Extensive Colitis Research Articles

OP09 Long-term Colectomy rates of Ulcerative Colitis over 40-year of Different Therapeutic eras – Results from a Western Hungarian Population-based Inception Cohort between 1977–2020

Abstract Background Few population-based studies have investigated the long-term colectomy rates of ulcerative colitis (UC). The present study is a continuation of the Veszprem IBD population based cohort with a follow-up of the incidence and disease course for over 40 years. We aimed to assess the colectomy rates over 40 years of different therapeutic eras in a prospective population-based inception cohort from Veszprem Province, Western Hungary. Methods Patient inclusion lasted between January1,1977 and December31, 2018. Patient follow-up ended December 31,2020. Both in-hospital and outpatient records were collected and comprehensively reviewed at diagnosis and during clinical follow-up. Disease extension was evaluated based on the Montreal classification. Colectomy rates and disease course were examined in three different eras based on the time of UC diagnosis; cohort-A(1977-1995),cohort-B(1996-2008), and cohort C(2009-2018). Results Data of 1,370 incident UC patients were analyzed (male/female: 702/668; median age at diagnosis: 37 years(y) [IQR: 26-51]), with a median of 17y (IQR 9-24) follow-up. Table 1. The overall colectomy rate was 76/1,370 patients during the total follow-up. The proportion of extensive colitis at diagnosis increased over time (24.2% / 24.3% / 34.9% in cohorts A/B/C; p=0.001). Overall immunosuppressive therapy exposure was increasing in the cohorts (11.3% / 20.9% / 34.4%; p<0.001), as well as the probability of biological therapy initiation within 5 years of diagnosis (0.0±0% / 3.3±0.7% / 13.9±1.8%; pLogRank<0.001). Figure 1. There was no significant difference in the cumulative probability of proximal disease progression from proctitis (E1) to left-sided colitis/extensive colitis (E2/E3) or from left-sided colitis (E2) to extensive colitis (E3) over time in cohorts A, B, and C (Long-rank=0.482). Figure 2. The cumulative probability of colectomy in the total population was 4.1±0.6% after 10 years, 6.3±0.8% after 20 years, and 8.8±1.2% after 30 years. There were no statistically significant differences in the cumulative probability of colectomies between cohorts A/B/C: 1.7±0.7% / 2.2±0.6% / 3.7±1.0% after 5 years; 3.5±1.0% / 3.9±0.8% / 4.5±1.2% after 10 years; and 6.9±1.4% / 5.3±1.0% (cohorts A/B) after 20 years [pLogRank=0.447]. Figure 3. Extensive disease (HR 2.3;95%CI 21.60-3.37) and continuous uncontrolled disease activity (HR 6.89;95%CI 4.15-11.46) were independent predictors for colectomy. Table 2. Conclusion No differences in proximal disease progression and colectomy rates have been observed in the incident UC patients over 40 years despite increasing use of immunomodulators and biological therapies.

P618 Long-term real-world data of Ustekinumab in Ulcerative Colitis – the Stockholm Ustekinumab study – STOCUSTE

Abstract Background Background: Ustekinumab (UST) is an anti-interleukin-12/23 antibody in the treatment of inflammatory bowel disease (IBD), mainly used in patients failing anti-TNF-agents. The STOCUSTE study includes patients treated at four hospitals in Stockholm to provide long-term real-world data. Methods Methods: This was a retrospective study including patients diagnosed with ulcerative colitis and treated with UST between years 2016 and 2021. The patients were followed from start of UST until withdrawal of treatment for any reason, or until end of study follow-up, July 31, 2021.We assessed disease activity; Physician Global Assessment (PGA); Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score, laboratory parameters and drug persistence. The primary outcome was remission (PGA = 0) and response (decrease PGA ≥ 1 from baseline) at 3 and 12 months, respectively. Results Results: 96 patients, 44 women and 52 men were included. The patients had either extensive colitis (68%), left-sided colitis (29%) or proctitis (3%). All but two patients were anti-TNF-experienced; 94 (98%) had failed ≥1, 59 (61%) ≥2 and 34 (35%) ≥3 anti-TNF-drugs. At inclusion 92 patients (96%) had active disease and 4 patients were in remission, 48 (50%) were on oral or topical corticosteroids, 13 (14%) had thiopurines. At 12 months only 9% were on oral or topical corticosteroids. Among patients who were treated with UST, 9/71 (6%) were in remission at 3 months, and 26/33 (78%) patients were in remission at 12 months. Withdrawal from treatment during the first 12 months was 36 (38 %), mainly due to persisting disease activity (20%); 8% were withdrawn due to adverse events, 2% needed bowel surgery, and 2% were lost to follow up. Conclusion Conclusions: In this group of difficult-to-treat patients with ulcerative colitis, Ust was shown to be effective in the majority, with high drug persistence at 12 months in combination with a favorable safety profile.

