Geboes Score Research Articles

P271 Variability in histologic activity of paired same-segment biopsies in Crohn’s disease dictates multiple biopsies needed to accurately evaluate histological status

Abstract Background At present, the significance of histologic remission in Crohn’s disease [CD] is unclear. One of the main reasons is the heterogeneous distribution of the lesions. This contrasts with ulcerative colitis, where histologic scoring systems have been applied with success on limited numbers of biopsies. We assessed the variability of histologic activity in paired same-segment biopsies from CD patients. Methods All CD patients undergoing ileocolonoscopy between January 2020 and July 2022 at our tertiary referral center were eligible for inclusion. Clinical data were retrospectively collected from medical records. Endoscopies were video-recorded and the Simple Endoscopic Score for Crohn’s Disease [SES-CD] was used to evaluate endoscopic activity. Paired biopsies were taken within the most affected area per segment, in accordance with ECCO guidelines. The Global Histology Activity Score (GHAS), the Geboes Score [GS], the Robart’s Histopathology Index [RHI] and the Nancy Histological Index [NHI] were determined for each biopsy by an experienced IBD pathologist [GDH] blinded to the endoscopic scores. The cut-off values for histologic remission were set at GHAS ≤4, GS <2B.1, RHI ≤3 and NI ≤1 (absence of neutrophils for RHI and NI). Variability was assessed by intraclass correlation coefficient [ICC] and Kappa statistics. Association between histologic and endoscopic scores was studied with Spearman’s rank correlation coefficient. Results A total of 151 biopsy pairs from 128 patients were analysed. Patient characteristics are summarised in Table 1. Endoscopic activity was observed in 79% of segments. In patients with endoscopic remission, histologic activity (presence of neutrophils) was found in 29% of cases. There was a moderate association between the endoscopic and histologic assessment, with correlation levels ranging from 0.48 to 0.52 [p<0.001]. Histologic indices showed fair agreement between paired biopsies [Table 2]. Looking at the predefined cut-offs, moderate variability across the different histological scores was seen [Table 3]. When comparing biopsies from segments with endoscopic activity and those without, overall higher variability in active segments and substantial agreement in paired biopsies from inactive segments was observed [Table 4]. Conclusion The patchy nature of microscopic inflammation in CD is reflected in the histologic scores of paired same-segment biopsies, with only moderate agreement across histologic scoring indices, although lower variability was seen in biopsies from endoscopic inactive segments. Endoscopic activity only moderately reflects histological status. Multiple biopsies per segment are therefore needed for accurate histological evaluation, the optimal number necessary remains to be explored.

P142 Evaluation of quantitative phase imaging for automated assessment of histopathological remission in patients with Ulcerative Colitis

Abstract Background Ulcerative colitis (UC) is characterized by chronic intestinal inflammation. Histological remission has become an efficacy outcome in clinical trials and might have the potential to modify the course of UC. Quantitative phase imaging including digital holographic microscopy (DHM) can be used for objective and automated evaluation of tissue morphology and density. Our study aimed to evaluate DHM for quantifying histological inflammation in UC patients. Methods In a monocentric prospective study, UC patients undergoing colonoscopy were included. Disease activity was measured by the total Mayo Score. DHM was used to determine the refractive index (RI) in mucosal biopsy samples obtained during colonoscopy. RI values were correlated with histological disease activity as assessed by the Nancy histological index [NHI]. Results In total, mucosal biopsy samples from 21 UC patients were included to the analysis. On average, UC patients had a moderate disease activity as reflected by a partial Mayo score of 3.1 (SEM ± 0.6), an endoscopic Mayo subscore of 1 (SEM ± 0.2) and a total Mayo score of 4.1 (SEM ± 0.8). The mean NHI was 1.3 (SEM ± 0.2) and the mean RI was 1.349 (SEM ± 0.0003). RI values as determined by DHM correlated strongly with the histological disease activity as determined the NHI (p<0,001 and R2=0.282). Similarly, a marked correlation was found using alternative histopathological indices (Geboes score, Riley index, Robarts histopathological index; all p<0.001). Conclusion Our data demonstrate that DHM is appropriate to assess intestinal inflammation in UC patients and that it may be an alternative or supplemental tool to conventional histopathological assessment.

P588 Interim results from the randomised VERDICT trial to determine the optimal treatment target in patients with ulcerative colitis

Abstract Background The optimal treatment target for ulcerative colitis (UC) is uncertain. The VERDICT trial in moderate to severe UC aims to determine if a treatment target of corticosteroid (CS)-free symptomatic + endoscopic + histologic remission is superior to CS-free symptomatic remission alone. Trial progress and the study cohort to date are described herein. Methods Our aim is to enrol 660 patients with moderately to severely active UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2). Patients are randomised to 3 treatment targets (2:3:5 ratio): CS-free symptomatic remission (Mayo RBS = 0) (Group 1); CS-free endoscopic remission (MES ≤1) + symptomatic remission (Group 2); or CS-free histologic remission (Geboes score <2B.0) + endoscopic + symptomatic remission (Group 3). Therapy is administered according to a treatment algorithm that is dependent upon each patient’s UC treatment at screening. Early introduction of vedolizumab (VDZ) and dose escalation up to 300 mg every 4 weeks until the target is met are central to each algorithm. Up to 3 opportunities to achieve the assigned target were prespecified in the algorithms (weeks 16, 32, or 48). Patients and central readers for endoscopy/histopathology are blinded to group allocation, and investigators are unblinded. Results As of 2 November 2022, 331 patients were enrolled at 55 sites across 10 North American and European countries. Mean (SD) baseline characteristics (Table) include a UC duration of 8.6 (8.3) years, Mayo Clinic score of 8.7 (1.7), C-reactive protein level of 13.3 (15.6) mg/dL, and a faecal calprotectin level of 1462.3 (1481.3) mg/kg. At baseline, 52% (172/331) and 11% (37/331) of patients were receiving concomitant CS and immunosuppressives, respectively, and 14% (47/331) had current/prior exposure to tumour necrosis factor antagonists. Most patients (85%) were receiving nonbiologic therapy. Of all randomised patients, 43/69 (Group 1), 65/98 (Group 2), and 115/164 patients (Group 3) have reached week 16; and 28 (65%), 25 (39%), and 42 (37%) met their target, respectively. After a median of 35 weeks (IQR 18-53), a total of 30 (Group 1), 32 (Group 2), and 50 patients (Group 3) have met their target and will be followed to relapse or study termination. The serious adverse event rate (8%; 36/483) was similar across groups. Conclusion VERDICT has randomised ~50% of its target enrolment. Enrolled patients represent a typical moderate to severe UC population and are primarily bionaive and receiving early VDZ initiation. Early results suggest the feasibility of achieving each treatment target, specifically histologic remission, and are consistent with expected values. No new VDZ safety signals were identified. Completion of enrolment is anticipated in late 2023.

