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BACKGROUND & AIMS: Microscopic inflammation has significant prognostic value in ulcerative colitis (UC); however, its assessment is complex with high interobserver variability. We aimed to develop and validate an artificial intelligence (AI) computer-aided diagnosis system to evaluate UC biopsies and predict prognosis. METHODS: A total of 535 digitalized biopsies (273 patients) were graded according to the PICaSSO Histologic Remission Index (PHRI), Robarts, and Nancy Histological Index. A convolutional neural network classifier was trained to distinguish remission from activity on a subset of 118 biopsies, calibrated on 42 and tested on 375. The model was additionally tested to predict the corresponding endoscopic assessment and occurrence of flares at 12 months. The system output was compared with human assessment. Diagnostic performance was reported as sensitivity, specificity, prognostic prediction through Kaplan-Meier, and hazard ratios of flares between active and remission groups. We externally validated the model in 154 biopsies (58 patients) with similar characteristics but more histologically active patients. RESULTS: The system distinguished histological activity/remission with sensitivity and specificity of 89% and 85% (PHRI), 94% and 76% (Robarts Histological Index), and 89% and 79% (Nancy Histological Index). The model predicted the corresponding endoscopic remission/activity with 79% and 82% accuracy for UC endoscopic index of severity and Paddington International virtual ChromoendoScopy ScOre, respectively. The hazard ratio for disease flare-up between histological activity/remission groups according to pathologist-assessed PHRI was 3.56, and 4.64 for AI-assessed PHRI. Both histology and outcome prediction were confirmed in the external validation cohort. CONCLUSION: We developed and validated an AI model that distinguishes histologic remission/activity in biopsies of UC and predicts flare-ups. This can expedite, standardize, and enhance histologic assessment in practice and trials. ispartof: GASTROENTEROLOGY vol:164 issue:7 pages:1180-+ ispartof: location:United States status: published

The response to SARS-CoV-2 vaccination of patients with inflammatory bowel disease (IBD) on immune-modifying therapies requires further investigation because previous studies indicate that patients on immune therapy might have decreased antibody concentrations.We present the antireceptor binding domain antibody response over a period of 3 months in 217 patients with IBD who completed standard 2-dose SARS-CoV-2 mRNA vaccine series.Almost all (98.6%) IBD vaccine recipients had a positive antireceptor binding domain antibody response at least 3 months after vaccination. Decreased antibody titers at 3 months were seen in a subset of patients on antitumor necrosis factor-alpha. Approximately 10% of the participants with high-titer antibodies at 1 month had a decrease to low-positive titers at 3 months, which was mostly observed in those on combination therapy and antitumor necrosis factor-alpha monotherapy.Larger longitudinal studies are required to define the response in IBD population and its clinical impact.

[EN] Background and Objective: Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) affecting the colon and the rectum characterized by a remitting-relapsing course. To detect mucosal inflammation as-sociated with UC, histology is considered the most stringent criteria. In turn, histologic remission (HR) correlates with improved clinical outcomes and has been recently recognized as a desirable treatment target. The leading biomarker for assessing histologic remission is the presence or absence of neutrophils. Therefore, the finding of this cell in specific colon structures indicates that the patient has UC activity. However, no previous studies based on deep learning have been developed to identify UC based on neu-trophils detection using whole-slide images (WSI). Methods: The methodological core of this work is a novel multiple instance learning (MIL) framework with location constraints able to determine the presence of UC activity using WSI. In particular, we put forward an effective way to introduce constraints about positive instances to effectively explore additional weakly supervised information that is easy to obtain and enjoy a significant boost to the learning process. In addition, we propose a new weighted embedding to enlarge the relevance of the positive instances. Results: Extensive experiments on a multi-center dataset of colon and rectum WSIs, PICASSO-MIL, demon-strate that using the location information we can improve considerably the results at WSI-level. In com-parison with prior MIL settings, our method allows for 10% improvements in bag-level accuracy. Conclusion : Our model, which introduces a new form of constraints, surpass the results achieved from current state-of-the-art methods that focus on the MIL paradigm. Our method can be applied to other histological concerns where the morphological features determining a positive WSI are tiny and similar to others in the image., This work has received funding from Horizon 2020, the European Unions Framework Programme for Research and Innovation, under grant agreement No. 860627 (CLARIFY) , the Spanish Ministry of Economy and Competitiveness through project PID2019-105142RB-C21 (AI4SKIN) and GVA through projects PROMETEO/2019/109 and INNEST/2021/321 (SAMUEL) . Roco del Amor and Adrin Colomer work have also been supported by the Spanish Government under FPU Grant (FPU20/05263) and the Universitat Politcnica de Valncia (PAID-10-21-Subprograma 1), respectively. We gratefully acknowledge the support from the Generalitat Valenciana (GVA) with the donation of the DGX A100 used for this work, action co-financed by the European Union through the Operational Program of the European Regional Development Fund of the Comunitat Valenciana 2014¿2020 (IDIFEDER/2020/030).

