Disease Course Of Ulcerative Colitis Research Articles

Clinical course of ulcerative colitis: Frequent use of biologics and low colectomy rate first year after diagnosis-results from the IBSEN III inception cohort.

The introduction of biologic therapies and the 'treat-to-target' treatment strategy may have changed the disease course of ulcerative colitis (UC). To describe the early disease course and disease outcome at 1-year follow-up in a population-based inception cohort of adult patients with newly diagnosed UC. The Inflammatory Bowel Disease in South-Eastern Norway (IBSEN) III study is a population-based inception cohort study with prospective follow-up. Patients newly diagnosed with inflammatory bowel disease during 2017-2019 were included. Patients ≥18 years at diagnosis of UC who attended the 1-year follow-up were investigated. We registered clinical, endoscopic and demographic data at diagnosis and 1-year follow-up. We included 877 patients with UC (median age 36 years (range: 18-84), 45.8% female). At diagnosis, 39.2% presented with proctitis, 24.7% left-sided colitis and 36.0% extensive colitis. At the 1-year follow-up, 13.9% experienced disease progression, and 14.5% had received one or more biologic therapies. The colectomy rate was 0.9%. Steroid-free clinical remission was observed in 76.6%, and steroid-free endoscopic remission in 68.7%. Anaemia and initiation of systemic steroid treatment at diagnosis were associated with biologic therapy within the first year after diagnosis. In this population-based inception cohort, colectomy rate in the first year after diagnosis was low, and a high proportion of patients were in remission at 1-year follow-up. The use of biologic therapy increases, consistent with findings from previous studies.

DOP25 Antibodies against Neutrophil Extracellular Traps (ANETAs) are associated with more severe disease course in Ulcerative Colitis

Abstract Background Antibodies against Neutrophil Extracellular Traps (ANETAs) have emerged as markers in multiple autoimmune disorders (i.e. rheumatoid arthritis and systemic lupus) associated with disease activity. We investigated the presence of ANETAs and their influence on disease course in Inflammatory Bowel Disease (IBD). Methods Serum samples from UC (n=33), Crohn's Disease (CD; n=28), and healthy controls (HC; n=8) underwent incubation with non-lytic Neutrophil Extracellular Traps (NETs) for immunofluorescence microscopy. For clinical relevance, these patients were followed over ten years to track treatment resistance, extraintestinal manifestations, surgeries, and disease recurrence (Table 1). For functional relevance, in vitro generated NETs were exposed to ANETAs, followed by quantifying macrophage-mediated clearance of these ANETA pre-treated NETs by real-time microscopy via pHrodo for 24 hours, as well as assessing pro-inflammatory cytokine (IL-6, TNF-α, IL-8, and IL-23) genetic expression levels in these macrophages. Results Among UC patients, ANETA positivity correlated with high rates of treatment resistance, extraintestinal manifestations, colorectal surgeries, and recurrence of disease like pouchitis (93.3% vs. 6.7%, 61.5% vs. 38.5%; 71.4% vs. 28.6%; 87.5% vs. 12.5%, for ANETA+ and ANETA- UC patients, respectively). CD patients with ANETAs exhibited high rates of resistance to treatment (75% vs 25%) and lower rates of extraintestinal manifestations, colectomy, and disease recurrence (38.1% vs 61.9%, 40% vs 60%, 33.3% vs 66.7%) (Fig 1A). Macrophages displayed robust engulfment of untreated NETs and those treated with healthy control sera, while ANETA-coated NETs exhibited reduced susceptibility to macrophage phagocytosis (Fig 1B). Gene expression analysis revealed a significant upregulation of pro-inflammatory cytokines (IL-6, TNF-α, IL-8, and IL-23) when NETs were incubated with serum from ANETA-positive individuals compared to sera from healthy controls (p<0.05). Conclusion ANETAs may serve as markers for a distinct subgroup of UC patients characterized by aggressive disease and poorer prognosis. The potential mechanism might involve impaired NETs clearance by, and inducing a proinflammatory response in macrophages. Discrepancies observed between UC and CD suggest diverse pathophysiological mechanisms in both diseases. Further research is imperative to comprehensively understand the underlying pathophysiology, function, and potential clinical applications of ANETAs in IBD.

