Nancy Index Research Articles

Predictive accuracy of fecal calprotectin for histologic remission in ulcerative colitis.

Accurate assessment of disease activity is crucial for effective management and treatment of ulcerative colitis (UC). This study evaluated the correlation between clinical, endoscopic, and histologic measures of disease activity in UC. Clinical, biochemical, endoscopic, and histologic disease activity was studied in 347 patients with UC. Agreements among various histologic classification systems, namely the Geboes Score (GS), Continuous GS, Nancy Index (NI), and Robarts Histopathology Index (RHI), were analyzed. The predictive accuracy of fecal calprotectin (FC) for endoscopic and histologic remission was assessed. We demonstrate a fair to moderate correlation between clinical, endoscopic, and histologic measures of disease activity in UC. There was a robust concordance among GS, Continuous GS, NI, and RHI in distinguishing between patients in histologic remission or activity. The NI detected 75% of patients who met the remission criteria according to the RHI, whereas the RHI identified all patients in remission as defined by the NI. FC levels below 150 μg/g had >70% accuracy in predicting endoscopic remission. FC levels below 150 μg/g showed ≥80% accuracy, and FC levels below 100 μg/g demonstrated ≥ 85% accuracy in predicting histologic remission, regardless of the scoring index applied. Elevated FC levels were associated with both acute and chronic inflammatory infiltrates in biopsy samples. FC is a reliable predictor of histologic remission, with higher accuracy at lower thresholds. The GS, Continuous GS, NI, and RHI demonstrate comparable performance. FC could help stratify patients' need for colonoscopy for the assessment of endoscopic and histologic remission.

Histologic healing and clinical outcomes in ulcerative colitis.

Growing evidence suggests histologic healing (HH) improves clinical outcomes in ulcerative colitis (UC) patients beyond endoscopic healing (EH). We hypothesize that HH is associated with better clinical outcomes in Asian UC patients, for whom data is lacking. We performed a retrospective study of UC patients in clinical remission (CR) with a follow-up colonoscopy and minimum 1-year follow-up post-colonoscopy. Primary outcome was clinical relapse (CRL), defined as either a Simple Clinical Colitis Activity Index score of > 2, medication escalation, hospitalization or colectomy. Predictors of CRL and HH were assessed. One hundred patients were included with a median follow-up of 22 months. At index colonoscopy, 80 patients were in EH. On follow-up, 41 patients experienced CRL. Of 80 patients in EH, 34 (42.5%) had persistent histologic activity (Nancy Index ≥ 2) and 29 (36.3%) relapsed during the follow-up period. Amongst patients in CR and EH, those with HH had lower CRL rate (26.1% vs. 50.0%, P= 0.028) and longer CRL-free survival (mean 46.1 months vs. 31.5 months, P= 0.015) than those with persistent histologic activity. On bivariable analysis of 100 patients in CR, HH, and Mayo endoscopic score (MES) of 0 were significantly associated with lower risk of CRL. On multivariable analysis, only MES 0 remained predictive of lower CRL risk. Above and beyond CR and EH, achieving HH improves clinical outcomes in Asian UC patients. However, HH may not confer incremental benefit if MES 0 has been achieved. Further prospective studies evaluating the benefit of histologically guided therapeutic decisions are needed.

Deployment of an Artificial Intelligence Histology Tool to Aid Qualitative Assessment of Histopathology Using the Nancy Histopathology Index in Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by increased stool frequency, rectal bleeding, and urgency. To streamline the quantitative assessment of histopathology using the Nancy Index in UC patients, we developed a novel artificial intelligence (AI) tool based on deep learning and tested it in a proof-of-concept trial. In this study, we report the performance of a modified version of the AI tool. Nine sites from 6 countries were included. Patients were aged ≥18 years and had UC. Slides were prepared with hematoxylin and eosin staining. A total of 791 images were divided into 2 groups: 630 for training the tool and 161 for testing vs expert histopathologist assessment. The refined AI histology tool utilized a 4-neural network structure to characterize images into a series of cell and tissue type combinations and locations, and then 1 classifier module assigned a Nancy Index score. In comparison with the proof-of-concept tool, each feature demonstrated an improvement in accuracy. Confusion matrix analysis demonstrated an 80% correlation between predicted and true labels for Nancy scores of 0 or 4; a 96% correlation for a true score of 0 being predicted as 0 or 1; and a 100% correlation for a true score of 2 being predicted as 2 or 3. The Nancy metric (which evaluated Nancy Index prediction) was 74.9% compared with 72.3% for the proof-of-concept model. We have developed a modified AI histology tool in UC that correlates highly with histopathologists' assessments and suggests promising potential for its clinical application.