Summary Serrated epithelial change (SEC) manifests in patients with long-standing inflammatory bowel disease (IBD) and is characterized by disorganized crypt architecture, irregular serrations, and goblet cell–rich epithelium. The serrated nature of SEC is reminiscent of serrated colorectal polyps, which frequently harbor KRAS/BRAF mutations. SEC is, however, not only histologically distinct from sporadic serrated polyps but also associated with colorectal neoplasia. Whether SEC is a precursor to IBD-associated neoplasia remains unclear. To further define the relationship of SEC with serrated colorectal polyps and IBD-associated neoplasia, we performed targeted next-generation sequencing on colorectal specimens to include the following: SEC without dysplasia/neoplasia (n = 10), SEC with separate foci of associated dysplasia/adenocarcinoma from the same patients (n = 17), and uninvolved mucosa (n = 10) from 14 patients. In addition, we molecularly profiled sessile serrated lesion (SSL)–like or serrated lesion, not otherwise specified (SL-NOS), specimens, from 11 patients who also had IBD. This control cohort included SSL-like/SL-NOS without dysplasia/neoplasia (n = 11), SSL-like/SL-NOS with associated low-grade dysplasia (n = 2), and uninvolved mucosa (n = 8). By next-generation sequencing, the most frequently mutated gene in SEC without neoplasia and associated dysplasia/adenocarcinoma from separate foci in the same patients was TP53. Recurrent TP53 mutations were present in 50% of SEC specimens without dysplasia/neoplasia. In addition, alterations in TP53 were detected at a prevalence of 71% in low-grade dysplasia, 83% in high-grade dysplasia, and 100% in adenocarcinoma. Paired sequencing of SEC and associated neoplasia revealed identical TP53 missense mutations for 3 patients. In contrast, 91% of SSL-like/SL-NOS specimens without dysplasia/neoplasia harbored KRAS/BRAF mutations, which were conserved in associated low-grade dysplasia. No genomic alterations were found in uninvolved mucosa from either patients with SEC or patients with SSL-like/SL-NOS. Based on our findings, we conclude SEC is distinct from SSL-like serrated colorectal lesions in patients with IBD and an early precursor to IBD-associated neoplasia that warrants colonoscopic surveillance.

Histological remission is evolving as an important treatment target in UC. We aimed to develop a simple histological index, aligned to endoscopy, correlated with clinical outcomes, and suited to apply to an artificial intelligence (AI) system to evaluate inflammatory activity.MethodsUsing a set of 614 biopsies from 307 patients with UC enrolled into a prospective multicentre study, we developed the Paddington International virtual ChromoendoScopy ScOre (PICaSSO) Histologic Remission Index (PHRI). Agreement with multiple other histological indices and validation for inter-reader reproducibility were assessed. Finally, to implement PHRI into a computer-aided diagnosis system, we trained and tested a novel deep learning strategy based on a CNN architecture to detect neutrophils, calculate PHRI and identify active from quiescent UC using a subset of 138 biopsies.ResultsPHRI is strongly correlated with endoscopic scores (Mayo Endoscopic Score and UC Endoscopic Index of Severity and PICaSSO) and with clinical outcomes (hospitalisation, colectomy and initiation or changes in medical therapy due to UC flare-up). A PHRI score of 1 could accurately stratify patients’ risk of adverse outcomes (hospitalisation, colectomy and treatment optimisation due to flare-up) within 12 months. Our inter-reader agreement was high (intraclass correlation 0.84). Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity and 86% accuracy.ConclusionsPHRI is a simple histological index in UC, and it exhibits the highest correlation with endoscopic activity and clinical outcomes. A PHRI-based AI system was accurate in predicting histological remission.