P678 Long-term efficacy, safety and health-related quality of life in patients who achieved comprehensive disease control with filgotinib in SELECTION: analysis of ~3 years in SELECTIONLTE

Abstract Background Filgotinib (FIL), an oral, once-daily, Janus kinase 1 inhibitor, was approved for Ulcerative Colitis (UC) treatment after the phase 2b/3 SELECTION trial (NCT02914522). In SELECTION, a greater proportion of FIL200 mg (FIL200)-treated than placebo-treated patients achieved comprehensive disease control (CDC), a stringent multi-component endpoint. We examined the long-term outcomes of achieving CDC in patients continuing on FIL200 in the ongoing long-term extension (LTE) study SELECTIONLTE (NCT02914535). Methods This interim analysis included adult patients with UC who completed SELECTION and received ≤144 weeks of FIL200 in the LTE (up to data cut-off 24/02/22). CDC (biomarker remission, endoscopic improvement, IBDQ remission and partial Mayo Clinic Score [pMCS] remission achieved concurrently) was assessed at SELECTION week 58 (LTE baseline [BL]). Mean pMCS and IBDQ score, use of corticosteroids (CS) and incidence of TEAEs and serious TEAEs in the LTE were compared between SELECTION CDC achievers and non-achievers. A mixed model for repeated measures was fitted on pMCS and IBDQ score, with CDC achiever status, study visit and the interaction between CDC achiever status and study visit as fixed effects; p values were nominal. Results We analysed 148 patients (CDC achievers, n=41; CDC non-achievers, n=107). Mean pMCS was stable in CDC achievers (0.44, LTE BL; 0.50, LTE week 144) and decreased in CDC non-achievers (1.49, LTE BL; 0.77, LTE week 144; Figure). Mean IBDQ score was stable in CDC achievers (204.05, LTE BL; 197.21, LTE week 144) and increased in CDC non-achievers (181.55, LTE BL; 196.37, LTE week 144; Figure). There was a significant beneficial effect of achieving CDC on pMCS and IBDQ score overall (pMCS: fixed effect estimate: −0.5542, p=0.0025; IBDQ score: fixed effect estimate: 13.1585, p=0.0042). There was a significant interaction between achieving CDC and study visit for IBDQ score (p=0.0183), with the benefit of achieving CDC lessening by week 144. Generally, a lower proportion of CDC achievers used CS than non-achievers; 2.4–7.3% of CDC achievers used CS vs 1.9–15.9% of CDC non-achievers. Incidence of TEAEs and serious TEAEs were stable over time and similar between CDC achievers and non-achievers. Conclusion Follow-up for ~3 years showed high levels of long-term benefit with continued FIL200 treatment. Achieving comprehensive disease control at the end of the randomized trial with FIL200 was associated with long-term efficacy, improved HRQoL and low overall use of CS. This may demonstrate the value of filgotinib-induced achievement of CDC in UC disease course. The safety profile of FIL200 was consistent between CDC achievers and non-achievers, suggesting an acceptable long-term benefit–risk profile.

Linking microbial genes to plasma and stool metabolites uncovers host-microbial interactions underlying ulcerative colitis disease course

Understanding the role of the microbiome in inflammatory diseases requires the identification of microbial effector molecules. We established an approach to link disease-associated microbes to microbial metabolites by integrating paired metagenomics, stool and plasma metabolomics, and culturomics. We identified host-microbial interactions correlated with disease activity, inflammation, and the clinical course of ulcerative colitis (UC) in the Predicting Response to Standardized Colitis Therapy (PROTECT) pediatric inception cohort. In severe disease, metabolite changes included increased dipeptides and tauro-conjugated bile acids (BAs) and decreased amino-acid-conjugated BAs in stool, whereas in plasma polyamines (N-acetylputrescine and N1-acetylspermidine) increased. Using patient samples and Veillonella parvula as a model, we uncovered nitrate- and lactate-dependent metabolic pathways, experimentally linking V.parvula expansion to immunomodulatory tryptophan metabolite production. Additionally, V.parvula metabolizes immunosuppressive thiopurine drugs through xdhA xanthine dehydrogenase, potentially impairing the therapeutic response. Our findings demonstrate that the microbiome contributes to disease-associated metabolite changes, underscoring the importance of these interactions in disease pathology and treatment.

GATA6-AS1 Regulates Intestinal Epithelial Mitochondrial Functions, and its Reduced Expression is Linked to Intestinal Inflammation and Less Favourable Disease Course in Ulcerative Colitis.