P796 Effectiveness and safety of ustekinumab for patients with ulcerative colitis: A single-centre retrospective study

Abstract Background Ustekinumab, a monoclonal antibody directed against the interleukin 12/23 p40 subunit, was approved worldwide in 2020 for the treatment of ulcerative colitis. The efficacy of ustekinumab in inducing and maintaining remission in moderate to severe ulcerative colitis was demonstrated in the phase 3 clinical study, the UNIFI trial; however, real-world data on the effectiveness and safety of ustekinumab for patients with ulcerative colitis is still scarce. We aimed to investigate the real-world effectiveness and safety of ustekinumab in patients with ulcerative colitis. Methods This was a single-centre retrospective study enrolling patients with ulcerative colitis who were aged 16 years or more and administered ustekinumab between March 2022 and March 2022 at Toho University Sakura Medical Center, a tertiary center. Data were extracted by chart review. Ustekinumab was administered as a single intravenous infusion (approximately 6 mg/kg) followed by 90mg subcutaneous injection at week 8 and then by 90mg subcutaneous injection every 8-12 weeks. The endpoints were 1) the proportion of patients achieving symptomatic remission, defined as a rectal bleeding score of 0 and a stool frequency score of 0 or 1 in patient-reported outcome-2 (PRO-2), at week 8, 2) time to discontinuation, and 3) safety during the observation periods. Results We enrolled 53 patients in this study, with a median age of 45 years (interquadrant range: 27-57). Thirty patients (56.6%) were male and 23 (43.4%) were female. The majority of patients (n=39; 73.6%) had extensive colitis. Notably, 21 (38.9%) patients were naïve to advanced therapies. Thiopurines had been administered to 24 (45.3%) patients. Twenty-one (39.6%) patients achieved symptomatic remission at week 8 after a single intravenous infusion. The proportion of patients with symptomatic remission was numerically higher in advanced therapy-naïve patients compared with advanced therapy-experienced patients (47.6% versus 34.4%) (Figure 1). Univariate analysis failed to identify clinical predictors for symptomatic remission at week 8. The time to discontinuation were significantly longer in advanced-therapy naïve patients compared with advanced therapy experienced patients, with a median observation period of 296 days (Figure 2). As for safety, one patient discontinued ustekinumab due to skin disorder. One death due to pneumonia was observed, which was unrelated to ustekinumab. Conclusion Ustekinumab was effective and safe in the real-world setting. Advanced-therapy naïve patients were more likely to continue ustekinumab compared with advanced therapy experienced patients.

P846 Epidemiological and Clinical Characteristics of Inflammatory Bowel Diseases in Patients from Greece

Abstract Background There are few reports from Greece about the epidemiological and clinical features of inflammatory bowel diseases (IBD), which were mainly evaluated in retrospective studies with data collection from hospital registries. We aimed to determine the epidemiological profile and clinical features as well as to detect any differences between patients with Crohn’s disease (CD) and ulcerative colitis (UC), based on retrospectively-prospectively collected data from a cohort of IBD patients followed in daily clinical practice. Methods Patients with biopsy-confirmed IBD aged 10–90 years old were included in the study. A comprehensive questionnaire was used to collect data on each site visit from July 2018 until March 2022. Logistic regression analysis and chi-squared test were used to compare the frequency of epidemiological and clinical characteristics between patients with UC and CD. Results We collected 300 patients diagnosed with IBD (180 with CD, 113 with UC, and 7 with indeterminate colitis). The median age of IBD patients was 42 years. The onset of disease in CD group was observed between 17 and 40 years of age in the majority of patients (58%). Ileocolonic location of CD was present in 70% of CD patients; 39% had stricturing behavior and 29% had perianal disease (abscesses and fistulas). CD patients developed more often aphthous stomatitis (34%) than patients with UC (13%, OR 3.45; 95% CI: 1.76-6.78; P< .001). Patients with CD had a 20-fold increased risk to undergo a surgical procedure (OR 19.87; 95% CI: 6.03-65.48; P< .001), mainly enterectomy (26%), as shown in table 1. At study entry, C-reactive protein (CRP) elevation was more frequently present in CD compared to UC patients (OR 1.93; 95% CI: 1.04-3.59; P< .05). Most patients with UC had extensive colitis (56%). Mesalamine was predominantly used in UC patients (81% vs 46% in CD, P< .005), and sulfasalazine and thiopurines in CD patients (60-70% vs 9-13% in UC, P< .005), as shown in table 2. The most commonly used anti-TNF agent was Infliximab, mainly in CD patients (24% vs 4% in UC, OR 0.12; 95% CI: 0.04-0.34; P< .001). Adalimumab was used in 12% of IBD patients and Vedolizumab in 8%. Around 4% of patients with complicated CD received Ustekinumab. Tofacitinib was used in 2% of patients with severe complicated UC and extraintestinal manifestations. Enteral diet (Modulen®) was used in 6% of CD patients and in only 2% of UC patients with severe UC pancolitis. Conclusion In this retrospective-prospective cohort study of 300 patients with IBD, CD patients had a significantly higher risk of developing aphthous stomatitis and increased levels of CRP. CD patients also required more often treatment with anti-TNF agents and immunosuppressants, and a surgical procedure, mainly enterectomy.

P849 Exposure to metals and minerals in hair samples of patients with preclinical inflammatory bowel disease

