Target In Ulcerative Colitis Research Articles

Mechanisms of Compound Sophora flavescens (Kushen) Decoction for the Treatment of Ulcerative Colitis based on Network Pharmacology and Molecular Docking Technology.

The compound Sophora flavescenes (Kushen) decoction was found to reduce the inflammatory symptom of Ulcerative Colitis (UC). However, there exists a very limited understanding of the molecular pharmacological mechanisms. This study aimed to explore the mechanism of compound Sophora flavescens (Kushen) decoction in treating ulcerative colitis from the perspective of network pharmacology. Active components and potential targets of compound Sophora flavescens (Kushen) decoction were obtained through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. GeneCards and other databases were used to predict and screen ulcerative colitis-related genes. Cytoscape software was applied to construct the "drugactive component-disease-target" network. GO function and KEGG pathway enrichment analyses revealed the potential pathway of the compound Sophora flavescenes (Kushen) decoction for UC. After the screening, a total of 124 active ingredients and 163 potential therapeutic targets for UC were obtained from the compound Sophora flavescens (Kushen) decoction. Protein interaction network analysis showed that 15 key targets could be identified for the possible treatment of UC. GO and KEGG analyses showed that the active ingredients in the compound Sophora flavescens (Kushen) decoction were mainly enriched in 2556 biological processes and 172 signaling pathways. The study showed that the compound Sophora flavescens (Kushen) decoction has therapeutic effects on UC through multi-component, multi-target, and multi-pathway.

Advances of Heat Shock Family in Ulcerative Colitis.

Ulcerative Colitis (UC) is a non-specific and chronic inflammatory disease of colonic mucosa whose exact etiology and mechanisms remain unclear. The incidence rate of UC is increasing year by year worldwide. What followed is that the medical costs are also rising rapidly. Therefore, it is urgent to understand the pathogenesis and find promising therapeutic targets for UC. Intestinal mucosal homeostasis is essential for normal bowel function, and its imbalance may be an important pathogenesis of UC. Endogenous homeostatic regulators play roles in repairing intestinal mucosa injury after stress. Heat shock family proteins are essential endogenous homeostasis factors. They can inhibit inflammation, regulate intestinal epithelial cells’ survival and death, and promote mucosal healing. Thus, they play important roles in sustaining intestinal mucosal homeostasis and protecting against UC progression. However, the heat shock family may promote UC carcinogenesis. Here, we summarize the advances in the research of the functions of the heat shock family in UC. And this review is an attempt to light on the etiopathogenesis of UC, highlighting the endogenous protective mechanisms, hoping to provide a novel therapeutic target for UC treatment.

Real-world Endoscopic and Histological Outcomes Are Correlated with Ustekinumab Exposure in Patients with Ulcerative Colitis.

Histo-endoscopic outcomes are being proposed as new treatment targets in ulcerative colitis [UC]. Little is known about the pharmacokinetic-pharmacodynnamic [PK-PD] relationship of ustekinumab [UST] in UC patients or whether serum UST concentrations reflect tissue drug exposure. We aimed to study UST serum concentrations and their relation to tissue exposure and drug effectiveness in a real-world setting. A total of 42 UC patients starting UST were prospectively followed by clinical, endoscopic and histological assessments at Week 16. Histological remission was defined as Nancy Histology Index of 0. Analogous to the UNIFI programme, histo-endoscopic mucosal improvement was defined as a combination of histological improvement [Geboes ≤3.1] and endoscopic improvement [MES ≤1]. Paired trough serum samples and colonic mucosal biopsies were collected for UST levels measurement. After 16 weeks [IQR 15.8-16.4] of therapy, histological remission and histo-endoscopic mucosal improvement were observed in 19 [45%] and 18 [43%] patients, respectively. Patients who achieved these outcomes had higher serum UST levels than those who did not. Patients with shorter disease duration and clinical response at Week 8 had higher odds to achieve histological remission. UST concentrations from paired serum and biopsy samples revealed a strong positive correlation [r = 0.88, p < 0.001], in both inflamed and uninflamed tissue. In this real-world cohort of refractory UC patients initiating UST, more than a third of the patients achieved histological remission. A drug exposure-response relationship was observed for histo-endoscopic outcomes, with no added value of measuring tissue exposure given the strong correlation with serum exposure.

