Histological Disease Activity Research Articles

Eosinophil Depletion as a Potential Therapeutic Strategy in Acute and Chronic Intestinal Inflammation Based on a Dextran Sulfate Sodium Colitis Model.

A role for eosinophils in intestinal inflammation and fibrosis in the context of inflammatory bowel disease has been suggested, yet the precise nature, whether causal or secondary remains debated. Hence, it remains unclear whether targeting eosinophils should be further explored as a treatment option in inflammatory bowel disease. Acute and chronic dextran sulfate sodium colitis was induced in wild-type C57BL/6 mice. Eosinophils were depleted by anti-CCR3 injections before colitis induction in a chronic model and after colitis onset in an acute model in order to investigate the impact of eosinophil depletion on pre-existing colitis. Inflammation was assessed using the disease activity index, macroscopic damage, and histological disease activity score. In the chronic model, fibrosis was assessed by examining colon weight/length ratio, collagen deposition through Martius Scarlet Blue staining, hydroxyproline assay, and COL1A1 expression. Protein and gene expression were assessed using the Meso Scale Discovery platform and real-time quantitative polymerase chain reaction. In the acute and chronic colitis model, eosinophil depletion resulted in reduced disease activity and faster recovery, as observed via the total area under the curve of the disease activity index (P = .004 and P = .02, respectively), macroscopic damage score (P = .009 and P = .08, respectively), and histological disease activity score (P = .09 and P = .002, respectively). In the acute model, the accelerated recovery was accompanied by an increase in interleukin (IL)-10 (P = .03) and a decrease in IL-4 (P = .03) and IL-6 (P = .009). Colon weight/length ratio and collagen deposition were not affected by eosinophil depletion. Eosinophil depletion prevents and decreases intestinal inflammation in a preclinical dextran sulfate sodium model without affecting fibrosis. These results pave the way for exploring eosinophil depletion as a novel treatment modality in addressing intestinal inflammation.

Adequacy of sigmoidoscopy as compared to colonoscopy for assessment of disease activity in patients of ulcerative colitis: a prospective study.

Patients of ulcerative colitis (UC) on follow-up are routinely evaluated by sigmoidoscopy. There is no prospective literature to support this practice. We assessed agreement between sigmoidoscopy and colonoscopy prospectively in patients with disease extent beyond the sigmoid colon. We conducted a prospective observational study at a tertiary care institute for agreement between sigmoidoscopy and colonoscopy. We assessed endoscopic activity using the Mayo Endoscopic Score (MES) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and histological activity using the Nancy Index (NI), Robarts Histopathology Index (RHI), and Simplified Geboes Score (SGS). Sigmoidoscopy showed a strong agreement with colonoscopy for MES and UCEIS with a kappa (κ) of 0.96 and 0.94 respectively. The misclassification rate for MES and UCEIS was 3% and 5% respectively. Sigmoidoscopy showed perfect agreement (κ = 1.00) with colonoscopy for assessment of the presence of endoscopic activity in the colon using MES ≥ 1 as activity criteria and strong agreement (κ = 0.93) using MES > 1 as activity criteria. Sigmoidoscopy showed strong agreement with colonoscopy for assessment of the presence of endoscopic activity using UCEIS (κ = 0.92). Strong agreement was observed between sigmoidoscopy and colonoscopy using NI (κ = 0.86), RHI (κ = 1.00), and SGS (κ = 0.92) for the detection of histological activity. The misclassification rate for the detection of histological activity was 2%, 0%, and 1% for NI, RHI, and SGS respectively. Sigmoidoscopy showed strong agreement with colonoscopy for endoscopic and histologic disease activity. Sigmoidoscopy is adequate for assessment of disease activity in patients with UC during follow-up evaluation.

