Diagnosis Of Ulcerative Colitis Research Articles

Identification of ferroptosis-related genes in ulcerative colitis: a diagnostic model with machine learning.

Ulcerative colitis (UC) is an idiopathic, chronic disorder characterized by inflammation, injury, and disruption of the colonic mucosa. However, there are still many difficulties in the diagnosis and differential diagnosis of UC. An increasing amount of research has shown a connection between ferroptosis and the etiology of UC. Therefore, our study aimed to identify the key genes related to ferroptosis in UC to provide new ideas for diagnosis UC. Gene expression profiles of normal and UC samples were extracted from the Gene Expression Omnibus (GEO) database. By combining differentially expressed genes (DEGs), Weighted correlation network analysis (WGCNA) genes, and ferroptosis-related genes, hub genes were identified and then screened using Lasso regression. Based on the key genes, gene ontology (GO) and gene set enrichment analysis (GSEA) analyses were performed. We used NaiveBeyas, Logistic, IBk, and RandomForest algorithms to build a disease diagnosis model using the hub genes. The model was validated using GSE87473 as the validation set. Gene expression matrices of GSE87466 and GSE75214 were downloaded from the GEO database, including 184 UC patients and 43 control samples. A total of 699 DEGs were obtained. From FerrDb, 565 genes related to ferroptosis were identified. The 1,513 genes with the highest absolute correlation coefficient value in the MEblue module were obtained from WGCNA analysis. Five hub genes (LCN2, MUC1, PARP8, PLIN2, and TIMP1) were identified using the Lasso regression algorithm based on the overlapped DEGs, WGCNA-identified genes, and ferroptosis-related genes. GO and GSEA analyses revealed that 5 hub genes were identified as being involved in the negative regulation of transcription by competitive promoter binding, cellular response to citrate cycle_tca_cycle, cytosolic_dna_sensing pathway, UV-A, and beta-alanine metabolism. The logistic algorithm's values of the area under the curve (AUC)were 1.000 and 0.995 for training and validation cohorts, and sensitivity is 0.962, specificity is 1.000, respectively, as determined by comparing various methods. The previously described hub genes were identified as being intimately related to ferroptosis in UC and capable of distinguishing UC patients from controls. By detecting the expression of several genes, this model may aid in diagnosing UC and understanding the etiology and treatment of the disease.

Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial

Despite the introduction of new monoclonal antibodies and oral therapies for the treatment of ulcerative colitis, clinical remission rates remain low, underscoring the need for innovative treatment approaches. We assessed whether guselkumab plus golimumab combination therapy was more effective for ulcerative colitis than either monotherapy. We did a randomised, double-blind, controlled, proof-of-concept trial at 54 hospitals, academic medical centres, or private practices in nine countries. Eligible adults (aged ≥18 to 65 years) had a confirmed diagnosis of ulcerative colitis at least 3 months before screening and moderately-to-severely active ulcerative colitis (Mayo score 6-12) with a centrally-read baseline endoscopy subscore of 2 or higher. Patients were randomly assigned (1:1:1) using a computer-generated randomisation schedule to combination therapy (subcutaneous golimumab 200 mg at week 0, subcutaneous golimumab 100 mg at weeks 2, 6, and 10, and intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab monotherapy 100 mg every 8 weeks for 32 weeks), golimumab monotherapy (subcutaneous golimumab 200 mg at week 0 followed by subcutaneous golimumab 100 mg at week 2 and every 4 weeks thereafter for 34 weeks), or guselkumab monotherapy (intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab 100 mg every 8 weeks thereafter for 32 weeks). The primary endpoint was clinical response at week 12 (defined as a ≥30% decrease from baseline in the full Mayo score and a ≥3 points absolute reduction with either a decrease in rectal bleeding score of ≥1 point or a rectal bleeding score of 0 or 1). Efficacy was analysed in the modified intention-to-treat population up to week 38, which included all randomly assigned patients who received at least one (partial or complete) study intervention dose. Safety was analysed up to week 50, according to study intervention received among all patients who received at least one (partial or complete) dose of study intervention. This trial is complete and is registered with ClinicalTrials.gov, NCT03662542. Between Nov 20, 2018, and Nov 15, 2021, 358 patients were screened for eligibility, of whom 214 patients were randomly assigned to combination therapy (n=71), golimumab monotherapy (n=72), or guselkumab monotherapy (n=71). Of the 214 patients included, 98 (46%) were women and 116 (54%) were men and the mean age was 38·4 years (SD 12·0). At week 12, 59 (83%) of 71 patients in the combination therapy group had achieved clinical response compared with 44 (61%) of 72 patients in the golimumab monotherapy group (adjusted treatment difference 22·1% [80% CI 12·9 to 31·3]; nominal p=0·0032) and 53 (75%) of 71 patients in the guselkumab monotherapy group (adjusted treatment difference 8·5% [-0·2 to 17·1; nominal p=0·2155). At week 50, 45 (63%) of 71 patients in the combination therapy group, 55 (76%) of 72 patients in the golimumab monotherapy group, and 46 (65%) of 71 patients in the guselkumab monotherapy group had reported at least one adverse event. The most common adverse events were ulcerative colitis, upper respiratory tract infection, headache, anaemia, nasopharyngitis, neutropenia, and pyrexia. No deaths, malignancies, or cases of tuberculosis were reported during the combination induction period. One case of tuberculosis was reported in the combination therapy group and one case of colon adenocarcinoma was reported in the guselkumab monotherapy group; both occurred after week 12. Two deaths were reported after the final dose of study intervention (poisoning in the combination therapy group and COVID-19 in the guselkumab monotherapy group). Data from this proof-of-concept study suggest that combination therapy with guselkumab and golimumab might be more effective for ulcerative colitis than therapy with either drug alone. These findings require confirmation in larger trials. Janssen Research and Development.