Abstract Background Previous data have shown that the inflammatory process underlying ulcerative colitis (UC) and Crohn’s disease (CD) can start years before the diagnosis, but the role of triggering factors and environmental exposures is still unknown. Hair element analysis is a valuable and inexpensive screen for physiological excess or deficiency of certain elements. Our aim was to determine if patients with an incidental diagnosis of UC or CD demonstrate exposure of minerals or toxic metals in the years preceding the symptomatic onset of the disease. Methods We performed a prospective single-center study including all asymptomatic subjects with a diagnosis of UC or CD during the colorectal cancer screening program between January 2021 – June 2022 in Vizcaya (Basque Country, Spain). The diagnosis of IBD was established by a combination of clinical data, endoscopic findings suggestive of UC or CD, and after histologic confirmation. Cases were compared with a healthy non-IBD control population. An approximate hair sample of 0.25 g was obtained up to 3 months since diagnosis. We used a commercial kit that allows the investigation of 17 metals (Al, Sb, As, Ba, Be, Bi, Cd, Pb, Hg, Pt, Tl, Th, U, Ni, Ag, Sn, Ti) and 22 minerals (Ca, Mg, Na, K, Cu, Zn, Mn, Cr, V, Mo, B, I, Li, P, Se, Sr, S, Co, Fe, Ge, Rb, Zr). Descriptive statistics and non-parametric tests were used for comparisons between both groups. Results Three patients with preclinical IBD were included (median age 53 years; 67% male; all former smokers). Two of them had a diagnosis of UC (one left-sided colitis and one extensive colitis) and one with ileal CD. Extraintestinal manifestations were observed in one patient (33%). No family history of IBD was reported. Thirteen healthy controls with no relevant environmental exposures (median age 34 years; 69% female; 92% non-smokers). We found that cases demonstrated statistically significant higher concentrations of bismuth, sodium and boron compared to controls (Figure). In contrast, there was a lower exposure to uranium, zinc and germanium, with a trend towards lower copper levels among cases. Conclusion A range of environmental exposures can be identified during the preclinical phase of IBD. However, their relationship with the symptomatic onset and disease progression should be further explored.

P408 Dual therapy with vedolizumab and tofacitinib in refractory ulcerative colitis patients – single centre experience

Abstract Background Despite significant impact biological treatment had on prospects of patients with ulcerative colitis, there is still a substantial proportion of patients with non-response to multiple drugs. Beside dose optimization and selection of agents with different mechanism of action, combination of two different targeted molecules has recently been proposed in cases where inflammatory activity cannot get under control. This case series provide promising results of vedolizumab in combination with tofacitinib in treatment resistent UC patients. Methods Patients with complicated refractory or acute severe colitis, in whom combined treatment with vedolizumab and tofacitinib based on shared clinical decision was started, were included. Data on demographics, treatment details, persistence and disease activity including laboratory markers, clinical activity index (partial Mayo score) during regular visits every 2 months up to one year after treatment initiation were collected. Currently available data were analyzed at 6 months. Endoscopic disease activity before and 2-6 months after dual therapy start was evaluated. Results In total, 21 UC patients who were started on vedolizumab and tofacitinib dual therapy between Oct 2020 and Sep 2022 were included. Tofacitinib dose was 10mg bid in all patients and all patients on vedolizumab maintenance treatment had intensified dosing regimen. Mean patients age was 36.4±8.1 years, 47.6% were males and 52.4% females. Mean disease duration at baseline was 7.5±5.8 years. All patients had advanced disease including 61.9% with extensive colitis and 38.1% with left-sided colitis. At least 2 previous biologics in monotherapy were used in 85.7% of patients. Mean pMayo score at baseline was 5.6±1.9 and decreased to 0.5±0.9 at 6 months (p=0.0020). Initial fecal calprotectin in the cohort was 1829±2520µg/g vs. 225±257µg/g at 6 months (p=0.0068) and mean CRP changed from 11.4±17.1 to 5.4±7.2mg/l (p=ns). Endoscopic Mayo score before dual treatment initiation averaged 2.8±0.5 indicating mostly severe disease activity and decreased to 1.4±1.2 during follow-up endoscopy (p=0.0005) with half of the patients having only no to mild activity (eMayo 0-1). Up to now, dual therapy had to be terminated in 7 patients – 4 patients failed on the treatment, 1 refused to continue with dual therapy, 1 patient experienced adverse event (liver lesion) and 1 was discontinued for reimbursement reasons. Conclusion In the presented small cohort of patients with refractory ulcerative colitis, in whom other modalities were depleted or colectomy was considered, combined vedolizumab and tofacitinib treatment has proven to be efficient with half of the patients reaching mucosal healing after 6 months and without raising significant safety concerns.

P562 Real world effectiveness and safety of ozanimod: One-year follow-up from a large tertiary center

Abstract Background Ozanimod is a first in class sphingosine-1-phosphate receptor modulator approved by the FDA for moderately-to-severely active ulcerative colitis (UC). Real world data describing use of ozanimod are limited. We provide one-year follow up results of our patient cohort treated with ozanimod. Methods This prospective, observational cohort study includes consecutive patients who initiated ozanimod at our center. We collected demographic, clinical, and laboratory data. Clinical disease activity was assessed using the Simple Clinical Colitis Activity Index (SCCAI). Clinical response was defined as a decrease in ≥3 points in SCCAI from baseline with only patients with clinically active disease included in the analysis, and clinical remission was defined as an SCCAI score of ≤ 2. Results 47 patients have initiated ozanimod therapy at our center: 45 patients with ulcerative colitis (UC), 1 patient with Crohn’s colitis and 1 patient with lymphocytic colitis. Only patients with UC were included in the effectiveness analysis. Demographics are in Table 1: in the UC cohort, the mean age was 40.6 ±16.6 years, mean disease duration was 9.6 ±9.2 years, 26 (58%) were male, 23 (51%) had extensive colitis, and 34 (76%) had previous advanced therapy exposure. 19 had baseline endoscopy with a mean Mayo endoscopic score of 2.6 ±0.5. Clinical response, remission, and corticosteroid free remission (CSFR) rates at weeks 2, 4, 10, 24, and 52 are in Figure 1. At week 10, follow-up was available for 41 patients: 18 patients (55%) achieved clinical response, 24 (59%) clinical remission, and 22 (54%) achieved CSFR. At week 52, follow-up was available for 30 patients: 5 (17%) achieved clinical response, 5 (17%) clinical remission, and 4 (13%) achieved CSFR. There were no significant differences between advanced therapy naïve and experienced patients, including when stratified by the number of previous advanced therapies or prior use of vedolizumab (Figures 2A+B and 3). Patients with a > 75% reduction in absolute lymphocytes had numerically greater induction clinical response and remission rates (80% vs 54%, p=0.4 and 75% vs 53%, p=0.4, respectively). 13 patients experienced adverse events (AEs): hypertension (n=2), transient nausea (n=2), fatigue (n=3), dry skin (n=2), transient liver enzyme elevation (n=2) and transient headache (n=3). Two AEs required discontinuation – hypertensive crisis in a patient with a prior dx of hypertension, and fatigue. There were no episodes of symptomatic bradycardia. Conclusion We present one-year real world follow-up of ozanimod in a largely treatment-refractory cohort of patients with UC, and describe modest one-year effectiveness and a safety profile that is not different from that described in the clinical trials.