Umbilical cord mesenchymal stem cells in ulcerative colitis treatment: efficacy and possible mechanisms

BackgroundMesenchymal stem cells (MSCs) possess powerful immunomodulatory ability. This study aimed to assess the efficacy and safety of human umbilical cord-derived mesenchymal stem cells (UMSCs) in patients with ulcerative colitis (UC) and to explore the potential mechanisms.MethodsThis prospective, self-controlled clinical study was conducted at Henan Provincial People’s Hospital. Patients with moderate-to-severe active UC, unresponsive to traditional drugs were continuously enrolled from September 2018 to March 2023. UMSCs were administered intravenously monthly for two months at a cell dosage of 1 × 106 per kg. The primary outcome was a clinical response at 2 months. The levels of cytokines and progerin in the plasma of the patients were analyzed using enzyme-linked immunosorbent assay kits, and longitudinal data was analyzed using generalized estimation equation.ResultsForty-one patients were enrolled and received UMSC therapy. At 2 months, 73.2% (30/41) of patients achieved a clinical response, and 41.5% (17/41) achieved a clinical remission. At 6 months, 2 patients were lost to follow-up; the corresponding figures were 70.0% (25/41) and 34.2% (14/41), respectively. After UMSC therapy, the Mayo score, Mayo endoscopy score, mean and maximum values of Ulcerative Colitis Endoscopic Index of Severity and Nancy index were significantly reduced compared with baseline values. Additionally, the levels of progerin and inflammatory markers, such as interleukin (IL)-1β, IL-6, IL-8, IL-12, and IL-17 A decreased, while hemoglobin, albumin, and IL-10/IL-17 A ratio increased, particularly in the response group. Multiple stepwise logistic regression analysis showed age was an independent risk factor affecting efficacy (odds ratio, 0.875 (95% confidence interval (0.787, 0.972)); the area under the receiver operating characteristic curve for age was 0.79. No serious adverse events were observed during or after UMSC therapy.ConclusionUMSCs are safe and effective for patients with UC, with age being an independent risk factor affecting efficacy. Mechanistically, UMSC treatment may ameliorate cell senescence and suppress the secretion of pro-inflammatory cytokines.Trial registrationThe study was retrospectively registered at www.chictr.org.cn/ (ChiCTR1900026035) on September 18, 2019.

Impact of completely histological remission on reducing flare-ups in moderate-to-severe, biologics-experienced ulcerative colitis patients with endoscopic remission

Background/purposeEndoscopic remission is presently recognized as the standard therapeutic target in the treatment of ulcerative colitis (UC). However, achieving histological remission is increasingly viewed as a pivotal objective. This study investigates the effects of attaining completely histological remission on the clinical outcomes for UC patients with a high disease burden who have already reached endoscopic remission. This is the inaugural study to concentrate on this specific patient demographic. MethodsThis retrospective cohort study enrolled moderate-to-severe, biologics-experienced UC patients with completely endoscopic remission (Mayo endoscopic subscore of 0) between June 2017 and October 2023 at Chang Gung Memorial Hospital, Linkou. Patients were classified into histological remission (HR) and non-histological remission (non-HR) groups based on the Nancy index (NI). HR was defined as an NI score of 0, with all other patients categorized as non-HR. The definition of flare-ups was based on both clinical and endoscopic evidence. Comparative analyses focused on baseline characteristics and clinical outcomes at follow-up. ResultsA total of 42 patients (HR group: 23, non-HR group: 19) were included. The average follow-up duration was 17.6 months. Baseline characteristics were comparable between the groups. At the end of follow-up, the HR group showed a significantly lower rate of acute flare-ups (26.1% vs. 68.4%, P = 0.006). Although not statistically significant, the HR group also experienced fewer emergency department visits and hospital admissions. ConclusionsFor moderate-to-severe, biologics-experienced UC patients in endoscopic remission, achieving completely histological remission is associated with a substantial reduction in flare-ups, suggesting its potential as a valuable therapeutic target.

Value of histological activity in predicting endoscopic relapse among patients of ulcerative colitis in endoscopic remission

Objective: To investigate the value of histological evaluation in predicting endoscopic relapse among patients with ulcerative colitis (UC) who were in endoscopic remission, and to compare the usefulness of various histological scoring systems. Methods: Histological sections from 61 patients with UC who were in endoscopic remission were retrospectively analyzed, at Peking University Third Hospital, Beijing, China from January 2015 to June 2021. They were subdivided into endoscopic persistent remission group (remission group, n=31, Mayo endoscopic score 0) and endoscopic relapse group (relapse group, n=30, Mayo endoscopic score≥1) according to the results of the first endoscopic reexamination after the biopsy. Histological evaluation was performed using the Geboes score (GS) and its simplified version (SGS), the Nancy index (NI) and the Robarts histopathological index (RHI). The median and maximum histological scores for each case in all biopsies were recorded. Univariate comparisons were performed using chi-squares and multivariate analysis using binary logistic regression. The values of four histological evaluation systems for predicting endoscopic relapse among UC patients in endoscopic remission were analyzed using receiver operating characteristic (ROC) curves. Results: Significant differences were observed between the remission and relapse groups. The differences were more pronounced in the maximum histological scores; the mean and highest results of area under the ROC curve scores (AUC) for GS, SGS, NI, and RHI were 0.657, 0.668, 0.682, 0.691, and 0.866, 0.863, 0.864, 0.869, respectively. The differences were statistically significant (P<0.05). The corresponding best cut-offs were GS≥2B.1, SGS≥2B.1, NI≥2, and RHI≥2.5, respectively, which meant mild active inflammation histologically, while there was no statistical difference of AUC among the four histological scoring indices (P>0.05). Univariate and multivariate analyses revealed statistically significant differences in the number of neutrophils in the epithelium and lamina propria (P<0.05). Conclusions: Biopsies from UC patients in endoscopic remission may still have histological active inflammation which appears to correlate with endoscopic relapse. Four commonly used histological scoring systems can be used to assess the risk of endoscopic relapse among UC patients in endoscopic remission. The patients who more likely have endoscopic relapse seem to have a histological score greater than the cut-off value (i.e., mild histological activity). The maximum histological scores can accurately predict the risk of endoscopic relapse, while the presence of epithelial and laminar propria neutrophil infiltrates can independently predict the endoscopic relapse in these patients. Considering the utility and convenience in routine practice, NI is recommended for evaluating histological inflammatory activity.

