Disease Activity In Ulcerative Colitis Research Articles

Infliximab Tissue Concentrations in Patients With Stable Ulcerative Colitis Are Correlated With More Durable Infliximab-associated Disease Remission.

We aimed to determine the correlation between tissue and plasma infliximab concentrations in an outpatient ulcerative colitis (UC) cohort based on histologic disease activity in addition to their relationship with long-term clinical outcomes. We assessed intraparticipant variability in infliximab concentrations between adjacent intestinal samples and the correlation between disease activity and tumor necrosis factor-α (TNF-α). A prospective cohort study was conducted in participants with UC receiving infliximab. Blood and 2 sigmoid colon biopsies were obtained at the index colonoscopy for infliximab and TNF-α quantification. Histological disease activity was assessed. Participants were followed for 2 years for the occurrence of hospitalization, surgery, disease relapse, and infliximab discontinuation. A positive correlation was observed between mean plasma and uninflamed tissue infliximab concentrations only (Rs = 0.75, P = .0071). Lower mean tissue infliximab concentrations correlated with a shorter time to disease relapse vs those with higher mean tissue concentrations (Rs = 0.77, P = .032). This was not seen when using plasma infliximab concentrations. Additionally, no significant intraparticipant variability of infliximab concentrations was observed for all participants independent of disease activity. Neither plasma nor tissue TNF-α correlated with disease activity. These findings support data generated in patients with Crohn's disease: plasma infliximab concentrations are reflective of infliximab exposure in tissue in the UC patient in remission, but not for those with active disease. Increasing tissue concentrations in the noninflamed tissues may improve durability of infliximab. Neither plasma nor tissue TNF-α appear to correlate with UC disease activity. Larger follow-up studies would be of benefit.

Fecal calprotectin and platelet count predict histologic disease activity in pediatric ulcerative colitis: results from a projection-predictive feature selection.

Especially for pediatric patients, proxies of mucosal inflammation are needed. The Pediatric Ulcerative Colitis Activity Index (PUCAI) has been established to predict clinical and endoscopic disease activity. However, histologic inflammation might persist. We applied a special variable selection technique to predict histologic healing in pediatric ulcerative colitis (UC) as parsimoniously (but still as precisely) as possible. The retrospective analysis included data from two study cohorts, comprising 91 visits from 59 pediatric patients with UC. A Bayesian ordinal regression model was used in combination with a projection-predictive feature selection (PPFS) to identify a minimal subset of clinical and laboratory parameters sufficient for the prediction of histologic disease activity. Following the PPFS, CEDATA-GPGE patient registry data were analyzed to investigate the relevance of the selected predictors in relation to PUCAI and Physician Global Assessment (PGA) in up to 6697 patient visits. Fecal calprotectin (FC) and platelet count were identified as the minimal subset of predictors sufficient for prediction of histologic disease activity in pediatric UC. FC and platelet count also appeared to be associated with increasing disease activity as measured by PUCAI and PGA in the CEDATA-GPGE registry. Based on the selected model, predictions can be performed with a Shiny web app. Conclusion: Our statistical approach constitutes a reproducible and objective tool to select a minimal subset of the most informative parameters to predict histologic inflammation in pediatric UC. A Shiny app shows how physicians may predict the histologic activity in a user-friendly way using FC and platelet count. To generalize the findings, further prospective studies will be needed. What is Known: • Histologic healing is a major endpoint in the therapy of ulcerative colitis (UC). • The PUCAI score has been established to predict disease activity in pediatric UC but is not suitable for the prediction of histologic healing. What is New: • Our Bayesian ordinal regression model in combination with a projection-predictive feature selection is a reproducible and objective tool to select the minimal subset of clinical and laboratory parameters to predict histologic inflammation in pediatric UC. • Histologic inflammation in pediatric UC can be non-invasively predicted based on the combination of fecal calprotectin levels and platelet count.

Eosinophils and risk of ulcerative colitis in European population: Evidence from Mendelian randomization study.

Observational studies have indicated that peripheral blood eosinophil count is elevated in individuals diagnosed with ulcerative colitis (UC) and correlates with the disease activity of UC. However, this conclusion contradicts with findings from other studies. Therefore, we employed Mendelian randomization (MR) method to assess the genetic link between eosinophil count and UC. This MR study utilized summary data from genome-wide association studies (GWAS) on eosinophil count and UC. The main approach used for conducting MR analysis was the inverse variance weighted (IVW) method. Meta-analysis of the IVW results was performed alongside multiple sensitivity analyses to confirm the robustness of the MR analysis results. The IVW method unveiled a causal relationship between eosinophil count and UC (OR = 1.18, 95% CI: 1.04-1.33, p = .01) in the discovery cohort. This finding was further corroborated by the replication cohorts (OR = 1.16, 95% CI: 1.04-1.29, p = .01; OR = 1.12, 95% CI: 1.01-1.24, p = .03). The meta-analysis indicated that the overall odds ratio (OR) for all studies was 1.15 (common effect model, 95% CI: 1.08-1.23, p < .01). Sensitivity analysis suggested the absence of heterogeneity and horizontal pleiotropy in all MR analyses. Based on bidirectional two-sample MR analysis, there is an indication that elevated eosinophil count may increase the risk of UC. However, potential confounding factors cannot be ruled out, and further research is necessary to explore how eosinophils contribute to the onset and progression of UC.

