Therapeutic Target In Ulcerative Colitis Research Articles

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.

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.

Identification of Common Differentially Expressed Genes and Potential Therapeutic Targets in Ulcerative Colitis and Rheumatoid Arthritis

Ulcerative colitis (UC) and rheumatoid arthritis (RA) are immune-mediated inflammatory diseases (IMIDs) with similar symptoms and common genomics. However, the relationship between UC and RA has not been investigated thoroughly. Therefore, this study aimed to establish the differentially expressed genes (DEGs) and potential therapeutic targets in UC and RA. Three microarray datasets (GSE38713, GSE1919, and GSE12251) were selected from the Gene Expression Omnibus (GEO) database for analysis. We used R software to identify the DEGs and performed enrichment analyses. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and Cytoscape software were used to construct the protein-protein interaction (PPI) network and identify the hub genes. A regulatory network based on the constructed PPI was generated using StarBase and PROMO databases. We identified a total of 1542 and 261 DEGs in UC and RA. There were 169 common DEGs identified in both UC and RA, including 63 upregulated genes (DEGs1) and nine downregulated genes (DEGs2). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of DEGs1 and DEGs2 in the PPI network revealed that the genes enriched were involved in immunity. A total of 45 hub genes were selected based on high scores of correlation; three hub genes (SRGN, PLEK, and FCGR3B) were found to be upregulated in UC and RA, and downregulated in UC patients with response to infliximab treatment. The identification of novel DEGs and hub genes in the current study contributes to a novel perception for latent functional mechanisms and presents potential prognostic indicators and therapeutic targets in UC and RA.

Cobitolimod for moderate-to-severe, left-sided ulcerative colitis (CONDUCT): a phase 2b randomised, double-blind, placebo-controlled, dose-ranging induction trial

Cobitolimod is a topically administered, DNA-based oligonucleotide that activates Toll-like receptor 9 (TLR9), and previous research has shown clinical efficacy in patients with moderate-to-severe ulcerative colitis. Here we assessed the efficacy and safety of different dose regimens of cobitolimod for induction therapy in patients with moderate-to-severe, left-sided ulcerative colitis. CONDUCT was a randomised, double-blind, five-arm, placebo-controlled, dose-ranging phase 2b study that recruited patients with moderate-to-severe, left-sided ulcerative colitis, with inadequate response to conventional or biological therapies, from 91 hospitals or outpatient clinics in 12 European countries. Eligible patients had a Mayo score of 6-12 with a centrally read endoscopic subscore (modified to exclude friability from grade 1) of 2 or higher and no individual subscore of less than 1, and confirmation of left-sided disease. Patients were randomised (1:1:1:1:1; block size of ten) via a computer-generated schedule and centralised interactive voice and web response system to receive rectal enemas of cobitolimod at 31 mg, 125 mg, or 250 mg at weeks 0 and 3 (2 × 31 mg, 2 × 125 mg, and 2 × 250 mg groups), cobitolimod at 125 mg at weeks 0, 1, 2, and 3 (4 × 125 mg group), or placebo. Randomisation was stratified by current glucocorticosteroid and previous tumour necrosis factor inhibitor treatment. Patients and all study personnel were masked to treatment allocation. The primary endpoint was the proportion of patients achieving clinical remission (Mayo subscores for rectal bleeding of 0, for stool frequency of 0 or 1 [with ≥1-point decrease from baseline], and for endoscopy of 0 or 1 [excluding friability]) at week 6. The primary analysis (based on intention to treat) and safety analysis were done in all randomly assigned patients who received at least one dose of active study drug or placebo. In this exploratory study, statistical tests were one-sided; p values of less than 0·10 were regarded as statistically significant, with no adjustment for multiplicity. This study is registered with ClinicalTrials.gov, NCT03178669, and is completed; the results here represent the final analysis. 213 patients were randomly assigned between June 30, 2017, and June 26, 2019. Of these, 211 patients received study treatment: 40 in the cobitolimod 2 × 31 mg group, 43 in the 2 × 125 mg group, 42 in the 4 × 125 mg group, 42 in the 2 × 250 mg group, and 44 in the placebo group. A greater proportion of patients were in clinical remission at week 6 in the cobitolimod 2 × 250 mg group than in the placebo group (nine [21%] of 42 patients vs three [7%] of 44; odds ratio [OR] 3·8 [80% CI 1·5-9·5]; one-sided p=0·025). We identified no significant difference in the proportion of patients with clinical remission in the cobitolimod 2 × 31 mg group (five [13%] of 40 patients; OR 2·0 [80% CI 0·7-5·5], p=0·18), 2 × 125 mg group (two [5%] of 43; 0·7 [0·2-2·2], p=0·66), or 4 × 125 mg (four [10%] of 42; 1·4 [0·5-3·9], p=0·33) compared with the placebo group. Treatment-emergent adverse events occurred in 21 (48%) patients in the placebo group, ten (25%) patients in the cobitolimod 2 × 31 mg group, 17 (40%) patients in the 2 × 125 mg group, 15 (36%) patients in the 4 × 125 mg group, and 18 (43%) patients in the 2 × 250 mg group. Severe adverse events occurred in eight (4%) of 211 patients (worsening of ulcerative colitis [seven patients] and abdominal hernia and wound dehiscence [one patient]). Ten patients (two [5%] in the placebo group, two [5%] in the cobitolimod 2 × 31 mg group, two [5%] in the 4 × 125 mg, and four [10%] in the 2 × 250 mg group) had a total of 13 serious adverse events; these were worsening of ulcerative colitis (eight events) and pruritus, rash, abdominal hernia, fascia dehiscence, and deep vein thrombosis (one event each). One patient in the placebo group died from total organ failure after receiving a colectomy for a serious adverse event of disease worsening. Two topical administrations of cobitolimod 250 mg were well tolerated and more effective than placebo in inducing clinical remission 6 weeks after the start of treatment. TLR9 activation is a promising novel therapeutic target in ulcerative colitis and warrants further testing, with phase 3 trials of cobitolimod planned. InDex Pharmaceuticals.