P691 Disparate care: rates of treat to target among patients with inflammatory bowel disease

Abstract Background Inflammatory bowel diseases (IBD) therapies are limited by low response rates and risks of loss of response. Treat to target (T2T) algorithms aim to maximize the benefit of therapies by establishing a framework for assessing patient reported outcomes, biochemical evaluation (C-reactive protein (CRP) or fecal calprotectin (FC)), and structural assessment via endoscopy or enterography. There are limited data on adoption rates of T2T in real-world clinical practice. We aimed to describe rates of T2T utilization in a large regional medical system in the United States. Methods A retrospective cohort study was conducted from 2015-2021. Individuals with IBD starting a new biologic therapy were identified. Collected data included demographics, laboratory data, current medications, and procedure and imaging data. Patients were categorized based on whether they completed T2T, defined as CRP or FC testing at 2-4 months after starting a new therapy, and structural assessment, defined as colonoscopy, sigmoidoscopy, capsule endoscopy, or enterography within 6-12 months after starting a new therapy. Complete adherence was defined as both of these criteria being met. Social deprivation index (SDI), with higher values associated with higher rates of social deprivation, was derived using mail codes. T-tests, Pearson chi-square tests, ANOVA and multivariable logistic regression were used for comparisons. Results 7,962 patients were identified (Table 1). Rates of T2T were low; only 7.81% of patients completed biochemical monitoring at 2-4 months (0.83% FC, 8.65% CRP, 1.76% both), 9.80% completed structural assessment, and 3.43% completed both. In univariable logistic regression, higher age (OR 0.98, p<0.01), IBD type (UC OR: 0.69, p<0.01), having no insurance (OR 0.84, p=0.02) and low social deprivation index (SDI) (OR 1.004, p<0.01) were associated with lower T2T completion rates. In multivariable logistic regression, ulcerative colitis (UC), younger age, and lower SDI score were significantly associated with likelihood of completing any T2T (Table 2). When considering biochemical monitoring at 2-4 months, Asian race, UC diagnosis, age, SDI score and year were significantly associated with completion (Table 3). UC diagnosis, year and age were significantly associated with completion of structural assessment (Table 4). Conclusion Treat to target completion rates among patients with IBD starting biologic therapies were low in this large cohort. Age and UC diagnosis were negatively associated with completing T2T. Social deprivation score was positively associated with biochemical monitoring. Further research is required to understand barriers to T2T monitoring.

P049 Proteomic characterization of serum extracellular vesicles from newly diagnosed patients with inflammatory bowel disease

Abstract Background The etiology and pathogenesis of inflammatory bowel disease (IBD), Crohn’s disease (CD), and ulcerative colitis (UC) are complex and the mechanisms that lead to the development of these diseases remain unclear. Extracellular vesicles (EVs) are small particles covered with a cell membrane, originating from the emitting cell, excreted into the extracellular medium, and subsequently captured by receptor cells. EVs have a role in multiple diseases and they could also have a function in IBD pathogenesis. Therefore, the analysis of EVs isolated from the serum of newly diagnosed IBD patients (before starting any treatment) may represent an appropriate experimental approach to elucidate their role in IBD pathogenesis. We aimed to evaluate EVs’ composition and potential effects in the pathogenesis of IBD. Methods The protein content of EVs isolated by size exclusion chromatography from the 500 µl of serum from 100 patients with IBD (50 patients with CD and 50 patients with UC) recently diagnosed and 50 healthy controls (HC) was characterized by proteomics and their size and concentration in serum by Nanoparticle tracking analysis (NTA). The biological function of EVs and alterations in signaling pathways related to IBD were determined using Ingenuity Pathways Analysis (IPA) to analyze the OMICs results. Results A total of 1,100 proteins have been identified, of which 105 proteins were differentially expressed by patients with CD versus HC, 111 proteins by patients with UC versus HC, and 32 proteins by patients with UC versus CD. IPA analysis revealed that proteins carried in EVs are involved in the dysregulation of immune pathways such as the acute phase response (Figure 1), LXR/RXR activation pathway (Figure 2), and the complement pathway. These pathways were regulated differentially in IBD patients compared with HC, but also when the CU group was compared with the CD group (Figure 3) being upregulated nuclear receptors signaling and cytotoxicity pathways. Conclusion EVs carry proteins that can be involved in the dysregulation of the immune system in IBD; this effect would be different in UC and CD since their EVs show a differential profile. Consequently, EVs may play role in IBD pathogenesis and source of strong biomarkers candidates for diagnosis in UC and CD. Further studies on their specific function during IBD are warranted.

P397 Advanced therapy persistence and need for dose optimisation in a cohort of Inflammatory Bowel Disease patients in Argentina: a real-world evidence multicenter study (REMAR study)

Abstract Background Treatment persistence, as well as time to dose optimisation, can be a proxy for a drug’s real-world therapeutic benefit. We sought to describe treatment persistence of biologics or small molecules in inflammatory bowel disease (IBD) patients and need for optimisation in patients with IBD in Argentina and their potential predictors. Methods A retrospective cohort study involving 13 hospitals from Argentina was undertaken. Adult patients with a diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC) who received therapy with a biologic or a small molecule were included. Initiation date was registered for every therapy each patient received; in addition, treatment finalization as well as need for optimisation were registered. Treatment persistence was defined as the time between treatment initiation and treatment finalization, or as time between treatment initiation and last follow-up if patient continued with the treatment. Time to optimisation was defined as the time between treatment initiation and treatment dose optimisation. In patients that received more than one type of advanced therapy, treatment persistence and need for optimisation was analyzed separately for each treatment received. Kaplan-Meier analysis as well as Cox regression model were used to determine predictors of treatment persistence and need for optimisation. Results A total of 403 patients were included; 55.28% had a diagnosis of UC, mean age was 44.57±16 and 47.71% were male. Median time of follow-up was 80 months [IQR 41-152]. Adalimumab was the most frequently used biologic as a first-line treatment for CD and UC (59.78% and 51.39%, respectively), whereas ustekinumab and vedolizumab were the most frequently used agents for CD and UC patients previously exposed to biologics, respectively (41.42% and 36.73%). Median treatment persistence duration was 68 months [IQR 22-146]. History of steroid-dependency [HR 2.87 (1.02-8.12)], CD [0.42 (0.22-0.78]), prior biologic exposure [HR 2.25 (1-5.06)], dose optimisation [HR 2.93 (1.36-6.33)] and need for systemic steroids 6 months from treatment initiation [HR 4.98 (1.57-15.75)] were significant predictors of shorter treatment persistence. Median time to optimisation was 34 months [IQR 9-132]. CD [0.81 (0.55-0.94)], moderate-to-severe endoscopic activity [HR 1.91 (1-3.95)], prior biologic exposure [HR 2.29 (1.27-4.14)] and biologic initiation after 2017 [2.06 (1.09-3.55)] were significant predictors of need for dose optimisation. Conclusion A considerable proportion of IBD patients required dose optimisation or treatment finalization. Lower treatment persistence and time for dose optimisation were observed in UC patients and other factors were identified.