P282 Isolated colonic Crohn’s disease and extensive ulcerative colitis: is there a reel difference?

Abstract Background The management of isolated colonic Crohn's disease (CDc) is often modeled on that of Ulcerative Colitis (UCc). The aim of our study was to compare epidemiological and evolutive profiles of CDc and UCc. Methods We conducted a retrospective, descriptive and comparative study, including patients diagnosed with CDc as well as UCc, who were hospitalized in our department over a 9-year period [January 2011 - January 2020]. The group 1 included patients with CDc and group 2 included patients with UCc. Patients with less than 2 years of follow-up were excluded. Data were recorded and analyzed by SPSS software version 26. Results We included 130 patients with a sex ratio M/F= 0.68. The mean age at diagnosis was 34.85 years [6-68 years]. Sixty-three patients had CDc, while 67 patients had UCc. The two groups were comparable for age (p=0.56) and sex (p=0.54). The percentage of patients with smoking and alcoholism was also comparable between the two groups (p=0.4 and p=0.8 respectively). The presence of at least one autoimmune disease and a family history of Inflammatory Bowel Disease were more noted in patients in group 1 than in group 2 (p= 0.011 and p=0.046 respectively). The mean BMI at diagnosis was 22.28 kg/m² and was comparable between the 2 groups. The main phenotype was inflammatory (93.6%) in group 1. Twenty-five patients in group 1 (39.6%) and 22 patients (32.8%) in group 2 had associated extra-intestinal involvement (p=0.41), represented mainly by rheumatological involvement (n=39, 30%). The mean albumin level at diagnosis was 29.21 g/L and 30.96 g/L in groups 1 and 2 respectively. The occurrence of Severe Acute Colitis during follow-up was more frequent in group 2 than in group 1 (58.2% vs. 46%), although the difference was not significant (p=0.13). However, the rate of colectomy was significantly higher in group 2 (p=0.029). The use of anti-TNF therapy was significantly higher in group 1 (p=0.046). The maximum duration of hospitalization and the number of relapses were not statistically different between the 2 groups (p=0.81 and p=0.8 respectively). Finally, there was no significant difference between the 2 groups considering the use of corticosteroid or immunosuppressive therapy (p=0.88 and p=0.96 respectively). The main limit of our study is that it was conducted only in hospitalized patients who had relatively severe disease. Conclusion CDc is more prone to intensive medical treatment, whereas colectomy is more noted in UCc.

EFFICIENCY OF DUAL THERAPY WITH VEDOLIZUMAB AND TOFACITINIB IN REFRACTORY ULCERATIVE COLITIS PATIENTS – SINGLE CENTRE EXPERIENCE

Abstract INTRODUCTION Despite significant impact biological treatment had on prospects of patients with ulcerative colitis, there is still a substantial proportion of patients with either secondary loss of response or primary non-response to multiple drugs. Beside dose optimization and selection of drugs with different mechanism of action, combination of two different targeted molecules has been proposed in cases where inflammatory activity cannot get under control. This case series provide promising results of vedolizumab in combination with tofacitinib in treatment resistent UC patients. METHODS Patients with complicated refractory or acute severe colitis, in whom combined treatment with vedolizumab and tofacitinib based on shared clinical decision was started, were included. Data on demographics, treatment details, persistence and disease activity including laboratory markers, clinical activity index (partial Mayo score) during regular visits every 2 months up to one year after treatment initiation were collected. Currently available data were analyzed at 6 months of treatment. Endoscopic disease activity before and 2-6 months after dual therapy start was evaluated. RESULTS In total, 21 ulcerative colitis patients who were started on vedolizumab and tofacitinib dual therapy between October 2020 and September 2022 were included. Tofacitinib dose was 10mg bid in all patients and all patients on vedolizumab maintenance treatment had intensified dosing regimen. Mean patients age was 36.4±8.1 years, 47.6% were males and 52.4% females. Mean disease duration at baseline was 7.5±5.8 years. All patients had advanced disease including 61.9% with extensive colitis and 38.1% with left-sided colitis. At least 2 previous biologics in monotherapy were used in 85.7% of patients. Mean pMayo score at baseline was 5.6±1.9 and decreased to 0.5±0.9 at 6 months (p=0.0020). Initial fecal calprotectin in the cohort was 1829±2520µg/g vs. 225±257µg/g at 6 months (p=0.0068) and mean CRP changed from 11.4±17.1 to 5.4±7.2mg/l (p=ns). Endoscopic Mayo score before dual treatment initiation averaged 2.8±0.5 indicating mostly severe disease activity and decreased to 1.4±1.2 during follow-up endoscopy (p=0.0005) with half of the patients having only no to mild activity (eMayo 0-1). Up to now, dual therapy had to be terminated in 7 patients – 4 patients failed on the treatment, 1 refused to continue with dual therapy, 1 patient experienced adverse event (liver lesion) and 1 was discontinued for reimbursement reasons. CONCLUSION In the presented small cohort of patients, however, with refractory and complicated ulcerative colitis in whom other modalities were depleted or colectomy was considered, combined vedolizumab and tofacitinib treatment has proven to be very efficient with half of the patients reaching mucosal healing after 6 months and without raising significant safety concerns.