Inhibiting Ferroptosis: A Novel Approach for Ulcerative Colitis Therapeutics

Ulcerative colitis (UC) is a recurrent and persistent nonspecific inflammatory bowel disease (IBD) that greatly affects human survival and social wealth. Despite the advances in the treatment of UC, there is still a high demand for novel therapeutic strategies for UC patients. Cell death is critical to the development and progression of UC. Understanding how intestinal cells die and how to prevent damage to intestinal cells is of great interest for the diagnosis and early treatment of UC. Ferroptosis, a novel form of regulated cell death (RCD) manifested by iron accumulation, lipid peroxidation, and excessive reactive oxygen species (ROS) production, has been shown to contribute to the development and progression of UC. Inhibitors of ferroptosis have been validated in models of UC. Here, we reviewed the mechanisms of initiation and control of ferroptosis and summarize the therapeutic activity of ferroptosis inhibitors in models of UC. We further discussed the possibility of inhibiting ferroptosis as a novel therapeutic target for UC. These findings revealed novel mechanisms to protect the colonic mucosa and highlighted the importance of ferroptosis in the disease process.

THE MICROBIAL LANDSCAPE OF ULCERATIVE COLITIS IN ENDOSCOPIC REMISSION

Abstract BACKGROUND Achieving endoscopic remission (Mayo endoscopic score of 1 or 0) appears to be the optimal clinical target in ulcerative colitis, reducing risk of relapse, hospitalizations, complications, and need for surgery. While attaining complete endoscopic remission (MES 0) appears to reduce these risks further over mild endoscopic activity (MES 1), the etiologic factors for why MES 0 might be the superior target is poorly understood. Given the putative role of the gut microbiome in driving underlying endoscopic activity and subsequent relapse risk, we sought to define the microbial landscape of UC among patients who achieve either MES 0 vs MES 1 endoscopic remission, especially since the colonic microbial constituents of UC in remission remain uncharacterized. METHODS We performed a retrospective cohort study, utilizing data from The Study of a Prospective Adult Research Cohort with IBD (SPARC IBD), part of the IBD Plexus network established by the Crohn’s and Colitis Foundation. SPARC IBD is a national, multi-center, longitudinal cohort study enrolling eligible (&amp;gt;= 18 years) patients with IBD that includes demographic and disease specific clinical data, endoscopic scores, and stool metagenomics. To examine the microbiome, we evaluated beta-diversity (Bray-curtis dissimilarity), and phylum and genera-level differential taxal abundance, utilizing linear models (limma), between patients with UC in either MES 1 vs MES 0 endoscopic remission. Statistical analysis was performed using phyloseq and limma packages in R (ver 4.1). RESULTS Within the SPARC cohort, we identified 77 patients in endoscopic remission (48 with MES 0, 29 with MES 1), of which 52% were female and 91% white, with median age of 48. Patients in MES 0 or MES 1 had no significant differences in exposure to anti-TNF therapy (50% vs 50%), vedolizumab (25% vs 19%) or mesalamine (69% vs 72%). Beta-diversity was similar between MES 0 and MES 1 remission [Figure 1]. Both MES 1 and MES 0 remission were dominated by Bacteroidetes and Firmicutes, and were specifically abundant for Bacteroides uniformis, unclassified Subdoligranulum, and Akkermansia mucuniphila. Compared to MES 1 remission, patients with MES 0 remission had increased abundance of Bacteroidetes, Firmicutes, and Actinobacteria, but reduced levels of Proteobacteria and Verrucomicrobia, although after adjusting for multiple comparisons, differential abundance at the phylum and taxa-level between both groups were comparable [Figure 2]. CONCLUSIONS The microbial landscape of ulcerative colitis in MES 1 vs MES 0 endoscopic remission is comparable with respect to beta-diversity, phylum and genera-level differential taxal abundance. Further investigation will include comparison of UC in remission to healthy controls, and whether the presence of specific microbial groups in remission can predict subsequent relapse.