P534 Dual biologic or small molecules therapy in refractory paediatric inflammatory bowel disease (DOUBLE-PIBD): A multi-center study from the paediatric IBD Porto group of ESPGHAN

Abstract Background Current data on dual biologic or small molecules therapy in children are limited. The aim of the study was to evaluate the effectiveness and safety of dual therapy in paediatric patients with IBD. Methods This was a retrospective multicenter study from 14 centers affiliated with the IBD interest and Porto groups of ESPGHAN. We included children with IBD who were treated with combination of biologic agents or biologic and small molecule, with at least 3 months of follow-up under this therapy. Demographic, clinical, laboratory, endoscopic and imaging data were collected. Adverse events were recorded. All analyses were done in the intention-to-treat population. Children that discontinued therapy were considered treatment failures and were imputed for non-response, while missing data was imputed according to the last observation carried forward method. Results Sixty-two children [35 Crohn’s disease (CD), 27 ulcerative colitis (UC)], with a median age of 15.5 (IQR 13.1-16.8) years and disease duration of 3.8 (IQR 2.5-6.1) years were included. All children failed previous biologics and 47 (76%) failed at least two biologic agents. The dual therapy included anti-TNF agent and vedolizumab in 30 children (48%), anti-TNF and ustekinumab in 21 children (34%), vedolizumab and ustekinumab in 8 children (13%), and tofacitinib and other biologics in 3 children (5%). Clinical remission was observed in 21 (35%), 30 (50%) and 38 (63%) children at 3, 6 and 12 months, respectively. Of 27 children who were treated with corticosteroids at baseline, 20 (74.1%) were weaned within 3 months after the initiation of dual therapy. At 12 months of follow up, normalization of C-reactive protein and decrease in fecal calprotectin to < 250 mcg/g were achieved in 75% and 64%, respectively. Endoscopic and transmural healing were observed in 2/23 (9%) and 5/16 (31%) children, respectively. Male sex and diagnosis of UC were associated with higher likelihood of clinical remission (p=0.017 and p=0.020, respectively). Adverse events were reported in 29 (47%) children. While most adverse event were mild, 8 were regarded as serious and 6 (10%) led to discontinuation of dual therapy. The serious adverse events included infusion reaction to infliximab, fatigue and headache following vedolizumab infusion, severe skin eruptions (3 patients), cellulitis and skin abscess, elevated liver enzymes and deep vein thrombosis. Conclusion Dual biologic or small molecules therapy may be effective in children with otherwise refractory IBD. The risk of serious adverse events should be considered before recommending dual therapy.

P264 Machine learning can accurately predict development of Inflammatory Bowel Disease

Abstract Background Prediction of inflammatory bowel disease (IBD) development is the subject of intense study. We have previously shown that significant changes occur in routine laboratory tests in the 5 years preceding IBD diagnosis. Using routinely collected laboratory results, we developed machine learning models to predict development of IBD. Methods We extracted data from the electronic medical records of Maccabi Health Services and included patients with IBD ≥ 16 years of age with a minimum of 5 years follow up and an age and sex matched healthy cohort. The outcome measured was entry into the IBD registry. The study population was split into training and validation cohorts and using laboratory values in the 5 years prior to IBD diagnosis as features, we assessed the performance of supervised learning models and performed interpretability analysis with unsupervised dimensionality reduction. Results 5643 patients with IBD and 17199 healthy people were included in this study. 3039 (53.8%) had Crohn’s disease (CD), 2322 (41.1%) ulcerative colitis (UC) and 282 (5%) indeterminate colitis. The mean age of the IBD and healthy cohorts at study inclusion was 39.3 ± 16.5 and 38.5 ± 15.6 years, respectively. Weighted nearest neighbour imputation was used to correct for data missingness. Unsupervised Uniform Manifold Approximation Projection dimensionality reduction correctly separated the cohort into healthy and IBD clusters (Figure 1A). Furthermore, this algorithm identified two distinct groups correlating to CD or UC diagnosis (Figure 1B). Supervised learning models, namely neural net (AUC 0.95), linear support vector machine (SVM) (AUC 0.93), radial basis function SVM (AUC 0.85) and logistic regression (AUC 0.93) models, accurately predicted IBD diagnosis (Figure 2). These models were repeated without C-reactive protein and the predictive value was not significantly changed. Moreover, we excluded data in the 2 years preceding IBD diagnosis to determine whether model performance was reduced and the predictive value remained the same. Interestingly, using only data from 3-5 years preceding IBD diagnosis, the model could better distinguish between CD and UC (Figure 3). Conclusion In this study, machine learning models could accurately predict a diagnosis of IBD using laboratory data from the 5 years preceding IBD diagnosis. Prospective studies are needed to test these models in a real world setting.

P143 Outcomes of ulcerative colitis-associated dysplasia patients treated with endoscopic submucosal dissection: An extended analysis of a single center cohort

Abstract Background Total proctocolectomy has been recommended for patients with ulcerative colitis (UC)-associated dysplasia due to the risk of its progression to colorectal cancer or metachronous recurrence. Recently, endoscopic resection has been considered as a therapeutic option for dysplasia in UC, and endoscopic submucosal dissection (ESD) has been recommended for lesions where endoscopic mucosal resection is unsuitable. We aimed to investigate the long-term outcomes of UC patients who underwent ESD for dysplasia or early colorectal cancer Methods We retrospectively reviewed 47 patients with UC-associated dysplasia/cancer referred for potential ESD to treat non-polypoid or sessile dysplasia between August 2009 and August 2022 at Asan Medical Center, a tertiary hospital in Seoul. Indications for ESD were determined according to the criteria applied for sporadic colorectal neoplasms based on magnifying endoscopy. Results The median age at UC diagnosis was 45 years, and 24 patients (51%) were male. The median duration of UC was 13 years. Colectomy was recommended for 11 patients, and the remaining 36 patients underwent ESD. The en bloc resection rate was 88.9% (32/36), and the histologic complete resection rate was 77.8% (28/36). Five patients underwent colectomy after ESD due to missed adenocarcinoma, deep submucosal cancer, and multiple dysplasia. A total of 31 patients were followed-up after ESD. Their mean (standard deviation) follow-up period was 45.9 (±30.6) months, and the mean number of post-ESD surveillance endoscopies was 3 (±2). Local recurrence of dysplasia occurred in 3 (3/31, 9.6%) patients; metachronous recurrence occurred in 7 patients (7/31, 22.6%). There were no cases of metachronous colorectal cancer. Conclusion ESD for discrete dysplastic lesions in UC patients is feasible and shows favorable outcomes in terms of colorectal cancer prevention. However, surveillance colonoscopy with short intervals is warranted due to the high metachronous recurrence rate.