REAL-WORLD EXPERIENCE FOR BIOLOGIC USE IN IBD IN THAI: A SINGLE-CENTER EXPERIENCE

Abstract BACKGROUND Biologics have been used for the treatment of inflammatory bowel disease (IBD) worldwide; however, their use is still limited in Southeast Asia. This study aimed to describe the pattern of biologic use and outcomes in a tertiary referral center in Thailand. METHOD All patients with IBD who used biologics from the first case in 2012 to present in our center were enrolled. The data were prospectively collected since 2017; the data of patients before 2017 were retrospectively reviewed. The treatment outcomes comprised cumulative clinical, endoscopic, radiologic response or remission, and quality of life assessed by SIBDQ. Furthermore, the biologic persistence was reported. RESULTS Of 296 cases currently in the IBD clinic, 85 used biologics, including infliximab (IFX), vedolizumab (VDZ), and ustekinumab (UST). The mean age was 44.4 years, and 62% were male. Fifty-eight (68.2%) had Crohn’s disease (CD) and 27 (31.8%) had ulcerative colitis (UC). In CD, 58% had ileocolonic disease, 48% had bowel stricture, 29% had fistula, and 19% had perianal diseases. In UC, 19% had left-sided colitis, and 81% had extensive colitis. Most patients (97%) failed conventional treatment. In CD, 60%, 31%, and 8.6% use IFX, VDZ, and UST as the first biologic, respectively. While 81.5% of UC used VDZ and 18.5% used IFX. Concomitant immunomodulator was used in 77.6%. The median duration of the first biologic use was 12.6 months. The outcomes of the treatment were shown in Table 1. The overall cumulative clinical response and remission at 1 year were 94% and 63%, respectively, without significant differences among each biologic. The cumulative rate of endoscopic remission was 29%, 64%, and 82% at 1, 3, and 5 years, respectively, also without significant differences among each biologic (p=0.21). However, subgroup analysis in Crohn’s disease showed a trend of a better endoscopic remission rate for IFX and UST when compared to VDZ (p=0.15). The radiologic remission rate was only 12% of 25 patients who underwent CT enterography. The SIBDQ increased from 52.0 to 57.4 after 1 year of treatment. Thirty-six (42%) stopped the medicine. As shown in Figure 1, the overall cumulative rate of biologic discontinuation was 19% and 39% in the first and second year, respectively, without significant differences among biologics. However, the reason for drug discontinuation was different as all adverse events occurred in only patients using IFX. CONCLUSION Biologics were mostly used in refractory patients in this cohort. The outcomes were comparable to those previously reported in western. Current biologics could significantly improve patients’ symptoms, quality of life, and mucosal healing, but not transmural healing. The adverse events were less in newer biologics.

DEVELOPMENT OF AN OPTIMAL MACHINE LEARNING MODEL USING TREATMENT NAÏVE DIAGNOSTIC PATHOLOGY IMAGES TO PREDICT STEROID-FREE CLINICAL REMISSION AT ONE YEAR IN PEDIATRIC ULCERATIVE COLITIS

Abstract BACKGROUND The majority of children with ulcerative colitis present with extensive colitis at diagnosis, but the response to therapy is heterogenous. Identifying the optimal window for biologic treatment and risk stratification of patients remains an unmet need. AIM To develop a pathology based histomic model to predict corticosteroid free clinical remission (CSF) with mesalamine alone at one year. METHODS 292 hematoxylin and eosin diagnostic treatment naïve rectal mucosal biopsies from the multi-center PROTECT study were digitized. Whole slide images (WSIs) underwent two-step pre-processing a)stain normalization and b)informative patch selection (size 512x512). We trained machine learning (ML) models using 250 histomic features (texture, color, histogram and nuclei features) with 5-fold cross-validation, for patch-level classification. Feature importance was determined by the Gini index. We re-trained the classifier using the top features. Slide-level prediction was defined by threshold voting. Performance metrics at the patch and WSI level was evaluated. A total of 161 patients underwent high-throughput RNA sequencing to define rectal gene expression. We undertook unsupervised weighted gene co-expression network analysis (WGCNA) to discover networks of co-expressed genes with shared biologic functions correlated with histomic features, histological traits, and outcomes. RESULTS 187571 informative patches from 292 patients (Male:55%; Age:12.7y (IQR:11-15); CSF remission:41%) were trained on 23 ML classifiers. The best model trained on 250 features at the patch-level was random forest (RF). At a remission ratio threshold of 0.48, WSI area under the receiver operator curve (AUROC) was 0.90 (95%CI:0.70, 1.00), accuracy 90.4%, precision 90.9% and recall 84.7%. 18 top features were identified and trained, and the corresponding WSI AUROC was 0.87 (95%CI:0.72, 1.00), accuracy 90.1%, precision 89.4%, and recall 83.9% (Fig. 1). We re-trained the 18 features on an independent real-world dataset of 131 UC patients and the model WSI AUROC was 0.85 (95%CI:0.74, 1.00) and an accuracy of 88.5%. Of the 13 modules identified by WGCNA analysis, six modules significantly correlated with clinical and/or histomic features (Fig. 2). Two of the gene co-expression modules were negatively associated with baseline clinical, endoscopic, and histologic measures of severity, and positively associated with nuclei features (Otsu area, perimeter, and equivalent diameter) and the outcome measure of CSF remission. Intersection of genes with adult single cell RNA seq data demonstrated enrichment for enterocytes (SLC26A3) and extracellular matrix (IHH) CONCLUSION We developed a predictive model for UC disease course using histomic features from standard of care pre-treatment pathology images. Characterization of the underlying molecular basis of the histomic features is ongoing.