A composite endoscopic-histologic remission is increasingly explored as an important endpoint in ulcerative colitis (UC). We investigated combined endoscopic-histologic remission for predicting clinical outcomes at 12 months compared with endoscopic remission alone using the high definition virtual chromoendoscopy (VCE) Paddington International virtual ChromoendoScopy ScOre (PICaSSO) and histology scores.Ulcerative colitis patients, prospectively enrolled from 11 international centres, underwent VCE with targeted biopsies and followed up for 12 months. Endoscopic activity was assessed by Mayo Endoscopic Score (MES), Ulcerative Colitis Endoscopic Index Severity (UCEIS) followed by VCE-PICaSSO. Robarts Histopathological Index|Robarts Histological index≤3 without neutrophils in mucosa, and Nancy Histological index (NHI)≤ 1 were used to define histologic remission. Combined endoscopic-histologic remission was compared with endoscopic remission alone by Cox proportional hazards model and by two- and three-proportion analysis using pre-specified clinical outcomes.307 patients were recruited and 302 analysed. There was no difference in survival without specified clinical outcomes between PICaSSO defined endoscopic remission alone and endoscopic plus histologic remission in the rectum (HR 0.42, 95%CI 0.16-1.11 and HR 1.03, 95%CI 0.42-2.52 for Robarts Histological index and NHI respectively) at 12 months. There was however a significant survival advantage without specified clinical outcome events for UCEIS combined with histology compared with UCEIS alone (HR 0.30, 95%CI 0.12-0.75, p = 0.02) at 12 months (but not combined with NHI). For MES there was no advantage for predicting specified clinical outcomes at 12 months for endoscopy alone versus endoscopy plus histology, but there were differences in two and three proportion analysis at 6 months.Endoscopic remission by VCE-PICaSSO alone was similar to combined endoscopic and histologic remission for predicting specified clinical outcomes at 12 months. Larger studies with specific therapeutic interventions are required to further confirm the findings.

Background and Aims Crohn’s disease [CD] recurrence following ileocolic resection [ICR] is common. We sought to identify blood-based biomarkers associated with CD recurrence. Methods CD patients undergoing ICR were recruited across six centres. Serum samples were obtained at post-operative colonoscopy. A multiplex immunoassay was used to analyse 92 inflammation-related proteins [Olink Proteomics]. Bayesian analysis was used to identify proteins associated with increasing Rutgeerts score. Identified proteins were used in receiver operating characteristic [ROC] analysis to examine the ability to identify CD recurrence [Rutgeerts score ≥i2]. Existing single cell data were interrogated to further elucidate the role of the identified proteins. Results Data from 276 colonoscopies in 213 patients were available. Median time from surgery to first and second colonoscopy was 7 (interquartile range [IQR] 6–9) and 19 [IQR 16–23] months, respectively. Disease recurrence was evident at 60 [30%] first and 36 [49%] second colonoscopies. Of 14 proteins significantly associated with Rutgeerts score, the strongest signal was seen for CXCL9 and MMP1. Among patients on anti-tumour necrosis factor drugs, CXCL9 and CXCL11 were most strongly associated with Rutgeerts score. Both are CXCR3 ligands. Incorporation of identified proteins into ROC analysis improved the ability to identify disease recurrence as compared to C-reactive protein alone: area under the curve [AUC] 0.75 (95% confidence interval [CI]: 0.66–0.82] vs 0.64 [95% CI 0.56–0.72], p = 0.012. Single cell transcriptomic data provide evidence that innate immune cells are the primary source of the identified proteins. Conclusions CXCR3 ligands are associated with CD recurrence following ICR. Incorporation of novel blood-based candidate biomarkers may aid in identification of CD recurrence.

A man in his 30s with ulcerative colitis (UC) on immunosuppressive agents and extensive travel history presented with subacute dyspnoea and dry cough. CT of the chest demonstrated numerous cavitary pulmonary nodules. An extensive infectious, malignant and autoimmune evaluation was pursued, ultimately with histopathology most consistent with necrobiotic lung nodules as an extraintestinal manifestation of UC. Steroids and ustekinumab were initiated with improvement in symptoms and resolution of cavitary lesions on follow-up imaging. In a patient with inflammatory bowel disease and cavitary lung lesions, necrobiotic lung nodules should be considered, particularly when evaluation for infectious causes is negative.

Background Crohn’s disease (CD) can affect any segment of the digestive tract but is most often localized in the ileal, ileocolonic, and colorectal regions of the intestines. It is believed that the chronic inflammation in CD is a result of an imbalance between the epithelial barrier, the immune system, and the intestinal microbiota. The aim of the study was to identify circulating markers associated with CD and/or disease location in CD patients. Methods We tested 49 cytokines, chemokines, and growth factors in serum samples from 300 patients with CD and 300 controls. After quality control, analyte levels were tested for association with CD and disease location. Results We identified 13 analytes that were higher in CD patients relative to healthy controls and that remained significant after conservative Bonferroni correction (P Conclusions Multiple serum analytes are elevated in CD. These implicate the involvement of multiple cell types from the immune, epithelial, and endothelial systems, suggesting that circulating analytes reflect the inflammatory processes that are ongoing within the gut. Moreover, the identification of distinct profiles according to disease location supports the existence of a biological difference between ileal and colonic CD, consistent with previous genetic and clinical observations.