P479 Reliability and responsiveness of histologic disease activity indices in Crohn’s Disease

Abstract Background The operating properties of histologic indices are poorly characterized in Crohn’s disease (CD) and no validated index exists. We assessed the reliability and responsiveness of histologic indices/items, developed an exploratory index, and compared different methods of scoring. Methods Using baseline and week 12 histologic image sets from the EXTEND placebo-controlled trial, blinded central readers scored 4 histologic indices (the Global Histologic Activity Score [GHAS], Geboes Score [GS], Robarts Histopathology Index [RHI], and Nancy Index [NHI]) and 3 additional novel items identified by an expert panel (mucin depletion, basal plasmacytosis, and pyloric gland metaplasia in the ileum). Reliability and responsiveness were evaluated for a global score (4 colonic segments + ileum), colonic score (4 colonic segments) and ileal score (ileum only) using the intraclass correlation coefficient (ICC) and area under the receiver operating curve (AUC), respectively. Change was defined using treatment assignment and improvement in histologic disease activity as measured on a 100-mm visual analogue scale (VAS) in responsiveness testing. Exploratory indices were developed using backward stepwise linear regression analysis. Candidate independent variables were items with an ICC ≥0.4 and AUC ≥0.56. The VAS served as the dependent variable. Results Paired histologic images were analysed from 55 subjects. Inter-rater reliability was substantial to almost perfect (ICC=0.73-0.85) and responsiveness was small to large (treatment assignment AUC=0.50-0.65; VAS AUC=0.71-0.94). The GHAS, GS, RHI, and NHI reached the minimum threshold for reliability (ICC ≥0.4) and responsiveness (AUC ≥0.56) regardless of whether the global and colonic scores were calculated using the worst affected segment, average of the included segments, or sum of the included segments (Table 1-3). Five items were tested as candidate predictors. Three exploratory indices were developed, each consisting of 3 items: a global index (neutrophils in the lamina propria, neutrophils in the epithelium, and erosion/ulceration), colonic index (chronic inflammatory infiltrate, neutrophils in the lamina propria, and erosion/ulceration) and ileal index (chronic inflammatory infiltrate, neutrophils in the epithelium, and erosion/ulceration). The novel indices highly correlated with the GHAS, GS, RHI, and NHI, with correlation coefficients ≥0.80 (Table 4). Conclusion The 4 existing indices were similarly reliable and responsive in measuring CD histologic activity, regardless of the method for calculating global and colonic scores and could be used in clinical trials. Attempts at novel index development did not offer benefit over current histologic indices.

P577 A Phase 1b Study to Evaluate Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of the Nucleotide-binding oligomerization domain, Leucine rich Repeat containing X1 (NLRX1) agonist NX-13 in Ulcerative Colitis

Abstract Background NLRX1 is a mitochondrial membrane protein whose activation reduces oxidative stress and decreases effector cell differentiation and cytokine release. NX-13 is a first-in-class, orally active, gut selective NLRX1 agonist with low systemic exposure. In preclinical studies of IBD, NX-13 effectively reduced inflammatory responses and disease severity. A phase 1a study (healthy subjects) showed NX-13 to be well tolerated with low systemic drug exposure suggesting a gut-selective drug delivery. We report the results of a phase 1b study in patients with Ulcerative colitis (UC) on the safety, target engagement and clinical efficacy of NX-13. Methods In this double-blind trial, 36 patients with active UC (Total Mayo Score [MCS] 4-10; Mayo endoscopic subscore [MES] 2-3) were randomly assigned to NX-13 250mg Immediate Release (IR), 500mg IR, 500mg Modified Release (MR) or Placebo to be taken QD for 4 weeks (safety visit at week 5). Biologic exposed patients, stable 5’ASAs dose and corticosteroids (oral ≤20mg/day prednisone or equivalent) were permitted. IV or topical corticosteroids use was prohibited. Primary endpoints were safety and pharmacokinetic (PK) analysis. The study was not powered for clinical efficacy, however MCS, histopathologic Geboes score, and NLRX1, cytokine, and gene expression were obtained at baseline and day 28 in exploratory analyses (Table 1). Results During the 5-week observation period, no serious adverse events (AEs) were reported. All AEs were classified as mild or moderate and were most common in the 500mg MR group. One patient was withdrawn before week 5 due to a flare of UC. IR dose plasma PK levels peaked at 1hour, while the MR dose was absorbed later and maintained a low exposure longer. Qualitative immunohistochemical analysis showed target engagement as indicated by increase of NLRX1 at all doses. Symptomatic efficacy was seen in 8/11 patients in the 250mg group with a PRO (RB+SF) score of 0 at week 4. The decrease in MCS was 2.1-3.4 in the NX-13 arms vs 1 point with placebo (Fig 1A) while clinical response rates ranged from 27-72% amongst the active arms with no placebo responders, though no dose-response relationship was observed (Fig 1B). Endoscopic response ranged from 27-40% (Fig 1C), with 5/32 dosed patients being in endoscopic remission. Histologic remission largely paralleled endoscopic response and cytokine and mRNA levels support target engagement. Conclusion In patients with active UC, NX-13 was well-tolerated and target engagement was achieved. The exploratory efficacy endpoints indicated rapid clinical, endoscopic, and histologic improvement at week 4, relative to placebo. This novel mechanism of action will be further evaluated in a phase 2 study.