Intestinal ultrasound scan predicts corticosteroid failure and colectomy risk in patients with ulcerative colitis.

Intestinal ultrasound (IUS) is an emerging modality for assessing disease activity, extent, and treatment response in ulcerative colitis. This study aimed to evaluate the potential of IUS in predicting severe flares, the need for rescue therapy (corticosteroid failure), and colectomy in patients with ulcerative colitis. We conducted a retrospective review of medical records, collecting clinical and IUS data. The Milan Ultrasound Criteria (MUC) score was used to assess ulcerative colitis severity. Group comparisons were performed to identify differences in MUC scores between mild-to-moderate and severe ulcerative colitis, between steroid responders and nonresponders, and between patients who underwent colectomy and those who did not. Receiver operating characteristic (ROC) analysis was used to predict outcomes in patients with ulcerative colitis. This analysis included 102 patients with ulcerative colitis categorized as mild/moderate (60) or severe (42). MUC scores were significantly higher in the severe ulcerative colitis group compared with the mild/moderate group (P < 0.001). Analysis (using ROC) identified a cutoff MUC score of >8.54 to indicate severe ulcerative colitis with good sensitivity (64.29%) and excellent specificity (93.33%). Similarly, a cutoff of MUC > 10.54 showed promise in predicting corticosteroid failure, with acceptable sensitivity (50%) and high specificity (90.91%). Finally, a cutoff MUC score >12.5 demonstrated potential for predicting colectomy, exhibiting moderate sensitivity (55.56%) but excellent specificity (96.97%). IUS may be useful for differentiating severe ulcerative colitis from mild-to-moderate disease, identifying early stage failure of corticosteroid therapy, and predicting the potential need for colectomy.

An artificial intelligence-driven scoring system to measure histological disease activity in ulcerative colitis.

Assessment and scoring of histological images in Ulcerative colitis (UC) is prone to inter- and intra-observer variability. This study aimed to investigate whether an artificial intelligence (AI) system developed using image processing and machine learning algorithms could measure histological disease activity based on the Nancy index. A total of 200 histological images of patients with UC were used in this study. A novel AI algorithm was developed using state-of-the-art image processing and machine learning algorithms based on deep learning and feature extraction. The cell regions of each image, followed by the Nancy index, were manually annotated and measured independently by four histopathologists. Manual and AI-automated measurements of the Nancy index score were conducted and assessed using the intraclass correlation coefficient (ICC). The 200-image dataset was divided into two groups (80% was used for training and 20% for testing). Intraclass correlation coefficient statistical analyses were performed to evaluate the AI tool and used as a reference to calculate the accuracy. The average ICC among the histopathologists was 89.3 and the average ICC between histopathologists and the AI tool was 87.2. The AI tool was found to be highly correlated with histopathologists. The high correlation of performance of the AI method suggests promising potential for inflammatory bowel disease clinical applications. A standardized automated histological AI-driven scoring system can potentially be used in daily inflammatory bowel disease practice to reduce training needs and resource use, eliminate the subjectivity of the pathologists, and assess disease severity for treatment decisions.

Accurate, Robust, and Scalable Machine Abstraction of Mayo Endoscopic Subscores From Colonoscopy Reports.

The Mayo endoscopic subscore (MES) is an important quantitative measure of disease activity in ulcerative colitis. Colonoscopy reports in routine clinical care usually characterize ulcerative colitis disease activity using free text description, limiting their utility for clinical research and quality improvement. We sought to develop algorithms to classify colonoscopy reports according to their MES. We annotated 500 colonoscopy reports from 2 health systems. We trained and evaluated 4 classes of algorithms. Our primary outcome was accuracy in identifying scorable reports (binary) and assigning an MES (ordinal). Secondary outcomes included learning efficiency, generalizability, and fairness. Automated machine learning models achieved 98% and 97% accuracy on the binary and ordinal prediction tasks, outperforming other models. Binary models trained on the University of California, San Francisco data alone maintained accuracy (96%) on validation data from Zuckerberg San Francisco General. When using 80% of the training data, models remained accurate for the binary task (97% [n = 320]) but lost accuracy on the ordinal task (67% [n = 194]). We found no evidence of bias by gender (P = .65) or area deprivation index (P = .80). We derived a highly accurate pair of models capable of classifying reports by their MES and recognizing when to abstain from prediction. Our models were generalizable on outside institution validation. There was no evidence of algorithmic bias. Our methods have the potential to enable retrospective studies of treatment effectiveness, prospective identification of patients meeting study criteria, and quality improvement efforts in inflammatory bowel diseases.