Concurrent inflammatory bowel disease and primary sclerosing cholangitis: a review of pre- and post-transplant outcomes and treatment options.

Primary Sclerosing Cholangitis (PSC) is a chronic cholestatic liver disease which is associated with Inflammatory Bowel Disease (IBD) in 70% of cases. It seems PSC/IBD is a distinct phenotype that is different from PSC, and IBD alone. Hence, we review the epidemiology, pathogenesis, natural course and management of PSC/IBD before and after LT for PSC. Extensive colitis, rectal sparing, backwash ileitis, and mild symptoms are the characteristics of IBD coexisting with PSC. Moreover, PSC patients with concurrent IBD have higher risk of cholangiocarcinoma, and colorectal neoplasia predominantly in right colon and at younger age. Therefore, it is essential to monitor these individuals continuously. It is interesting to note that the course of IBD (ulcerative colitis) after liver transplantation (LT) for PSC varies greatly, and some patients may develop worsening colitis after LT despite immunosuppressive regimens. As well, management of these patients was discussed in this review.

Presence of risk factors associated with colectomy among patients with ulcerative colitis: a post hoc analysis of data from the tofacitinib OCTAVE ulcerative colitis clinical program.

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). To assess colectomy incidence rates (IRs) and baseline characteristics for the presence of identified colectomy risk factors among patients in the tofacitinib OCTAVE UC clinical program. This post hoc analysis evaluated patients in the 8-week OCTAVE Induction 1 and 2, 52-week OCTAVE Sustain, and OCTAVE Open (open-label, long-term extension) studies. IRs [95% confidence interval (CI)] for colectomy were analyzed. Baseline risk factors based on clinical guidelines: aged <40 years at diagnosis, extensive colitis, severe endoscopic disease [Mayo endoscopic subscore (MES) = 3], hospitalization for UC within 12 months, C-reactive protein (CRP) >3 mg/L, and serum albumin <3.5 g/dL. Baseline risk factors were evaluated in patients who underwent colectomy by study and summarized descriptively. Over a maximum of 7.8 years of tofacitinib exposure, 14 patients underwent colectomy: 3/1139 (0.3%) in OCTAVE Induction 1 and 2 [tofacitinib 10 mg twice daily (BID): n = 2; placebo: n = 1], 3/593 (0.5%) in OCTAVE Sustain (placebo: n = 3), and 8/944 (0.8%) in OCTAVE Open (tofacitinib 10 mg BID: n = 8). Colectomy IR per 100 patient-years for all patients who received ⩾1 tofacitinib dose was 0.34 (95% CI: 0.16-0.63). All patients who underwent colectomy had ⩾1 risk factor and prior tumor necrosis factor inhibitor (TNFi) failure, among which the most common risk factors were a MES of 3 (n = 13), CRP >3 mg/L (n = 11), and aged <40 years at diagnosis (n = 9). Among patients with moderate to severe UC receiving tofacitinib, colectomies were infrequent; all patients undergoing colectomy had prior TNFi failure, and most had multiple additional risk factors. This provides important information to discuss with patients and inform management decisions. NCT01465763; NCT01458951; NCT01458574; and NCT01470612.

Common laboratory blood test immune panel markers are useful for grading ulcerative colitis endoscopic severity

BackgroundAt present, many indicators reflect the clinical disease activity of ulcerative colitis (UC). However, commonly used inflammatory markers do not show good utility for indicating endoscopic disease activity. The purpose of this study was to evaluate high sensitivity C-reactive protein (hs-CRP), C-reactive protein to albumin ratio (CAR), inflammatory markers, and complete blood count (CBC) related parameters in patients with UC as simple, non-invasive, and independent markers of endoscopic activity (EA).MethodsWe retrospectively collected extensive data from the hospital medical records of 386 patients who presented with UC to the First Affiliated Hospital of Xinjiang Medical University (Urumqi, China) from 2018 to 2022 January. The Mayo endoscopic score (MES) was used to evaluate endoscopic disease activity. All included patients were defined as the MES-All group; those with extensive colitis (E3) were defined as the MES-E3 group. Demographics, laboratory parameters, endoscopic results, the extent of disease, and drug history were recorded and analyzed.ResultsFor patients in the MES-All or MES-E3 group, hs-CRP, CAR, neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) were significantly higher in EA UC patients than in those with mucosal healing. The mean platelet volume (MPV) and lymphocyte to monocyte ratio were significantly lower in active disease than in the patient’s remission (p < 0.001). ROC analysis showed that in the MES-All and MES-E3 groups, the cutoff values of hs-CRP activity under endoscopy were 5.32 mg/L (AUC 0.850, sensitivity 77.6%, specificity 81.9%) and 5.16 mg/L (AUC 0.902, sensitivity 86.9%, specificity 85.4%) respectively, and the cutoff values of CAR were 0.14 (AUC 0.853, sensitivity 76.8%, specificity 84.8%) and 0.18 (AUC 0.904, sensitivity 81.8%, specificity 89.6%) respectively. Multivariate logistic regression analysis showed that hs-CRP, CAR, NLR, and PLR identified UC EA, while decreased MPV reflected inflammatory activity in the UC mucosa.ConclusionEspecially in patients with extensive colitis, hs-CRP and CAR are closely related to EA and show a higher diagnostic value compared to the related CBC parameters. The aforementioned indicators are simple and non-invasive independent markers that reflect the EA in UC.