MACHINE LEARNING-BASED PREDICTION OF GEBOES SCORE AND HISTOLOGIC IMPROVEMENT AND REMISSION THRESHOLDS IN ULCERATIVE COLITIS

Abstract BACKGROUND Histology is emerging as a key therapeutic endpoint for ulcerative colitis driven by associations between histologic response and long-term outcomes. However, existing scoring systems are subjective and consequently have variable inter- and intra-reader variability. Geboes scoring is a well-established system for ulcerative colitis histologic assessment that has previously been used to define thresholds for histo-endoscopic mucosal improvement (Geboes Score ≤3.1, together with Mayo score 0 or 1) and histologic remission (Geboes Score <2). Here we report the first machine learning (ML)-based prediction of the Geboes Score, and Geboes Score-derived thresholds of histologic improvement and remission, directly from whole slide images (WSI) of hematoxylin and eosin (H&E)-stained mucosal biopsies. METHODS 3,148 WSI were scored by three expert gastrointestinal pathologists and the median consensus score was used to determine the Geboes score for each slide as ground truth. ML models were trained on median consensus scores to predict the Geboes score and subscores for each slide. Model performance vs. pathologist median consensus score was measured using accuracy and the F1 score, which accounts for both false positive and false negative errors. RESULTS The ML-based model performance, measured against median consensus scores of three pathologists, showed strong performance at predicting overall Geboes Score, with a quadratic kappa of 0.89. The model was also able to predict both histologic improvement and histologic remission with high accuracy. For predicting histological improvement as defined by a Geboes Score of ≤3.1, the model showed accuracy of 0.92 and F1 score of 0.92 (Figure 1). For predicting histological remission as defined by a Geboes Score of < 2, the model showed accuracy of 0.91 and F1 score of 0.89 (Figure 2). CONCLUSIONS We report a ML-based approach for predicting Geboes score and Geboes score-based key thresholds of histologic improvement and histologic remission. Model predictions show high accuracy compared to median consensus pathologist scores. This approach may enable standardized, reproducible and accurate prediction of these clinically relevant thresholds to better measure histologic disease activity and treatment response in clinical trials.

MULTIPLE ENVIRONMENTAL AND SOCIAL DETERMINANTS OF HEALTH FACTORS WERE NOT ASSOCIATED WITH THE GASTROINTESTINAL SYMPTOMATIC BURDEN OF ULCERATIVE COLITIS WITH MUCOSAL HEALING

Abstract INTRODUCTION In a biopsychosocial interdisciplinary model, complex interactions between the hosts (individuals/patients), disease (e.g., ulcerative colitis [UC]), and environment (e.g., social determinants of health [SDOH]) may all contribute to the disease burden. Whether SDOH contributes to the symptomatic burden of UC in deep remission is unclear. METHODS We performed a secondary analysis on prospectively collected data from adults with UC enrolled in the biobank at a tertiary referral center in southern California from 2014-2021. Standardized clinical (unweighted two-item patient-reported outcome [PRO-2] for stool frequency [SF] and rectal bleeding [RB]; remission=SF0/RB0), endoscopic (Ulcerative Colitis Endoscopic Index of Severity [UCEIS]; remission UCEIS=0), and histologic (Geboes score; remission <2B.0) disease activity assessments were performed within 30 days of a colonoscopy (case) with segmental colonic biopsies. SDOH were assessed using the California Healthy Places Index (SDOH Index), a publicly available zip code-based system that ranks SDOH domain and subdomain scores from the least to most healthy (0-100 percentile) using weighted z-scores. Patients without SDOH scores (e.g., reside outside of California; n=88 cases) were excluded. We used χ2-square and Wilcoxon-Mann Whitney tests to investigate for associations between SDOH factors (non-parametric, independent variables dichotomized as below vs above the median) and cardinal GI symptoms (continuous unweighted PRO-2 symptomatic severity and dichotomized clinical remission/active disease), patient-, and disease-related factors. In adults with UC in endoscopic or endo-histologic remission, we used univariate logistic regression to assess the risk of health disadvantage (SDOH score below median) and the presence of GI symptoms. RESULTS Of the 166 UC cases, 46% (76/166), 38% (63/166), and 30% (49/166) were in clinical, endoscopic, and endo-histologic remission, respectively. Approximately one-fifth of cases (21%, 35/166) had SDOH scores below the state median. However, health disadvantage (below SDOH index median) was not associated with clinical, endoscopic, or endo-histologic disease activity; and neither were IBD duration; gender or race/ethnicity (all p>0.05) (Tab 1). Approximately one-third of cases had active GI symptoms despite endoscopic (32%, 20/63) and endo-histologic remission (29%, 14/49). However, none of the eight investigated SDOH domains were associated with increased risks for GI symptoms when UC had objective mucosal healing on colonoscopy (Tab 2) CONCLUSION Although one-third of adults with mucosal healing of UC report GI symptoms (diarrhea/rectal bleeding), there was no association with multiple social determinants of health factors (e.g., education, neighborhood, economic, social, and environmental) in this secondary analysis of a prospective cohort.

Mayo Endoscopic Score (MES) as a reference for the histological active disease of ulcerative colitis

Background: The degree of inflammation dramatically affects the morbidity of ulcerative colitis. Local and systemic inflammation features are modalities to determine disease severity and evaluation. Furthermore, local inflammation can be seen from endoscopic and histological examinations. This study aimed to examine the relationship of histological inflammatory profile with endoscopic scoring in ulcerative colitis patients. Method: A retrospective study was conducted using colonoscopic and histologic data from 68 ulcerative colitis patients. The endoscopic grade was assessed based on the Mayo Endoscopic Score (MES). The histological grade was analyzed using a microscope by assessing acute and chronic inflammatory cells and the presence of ulceration and crypt changes based on the Nancy Score Index and Geboes Score Index. Furthermore, the analysis test used Spearman and Mann-Whitney. Results: There is a significant positive relationship between endoscopic and histology scoring. The Nancy Score Index and MES combination yields 95% CI: 0.000-0.043, p=0.000, Correlation coefficient (r)=0.810, and odds ratio (OR)=3.272. Meanwhile, the combination of the Geboes Score Index with MES yields 95% CI: 0.000-0.043; p=0.000; r=0.727; and OR=1.347. In each histological scoring, there was a significant difference between the Nancy Score Index and Geboes Score Index tα (r = 0.018; p<0.05). Conclusion: There is a significant relationship between histological and endoscopic scoring. Therefore, an endoscopic examination can be a reference for histologically active disease.