Background and Aims Interleukin 6 [IL-6] or its receptor is currently a candidate for targeted biological therapy of inflammatory bowel disease [IBD]. Thus, a comprehensive understanding of the consequences of blocking IL-6 is imperative. We investigated this by evaluating the effects of IL-6 deletion on the spontaneous colitis of IL-10-deficient mice [IL-10−/−]. Methods IL-6/IL-10 double-deficient mice [IL-6−/−/IL-10−/−] were generated and analysed for intestinal inflammation, general phenotypes and molecular/biochemical changes in the colonic mucosa compared with wild-type and IL-10−/− mice. Results Unexpectedly, the IL-6−/−/IL-10−/− mice showed more pronounced gut inflammation and earlier disease onset than IL-10−/− mice, both locally [colon and small bowel] and systemically [splenomegaly, ulcerative dermatitis, leukocytosis, neutrophilia and monocytosis]. IL-6−/−/IL-10−/− mice exhibited elevations of multiple cytokines [IL-1β, IL-4, IL-12, TNFα] and chemokines [MCP-1 and MIG], but not IFN-γ [Th1], IL-17A and IL-17G [Th17], or IL-22 [Th22]. FOXP3 and TGF-β, two key factors for regulatory T [Treg] cell differentiation, were significantly down-regulated in the colonic mucosa, but not in the thymus or mesenteric lymph nodes, of IL-6−/−/IL-10−/− mice. CTLA-4 was diminished while iNOS was up-regulated in the colonic mucosa of IL-6−/−/IL-10−/− mice. Conclusion In IL-10−/− mice, complete IL-6 blockade significantly aggravates gut inflammation, at least in part by suppressing Treg/CTLA-4 and promoting the IL-1β/Th2 pathway. In addition, the double mutant exhibits signs of severe systemic inflammation. Our data define a new function of IL-6 and suggest that caution should be exercised when targeting IL-6 in IBD patients, particularly those with defects in IL-10 signalling.

BackgroundPerianal Crohn’s disease (pCD) is a debilitating complication affecting up to 30% of Crohn’s disease (CD) population, leading to increased morbidity, mortality and decreased quality of life. Despite the growing armamentarium of medications for luminal CD, their efficacy in pCD remains poorly studied.AimTo determine the efficacy of ustekinumab, a biologic approved for luminal CD, in pCD through a retrospective cohort study and systematic review.MethodsA retrospective cohort study on patients with CD with active perianal fistulae treated with ustekinumab from September 2013 to August 2019 was performed to determine perianal fistula response and remission at 6 and 12 months after ustekinumab induction. A systematic review was performed to further establish rates of fistula response and remission with ustekinumab.ResultsAt 6 months, 48.1% (13/27) patients achieved fistula response with none achieving fistula remission on provider exam, and 59.3% (16/27) achieved patient-reported symptomatic improvement with 3.7% (1/27) achieving symptomatic remission. At 1 year, on provider exam, 55.6% (5/9) had fistula response with none achieving fistula remission, and 100% (9/9) had symptomatic improvement with 22.2% (2/9) achieving symptomatic remission. There were no major safety signals during 1-year follow-up. The systematic review of 25 studies found 44% (92/209) of patients with active perianal fistulas had a clinical response within 6 months of follow-up, and 53.9% (85/152) of patients with 12 months of follow-up achieved clinical response.ConclusionUstekinumab presents a safe and effective therapy for treatment of pCD. Prospective, randomised trials are needed to further elucidate long-term efficacy of ustekinumab for pCD.

Background People with autoimmune or inflammatory conditions taking immunomodulatory/suppressive medications may have higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences. Methods We included participants with autoimmune or inflammatory conditions followed by specialists at Johns Hopkins. Participants completed periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. We assessed whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterized pandemic-associated changes to care and mental health. Results In total, 265 (5.6%) developed COVID-19 over 9 months of follow-up (April–December 2020). Patient characteristics (age, race, comorbidity, medications) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in models incorporating behavior and other potential confounders (odds ratio [OR]: 1.43; 95% confidence interval [CI]: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95% CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95% CI: 1.24, 2.28), and kidney disease (OR: 1.76; 95% CI: 1.04, 2.97) were associated with higher odds of COVID-19. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions therein, which disproportionately affected individuals experiencing changes to employment or income. Conclusions Glucocorticoid exposure may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.