P735 Real-life experience with the use of Tofacitinib in Colombian patients with moderate to severe Ulcerative Colitis: a descriptive study

Abstract Background In Latin America the experience in clinical practice with tofacitinib for moderate to severe Ulcerative Colitis (UC), in terms of both effectiveness and safety, is still limited. In Colombia, the incidence of UC as well as the availability of these new therapeutic options has been increasing, also, patients are frequently more refractory to treatments with higher rates of hospitalizations and surgeries. The aim of this study is to describe the real-life experience in Colombian patients with UC treated with Tofacitinib. Methods descriptive observational study, patients with moderate-severe UC as defined by the American College of Gastroenterology Ulcerative Colitis Activity Index (ACG score) treated with tofacitinib in induction phase (10mg every 12 hours) and maintenance (5mg every 12 hours), in different reference centers nationwide. Therapeutic response was evaluated in endoscopic (Mayo score), paraclinical (CRP, ESR, fecal calprotectin, hemoglobin) and clinical (absence of abdominal pain, diarrhea and rectorrhagia) terms. Additionally, the frequency of adverse events, steroid use and extraintestinal manifestations were measured. Results 51 patients, 55% women, the average age was 37,14 years (range14-72). All patients had moderate to severe UC; 73% patients with pancolitis, and 21,6% with left colitis. The mean age at UC diagnosis was 29,77 (SD17,8) years (range 12.77-66,4). And the mean time between disease onset and tofacitininb initiation was 7,33 (SD17,1) years (range 0.001-22.72). 42/51(82,4%) patients had previously failed tumor necrosis factor inhibitors and 15/51(29,4%) had failed alpha4 beta7 integrin inhibitor (Vedolizumab). Six patients were naïve to any biologic drug. Ten patients had extraintestinal manifestations. During the induction phase, 68,6% achieved clinical remission, 58,8% endoscopic remission, and 60,8% paraclinical remission. During maintenance phases, information was obtained from 18 patients during the first 6 months, 16 of whom reported clinical, paraclinical and endoscopic remission, while information was obtained from 7 patients at 12 months, 5 of whom showed clinical remission, and 6/7 endoscopic and paraclinical remission. Four patients reported adverse events No thromboembolic or cardiovascular events were reported. Conclusion Tofacitinib is an effective and safe therapeutic alternative in the management of moderate-severe UC in our population. It is safe in patients with previous use of anti-TNF and anti-integrin, without presenting thrombotic or cardiovascular events. Also, it is a promising alternative in the bio-naïve patient. Its use in pediatric patients is off-label, the patients included presented clinical and paraclinical remission.

P177 C-reactive protein/albumin ratio: a novel biomarker for monitoring of the disease activity in Ulcerative Colitis patients

Abstract Background Fecal calprotectin (FC) is a reliable laboratory test for non-invasive assessment of disease activity in ulcerative colitis (UC) patients; it's high cost, absence of widespread availability and low patient adherence limits it's use as a potential surrogate for endoscopy. The association of higher C-reactive protein (CRP) and low albumin levels, both obtained from patient's sera, with disease acitivity in UC, is well established. C-reactive protein/albumin ratio (CAR) is suggested as a biomarker for evaluating disease activity in various inflammatory conditions. We aimed to evaluate association between CAR, FC, CRP and serum albumin values with disease activity in UC patients. Methods A single center, noninterventional retrospective chart review of adult UC patients treated with biologics at a tertiary center was performed. Routine clinical (stool frequency score – SFS, and rectal bleeding score – RBS), biochemical (CRP, serum albumin, FC), and endoscopic (Mayo Endoscopic Subscore – MES) findings were assessed prior to initiating biologics. Active UC was defined as SFS 2/3 + RBS 2/3 + MES 2/3. Differences between continuous variables were calculated using independent sample t-tests and Mann–Whitney U test. Sperman’s correlation and ROC curve analysis were carried out. The Z statistic was used to compare correlation coefficients and AUC. Results Total of 82 patients (52.2% females, mean age 40.3 ± 15.3 years, smokers 16.9%) with dominantly extensive UC (57.3%) were analysed. The CAR (0.175 vs 0.025; p=0.02) and FC (1363.5 vs 65.5; p=0.01) levels were significantly higher in active vs inactive UC patients. Positive correlation was observed between CAR (rs = 0.354, p = 0.01), FC (rs = 0.448, p = 0.001) and CRP (rs = 0.316, p = 0.005) with active UC. Although serum albumin (r's = - 0.093, p = 0.532) negatively correlated with disease activity it didn't reach statistical significance. There was no statistically significant difference between CAR and FC correlation coefficients. The area under the curve (AUC) for the diagnosis of active UC was 0.896 (SE: 0.058; 95% CI 0.73 - 0,983, p=0.015) and 0.994 (SE: 0.009; 95% CI 0.98 - 1, p=0.001) for CAR and FC, respectively. Although AUC for FC was higher compared to CAR it didn’t reach statistical significance (p = 0.1). The cut-off value associated with the active UC for CAR was 0.06 (sensitivity 77,2%, specificity 100%), and 120 mcg/g for FC (sensitivity 97.6%, specificity 100%). Conclusion There is good correlation between CAR and clinical as well as endoscopic disease activity in patients with UC, comparable to FC. CAR could be offered as a cheap and practical biomarker for detection of active UC disease.