Knowledge and attitudes towards the use of histological assessments in ulcerative colitis by gastroenterologists vs pathologists.

Histological remission is increasingly accepted as a treatment endpoint in the management of ulcerative colitis (UC). However, the knowledge of histology guidelines and the attitudes towards their use in clinical practice by gastroenterologists and pathologists is unknown. To evaluate the knowledge of histology guidelines and attitudes towards the use of histology in UC by gastroenterologists and pathologists. A prospective, cross-sectional nationwide survey of gastroenterologists and pathologists who analyse UC specimens was conducted. The survey consisted of 34 questions to assess gastroenterologists' and pathologists' knowledge (score out of 19) and attitudes towards histological assessment in UC. Survey questions were formulated using the European Crohn's and Colitis position paper on histopathology and the British Society of Gastroenterology biopsy reporting guidelines. It included knowledge of histological assessment of disease activity and dysplasia, knowledge of histological scoring systems for ulcerative colitis, uptake of histology scoring systems in routine practice, attitudes towards the role of histological activity, and the use of histological activity in clinical scenarios. Of 89 responders (77 gastroenterologists, 12 pathologists), there was almost universal acceptance that histological assessment should form part of UC evaluation [95% gastroenterologists, 92% pathologists]. However, gastroenterologists reported that 92% of their pathologists do not use a histological scoring system. Utilisation of a formal histological scoring system was preferred by 77% of gastroenterologists and 58% of pathologists. Both groups lacked awareness of the Geboes Score, Nancy Index and Robarts Histopathological Index scoring systems with 91%, 87%, and 92% of gastroenterologists respectively; and 83%, 83%, and 92% pathologists respectively, being uncertain of scoring systems' remission definitions. Histology knowledge score was not significantly different between gastroenterologists and pathologists [9/19 (IQR: 8-11) vs 8/19 (IQR: 7-10), P = 0.54]. Higher knowledge scores were predicted by hospital attending gastroenterologists (P = 0.004), participation in inflammatory bowel disease (IBD) multidisciplinary teams (P = 0.009), and self-declared IBD sub-specialist (P = 0.03). Histological remission is a recognised target for both gastroenterologists and pathologists. Despite this, knowledge of histological scoring systems and their utilisation is poor.

S16 Association of Quality of Life With Clinical Remission, HEMR, and Bowel Urgency in Patients With Ulcerative Colitis Treated With Mirikizumab

Background: Mirikizumab, a p19-directed anti-IL-23 antibody, has demonstrated efficacy and safety in patients with moderately-to-severely active ulcerative colitis (UC) in the Phase 3 LUCENT-1 induction trial (NCT03518086) and LUCENT-2 maintenance trial (NCT03524092). Secondary analyses of LUCENT trials showed that mirikizumab treated patients had significantly improved quality of life compared to patients with placebo. This analysis evaluated the relationships between quality of life assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ) and patients’ status of achieving clinical remission, histologic-endoscopic mucosal remission (HEMR), bowel urgency clinically meaningful improvement (CMI), and bowel urgency remission. Methods: In LUCENT-1, 1,281 patients were randomized 3:1 to mirikizumab 300 mg intravenous infusion or placebo every 4 weeks (Q4W). Patients who achieved clinical response to mirikizumab by Week 12 (W12) of induction (N=544), were re-randomized 2:1 to subcutaneous mirikizumab 200mg or placebo Q4W for 40 weeks in LUCENT-2 (52-weeks of continuous treatment). The primary endpoint was proportion of patients with clinical remission at W12 in LUCENT-1 and Week 40 in LUCENT-2. The clinical outcomes of interest in this analysis include: IBDQ (a 32-item patient-completed questionnaire with higher scores indicating better disease-specific quality of life ), clinical remission (stool frequency subscore = 0 or 1 with a ≥1-point decrease from baseline; rectal bleeding subscore = 0; and endoscopic subscore (ES)= 0 or 1), HEMR (Geboes score of ≤2B and ES = 0 or 1), and bowel urgency [assessed using the Urgency Numeric Rating Scale (UNRS), a 11-point scale ranging from 0 (“no urgency”) to 10 (“worst possible urgency”)]. Bowel urgency CMI is a ≥3-point change and bowel urgency remission is a UNRS score of 0 or 1, both among patients with a baseline UNRS of ≥3. Association between IBDQ total score change from baseline and clinical outcomes were assessed at W12 and Week 52 (W52) using analysis of covariance models adjusting for treatment, clinical parameter, baseline IBDQ value, and randomization stratification factors. Results: Overall, significantly greater increase in IBDQ total score were observed in patients who achieved clinical remission, HEMR, bowel urgency CMI or bowel urgency remission compared to those who did not. As for patients treated with mirikizumab, the least square mean (LSM) change of IBDQ total score [LSM(SE)] by clinical outcome status (Yes vs No) were: Clinical Remission: W12: 55.0 (2.02) vs 33.7 (1.16), P< 0.001; W52: 60.7 (2.38) vs 39.8 (2.43), P< 0.001; HEMR: W12: 50.3 (2.15) vs 35.2 (1.19), P< 0.001; W52: 59.3 (2.60) vs 43.4 (2.40), P< 0.001; Bowel Urgency CMI: W12: 52.8 (1.41) vs 27.4 (1.36), P< 0.001; W52: 62.5 (2.20) vs 34.4 (2.77), P< 0.001; and Bowel Urgency Remission: W12: 57.6 (1.92) vs 32.3 (1.15), P< 0.001; W52: 64.9 (2.54) vs 40.8 (2.18), P< 0.001. Placebo-treated patients were similar to the mirikizumab group across the studied clinical outcomes endpoints, with smaller magnitude of IBDQ improvements. Conclusion(s): The achievement of clinical remission, histologic-endoscopic mucosal remission, bowel urgency clinically meaningful improvement and bowel urgency remission was associated with significant improvement in quality of life by IBDQ in patients with UC from LUCENT-1 and 2 trials.