Adequacy of sigmoidoscopy as compared to colonoscopy for assessment of disease activity in patients of ulcerative colitis: a prospective study.

Patients of ulcerative colitis (UC) on follow-up are routinely evaluated by sigmoidoscopy. There is no prospective literature to support this practice. We assessed agreement between sigmoidoscopy and colonoscopy prospectively in patients with disease extent beyond the sigmoid colon. We conducted a prospective observational study at a tertiary care institute for agreement between sigmoidoscopy and colonoscopy. We assessed endoscopic activity using the Mayo Endoscopic Score (MES) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and histological activity using the Nancy Index (NI), Robarts Histopathology Index (RHI), and Simplified Geboes Score (SGS). Sigmoidoscopy showed a strong agreement with colonoscopy for MES and UCEIS with a kappa (κ) of 0.96 and 0.94 respectively. The misclassification rate for MES and UCEIS was 3% and 5% respectively. Sigmoidoscopy showed perfect agreement (κ = 1.00) with colonoscopy for assessment of the presence of endoscopic activity in the colon using MES ≥ 1 as activity criteria and strong agreement (κ = 0.93) using MES > 1 as activity criteria. Sigmoidoscopy showed strong agreement with colonoscopy for assessment of the presence of endoscopic activity using UCEIS (κ = 0.92). Strong agreement was observed between sigmoidoscopy and colonoscopy using NI (κ = 0.86), RHI (κ = 1.00), and SGS (κ = 0.92) for the detection of histological activity. The misclassification rate for the detection of histological activity was 2%, 0%, and 1% for NI, RHI, and SGS respectively. Sigmoidoscopy showed strong agreement with colonoscopy for endoscopic and histologic disease activity. Sigmoidoscopy is adequate for assessment of disease activity in patients with UC during follow-up evaluation.

Development and validation of a novel criterion of histologic healing in ulcerative colitis defined by inflammatory cell enumeration in lamina propria mucosa: A multicenter retrospective cohort in China.

Histological healing is closely associated with improved long-term clinical outcomes and lowered relapses in patients with ulcerative colitis (UC). Here, we developed a novel diagnostic criterion for assessing histological healing in UC patients. We conducted a retrospective cohort study in UC patients, whose treatment was iteratively optimized to achieve mucosal healing at Shanghai Tenth People's Hospital of Tongji University from January 2017 to May 2022. We identified an inflammatory cell enumeration index (ICEI) for assessing histological healing based on the proportions of eosinophils, CD177 + neutrophils, and CD40L + T cells in the colonic lamina propria under high power field (HPF), and the outcomes (risks of symptomatic relapses) of achieving histological remission vs . persistent histological inflammation using Kaplan-Meier curves. Intrareader reliability and inter-reader reliability were evaluated by each reader. The relationships to the changes in the Nancy index and the Geboes score were also assessed for responsiveness. The ICEI was further validated in a new cohort of UC patients from other nine university hospitals. We developed an ICEI for clinical diagnosis of histological healing, i.e., Y=1.701X 1 + 0.758X 2 + 1.347X 3 - 7.745 (X 1 , X 2 , and X 3 represent the proportions of CD177 + neutrophils, eosinophils, and CD40L + T cells, respectively, in the colonic lamina propria under HPF). The receiver operating characteristics curve (ROC) analysis revealed that Y <-0.391 was the cutoff value for the diagnosis of histological healing and that an area under the curve (AUC) was 0.942 (95% confidence interval [CI]: 0.905-0.979) with a sensitivity of 92.5% and a specificity of 83.6% ( P <0.001). The intraclass correlation coefficient (ICC) for the intrareader reliability was 0.855 (95% CI: 0.781-0.909), and ICEI had good inter-reader reliability of 0.832 (95% CI: 0.748-0.894). During an 18-month follow-up, patients with histological healing had a substantially better outcome compared with those with unachieved histological healing ( P <0.001) using ICEI. During a 12-month follow-up from other nine hospitals, patients with histological healing also had a lower risk of relapse than patients with unachieved histological healing. ICEI can be used to predict histological healing and identify patients with a risk of relapse 12 months and 18 months after clinical therapy. Therefore, ICEI provides a promising, simplified approach to monitor histological healing and to predict the prognosis of UC. Chinese Clinical Trial Registry, No. ChiCTR2300077792.

