonography (IUS), which allows frequent evaluation of CD.1,2 Real-world evidence on the effectiveness of current treatments to induce and maintain transmural response to inform treatment decisions is limited. The SUNRISE study aims to describe pts with CD treated with VDZ achieving a composite outcome of complete remission, and transmural response, utilizing IUS. Methods SUNRISE is an ongoing observational, prospective study (NCT05192863) being conducted across 10 sites in Canada, Israel and Italy. Adults with moderately to severely active CD, with a bowel wall thickness of &amp;gt;3 mm based on IUS, and who newly initiated intravenous VDZ are eligible. Complete remission (defined as a composite endpoint of clinically corticosteroid-free [Harvey–Bradshaw Index score of &amp;lt;5 points and no concomitant corticosteroids], biochemical [C-reactive protein and faecal calprotectin normalization] and transmural remission [assessed by IUS]), and transmural response after VDZ treatment are reported after induction with VDZ (Weeks 10/14) and every 6 months until Month 18 or early discontinuation. Methodological details are shown in the Figure. Results This interim analysis included 70 pts; median (interquartile range [IQR]) age was 50.0 (39.0–67.0) years, time since CD diagnosis was 4.0 (0.9–17.2) years and treatment duration (n=69) was 5.0 (3.2–6.1) months. At Month 6, the proportion of pts achieving complete remission, and transmural remission and response were 3/11 (27.3%), 9/28 (32.1%) and 12/28 (42.9%) pts, respectively; data at Weeks 10/14 are shown in the Table. Median (IQR) Short Inflammatory Bowel Disease Questionnaire total score was 4.3 (3.7–5.6) at baseline, 4.5 (3.4–5.3) at Week 10, 4.7 (3.9–5.6) at Week 14 and 5.0 (4.4–6.1) at Month 6. At Month 6, 10/21 pts (47.6%) ranked IUS as their preferred test over colonoscopy, magnetic resonance elastography and computed tomography enterography. Of 40 pts with available data at Month 6, 6 (15.0%) discontinued treatment, 5 (12.5%) switched to subcutaneous VDZ and 1 (2.5%) skipped ≥1 dose of VDZ. During the observation period, 2/70 pts (2.9%) had a CD-related hospitalization, and 1/70 pt (1.4%) each had a CD-related emergency room visit or CD-related surgery (fistula removal). Conclusion The SUNRISE study provides real-world evidence for the use of VDZ to achieve transmural healing in pts with CD and supports pt preference for IUS over other monitoring modalities. Additional follow-up data are required to confirm these findings.

P0491 Cumulative Inflammatory Burden and Structural Bowel Changes as Independent Risk Factors for Colonic Dysplasia in Ulcerative Colitis: A Case-Control Study

Abstract Background Long-standing inflammation has been implicated in the development of colonic dysplasia in ulcerative colitis (UC). However, the relationship between varying degrees of inflammatory exposure and dysplasia risk remains poorly understood. We aimed to identify risk factors for colonic dysplasia in UC patients, with particular focus on quantifying long-term inflammatory exposure. Methods In this retrospective single-center case-control study, we reviewed 55 UC patients diagnosed with colonic dysplasia (low-grade, high-grade, or cancer) between 2013 and 2022, and 110 randomly selected UC patients without dysplasia as controls. Endoscopic inflammation was scored using the Mayo endoscopic subscore (0-3), and cumulative inflammatory exposure was calculated by multiplying these scores with the duration of each endoscopic follow-up period. Clinical factors and endoscopic findings were compared between groups, and logistic regression analysis was performed to identify independent predictors of dysplasia. Results Univariate analysis showed that the dysplasia group had significantly higher frequencies of anemia (hemoglobin &amp;lt;10 g/dL), elevated ESR (&amp;gt;18 mm/hr at diagnosis), steroid and biologics use, tubular or shortened colon, and high cumulative endoscopic inflammation scores (&amp;gt;10). In multivariate analysis, after adjusting for age, gender, and disease duration, both tubular or shortened colon (OR 3.172, 95% CI: 1.029-9.780) and high cumulative endoscopic inflammation score(&amp;gt;10) (OR 4.205, 95% CI: 1.065-16.600) were independently associated with increased dysplasia risk. Conclusion High cumulative inflammatory burden, as indicated by elevated endoscopic inflammation scores and structural bowel changes, significantly increases the risk of colonic dysplasia in UC patients. More intensive surveillance strategies may be warranted for patients with these objective risk indicators to enable early detection of colitis-associated dysplasia.