Molecular Signature of Persistent Histological Inflammation in Ulcerative Colitis with Mucosal Healing.

Therapeutic targets in ulcerative colitis (UC) have evolved over time from clinical remission to biological and endoscopic remission. Histologic remission remains a debatable outcome due to lack of data regarding its impact on long-term evolution. The development of histologic activity scores has brought standardization. We aimed to identify mucosal markers differentiating histological inflammation from histological remission in UC patients. The gene expression levels of 84 genes associated with inflammatory bowel diseases have been analyzed in 43 colonic mucosa samples from 30 patients with UC. The gene expression levels have been correlated with histological inflammation score of Geboes. Patients with endoscopic remission were divided by histological activity into two groups and molecular results were compared in order to identify differences in the mucosal gene expression. We found a significant Pearson correlation (p<0.001 and r>0.5) between the Geboes score and the expression of 29 genes, whereas negative correlation (p<0.001 and r<-0.50) was observed with two genes in the entire UC cohort. In the subgroup of patients with endoscopic remission three transcripts: formyl-peptide receptor 1 (FPR1), matrix metalloproteinases 1 (MMP1) and mucine 1 (MUC1) were significantly up-regulated in patients with histological inflammation compared to patients with histologic remission. Our study further emphasizes the importance of histological assessment when endoscopic mucosal healing is present, as FPR1, MMP-1 and MUC1 were all significantly upregulated in patients with histological alterations.

Development of Mucosal PNAd+ and MAdCAM-1+ Venules during Disease Course in Ulcerative Colitis.