Effects of Thiopurine Withdrawal on Vedolizumab-Treated Patients With Ulcerative Colitis: A Randomized Controlled Trial

Background and aimsThe impact of thiopurine de-escalation whilst on vedolizumab versus continuing thiopurine therapy in ulcerative colitis (UC) is unclear. We aimed to determine the effect of thiopurine withdrawal for patients with UC in remission on vedolizumab. MethodsThis multi-centre randomized controlled trial recruited UC patients on vedolizumab 300mg IV every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore[MES]≤1) were randomized 2:1 to withdraw or continue thiopurine. Primary outcome was comparing week 48 vedolizumab trough concentrations. Secondary outcomes were clinical relapse (partial Mayo score≥3 and fecal calprotectin>150μg/g or increase in MES≥1 from baseline), fecal calprotectin remission (<150μg/g), C-reactive protein remission (<5mg/L), centrally-read endoscopic remission (MES=0), histologic remission (Nancy index=0), histo-endoscopic remission and adverse events. ResultsIn total, 62 patients were randomized to continue (n=20) or withdraw (n=42) thiopurine. At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7μg/mL [IQR:12.3-18.5μg/mL] versus 15.9μg/mL [IQR:10.1-22.7μg/mL] respectively, P=0.36). The continue group had significantly higher fecal calprotectin remission (95.0% [19/20] versus 71.4% [30/42], P=0.03), histologic remission (80.0% [16/20] versus 48.6% [18/37], P=0.02) and histo-endoscopic remission (75.0% [15/20] versus 32.4% [12/37], P=0.002) than the withdrawal group. Histological activity (HR:15.5 [95%CI:1.6-146.5],P=0.02) and prior anti-TNF exposure (HR:6.5 [95%CI:1.3-33.8],P=0.03) predicted clinical relapse after thiopurine withdrawal. ConclusionThiopurine withdrawal did not affect vedolizumab trough concentrations. However, it may increase fecal calprotectin, histologic and histo-endoscopic activity. Histological activity and prior anti-TNF exposure may predict disease relapse upon thiopurine withdrawal for patients using vedolizumab for UC; Australian and New Zealand Trial Registry, number ACTRN12618000812291.

An artificial intelligence-driven scoring system to measure histological disease activity in ulcerative colitis.

Assessment and scoring of histological images in Ulcerative colitis (UC) is prone to inter- and intra-observer variability. This study aimed to investigate whether an artificial intelligence (AI) system developed using image processing and machine learning algorithms could measure histological disease activity based on the Nancy index. A total of 200 histological images of patients with UC were used in this study. A novel AI algorithm was developed using state-of-the-art image processing and machine learning algorithms based on deep learning and feature extraction. The cell regions of each image, followed by the Nancy index, were manually annotated and measured independently by four histopathologists. Manual and AI-automated measurements of the Nancy index score were conducted and assessed using the intraclass correlation coefficient (ICC). The 200-image dataset was divided into two groups (80% was used for training and 20% for testing). Intraclass correlation coefficient statistical analyses were performed to evaluate the AI tool and used as a reference to calculate the accuracy. The average ICC among the histopathologists was 89.3 and the average ICC between histopathologists and the AI tool was 87.2. The AI tool was found to be highly correlated with histopathologists. The high correlation of performance of the AI method suggests promising potential for inflammatory bowel disease clinical applications. A standardized automated histological AI-driven scoring system can potentially be used in daily inflammatory bowel disease practice to reduce training needs and resource use, eliminate the subjectivity of the pathologists, and assess disease severity for treatment decisions.

P375 Histological activity predicts the risk of colectomy after biological treatment in biological-naive patients with Ulcerative Colitis