Identification of immune cell markers associated with ulcerative colitis histological disease activity in colonic biopsies

AimsAccurate determination of histological activity in ulcerative colitis (UC) is essential given its diagnostic and prognostic importance. Data on the relationship between histology and immune cell markers are limited. We...

Enhancing Calprotectin's Predictive Power as a Biomarker of Endoscopic Activity in Ulcerative Colitis: A Machine Learning Use Case.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by periods of exacerbation and remission, making disease monitoring and management challenging. Endoscopy, the gold standard for assessing disease activity and severity, involves invasive procedures and is associated with patient discomfort and risks. Using machine learning (ML) to combine fecal calprotectin with other clinical or biological tests can significantly enhance the non-invasive prediction of endoscopic disease activity (EDA) in UC. Aim: To prove that by fusing fecal calprotectin with other clinical data into an ML model, the performance of the non-invasive prediction of EDA can be significantly improved. Methods: We conducted a prospective, observational, single-center study encompassing 103 patients diagnosed with UC. We employed multilayer perceptron models as the core ML algorithm for predicting EDA. For the constructed models, we utilized the varImp function from the caret library in R to assess the significance of each variable in predicting the outcome. Results: Calprotectin as a sole predictor obtained an accuracy of 70% and an area under the curve (AUC) of 0.68. Combining calprotectin with the list of selected predictors that were fed to the MLP models improved accuracy and the AUC. The accuracy of the algorithm on the test set was 85%. Similarly, the AUC increased to 0.93. This is the first study to propose the use of calprotectin as a predictor in an ML model to estimate UC endoscopic disease activity. Conclusion: The deployment of this ML model can furnish doctors and patients with valuable evaluation of endoscopic disease activity which can be highly beneficial for individuals with UC who need long-term treatment.

Differences in Mucosal Permeability Among Patients With Ulcerative Colitis Classified Based on the Colonic Location and Disease Activity.

Factors affecting mucosal permeability (MP) in ulcerative colitis (UC) are largely unknown. We aimed to investigate the difference in MP among patients with UC classified according to the colonic locations and to evaluate the correlations between local MP and endoscopic or histological activity of UC. The transepithelial electrical resistance (TER), which is inversely proportional to permeability, of tissue samples from the mucosa of the ascending colon, descending colon, and rectum of patients with UC and healthy individuals (HIs) was measured by using the Ussing chamber. TERs were compared between patients with UC and HIs and evaluated according to colonic locations and disease activity of UC. Thirty-eight patients with UC and 12 HIs were included in this study. Both in HIs and patients with UC, MP tends to be higher in the anal side. TER in the ascending colon was significantly lower in patients with UC than in HIs (45.3 ± 9.0 Ω × cm 2 vs 53.5 ± 9.7 Ω × cm 2 , P = 0.01). The increased permeability in UC was observed also in the descending colon, only when the inflammation involved the location. A significant correlation between TER and endoscopic activity was found in the rectum only ( r = -0.49, P = 0.002). There were no significant correlations between TERs and UC histology. The MP in the colon differs according to the colonic location. The ascending colon among patients with UC showed disease-specific changes in MP, whereas the MP is increased in proportion to the endoscopic activity in the rectum.

Ultra-Processed Food, Disease Activity, and Inflammation in Ulcerative Colitis: The Manitoba Living With IBD Study.

The purpose of this study was to investigate the relationship between ultra-processed food (UPF) consumption and (i) symptomatic disease and (ii) intestinal inflammation among adults with inflammatory bowel disease (IBD). We identified participants (Crohn's disease [CD] and ulcerative colitis [UC]) from the Manitoba Living with IBD study. Active disease was defined using the IBD Symptom Inventory (score >14 for CD; >13 for UC); fecal calprotectin was measured for intestinal inflammation (>250 μg/g). Diet data were collected using the Harvard Food Frequency Questionnaire. UPF consumption was determined by the NOVA classification system. Percentage of energy consumption from UPFs was calculated and divided into 3 tertiles (T1 = low; T3 = high). Multiple linear regression analysis was used for active disease and inflammation predicted by UPF consumption. Among 135 participants (65% with CD), mean number of episodes of active disease (14.2 vs 6.21) and active inflammation (1.6 vs 0.6) was significantly higher among participants with UC in T3 compared with T1 of UPF consumption ( P < 0.05). When adjusting for age, sex, disease type, and duration, number of episodes of active disease was lower in T1 compared with T3 (β = -7.11, P = 0.02); similarly, number of episodes of intestinal inflammation was lower in T1 (β = -0.95, P = 0.03). No significant differences were observed among participants with CD. UPF consumption may be a predictor of active symptomatic disease and inflammation among participants with UC. Reducing UPF consumption is a dietary strategy that can be suggested for minimizing symptoms and inflammation among people living with IBD.