Widespread dysregulation of long non-coding RNAs [lncRNAs] including a reduction in GATA6-AS1 was noted in inflammatory bowel disease [IBD]. We previously reported a prominent inhibition of epithelial mitochondrial functions in ulcerative colitis [UC]. However, the connection between reduction of GATA6-AS1 expression and attenuated epithelial mitochondrial functions was not defined. Mucosal transcriptomics was used to conform GATA6-AS1 reduction in several treatment-naïve independent human cohorts [n=673]. RNA pull-down followed by mass spectrometry was used to determine the GATA6-AS1 interactome. Metabolomics and mitochondrial respiration following GATA6-AS1 silencing in Caco-2 cells were used to elaborate on GATA6-AS1 functions. GATA6-AS1 showed predominant expression in gut epithelia using single cell datasets. GATA6-AS1 levels were reduced in Crohn's disease [CD] ileum and UC rectum in independent cohorts. Reduced GATA6-AS1 lncRNA was further linked to a more severe UC form, and to a less favourable UC course. The GATA6-AS1 interactome showed robust enrichment for mitochondrial proteins, and included TGM2, an autoantigen in coeliac disease that is induced in UC, CD and coeliac disease, in contrast to GATA6-AS1 reduction in these cohorts. GATA6-AS1 silencing resulted in induction of TGM2, and this was coupled with a reduction in mitochondrial membrane potential and mitochondrial respiration, as well as in a reduction of metabolites linked to aerobic respiration relevant to mucosal inflammation. TGM2 knockdown in GATA6-AS1-deficient cells rescued mitochondrial respiration. GATA6-AS1 levels are reduced in UC, CD and coeliac disease, and in more severe UC forms. We highlight GATA6-AS1 as a target regulating epithelial mitochondrial functions, potentially through controlling TGM2 levels.

Acute idiopathic pancreatitis is associated with more aggressive disease course in Crohn’s disease but not in ulcerative colitis

PurposePatients with inflammatory bowel disease (IBD), whether Crohn’s disease (CD) or ulcerative colitis (UC), have an increased risk of acute pancreatitis. The prognostic value of diagnosing acute idiopathic pancreatitis in patients with IBD is not well understood.MethodsA retrospective review of 56 patients with IBD and acute pancreatitis was conducted in a tertiary center from 2011 to 2020. Aggressive disease course was defined as (i)biologic change, (ii)biologic dose escalation, or (iii)IBD-related surgeries occurring within 1 year of acute pancreatitis diagnosis. Logistic regression modelling identified associations between covariates and an aggressive disease course.ResultsBaseline characteristics between idiopathic pancreatitis and other causes of acute pancreatitis, in both CD and UC cohorts, were similar. Idiopathic pancreatitis was significantly associated with an aggressive disease course in CD (P = 0.04). No confounding factors were associated with an aggressive disease course in CD. Idiopathic pancreatitis, however, was not associated with an aggressive disease course in UC (P = 0.35).ConclusionThe diagnosis of acute idiopathic pancreatitis may provide a prognostic indicator of a more severe disease course in CD. No such association appears to exist with UC. To the best of our knowledge, this is the first study that identifies an association and possible prognostic value between idiopathic pancreatitis and a more severe disease course in CD. More studies with a larger sample size are needed to validate these findings, further define idiopathic pancreatitis as an extraintestinal manifestation of IBD and elucidate a clinical strategy to optimize care in patients with aggressive CD and idiopathic pancreatitis.

Low Adherence is Associated with Chronic Active Disease in Ulcerative Colitis: A Retrospective Study from a Single Referral Center.

New therapeutic approaches for ulcerative colitis (UC) are now available, but there is still no robust evidence for predictors of poor outcomes. We aimed to evaluate the factors associated with a chronic active UC disease course. Data of all UC outpatients followed for at least 3 years after diagnosis between 2005 and 2018 were retrospectively collected. The primary aim was to identify risk factors for chronic active disease 3 years after diagnosis. Moreover, the following variables were investigated: proximal disease extension or disease regression, proctocolectomy, early use of biologics (BIO) or immunomodulators (IMM), hospitalization, colorectal cancer, and adherence. We defined adherence as both, taking the prescribed therapy and constancy in scheduled follow-up visits. A total of 345 UC patients followed for a median period of 82 months were included. Patients with extensive colitis at diagnosis had a higher rate of chronic active disease 3 years after diagnosis (p<0.012) together with a higher rate of surgery (p<0.001) at maximum follow-up. Patients with pancolitis showed significant disease regression over time (51%) without differences in treatment. The only factor associated with chronic active disease was non-adherence (p < 0.03; OR 0.49, 95% CI: 0.26-0.95). Adherent patients developed chronic active disease (p<0.025) less frequently but did receive more frequent IMM (p<0.045) or BIO (p<0.009) therapy. Patients diagnosed with pancolitis were more likely to have chronic active disease and to undergo colectomy. The only predictor for developing chronically active UC regardless of disease extension was the lack of adherence to therapy within the first 3 years after diagnosis, underlining the importance of tight control of UC patients and the need to timely identify potential risk factors for non-adherence.