Abstract Background Treatment failure with biological agents is common in patients with ulcerative colitis (UC), but the impact of baseline histological disease activity is unknown. We aimed to investigate the predictive role of histopathological findings for biological treatment failure in UC patients. Methods This is a sub-study of the Danish IBD Biobank Project. Adult bio-naïve patients with UC (n=129) were followed prospectively while undergoing biological treatment. Histological activity was assessed using the Nancy Index and the Geboes score in intestinal biopsies sampled before treatment. Endoscopic activity was assessed using the Mayo Endoscopic Subscore, and clinical activity was measured using the Simple Clinical Colitis Activity Index (SCCAI). Associations between histological activity and treatment outcomes were assessed in multivariable models which incorporated the following fixed covariates: age, gender, disease duration, body mass index &amp;gt;30, disease extent, the SCCAI, and the Mayo Endoscopic Subscore. Correlations between histological, endoscopic, clinical, and biochemical activity were assessed using Spearman’s rank correlation. Results Colectomy was needed in 17.1% (n=22) of UC patients during follow-up (Table 1). Histological activity at baseline measured using the Nancy Index was the only significant predictor of the risk of colectomy during follow-up (Nancy 2 vs. 4: HR 0.14, 95% CI 0.02-0.84, p=0.03; Nancy 3 vs. 4: HR 0.11, 95% CI 0.02-0.53, p=0.01) beside baseline haemoglobin concentration (HR 0.32, 95% CI 0.16-0.64, p&amp;lt;0.01. Figure 1). The risk of colectomy was also significantly predicted by a Geboes grade above 5.0 at baseline (HR 2.72, 95% CI 1.14-6.50, p=0.02). In contrast, endoscopic and clinical activity did not predict the risk of colectomy. At baseline, the Nancy Index and the Geboes score were moderately correlated to endoscopic activity, and weakly, but significantly correlated to biochemical markers haemoglobin, albumin, and C-reactive protein. Meanwhile, poor correlations were found between histological activity and clinical activity. Conclusion The risk of colectomy during biological treatment in bio-naïve UC patients was significantly predicted by histological disease activity, but not endoscopic or clinical disease activity. Our study suggests that histological assessment before initiating biological treatment should be encouraged in UC patients. Funding This study is funded by a restricted grant from Takeda A/S, Louis-Hansen Fonden, and a public fund hosted by Hvidovre Hospital.

P246 Histologic remission is an important therapeutic target in patients who achieve endoscopic remission of ulcerative colitis

Abstract Background Histologic activity has been established as a crucial prognostic determinant in individuals diagnosed with ulcerative colitis(UC), while achieving histologic remission is increasingly recognized as a significant long-term therapeutic goal. However, the available literature still lacks adequate evidence concerning the selection of an optimal histological index and its utility in predicting prognosis Methods This retrospective study involved the analysis of medical records and endoscopic results from patients diagnosed with UC between January 2015 and December 2022. Endoscopic remission was defined as a Mayo endoscopic sub-score of ≤1. Histological assessment utilized the Nancy index, with a score of ≤1 indicating histological remission. Among patients with UC who achieved endoscopic remission, the study assessed the maintenance of remission and the occurrence of recurrence based on histological remission Results A total of 114 patients with UC who achieved mucosal healing were enrolled for histological evaluation. Among them, 16.7% (19/114) experienced flare-ups, and a statistically significant inverse correlation was observed with histologic remission (see Table). Multivariate analysis further identified non-histologic remission (Nancy index &amp;gt;2) as an independent risk factor for recurrence (Hazard ratio: 3.513, CI: 1.334-9.257, P=0.011). Particularly noteworthy was the significantly lower recurrence rate when histologic remission is achieved, especially in patients with MES 1 (see Figure) Conclusion Our study demonstrated a robust correlation between histologic remission assessed by the Nancy index and sustained clinical remission. The Nancy index, reflecting relatively straightforward histological activity, is considered a valuable metric that can aid in establishing treatment goals

P577 Histological Remission Leads to Less Endoscopic Flare-up in Moderate-to-Severe, Biologics Experienced Ulcerative Colitis Patients: A Comprehensive Retrospective Cohort Study

Abstract Background In the management of inflammatory bowel disease (IBD), adopting a treat-to-target strategy has proven beneficial. Current therapeutic targets primarily focus on achieving endoscopic remission. However, the significance of histological remission as a potential target. However, it remains underexplored in Asian populations. We aimed to investigate the role of histological remission in clinical outcomes among ulcerative colitis (UC) patients already in endoscopic remission. Methods In this retrospective cohort study, we enrolled moderate to severe, biologics experienced UC patients with endoscopic remission, defined as endoscopic Mayo subscore 0 point during June 2017 and September 2023 in Chang Gung Memorial Hospital, Linkou. Then the patients were divided into histological remission (HR) and non-histological remission (non-HR) groups according to histological Nancy index (NI). HR was defined as NI 0 point, and others belonged to non-HR group. Comparative analyses were performed between two groups regarding baseline characteristics, one year follow up and end of follow-up clinical outcomes. The location of biopsy was active inflammatory lesion, if no active lesion, we performed routine biopsy over rectum, 15cm level from anal verge. We took at least 4 pieces biopsy over each location. Results We enrolled 42 moderate-to-severe, biologics experienced UC patients (HR group, 23 patients and non-HR group, 19 patients) with endoscopic remission. The average follow-up duration was 17.6 months. In non-HR group, NI scores were categorized as follows: 1 point (42.1%), 2 points (31.6%), 3 points (21.1%), and 4 points (5.3%). Baseline characteristics showed no significant differences between the two groups. In terms of outcomes, the HR group demonstrated a significantly lower endoscopic relapse rate (26.1% vs. 68.4%, P=0.006) and better results in Kaplan-Meier survival analysis (log-rank P=0.015) at the end of the follow-up period. The HR group also exhibited a reduction in clinical relapses, emergency department visits, and hospital admissions. Although these differences did not attain statistical significance, this phenomenon is likely attributable to the study's constrained sample size. Conclusion In moderate-to-severe UC patients who are biologics-experienced and in endoscopic remission, achieving histological remission is associated with a reduced rate of endoscopic relapse.