#2168 Lupus nephritis histopathological classification system: a questionnaire-based survey of the Renal Pathology Society (RPS)

Abstract Background and Aims Kidney biopsy is the gold standard for lupus nephritis diagnosis, defining histologic class, disease activity and chronicity in detail and providing guidance for treatment. The updated 2018 ISN/RPS histopathological classification in lupus nephritis is widely used for prognosis and treatment decisions. Given the evolving phenotypes of lupus nephritis and the success of new targeted agents in clinical trials, there is ongoing discussion about the need for updating existing classification systems. A survey to assess the current use of the lupus nephritis histopathological classification systems in everyday practice was conducted on behalf of the RPS. Method An online survey was sent between September 27th and October 24th, 2023 to active members of the RPS. The survey used an internet platform and contained both multiple-choice and open-ended questions; results were analyzed anonymously. Results 185 of 562 RPS members replied to the questionnaire. 179 (97%) were pathologists and the level of expertise in lupus nephritis was good: 120 (65%) participants indicated they encounter more than 20 biopsies with lupus nephritis per year, while only 13% encounter fewer than 10. Almost 90% of responders discuss kidney biopsy results in a multidisciplinary meeting involving both clinicians and pathologists, on a weekly or monthly basis. The 2018 ISN/RPS lupus nephritis classification is used in most cases (92%), while 7% of participants prefer the earlier 2004 version. The average grade on the utility of the 2018 ISN/RPS classification was 8 (IQR 7-9) on a scale from 0 (not useful) to 10 (extremely useful). Almost 90% of the pathologist responders indicated they include the NIH activity/chronicity indices in biopsy reports. Reasons for not adding the activity/chronicity indices were given as responses to open-ended questions: (1) clinicians usually do not ask for activity/chronicity indices—(2) the extra workload outweighs the perceived clinical benefit—(3) a quantitative description of the degree of activity/chronicity is less time-consuming and more understandable than the indices—(4) reproducibility is not guaranteed. The average grade on the utility of the activity/chronicity indices was 7 (IQR 7-9) on a scale from 0 (not useful) to 10 (extremely useful). Pathologists rated treating clinicians' understanding of kidney biopsy reports and lupus classification at light microscopy with an average score of 8 (IQR 7-9) on a scale from 0 (no understanding) to 10 (complete understanding). Suggested improvements of the 2018 ISN/RPS lupus nephritis classification were further standardization and simplicity. Clearer definitions were requested for: class III vs class IV; segmental sclerosis vs fibrotic crescents; the role of globally sclerosed glomeruli; lupus-like entities; and lupus podocytopathy. Furthermore, there was a request on guidelines for new parameters: e.g., focus on extraglomerular involvement, laboratory and clinical features and biomarkers; CD68+ staining to detect endocapillary hypercellularity; and EXT1/2 immunostaining. Conclusion Our survey shows the 2018 ISN/RPS lupus nephritis classification is widely used in everyday practice by pathologists, and well known by clinicians. The results obtained by the RPS survey serve as a starting point for the new Working Group of lupus nephritis classification. We will consider the ideas and suggestions of the international community to evaluate biopsies from extensively phenotyped cohorts, to modify the classification and to facilitate improved targeted treatment decisions—a current unmet need.

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.

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.

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...