P823 Biologic Penetration, hospitalization rates and need for major abdominal surgery in inflammatory bowel diseases: a comparative observational study between pediatric and adult patients

Abstract Background There is lack of epidemiological data in regard to the accurate situation of Inflammatory Bowel Disease (IBD): Crohn’s disease (CD) and ulcerative colitis (UC) in Brazil. It is known that both diseases' progression is variable and the chronic iinflammation results in structural bowel damage. Comparative data between adult and pediatric patients in the IBD field, regarding different outcomes, is lacking globally. We aimed to analyze the proportion of use of biologicals, need for major abdominal surgery and hospitalizations in CD and UC , between adult and pediatric patients. Methods Cross-sectional and multicenter study. Data was collected from all consecutive IBD patients seen as outpatients or admitted to hospital, from 2015 – 2021, in two IBD tertiary centers from a capital from south Brazil. We included all patients with clinical, endoscopic, radiological or histological diagnosis of CD and UC. Patients with unclassified colitis or without available data in medical records for investigating variables of interest were excluded. Patients were classified in two main groups (CD and UC) and in two subgroups each, according to age range: adults and pediatrics. Analyses were made by frequency, proportion, Fisher’s exact test and Chi-squared test, through software IBM SPSS Statistics 28. Results Eight hundred and twenty-nine patients were included: 509 with CD (378 adults/131 pediatrics) and 320 with UC (225/95). There was significantly difference between diseases in the proportion of biological use 75.0% in CD and 31.6% in UC (p<0.001), surgeries 49.7%/14,1% (p<0.001) and hospitalizations 58.9%/30.9% (p<0.001), respectively. In CD, there was no difference regarding biological use (80.2% in pediatric group vs. 73.3% in adults; p=0.129), surgeries (46.6% vs. 50.8%; p=0.419) and hospitalizations (64.9% vs. 56.9%; p=0.122). There was significantly difference in biological use (40.0% vs. 28.0%; p=0.048) and hospitalizations (47.4% vs. 24.0%; p< 0.001) in UC and there was no difference regarding surgery necessity between age ranges (17.9% vs. 12.4%; p=0.219). Conclusion There was a higher proportion of biological use, surgery and need for hospitalizations in CD as compared to UC. Comparing age ranges, pediatric patients with UC used more biologicals and required more hospitalizations than adults, but there was no difference in the need for abdominal surgery. In CD, there was no significant difference in the three main outcomes, between the age groups.

P207 Colonic location at diagnosis of pediatric-onset Crohn’s disease is associated with a pejorative disease course: a two decades population-based study

Abstract Background Crohn's disease (CD) location would influence the risk of complications and therapeutic strategies. The objective of this study was to compare the clinical presentation at diagnosis and the natural history of colonic CD in comparison to ileal CD and ulcerative colitis (UC) in pediatric-onset inflammatory bowel disease. Methods All children (< 17 years) with a diagnosis of CD or UC made between 1988 and 2011 in a population-based registry were followed retrospectively until 2013. Presentation at diagnosis, risks of complicated disease, surgery, hospitalization and exposure to treatments in ileal CD (L1), colonic CD (L2) and UC were compared. Disease location was defined at diagnosis. In case of extension of the disease (L1 or L2 to L3), follow-up was censored. Results A total of 215 L1 patients, 234 L2 patients and 337 UC patients were included. At diagnosis, the proportion of males (L1 53.5%; L2 53.4%; UC 42.7%; p=0.012), age at diagnosis (15.0; 13.7; 14.0 years; p=0.003), family history of IBD (12.6%; 12.7%; 5.0%; p=0.005), diagnostic delay (3.0; 3.0; 2.0 months; p=0.001) and smoking prevalence (11.6%; 8.1%; 5.6%; p=0.041) were different between the three groups. Bloody stool and diarrhea at diagnosis was observed in respectively 14.9%, 44.4%, and 91.1% (p < 0.001) and 47.0%, 71.8%, and 65.0% (p < 0.001) of L1, L2 and UC. At diagnosis, granuloma was identified in 12.6% of L1 patients and 31.2% of L2 patients (p<0.001). The risk of extension to L3 was significantly higher in the L2 group than in the L1 group (at 5 years - 37% vs. 14%, p<0.001). Compared to L1 location, L2 was associated with a lower risk of luminal fistula (HR 0.41 [0.21-0.79], p=0.008) but a higher risk of anoperineal lesion (HR 2.11 [1.29-3.45], p=0.003). The prevalence of extra-intestinal manifestations, articular (p<0.001) and cutaneous (p<0.001) was higher in L2. While the risk of surgery was significantly higher in case of L1 (at 5 years – L1 37%, L2 13% and UC 13%; p<0.001), the risk of hospitalization (at 5 years - 22%, 39% and 33%; p=0.01), exposure to corticosteroids (at 5 years - 55%, 69% and 67%; p<0.001), immunosuppressants (at 5 years - 47%, 61% and 42% - p<0.001) and anti-TNF (at 5 years - 16%, 35% and 22%; p<0.001) were higher in case of L2. Conclusion The clinical presentation at diagnosis and natural history of ileal and colonic CD differ significantly. Colonic location is associated with a high risk of perianal CD, extra-intestinal manifestations, hospitalization as well as exposure to steroids, immunosuppressants and anti-TNF. These differences may justify different therapeutic strategies in the future.