USEFULLNESS OF SERUM LEUCINE-RICH ALPHA2-GLYCOPROTEIN AND FECAL CALPROTECTIN ASSURROGATE MARKERS IN ULCERATIVE COLITIS

Abstract BACKGROUND AND AIM Serum Leucine-rich alpha-2 glycoprotein (LRG) was identified as a novel biomarker for rheumatoid arthritis and IBD by using a proteomics approach. Several studies have suggested that serum LRG levels and fecal calprotectin (fCal) were correlated with clinical activities in patients with ulcerative colitis (UC). We compared utility of these biomarkers for monitoring disease activity in UC. METHODS A single-center observational study was conducted at Kyushu University Hospital. A total of 101 patients who underwent colonoscopy during the period from February to December 2021 were enrolled. The associations between endoscopic and histological activity and biomarkers were investigated. Endoscopic activity was defined as Mayo endoscopic score (MES) of 1 or less for mucosal healing and 0 for complete mucosal healing. For histological activity (n=90), Geboes score of 2 or less was defined as histological remission. RESULTS Subjects ranged in age from 16 to 80 years (35 males and 66 females). There were 63 cases of total colitistype, 32 cases of left-sided colitis type, and 6 cases of proctitis type. The MES at enrollment were as follows: MES 0 in 41 cases, MES 1 in 33 cases, MES 2 in 19 cases, and MES 3 in 8 cases. In comparison between the mucosal healing and non-mucosal healing groups, LRG was significantly lower in the mucosal healing group (p&amp;lt;0.0001). The correlation coefficient of LRG with MES was r=0.614 (p&amp;lt;0.0001), which was higher than that of fCal, r=0.414 (p&amp;lt;0.0001). In ROC analysis with mucosal healing as the outcome, the AUC and cut-off value of LRG were 0.781 and 17.9 μg/ml, respectively, and for fCal were 0.850 and 396 μg/g, respectively. In the ROC analysis with complete mucosal healing as the outcome, the AUC for LRG was 0.690, which was lower than the AUC of 0.846 for fCal . When compared by histological remission, LRG was lower in the histological remission group (p&amp;lt;0.001). In the ROC analysis with histological remission as the outcome, the AUC for LRG was 0.722 (cutoff value 14.2 μg/ml) and for fCal was 0.837 (cutoff value 119 μg/g). CONCLUSION Both LRG and fCal are valuable biomarkers reflecting disease activity in UC.

P336 Exploring Extracellular Matrix Markers in Ulcerative Colitis: Degradation and Formation Insights

Abstract Background The gold standard for assessing disease activity in ulcerative colitis (UC) is endoscopy, which is uncomfortable for the patient, and only evaluates the superficial layers of the colon. Intestinal extracellular matrix (ECM) remodeling is highly dynamic during disease activity and blood spillover of ECM components might reflect transmural disease burden. The aim of this study was to evaluate baseline serum markers of ECM formation (PRO-C11, PRO-C22, and PRO-C7) and degradation (C7M) to assess disease activity and treatment response in UC. Methods Forty-nine UC patients with active disease and 50 healthy controls (HC) were included. All underwent endoscopy and blood sampling at inclusion. UC patients additionally had fecal calprotectin (FCP) measured at baseline and had treatment adjusted at the discretion of the attending physician. Subsequent follow up of UC patients included clinical activity score, FCP, and blood samples at 3 and 6 months as well as an endoscopy at 6 months. Ulcerative Colitis Endoscopic Index of Severity (UCEIS), total Mayo score (TMS), and disease extent (E1-E3) was registered. Response was defined as a reduction from severe to moderate or mild disease based on TMS. If no follow-up endoscopy was performed (n=9), partial Mayo was used. Spearman’s correlation and one-way-ANOVA with Turkey correlation and correction for multiple testing were applied for statistical analysis. Results All markers of ECM degradation and formation were elevated in patients with severely active UC measured by both UCEIS and TMS compared to HC (adjusted p&amp;lt;0.0001 for each marker). CM7 and PRO-C22 differentiated moderate from severe UC by TMS (p&amp;lt;0.0001) and UCEIS (p&amp;lt;0.05) (Figure 1A-B). Baseline C7M, PRO-C7, and PRO-C11 correlated with CRP (Spearman’s: r=0.82, p&amp;lt;0.0001; r=-0.45, p=0.0012; and r=-0.33, p=0.032, respectively). None of the markers correlated with FCP. Elevated C7M, PRO-C7, and PRO-C11 levels for E3 could differentiate E3 from E1 (Difference ng/ml: 3.89 (SE of diff: 1.47), 13.15 (4.55), 10.08 (4.09), respectively, all p&amp;lt;0.05) (Figure 1C-E). Remission was achieved in 18/49 patients at 6 months. Both C7M and PRO-22 exhibited acceptable discriminative capabilities at baseline for 6-month TMS between remission and non-remission (AUC 0.72 (95% CI 0.58-0.87) p=0.01 and AUC 0.68 (95% CI 0.53-0.83) p=0.04, respectively) (Figure 1F-G). Conclusion This study demonstrates that ECM markers correlate with disease activity, disease extent, and predict future disease outcome in UC. ECM markers hold great promise as they provide a 'window' into transmural tissue remodeling and inflammatory and fibrotic burden, warranting further investigation.