NON-INVASIVE DETERMINATION OF DISEASE ACTIVITY IN CROHN’S DISEASE BY SERUM LUMINEX PROFILING

Abstract BACKGROUND & AIMS Crohn’s disease (CD) is a chronic inflammatory disease with a complex pathogenesis; treatment and management largely depend on disease activity assessment, which can be challenging and invasive. The aim of this study was to assess the ability of multiplex Luminex technology to identify serum cytokine and/or chemokine markers of disease activity. METHODS Serum samples were prospectively obtained from 103 CD and 40 healthy controls undergoing colonoscopy. CD activity was determined by histologic assessment of colonoscopic biopsies. The Simple Endoscopic Score for Crohn’s Disease (SES) was available for 94 CD patients. We determined if the SES score was predictive of histologic activity (normal, quiescent, mild, moderate, or severe). Patient demographics and clinical history were obtained by chart review. Serum cytokines and chemokines were measured by a 47-plex Luminex assay. Analytes that had more than 70% of values below the lower limit of detection were excluded (GMCSF, IL3, IL17A, IL22, and TNFβ). Analyte profiles in controls v. CD patients were compared using the Mann-Whitney U test with Benjamini-Hochberg (BH) adjustment given multiple comparisons, and by disease activity (control v. inactive v. active) using the Kruskal-Wallis test, with post-hoc Dunn’s test with BH adjustment. RESULTS 34 CD patients were inactive (normal, quiescent) and 69 CD patients had active disease (mild, moderate, severe) on histology. Use of steroids, immunomodulators, and biologics did not differ significantly between the active and inactive CD groups. There was a strong positive correlation between SES score and histologic disease severity (Spearman’s r = 0.58, p<0.001). After BH adjustment, 16 analytes were significantly increased in CD v. controls: Fractalkine, GROα, IFNα2, IL1β, IL4, IL6, IL10, IL13, IL25, IL17F, IL18, MCP3, MCSF, PDGFAA, PDGFABBB, and TGFα. As shown in Table 1, when categorized by disease activity, 4 analytes were significantly increased and one analyte was significantly decreased in inactive disease v. control; 18 analytes were significantly increased in active v. control; and one analyte, CXCL9, which attracts effector T cells to sites of inflammation, was significantly increased in active v. inactive disease. CONCLUSIONS In CD patients, 16 of 42 serum cytokines and chemokines detectable by Luminex assay were increased v. healthy controls. When stratified by histologic disease activity, multiple analytes were found to be increased in inactive or active CD v. controls. Thus, CD is associated with alterations in serum cytokines and chemokines, which was much more frequent in CD patients with histologically active disease. Serum cytokine/chemokine profiling may be a non-invasive strategy to reduce the need for frequent colonoscopy in CD to assess disease activity. Table 1 Serum analyte profiles compared by disease activity (control v. inactive v. active). Data are shown in pg/mL as mean ± SD. p-values are calculated using Kruskal-Wallis test with post-hoc Dunn’s test with BH adjustment for multiple comparisons where 0.05 was considered significant. *p

P432 Real-time automated assessment of histological disease activity in patients with ulcerative colitis using single wavelength endoscopy technology

Abstract Background Assessment of mucosal healing as a key denominator in the treat-to-target strategy for managing ulcerative colitis remains challenging. To address this, objective evaluation of histological disease activity holds promise. Recent offline research shows encouraging results using a new deep-learning convolutional neural network based on single wavelength endoscopy technology (SWE-CAD) (Fujifilm Co, Japan). We aimed to validate the real-time performance of a new bedside prototype SWE-CAD model during standard colonoscopy. Methods A bedside module for real-time use was integrated in the endoscopy room to evaluate histological disease activity in patients with ulcerative colitis with Mayo Endoscopic Scoring (MES) ranging between 0 and 3. Imaging was performed in rectum and sigmoid following a standardized protocol based on white light and SWE (i.e. monochromatic light of 410nm). Biopsies were taken as reference at the center of the imaged region and were scored for the Geboes score (GBS). The SWE-CAD output was displayed on the separate monitor of the bedside module as a blue or red-colored indication, corresponding to histological remission or non-remission, respectively. Each region (2 in rectum and 2 in sigmoid) was simultaneously scored for MES by the endoscopist. Results In a total of 36 patients histological disease activity was automatically scored using the SWE-CAD. On a section level this CAD-system showed an accuracy of 96.4%, corresponding sensitivity was 99.3% and specificity was 85.5%. When differentiating for disease activity as mild, moderate and severe, accuracy was 97.7%, 62.8% and 95.0%, respectively. On a per-patient level, overall diagnostic accuracy remained high with 94.4%, with only 2/36 underestimations when compared to GBS. Conclusion In this pilot trial, we successfully tested a novel CAD-system, utilizing SWE technology, for real-time assessment of histological disease activity in patients with UC. The system demonstrated exceptional clinical accuracy at 94.4% per-patient level, potentially aiding physicians in interpreting subtle endoscopic abnormalities, leading to cost-effective and individualized patient management.