PNAd and MAdCAM-1 addressins on venules are of importance in T-cell homing and potential therapeutic targets in ulcerative colitis (UC). Normally, PNAd+ high endothelial venules (HEVs) are only present in lymphoid organs, whereas small numbers of MAdCAM-1+ venules can be seen in non-lymphoid tissue. We aimed to study their presence in the intestinal mucosa of UC patients at diagnosis and during follow-up, and their correlation with disease activity. Colonic biopsy specimens of 378 UC patients were analyzed by immunohistochemistry for CD3, CD20, ERG, MECA-79 (PNAd) and MECA-376 (MAdCAM-1) and compared to healthy controls (HC). The proportion of PNAd+HEVs in UC at diagnosis was 4.9% (IQR 2.0%–8.3%), while none were detected in HC. During follow-up, PNAd+HEVs completely disappeared in remission (n = 93), whereas the proportion in active disease was similar to baseline (n = 285, p = 0.39). The proportion of MAdCAM-1+venules in UC at baseline was 5.8% (IQR 2.6–10.0). During follow-up, the proportion in remission was comparable to diagnosis, but upregulated (7.5% (IQR 4.4–10.9), p = 0.001) in active disease. In conclusion, PNAd+HEVs appear in UC during active inflammation which could thus serve as a marker for disease activity, whereas MAdCAM-1+venules remain present after inflammation is resolved and increase after subsequent flares, reflecting chronicity and potentially serving as a therapeutic target.

Aggravated ulcerative colitis caused by intestinal Metrnl deficiency is associated with reduced autophagy in epithelial cells

Metrnl is a newly identified secreted protein highly expressed in the intestinal epithelium. This study aimed to explore the role and mechanism of intestinal epithelial Metrnl in ulcerative colitis. Metrnl−/− (intestinal epithelial cell-specific Metrnl knockout) mice did not display any phenotypes of colitis under basal conditions. However, under administration of 3% dextran sodium sulfate (DSS) drinking water, colitis was more severe in Metrnl−/− mice than in WT mice, as indicated by comparisons of body weight loss, the presence of occult or gross blood per rectum, stool consistency, shrinkage in the colon, intestinal damage, and serum levels of inflammatory factors. DSS-induced colitis activated autophagy in the colon. This activation was partially inhibited by intestinal epithelial Metrnl deficiency, as indicated by a decrease in Beclin-1 and LC3-II/I and an increase in p62 in DSS-treated Metrnl−/− mice compared with WT mice. These phenomena were further confirmed by observation of autophagosomes and immunofluorescence staining for LC3 in epithelial cells. The autophagy-related AMPK-mTOR-p70S6K pathway was also activated in DSS-induced colitis, and this pathway was partially blocked by intestinal epithelial Metrnl deficiency, as indicated by a decrease in AMPK phosphorylation and an increase in mTOR and p70S6K phosphorylation in DSS-treated Metrnl−/− mice compared with WT mice. Therefore, Metrnl deficiency deteriorated ulcerative colitis at least partially through inhibition of autophagy via the AMPK-mTOR-p70S6K pathway, suggesting that Metrnl is a therapeutic target for ulcerative colitis.

P148 Reproducibility of PICaSSO score by using narrow banding images (NBI) to assess mucosal and histological healing in ulcerative colitis (UC) patients

Abstract Background The endoscopic and histological healing are key therapeutic targets in ulcerative colitis(UC) patients. PICaSSO (Paddington International virtual ChromoendoScopy ScOre)1,2 is a new Virtual Chromoendoscopy Endoscopic (VCE) score to better define mucosal healing by mucosal and vascular features. Originally validated using iSCAN platform, the aim of this study was to evaluate the reproducibility of PICaSSO with NBI near focus platform and to assess if this could predict histological healing. Methods We prospectively studied 78 UC patients (mean age 43.4 years, 52.6% male) who underwent colonoscopy for colitis assessment or surveillance using NBI near focus (Olympus, Japan). Endoscopic activity was assessed by using ulcerative colitis Endoscopic Index of Severity (UCEIS) and PICaSSO; whilst histological activity was scored by the Robarts Histology Index (RHI). ROC curves were performed to evaluate sensitivity, specificity and accuracy of endoscopy scores to predict histological healing. Results Out of 78 patients, 47 (60.3%) were in clinical remission according to the partial Mayo score. 28(35.9%) and 32(41.0%) were in endoscopic remission according to UCEIS≤1 and PICaSSO≤3, respectively. The best cut-off of UCEIS to predict histological healing was less or equal to 1. Sensitivity, specificity and accuracy were 84.6% (95% CI 63.5, 96.4), 88.5% (95% CI 70.1, 97.8) and 87.2% (95% CI 75.6, 93.6), respectively. The Area Under the ROC curve (AUROC) was 93.3% (95% CI 88.2, 98.3). The best threshold of PICaSSO in the prediction of histological healing was less or equal to 3. PICaSSO ≤ 3 have sensitivity of 96.2% (95% CI 76.9, 100), specificity of 86.5% (95% CI 67.3, 96.2) and accuracy of 89.7% (95% CI 77.6, 96.2) to predict histological healing, estimated as RHI ≤ 3. The AUROC was 95.3% (95% CI 91.1, 99.5). Conclusion PICaSSO VCE score can be easily and accurately reproduced with NBI near focus platform and it has better operating characteristics than UCEIS to predict histological healing defined by RHI. Reference