P436 The AI based Red Density score is correlated with the established and new histological indices for Ulcerative Colitis in an independent cohort

Abstract Background Red Density (RD) is an automated endoscopic tool that is developed for the objective evaluation of disease activity in ulcerative colitis (UC). The initial development integrated histological disease activity based on Robarts histological index (RHI) in the machine learning algorithm. New histological scores for UC have been developed since. The aim of this study was to establish the correlation between RD and the Nancy histological index (NHI) and PICaSSO Histologic Remission Index (PHRI). Methods Patients included in 4 centers in the ongoing PROCEED-UC study (NCT04408703) had assessment with RD in the rectum and sigmoid at baseline, w52 or early termination visit. Biopsies were taken according to protocol. Biopsies were scored for the Geboes score (GBS), RHI, NHI, PHRI in a blinded way after initial scoring convention training. Correlation was tested on patient level between mean RD per segment and the different histological indices based on Spearman correlation. Results In total 96 patients from 4 centers were included representing 2634 RD images from 400 colonic segments with biopsies and corresponding RD score. Mean (± SEM) rectal RD score was 32.7 (± 4.54), 33.69 (± 5.25) and 64.86 (± 31.71) at baseline, w52 and ET respectively. Mean sigmoidal RD score was 38.13 (± 3.68), 42.82 (± 11.80) and 77.33 (± 24.65) at baseline, w52 and ET respectively. Analysis based on the segment with the highest mean RD score per patient showed significant correlation with NHI (r=0.60, p&amp;lt;0.0001), PHRI (r=0.62, p&amp;lt;0.0001). In the rectum the RD score at all time points correlated significant with NHI (r =0,53, p&amp;lt;0.0001) and PHRI (r=0.63, p&amp;lt;0.0001). Similar correlation was seen in the sigmoid for NHI (r=0.51, p&amp;lt;0.0001) and PHRI (r=0.22, p0.0108). A RD score of &amp;lt;57.5 (Likelihood Ratio (LR) 4.176; AUC 0.7820 (95CI 0.7047 - 0.8593), p&amp;lt;0.0001) was associated with histological remission based on NHI (&amp;lt;2) and a RD score of &amp;lt; 64.5 (LR 9.821; AUC 0.8133 (95%CI 0.7053 - 0.9212), p&amp;lt;0.0001) with histological remission based on PHRI (=0). The current dataset demonstrated to be stable in line with the previously established RD cut-off with GBS and RHI. 1 Conclusion In an independent cohort of patients with UC the correlation with the established and new histological indices for UC is confirmed. This underlines the value of RD as an objective endoscopic tool for the assessment of histological and endoscopic disease activity in UC. Ref 1: Bossuyt P, Nakase H, Vermeire S, De G, Eelbode T, Ferrante M, et al. Automatic, computer-aided determination of endoscopic and histological inflammation in patients with mild to moderate ulcerative colitis based on red density. Gut. 2020;69:1778–86.

P472 A Real World Practice of Intestinal Ultrasound in the Monitoring of Disease Activity in Ulcerative Colitis

Abstract Background Intestinal ultrasound (IUS) has emerged as an important monitoring tool in the clinical course of ulcerative colitis (UC). Previously known factors about UC have been considered in terms of the associations with IUS. However, a few studies reported about the associations between the findings of IUS and clinical factors. Methods We performed a multi-center, cross-sectional study of patients with UC who received IUS and clinical exams including endoscopy simultaneously. The primary endpoint was the association between endoscopic disease activity as Mayo endoscopic score (MES) and IUS finding as Milan ultrasound criteria (MUC). The secondary endpoint comprised the various clinical factors associated with MUC. Patients with MUC&amp;lt;6.2 were defined as low MUC group and others as high MUC group. Results A total of 35 patients were enrolled in this study. The numbers of Low- and high-MUC groups were 23 and 12, respectively. The median age in each group was 41 and 53 years old. The portion of male sex in each group was 57% and 75%. There were no significant differences in terms of body mass index, onset age, disease duration, current medication such as 5-aminosalicylic acid, steroid, immunomodulator, and biologics and small molecules between both groups. Compared with low and high MUC groups, endoscopic remission was more significantly associated with the low MUC group than the high MUC group (35% vs. 0, p = 0.032). In addition, the rate of disease activity ranged from remission to mild, as tolerable clinical activity, was also significantly higher in the low MUC group than the high MUC group (91% vs. 58%, p = 0.033). Other outcomes such as symptomatic remission, histologic remission, and biochemical response revealed similar rates between the two groups. Conclusion Low MUC of IUS in the patients with UC showed significant clinical association such as endoscopic remission and tolerable clinical activity. This study is now ongoing prospective research and further investigation into the relationship between IUS and clinical outcomes of UC will elicit robust results.