Psychometric evaluation of the Urgency NRS as a new patient-reported outcome measure for patients with ulcerative colitis

BackgroundThe Urgency Numeric Rating Scale (NRS) was developed as a content-valid single-item patient-reported outcome measure to assess severity of bowel urgency. Here, we evaluated the psychometric properties of the Urgency NRS.MethodsData were from a multicenter, randomized, placebo-controlled phase 3 trial in adults with moderately to severely active ulcerative colitis (NCT03518086). Patients completed the Urgency NRS using a daily electronic diary, from which weekly average Urgency NRS scores were calculated. Test–retest reliability, known-groups validity, construct validity, responsiveness, and score interpretation were assessed using the modified Mayo score, Inflammatory Bowel Disease Questionnaire (IBDQ), Patient Global Rating of Severity (PGRS), Patient Global Rating of Change (PGRC), and Geboes score.ResultsThe study sample comprised 1,162 participants (40.2% female). Mean Urgency NRS score was higher (worse) at baseline than at week 12 (6.2 vs. 3.7). Test–retest reliability was strong, with intra-class correlation coefficients of 0.76–0.89. Baseline least-square mean Urgency NRS score was higher for participants with a PGRS score greater than the median (worse symptoms) than for those with a PGRS score less than or equal to the median (7.5 vs. 5.4; p < 0.0001), indicating good known-groups validity. Urgency NRS score was moderately correlated with IBDQ total and domain scores, PGRS, PGRC, and modified Mayo stool frequency, establishing its convergent validity. Correlations were weak for Geboes score and weak to moderate for modified Mayo endoscopic subscore and modified Mayo rectal bleeding, indicating that the Urgency NRS also had discriminant validity. Patients achieving clinical remission, clinical response, IBDQ remission, and PGRS score improvement showed significantly greater improvement on the Urgency NRS (p < 0.0001 for all), demonstrating responsiveness to change. A ≥ 3-point improvement in Urgency NRS score represented a meaningful improvement in bowel urgency and an Urgency NRS score of ≤ 1 point represented a bowel urgency remission threshold that was closely associated with clinical, endoscopic, and histologic remission.ConclusionsThe Urgency NRS is a valid and reliable patient-reported outcome measure that is suitable for evaluating treatment benefits in clinical trials in patients with moderately to severely active ulcerative colitis.

S1028 Symptoms and Laboratory Values as Proxies for Endoscopic and Histologic Clinical Endpoints in Ulcerative Colitis: A Mediation Analysis Based on Upadacitinib Phase 3 Induction Trials

Introduction: We evaluate the extent to which commonly available measures in clinical practice (i.e., signs, symptoms, and laboratory values) mediate endoscopy-based clinical measures. Methods: We analyzed, in the intent-to-treat population from upadacitinib’s (UPA) phase 3 induction trials (U-ACHIEVE Induction, U-ACCOMPLISH in moderately to severely active UC, relationships between deep mucosal healing (DMH), histologic endoscopic mucosal improvement (HEMI), and change from baseline in endoscopic score as outcomes, and signs/symptoms and lab values as mediators (fecal calprotectin, high sensitivity C-reactive protein [hs-CRP], abdominal pain [AP], bowel urgency [BU], and Partial Adapted Mayo Score [PA-Mayo]). The mediated proportion of effect at week (wk) 8 was calculated as the difference in mean outcomes due to a one-unit change in mediators while controlling for baseline characteristics.The effects of mediators at wks 2 and 8 were assessed. Analyses assumed mediators were unrelated to each other and used linear models for all variables. Missing values for DMH and HEMI at wk 8 were imputed via non-responder imputation per trial protocol, while other variables were analyzed as-observed. Standard errors were computed via bootstrap. Results: A total of 878 patients were included; mean (standard deviation [SD]) age was 42.9 (14.4) years and disease duration was 8.0 (7.2) years. At wk 8, 9.0% of patients achieved DMH and 25.7% achieved HEMI, and mean (SD) change from baseline of the endoscopic score was -0.70 (0.97). All outcomes were mediated by PA-Mayo and BU (Table). PA-Mayo mediated around a third of the total effect for all outcomes with similar mediation at wk 2 and 8 (all P< 0.05). The proportion mediated by BU was larger at wk 8 and ranged from one to two thirds of the total effect (all P< 0.05 except for wk 2 for DMH). In contrast, hs-CRP at wk 2 only mediated 2-3% across outcomes (all P< 0.05). The predictive power of the models was similar using wk 2 and 8 mediators and explained 15% (DMH), 40% (HEMI), and 50% (endoscopic score) of variation. Conclusion: Our study found that easily accessible measures such as Partial Adapted Mayo Score and bowel urgency can mediate endoscopy-based endpoints for UC as early as wk 2 of induction, with mediation effects persisting for concurrently assessed signs and symptoms. Our findings suggests that symptom-based measures for UC in clinical practice could be useful proxies for endoscopic and histologic outcomes. Table 1. - Proportion mediated as estimated from mediation analyses for week 8 outcomes using week 2 or week 8 mediators Deep mucosal healingc HEMId Change from baseline in endoscopic score Variance explained Week 2 (R2= 0.15b) Week 8 (R2= 0.15 b) Week 2 (R2= 0.39 b) Week 8 (R2= 0.40 b) Week 2 (R2= 0.50 b) Week 8 (R2= 0.52 b) Bowel urgency, proportion mediated, %a 30.2 66.2* 48.12* 49.4* 37.4* 45.1* Partial Adapted Mayo Score, proportion mediated, %a 33.6* 30.1* 34.6* 33.2* 27.6* 29.1* Abdominal pain, proportion mediated, %a -4.3 -17.4 -13.7 0.4 -5.1 -5.0 hs-CRP (mg/L), proportion mediated, %a 1.8* -0.1 2.6* 1.3 2.3* 1.3 Fecal calprotectin (mg/kg), proportion mediated, %a -0.0 -1.7 -0.0 -1.6 -0.2 -1.9 Abbreviations: HEMI: Histologic Endoscopic Mucosal Improvement, hs-CRP: High sensitivity C-reactive protein.* denotes statistical significance (alpha < 0.05).Note: [a] Proportion mediated denotes the proportion of the mediated effect of changing one unit of the mediator relative to the total effect; for fecal calprotectin, a change of 100 mg/kg was considered.[b] The R2 was calculated for the model regressing the outcome on all control variables and all mediators.[c] Deep mucosal healing was defined as endoscopic score of 0 and Geboes score < 2.0.[d] HEMI was defined as endoscopic score of 0 or 1 and Geboes score ≤ 3.1.