P875 Disease course of Ulcerative Colitis during the first ten years following diagnosis in a prospective European population-based inception cohort – the Epi-IBD cohort

Abstract Background The Epi-IBD cohort is a prospective European population-based cohort of 1,390 patients diagnosed in 2010 and 2011 with inflammatory bowel disease (IBD) according to Copenhagen criteria in centres from Eastern and Western European countries. The study aims at describing differences in incidence, treatment strategies, disease course and prognosis of ulcerative colitis (UC) Eastern and Western Europe. Methods UC patients were followed prospectively from the time of diagnosis until December 31st, 2020, death, emigration or loss of follow-up. Clinical data on surgery, hospitalizations and medical treatment were captured throughout the follow-up period and entered in a validated web-database, www.epi-ibd.org. Associations between colectomy and covariates were analysed by multivariate Cox regression analyses. Results A total of 816 UC patients aged ≥15 years from 21 centres in 5 Eastern and 11 Western European countries were included. Overall, 51 (6%) patients underwent colectomy. A total of 190 (23%) patients were hospitalized at least once for their UC. Cancer was diagnosed in 28 (3%) patients, including 4 colorectal cancers. The use of medical therapy was comparable across Eastern and Western European centres (Table 1). During follow-up, 121 out of 776 (16%) patients with limited UC (proctitis or left-sided colitis) progressed to extensive colitis. The median time to progression was 21 (IQR: 8-48) months from diagnosis. No patients from Eastern Europe were exposed to biological therapy prior to change in disease extent, compared to 6 out of 98 patients (6%) from Western Europe. Multivariate Cox regression analysis showed no difference in risk of colectomy according to European region (Eastern vs. Western Europe, HR: 1.05, 95%CI: 0.48-2.29). Early intervention with biologicals (within 6 months) was associated with higher risk of colectomy (HR: 3.06, 95% CI: 1.23-7.58), and so was early introduction of immunomodulators (HR: 2.35, 95%CI: 1.16-4.76). Progression in disease extent to extensive colitis was significantly associated with higher risk of surgery (HR: 5.30, 95% CI: 2.36-11.90) and similarly extensive colitis at diagnosis compared to proctitis (HR: 3.48, 95% CI: 1.12-10.82). Conclusion After 10 years of follow up in this European multicentre study, only 6% percent had a colectomy performed. Despite the widespread use of immunomodulators and biologicals, 16% of patients with limited disease extent progressed to extensive colitis which was associated with higher risk of surgery. The need for early introduction of biological therapy and immunomodulators might predict risk of surgery.

30 An Update on the Impact of Appendicectomy and Deprivation on Disease Course in Ulcerative Colitis

Abstract Aim The impact of appendicectomy on the natural history of ulcerative colitis (UC) is unclear. We aimed to assess our cohort of patients with UC to examine the incidence of appendicectomy and association with disease severity. We also examined association of social deprivation with disease severity. Method Patients with UC in the health board region were identified by the Gastroenterology consultants. These were divided into moderate-severe (defined as current biologic therapy) and mild-moderate disease (no or 5-ASA therapy only). Two cohorts were sex-matched on a 1:1 basis. Demographic data was identified by review of the patients’ Electronic Patient Record (EPR) and the Scottish Index of Multiple Deprivation 2020. The EPR was reviewed for evidence of previous appendicectomy. Results A total of 664 patients were identified: 328 mild-moderate and 336 moderate-severe. 145 patients (44%) in the mild-moderate group and 145 patients (43%) in the moderate-severe group were female. The majority of patients had left-sided disease. There were no significant differences in smoking status. Rates of appendicectomy in the moderate to severe group were double that of the mild to moderate group (8 v 4; p= .25). Mild-moderate disease was associated with increased social deprivation (X2 (2, N = 664) = 10.60, p = .03) (Fig. 3). Conclusions There were double the number of appendicectomies in the mild-moderate cohort, however the relationship between severity and previous appendicectomy was not significant. Disease severity appears to be negatively associated with social deprivation. Further collaborative work across Scotland is planned.

Predictive value of Milan ultrasound criteria in ulcerative colitis: A prospective observational cohort study.