ELR positive CXCL chemokines are highly expressed in an animal model of ulcerative colitis.

Background: The presence of neutrophil-rich inflammation in colon tissues of patients with ulcerative colitis (UC) is one of the most important histological characteristics of this disease. However, the expression of CXCL chemokines governing the infiltration of neutrophils in UC has not been well elucidated.Materials and methods: In this experimental study, the UC model was induced in Wistar rats by administration of 2 mL 4% acetic acid into the large colon through the rectum. Animals were anesthetized after 48 hrs; their colon tissue samples were isolated for macroscopic and histopathological examinations. The expression of CXCL family was assessed by reverse transcription polymerase chain reaction (qRT-PCR) technique.Results: Heavy infiltration of neutrophils, coagulation necrosis, and ulcers were observed in H&E staining, which pathologically proved the UC model. qRT-PCR results showed that ELR+ CXC chemokines such as CXCL6 and CXCL3 had the highest expression in the UC group, which was 49 and 28 times higher than that of the control group, respectively. In addition, other chemokines of this group including CXCL1, CXCL2, and CXCL7 had a significant increase compared to the control group (P≤0.05). However, ELR− CXC chemokines such as CXCL4, CXCL13, and CXCL16 showed a smaller upregulation, while CXCL14 chemokine showed a significant decrease compared to the control group (P≤0.05). However, the expression of CXCL9-12 and CXCL17 did not change.Conclusion: The results showed that the ELR+ CXC chemokines, especially CXCL6 and CXCL3, many involved in the pathogenesis of UC; therefore, CXCL6 and CXCL3 chemokines can be used as therapeutic targets for UC, although more studies using human samples are required.

Mo1878 – Lymphocyte Activation Gene (LAG)-3 on T Cells is a Potential Therapeutic Target in Ulcerative Colitis

Mo1878 – Lymphocyte Activation Gene (LAG)-3 on T Cells is a Potential Therapeutic Target in Ulcerative Colitis

Whole Exome Sequencing of Ulcerative Colitis-associated Colorectal Cancer Based on Novel Somatic Mutations Identified in Chinese Patients.