P386 Persistence of bowel urgency despite clinical remission after induction therapy is associated with unfavorable long-term outcomes in patients with ulcerative colitis: results from the multicenter UC-RGENCY study

Abstract Background STRIDE 2 recommendations define clinical remission as no rectal bleeding and normalization of stool frequency in patients with ulcerative colitis (UC), without including bowel urgency (BU) despite its negative impact on quality of life. In this large multicenter cohort, we aimed to assess whether the persistence of BU after induction therapy is independently associated with poor long-term outcomes in patients with UC. Methods From a multicenter retrospective study, we included consecutive UC adult patients previously exposed to at least one anti-TNF agent, with partial Mayo score (pMS) &amp;gt; 2, who started biologics or small molecules between Jan2019 and June2022. BU was defined as a binary criterion based on the SCCAI definition. The primary endpoint was the time to drug discontinuation due to active UC. Secondary endpoints were time to relapse, time to colectomy as well as steroid-free clinical remission (pMS ≤ 2) (CFREM), endoscopic remission (CFREM + Mayo endoscopic score (MES) ≤ 1), and mucosal healing (CFREM + MES ≤ 1 + histological remission i.e. Nancy index ≤ 1) at last follow-up. Results Among 473 patients with UC, 270 were assessed for BU after induction therapy (week 16) (mean age 43.0±17.0 years-old, median UC duration 6 [3-11] years, female gender=54.0%, pancolitis=45.9%). The median follow-up was 14 [8-22] months. The rate of CFREM after induction therapy was 54.4% (147/270) while 21.5% (58/270) had remaining bowel urgencies after induction therapy. Among the 147 patients achieving remission after induction therapy, 12 had persistent BU (8.2%), while 62.6% (77/123) of patients with no CFREM after induction therapy did not have any BU. The agreements between BU and rectal bleeding (75.2%, κ-coefficient = 0.33±0.06) or normalization of stools frequency (67.9%,κ-coefficient = 0.35±0.05) were mild. Among the patients with persistent BU after induction therapy, only 3.7% had no endoscopic activity (MES = 0). In multivariable analyses including CFREM at week 16, persistence of BU after induction therapy was independently associated with the time to drug discontinuation (HR=2.0[1.1-3.5], p=0.016) and colectomy (HR=4.4[2.3-8.4], p&amp;lt;0.001), and absence of mucosal healing (OR = 5.0[1.1-24.8], p=0.046) at last follow-up. A trend was also observed regarding the association between remaining BU after induction therapy and no CFREM (OR=6.1[0.8-48.0], p=0.085) or absence of endoscopic remission (OR=2.4[0.9-6.1], p=0.077) at last follow-up. Conclusion Persistence of BU despite clinical remission is associated with higher risk of drug discontinuation due to active UC, colectomy and lower likelihood of mucosal healing. Bowel urgency should be implemented into international guidelines to define clinical remission in patients with UC.

P184 Challenging Barriers in Inflammatory Bowel Disease: First Observational Analysis of Double Biological Therapy in Mexico

Abstract Background Inflammatory bowel disease is a chronic inflammation of the GI tract, despite advances in treatment with biologic therapy, some patients may develop an inadequate response, known as refractory IBD (rIBD).Given this reality, the approach of double biological therapy (DBT) has emerged to effectively address and improve control of inflammation, providing them with an additional therapeutic option Methods Pilot prospective observational study evaluateing response to DBT in patients with refractory IBD Results A total of 7 patients with rIBD who received DBT were included, the average age was 29 ± 9, all female. The average duration of illness before starting dual therapy was 8 ± 2years. Patients had received an average of 2 previous biological treatments, 4 (57%) had a history of surgery related to IBD, 5 (71%) and 2(29%) had a history of stenosis and fistulas respectively and 100% used steroids and immunomodulators before starting DBT. Four DBT combinations were evaluated: CERTOLIZUMAB+VEDOLIZUMAB (group 1), USTEKINUMAB+VEDOLIZUMAB (group 2), INFLIXIMAB+USTEKINUMAB (group 3) and INFLIXIMAB+VEDOLIZUMAB (group 4).Group 1 included 1 patient with improvement in clinical activity, with a decrease in endoscopic activity from i4 to i2 by Rutgeerts criteria and Nancy index 1.Group 2 included 4 patients showed improvement in clinical and endoscopic activity, there was a reduction in clinical activity by CDAI from 225 to 66, and improvement in endoscopic activity from L1 B2 to L1 B1, i0 L2 B3P to i0 L1 B1 and i3 L3 B2 to i2 L3 B1 with different activity rates, Nancy's histology that varied from 0 to 3.Group 3 included 1 patient showed a reduction in clinical activity by CDAI from 210 to 166, endoscopic activity also decreased from i0 L2B3P to i0 L1 B1 with Nancy index of 2.Group 4 includes 1 with a decrease in clinical activity by Truelove-Witts from 2 to 2, endoscopic activity also decreased from 8 to 5 accordingto UCEIS with Nancy index of 1.In all groups, a reduction in the use of steroids was observed and no cases of infections associated with dual biological therapy were reported Conclusion This prospective observational pilot study represents the first analysis in Mexico and, to our knowledge, in Latin America, on the use of DBT in patients with rIBD who showed clinical, endoscopic and histopathological improvement in the majority of cases. It is important to recognize the limitations of this study, such as its pilot design and sample size. This pioneering study in refractory IBD presents encouraging results that suggest clinical and endoscopic benefits in the treated patients. These results justify the conduct of larger studies to strengthen the evidence and provide a solid basis for thepotential use of this therapy in clinical practice