P0162 Distinct mucin RNA isoform expression in the blood of Inflammatory Bowel Disease patients with variable degree of inflammation

Abstract Background Mucosal healing is considered as a key therapeutic endpoint in inflammatory bowel diseases (IBD) and comprises endoscopic improvement of inflammation without taking barrier healing into account. Mucins are critical components of the intestinal mucosal barrier function that give rise to structurally diverse isoforms. In a recent study, we demonstrated that intestinal region-specific mucin RNA isoform expression captured the heterogeneity of the IBD patient population and showed great potential to indicate barrier function enhancing IBD management [1]. Given that epithelial cells can enter the bloodstream because of epithelial barrier injury upon inflammation, we further investigated whether intestinal-type mucin RNA isoforms have the potential as non-invasive biomarkers for IBD disease monitoring. Methods Using bulk RNA sequencing data (Illumina) mapped to our recently designed mucin RNA isoform landscape [1], we assessed mucin RNA isoform expression in the blood from 45 IBD patients (22 UC, 23 CD) and 19 controls and correlated the data to clinical outcome parameters (i.e. endoscopic activity (Mayo or SES-CD), inflamed intestinal region, histological activity (Geboes score), C-reactive protein level). Additionally, random forest-based feature selection, using a publicly available dataset (PRJNA774251), was carried out to select peripheral mucin RNA isoforms that accurately stratified UC patients (n=79) from controls (n=209). Results Overall, expression of MUC1, MUC4, MUC6, MUC12, MUC12-AS1, MUC16, MUC20, MUC20P1, and MUC20-OT1 mRNA was identified in the blood of IBD and control patients, with MUC1, MUC20 and MUC20-OT1 being abundantly present in both cohorts. At mucin RNA isoform level, 50 originated from the intestinal mucin RNA isoform landscape [1] with RNA isoforms derived from MUC20 and MUC20-OT1 classified as the top 10 most predominantly expressed isoforms. Interestingly, expression of several MUC20-OT1 RNA isoforms was decreased in UC or CD patients with moderate to severe inflammation compared to controls (Figure 1). In addition, four MUC20-OT1 isoforms and two MUC20 were correlated to the endoscopic inflammation score. Feature selection based on random forest modeling to distinguish UC patients with moderate to severe inflammation from controls unveiled a panel of 5 mucin RNA isoforms (MUC6 (ENST00000421673.7), MUC20-OT1(ENST00000429897.5), MUC4(ENST00000467235.1), MUC20-OT1(ENST00000626852.2) and MUC5AC(PB.2811.15); area under the curve of 75.7% (train set) and 60.3% (test set); Figure 2). Conclusion Peripheral blood mucin RNA isoform expression can be monitored in IBD patients, with MUC20-OT1 RNA isoforms as potential non-invasive biomarkers for intestinal barrier dysfunction.

The adductor pollicis muscle thickness is not associated with physical function, lean mass, and nutritional status in patients on maintenance hemodialysis

BackgroundThe adductor pollicis muscle thickness (APMT) may be associated with the muscle strength in patients on hemodialysis. However, the association of APMT with other physical function assessment tests has not yet been tested. Moreover, because it is considered a good nutritional indicator and not influenced by fluid overload, the APMT may be associated with the muscle mass and nutritional status of these patients. Therefore, the objective was to assess the association of APMT with physical function, muscle mass and nutritional status in patients on hemodialysis.MethodsThe APMT was measured using a skinfold caliper between pollicis finger and index finger. Physical function was evaluated by handgrip strength (HGS), Short Physical Performance Battery (SPPB), the sit-to-stand test, gait speed test, and timed up and go (TUG). Appendicular muscle mass index (AMMI) was estimated using bioelectrical impedance. The nutritional status was evaluated by the Malnutrition Inflammation Score (MIS).ResultsFifty-one patients were included, 60.8% men, mean age 58.4 ± 12.6 years. There were no significant correlations of APMT with physical function, muscle mass and nutritional status. Values of APMT were not different between the groups according to adequate physical function or muscle mass. In the multiple linear regression analysis adjusted for sex, age and diabetes, APMT was not significantly associated with physical function tests, as HGS (β = 0.101; p = 0.778), gait speed (β = −0.014; p = 0.180), SPPB (β = −0.054; p = 0.590), TUG (β = 0.202; p = 0.109), lean mass AMMI (β = 0.058; p = 0.147).ConclusionThere were no associations of APMT with physical function, muscle mass and nutritional status in patients on hemodialysis. We suggest APMT should not be used in physical function and nutritional assessments of these patients.