S814 Bile Acid Malabsorption Is a Common Risk Factor for Diarrhea in Adults With Mucosal Healing in Crohn’s Disease

Introduction: Bile acid malabsorption (BAM) accounts for over one-quarter of patients with diarrhea-predominant irritable bowel syndrome (IBS-D) and chronic diarrhea. However, the prevalence of BAM in adults with Crohn’s disease (CD) independent of ileal resection is not well characterized. We herein aim to identify the prevalence of BAM and determine its associations with diarrhea in adults with mucosal healing of CD on ileocolonoscopy. Methods: We analyzed a prospective cohort of adults with CD enrolled at a single institution biobank who underwent ileocolonoscopies from Jun 2014 to Mar 2021. Exclusion criteria were isolated upper GI CD (n=1) or prior bowel resection (n=9). Diarrhea was defined as an average of >3 liquid or very soft stools per day (SF>3) on the 2-item patient-reported outcome (PRO-2) measure over a 7-day period starting 48 hours before beginning bowel preparation. Endoscopic remission was defined as ≤2 on the Simple Endoscopic Score for Crohn's Disease (SES-CD). Histologic remission was defined as Geboes score < 2B.0 on biopsies from pre-determined ileocolonic segments (terminal ileum; ascending, descending, and rectosigmoid colon). Serum concentrations of 7α-hydroxy-4-cholesten-3-one (7C4), a precursor bile acid synthesis, were measured by liquid chromatography and mass spectrometry (Prometheus Laboratories) with BAM defined as a concentration ≥48.3 ng/mL (PMID: 30448597). We performed univariable analysis (χ2) and multivariable logistic regression to identify factors associated with diarrhea. Results: In 181 patients with CD in endoscopic remission, 29% (53/181) had diarrhea, and 29% (40/136) of those with 7C4 testing had BAM. Increased risk for diarrhea existed among those with BAM (OR 4.6, 95% CI 2.1-10.3, p< 0.01) and females (OR 2.2, 95% CI 1.1-4.3, p=0.02) (Table). On multivariate analysis, only BAM was a predictor of diarrhea (aOR 4.0, 95% CI 1.5-10.8, p< 0.01), but gender, ethnicity, and CD phenotype/location/duration were not predictors (Figure). Of the 57 patients with CD in endoscopic and histologic (endo-histologic) remission, BAM remains a risk factor for diarrhea (26%, 15/57; OR 35.8, 95% CI 6.9-184.2, p< 0.01). Conclusion: Bile acid malabsorption occurred in 29% and 26% of our cohort of adults with Crohn’s disease in endoscopic remission and endo-histologic remission, respectively, and conferred a 4-fold increased risk for diarrhea despite mucosal healing in Crohn’s disease.Figure 1.: Multivariable analysis of factor associated with diarrhea in adults with Crohn’s disease in endoscopic remission Key: aOR; adjusted odds ratio. CD, Crohn’s disease. Multivariable analysis of factor associated with diarrhea in adults with Crohn’s disease in endoscopic remission. Independent variables gender, ethnicity; CD phenotype, location, duration; and bile acid malabsorption. Dependent variable: diarrhea (SF >3) or diarrhea (stool frequency, SF >3). Table 1. - Crohn’s disease in Endoscopic remission (N=181) Characteristics n (%) Diarrhea (n=53) No Diarrhea (n=128) p-value OR (95% CI) p-value Gender 0.02 Female 36 (68%) 63 (49%) 2.2 (1.1-4.3) 0.02 Male 17 (32%) 65 (51%) Ref / Ethnicity 0.38 Caucasian Non-Caucasian 39 (74%) 101 (80%) 0.7 (0.3-1.5) 0.38 Missing n=1 14 (26%) 26 (20%) Ref / CD phenotype 0.08 Inflammatory Stricturing 18 (43%) 65 (63%) Ref / Fistulizing 12 (29%) 20 (19%) 2.2 (0.9-5.3) 0.0871 Missing n=36 12 (29%) 18 (17%) 2.4 (1.0-5.9) 0.0551 CD disease location Ileal Colonic Ileocolonic Missing n=22 0.14 22 (47%) 36 (32%) 1.5 (0.6-3.4) 0.38 14 (28%) 31 (28%) Ref / 12 (26%) 45 (40%) 0.6 (0.3-1.6) 0.33 CD duration 11 (21%)16 (31%)25 (48%) 31 (25%)51 (41%)43 (63%) 0.23 Ref0.9 (0.4-2.1)1.6 (0.7-3.8) /0.790.25 < 5 years 5-15 years >15 years Missing n=4 Bile acid malabsorption < 0.01 < 0.01 Yes No 22 (52%) 18 (19%) 4.6 (2.1-10.3) Missing n=45 20 (48%) 76 (81%) Ref Key: CD, Crohn’s disease; OR, odds ratio.

Long-Term Outcomes of Early vs Delayed Responders to Vedolizumab and Adalimumab: A Post Hoc Analysis of the VARSITY Study.