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 > 1 despite clinical remission, yielding sensitivity of 59% and specificity of 74%. A FCP ≥ 123 predicts MES > 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 > 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 > 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.

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<0.0001), PHRI (r=0.62, p<0.0001). In the rectum the RD score at all time points correlated significant with NHI (r =0,53, p<0.0001) and PHRI (r=0.63, p<0.0001). Similar correlation was seen in the sigmoid for NHI (r=0.51, p<0.0001) and PHRI (r=0.22, p0.0108). A RD score of <57.5 (Likelihood Ratio (LR) 4.176; AUC 0.7820 (95CI 0.7047 - 0.8593), p<0.0001) was associated with histological remission based on NHI (<2) and a RD score of < 64.5 (LR 9.821; AUC 0.8133 (95%CI 0.7053 - 0.9212), p<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.

P375 Histological activity predicts the risk of colectomy after biological treatment in biological-naive patients with Ulcerative Colitis

Abstract Background Treatment failure with biological agents is common in patients with ulcerative colitis (UC), but the impact of baseline histological disease activity is unknown. We aimed to investigate the predictive role of histopathological findings for biological treatment failure in UC patients. Methods This is a sub-study of the Danish IBD Biobank Project. Adult bio-naïve patients with UC (n=129) were followed prospectively while undergoing biological treatment. Histological activity was assessed using the Nancy Index and the Geboes score in intestinal biopsies sampled before treatment. Endoscopic activity was assessed using the Mayo Endoscopic Subscore, and clinical activity was measured using the Simple Clinical Colitis Activity Index (SCCAI). Associations between histological activity and treatment outcomes were assessed in multivariable models which incorporated the following fixed covariates: age, gender, disease duration, body mass index >30, disease extent, the SCCAI, and the Mayo Endoscopic Subscore. Correlations between histological, endoscopic, clinical, and biochemical activity were assessed using Spearman’s rank correlation. Results Colectomy was needed in 17.1% (n=22) of UC patients during follow-up (Table 1). Histological activity at baseline measured using the Nancy Index was the only significant predictor of the risk of colectomy during follow-up (Nancy 2 vs. 4: HR 0.14, 95% CI 0.02-0.84, p=0.03; Nancy 3 vs. 4: HR 0.11, 95% CI 0.02-0.53, p=0.01) beside baseline haemoglobin concentration (HR 0.32, 95% CI 0.16-0.64, p<0.01. Figure 1). The risk of colectomy was also significantly predicted by a Geboes grade above 5.0 at baseline (HR 2.72, 95% CI 1.14-6.50, p=0.02). In contrast, endoscopic and clinical activity did not predict the risk of colectomy. At baseline, the Nancy Index and the Geboes score were moderately correlated to endoscopic activity, and weakly, but significantly correlated to biochemical markers haemoglobin, albumin, and C-reactive protein. Meanwhile, poor correlations were found between histological activity and clinical activity. Conclusion The risk of colectomy during biological treatment in bio-naïve UC patients was significantly predicted by histological disease activity, but not endoscopic or clinical disease activity. Our study suggests that histological assessment before initiating biological treatment should be encouraged in UC patients. Funding This study is funded by a restricted grant from Takeda A/S, Louis-Hansen Fonden, and a public fund hosted by Hvidovre Hospital.