BACKGROUND & AIMS: Endoscopic and histologic remission are important goals in the treatment of ulcerative colitis (UC). We investigated the correlation of the recently developed Paddington International Virtual ChromoendoScopy ScOre (PICaSSO) and other established endoscopic scores against multiple histological indices and prospectively assessed outcomes. METHODS: In this prospective multicenter international study, inflammatory activity was assessed with high-definition and virtual chromoendoscopy in the rectum and sigmoid using the Mayo Endoscopic Score (MES), UC Endoscopic Index of Severity (UCEIS), and PICaSSO. Targeted biopsies were taken for assessment using Robarts Histological Index (RHI), Nancy Histological index (NHI), ECAP (Extent, Chronicity, Activity, Plus score), Geboes, and Villanacci. Follow-up data were obtained at 6 and 12 months after colonoscopy. RESULTS: A total of 307 patients were recruited. There was strong correlation between PICaSSO and histology scores, significantly superior to correlation coefficients of MES and UCEIS with histology scores. A PICaSSO score of ≤3 detected histologic remission by RHI (≤3 + absence of neutrophils) with area under the receiver operating characteristic curve (AUROC) 0.90 (95% confidence interval [CI] 0.86-0.94) and NHI (≤1) AUROC 0.82 (95% CI 0.77-0.87). The interobserver agreement for PICaSSO was 0.88 (95% CI 0.83-0.92). At 6- and 12-months follow-up, PICaSSO score ≤3 predicted better outcomes than PICaSSO >3 (hazard ratio [HR] 0.19 [0.11-0.33] and 0.22 [0.13-0.34], respectively),} as well as PICaSSO 4-8 (HR 0.25 [0.12-0.53] and 0.22 (0.12-0.39), respectively) and similar to histologic remission. CONCLUSION: In this first real-life multicenter study, the PICaSSO score correlated strongly with multiple histological indices. Furthermore, PICaSSO score predicted specified clinical outcomes at 6 and 12 months, similar to histology. Thus, PICaSSO can be a useful endoscopic tool in the therapeutic management of UC. ispartof: GASTROENTEROLOGY vol:160 issue:5 pages:1558-+ ispartof: location:United States status: published

Introduction: In the SARS-CoV2 mRNA vaccine trials, post-vaccination gastrointestinal (GI) symptoms were reported in 10-20% of participants. These symptoms could be perceived as inflammatory bowel disease (IBD) flare which could lead to patient anxiety, and unnecessary tests or treatment. We aimed to assess GI symptoms after SARS-CoV2 mRNA vaccination in patients with IBD relative to non-IBD healthcare workers (HCW). Methods: We assessed GI symptoms in adults with IBD and HCW at baseline and after each dose of a SARS-CoV-2 mRNA vaccine. We analyzed patient-reported IBD-specific disease activity (PRO2) after each dose (stool frequency (SF) and rectal bleeding for ulcerative colitis (UC), SF and abdominal pain for Crohn's disease (CD)). We also compared the frequency, severity, and duration of postvaccination GI symptoms in IBD patients compared to HCW. Severity was defined by impact on daily activities (mild, did not interfere;moderate, some interference;severe, prevented routine activity;extreme, required hospitalization). Severe and extreme were combined and designated as severe+. Duration was classified as 7 days. Results: Post-vaccination GI symptoms were assessed after dose 1 (D1) (1391 IBD, 933 HCW) and dose 2 (D2) (1271 IBD, 884 HCW) (Table). About 60% of IBD and>99% of HCW received the BNT162b vaccine (Pfizer);the remainder received mRNA-1273 (Moderna). New GI symptoms after D1 were more frequent among IBD than HCW (6.0% vs 2.9%, p=0.001) but not after D2 (12.1% vs 12.7%, p=NS). Relative to HCW, IBD patients reported more diarrhea (3.8% vs. 1% (p

BackgroundPeople with autoimmune or inflammatory conditions who take immunomodulatory/suppressive medications may have a higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences.ObjectiveAssess whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterize pandemic-associated changes to care.DesignLongitudinal registry studyParticipants4666 individuals with autoimmune or inflammatory conditions followed by specialists in neurology, rheumatology, cardiology, pulmonology or gastroenterology at Johns HopkinsMeasurementsPeriodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcareResultsA total of 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medication exposure) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in multivariable models incorporating behavior and other potential confounders (OR: 1.43; 95%CI: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95%CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95%CI: 1.24, 2.28), and chronic kidney disease (OR: 1.76; 95%CI: 1.04, 2.97) were each associated with higher odds of COVID-19. Pandemic-related disruption to care was common. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions. Individuals experiencing changes to employment or income were at highest odds of care disruption.LimitationsResults may not be generalizable to all patients with autoimmune or inflammatory conditions. Information was self-reported.ConclusionsExposure to glucocorticoids may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.