PREDICTORS OF CLINICAL RELAPSE AMONG PATIENTS WITH ULCERATIVE COLITIS IN ENDO-HISTOLOGIC REMISSION

Abstract BACKGROUND AND AIMS In patients with ulcerative colitis (UC), endo-histologic (deep) remission has been increasingly recognized to reduce the risk of clinical relapse above and beyond attainment of endoscopic remission alone. However, relapse rates among patients in deep remission, and predictors of relapse in this population remain uncharacterized. METHODS We performed a retrospective cohort study utilizing electronic medical records at Tufts Medical Center to identify patients in deep remission, classified as having both endoscopic remission [Mayo Endoscopic Score [MES] of 0 or 1] and histologic remission [Nancy Histologic Index [NHI] of grade 0 or grade 1]. We evaluated the cumulative risk of clinical relapse following attainment of deep remission, defined as patient-reported outcome (PRO-2 &amp;gt; 2), adjusted for gender, age, disease duration, time duration of follow-up, baseline Mayo Endoscopic Score, and baseline depth of histologic remission. RESULTS Among 128 patients with UC in deep remission, 69 were female (54%). The median age was 55 years with median disease duration of 13 years. At time of deep remission, n=29 (23%) had a MES score of 1 and n=92 (72%) had a MES score of 0, with n=82 (64%) demonstrating a NHI of 1, and n=38 (30%) with a NHI of 0. Over a median follow up time of 10.5 years, 33% of patients had clinical relapse and 66% remained in remission. The cumulative risk of relapse among patients in deep remission was 12.2% at one year and 23% at three years. On univariate analysis, age, gender, disease duration, and baseline MES score did not predict relapse risk. However, the depth of histologic remission at time of deep remission was predictive of clinical relapse, with those demonstrating normalized mucosa (NHI of 0) less likely to relapse than those with chronic architectural changes (NHI of 1) at one year (5% vs 16%, HR = 2.80, p &amp;lt; .05) and at three years (9% vs 27%) [Table 1, Figure 1]. CONCLUSIONS Cumulative risk of relapse among patients in endo-histologic remission is as low as &amp;lt;15% and &amp;lt;25% at one and three years, respectively. Attainment of complete normalization reduces the risk of relapse to &amp;lt;5% over the first year compared to histologic remission with chronic architectural changes (&amp;lt;16%), with other clinical criteria unable to prognosticate risk of relapse. Achieving endo-histologic remission with complete normalization of mucosa may be the ideal clinical target in ulcerative colitis.

P406 Disease clearance in patients with ulcerative colitis treated with aminosalicylates

Abstract Background Current treatment goals in inflammatory bowel disease include clinical remission and endoscopic healing. A new concept of disease clearance (DC) is emerging as a new therapeutic target in ulcerative colitis (UC). Although not yet clearly defined, it reflects a combination of clinical, endoscopic, and histological remission1. Preliminary data suggest that DC is achievable with biologic therapy. Aim: to evaluate if patients treated with, 5-ASA with DC can maintain sustained remission and the incidence of negative disease outcomes. Methods We performed a retrospective cohort study including adult patients with confirmed UC treated with, 5-ASA. Patients performing colonoscopy with biopsies between, 2017 and, 2019, with at least, 1 year of follow-up were eligible for inclusion. DC was measured at baseline and was defined as clinical (partial Mayo score ≤2), endoscopic (endoscopic Mayo score ≤1) and histological remission (chronic inactive/quiescent colitis)1. Negative disease outcomes included need for systemic steroids, therapy escalation (immunomodulators and/or biologics) and UC-related hospitalization or surgery during follow-up. Kaplan-Meier analysis was performed. Results We included, 56 patients with UC treated with, 5-ASA and with DC at baseline. Mean age at diagnosis was, 41.2 ±, 15 years, 59% (n=33) were female and mean disease duration was, 6.9 ±, 7.3 months. History of smoking (current or former) was present in, 36% (n=20) of the patients. Most of the patients (54%) presented with left-sided colitis. Mean follow-up was, 34.6 ±, 10.7 months. During the follow-up, 14.3 % (n=8) had a negative outcome (flare requiring systemic corticosteroids (n=6), therapy escalation to immunomodulator or biologic treatment (n=6) or hospitalization (n=1)). None of the patients needed surgery. Negative outcomes were associated with shorter disease duration (3.4 vs, 7.4 years, p=0.003). No other factors were associated with the outcomes namely sex, UC extent, smoker status, age at diagnosis or previous use of corticosteroids. There was no difference on prognosis between patients with baseline endoscopic Mayo score, 0 or, 1 (p=, 0.066). In the survival analysis, the cumulative probability of maintaining remission was, 76% at, 3 years. Conclusion DC in UC patients treated with, 5-ASA was associated with a high cumulative probability of maintaining remission, suggesting that the benefits of such stringent endpoint may be independent of the therapy used. Reference 1. S Danese, S Schreiber, E Loftus, Jr., J F Colombel, L Peyrin-Biroulet, C Agboton, D Lindner, R Lirio, B Sands, P271 Evolving Targets in Ulcerative colitis: Defining Disease Clearance in the VARSITY Study, Journal of Crohn’s and Colitis,Volume, 15, Issue Supplement1, May, 2021, Page S305

P442 Real-world endoscopic and histologic outcomes are linked to ustekinumab exposure in Ulcerative Colitis