It is uncertain whether patients with ulcerative colitis (UC) and delayed symptomatic response to therapy have as robust and durable a response as earlier responders to therapy. We compared clinical outcomes of early and delayed responders to vedolizumab and adalimumab for patients with moderate-severe UC. This was a post hoc analysis of the VARSITY study. Patients with early partial Mayo score (PMS) remission (PMS ≤1 at week 4/6 of therapy) were compared with those with delayed PMS remission (PMS ≤1 at week 14 and not week 4/6). Differences in proportions of patients achieving week 52 clinical remission (CR) (PMS = 0), endoscopic improvement (EI) (Mayo endoscopic subscore ≤1), and histoendoscopic mucosal improvement (HEMI) (Mayo endoscopic subscore ≤1 and Geboes score highest grade <3.2) were assessed. Confounders were adjusted for using multivariate logistic regression. A total of 147 vedolizumab-treated and 110 adalimumab-treated patients attained early or late PMS remission. Those who attained early PMS remission with vedolizumab were more likely to attain week 52 CR than participants with delayed PMS remission with vedolizumab (69.1% [67/97] vs 50.0% [25/50], aOR 2.43 [95% CI 1.11-5.33], P = 0.027). Week 52 HEMI was more likely among early vedolizumab PMS remitters (63.9% [62/97] vs 40.0% [20/50], aOR 2.60 [95% CI 1.20-5.62], P = 0.015). Week 52 EI was similar between early and delayed PMS remitters to vedolizumab. No differences were observed in week 52 CR, EI, or HEMI between early and delayed PMS remitters to adalimumab. Patients with UC who achieve early PMS remission with vedolizumab have greater odds of week 52 remission compared with delayed responders.

Impact of Endoscopic and Histologic Activity on Disease Relapse in Ulcerative Colitis.

Endoscopic healing is currently considered the main target in the management of ulcerative colitis (UC). There are conflicting data about the role of histology as a stricter treatment objective. We aim at evaluating the additional benefit of histologic remission over endoscopic remission. We performed a prospective observational study at the McGill University Health Center. We enrolled adult patients with UC in clinical remission for at least 3 months undergoing a colonoscopy. Endoscopic disease activity was based on the Mayo endoscopic score. Rectal biopsies were obtained, and the histologic activity was evaluated using the Geboes score (active disease defined as Geboes score ≥ 3.1) with the addition of assessing the presence of basal plasmacytosis. Patients were followed up for 12 months for disease relapse defined as a partial Mayo score of > 2. At the time of relapse or end of follow-up, all patients underwent repeat endoscopic evaluation. The primary end point was clinical relapse. Two hundred fifty-three patients were included. The presence of basal plasmacytosis was associated with relapse (adjusted odd ratio = 2.07, 95% confidence interval [CI] 1.06-4.18, P = 0.042). Time to clinical relapse was significantly higher for patients with Mayo endoscopic score > 0 with adjusted hazard ratio = 2.65, 95% CI 1.31-5.39, and P = 0.007. Time to clinical relapse was not significantly higher for Geboes score ≥ 3.1 with adjusted hazard ratio = 1.29, 95% CI 0.67-2.49, and P = 0.45. Active histologic disease did not affect time to clinical relapse in patients with UC who achieved endoscopic remission while the presence of basal plasmacytosis is associated with relapse.

CORE-IBD: A Multidisciplinary International Consensus Initiative to Develop a Core Outcome Set for Randomized Controlled Trials in Inflammatory Bowel Disease

End points to determine the efficacy and safety of medical therapies for Crohn's disease (CD) and ulcerative colitis (UC) are evolving. Given the heterogeneity in current outcome measures, harmonizing end points in a core outcome set for randomized controlled trials is a priority for drug development in inflammatory bowel disease. Candidate outcome domains and outcome measures were generated from systematic literature reviews and patient engagement surveys and interviews. An iterative Delphi process was conducted to establish consensus: panelists anonymously voted on items using a 9-point Likert scale, and feedback was incorporated between rounds to refine statements. Consensus meetings were held to ratify the outcome domains and core outcome measures. Stakeholders were recruited internationally, and included gastroenterologists, colorectal surgeons, methodologists, and clinical trialists. A total of 235 patients and 53 experts participated. Patient-reported outcomes, quality of life, endoscopy, biomarkers, and safety were considered core domains; histopathology was an additional domain for UC. In CD, there was consensus to use the 2-item patient-reported outcome (ie, abdominal pain and stool frequency), Crohn's Disease Activity Index, Simple Endoscopic Score for Crohn's Disease, C-reactive protein, fecal calprotectin, and co-primary end points of symptomatic remission and endoscopic response. In UC, there was consensus to use the 9-point Mayo Clinic Score, fecal urgency, Robarts Histopathology Index or Geboes Score, fecal calprotectin, and a composite primary end point including both symptomatic and endoscopic remission. Safety outcomes should be reported using the Medical Dictionary for Regulatory Activities. This multidisciplinary collaboration involving patients and clinical experts has produced the first core outcome set that can be applied to randomized controlled trials of CD and UC.

Endoscopic mucosal healing and histologic remission in ulcerative colitis: a systematic literature review of clinical, economic and quality-of-life outcomes