Carcinogenesis is a severe consequence of chronic ulcerative colitis. We investigated the somatic mutations and pathway alterations in ulcerative colitis-associated colorectal cancer (CRC) in Chinese patients compared with sporadic CRCs to reveal potential therapeutic targets in ulcerative colitis-associated CRC. Whole exome sequencing was performed on archival tumor tissues and paired adjacent nondysplastic mucosa from 10 ulcerative colitis-associated CRC patients at a high risk of carcinogenesis. Genomic alteration profiles from 223 primary CRCs from The Cancer Genome Atlas served as sporadic CRC controls. A meta-analysis was performed to investigate differences in major genetic mutations between ulcerative colitis-associated and Crohn's disease-associated CRCs. We identified 44 nonsilent recurrent somatic mutations via whole exome sequencing, including 25 deleterious mutations involved in apoptosis and the PI3K-Akt pathway (COL6A3, FN1), autophagy (ULK1), cell adhesion (PODXL, PTPRT, ZFHX4), and epigenetic regulation (ARID1A, NCOR2, KMT2D, NCOA6, MECP2, SUPT6H). In total, 11 of the 25 mutated genes significantly differed between ulcerative colitis-associated CRC and sporadic CRC (APC, APOB, MECP2, NCOR2, NTRK2, PODXL, RABGAP1, SIK3, SUPT6H, ULK1, USP48). Somatic TP53 mutations occurred in 33% of ulcerative colitis-associated CRCs. Subsequent meta-analysis revealed distinct mutation profiles for Crohn's disease- and ulcerative colitis-associated CRCs. Mutations involving the NF-kB pathway and epigenetic regulation were more common in ulcerative colitis-associated CRCs than in sporadic CRCs. Distinct genomic alteration profiles of deleterious somatic mutations were found in ulcerative colitis-associated and sporadic CRCs. Mutations of epigenetic regulators, such as KMT2D and NCOA6, were common, suggesting an epigenetic pathomechanism for colitis-associated carcinoma in Chinese patients.

DOP11 Lymphocyte activation gene (LAG)-3 on T cells is a potential therapeutic target in ulcerative colitis

DOP11 Lymphocyte activation gene (LAG)-3 on T cells is a potential therapeutic target in ulcerative colitis

High-dimensional single-cell proteomics analysis identifies immune checkpoint signatures and therapeutic targets in ulcerative colitis.

Immune checkpoints are regulators of immune cells and play key roles in the modulation of immune responses. The role of checkpoints in autoimmune disease is poorly understood but likely to be central since checkpoint inhibition during cancer treatment can cause autoimmunity. We generated a high-dimensional single-cell proteomics data set from PBMCs of healthy individuals and patients with ulcerative colitis (UC) by mass cytometry, enabling systems-wide analyses of immune cell frequencies and cell type-specific expression patterns of 12 immune checkpoints. Subtle but significant changes in immune cell frequencies and checkpoint expression were observed between UC patients on different treatment regimens and between patients and healthy controls. Most strikingly, UC patients showed a reduced number of peripheral NK-cells and those cells showed an altered phenotype including increased TIGIT expression. Based on these results, we modulated NK-cell function ex vivo through targeting of TIGIT pathway members. In summary, we describe a pattern of changes in immune cell abundance and checkpoint expression as a basis for UC patient stratification and we show modulation of a corresponding immune cell subset through checkpoint targeting. Our approach can be used for the identification of pathogenic immune cell subsets and guide target selection in autoimmunity and chronic inflammation.

The possible ameliorative effect of simvastatin versus sulfasalazine on acetic acid induced ulcerative colitis in adult rats

ObjectiveInflammatory bowel diseases (IBD) are chronic and recurrent disorders of the gastrointestinal tract with unknown etiology and have two major forms, ulcerative colitis (UC) and Crohn diseases. In view of the adverse effects and incomplete efficacy of currently administered drugs, it is essential to investigate new and harmless drugs with more desirable beneficial effects. Statins have many additional pleiotropic effects other than their lipid-lowering effect. This study aims to investigate the role of simvastatin (SIM) at different doses against induced UC in rats. MethodsSIM (10, 20 mg/kg), and sulfasalazine as a standard therapy (100 mg/kg) were given from five days before and seven days after induction of UC by acetic acid (AA). Colonic mucosal inflammation was evaluated macroscopically and microscopically. Furthermore, the colonic tissue tumor necrosis factor-α (TNF-α), interleukin 1beta (IL 1B), nod-like receptor family pyrin domain-1 containing 3 (NLRP3), malondialdehyde (MDA), reduced glutathione (GSH) and super oxide dismutase (SOD) were assayed in addition to immunohistochemistry of caspase-1 and cyclooxygenase-2 (COX2). ResultsSIM in a dose dependant manner significantly improved macroscopic and histological scores, diminished colonic levels of IL 1B, TNF-α, NLRP3, MDA, caspase-1 and COX2 and elevated GSH and SOD. ConclusionSIM has anti-inflammatory, cytoprotective and antioxidants effects that are not directly related to its cholesterol lowering activity against AA induced colitis this makes it a new therapeutic target for UC.