Abstract Background Histologic healing is being proposed as new treatment target in ulcerative colitis (UC), and the concept of histo-endoscopic mucosal improvement was introduced in the UNIFI study with ustekinumab (UST) in moderate–to-severe UC. Very little is known about the Pk-PD relationship of ustekinumab in UC patients, and especially whether serum UST concentrations correlate well with colonic tissue drug exposure and with histologic healing. The aim of this study is to provide real-world data including histology, and to study UST serum concentrations and its relation to tissue levels and drug efficacy. Methods UC patients starting UST in standard dosage at our referral centre were prospectively followed by clinical and endoscopic assessments at week, 16 or week, 24, and colonic biopsies were taken for histopathologic scoring. Histologic remission was defined as Nancy histology index (NHI) of, 0. Other collected outcomes were clinical response, clinical remission, endoscopic improvement, endoscopic remission and mucosal healing (definitions in Figure, 1). Paired trough serum sample and colonic mucosal biopsy were collected for UST levels measurement using a CE marked in-house developed ELISA. Results A total of, 42 UC patients started ustekinumab between June, 2019 and May, 2021, allowing a follow-up of at least, 6 months (Table, 1). By week, 24, clinical response, clinical remission, endoscopic improvement, endoscopic remission, and mucosal healing were observed in, 31 (74%), 24 (57%), 22 (52%), 11 (26%) and, 10 (24%) patients, respectively (Figure, 1). Histologic remission was observed in, 19 (45%) patients, of whom, 10 and, 9 with endoscopic Mayo, 0 and, 1, respectively. Multivariate analysis identified clinical response at week, 8 as a predictor for histologic remission at week, 24 [OR, 8.84, p = 0.024], and inversely correlated with therapy discontinuation [OR, 0.10, p = 0.006]. A trend of higher UST serum trough levels was observed in patients achieving histologic and endoscopic outcomes in comparison with patients who did not reach these outcomes, with a significant statistical difference at week, 8 for endoscopic outcomes (Figure, 2). UST concentrations from paired serum and biopsy samples revealed a strong positive correlation (Spearman r=0.88, p&amp;lt;0.001, n=17), both in inflamed (mayo endoscopic score &amp;gt;1) (r=0.89, p&amp;lt;0.001, n=10) and uninflamed (mayo endoscopic score ≤, 1) tissue (r=0.88, p&amp;lt;0.008, n=7) (Figure, 3). Conclusion In this real-word cohort of UC patients initiating UST, more than a third of the patients achieved histologic remission. Serum UST levels were furthermore strongly correlated with tissue levels of UST. A drug exposure-response relationship was observed for histologic and endoscopic outcomes.

OP15 A new simplified histology artificial intelligence system for accurate assessment of remission in Ulcerative Colitis

Abstract Background Histological remission (HR) is evolving as a treatment target in ulcerative colitis (UC). Several histological indices have been developed, however, their widespread adoption beyond clinical trials is limited by practical difficulties and interobserver variability. Furthermore, the relative complexity of available scores hinders the development of an AI algorithm. We aimed to develop a simple histologic index, aligned to endoscopy, and apply it to a computer-aided diagnosis (CAD) system to evaluate HR. Methods 614 digitalised biopsies (WSI) from 307 UC patients enrolled into a prospective multicentre study1 were analysed. First, the simple PICASSO Histologic Remission Index (PHRI) based only on the presence of neutrophils, was developed and validated by expert pathologists. Table 1 To implement PHRI in a CAD system we designed a semi-supervised inductive transfer learning strategy composed of two modules. The first consists of a novel deep learning strategy based on a convolutional neural network architecture. This detected neutrophils in areas (patches) of a subset of 314 biopsies (172 remission, 142 active), in 158 of which the presence of neutrophils had been meticulously annotated at pixel level. WSI were then divided in training (172), validation (47), and testing sets (95). Following a multiple instance learning paradigm, a second model combined the features of all patches of each biopsy into a dichotomous result: presence/absence of disease activity. Figure 1 and 2. Finally, we compared the AI prediction with the pathologists’ assessment. Results PHRI correlated strongly with all endoscopic scores (MES, UCEIS and PICaSSO) of the same bowel areas (rectum and sigmoid) (Spearman’s ρ= 0.55 to 0.78). Inter-reader agreement between pathologists was almost perfect (ICC 0.84). In the validation and testing sets our model predicted the presence of neutrophils respectively with 61% and 72% sensitivity, 98% and 84% specificity, 93% and 75% positive predictive value (PPV), and 86% and 83% negative predictive value (NPV) respectively (Table 2). When predicting remission in whole biopsies, in the validation cohort the AI system had 65% sensitivity, 93% specificity, 86% PPV, and 78% NPV. In the testing cohort the same metrics were 62%, 94%, 90%, and 73% (Table 2). Conclusion PHRI is the simplest histological index in UC and correlates strongly with endoscopic activity. Based on PHRI we developed the first artificial intelligence model able to accurately predict histological remission in biopsies of UC. This tool can effectively expedite, support, and standardise the histological assessment of UC in clinical practice. Reference 1. Iacucci et al. Gastroenterology 2021

OP16 The first virtual chromoendoscopy artificial intelligence system to detect endoscopic and histologic remission in Ulcerative Colitis