P0197 Comparison of pharmacodynamic and mechanistic response of guselkumab intravenous and subcutaneous induction in moderately to severely active Crohn’s disease: molecular analysis of the GRAVITI and GALAXI Phase 3 studies

Abstract Background Guselkumab (GUS) is a selective dual-acting IL-23p19 subunit inhibitor that potently blocks IL-23 and binds to CD64 demonstrated efficacy with intravenous (IV) induction in patients with moderately to severely active Crohn’s disease (CD) in the GALAXI trials.1 Subcutaneous (SC) induction with GUS evaluated in the Ph3 GRAVITI trial was also efficacious in treating patients with CD.2 Here we present a comparison of the pharmacodynamic and mechanistic response of GUS SC and GUS IV induction therapy in CD. Methods Serum proteins were evaluated from 290 GRAVITI patients randomised to PBO or GUS 400mg SC q4w, and a subset of 292 GALAXI patients randomised to PBO or GUS 200mg IV q4w at Weeks 0 and 12 using a 92-analyte inflammatory protein panel. Transcriptional profiling from each of the five anatomic segments in GRAVITI was conducted with samples from 277 patients at WK0 and WK12 using RNA sequencing. A tissue inflammation score (bMIS3) was used to assess segmental molecular inflammation which correlated with segmental histology scores defined by Global Histologic Activity Score (GHAS), endoscopic scores and subscores defined by Simple Endoscopic Score for CD (SES-CD).3 Analysis of treatment effect was performed using molecularly inflamed samples (defined as bMIS &amp;gt;0) from segments with SES-CD &amp;gt;0 at baseline. Transcriptional gene modules were evaluated for differential expression. Results In serum, protein changes observed with GUS 400mg SC q4w induction at WK12 were highly correlated with those observed with GUS 200mg IV q4w induction at WK12 (R=0.96, p&amp;lt;0.05), including similar reduction of IFNγ, IL-17A, CRP and fecal calprotectin (p&amp;lt;0.05; Figure 1). In tissue, segmental molecular inflammation assessed by bMIS correlated with segmental histological and endoscopic subscores (percent affected tissue and ulceration severity). In each anatomic segment, GUS SC induction reduced key cellular and inflammatory transcriptional modules at WK12 including plasma cell, inflammatory epithelial, neutrophil, and IL-23/Th17 biology consistent with molecular analysis from GUS IV induction in GALAXI Ph2b.4 The decrease in molecular inflammation in 5 anatomic segments corresponded to the segmental endoscopic improvement observed in isolated ileal, ileocolonic and colonic patient subgroups. Conclusion Following SC induction, the protein changes observed in serum at WK12 in GRAVITI were highly correlated with those seen with GUS IV induction from GALAXI Ph3. These data demonstrate similar molecular effects of GUS SC and IV induction doses and are aligned with previously reported similar efficacy results, supporting the flexible choice for patients and healthcare professionals between GUS SC and IV to treat patients with CD.

P0805 Sigmoidoscopy is sufficient as a surveillance tool in pediatric Ulcerative Colitis; full colonoscopy is not typically needed

