Existing Bowel Preparation Quality Scales Are Reliable in the Setting of Centralized Endoscopy Reading.

BACKGROUND: Development of bowel preparation products has been based upon colon cleansing rating by a local endoscopist. It is unclear how bowel preparation scales perform when centrally evaluated. AIMS: To evaluate the reliability of bowel preparation quality scales when assessed by central readers. METHODS: Four central readers evaluated 52 videos in triplicate, 2 weeks apart, during the entire endoscopic procedure (insertion/withdrawal of the colonoscope) and exclusively on colonoscope withdrawal using the Boston Bowel Preparation Scale (BBPS), Chicago Bowel Preparation scale, Harefield Cleansing Scale, Ottawa Bowel Preparation Quality Scale (OBPQS), Aronchick score, a visual analogue scale, and additional items proposed in a modified Research and Development/University of California Los Angeles appropriateness process. Reliability was assessed with intraclass correlation coefficients. RESULTS: Intraclass correlation coefficients (95% confidence interval) for inter-rater reliability of the quality scales ranged from 0.51 to 0.65 (consistent with moderate to substantial inter-rater reliability) during the entire procedure. Corresponding intraclass correlation coefficients for intra-rater reliability ranged from 0.69 to 0.77 (consistent with substantial intra-rater reliability). Reliability was highest in the right colon and lowest in the left colon. No differences were observed in reliability when assessed for the procedure overall (insertion/withdrawal) relative to assessment on withdrawal alone. CONCLUSION: All five bowel preparation quality scales had moderate to substantial inter-rater reliability. Panelists considered the Aronchick score too simplistic for clinical trials and recognized that assessment of residual fluid in the Ottawa Bowel Preparation Quality Scale was not amenable to central assessment.

Multimorbidity among inflammatory bowel disease patients in a tertiary care center: a retrospective study.

BACKGROUND AND OBJECTIVES: Inflammatory bowel disease (IBD) is a chronic systemic inflammatory condition that debilitate the quality of life. Multimorbidity, a concept only beginning to emerge in IBD, is defined as two or more comorbidities present in the same individual. Notably, we used the term multimorbidity to refer to two or more comorbidities excluding IBD. Multimorbidity is linked to decreased quality of life, poorer disease outcomes, increased hospitalizations, healthcare costs and polypharmacy complications. We aim to estimate the prevalence of multimorbidity and to explore its effect on IBD patients. METHODS: We retrospectively reviewed all IBD patients registered in a validated web-based registry since February 2018. Data on patient demographics, comorbidities, IBD and extraintestinal complications were obtained. We analyzed the date using univariate, bivariate and multivariable analysis. RESULTS: Among 767 IBD patients, 54.6% had Crohn's disease (CD), 41.9% had ulcerative colitis (UC) and 3.5% had IBD unclassified. The median age at diagnosis was 22 years (IQR: 15-29). Males compromised 50.2% of patients. According to the Montréal IBD classification, most UC patients had moderate UC (47.8%) while most CD patients had non-stricturing non-penetrating CD (49.8%). Overall, 10.3% IBD patients had multimorbidity and 23.9% had at least one comorbidity. The most common comorbidity was diabetes mellitus (4.9%) followed by essential hypertension (4%) and iron deficiency anemia (3%). Female gender (P = 0.008) and UC (P = 0.005) were more likely to have multimorbidity. Multimorbid IBD patients were more likely to develop thrombosis than non-multimorbid peers (16.7% vs. 1.6%; P < 0.001). Higher age at diagnosis (OR = 1.04, 95%CI: 1.01-1.07) and having a history of thrombosis (OR = 7.82, 95% CI: 2.67-22.92) are associated with increased risk of multimorbidity. CONCLUSION: Multimorbidity is not uncommon among IBD patients, especially females diagnosed with UC. Our findings indicate that future studies are needed to explore the effects of multimorbidity on IBD patients.

The Prevalence of Barrett's Esophagus Among a Saudi Arabian Population.

BACKGROUND: While gastroesophageal reflux disease (GERD) is common in Middle Eastern countries, little data exists on the epidemiology of Barrett's esophagus (BE). AIMS: We aimed to determine the prevalence of BE among patients undergoing esophagogastroduodenoscopy (EGD) in a cohort of Saudi patients. METHODS: We retrospectively reviewed the endoscopy database at an academic tertiary care center. Consecutive adult patients who underwent an EGD for any indication between May 2014 and December 2018 were included. The prevalence of both endoscopically and histologically reported BE was determined. Multivariate regression analysis was used to identify factors associated with BE. RESULTS: A total of 2805 patients were included. The mean age was 48 years (± 18.6) and 38.7% were male patients. BE was reported endoscopically in 18 (0.64%) and confirmed histologically in 9 patients (0.32%). Among patients with endoscopically reported BE, the mean age was 50.3 (± 16.1) years and 13 (72.2%) were male patients. Of patients with BE, short-segment BE was reported in 14 (77.8%) patients. Among the 9 patients with histologically confirmed BE; only one patient had dysplastic BE. On univariate analysis, BE was associated with male gender (p < 0.01), but not with age > 50, hiatal hernia, obesity or EGD performed for GERD related indications. On multivariate regression analysis, male gender was the only factor associated with BE (aOR 3.77, 95% CI 1.39-11.97, p = 0.01). CONCLUSION: BE was endoscopically reported in 0.64% and histologically confirmed in 0.32% of this cohort of Saudi patients. Male gender was the only factor associated with BE.