BackgroundEndoscopic healing is an established treatment target for ulcerative colitis (UC). We have recently validated the Milan ultrasound criteria (MUC) to assess endoscopic activity in UC; a MUC score > 6.2 is a valid cut‐off to discriminate endoscopic activity (Mayo endoscopic subscore > 1).ObjectiveThe aim of this study was to assess the predictive value of MUC on disease course in a prospective cohort of UC patients.MethodsUC patients regardless of disease activity and current therapy, underwent colonoscopy and bowel ultrasound (US) at baseline in a blinded fashion. Correlations between baseline MUC and Mayo endoscopic subscore were assessed using Spearman's rank correlation. UC‐related negative course (defined as the need for corticosteroids, or treatment escalation, or hospitalization, or need for colectomy: a composite outcome) over a median 20 months follow‐up, was investigated using the Kaplan‐Meier method and Cox regression analysis.Results98 UC patients were followed up for a median time of 1.6 years (IQR 0.9¬2.7). Milan ultrasound criteria and Mayo endoscopic subscore significantly correlated at baseline (ρ = 0.653; p < 0.001). 70 patients (71%) had negative disease course during the follow‐up period. Milan ultrasound criteria > 6.2 at baseline was statistically significantly associated with negative disease course (HR: 3.87, 95% CI: 2.25–6.64, p < 0.001). Kaplan–Meier analyses drawed a statistically significantly lower cumulative probability of treatment escalation, need of corticosteroids, hospitalization and colectomy, among patients who had MUC ≤ 6.2 at baseline as compared to patients with MUC > 6.2 (p < 0.05 for all outcomes).Conclusionwe have demonstrated for the first time the value of bowel US and an US score in predicting disease course in UC. Milan ultrasound criteria, a validated US‐based score, predicts disease course in UC. Milan ultrasound criteria ≤ 6.2 may be the new treatment target to achieve to reduce the risk of worse outcomes.

P238 Symptom burden and indolent disease in newly diagnosed patients with ulcerative colitis and Crohn’s disease - a Copenhagen IBD Inception Cohort Study

Abstract Background The early course of ulcerative colitis (UC) and Crohn’s disease (CD) is difficult to predict, particularly regarding identifying patients for whom an indolent course might be expected. Therefore, we aimed to investigate the initial course of UC and CD and clinical predictors hereof in a generalizable population-based inception cohort. Methods We initiated a prospective population-based inception cohort of newly diagnosed patients with UC and CD between May 1st, 2021 and November 1st, 2021, according to the Copenhagen IBD Criteria within the geographical uptake area of Hvidovre University Hospital and Herlev University Hospital. All patients were examined systematically by IBD specialists at diagnosis using endoscopy, magnetic resonance (MR) enterography, and patient-reported measures including Simple Clinical Colitis Index (SCCAI) and Harvey-Bradshaw Index (HBI) for UC and CD, respectively. Indolent disease presentation was defined as the absence of UC or CD-related hospitalization, surgery, or decision to start steroid, immunomodulator, or biologic therapy within three months of follow-up. In addition, well-recognized predictors of long-term disease course of UC and CD were a priori defined and implemented in a univariate logistic model, and factors with a p-value smaller than 0.10 were included in the multivariate model. Results The study included 63 adult patients with UC and 50 with CD. At diagnosis, 23 (36.5%) and 13 (26.0%) patients with UC and CD were in clinical remission according to their SCCAI or HBI score, respectively (Table 1). The symptomatic disease burden is outlined in Table 2–3. Interestingly, well-recognized risk factors for the long-term disease course of UC and CD, including disease extent, behavior, baseline endoscopy, MR enterography, and serologic data, did not predict the initial disease course in a multivariable analysis (Table 4). However, C-reactive protein &amp;lt;10 mg/L were associated with an indolent course of UC (adjusted odds ratio=6.2 (95% confidence interval 1.3–38.9), p=0.03). Conclusion The preliminary data from the ongoing prospective population-based cohort study indicate that very heterogenous disease course patterns might be experienced very early. As initial disease control is considered critical for long-term outcomes, this study highlights the inapplicability of long-term predictors for the short-term disease course. It emphasizes the need for further development of simple clinical tools or biomarkers for early patient stratification.

P252 Low adherence is associated with worse disease course in Ulcerative Colitis: a retrospective study from a single referral center

Abstract Background New therapeutic approaches for ulcerative colitis (UC) are becoming available but still there is no robust evidence for predictors of poor outcome. We aimed to evaluate factors associated with a more aggressive UC course. Methods Data of all UC outpatients followed for at least 3 years after diagnosis were retrospectively collected. Demographic, anamnestic data, disease characteristics and treatment were collected. Disease patterns were defined according to the IBSEN study (Henriksen M. et al1). Disease worsening at 3 years was defined as the presence of disease extension at endoscopy, proctocolectomy and or early use of biologics. Risk factors for chronically active disease were assessed. Moreover, the following outcomes were explored according to disease extent at diagnosis (E1-E2 vs E3): corticosteroid free remission, hospitalization, early use of immunomodulators and biologics, colorectal cancer, adherence, mucosal healing at 3 years. Survival analysis was carried out to estimate the probability of receive a biological treatment within 3 and 5 years from diagnosis according to disease extent (E1 vs E2 vs E3) and disease patterns. Results A total of 345 UC patients were included and followed for a mean period of 94 months. Patients with extensive colitis had a higher rate of colectomy (p &amp;lt; 0.001), hospitalizations (p=0.004) and of chronically active disease 3 years after diagnosis (p &amp;lt; 0.001) and were more likely to receive early biologics and IMM (p= 0.04 and p=0.01 respectively) (Figure 1). The only factor associated with chronic active disease was non-adherence (p &amp;lt; 0.03; OR 0.49, 95% CI: 0.26–0.95) (Table 1). No differences were found for the probability to receive biologics within 3 and 5 years from diagnosis according to Montreal extension at diagnosis and disease pattern. Conclusion Patients diagnosed with pancolitis were more likely to underwent colectomy or to have a chronically active disease with a higher rate of hospitalization, early use of IMM or biologics. The only predictor for chronically active UC was the lack of adherence to therapy within the first 3 years after diagnosis. Reference 1. Henriksen M, et al; IBSEN Study Group. Ulcerative colitis and clinical course: results of a 5-year population-based follow-up study (the IBSEN study). Inflamm Bowel Dis. 2006;12:543–50. The study was supported by a grant from Ferring S.p.A.