P1014 Faecal loss of vedolizumab is associated with UC severity, lower serum vedolizumab levels and rates of clinical response – Results from the FAVOUR study

Abstract Background Infliximab is detectable in the faeces of patients with active UC and faecal loss is associated with more severe disease and with primary non-response. Detection of vedolizumab (VED) in faeces and its importance in patients with UC has not been investigated. We conducted a prospective, observational study of patients with UC commencing VED to investigate faecal VED loss as well as its impact on serum VED levels (SVL) and association with treatment outcomes. Methods The FAVOUR study recruited UC patients with moderate to severe UC commencing vedolizumab between April 2019 and May 2022. Patients were treated with 300mg VED IV at weeks 0, 2, 6 and 14. Trough SVL were measured at weeks 2, 6 and 14. Faecal samples at days 1, 4, 7 and at weeks 2, 6 and 14 were homogenised and centrifuged to produce supernatants which were analysed for faecal VED levels (FVL) using a commercially available ELISA (LISA TRACKER, Theradiag, France). Clinical (SCCAI) and biochemical disease activity (CRP and faecal calprotectin) were measured at each infusion. Endoscopy was performed at baseline and week 14 to measure endoscopic (UCEIS/Mayo) and histologic activity (NHI). Correlations were calculated using the Spearman correlation coefficient (r). Categorical variables were compared using Mann-Whitney U. Results 36 patients (median age 34 (range 18-73); 13 Female) were recruited, of whom 33 completed induction therapy (3 withdrew early and were considered non-responders). 26/36 (72%) achieved a clinical response (SCCAI≤5 and reduction of ≥2) and 18/36 (50%) achieved endoscopic remission (UCEIS≤2). Faecal VED was detectable in 80/203 (39%) samples. Statistically significant correlations were observed between FVL and markers of clinical, biochemical, baseline endoscopic and histologic disease activity at day 1, and weeks 2 and 6 (table 1). Week 14 clinical non-responders had higher FVL than responders at that time point (median 1.0 vs 0.0ug/mL, p=0.004) but not at other timepoints. A statistically significant negative correlation was observed between week 2 FVL and SVL measured at weeks 6 and 14 (table 1). SVL did not differ significantly between week 14 responders and non-responders at any time point. Conclusion Active colonic inflammation results in faecal loss of vedolizumab. This appears to correlate with lower SVL and rates of response to treatment. However, SVL were not observed to directly influence rates of response. It is possible that FVL may be a marker of disease activity or that faecal loss results in lower rates of drug exposure at a tissue level and negatively impacts rates of response by this mechanism.

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&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.

Lactobacillus fermentum CKCC1858 and Lactobacillus plantarum CKCC1312 ameliorate the symptoms of ulcerative colitis in mouse model induced by dextran sulfate sodium

The objective of this study was to investigate the therapeutical action of Lactobacillus fermentum CKCC1858 and Lactobacillus plantarum CKCC1312 on ulcerative colitis (UC) and its mechanism. The results showed that L. fermentum CKCC1858 and L. plantarum CKCC1312 were able to relieve UC in DSS-induced mice, manifested in a noticeable increase in food intake, colon length, water intake and weight, and a marked decrease in histological scores and disease activity index. Further studies showed that L. fermentum CKCC1858 and L. plantarum CKCC1312 had the capacity to increase the level of mucin-2, zonula occludens-1 and interleukin-10, decrease the levels of interleukin-1β, interleukin-17A, interferon-γ, interleukin-6 and tumor necrosis factor-α, and regulated the genes correlated with immune. Simultaneously, we suggested that L. fermentum CKCC1858 and L. plantarum CKCC1312 possess the ability to alleviate UC via regulating the intestinal microbiome and genes expression, improving intestinal mucosa and promoting the synthesis of short-chain fatty acids.

Targeting complement in IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Recent years have witnessed significant improvements in the understanding of the pathogenesis of IgAN and particularly, the pathogenic role of complement activation. The alternative complement pathway is the major complement cascade activator in IgAN, and glomerular C3 deposition has been shown to correlate with disease progression. In addition, several studies have provided insight into the pathogenic role of factor H-related proteins -1 and -5 in IgAN, as independent players in complement dysregulation. The lectin pathway has also been shown to be associated with the severity of IgAN. Glomerular deposition of C4d has been associated with increased histologic disease activity, faster decline in estimated glomerular filtration rate and higher risk of kidney failure. On the other hand, although overlooked in the Oxford classification, numerous studies have shown that the coexistence of thrombotic microangiopathy in IgAN is a significant indicator of a poorer prognosis. All the breakthroughs in the understanding of the contributing role of complement in IgAN have paved the way for the development of new complement-targeted therapies in this disease. Several ongoing trials are evaluating the efficacy of new agents against factor B (iptacopan, Ionis-FB-LRX), C3 (pegcetacoplan), factor D (vemircopan, pelecopan), C5 (ravulizumab, cemdisiran) and C5a receptor 1 (avacopan). In this study, we provide a comprehensive review of the role of complement in IgAN, including the emerging mechanisms of complement activation and the promising potential of complement inhibitors as a viable treatment option for IgAN.