Abstract Background Endoscopic and histologic activity are important therapeutic targets in ulcerative colitis (UC). The Paddington International Virtual ChromoendoScopy ScOre (VCE-PICaSSO)1 demonstrated that enhanced visualisation of subtle mucosal and vascular inflammatory changes correlated strongly with histology. However, without adequate training, the subjective evaluation of white light (WL) and VCE endoscopic scores varies between observers. We aimed to develop an artificial intelligence (AI) system for objective assessment of endoscopic disease activity and predict histology related to both white light and VCE videos. Methods 469 endoscopy videos (48512 frames) from 235 patients representative of all grades of inflammation, from our prospective PICaSSO multicentre study1 were used to develop a convolutional neural network (CNN). 316 videos were divided into training (254) and validation (62) sets. 153 additional videos (78 patients) were used as test cohort. The videos were edited to separate clips with WL and with VCE, and assessed using Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and PICaSSO, respectively. The classification stage of a pre-trained ResNet50 CNN classifier was trained to predict the healing or active inflammation on video frames. One network was trained to predict endoscopic remission (ER) as UCEIS≤1 from WL frames, and a second network was trained to predict PICaSSO≤3 from VCE. Histological remission (HR) was defined as Robarts Histological Index (RHI) ≤3 with no neutrophils in lamina propria or epithelium. Results In the validation cohort, our system predicted ER (UCEIS ≤1) in WL videos with 82% sensitivity (Se), 94% specificity (Sp) and an area under the ROC curve (AUROC) of 0.92. For the detection of remission in VCE videos (PICaSSO ≤3) Se was 74%, Sp 95%, and AUROC 0.95. In the testing cohort of independent videos, the diagnostic performance for both cut offs of ER remained similar. Our system also had an excellent diagnostic performance for the prediction of HR in the validation set, with Se, Sp, and Accuracy of 92%, 83%, and 85% respectively, using VCE, and 83%, 87%, and 86% respectively, with WL. In the testing set performance declined modestly while remaining good. Of note, the algorithm’s prediction of histology was similar with VCE and WL videos. Table 1 Table 2 Conclusion Our AI system accurately recognize endoscopic remission in videos and predict histological remission equally well. This is the first AI model developed to analyse inflammation and endoscopic remission in VCE through the PICaSSO score, and the first multi-domain system providing a complete endoscopic and histologic assessment. Reference 1. Iacucci et al. Gastroenterology 2021

THE MICROBIAL LANDSCAPE OF ULCERATIVE COLITIS IN ENDOSCOPIC REMISSION

Achieving endoscopic remission (Mayo endoscopic score of 1 or 0) appears to be the optimal clinical target in ulcerative colitis, reducing risk of relapse, hospitalizations, complications, and need for surgery. While attaining complete endoscopic remission (MES 0) appears to reduce these risks further over mild endoscopic activity (MES 1), the etiologic factors for why MES 0 might be the superior target is poorly understood. Given the putative role of the gut microbiome in driving underlying endoscopic activity and subsequent relapse risk, we sought to define the microbial landscape of UC among patients who achieve either MES 0 vs MES 1 endoscopic remission, especially since the colonic microbial constituents of UC in remission remain uncharacterized.

P2RY13 Exacerbates Intestinal Inflammation by Damaging the Intestinal Mucosal Barrier via Activating IL-6/STAT3 Pathway.

The pathogenesis of ulcerative colitis (UC) is unclear, while genetic factors have been confirmed to play an important role in its development. P2RY13 is a G protein-coupled receptor (GPCRs), which are involved in the pathogenesis of inflammation and immune disorders. According to GEO database analysis, we first observed that the expression of P2Y13 was increased in UC patients. Therefore, we sought to determine the role of P2Y13 in the development of colitis. Our data showed that P2RY13 was highly expressed in the inflamed intestinal tissues of UC patients. In mice, pharmacological antagonism of P2Y13 can significantly attenuate the intestinal mucosal barrier disruption. In LPS-induced NCM460 cell, knockdown or pharmacological inhibition of P2RY13 increased the expression of intestinal tight junction protein and reduced apoptosis. In addition, we found that the effect of P2Y13 on colitis is related to the activation of the IL-6/STAT3 pathway. Activation of P2Y13 increases IL-6 expression and promotes STAT3 phosphorylation and nuclear transport. Deletion of the STAT3 gene in the intestinal epithelial cells of mice significantly mitigated the exacerbation of colitis due to P2Y13 activation. Thus, P2Y13 can aggravate intestinal mucosal barrier destruction by activating the IL-6/STAT3 pathway. P2Y13 might be a potential drug target for UC.

Treatment Targets in Ulcerative Colitis: Is It Time for All In, including Histology?