Fecal Calprotectin Levels Predict Histological Healing in Ulcerative Colitis

Introduction: Endoscopic healing (EH) is the therapeutic target for ulcerative colitis (UC). Recent data has suggested that patients who achieve histological healing (HH) may have even better outcomes. It has been shown that fecal calprotectin (FC) levels may be utilized as a proxy for assessment of endoscopic and histological remission. Our aim was to assess the clinical utility of FC levels to predict depth of remission in UC in a real-world military population. Methods: We performed a retrospective cohort study of UC patients who underwent a full colonoscopy and had FC measured within 6 weeks prior to colonoscopy at a large military treatment facility. Clinical, endoscopic, and histologic disease activity was assessed by Patient Reported Outcomes (PRO2), Mayo Endoscopic Score (0-3), and Nancy score (0-4), respectively. Outcomes of interest included 1) Deep remission (PRO2 remission and Mayo score 0) and 2) deeper remission (deep remission plus Nancy score 0 or 1). Median FC levels were expressed in μg/g. The association of FC with outcomes of interest were compared using Mann-Whitney U tests. The diagnostic ability of FC for endoscopic and mucosal healing was analyzed using receiver operating curve (ROC) analysis. Results: In 104 patients (median age 34 years), 24% had proctitis (E1), 23% left-sided (E2), and 53% pan-colitis (E3). Higher FC levels significantly correlated with Mayo score (p<0.001) and Nancy scores (p<0.001). FC levels werelower in Mayo 0 compared to Mayo 1, 2, and 3 (20 vs. 111, 362, and 915; p<0.001). FC levels were significantly lower in Nancy 0/1 compared to Nancy 2, 3, and 4 (20/68 vs. 429, 420, and 1250, respectively; p<0.001). Patients with endoscopic remission and Nancy score ≤1 (n=22) had significantly lower FC lovels compared to those with endoscopic remission and Nancy ≥2 (48 vs. 499, p<0.0001). FC levels of ≤45 predicted deep and deeper remission (AUC = 0.87, sensitivity 85%, specificity 78%). Conclusion: FC levels significantly correlated with endoscopic mucosal and histologic activity, and reflect microscopic disease activity even in the face of macroscopic healing. We validated an FC level of ≤ 45 μg/g robustly predicted depth of remission. We suggest that FC can be used instead of colonoscopy in a treat-to-target paradigm in patients with UC.

Efficacy of Therapeutic Intervention for Patients With an Ulcerative Colitis Mayo Endoscopic Score of 1.

Mucosal healing (MH) is proposed as a therapeutic target for ulcerative colitis (UC). Recent studies have indicated that the rate of clinical relapse in patients with a Mayo endoscopic score (MES) of 1 is higher than that of patients with an MES of 0. However, no study has yet investigated whether therapeutic intervention prevents clinical relapse in patients with an MES of 1. Patients with UC with an MES of 1 and partial Mayo score ≤2 were included in this study. All patients were followed from first colonoscopy (CS) until follow-up CS. Differences in the rate of clinical relapse (requiring additional treatment for UC) or endoscopic exacerbation (MES ≥2 and proximal extension) were compared between the therapeutic intervention (immediately after first CS) group and the nontherapeutic intervention group; risk factors for relapse were also assessed. Among 1523 patients with UC who underwent CS between 2013 and 2016, 220 patients were included in this study. The rate of clinical relapse (P = 0.005) and endoscopic exacerbation (P = 0.11) in patients with therapeutic intervention was lower than that in patients without therapeutic intervention. Multivariable analysis indicated that absence of therapeutic intervention (P = 0.001 for clinical relapse, P = 0.050 for endoscopic exacerbation) and a higher Ulcerative Colitis Endoscopic Index of Severity vascular pattern score immediately after first CS (P = 0.021 for clinical relapse, P = 0.019 for endoscopic exacerbation) were risk factors for both clinical relapse and endoscopic exacerbation. Therapeutic intervention for patients with UC with an MES of 1 might prevent disease relapse.