P629 Real-life treatment persistence and treatment outcomes of Finnish patients with Inflammatory Bowel Disease receiving vedolizumab as first-line biological treatment

Abstract Background Vedolizumab is a gut selective anti-lymphocyte trafficking monoclonal antibody directed towards the integrin α 4β 7. The efficacy and safety of vedolizumab in the treatment of adults with moderately to severely active Crohn’s disease (CD) or ulcerative colitis (UC) are well-established in randomized clinical trials and real-world evidence studies. However, real-world data are limited on vedolizumab therapy used on biological naïve CD and UC patients. Here, we analyse treatment persistence, treatment outcomes, and reasons for treatment discontinuation of vedolizumab as a first-line biological treatment in CD and UC patients in a Finnish real-world setting. Methods This was an observational, retrospective, multi-centre registry study. The cohort included all adult (≥ 18 years of age) patients with a diagnosis of CD or UC who initiated vedolizumab as a first-line biological treatment between May 2014, and June 2020, in the five Finnish university hospital districts. Clinical data were collected from electronic health records. The Prescription Register by the Finnish Social Insurance Institution was the data source for prescribed IBD treatments. Treatment persistence was defined as the time from initiation to discontinuation of therapy. P-values were calculated by using paired t-test. Results The cohort consisted of 54 CD and 69 UC patients treated with vedolizumab as a first-line biological treatment. The mean ages were 61.9 and 56.8 years for CD and UC at the time of vedolizumab start, respectively. Disease duration was 10.9 years in CD and 10.5 years in UC. Altogether, 35.8% of patients had a history of cancer. At month 12, treatment persistence was 84.9% (n=44) in CD and 64.7% (n=41) in UC cohorts (Figure 1). Most vedolizumab discontinuations (CD, n=11; UC, n=26) were due to lack of efficacy, and treatment discontinuations due to adverse events were rare (n<5). Vedolizumab was associated with favourable treatment outcomes, as indicated by efficacy improvements at 12 months compared with baseline in Harvey-Bradshaw Index (CD, 3.2 vs 4.9, p=0.025), Partial Mayo Score (UC, 3.8 vs 5.1, p=0.021), Physician’s Global Assessment (CD, 0.9 vs 1.8, p<0.001; and UC, 0.4 vs 2.1, p<0.001) scores, and positive endoscopic Mayo Score (UC, 0.7 vs 2.2, p<0.001) and biochemical outcomes. Conclusion Vedolizumab showed high treatment persistence and positive treatment outcomes such as improvements in efficacy, endoscopic activity, and biochemical parameters when used as the first-line biological treatment.

P876 Disease course of Inflammatory Bowel Disease Unclassified in adult patients : a population-based study (1988-2014)

Abstract Background Inflammatory bowel disease unclassified (IBDU) represents 1 to 20 % of inflammatory bowel disease (IBD). There are few data on the natural history of IBDU. The aim of this study was to evaluate the disease course of IBDU in a population-based cohort. Methods All patients diagnosed with IBDU between 1988 and 2014, aged > 17 years at diagnosis, and prospectively enrolled in a population-based registry, were followed until diagnostic reclassification as Crohn’s disease (CD) or ulcerative colitis (UC), or date of loss of follow-up. Clinical presentations at diagnosis of IBDU, CD or UC were compared. The probability of diagnostic reclassification of IBDU during follow-up was studied by the Kaplan-Meier method, and its variation factors by Cox models. Results A total of 480 patients with an initial diagnosis of IBDU were included, representing 3.6% of incident IBD cases in the registry. The probability of IBDU diagnosis within IBD significantly decrease over the study period (6.2% from 1988 to 1996, 3.3% from 1997 to 2005 and 2.1% from 2006 to 2014, p<0.0001). Small bowel exploration and gastroscopy rates at diagnosis were significantly lower in IBDU than in UC and CD. Of these 480 patients, 388 were followed up, with a median duration of 2.4 years (IQR: 0.5-9.5). The cumulative probability of reclassification of IBDU was 17% at 1 year, 41% at 5 years, and 54% at 10 years (median time since initial diagnosis: 8.0 years (IQR: 6.3-12.0)); the probability of reclassification to UC was 10% at 1 year, 22% at 5 years, and 30% at 10 years, and to CD was 5%, 13%, and 18%, respectively. The median time to diagnostic reclassification decreased over the study period (14.3 years (IQR: 9.0-17.2) in 1988-1996, 5.1 years (3.1-9.4) in 1997-2005, and 5.6 years (3.4-8.3) in 2006-2014, p<0.0001), in parallel with an increased rate of reclassification during the most recent periods of diagnosis (HR: 1.76 in 1997-2005 and 1.67 in 2006-2014). Presence of rectal bleeding at diagnosis and 1st degree family history of IBD were respectively associated with risk of reclassification to UC (HR: 1.65, p=0.044) and CD (HR: 2.72, p=0.0134). Exposure to anti-TNF increased significantly after diagnostic reclassification (HR: 4.05, p<0.0001). During follow-up, 13.4 % of patients with IBDU required surgery. Conclusion In this population-based study, almost half of the patients with an initial diagnosis of IBDU were reclassified during follow-up, after a median time from diagnosis of 8 years. The rate of IBDU and the delay to diagnostic reclassification decreased over the study period, presumably due to an improvement in primary diagnostic evaluation.

DOP16 Anti-integrin αvβ6 autoantibodies predate Ulcerative Colitis diagnosis by up to 10 years and are associated with adverse disease-related outcomes

Abstract Background Biomarkers for predicting the development of Ulcerative Colitis (UC) and disease-related complications are lacking. Anti-integrin αvβ6 IgG autoantibodies (anti-αvβ6) have been recently described in patients diagnosed with UC. Here, we sought to determine if anti-αvβ6 autoantibodies predate UC development and to study associations between anti-αvβ6 and disease outcomes in newly diagnosed UC patients. Methods In a unique pre-clinical IBD cohort from the PRoteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects (PREDICTS), anti-αvβ6 were measured in longitudinal pre-diagnosis serum samples from 82 subjects who later developed UC as well as in 82 matched subjects that did not develop IBD (HC). Sample A was at the time of UC diagnosis, Sample B was at a median of 2 years before Sample A, Sample C was at a median of 4 years before Sample A and Sample D was at a median of 10 years before Sample A. In a distinct, external validation cohort (the Crohn’s and Colitis Canada Genetics Environment Microbial (GEM) Project), we tested samples from 12 subjects who later developed UC and compared those with 49 matched subjects who remained asymptomatic. Further, anti-αvβ6 were measured in 2 incident IBD cohorts (COMPASS, n=55 and OSCCAR, n=104 UC subjects) and associations between anti-αvβ6 and adverse UC-outcomes were defined using Cox proportional-hazards model. Results Anti-αvβ6 were significantly higher in the PREDICTS cohort among individuals who developed UC compared to HC up to 10 years prior to diagnosis (Figure 1A). The anti-αvβ6 seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 timepoints. Additionally, the predictive performance of anti-αvβ6 autoantibodies as assessed via area under the receiver operator curves (AUROC) with 10-fold cross validation was at least 0.8 up to 10 years before diagnosis (Figure 1B). Elevated levels of anti-αvβ6 in pre-clinical UC samples were further validated in the GEM cohort (Figure 1C). Finally, high anti-αvβ6 were associated with a composite of adverse UC-outcomes including hospitalization, disease extension, colectomy, systemic steroid use and/or escalation to biologic therapy in both incident cohorts (Figure 1D). Conclusion Anti-integrin αvβ6 autoantibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.