Fibrin(ogen) Promotes Immune Cell Infiltration, Dysbiosis and ROS Production in Experimental Colitis

Elevated stool fibrinogen has recently been shown to predict disease course in ulcerative colitis (UC), suggesting that fibrin(ogen) in the colitis microenvironment promotes UC pathogenesis. This conclusion is consistent with previous studies from our laboratory showing that fibrin(ogen)/leukocyte interactions mediated by the integrin receptor α Mβ 2 promote experimental colitis and colitis-associated cancer, but the mechanisms are not well defined. To delineate the mechanism coupling fibrinogen to colitis pathogenesis, we induced colitis in Fib WT and mice carrying a mutant fibrinogen lacking the α Mβ 2 binding motif (Fibg 390-396A) with Dextran Sulfate Sodium (DSS). We performed flow cytometric, protein analyses of colons and fecal microbiome and metabolomics analyses after DSS exposure. Five days after DSS challenge, a timepoint prior to significant epithelial damage, we observed significantly diminished infiltration of natural killer cells, T cells, dendritic cells, macrophages and neutrophils in colons harvested from DSS-challenged Fibg 390-396A mice relative to Fib WT mice. We also observed significantly diminished proinflammatory cytokine production by NK cells, macrophages and dendritic cells isolated from DSS-challenged Fibg 390-396A colons. It is well-established that the microbiome composition is a major determinant of colitis in humans and mice. One mechanism by which microbiome contents alter the course of colitis is by the elaboration of certain fecal metabolites. NMR-based fecal metabolomics analyses demonstrated no significant changes in short-chain fatty acids (acetate, propionate, and butyrate) and various amino acids (valine, proline, alanine) however we found significantly less uracil in fecal from Fibg 390-296A relative to Fib WT mice following DSS exposure. Uracil is a key ligand for Duox2 (dual NADPH oxidase), a gut epithelial specific enzyme, that drives reactive oxygen species production by gut epithelial in response to dysbiosis. Notably, Duox2 is the highest induced gene in inflammatory bowel disease (IBD) and has been identified as a risk gene. Our molecular analyses showed no difference in colonic Duox2 expression between genotypes at baseline, but Duox2 expression significantly increased in Fib WT relative to Fibg 390-296A after just 5 days of DSS exposure. Further western blot analyses revealed that Duox2 expression only in the colonic epithelial cells and not in the lamina propria cells. To determine if fibrinogen cause dysbiosis in DSS-induced colitis model, we performed shotgun sequencing on fecal samples from Fib WT and Fibg 390-396A mice at baseline and after 7 days of DSS challenge. Interesting shotgun sequencing analyses revealed major fibrin genotype dependent significant differences in the microbiomes of Fib WT and Fibg 390-396A mice at baseline as well as following DSS challenge. Our studies are the first to show that fibrin(ogen) is a major determinant of the gut-microbiome in the context of experimental colitis. Altogether, these studies demonstrate that fibrin(ogen) in the colitis microenvironment promotes the infiltration and activation of multiple leukocyte subsets that drive colitis pathogenesis. These results also suggest that fibrin(ogen) promotes colitis-associated dysbiosis and Duox2 expression, leading to ROS production that contributes to colitis pathogenesis and possibley tumorigenesis. Overall, these studies suggest that fibrin(ogen)-α Mβ 2 interactions represent an attractive therapeutic target for IBD without incurring the potential bleeding risks associated with anticoagulants or other modalities targeting fibrin deposition. DisclosuresNo relevant conflicts of interest to declare.