CD1a expressing monocytes as potential therapeutic targets in ulcerative colitis

CD1a expressing monocytes as potential therapeutic targets in ulcerative colitis

The Role of Combining Biochemical Markers in Assessing the Endoscopic Activity in Ulcerative Colitis

Ulcerative colitis (UC) isa chronic, idiopathic and recurrent inflammatory bowel disease (IBD), characterized by periods of activity and remissionwhose monitoring requires invasive explorations associated with discomfort for the patient and important costs. Mucosal healing became one of the most important therapeutic targets in UC. The aim of our study was to identify a score, made up of noninvasive, available, used in current clinical practice biochemical markers, which should correlate with endoscopic activity in UC. We conducted a prospective study on 114 patients with UC. All patients were assessed both for biological inflammatory markers: erythrocyte sedimentation rate (ESR),C- reactive protein (CRP), fibrinogen, platelets, albumin, fecal calprotectin (FC) and by colonoscopy to estimate the endoscopic activity using Mayo score. By linear regression, we tried to identify a biochemical score correlated with endoscopic activity. Out of the serological markers,ESR (p=0.014), CRP(p= 0.021) and fibrinogen (p=0.035) correlated with the endoscopic activity of the disease. The best sensitivity to determine the endoscopic activity was given by FC (96.05%) with a predictable negative value of 91.1% (p=0.001). The score determined by linear regression: 1 (ESR]15mm/1h) x 0.305 + 1(fibrinogen]340.5mg/dL) x 0.309+1 (CRP] 5 mg/L) + 1 (calprotectin]200 μg/g) had an increased positive predictive value compared to each and one biomarker, nevertheless, with a sensitivity and specificity inferior to that of FC. Up to now, it is the first attempt to achieve a score made up exclusively of biological markers. The obtained score, although with an increased accuracy, has proven to have a lower predictability in comparison with FC used individually and cannot entirely replace colonoscopy.

YAP triggers the Wnt/\u03b2-catenin signalling pathway and promotes enterocyte self-renewal, regeneration and tumorigenesis after DSS-induced injury

Impaired epithelial regeneration is a crucial pathophysiological feature of ulcerative colitis (UC). Yes-associated protein (YAP1) appears to control cell proliferation and differentiation. In this study, we sought to identify the roles of YAP in intestinal epithelial cell (IEC) self-renewal, regeneration and tumorigenesis. We first observed that YAP was significantly reduced in 62.5% (45/72) of human UC tissues and it was dramatically enhanced during epithelial regeneration in a murine colitis model. Using lentiviral infection, we established a YAP-overexpression (YAPWT) mouse model. We then found that after tissue injury, YAPWT mice had increased epithelial cell self-renewal capacity and drastically restored intestinal crypt structure. Strikingly, these mice were more susceptible to colitis-associated cancer (CAC) in chemically induced carcinoma. Mechanistically, YAP and β-catenin showed increased nuclear co-localization during regeneration after inflammation. Overexpressing YAP significantly improved IEC ‘wound-healing’ ability and increased the expression of both β-catenin and the transcriptional targets of Wnt signalling Lgr5 and cyclin D1, whereas silencing β-catenin in YAPWT cells attenuated this effect. Remarkably, we observed that YAP could directly interact with β-catenin in the nucleus and formed a transcriptional YAP/β-catenin/TCF4 complex; Lgr5 and cyclin D1 were confirmed to be the target genes of this complex. In contrast, cancer cell proliferation and tumour development were suppressed by the phospho-mimetic YAP mutant. In summary, nuclear YAP-driven IEC proliferation could control epithelial regeneration after inflammation and may serve as a potential therapeutic target in UC. However, excessive YAP activation promoted CAC development.