P131 Therapeutic effects of KPG-818 in a trinitrobenzene sulfonic acid - induced mouse Crohn's/Ulcerative Colitis model

Abstract Background Immunomodulatory drugs have the potential therapeutic benefit not only in malignancy but also in diseases characterized by an inflammatory phenotype. In inflammatory bowel diseases (IBD), colonic inflammation results from dysregulation of the mucosal immune responses to intestinal flora together with genetic and environmental factors. Inflammatory cytokines are implicated in pathogenesis of IBD. Treatments for IBD that improve clinical outcomes and limit adverse effects are needed. KPG-818 is a novel generation of lenalidomide derivative and small molecule immunomodulatory drug. KPG-818 is currently under clinical development for therapy of multiple myeloma, lymphoma (phase 1), and systemic lupus erythematosus (SLE) (phase 2a). Remarkable immunomodulatory effects of KPG-818 are observed in SLE patients. In preclinical studies, KPG-818 significantly inhibits inflammatory cytokines interleukin-6 and TNF-α in human peripheral blood mononuclear cells, inhibits tumor growth in multiple myeloma and lymphoma xenograft tumor models. Here we report the significant therapeutic effects of KPG-818 in a chronic Crohn’s/ulcerative colitis mouse model. Methods Trinitrobenzene Sulfonic Acid (TNBS) was intra-colonially administered to induce Balb/c mouse Crohn’s/ulcerative colitis model at 50 mg/kg, once a week for 4 weeks. KPG-818 was orally administered at doses of 0.03, 0.12, 0.4, and 1.0 mg/kg, once a day for 6 consecutive weeks. Upadacitinib served as a positive control drug. Vehicle solution served as a negative control. To evaluate the therapeutic effects of the KPG-818, disease activity index (DAI) of ulcerative colitis, the degree of weight loss, fecal morphology, and rectal bleeding were scored once every other day for six consecutive weeks. At the end of the study, colonic samples were collected for gross observation and scoring of macroscopic damage, measurement of length and weight, and histopathological diagnosis and scoring. At the end of study, peripheral blood samples were also collected for analyses of immune cells and cytokines. Results Compared to the vehicle control, KPG-818 significantly improved the body weight loss, disease activity of ulcerative colitis, gross degree of colorectal injury, pathological lesions of colorectal tissue, inhibited the inflammatory cytokines in a dose-response manner. The effective dose was as low as 0.03 mg/kg. KPG-818 showed similar therapeutic effects to Upadacitinib. Conclusion In this mouse model of chronic Crohn’s/ulcerative colitis, KPG-818 showed remarkable therapeutic effects in a dose-dependent manner. These data encourage the clinical evaluation of KPG-818 in inflammatory bowel diseases.

P280 Comparative responsiveness of disease activity indices in moderately-to-severely active Ulcerative Colitis: a post-hoc analysis of the UNIFI trial

Abstract Background Clinical, endoscopic, histological, and composite instruments are used to measure disease activity in ulcerative colitis (UC). We compared responsiveness of the Mayo Clinic Score (MCS), modified Mayo Clinic Score (mMS), partial Mayo Clinic Score (pMS), Robarts Histopathology Index (RHI), and UC-100 score after treatment with ustekinumab in patients with moderately-to-severely active UC. Methods Publicly available data from the phase 3 UNIFI induction trial (NCT02407236) comparing the efficacy and safety of ustekinumab versus placebo in patients with moderate-to-severe UC were obtained from Vivli (Vivli ID #7549) and Yale University Open Data Access Project (#2021-4848). Post-hoc analyses were performed on patient level data to ascertain outcomes of interest. Treatment assignment was the criterion for change in evaluation of responsiveness, which was quantified using the probability of a treated patient having a larger change than a placebo patient (win probability [WinP]) and estimated using nonparametric methods. Extent of responsiveness was interpreted according to Cohen’s benchmarks as very small (WinP&amp;lt;0.56); small (0.56≤ WinP&amp;lt;0.64); medium (0.64≤ WinP&amp;lt;0.71); and large (WinP≥0.71). Results Data from 961 patients with moderately-to-severely active UC randomised in UNIFI were included. At baseline, 319 patients received placebo and 624 patients received ustekinumab. A total of 912 (94.9%) patients completed the induction trial. Overall mean baseline index scores were: MCS 8.9 (±1.6), mMS 6.6 (±1.3), pMS 6.2 (±1.4), RHI 16.6 (±8.1), and UC-100 score 71.4 (±16.5) (Table). The UC-100 demonstrated a large degree of responsiveness (WinP 0.72 [95% CI: 0.66, 0.78]). The MCS (0.68 [0.62, 0.73]), mMS (0.69 [0.63, 0.75]), and pMS (0.65 [0.59, 0.71]) demonstrated similar, medium effect sizes (all comparisons p&amp;gt;0.05) (Figure). The RHI alone had a relatively small effect size (WinP 0.63 [0.56-0.70]). Among individual UC-100 components (Mayo Clinic stool frequency subscore, Mayo Clinic endoscopic subscore, and RHI), the endoscopic score was most responsive (WinP 0.59 [0.36-0.82]). The combination of endoscopy and RHI was associated with a medium degree of responsiveness (WinP 0.69 ([0.34, 1.00]). Conclusion UC disease activity indices are similarly responsive to change. Depending on trial design and measurement feasibility, different instruments can be considered optimal for evaluation of efficacy. The mMS is similarly responsive to the MCS without including the physician global assessment and may be more appropriate for determining trial eligibility and defining primary endpoint, whereas the UC-100 may be more appropriate for measuring treatment effect when an objective continuous measure is needed.