P783 Symptom Improvement of ulceRative colitis after an Injection dose of Ustekinumab in Japanese clinical practice, measured using patient-reported outcomes (SIRIUS) study, Interim Analysis

Abstract Background Ustekinumab (UST) is treated to moderate to severe adult ulcerative colitis (UC) patients. We conducted the SIRIUS study (Symptom Improvement of ulceRative colitis after an Injection dose of UStekinumab in Japanese clinical practice, measured using patient-reported outcomes (PRO)) to record daily symptoms for 8 weeks after the introduction of intravenous ustekinumab in moderate to severe UC patients, which aimed to reveal early response patterns of symptoms during the induction of remission period with ustekinumab, and to explore symptoms suitable for monitoring and predicting treatment effect. This interim analysis focuses on stool frequency (SF) and rectal bleeding (RB) scores in the PRO-2 during the 8-week induction period. Methods This single-arm prospective observational study conducted in 23 centers in Japan aimed to recruit 140 patients with moderate-to-severe UC between July 2021 and July 2022. RB score, SF score, abdominal pain, nocturnal diarrhea, tenesmus, and patient perception of improvement were recorded daily using a smartphone app. To be eligible for the study, participants must have a documented diagnosis of UC, be ≥16 years of age, have UC (partial Mayo score of 5~9), have had an inadequate response or intolerance to prior UC therapies, and be able to understand and complete PRO instruments using a smartphone. Patients who had prior exposure to UST, history of extensive colectomy, or were hospitalized when UST was started were excluded. Results In this analysis,137 patients were included. Seventy-four (54.4%) patients were male and the median age was 35 years. Seventy-six (55.9%) patients were Bio-naïve. This high proportion of Bio-naïve patients reflects the fact that UST can be used for Bio-naive patients without restrictions in the Japanese health insurance. At weeks 2 and 4, 56 (41.2%) and 57 (41.9%) patients attended outpatient clinics, respectively. The data collection rate of the PROs was 95%. Mean SF and RB scores were demonstrated stratified by prior treatment with Bio (Figure 1&3). Significant decreases in mean SF and RB scores were observed within 1 week in both Bio-naïve and -experienced patients. the time-course change in SF was similar between Bio-naïve and -experienced patients, but the decrease in RB scores was greater in the Bio-naïve patients than the Bio-experienced patients. Conclusion A daily PRO-based analysis was conducted in the Sirius study to monitor symptoms during the first 8 weeks after the introduction of UST in patients with moderate-to-severe UC. This interim analysis revealed that SF and RB scores started to decrease within 1 week, demonstrating a rapid symptomatic response to UST. The analysis of the other PROs and predictors of efficacy will be performed in further studies.

P704 The effect of antiTNFα and anti-integrin agents on liver steatosis in inlamatory bowel disease patients with non-alcoholic fatty liver disease

Abstract Background Non-alcoholic fatty liver disease (NAFLD) has been recognized as a common condition in inflammatory bowel disease (IBD) patients and could contribute to their overall morbidity. Anti-TNFα and anti-integrin agents have been the cornerstones of IBD therapy with proven clinical efficacy, but it΄s effect on liver steatosis is still unclear. Therefore this study aimed to evaluate the impact of anti-TNFα and anti-integrin agents on liver steatosis in IBD patients with proven NAFLD. Methods A total of 32 IBD patients with NAFLD, naive to biologic agents, 21 with an established diagnosis of ulcerative colitis, and 11 with Crohn’s disease were prospectively recruited for the study. NAFLD was defined by a baseline attenuation (ATT) coefficient measured by shear-wave (SW) elastometry of 0.63 dB/cm/MHz or higher and a baseline alanine aminotransferase (ALT) of more than 40 IU/L for males and 35 IU/L for females. The exclusion criteria were alcohol use (consuming > 40 g alcohol/day for men and > 20 g/day for women in the preceding 12 months), concomitant chronic viral hepatitis, the presence of hepatic carcinoma, biliary disease, drug use, and hypothyroidism. A total of 11 patients were treated with Adalimumab, 9 patients with Infliximab, and 12 patients with Vedolizumab. The SW elastometry and laboratory exams were performed at the moment of therapy induction and after the 6-month course of therapy. Results The anti-TNFα treatment significantly reduced liver steatosis according to the ATT coefficient dynamic (0.70±0.07 vs 0.66±0.03 dB/cm/MHz, p=0.021) and ALT level dynamic came on the verge of statistical significance (44±7 vs 40±6 IU/L, p=0.058). We did not observe a significant difference between the Infliximab- and Adalimumab-treated patients. The anti-integrin agent, Vedolizumab, had no impact on liver steatosis (0.66±0.03 vs 0.67±0.04 dB/cm/MHz) and ALT level dynamic (47±4 vs 45±5, p=0.29). Both groups of agents had no impact on patients’ lipid profile dynamic. We found no correlation between liver steatosis level and CRP and fecal calprotectin dynamic. Conclusion In the short term, we observed potential beneficial effects of anti-TNFα agents on liver steatosis of IBD patients with proven NAFLD.