Prevalence and Predictors of Reduced Bone Density in Child and Adolescent Patients With Crohn's Disease.

Reduced bone mineral density (BMD) has broadly been found to be associated with inflammatory bowel disease across a number of geographical locations and cultures. We aimed to estimate the prevalence of reduced BMD and identify clinical predictors in a cohort of Crohn's disease patients (CD) in Saudi Arabia. We conducted a retrospective study involving children and adolescents with CD between 2013 and 2018. BMD was evaluated using dual-energy X-ray absorptiometry scans of the spine and body. A multivariate analysis was performed for the detection of predictors of low BMD. Sixty-four patients were enrolled. The median age was 16 years (range, 8-19 years) and 55% of patients were males. Total body BMD scanning identified 25 patients (39%) with osteoporosis. Twenty patients (31.3%) were found to have z scores consistent with osteopenia. A multivariate regression analysis identified a low weight-for-age z score (B coefficient = 0.347, 95% confidence interval [CI] = 0.211-0.482, p < 0.001 for Spine BMD and B coefficient = 0.321, 95% CI = 0.170-0.472, p < 0.001 for total body BMD), a low height-for-age z score (B coefficient = 0.187, 95% CI = 0.035-0.338, p = 0.017 for spine BMD and B coefficient = 0.0.258, 95% CI = 0.089-0.427, p = 0.004 for total body BMD), a low 25-hyroxyvitamin D level (B coefficient = 0.026, 95% CI = 0.013-0.038, p < 0.001 for spine BMD and B coefficient = 0.016, 95% CI = 0.002-0.031, p = 0.026 for total body BMD), and a higher number of corticosteroid induction courses (B coefficient = -0.567, 95% CI = -0.923 to -0.212, p = 0.003 for spine BMD and B coefficient = -0.566, 95% CI = 0.963-0.169, p = 0.007 for total body BMD) as predictors of low BMD. In the spine BMD analysis, older age at the time of presentation was identified as a significant predictor for low bone density (B coefficient = 0.254, 95% CI = 0.141-0.368, p < 0.001). In conclusion, Saudi Arabian children and adolescents with CD have a high prevalence rate of low bone density compared to Western populations. Several clinical characteristics are identified as significant predictors for low BMD.

Body composition profile of children and adolescent patients with inflammatory bowel disease.

BACKGROUND AND AIMS: Children with inflammatory bowel disease (IBD) generally show an alteration in their fat and soft tissue mass contents. These alterations may influence disease severity and increase the risk of post-operative complications. METHODS: This is a retrospective cross-sectional study of patients with IBD, diagnosed and followed up between 2013 and 2018, in Jeddah, Saudi Arabia, who had dual-energy x-ray absorptiometry (DXA) scans for bone density evaluation. Obesity was defined based on fat mass index (FMI) and myopenia based on appendicular skeletal muscle mass (SMMa). RESULTS: This study incorporated 95 child and adolescent patients (52% female) with IBD: 59 with Crohn's disease (CD) and 36 with ulcerative colitis (UC), mean age 11.8 ± 3.3 years and mean duration of illness 1.8 ± 1.9 years. The most common disease phenotype and behaviour for CD patients were ileocolonic (57.6%) and non-stricturing and non-penetrating (76.3%). Of UC patients, 75% had extensive disease (pancolitis). Body composition profile in the total IBD cohort was classified as normal in 49.5%, obese in 26.3%, myopenic in 23.2% and myopenic-obese in 1.1%. The use of biological therapy was identified as a negative predictor for both obesity (OR = 7.0, 95% CI: 1.3-37.9, P = .02) and myopenia (OR = 0.11, 95% CI:0.02-0.47, P = .003), and female gender was shown to predict myopenia (OR = 3.5, 95% CI: 1.0-11.8, P = .04). CONCLUSIONS: Saudi Arabian children with IBD showed comparable body composition profiles to adult patients with IBD. Biological therapy was associated with a decreased incidence of both obesity and myopenia, and female gender was found to predict myopenia.