P1041 Coconut water modulates dietary potassium and gut microbiome to induce remission in ulcerative colitis: randomized controlled trial

Abstract Background High potassium intake is associated with decreased risk of inflammatory bowel disease(IBD), urinary potassium has been correlated with disease activity in ulcerative colitis(UC), and gut microbiome modulation improves outcomes in UC. We evaluated coconut water as potassium rich diet and gut microbiome modulator in patients with mild-moderate UC. Methods This single-center double-blind placebo-controlled trial randomized patients with mild-moderate (simple clinical colitis activity index-SCCAI:3–9) endoscopically active UC (ulcerative colitis endoscopic index of severity-UCEIS&amp;gt;1) in 1:1 ratio to coconut water + standard medical therapy-SMT(CW) vs placebo + SMT. 400ml of coconut water (200-250mg potassium/100ml) was administered for 8 weeks. Primary outcome measure was clinical remission (SCCAI ≤ 2) and secondary outcome measures were clinical response (SCCAI decline ≥ 3) and adverse events at 8 weeks. Microbiome was analyzed at baseline and 8 weeks. Results Of 121 patients screened, 95 were included for modified intention to treat analysis(49-CW, 46-placebo)[mean age-37.2 ± 11.2years; males-54.1%; disease duration-48 (IQR:24–90) months; pancolitis - 26.1%; SCCAI-5 (IQR:4 – 6); UCEIS-4 (IQR:3 – 5)]. There was significant increase in dietary potassium and decline in sodium/potassium ratio at 8 weeks in CW. Clinical response [57.1% vs 28.3%, p=0.01, OR-3.4 (95%CI:1.4 – 7.9)], remission [53.1% vs 28.3%, p=0.02, OR-2.9(95%CI:1.2 – 6.7)] and proportion of patients with fecal calprotectin (FCP)&amp;lt;150μg/g [53.6% vs 14.3%, p=0.01, OR-6.9(95%CI:1.6 – 28.9)] were significantly higher in CW. The relative abundance of bacterial taxa which had a significant or trend towards negative correlation with SCCAI, UCEIS, or FCP, increased at 8 weeks in CW. Adverse events were comparable and no patient developed hyperkalemia. Conclusion Coconut water increased dietary potassium, modulated the gut microbiome and was more effective than placebo for induction of remission in mild-moderate UC.

P412 Faecal Calprotectin as a predictor of endoscopic and histologic remission in patients with Ulcerative Colitis

Abstract Background Faecal calprotectin (FCP) is a reliable surrogate marker for disease activity in ulcerative colitis (UC). However, there are no consensus cut-off values for histoendoscopic remission. The aim of the study is to correlate FCP with Mayo Endoscopic Score (MES) and histological disease activity (Geboes score) of UC patients in clinical remission. Methods We performed a prospective study including adult UC patients at the McGill IBD Center between 2013 and 2017. Patients in clinical remission (partial Mayo score ≤2) or disease relapse, undergoing endoscopy for disease activity or dysplasia surveillance, were enrolled. Before bowel preparation, FCP was collected. MES was documented during colonoscopy. Biopsies were taken throughout the colon and histological activity was assessed using Geboes score (GS) by a blinded expert gastrointestinal pathologist. Results The study included 253 patients, of which 117 (46%) were male with a mean age of 38.2 years (standard deviation [SD] ± 24.8). 46% of the patients had pancolitis at the time of colonoscopy. 5-aminosalicylate were used by 68.4% of patients while 20.9% were on immunomodulators, 19% on biologics and 0.4% on small molecules as treatment. Regarding endoscopic correlation, it showed that an FCP ≥ 200 μg/g predicts MES &amp;gt; 1 despite clinical remission, yielding sensitivity of 59% and specificity of 74%. A FCP ≥ 123 predicts MES &amp;gt; 0 despite clinical remission (58% sensitivity and 70% specificity), also aiding to differentiate MES 0 from MES 1 (61% sensitivity and 70% specificity). As to histologic correlation, a FCP ≥ 80 μg/g identified histological disease activity using Geboes criteria (GS score &amp;gt; 3.1) in patients with clinical remission, yielding 64.7% sensitivity, 58.7% specificity and 77% positive predictive value (Figure 1). When using a GS score threshold of &amp;gt; 2, a cut-off value of FCP ≥ 50 μg/g, appears to be the most clinically relevant to identify patients in clinical remission who continue to have active histologic inflammation, with an 49.6% sensitivity, 41.6% specificity and 40% positive predict value. Results are summarized in Table 1. Conclusion FCP correlates very well with endoscopic and histologic disease activity and can be used as a surrogate marker for disease activity. Our study prospectively demonstrated the optimal cut-off values helping to discriminate endoscopic healing and histologic remission.