Introduction Mucosal healing (MH)is an important goal in the treatment of ulcerative colitis (UC). The newly published PICaSSO score characterises subtle mucosal and vascular changes and defines MH. We aimed to validate in real-life the PICaSSO score and assess its ability to predict relapse. Methods Patients with UC were prospectively recruited from 11 international centres. Participating endoscopists experienced in IBD received training on PICaSSO before starting the study. The rectum and sigmoid were examined using iScan 1,2&3 (Pentax, Japan) and inflammatory activity was assessed using Mayo, UCEIS and PICaSSO. Biopsies were taken for histological assessment using Robarts Histological Index (RHI), Nancy, ECAP, Geboes and Villanacci. Follow up data was obtained at 12 months. Results A total of 307 patients were recruited.The interobserver agreement for the PICaSSO score was 0.879 (95% CI 0.826–0.924). The PICaSSO total and PICaSSO mucosal scores strongly correlated with histology scores and was statistically better than MES and UCEIS as show in figure 1. When using a PICaSSO total score of ≤3 the AUROC to predict MH by RHI (≤3 + absence of neutrophils) was 0.90 (95% CI 0.86–0.94) and when we compare the AUROC of Picasso vs Mayo p was =0.06. When using the Nancy score (≤1) the AUROC was 0.816 (95% CI 0.77–0.87). A Kaplan-Meier curve shows a significant favourable survival probability without relapse with a PICASSO score of ≤3 Likelihood ratio test=26.41, p Conclusions This real-life validation study shows the electronic chromoendoscopy score, PICaSSO, can predict accurately histological healing and long-term remission and can be a useful tool in the management of UC.

Background Patients with long-standing ulcerative colitis (UC) are at an increased risk of colorectal cancer. Risk stratification is important to identify patients who require more frequent endoscopic surveillance. Serrated epithelial change (SEC) found in patients with long-standing colitis may be associated with neoplasia and serve as a marker to stratify patients at higher risk of colorectal cancer (CRC). Methods A case-control study was performed to compare the rates of neoplasia between UC patients with SEC and UC patients without SEC who were matched for age, disease duration, and disease extent. Paired tests, conditional logistic regression, and Kaplan-Meier analyses were used to compare groups. A systematic review with meta-analysis was performed, combining our local data with previously published data. Results This study included 196 UC patients without prior neoplasia, 98 with SEC and 98 without SEC. Ulcerative colitis patients with SEC had a significantly higher rate of synchronous or metachronous neoplasia than UC patients without SEC (26.5% vs 3.1%; P < 0.001). Synchronous or metachronous high-grade dysplasia and CRC were found more frequently in UC patients with SEC than UC patients without SEC (11.2% vs 2.0%; P = 0.02). A meta-analysis was consistent with these findings, showing a higher rate of neoplasia in patients with SEC compared with those without SEC (16.4% vs 3.9%; P < 0.001). Conclusion Serrated epithelial change is associated with a significantly increased risk of synchronous and metachronous neoplasia including high-grade dysplasia and CRC in patients with UC. Histopathological findings of SEC should warrant closer endoscopic surveillance for CRC.

BACKGROUND: Cigarette smoking is thought to increase the risk of Crohn’s disease (CD) and exacerbate the disease course, with opposite roles in ulcerative colitis (UC). However, these findings are from Western populations, and the association between smoking and inflammatory bowel disease (IBD) has not been well studied in Asia. AIMS: We aimed to compare the prevalence of smoking at diagnosis between IBD cases and controls recruited in China, India, and the USA, and to investigate the impact of smoking on disease outcomes. METHODS: We recruited IBD cases and controls between 2014 and 2018. All participants completed a questionnaire about demographic characteristics, environmental risk factors and IBD history. RESULTS: We recruited 337 participants from China, 194 from India, and 645 from the USA. In China, CD cases were less likely than controls to be current smokers (adjusted odds ratio [95% CI] 0.4 [0.2–0.9]). There was no association between current or former smoking and CD in the USA. In China and the USA, UC cases were more likely to be former smokers than controls (China 14.6 [3.3–64.8]; USA 1.8 [1.0–3.3]). In India, both CD and UC had similar current smoking status to controls at diagnosis. Current smoking at diagnosis was significantly associated with greater use of immunosuppressants (4.4 [1.1–18.1]) in CD cases in China. CONCLUSIONS: We found heterogeneity in the associations of smoking and IBD risk and outcomes between China, India, and the USA. Further study with more adequate sample size and more uniform definition of smoking status is warranted.