Long-term Colectomy Rates of Ulcerative Colitis over 40 Years of Different Therapeutic Eras-Results from a Western Hungarian Population-based Inception Cohort Between 1977 and 2020.

Few populaion-based studies have investigated the long-term colectomy rates of ulcerative colitis [UC]. We aimed to assess the colectomy rates over 40 years of different therapeutic eras in a prospective population-based inception cohort from Veszprem Province, Western Hungary. Patient inclusion lasted between January1, 1977, and December31, 2018. Patient follow-up ended December 31, 2020. Colectomy rates and disease course were examined in three different eras based on the time of UC diagnosis; cohort A [1977-1995], cohort B [1996-2008], and cohort C [2009-2018]. A total of 1370 incident UC patients were included [male 51.2%, median age at diagnosis 37 years]. Median follow-up was 17 years (interquartile range [IQR] 9-24); 87 patients [6.4%] underwent colectomy. The cumulative probability of colectomy in the total population was 2.6% (95% confidence interval [CI] 2.2-3.0), 4.2% [95% CI 3.6-4.8], 7.0% [95% CI 6.2-7.8], and 10.4% [95% CI 9.1-11.7] after 5, 10, 20, and 30 years, respectively. The proportion of extensive colitis at diagnosis increased over time [24.2%/24.3%/34.9% in cohorts A/B/C, respectively, p = 0.001]. Overall exposure to immunomodulators [11.3%/20.9%/34.4% in cohorts A/B/C, respectively, p <0.001], as well as the probability for biologic therapy initiation increased over time (0%/3.3% [95% CI 2.6-4.0]/13.9% [95% CI 12.1-15.7], p <0.001). There were no statistically significant differences in the cumulative probability of colectomies between cohorts A/B/C: 1.7% [95% CI 1.0-2.4], 2.5% [95% CI 1.9-3.1], and 3.7% [95% CI 2.7-4.7] after 5 years; 3.5% [95% CI 2.5-4.5], 4.2% [95% CI 3.4-5.0], and 4.5% [95% CI 3.3-5.7] after 10 years; and 7.5% [95% CI 6.1-8.9] and 6.3% [95% CI 5.2-7.4] in cohorts A/B after 20 years [log-rank = 0.588]. Extensive colitis (hazard ratio [HR] 2.24, 95% CI 1.55-3.23) and continuous active disease activity [HR 6.36, 95% CI 3.46-11.67] were independent predictors for colectomy. No differences in colectomy rates have been observed in the incident UC patients over 40 years despite increasing use of immunomodulators and biologic therapies.

A variant rs6214 within IGF-1 confers risk for ulcerative colitis in Chinese Han populations.

Insulin growth factor-1 (IGF-1) has been found to correlate with various diseases such as cancer and cardiovascular diseases including ulcerative colitis (UC). The present study aimed to investigate the plausible association of rs6214 (C > T) within IGF-1 and UC susceptibility in Chinese Han populations. A total of 977 UC patients and 1029 healthy controls were enrolled, and rs6214 was genotyped with PCR and direct sequencing on the ABI 3730XL DNA analyzer platform. Logistic regression analysis was applied for the correlation of rs6214 and UC susceptibility via calculation of odds ratio (OR) with a 95% confidence interval (95% CI) adjusted for age and sex under different genetic models. The difference of clinical parameters between genotypes was measured by one-way analysis of variance (ANOVA). Additional functional assays were conducted to establish the probable relationship. The results indicated that the T allele of rs6214 showed roughly 37% greater risk for UC risk in the additive model (OR = 1.37, 95% CI = 1.21-1.55, P < 0.000001) when compared with C allele carriers, and the pattern was similar in other three genetic models. Further stratified analysis suggested that the association was particularly noteworthy in UC patients with extensive colitis and severe condition. Moreover, the blood level of IGF-1 was downregulated in UC patients, and the mRNA level was lower in T allele carriers in rectal tissues of UC cases. Additional luciferase assay demonstrated that rs6214 regulates IGF-1 expression via promoting miR-2053. Collectively, rs6214 increased UC susceptibility and suppresses IGF-1 expression by enhancing miR-2053 binding. The current findings provided evidence that rs6214 is a promising biomarker for UC prediction and prognosis.