P224 JAK-STAT-Driven Tryptophan Degradation Fuels Mucosal Inflammation through QPRT Suppression-Induced Quinolinic Acid Overflow

Abstract Background Inflammatory bowel disease is characterized by disturbed metabolism, including disrupted tryptophan (TRP) metabolism along the kynurenine pathway (KP). However, the molecular mechanism how this fuels inflammation is not understood. Here, we unravel rewiring of TRP metabolism in IBD by combining murine DSS colitis with multi-omics of longitudinal IBD cohorts. Methods Serum metabolites were associated with CRP, e/pMayo, SESCD and CDAI (n=83 UC, n=51 CD). Mucosal IDO1 and QPRT expression (both KP enzymes; indoleamine2,3-dioxygenase1, quinolinate phosphoribosyltransferase; n=273 UC) was correlated with Nancy index and eMayo. Murine enterocytes were treated with Qprt siRNA, LPS or IFNγ and cytokines measured by RT-qPCR. Tissue and serum of DSS colitis (C57BL/6, 2.5%, 5 days) and human PBMC or colon organoids (hOG) treated with IFNγ or Tofacitinib (Tofa) were analysed by LC-MS. Blood and biopsies for metabolomics and transcriptomics were obtained over 14 weeks from IBD patients (n=62) first introduced to biologics. Mucosal IDO1/QPRT expression was assessed at week 0, 8 and 16 in Tofa-treated UC (n=15). Results In longitudinal IBD therapy intervention cohorts, restoration of serum TRP metabolism was associated with 12-month disease control. Quinolinic acid (QUIN) levels relative to other TRP derivatives positively correlated with several disease activity metrics. Increased mucosal IDO1 and decreased QPRT expression upon proceeding disease severity suggested unbalanced QUIN levels as a joint result of augmented TRP turnover by IDO1 and blocked QUIN conversion by QPRT in active disease. In-vitro, QUIN overflow exaggerated pro-inflammatory cytokine responses. Accumulation of colonic QUIN was reproduced in DSS colitis and resulted in NAD+ (nicotinamide adenine dinucleotide) exhaustion, suggesting a local KP roadblock due to QPRT suppression. Integrated metabolomics and transcriptomics of IBD blood and biopsies confirmed TRP hyper-degradation at the inflammation site and revealed common JAK/STAT pathway upregulation in blood and mucosa. As IDO1 exerts the KP via JAK/STAT, IFNγ-induced KP-activation was rescued by JAK inhibition (JAKi) in human PBMC and hOG. Ultimately, we found mucosal QPRT and IDO1 expression to be significantly associated with therapy response to Tofa in UC, suggesting their baseline expression as an a priori predictor of JAKi therapy response. Conclusion TRP wasting in IBD appears to fuel mucosal inflammation due to QPRT suppression and subsequent QUIN overflow. Whether this mechanism is unique to IBD remains to be shown. Obvious future applications may include diagnostic patient classification and targeting therapeutic interventions in the TRP pathway.

Histologic features and predicting prognosis in ulcerative colitis patients with mild endoscopic activity.

We aimed to evaluate the histologic features predictive of prognosis and correlate them with endoscopic findings in patients with ulcerative colitis (UC) having complete or partial mucosal healing (MH). We prospectively collected and reviewed data from patients with UC who underwent colonoscopy or sigmoidoscopy with biopsy. Complete and partial MH were defined as Mayo endoscopic subscores (MESs) of 0 and 1, respectively. Histologic variables, including the Nancy index (NI), predicting disease progression (defined as the need for medication upgrade or hospitalization/surgery), were evaluated and correlated with endoscopic findings. Overall, 441 biopsy specimens were collected from 194 patients. The average follow-up duration was 14.7 ± 7.4 months. There were 49 (25.3%) and 68 (35.1%) patients with MESs of 0 and 1, respectively. Disease progression occurred only in patients with an MES of 1. NI ≥ 3 was significantly correlated with disease progression during follow-up. Mucosal friability on endoscopy was significantly correlated with NI ≥ 3 (61.1% in NI < 3 vs. 88.0% in NI ≥ 3; p = 0.013). Histological activity can help predict the prognosis of patients with UC with mild endoscopic activity. Mucosal friability observed on endoscopy may reflect a more severe histological status, which can be a risk factor for disease progression.