P209 Delayed IBD diagnosis increases risk of requiring biologics in first 4-years - an Inception cohort study

Abstract Background Delays in diagnosis can be due to patient and health-system related factors. The impact of such delays in Inflammatory Bowel Diseases (IBD), particularly on biological therapies, continues to be of interest. The aim of the study was to investigate if delays could predict need for biologics and report on related adverse outcomes (AOs). Methods New patients referred for suspected IBD to a single tertiary care centre between Jan 2013 to Dec 2017 were identified using EMR. For this study, delay-types and cut-off times for each type were set based on best average hospital waiting times. The reasons for delays until start of treatment were recorded; data on the start of biologics, duration, and reasons for switch (if required) were recorded. Data was analysed using multiple Pearson correlations and Cox proportional Hazard model to determine whether any delay-types could predict need for biologics and compare the risk between patients with or without delay. Results 105 patients were identified using stringent criteria (M=58; median age=32y) with a median follow-up of 55 months. 65, 27 and 13 patients had a final diagnosis of Ulcerative colitis, Crohn’s disease, and Unclassified colitis respectively, and were analysed collectively. A model that combined delay in seeking medical attention, and time taken from specialty review to index endoscopy exhibited the best predictive power with average AUROC of 0.67. When individual delay-types were analysed, it was noted that most delay-types increased the risk of biologic use: a) delay in seeking medical attention [OR-1.08(1.03 1.17)] b) delay from GP referral to specialty review [OR-1.10(1.0 1.23)] c) delay from specialty review to index endoscopy [OR-1.09(1.01 1.21)] On further analysis, there was a statistically significant increase noted in the risk of requiring biologics at any time during the follow-up period. Fig 1A illustrates survival without biologics when there is a delay of >2 weeks in seeking medical attention (p=0.042). Figure 1B illustrates survival without biologics when there is delay of >6 weeks from GP referral to index endoscopy (p=0.021). Figure 1A- Patient-related delay of >2weeks and risk of needing biologics (p=0.042) Figure 1B- Health-system related delay of >6weeks and risk of needing biologics (p=0.021) Conclusion The risk of requiring biologic therapy is higher in those patients who have faced any type of delay in their diagnosis of IBD. A patient-related delay of >2weeks and cumulative health-system related delay of >6weeks increase the risk of requiring biologic therapy at any time during their follow-up. Both primary and secondary care must work to reduce any delays as this has long-term implications for patients and economic implications for health care providers.

P190 Delayed IBD diagnosis leads to worse outcomes over years, with multiple implications on service delivery

Abstract Background Delays in diagnosis can be patient and health-system related. Such delays have been reported to increase overall complications in Inflammatory Bowel Diseases (IBD). The aim of our study was to report on the impact of delays on IBD-related adverse outcomes (AOs), as hospitals currently face challenges with long waiting lists in the post-COVID-19 era. Methods New patients referred for suspected IBD to a single tertiary care centre between Jan 2013 to Dec 2017 were identified using EMR. A cut-off time was set for each delay-type based on best average hospital waiting times. Reasons for delays until start of treatment and data on pre-defined AOs (steroid & other rescue therapies, hospitalisations, surgery) were recorded for each patient until end of June 2021. Data was analysed using multiple Pearson correlations and Cox proportional Hazard model to determine if there was a difference in survival without AOs between patients with and without delay. Results 105 patients were identified using strict criteria (M=58; median age=32y) with a median follow-up of 55 months. The most frequent presenting complaints were abdominal pain (44, 41.9%), loose stools (40, 38.1%), bloody diarrhoea (37, 35.2%) and bleeding per-rectum (33, 31.4%). 65, 27 and 13 patients had a final diagnosis of Ulcerative colitis, Crohn’s disease and Unclassified colitis respectively, and were analysed jointly. The longest delay-types noted: patients seeking medical attention (median=4 months; range 1 to 84 months); arranging gastroenterology clinic review after GP referral (median=5 weeks; 1 to 30 weeks); and waiting for index endoscopy (median=3 weeks; 1 to 36 weeks). Patient stratification based on delay-type, using specific cut-off times for each showed a statistically significant difference in survival without AOs for all (when comparing delay vs no delay). - delay in seeking medical attention (cut-off=1m; p=0.004) (Fig 1A) - delay in GP referral to specialty review (cut-off=1w; p=0.048) - delay in index endoscopy (cut-off=4w; p=0.01) (Fig 1B) - delay in starting treatment (cut-off=4w; p=0.03) Fig 1A-Time to seek medical attention (survival without AOs; p=0.004) Fig 1B-Time from clinic review to index endoscopy (survival without AOs; p=0.01) Conclusion Several bottlenecks of delays increase AOs in IBD over the follow-up period. A delay as short as a week, between GP referral to specialty review, is significant in determining AOs, relevant for specialist IBD centres particularly in the post-Covid period. Endoscopy units should prioritise suspected IBD patients to reduce AOs, which is likely to have implications on service delivery and planning. Long delays observed in patients seeking medical attention highlights the need for better patient education in the community.

P372 Endoscopic ultrasonography in the differential diagnosis of Ulcerative colitis and Crohn's disease.

Abstract Background Background & Aim: Differential diagnosis between Crohn's disease (CD) and ulcerative colitis (UC) could be a challenge, since the endoscopic and clinical characteristics of both may resemble. Furthermore, radiological methods do not provide complete information.To assess the possibilities of endoscopic ultrasonography (EUS, endosonography) for the differential diagnosis between ulcerative colitis (UC) and Crohn's disease (CD) in doubtful or controversial cases. Methods Methods: We examined 50 IBD patients during the active phase: CD-28 patients (M: W=16:12,average age 27.3 ± 0.7 years), UC-22 patients (M: W=8:14, average age 32 .6 ±1.7 years). The control group included 15 patients without UC or CD. All patients underwent EUS colonoscopy for measurement of wall thickness, assessment vascularization degree and compression elastography was perform. Results Results.It was found that wallthickness in CD was 5.66 ± 0.36 mm, was 1.5 times more than in UC (3.96 mm ± 0.13 mm) and 2 times more than in controls(2, 62 ± 0.11mm). Frequency of all intestinallayers in CD was noted in 68% vs 9% in UC (p < 0.02). On the contrary, in UC, wall thickening due to the mucosa and submucosa was significantly more common than in CD (82% and 7.2%, respectively, p < 0.05). Vascularizationdegree of colon wall in UC in most cases was reduced, while in CD, on the contrary, it was increased. According to elastometry, type 1 staining according to Ueno E., corresponding to the soft-elastic structure of colon wall, was detected in UC in 78% of cases, in CD in 54%. Type 2 according to Ueno E. was verified in 22% in UC, in 45% in CD, which indicates the presence of fibrosis foci in colon wall, mainly in CD patients. Conclusion Conclusion. The obtained EUS data can be as criteria for differential diagnosis between UC and CD in compound cases and clarify the presence and degree of fibrosis, for example, if strictures in CD.