Predicting disease course in ulcerative colitis using stool proteins identified through an aptamer-based screen

In the search for improved stool biomarkers for inflammatory bowel disease (IBD), an aptamer-based screen of 1129 stool proteins was conducted using stool samples from an IBD cohort. Here we report that of the 20 proteins subsequently validated by ELISA, stool Ferritin, Fibrinogen, Haptoglobin, Hemoglobin, Lipocalin-2, MMP-12, MMP-9, Myeloperoxidase, PGRP-S, Properdin, Resistin, Serpin A4, and TIMP-1 are significantly elevated in both ulcerative colitis (UC) and Crohn’s disease (CD) compared to controls. When tested in a longitudinal cohort of 50 UC patients at 4 time-points, fecal Fibrinogen, MMP-8, PGRP-S, and TIMP-2 show the strongest positive correlation with concurrent PUCAI and PGA scores and are superior to fecal calprotectin. Unlike fecal calprotectin, baseline stool Fibrinogen, MMP-12, PGRP-S, TIMP-1, and TIMP-2 can predict clinical remission at Week-4. Here we show that stool proteins identified using the comprehensive aptamer-based screen are superior to fecal calprotectin alone in disease monitoring and prediction in IBD.

Endoscopic and Histologic Predictors of Outcomes in Pediatric Ulcerative Colitis-Caveat Emptor.

The impact of endoscopic and histological mucosal healing on outcomes in adult settings is impressive. Despite many clinical parallels, pediatric ulcerative colitis (UC) is set apart from adult disease in several respects. Many frequently used indices are not fully validated, especially in pediatric settings, and consensus on precise definitions in clinical settings are lacking. Endoscopic mucosal healing is an acceptable long-term treatment goal in pediatrics, but not histologic normalization. Early prediction of disease course in UC may allow treatment stratification of patients according to risks of relapse, acute severe colitis, and colectomy. Putative endoscopic and histologic predictors of poor clinical outcomes in adults have not held true in pediatric settings, including baseline endoscopic extent, endoscopic severity, and specific histologic characteristics which are less prevalent in pediatrics at diagnosis. In this mini-review we appraise predictive endoscopic and histologic factors in pediatric UC with reference to relapse, severe colitis, and colectomy risks. We recommend that clinicians routinely use endoscopic and histologic sores to improve the quality of clinical and research practice. The review summarizes differences between adult and pediatric prediction data, advises special consideration of those with primary sclerosing cholangitis, and suggests areas for future study in this field.

Ulcerative Colitis-Diagnostic and Therapeutic Algorithms.

Ulcerative colitis is a chronic inflammatory bowel disease with an estimated 150 000 patients in Germany alone. This review is based on publications about current diagnostic and therapeutic strategies for ulcerative colitis that were retrieved by a selective search in PubMed, and on current guidelines. The primary goal of treatment is endoscopically confirmed healing of the mucosa. Mesalamine, in various forms of administration, remains the standard treatment for uncomplicated ulcerative colitis. Its superiority over placebo has been confirmed in meta-analyses of randomized, controlled trials. Glucocorticoids are highly effective in the acute treatment of ulcerative colitis, but they should only be used over the short term, because of their marked side effects. Further drugs are available to treat patients with a more complicated disease course of ulcerative colitis, including azathioprine, biological agents, JAK inhibitors (among them TNF antibodies, biosimilars, ustekinumab, vedolizumab, and tofacitinib), and calcineurin inhibitors. Proctocolectomy should be considered in refractory cases, or in the presence of high-grade epithelial dysplasia. Ulcerative colitis beginning in childhood or adolescence is often characterized by rapid progression and frequent comorbidities that make its treatment a special challenge. A wide variety of drugs are now available for the treatment of ulcerative colitis, enabling the individualized choice of the best treatment for each patient. Regular surveillance colonoscopies to rule out colon carcinoma should be scheduled at intervals that depend on risk stratification.

Status of Gene Methylation and Polymorphism in Different Courses of Ulcerative Colitis and Their Comparison with Sporadic Colorectal Cancer.

The objective of this study is to explore the common genetic and epigenetic mechanism of ulcerative colitis (UC) and sporadic colorectal cancer (SCRC) by observing genes methylation level and single nucleotide polymorphisms (SNPs) of different disease courses in UC and SCRC. Two hundred subjects were enrolled, including 40 in the healthy control (HC) group, 50 in the short disease course UC group (SUC), 52 in the long disease course UC group (LUC), and 58 in the SCRC group. Methylation-specific polymerase chain reaction was used to detect the methylation of MINT1 and cyclooxygenase 2 (COX-2) gene. Single nucleotide polymorphisms of interleukin (IL)-23R rs10889677 and IL-1β rs1143627 were detected by Sanger sequencing. Compared with HCs (32.5%), methylation level of MINT1 was significantly increased in SCRC (67.2%; P = 0.001) and was a risk factor for CRC (odds ratio, [OR] 4.26). The methylation ratios of COX-2 were 95.0%, 58.0%, 23.1%, and 24.1% in HC, SUC, LUC, and SCRC, respectively, which were negatively correlated with the disease course of UC (r = -0.290). Hypermethylation of COX-2 was a protective factor for SUC (OR, 0.11), LUC (OR, 0.02), and SCRC (OR, 0.03; P < 0.05). Compared with HCs, rs10889677 allele A was a risk factor for SUC and LUC, and rs1143627 allele T was a protective factor for SUC and LUC. Genotype TT was a protective factor for SUC. The hypomethylation of COX-2 gene was a common risk factor and epigenetic modification for UC and SCRC, which might be one of the mechanisms through which UC patients were susceptible to CRC. The hypermethylation of MINT1 was a risk factor for SCRC but not for UC; alleles of IL-23Rrs10889677 and IL-1βrs1143627 were related to UC but not to SCRC.