Background In inflammatory bowel disease (IBD), many scenarios call for fecal diversion, leaving behind defunctionalized bowel. The theoretical risk of colorectal cancer (CRC) in this segment is frequently cited as a reason for resection. To date, no studies have characterized the incidence of neoplasia in the diverted colorectal segments of IBD patients. Methods A retrospective cohort analysis was conducted for IBD patients identified through a tertiary care center pathology database. Patients that had undergone colorectal diversion and were diverted for ≥ 1 year were included. Incidence of diverted dysplasia/CRC was calculated for Crohn’s disease (CD) and ulcerative colitis (UC) with respect to diverted patient-years (dpy) and patient-years of disease (pyd). Results In total, 154 patients comprising 754 dpy and 1984 pyd were analyzed. Only 2 cases of diverted colorectal dysplasia (CD 1, UC 1) and 1 case of diverted CRC (UC) were observed. In the UC cohort (n = 75), the rate of diversion-associated CRC was 4.5 cases/1000 dpy (95% CI 0.11–25/1000) or 1.5 cases/1000 pyd (95% CI 0.04–8.2/1000). In the CD cohort (n = 79), no patients developed CRC, although a dysplasia rate of 1.9 cases/1000 dpy (95% CI 0.05–11/1000) or 0.77 cases/1000 pyd (95% CI 0.02–4.3/1000) was observed. All patients developing neoplasia had disease duration > 10 years and microscopic inflammation. Conclusions Diverted dysplasia occurred infrequently with rates overlapping those reported in registries for IBD-based rectal cancers. Neoplasia was undetected in patients with < 10 pyd, regardless of diversion duration, suggesting low yield for endoscopic surveillance before this time.

Crohn's disease (CD) is a manifestation of inflammatory bowel disease (IBD), which can result in significant morbidity. Biologic therapy with anti-TNF medication has been effective in treating inflammation and reducing complications in CD. It is important for clinicians to have better knowledge of the various biologic therapies including mechanisms of action and optimization strategies.The review describes optimization of biologic therapy in CD including different mechanisms of loss of response, therapeutic drug monitoring in CD, clinical implications and management strategies which utilize drug monitoring, and areas of future development and research in optimization of biologic therapy.Achieving adequate levels of the drug (antibody unbound) is one of the most important determinants of attaining clinical remission and mucosal healing. Drug level is also critical in determining if a patient requires combination therapy with an immunomodulator. Certain populations, including those with active perianal disease, may require higher serum levels to achieve healing or closure. Treat to target level is an algorithm that is not universally accepted and more data is need. Additionally, there are numerous assays that don't always correlate, especially regarding measuring anti-drug antibodies.

Background: Creation of a J pouch is the gold standard surgical intervention in the treatment of chronic ulcerative colitis (UC). Pouchoscopy prior to ileostomy takedown is commonly performed. We describe the frequency, indication, and findings on pouchoscopy, and determine if pouchoscopy affects rates of complications after takedown. Methods: All UC or indeterminate inflammatory bowel disease patients with a J pouch were retrospectively evaluated from January 1994 to December 2014. Cases were defined as having routine (asymptomatic) pouchoscopy after pouch creation but before ileostomy takedown. Controls were defined as having no pouchoscopy or pouchoscopy on the same day as that of takedown. Results: The study included 178 patients (81.5% cases, 18.5% controls). Fifty two percent of pouchoscopies were reported as normal. Common abnormal endoscopy findings included stricture (35%), pouchitis (7%), and cuffitis (0.7%). Length of stay during takedown hospitalization was shorter for cases than controls (3 vs. 5 days; p = 0.001), but neither short- nor long-term complications were statistically different between cases and controls. Abnormalities on pouchoscopy were not predictive for short-term complications (p = 0.73) or long-term complications (p = 0.55). Routine pouchoscopy did not delay takedown surgery in any of the included patients. Conclusions: Routine pouchoscopy may not be necessary prior to ileostomy takedown; its greatest utility is in patients with suspected pouch complications.