Histological healing induced by tofacitinib in ulcerative colitis: A multicentre study

BackgroundWhile the efficacy of tofacitinib to induce and maintain clinical and endoscopic remission is well established in ulcerative colitis (UC), little is known about its efficacy to induce histological remission. MethodsWe conducted a retrospective multicentric cohort study. UC patients ≥ 16 years treated by tofacitinib in whom histological activity has been evaluated before and after induction were eligible. The primary endpoint was the histological remission at the end of induction, assessed by the Nancy index and the epithelial neutrophilic infiltrate. ResultsA total of 42 patients with UC (93% previously exposed to an anti-TNF and 81% to vedolizumab) were included between July 2018 and April 2022 and were followed for a median duration of 84 weeks [IQR, 35–134]. At the end of induction period (whether prolonged or not), 19% and 24% of patients achieved histological remission, using the Nancy index and the epithelial neutrophilic infiltrate, respectively. Survival without tofacitinib discontinuation was significantly longer in patients without epithelial neutrophilic infiltrate at the end of induction (whether prolonged or not) compared with patients with epithelial neutrophilic infiltrate (p = 0.036). ConclusionTofacitinib induced histological remission in one fifth to one quarter of patients with UC who have previously failed anti-TNF or/and vedolizumab after induction (whether prolonged or not).

Histologic findings at diagnosis as predictive markers of clinical outcome in pediatric ulcerative colitis

BackgroundThe role of histological inflammation at diagnosis as a possible prognostic factor for disease course has not been investigated. AimsTo assess whether histologic findings at diagnosis could predict clinical outcomes and evaluate the association between clinical, biochemical, endoscopic, and histological findings. MethodsProspective single-center study including pediatric UC patients with a minimum follow-up of 12 months. The association between histological activity (Nancy Index, Robarts Histopathology Index, and Geboes Score) and 12-month clinical outcomes was evaluated. Secondarily, we assessed the correlation between histological scores and endoscopic and inflammatory markers at the diagnosis. Inter-observer agreement for histologic and endoscopic scores was also evaluated. ResultsForty-nine UC patients were included. No association was found between 1-year clinical relapse and the three histological indices at diagnosis (p > 0.05). Good concordance was found among the three histological scores (p < 0.001), and between all histological and endoscopic indices (p < 0.05). No correlation was found between histologic scores and serum inflammatory markers. Inter-observer agreement was good for eMayo, Nancy and Robarts score (k = 0.71, k = 0.74 and k = 0.68, respectively) and moderate for Geboes (k = 0.46). ConclusionsHistological findings at diagnosis cannot be used as a predictor of the disease course. The three histological scores used in routine clinical practice show an overall good correlation and reliability.

Quantitative Phase Imaging Using Digital Holographic Microscopy to Assess the Degree of Intestinal Inflammation in Patients with Ulcerative Colitis.

Ulcerative colitis (UC) is characterized by chronic inflammation of the colorectum. Histological remission has emerged as a potential future treatment goal; however, the histopathological assessment of intestinal inflammation in UC remains challenging with a multitude of available scoring systems and the need for a pathologist with expertise in inflammatory bowel disease (IBD). In previous studies, quantitative phase imaging (QPI) including digital holographic microscopy (DHM) was successfully applied as an objective method for stain-free quantification of the degree of inflammation in tissue sections. Here, we evaluated the application of DHM for the quantitative assessment of histopathological inflammation in patients with UC. In our study, endoscopically obtained colonic and rectal mucosal biopsy samples from 21 patients with UC were analyzed by capturing DHM-based QPI images that were subsequently evaluated using the subepithelial refractive index (RI). The retrieved RI data were correlated with established histological scoring systems including the Nancy index (NI) as well as with endoscopic and clinical findings. As a primary endpoint, we found a significant correlation between the DHM-based retrieved RI and the NI (R2 = 0.251, p < 0.001). Furthermore, RI values correlated with the Mayo endoscopic subscore (MES; R2 = 0.176, p < 0.001). An area under the receiver operating characteristics (ROC) curve of 0.820 confirms the subepithelial RI as a reliable parameter to distinguish biopsies with histologically active UC from biopsies without evidence of active disease as determined by conventional histopathological examination. An RI higher than 1.3488 was found to be the most sensitive and specific cut-off value to identify histologically active UC (sensitivity of 84% and specificity of 72%). In conclusion, our data demonstrate DHM to be a reliable tool for the quantitative assessment of mucosal inflammation in patients with UC.