Reliability and Responsiveness of Histologic Indices for the Assessment of Crohn’s Disease Activity

The operating properties of histologic indices for evaluating Crohn's disease (CD) activity are poorly characterized. We assessed the reliability and responsiveness of existing histologic indices/items used in CD and ulcerative colitis (UC), in addition to 3 novel items, and developed exploratory ileal, colonic, and colonic-ileal CD instruments. Blinded central readers independently reviewed paired baseline and week 12 image sets from the EXTEND trial. Disease activity was scored using 4 indices (the Global Histologic Activity Score, Geboes Score, Nancy Histological Index, and Robarts Histopathology Index) and 3 items identified by an expert panel (mucin depletion, basal plasmacytosis, and ileal pyloric gland metaplasia). Reliability and responsiveness were quantified using the intraclass correlation coefficient (ICC) and area under the receiver operating curve (AUC), respectively. Exploratory indices were developed using backward stepwise linear regression analysis. Candidate independent variables were items with an inter-rater ICC ≥0.40 and AUC ≥0.56. The dependent variable was histologic disease activity measured by a 100-mm visual analogue scale. Paired image sets were available from 55 patients. Substantial to almost perfect inter-rater reliability (ICC, 0.63-0.87) and some responsiveness (AUC, 0.57-0.94) were observed for all existing indices regardless of whether individual colonic and ileal segments, combined colonic segments, or combined colonic and ileal segments were assessed and the calculation method used. Five items were tested as candidate items, and exploratory colonic, ileal, and colonic-ileal indices were developed. CD and UC indices were similarly reliable and responsive in measuring histologic CD activity. Exploratory index development did not offer benefit over current histologic instruments.

Liver inflammation activity in patients with autoimmune hepatitis with normal alanine aminotransferase and immunoglobulin G levels

Background and aimsNormal serum transaminases and immunoglobulin G (IgG) levels are surrogate markers for hepatic histologic disease activity in autoimmune hepatitis (AIH). This study aimed to evaluate liver inflammation in patients with AIH with normal serum alanine aminotransferase (ALT) and IgG levels. MethodsTwo hundred and five AIH patients who underwent liver biopsy in four medical centers were included. Logistic regression analysis was used to identify risk factors associated with advanced inflammation. ResultsOne hundred and thirty-one (63.9 %) AIH patients had advanced liver inflammation, and 108 (52.7 %) patients had advanced liver fibrosis. 60.0 % of patients with normal ALT and 51.7 % of patients with normal ALT and IgG had advanced inflammation. However, 76.7 % and 35.0 % of patients with or without advanced fibrosis with normal ALT had advanced inflammation, while the corresponding proportions of advanced inflammation were 78.6 % and 26.7 % in patients with normal ALT and IgG, respectively. Moreover, 81.0 % and 44.8 % of patients with and without cirrhosis with normal ALT had advanced inflammation, while the corresponding proportions were 83.3 % and 29.4 % in patients with normal ALT and IgG, respectively. Red cell distribution width (OR = 1.325, 95%CI 1.045–1.681, P = 0.020) and PT (OR = 1.514, 95%CI 1.138–2.014, P = 0.004) were independent factors associated with advanced inflammation. ConclusionsHigh proportion of advanced inflammation was found in AIH patients with normal ALT and IgG levels despite without advanced fibrosis. Although using non-invasive methods may contribute to rule out liver fibrosis in AIH patients with normal ALT and IgG levels, liver biopsy is encouraged to assess liver inflammation.