Abstract Background Sigmoidoscopy is a less invasive procedure than full colonoscopy, demands simpler preparation, requires shorter procedure time, and may be conducted with lighter sedation. Despite these advantages and the continuous nature of inflammation in ulcerative colitis (UC), which typically decreases from distal to proximal colon, the FDA recently requests full colonoscopy to assess UC in clinical trials (i.e. 3 colonoscopies in 54 weeks). Data to support this requirement are scarce in children. We, thus, aimed to assess the necessity of full colonoscopy versus limited sigmoidoscopy in pediatric UC. Methods We included two prospectively enrolled cohorts of children (0-18 years) with UC, both with identical data collection relevant to this study: one from a single-center prospective registry, and the other from a prospective validation of the TUMMY-UC, a patient-reported signs and symptoms for pediatric UC. In addition to explicit clinical, disease activity, labs and demographic data, the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) was recorded prospectively for each colonic segment. The first colonoscopy available after the time of diagnosis was included to better mirror the scenario of post-treatment follow-up monitoring, since the diagnostic procedure should always be full colonoscopy. Results A total of 85 patients were included (mean age 14 ± 3.4, 11 [13%] with endoscopic healing, 45 [53%] with mild colitis and 29 [34%] with moderate-severe colitis). The median UCEIS scores decreased progressively from the rectum and sigmoid (2, IQR:0-4) to the more proximal colon (descending 1, IQR:0-3; transverse and ascending 0, IQR:0-2; p &amp;lt; 0.001). Only 3 patients (3.5%) had inflammation in proximal segments without having inflammation in the rectosigmoid region. Another 10 patients (12%) had higher inflammation scores in the proximal colon than in the rectosigmoid (i.e. reverse gradient), though inflammation was still present in the rectosigmoid region. Conclusion In 96.5% of cases, endoscopic healing in the rectosigmoid region reflected endoscopic healing in the entire colon in children with UC. When inflammation was present in the rectosigmoid, in 86% the degree of colitis reflected the maximal endoscopic severity of the entire colon. These findings suggest that sigmoidoscopy may be a suitable routine post-treatment surveillance tool for pediatric UC patients and in the research setting in order to maximize feasibility and ethical considerations of clinical trials.

P0102 Isatin: An indole alkaloid with intestinal anti-inflammatory activity in the trinitrobenzene sulfonic acid colitis model

Abstract Background Inflammatory bowel disease (IBD) is a complex and recurring inflammatory disorder that affects the gastrointestinal tract.1 Various drugs have been developed for treating IBD, but there are still limitations due to adverse effects experienced by patients.2 Plant-derived molecules with anti-inflammatory properties represent a valuable alternative as a complementary therapy for IBD.3 Isatin is a compound found in several medicinal plant species with various biological activities, including a modulatory effect on pro-inflammatory mediators. This study aimed to evaluate the effect of isatin in experimental colitis. Methods Rats were divided into three groups (10 animals/group): Saline (non-colitic control), TNBS (colitic untreated), and isatin (colitic treated with isatin 6 mg/kg). After anesthesia with ketamine (50 mg/kg) and xylazine (10 mg/kg), the TNBS and isatin groups received a single dose of TNBS (10 mg) dissolved in 0.25 mL of 50% ethanol (v/v) by rectal administration. To evaluate the intestinal anti-inflammatory activity of isatin, animals were treated 2, 24, and 48 hours after the TNBS challenge and euthanized after 72 hours by CO2 overdose. The colons were removed, the macroscopic inflammation and the colon weight/length ratio were measured and the cytokines IL-1β, IL-12, IFN-γ, and TNF-α were quantified by ELISA. Median (minimum-maximum) or mean ± SEM values were compared through the Kruskal-Wallis test (Dunn’s test) or two-way ANOVA (Tukey’s test). The experiments were approved by the Ethics Commission in Animal Use (Protocol number 2773-1). Results The TNBS group showed increased colonic wall thickness and inflammatory cell infiltration. Isatin reduced the macroscopic inflammation score [Isatin: 6 (6-7) versus TNBS: 9 (8-10); p &amp;lt; 0.01] promoted by TNBS instillation. Oral administration of isatin prevented the increase in the colon weight/length ratio (0.151 ± 0.017 versus 0.192 ± 0.015; p &amp;lt; 0.01). The colonic damage caused by TNBS instillation was also characterised by an increase in the levels of pro-inflammatory cytokines compared to the Saline group. In contrast, isatin reduced the levels of TNF-α (2.42 ± 0.72 versus 6.32 ± 1.91; p&amp;lt;0.001), IFN-γ (4.26 ± 1.15 versus 7.34 ± 0.48; p&amp;lt;0.01), IL-1β (16.54 ± 4.76 versus 35.91 ± 4.11; p&amp;lt;0.001), and IL-12 (13.38 ± 3.65 versus 28.87 ± 8.39; p&amp;lt;0.01) while increased the levels of IL-10 (6.41 ± 0.60 versus 4.82 ± 0.26; p&amp;lt;0.01) when compared with TNBS group. Conclusion Isatin decreased the macroscopic inflammation score and the colon weight/length ratio. The action of isatin on colitis involves the reduction of pro-inflammatory mediators such as TNF-α and IL-1β and increase of the anti-inflammatory cytokine IL-10, suggesting a potential curative role of isatin in colitis therapy.