Background Mucosal healing is an important goal in the treatment of ulcerative colitis (UC). The newly published PICaSSO score characterises subtle mucosal and vascular changes and defines mucosal healing. We aimed to validate in real-life the PICaSSO score and assess its ability to predict relapse. Methods Patients with UC were prospectively recruited from 11 international centres. Participating endoscopists experienced in IBD received training on PICaSSO before starting the study. The rectum and sigmoid were examined using iScan 1,2 and 3 (Pentax, Japan) and inflammatory activity was assessed using UCEIS and PICaSSO. Biopsies were taken for the histological assessment using Robarts Histological Index (RHI) and Nancy. Follow-up was obtained at 12 months. Results A total of 278 patients were recruited (Table 1). The diagnostic performance in predicting histologic healing is shown in Table 2. When using PICaSSO score of ≤3 for mucosal and vascular architecture the AUROC to predict healing by RHI is 0.79 (95% CI 0.74–0.85) and 0.73 (95% CI 0.68–0.80) respectively and when using the Nancy score the AUROC is 0.78 (95% CI 0.72–0.84) and 0.77 (0.71–0.84). A total PICaSSO score of ≤8 and UCEIS score of ≤1 predicts remission at 12 months with an AUROC of 0.73 (0.65–0.80) and 0.71 (0.64–0.79). A Kaplan–Meier curve shows a favourable survival probability without relapse with a PICASSO score of ≤8 (Figure 1). Conclusion This real-life validation study shows the PICaSSO score can predict accurately histological healing and long-term remission and can be a useful tool in the management of UC.

In inflammatory bowel disease, prolonged disease duration, pancolitis, histological inflammation, and subsequent dysplasia are associated with an increased risk for colorectal cancer. Recommendations regarding treatment of low-grade dysplasia (LGD) indicate an individualized approach between colectomy and surveillance. We present a unique case of a patient with ulcerative colitis who had multifocal LGD on 2 consecutive colonoscopies. However, after 10 years and 16 surveillance colonoscopies, she had no further evidence of dysplasia. This appears to be the first case of proven, permanently resolved multifocal LGD in inflammatory bowel disease that challenges our understanding of the natural history of LGD.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract, most commonly divided into ulcerative colitis (UC) and Crohn’s disease. We have seen an increase in incidence in IBD over the last few decades worldwide. UC and Crohn’s disease have strong genetic underpinnings which have been steadily elucidated over the past 20 years. Additionally, there are number of environmental factors that have been recognized as triggers of disease, including dietary/microbiome and smoking. In this chapter, we lay out the primary phenotypes observed in Crohn’s and UC. We next discuss the approach to diagnosis, which is generally multifactorial, including blood and stool testing, abdominal imaging, and colonoscopy with biopsy. Next, we summarize the treatment algorithms for both disease, including the pre- and post-biologic era. Greater concentration is given to the discussion of the anti-tumor necrosis factor (TNF) alpha, which to date has been the greatest game changer in IBD management. We also discuss the newer pharmacologic mechanisms of targeting the disease including lymphocyte adhesion blockers, anti-IL 12/23 inhibitors, and drugs that target the JAK/STAT pathway. Some of the newer agents in the pipeline are also briefly discussed. In the final section, we explore clinical correlates of the genetic findings to date. We delve into some of the key findings including the discovery of the NOD2 risk gene, as well as the most up-to-date genome wide association studies (GWAS) findings. Through this we explore how these genetic findings correlate with specific disease phenotypes, and how the findings have helped choose targets for pharmacologic therapy.

Objectives Early appendectomy is inversely associated with the development of UC. However, the impact of appendectomy on the clinical course of UC is controversial, generally favouring a milder disease course. We aim to describe the effect appendectomy has on the disease course of UC with focus on the timing of appendectomy in relation to UC diagnosis. Design Using the National Institute of Diabetes and Digestive and Kidney Diseases Inflammatory Bowel Disease Genetics Consortium database of patients with UC, the risk of colectomy was compared between patients who did and did not undergo appendectomy. In addition, we performed a meta-analysis of studies that examined the association between appendectomy and colectomy. Results 2980 patients with UC were initially included. 111 (4.4%) patients with UC had an appendectomy; of which 63 were performed prior to UC diagnosis and 48 after diagnosis. In multivariable analysis, appendectomy performed at any time was an independent risk factor for colectomy (OR 1.9, 95% CI 1.1 to 3.1), with appendectomy performed after UC diagnosis most strongly associated with colectomy (OR 2.2, 95% CI 1.1 to 4.5). An updated meta-analysis showed appendectomy performed either prior to or after UC diagnosis had no effect on colectomy rates. Conclusions Appendectomy performed at any time in relation to UC diagnosis was not associated with a decrease in severity of disease. In fact, appendectomy after UC diagnosis may be associated with a higher risk of colectomy. These findings question the proposed use of appendectomy as treatment for UC.