P357 Automated assessment of histological disease activity in Ulcerative Colitis using a deep learning algorithm

Abstract Background Assessment of histological disease activity in patients with ulcerative colitis (UC) is becoming more important. Therefore, the DCA score was developed for use in clinical practice. Distribution (D), chronicity (C) and activity (A) are each scored on a three-point scale with distribution being dependent on the percentage of biopsy area affected by inflammatory changes. A major problem for implementation of any score is interobserver heterogeneity. To overcome this hurdle, we developed a deep learning algorithm to automatically compute the DCA score. Methods A retrospective cohort was created consisting of 117 adult patients with ulcerative colitis from which biopsies were taken during a colonoscopy performed in the setting of routine clinical evaluation (training set of 537 slides). From 75 cohort patients, an additional set of biopsies was available (test set of 299 slides). An expert gastrointestinal pathologist performed the DCA score. The model was trained on H&amp;E-stained whole slide images scanned at 40x (0.243-μm pixel) resolution. Training was performed in a weakly supervised multiple-instance learning setup, using slide-level labels without region of interest annotations. The features from the convolutional neural network-based model trained at 2.5x, 5x, and 10x magnification were incorporated using a random forest classifier for final prediction. Model accuracy was evaluated using the test set. Results The algorithm differentiates between normal and inflamed with an accuracy of 90.9% (Table 1). Model performance from features aggregated across all magnification levels (i.e., 2.5x, 5x, and 10x) was superior to features from individual levels. This can be explained with the help of GradCam heatmaps (Figure 1), where we show that features learned at different magnification levels correspond to different aspects of histological changes in UC. The multiple instance approach did not appear to detect crypt abscesses, which may have resulted in a relatively poor performance in differentiating A1 from A2. The model accuracy for the 9-class DCA was 64.8%. Conclusion The algorithm first appears to assess architectural distortions at lower magnification and then the presence of cellular elements like neutrophils at higher magnification. This closely mirrors the approach of pathologists. The present model automates the scoring process and by supporting the daily diagnostic practice highlights the potential of deep learning technologies in assessment of histological disease activity in UC.

P138 Novel serum markers for predicting disease activity in ulcerative colitis: results from a retrospective case-control study

Abstract Background Commonly used serum or faecal markers, such as C-reactive protein (CRP) and feacal calprotectin have several limitations and do not always correlate well with the degree of mucosal inflammation in the intestine as established by endoscopy. The aim of the current study was to evaluate the utility of a panel of serum markers (Visfatin, serum amyloid, LRG1, MMP-1, MMP-2, TFF3, Lipocalin-2 (NGAL), IL-6, IL-4, IL-7, IL-17) in predicting mucosal inflammation in ulcerative colitis(UC) patients. Methods We conducted an unmatched case-control retrospective study. Patients were selected consecutively, based on their enrollement date, from a prospective IBD cohort. We selected two groups of UC patients, each of them with active disease at baseline and different outcomes during follow-up: mucosal healing and persistant disease activity, as resulted from clinical and endoscopic evaluation. Inflammatory burden was investigated using the C-reactive protein and endoscopic activity was reported using the Mayo endoscopic score. Quality of life was also evaluated at each visit using The Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Clinical disease activity was quantified using the partial Mayo score. Clinical remission was defined as a partial Mayo score &amp;lt; 2. Endoscopic activity was assessed using the Mayo endoscopic score[i] . Mucosal healing was defined as Mayo endoscopic score of 0. The selection of investigated biomarkers was based on the results of a systematic review previously published by the research team [i] State M, Negreanu L, Voiosu T, Voiosu A, Balanescu P, Mateescu RB. Surrogate markers of mucosal healing in inflammatory bowel disease: A systematic review. World J Gastroenterol. 2021 Apr 28;27(16):1828-1840. doi: 10.3748/wjg.v27.i16.1828. Results 84 serum samples from 42 patients were retrospectively analyzed (21 patients with mucosal healing and 21 patients with persistant activity during follow-up). Lipocalin proved to be a reliable marker for the noninvasive assessment of endoscopic activity, with 90% sensitivity and 95% specificity at a cut-off level of 0,421μg/ml (AUROC 0,677). The combination of lipocalin, age, gender and BMI (Figure 1) is a good predictor of persistant activity during follow-up (AUROC 0.87, 95% CI, 0.762-0.979). Conclusion Our findings provide support for the use of lipocalin as a surrogate marker for mucosal inflammation. The combination of lipocalin, age, gender and BMI might be useful for guiding treatment and monitoring decisions.