The main therapeutic goal of ulcerative colitis (UC) is to induce and maintain remission to prevent long-term disease progression. Treat-to-target strategies, first introduced by the STRIDE consensus and updated in 2021, have shifted focus from symptomatic control toward more stringent objective endpoints. Today, patient monitoring should be based on a combination of biomarkers and clinical scores, while patient-reported outcomes could be used as short-term targets in monitoring disease activity and therapeutic response. In addition, endoscopic healing was the preferred long-term goal in UC. A Mayo endoscopic score (MES) ≤ 1 can be recommended as a minimum target. However, recent evidence suggests that more stringent endoscopic goals (MES of 0) are associated with superior outcomes. Recently, emerging data support that histological remission (HR) is a superior prognostic factor to endoscopic healing in predicting long-term remission. Despite not yet being recommended as a target, HR may become an important potential therapeutic goal in UC. However, it remains questionable if histological healing should be used as a routine assessment in addition to clinical, biomarker, and endoscopic targets in all patients. Therefore, in this review, our aim was to discuss the current evidence for the different treatment targets and their value in everyday clinical practice.

A randomised, placebo-controlled study of RIPK1 inhibitor GSK2982772 in patients with active ulcerative colitis

ObjectiveTumour necrosis factor signalling via the receptor-interacting protein kinase 1 (RIPK1) pathway regulates colonic inflammation suggesting that RIPK1 inhibition may be a potential therapeutic target in ulcerative colitis (UC). This...

MiRNA-Based Potential Biomarkers and New Molecular Insights in Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic non-specific inflammatory bowel disease, which usually manifests as abdominal pain, diarrhea and hematochezia. The disease often recurs and is difficult to cure. At present, the pathogenesis is not clear, but it is believed that the disease is caused by a complex interaction among immunity, heredity, environment and intestinal microflora disorders. MicroRNA (miRNA) is endogenous single-stranded non-coding RNA of 17–25 nucleotides (nts). They target the 3'Untranslated Region of a target gene and inhibit or degrade the target gene according to the extent of complementary bases. As important gene expression regulators, miRNAs are involved in regulating the expression of most human genes, and play an important role in the pathogenesis of many autoimmune diseases including UC. Studies in recent years have illustrated that abnormal expression of miRNA occurs very early in disease pathogenesis. Moreover, this abnormal expression is highly related to disease activity of UC and colitis-associated cancer, and involves virtually all key UC-related mechanisms, such as immunity and intestinal microbiota dysregulation. Recently, it was discovered that miRNA is highly stable outside the cell in the form of microvesicles, exosomes or apoptotic vesicles, which raises the possibility that miRNA may serve as a novel diagnostic marker for UC. In this review, we summarize the biosynthetic pathway and the function of miRNA, and summarize the usefulness of miRNA for diagnosis, monitoring and prognosis of UC. Then, we described four types of miRNAs involved in regulating the mechanisms of UC occurrence and development: 1) miRNAs are involved in regulating immune cells; 2) affect the intestinal epithelial cells barrier; 3) regulate the homeostasis between gut microbiota and the host; and 4) participate in the formation of tumor in UC. Altogether, we aim to emphasize the close relationship between miRNA and UC as well as to propose that the field has value for developing potential biomarkers as well as therapeutic targets for UC.

P271 Evolving Targets in Ulcerative colitis: Defining Disease Clearance in the VARSITY Study