Effects of Mirikizumab on Histologic Resolution of Crohn's Disease in a Randomized Controlled Phase 2 Trial

Histologic evaluation of mucosal healing in Crohn's disease (CD) is an evolving treatment target. We evaluated histologic outcomes for mirikizumab efficacy and associations with endoscopic and 1-year outcomes. Biopsies from 1 ileal and 4 colonic segments were evaluated at Weeks 0, 12, and 52 from each 170 SERENITY participants. Criteria for the Weeks 12 and 52 histologic response (a) no epithelial neutrophils or epithelial damage, or (b) >50% decrease in either Robarts Histopathology Index or active Global Histologic Disease Activity Score and remission (no mucosal neutrophils and no epithelial damage) had to be met in all biopsies. Agreement was evaluated between histologic and endoscopic endpoints. Associations between 1-year outcomes and Week 12 histologic and endoscopic response were evaluated. At Week 12, 1000 mg mirikizumab resulted in greater rates of histologic response (66% vs 27%, P<0.001) and remission (26% vs 6%, P<0.01) than placebo. Rates were numerically similar at 1-year (mirikizumab pooled response: 46-69%, remission: 13-31%). Agreement between Week 12 histologic and endoscopic response was 69% (Cohen's Kappa coefficient (κ)=0.40) and remission was 83% (κ=0.38) in all pooled arms, including placebo. At 1-year, the percentage of participants who received any dose of mirikizumab and achieved endoscopic remission differed by their Week 12 response: histologic (20%), endoscopic (25%), combined histology-endoscopy (45%), or neither (4%) (.003). In a post-hoc analysis of phase 2 data, mirikizumab induced and sustained histologic response and remission in CD over 52 weeks. Early combined histologic-endoscopic response was associated with endoscopic remission after 1 year of treatment with mirikizumab (ClinicalTrials.gov NCT02891226.

Histologic Activity in Inflammatory Bowel Disease and Risk of Serious Infections: A Nationwide Study

Individuals with inflammatory bowel disease (IBD) are at increased risk of serious infections, but whether this risk varies by histologic disease activity is unclear. This was a national population-based study of 55,626 individuals diagnosed with IBD in 1990 to 2016 with longitudinal data on ileocolorectal biopsy specimens followed up through 2016. Serious infections were defined as having an inpatient infectious disease diagnosis in the Swedish National Patient Register. We used Cox regression to estimate hazard ratios (HRs) for serious infections in the 12 months after documentation of histologic inflammation (vs histologic remission), adjusting for social and demographic factors, chronic comorbidities, prior IBD-related surgery, and hospitalization. We also adjusted for IBD-related medications in sensitivity analyses. With histologic inflammation vs remission, there was 4.62 (95% CI, 4.46-4.78) and 2.53 (95% CI, 2.36-2.70) serious infections per 100 person-years of follow-up, respectively (adjusted HR [aHR], 1.59; 95% CI, 1.48-1.72). Histologic inflammation (vs remission) was associated with an increased risk of serious infections in ulcerative colitis (aHR, 1.68; 95% CI, 1.51-1.87) and Crohn's disease (aHR, 1.59; 95% CI, 1.40-1.80). The aHRs of sepsis and opportunistic infections were 1.66 (95% CI, 1.28-2.15) and 1.71 (95% CI, 1.22-2.41), respectively. Overall, results were consistent across age groups, sex, and education level, and remained largely unchanged after adjustment for IBD-related medications (aHR, 1.47; 95% CI, 1.34-1.61). Histologic inflammation of IBD was an independent risk factor of serious infections, including sepsis, suggesting that achieving histologic remission may reduce infections in IBD. The study was approved by the Stockholm Ethics Review Board (approval numbers 2014/1287-31/4, 2018/972-32, and 2021-06209-01).