Caracterización clínica y terapéutica de una cohorte multicéntrica de pacientes con enfermedad inflamatoria intestinal en Colombia

IntroductionIn Latin America and Colombia there are few studies about the clinical and therapeutic characteristics of patients with inflammatory bowel disease (IBD). The objective of this study is to obtain an approximation to these data from a sample of patients from different reference centres in Colombia. Patients and methodsCross-sectional study in adult and paediatric patients, with IBD, attended ambulatory in 6 institutions in different cities, between 2017 and 2020 information was collected on different dates, about demographic, clinical, and therapeutic aspects. ResultsSix hundred and five subjects, 565 (93.4%) adults, mean age 43 years (SD 12.78), 64% with ulcerative colitis (UC). The age at diagnosis of UC was 41.9 years, while in Crohn's disease (CD) it was 47.9 years. In UC, there was greater left involvement (47.2%), and in CD, 42.8% ileocolonic (L3). More than 50% were in mild activity or clinical remission. In UC, the biologic requirement was 27.2%, while in CD, 78%. Overall hospitalisation requirement was 39.5%, and the need for surgery was 37.5% in UC and 62.5% in CD. Also, 40 pediatric patients, 90% female, with UC being more frequent (80%). In UC, 83.3% presented extensive colitis, and in CD, all with ileocolonic localization (L3). More than 95% were in mild activity or remission. Biologic therapy was required in 16.6% and 75% for UC and CD, respectively. The frequency of hospitalisations and surgery was 2.7%. ConclusionsThis study shows some unique characteristics of patients with IBD in Colombia. An earlier diagnosis is required, with a better therapeutic approach.

Recent advances in surveillance colonoscopy for dysplasia in inflammatory bowel disease.

Inflammatory bowel disease (IBD) has a global presence with rapidly increasing incidence and prevalence. Patients with IBD including those with ulcerative colitis and Crohn's disease have a higher risk of developing colorectal cancer (CRC) compared to the general population. Risk factors for CRC in patients with IBD include long disease duration, extensive colitis, primary sclerosing cholangitis, family history of CRC, stricture, and prior dysplasia. Surveillance colonoscopy for CRC in patients with IBD should be tailored to individualized risk factors and requires careful monitoring every year to every five years. The current surveillance techniques are based on several guidelines. Chromoendoscopy with targeted biopsy is being recommended increasingly, and high-definition colonoscopy is gradually replacing standard-definition colonoscopy. However, it remains unclear whether chromoendoscopy, virtual chromoendoscopy, or white-light endoscopy has better efficiency when a high-definition scope is used. With the development of new endoscopic instruments and techniques, the paradigm of surveillance strategy has gradually changed. In this review, we discuss cutting-edge surveillance colonoscopy in patients with IBD including a review of literature.

Optimising inflammatory bowel disease surveillance and dysplasia management-Where do we stand?

Patients with longstanding extensive colitis are at an increased risk of developing colorectal cancer (CRC), and are therefore enrolled into colonoscopy screening programmes with the aim of detecting pre-cancerous dysplastic change. However, current surveillance programs face multiple limitations relating to low levels of patient enrolment, missed lesions resulting in interval cancers, and uncertainties in the management of dysplasia. Patient counselling regarding the endoscopic and surgical management options of dysplastic lesions can prove particularly challenging, due to the variable risk of progression to cancer. In this review, we discuss the histopathological diagnosis of inflammatory bowel disease (IBD)-associated dysplasia, describe the techniques to maximise dysplasia detection, and present a standardised multi-disciplinary approach to managing patients with dysplasia. The challenges presented by this patient cohort highlight the clear clinical need for further research into the development and validation of non-invasive markers of CRC risk in IBD patients undergoing surveillance.

Histological remission in inflammatory bowel disease and risk of adverse pregnancy outcomes: A nationwide study.

Inflammatory bowel disease (IBD) has been linked to adverse pregnancy outcomes, but it is unclear how risks vary by histological activity. We performed a nationwide study of Swedish women diagnosed with IBD 1990-2016 and a pre-pregnancy (<12 months) colorectal biopsy with vs. without histological inflammation (1223 and 630 births, respectively). We also examined pregnancy outcomes in 2007-2016 of women with vs. without clinically active IBD (i.e., IBD-related hospitalization, surgery, or medication escalation) <12 months before pregnancy (2110 and 4993 births, respectively). Accounting for smoking, socio-demographics, and comorbidities, generalized linear models estimated adjusted risk ratios (aRRs) for preterm birth (<37 gestational weeks) and small-for-gestational age (SGA, <10th percentile weight for age). Of infants to women with vs. without histological inflammation, 9.6% (n=117) and 6.5% (n=41) were preterm, respectively (aRR=1.46; 95%CI=1.03-2.06). Histological inflammation was associated with preterm birth in ulcerative colitis (UC) (aRR=1.64; 95%CI=1.07-2.52), especially extensive colitis (aRR=2.37; 95%CI=1.12-5.02), but not in Crohn's disease (aRR=0.99; 95%CI=0.55-1.78). Of infants to women with vs. without histological inflammation, 116 (9.6%) and 56 (8.9%), respectively, were SGA (aRR=1.09; 95%CI=0.81-1.47). Clinically active disease before pregnancy was linked to preterm birth (aRR=1.42; 95%CI=1.20-1.69), but not to SGA birth (aRR=1.13; 95%CI=0.96-1.32). Finally, of infants to women without clinical activity, histological inflammation was not significantly associated with preterm birth (aRR=1.20; 95%CI=0.68-2.13). Histological and clinical activity in IBD, especially in UC, were risk factors for preterm birth. Further research is needed to determine the importance of pre-pregnancy histological activity in women without clinically-defined disease activity. The Swedish Society of Medicine.