Abstract Background In VARSITY, the first head-to-head randomized controlled trial of biologics, vedolizumab (VDZ) was superior vs adalimumab (ADA) in achieving clinical remission (CR) at Week 52 in patients (pts) with moderate to severe ulcerative colitis (UC).1 Current treatment goals in UC are based on clinical symptoms and endoscopy, with histologic improvement considered an aspirational goal.2-4 In pts with CR in VARSITY, greater treatment differences between VDZ and ADA at Week 52 were seen in endoscopic improvement and histologic response. Here, data from VARSITY were used to define disease clearance: a novel composite outcome in UC comprising clinical and endoscopic remission plus minimal histologic disease activity. Methods VARSITY was a phase 3b, randomized, double-blind, double-dummy, active-control trial of treatment with VDZ (300mg IV Q8W) vs ADA (40mg SC Q2W) maintenance after induction. Pts were randomized in a treat through design, and no dose escalation was allowed. For these analyses, based on pts who completed the study until Week 52, disease clearance was defined as a composite outcome based on 1) CR: partial Mayo score ≤2 and no individual subscore &amp;gt;1 (excluding sigmoidoscopy subscore); 2) endoscopic improvement: endoscopic subscore ≤1; and 3) absence of active histologic disease (minimum histological disease activity [MHDA]): Robarts Histology Index (RHI) &amp;lt;5. Treatment failure was defined as discontinuation from treatment or completion of treatment but failure to achieve any of CR, endoscopic improvement, or MHDA. The rates of disease clearance and failures were compared between treatment groups and stratified by presence of inflammatory burden at baseline: C-reactive protein ≥5 mg/L and fecal calprotectin &amp;gt;100 µg/g. Results More pts in the VDZ treatment group than the ADA group achieved disease clearance at Week 52 (VDZ: 112/383, 29.2%, 95% CI 24.7-34.1 vs ADA: 63/386, 16.3%, 95% CI 12.8-20.4). Compared with treatment failures (VDZ: 92/383, 24.0% vs ADA: 134/386, 34.7%, Table 1), disease clearers had lower C-reactive protein (CRP) baseline mean values (7.4mg/L and 6.4mg/L vs 13.6mg/L and 9.4mg/L for disease clearers vs treatment failures, for VDZ and ADA, respectively). Fewer pts with inflammatory burden at baseline (CRP ≥5 mg/L and fecal calprotectin &amp;gt;100 µg/g) achieved disease clearance (Fig 1). Baseline corticosteroid use was more frequent in ADA disease clearers (42.9%) compared with VDZ disease clearers (32.1%). Conclusion Disease clearance is a novel and achievable composite outcome that is achieved by almost one third of pts in the VDZ treatment group in VARSITY. Analyses are ongoing to further characterize the trajectory leading to disease clearance as well as the role of baseline characteristics.

P084 C-Reactive Protein Correlates with Tumor Necrosis Factor-α in Ulcerative Colitis

Abstract Background Monitoring disease activity in Ulcerative colitis (UC) is essential. Inflammatory markers like C-Reactive Protein (CRP) and faecal calprotectin have been shown to correlate with clinical and endoscopic disease activity. To date the relationship between CRP and the inflammatory analytes within the colonic microenvironment have not been analysed. Methods Our primary aim was to evaluate the relationship between CRP and key inflammatory cytokine, TNF-α, in UC patients. We also sought to investigate whether CRP correlates with clinical parameters. Ethical approval was granted by our Research Ethics Committee. Patients over the age of 17 with a confirmed diagnosis of UC presenting for colonoscopy were offered the opportunity to participate. Basic patient demographics and Mayo score were recorded. At endoscopy colonic biopsies were taken and cultured in dimethyl sulfoxide (DMSO). Multiplex inflammatory and angiogenic enzyme-linked immunosorbent assay (ELISAs) were performed to evaluate the colonic microenvironment and assess real time secretion of TNF-α. Correlations were carried out on SPSS 24 and plotted using R Studio corrplot. Results 26 patients with UC participated in the study. The mean Mayo score was 4 (range 0–10). At endoscopy 15% had severe colitis (Mayo endoscopy sub-score 3), 31% had moderate disease, 54% had mild disease. 35% of patients were receiving biologic therapy. The mean CRP was 6.19mg/L (range 1–48.35mg/L), albumin 43.5g/L (range 31-49g/L). CRP had a negative correlation with albumin (r=-0.585, p-value 0.002). CRP had a statistically significant positive correlation with clinical, endoscopic and total Mayo scores (r= 0.469, 0.543, 0.526. p-values 0.016, 0.004, 0.006, respectively). Bleeding at colonoscopy also correlated very strongly with an elevated CRP (r=0.859, p-value=0.00). CRP had a moderate positive correlation with TNF-α (r=0.603, p-value=0.001) and VEGF receptor (r=0.492, p-value=0.011) levels. Conclusion CRP displayed a statistically significant positive correlation with the Mayo score. There was a significant correlation between the CRP and TNF-α expression within the colonic micro-environment. TNF-α is a key cytokine and therapeutic target in UC, its relationship with CRP has not been previously assessed. CRP is produced primarily by hepatocytes and is activated by TNF-α, interleukin 6 and interleukin 1β. It therefore stands to reason that there would be correlation between the two. The importance of TNF-α in UC is well known, this study supports and provides new evidence for the use of CRP as a non-invasive marker of disease activity.