Objective This systematic literature review (SLR) assessed the effects of endoscopic mucosal healing and histologic remission on clinical, quality-of-life (QoL), and economic outcomes in adults with ulcerative colitis (UC) in the real-world setting. Methods Literature searches of Embase and MEDLINE (6 July 2020) and conference proceedings (2017–2020) were performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Eligible studies included adults with UC with documented endoscopic mucosal healing or histologic remission. Clinical, QoL, and economic outcomes were extracted and narratively synthesized. Results Of 1603 studies screened, 25 met eligibility criteria and collectively included 2813 patients (mean age: 34–60 years). The most commonly reported indices were Mayo endoscopic score (MES) for endoscopic mucosal healing (n = 22, 88%) and Geboes score (n = 5, 20%) for histologic outcomes. The most frequently reported clinical outcome was relapse-free survival (n = 15, 60%). Less commonly reported outcomes were avoidance of colectomy (n = 5, 20%), hospitalization (n = 4, 16%), clinical remission (n = 4, 16%), and steroid-free clinical remission (n = 3, 12%). Most studies reported relapse-free survival rates up to 50% over 6 to 48 months of follow-up in endoscopic mucosal healing cohorts. Studies reporting results by MES demonstrated higher relapse-free survival rates among patients with MES 0 than with MES 1 (32%–100% vs 26%–86%, respectively). Similarly, patients with histologic remission had better relapse-free survival rates over 12 to 24 months of follow-up compared with those without histologic remission (72%–91% vs 40%–63%, respectively). Rates of clinical remission, steroid-free remission, hospitalization, and colectomy avoidance were also better among patients with endoscopic mucosal healing and histologic remission. Two studies examining QoL reported endoscopic mucosal healing was associated with improved QoL. No study reported economic outcomes. Conclusions This SLR demonstrated consistent evidence of improved clinical outcomes among UC patients with endoscopic mucosal healing and histologic remission.

Low Fecal Calprotectin Predicts Histological Healing in Patients with Ulcerative Colitis with Endoscopic Remission and Leads to Prolonged Clinical Remission.

Consensus regarding the cutoff value of fecal calprotectin (FC) for predicting histological healing (HH) in ulcerative colitis (UC) is lacking. This study aimed to determine an optimal FC cutoff value for predicting HH in patients with UC with clinical and endoscopic remission. Furthermore, FC's predictability for prolonged clinical remission (CR) was investigated. Patients with UC in clinical and endoscopic remission, defined as a partial Mayo score (PMS) ≤ 2 points and a Mayo endoscopic subscore 0-1, were prospectively enrolled. Biopsy samples were evaluated by Geboes score (GS), with HH defined as a GS < 2.0. Patients were followed for 2 years or until relapse, defined as a PMS > 2 or medication escalation. Seventy-six patients with UC were included. The median FC value in patients with HH (n = 40) was 56.2 µg/g, significantly lower than that in those with histological activity (118.1 µg/g; P < .01). The area under the curve (AUC) in a receiver operating characteristic (ROC) curve analysis to predict HH for FC was 0.71 (95% confidence interval [CI], 0.59-0.83), with an optimal cutoff value of 82.7 µg/g (73% sensitivity; 64% specificity; P < .01). Of 74 patients observed for 2 years, 54 (73%) had prolonged CR. In the ROC curve analysis, the AUC to predict prolonged CR for FC was 0.79 (95% CI, 0.68-0.90), equivalent to that for HH (0.73; 95% CI, 0.64-0.86; P = .40). The optimal FC cutoff value to predict prolonged CR was 84.6 µg/g (72% sensitivity; 85% specificity; P < .01). Fecal calprotectin < 82 µg/g predicts HH in patients with UC with clinical and endoscopic remission. Low FC leads to prolonged CR, equivalent to HH.

One-year clinical efficacy and safety of indigo naturalis for active ulcerative colitis: a real-world prospective study.

Background/Aims Recent studies suggested a favorable effect of indigo naturalis (IN) in inducing remission for refractory ulcerative colitis (UC), however, the maintenance effect of IN for patients with UC remains unknown. Therefore, we conducted a prospective uncontrolled open-label study to analyze the efficacy and safety of IN for patients with UC.Methods Patients with moderate to severe active UC (clinical activity index [CAI] ≥ 8) took 2 g/day of IN for 52 weeks. CAI at weeks 0, 4, 8, and 52 and Mayo endoscopic subscore (MES) and Geboes score (GS) at weeks 0, 4, and 52 were assessed. Clinical remission (CAI ≤ 4), mucosal healing (MES ≤ 1), and histological healing (GS ≤ 1) rates at each assessment were evaluated. Overall adverse events (AEs) during study period were also evaluated. The impact of IN on mucosal microbial composition was assessed using 16S ribosomal RNA gene sequences.Results Thirty-three patients were enrolled. The rates of clinical remission at weeks 4, 8, and 52 were 67%, 76%, and 73%, respectively. The rates of mucosal healing at weeks 4 and 52 were 48% and 70%, respectively. AEs occurred in 17 patients (51.5%) during follow-up. Four patients (12.1%) showed severe AEs, among whom 3 manifested acute colitis. No significant alteration in the mucosal microbial composition was observed with IN treatment.Conclusions One-year treatment of moderate to severe UC with IN was effective. IN might be a promising therapeutic option for maintaining remission in UC, although the relatively high rate of AEs should be considered.

Histological Indices and Risk of Recurrence in Crohn's Disease: A Retrospective Study of a Cohort of Patients in Endoscopic Remission.

Although histological healing is raising interest in ulcerative colitis to predict recurrence, its meaning in Crohn's disease (CD) remains unknown. We aimed to study the performances of different histological indices to predict recurrence of CD patients with mucosal healing. Crohn's disease patients with mucosal healing diagnosed between 2010 and 2018 were included if there was available clinical and endoscopical data. Nancy Histological index (NHI), Geboes score (GS), Robarts Histopathology index (RHI), Global Histological Disease Activity Score (GHAS), and Inflammatory Bowel Disease-Distribution Chronicity Activity score (IBD-DCA) were independently assessed by 3 pathologists. Eighty-eight patients were included, of which 28 relapsed (32%) within 30.5 months. All 4 histological indices were associated with recurrence, with significant relapse risk (NHI, odds ratio [OR], 1.67; GHAS, OR, 2.33; RHI, OR, 1.19; GS, OR, 2.09; and IBD-DCA, OR, 2.14). Microscopic activity was significantly associated with relapse only with the IBD-DCA score. Predicting performances of all these scores were poor. Calibration curves indicate that the GHAS and IBD-DCA are the closest to the ideal predicted probability curve and thus could better predict recurrence than the other scores. Interobserver agreement varied from poor for GHAS (k = .39) to good for RHI (k = .68). Histological scores are valuable indicators to predict recurrence. Histological assessment of activity seems insufficient to predict CD course with most of the score evaluated, highlighting the need for new indices or adaptation of actual scores to CD specificities.