The Role of Rotavirus in Exacerbated Ulcerative Colitis

The Ulcerative colitis disease course is characterized by exacerbations and remissions. Studies of the roleof viral composition within patients with changing disease activity are currently deficient. The rotavirusgastroenteritis is an important cause of morbidity and mortality worldwide. This study aimed to identifythe associated role of Rotavirus during exacerbation of ulcerative colitis. A Fifteen (50) stool and biopsysamples from patients with exacerbated colitis were collected at different age groups and gender. Thesesamples were taken from Morjan Hospital Consultant Gastroenterology and Liver Center, and the lmamSadiq Hospital during the period from October to April 2019. The stool samples were screened for Rotavirusby using Rapid CERtest Rotavirus Kit,PCR The occurrences of UC and age revealed that the age group &lt;25year show ten with UC 83% followed by the age group (26-35) which give seven with UC 70%. The relationbetween existence of UC and gender shown that the positive among male were (20) of patients UC 71%while negative (8) among female the positive were 17 (77%)the results statistically non- significant. Thefrequency of rotavirus positivity during exacerbated UC as tested by Rapid CER test at different age groupthe results gives (23) positive samples for Rotavirus 46% and negative (27) 54%. The Rotavirus existencein stool of patients with positive biopsy for ulcerative colitis by using chromatography test revealed that thenumber of positive were 20 out of 50 at a rate of 40%. While the RT-PCR product analysis of VP4 gene inRotavirus from in RNA extracted from stool patients samplesthe positive were 24 out of 50 with rate of 48%.

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.

3149 Ulcerative Colitis in an Octogenarian: A Diagnostic and Therapeutic Challenge

INTRODUCTION: Individuals aged &gt;60 years contribute to 10%-15% of inflammatory bowel disease diagnoses with merely 10% of them being over 80 years of age. Older-onset ulcerative colitis (UC) is more common than Crohn's disease, with a male preponderance. Compared to younger patients, UC in the elderly manifests more as proctitis, has a subtler presentation with lesser bleeding, diarrhea, and abdominal pain, and a lower risk of relapse, but with increased severity. Till date, literature regarding UC in the octogenarian age group is limited to a handful of case reports. CASE DESCRIPTION/METHODS: An 81-year-old-male, non-smoker, with a history of coronary artery disease and family history significant for systemic lupus erythematosus, presented with moderate to severe, dull, periumbilical abdominal pain of one-month duration, associated with mucoid diarrhea, intermittent high-grade fever, anorexia, and unintentional weight loss. He denied any nausea, vomiting, blood in vomit or stools, icterus or pruritus. He did not report any history of high-risk behavior or recent travel. His examination was unremarkable except periumbilical and diffuse lower abdominal tenderness. Laboratory evaluation was notable for leucocytosis (13.5 K/ul), hyponatremia (128 mEq/L) and hypokalemia (3.1 mEq/L). U/S abdomen showed intestinal distension and a trial of opioid receptor agonists and probiotics was initiated for a probable diagnosis of irritable bowel syndrome, which failed to show clinical improvement. Treatment with broad-spectrum antibiotics, based on CT findings suggestive of colitis, led to partial symptomatic relief. Colonoscopy was performed following a recurrence of symptoms that revealed multiple areas of ulcerations and a biopsy confirmed the diagnosis of UC. The patient received guideline-directed medical therapy with 5-aminosalicylates and corticosteroids, which led to clinical improvement, and since then, the patient has been in remission. DISCUSSION: The unique pathophysiology, clinical manifestations and disease course of UC in the elderly add to its diagnostic challenge. Additionally, the scarcity of literature regarding treatment guidelines and lack of clarity of appropriate clinical endpoints (objective vs.symptom control) limits evidence-based decision in this population with a higher hospitalization and mortality rate. Consequently, a high degree of suspicion needs to be maintained in the aging population presenting with clinical features of colitis to ensure prompt treatment and limit complications.