DOP87 Disease clearance as a new therapeutic target in patients with Ulcerative Colitis: A multicenter retrospective cohort study

Abstract Background Symptom control and endoscopic endoscopic healing have been the main treatment targets in patients with ulcerative colitis (UC). Recently, the concept of disease clearance has been proposed as a potential target in UC. We aimed to evaluate the impact of disease clearance on long-term outcomes in patients with UC. Methods A multicenter retrospective cohort study was conducted at the Humanitas Research Hospital-IRCCS (Italy) and at the Nancy University Hospital (France) between January 2014 and February 2021. All consecutive adult patients with confirmed UC undergoing colonoscopy with biopsies and available histological reports and clinical data within one month of colonoscopy were eligible for inclusion. Disease clearance was defined as clinical (partial Mayo score ≤2 with no subscore &amp;gt;1), endoscopic (endoscopic Mayo score= 0), and histological (Nancy index= 0) remission of disease. The first available endoscopic procedure was considered as baseline. Disease clearance was measured at baseline and during follow-up by comparing the occurrence of negative disease outcomes in patients who achieved or not disease clearance. Results A total of 302 patients were included (46.4% female). Disease clearance was detected in 42 patients (13.9%) at baseline. Median follow-up was 32.2 ± 20.2 months. No patient achieving disease clearance underwent surgery during follow-up compared with 22 subjects in the non-disease clearance group (0.0% vs 8.5%, p=0.1). Similarly, a lower hospitalization rate was detected in patients with disease clearance at baseline compared with the control group (7.1% vs 25.4%, p=0.01). Interestingly, 51/302 patients (16.9%) achieved both endoscopic and histologic remission. This subgroup experienced a significantly lower rate of hospitalization (7.8% vs 25.9%, p=0.008) and surgery (0.0% vs 8.8%, p=0.05) compared with patients with endoscopic and/or histologic disease activity. The Kaplan Meier curves confirmed that patients with disease clearance at baseline had a lower risk for surgery (p=0.04) and hospitalization (hazard ratio (HR)= 0.49, 95% confidence interval (CI) 0.08–2.29, p=0.009) (Figures 1–2). Conclusion Disease clearance is a new outcome that simultaneously takes into account remission of symptoms, endoscopy and histology. Patients with disease clearance are at significant lower risk for hospitalization and surgery and could be the ultimate therapeutic target for full disease control.

Effect of MicroRNA145 on the multidrug resistance gene of ulcerative colitis in rats

Multidrug resistance gene (MDR1a) and P-glycoprotein (P-gp) play an important role in the development of ulcerative colitis (UC) and influence the therapeutic effect of glucocorticoids, which may lead to drug resistance mechanically. UC may be related to miR-145 to some extent, and the relationship still needs further exploration. In this study we found that the expression of miR-145 was downregulated in the colonic tissues of rats with Dextran sodium sulfate (DSS)-induced UC. Also, the expression of MDR1a in colon tissues of each group negatively correlated with the expression of miR-145 in rats. The change in the plasma peak concentration (Cmax) in each group positively related to the miR-145 level. Mechanistically, miR-145 negatively regulated the expression and function of P-gp via acting directly on the 3′-UTR of MDR1 mRNA. Overall, these results indicated that miR-145 had a protective effect on the colorectal mucosa, and its downregulation may enhance the expression and function of MDR1a and P-gp, promoting the occurrence and development of UC. The downregulation of miR-145 reduced the drug sensitivity of 5-aminosalicylic acid (5-ASA) and glucocorticoids in treating UC, indicating that miR-145 might be a potential therapeutic target for UC.

Increased Gene Copy Number of DEFA1A3 Is Associated With the Severity of Ulcerative Colitis.

INTRODUCTION:DEFA1A3 encodes human neutrophil peptides (HNPs) 1–3 and has multiple copy number variations (CNVs). HNPs are associated with innate immunity. Ulcerative colitis (UC), a chronic inflammatory gastrointestinal disorder, is a life-threatening condition, and predictive markers of UC severity are needed. This study investigated the relationship between DEFA1A3 CNV and UC severity.METHODS:This study enrolled 165 patients with UC. The relationship between DEFA1A3 CNV and disease severity was analyzed based on Mayo score, patient characteristics, and treatment methods. In addition, serum and stimulated neutrophil-derived HNP concentrations were also measured in patients with high and low DEFA1A3 CNV.RESULTS:DEFA1A3 CNV was significantly correlated with Mayo score and white blood cell count (R = 0.46, P < 0.0001; R = 0.29, P = 0.003, respectively), and only high copy numbers of DEFA1A3 were independent factors for severe UC (P < 0.001, odds ratio: 1.88, 95% confidence interval, 1.34–2.61). The number of severe UC patients with high DEFA1A3 CNV was significantly greater than those with low CNV. We confirmed the associations between DEFA1A3 and UC severity using a validation cohort. In addition, the HNP concentration in high-copy number patients was significantly higher after neutrophil stimulation than that in low-copy number patients.DISCUSSION:This study demonstrated that there is a correlation between DEFA1A3 copy number and severity in patients with UC. In addition, neutrophils from UC patients with higher DEFA1A3 CNV had high reactivity of secretion of HNPs after stimulation. DEFA1A3 CNV may be a novel severity marker and a potential therapeutic target for UC.