Incorporating Fecal Calprotectin Into Clinical Practice for Patients With Moderate-to-Severely Active Ulcerative Colitis Treated With Biologics or Small-Molecule Inhibitors.

INTRODUCTION: We applied the Grading of Recommendations, Assessment, Development, and Evaluation framework to evaluate the performance of fecal calprotectin (FC) as an alternative to endoscopy in patients with moderate-to-severe ulcerative colitis (UC) treated with a biologic agent or tofacitinib. METHODS: Individual participant data from the trials of infliximab, golimumab, vedolizumab, and tofacitinib for UC were pooled to generate prevalence of endoscopic activity (Mayo endoscopy score) across different combinations of the rectal bleeding score (RBS) and stool frequency score (SFS). These estimates were then combined with the data from an updated systematic review of the operating properties of FC to generate clinical scenario-specific assessments of the performance of FC as a predictor of endoscopic disease activity. A prespecified threshold of acceptability for false-negative (FN) and false-positive (FP) test results was set at 5%. RESULTS: For patients with UC achieving RBS 0 + SFS 0/1, FC ≤ 50 µg/g may avoid endoscopy in 50% patients with a FN rate <5%. Similarly, for patients with RBS 2/3 + SFS 2/3, FC ≥ 250 µg/g potentially avoids endoscopy in approximately 50% patients with an FP rate <5%. The greatest uncertainty in the diagnostic performance for FC was observed in patients with UC achieving RBS 0 but having SFS 2/3, where FN and FP rates were consistently >10%, and endoscopic evaluation may be warranted. DISCUSSION: Two clinical scenarios were identified where FC can be used with confidence for monitoring treatment response to biologics or tofacitinib in patients with UC without the requirement for endoscopy.

Improving the understanding of originator and biosimilar biologics among healthcare providers in Saudi Arabia.

The loss of patentability of many originator biologics has led to the rapid introduction of biosimilar agents. The anticipated economic benefit of introducing such agent has been accompanied by vagueness surrounding their biotechnology, approval requirements, positioning in treatment paradigms and potential for adverse events. The Second Symposium on Biologics and Biosimilars "Beyond Clinical Practice" was held on 24th-26th January 2020 aiming at improving the understanding of these new agents in a diverse interactive conference and to guide stakeholders how to introduce biosimilars into clinical practice. The symposium consisted of 4 tracks and 3 workshops. A total of 217 participants attended the meeting. The majority were pharmacists (78.8%) followed by physicians (18.9%) and other healthcare providers (2.3%). The workshops covered the following topics: basics of pharmacoeconomics, pharmacovigilance and patients' perspective toward biosimilar biologics. While, the 4 main tracks included: Introduction to biosimilars, challenges in clinical practice, regulatory and pharmacoeconomic aspects and Challenges in biosimilar pharmacovigilance.

Inflammatory bowel disease and restless leg syndrome.

OBJECTIVE: Inflammatory bowel disease (IBD) has been associated with restless leg syndrome (RLS). This study aims to explore the prevalence, clinical predictors, and severity of RLS in IBD patients compared to controls. METHODS: We conducted a case-control study between January and December of 2019 comparing IBD patients with controls. Assessment of RLS was performed using the previously validated diagnostic restless leg syndrome questionnaire (RLSQ). Logistic regression analyses were applied to investigate associations between patient demographics and clinical features and RLS diagnosis. RESULTS: A total of 218 IBD patients and 211 healthy controls were incorporated after excluding 6 patients with positional discomfort and 4 patients with habitual foot tapping. The mean age was 30.2+/-11.7 and 64% were females. The prevalence of RLS was 16/218 (7.34%) and 17/211 (8.06%) among cases and controls, respectively. Based on the RLSQ severity score, 6/16 (37.5%), 4/16 (25%) and 1/16 (6.3%) of the IBD patients with RLS had mild, moderate and severe RLS; respectively. The odds of IBD were lower among patients with confirmed RLS (OR=0.90, 95% CI=0.44-1.84, p=0.78). In the logistic regression analysis, only vitamin B12 deficiency (OR=10.20, 95% CI=1.40-74.10, p=0.022) was associated with RLS diagnosis among IBD patients. CONCLUSION: No difference was found in the prevalence of RLS between IBD patients and non-IBD controls. Vitamin B12 deficiency was associated with RLS diagnosis among patients with IBD.

Responsiveness of histological disease activity indices in ulcerative colitis: a post hoc analysis using data from the TOUCHSTONE randomised controlled trial.

OBJECTIVE: We evaluated the reliability and responsiveness of available but incompletely validated UC histological disease activity indices using standardised rules for centralised assessment. DESIGN: Disease activity was assessed in biopsies collected in a phase II placebo-controlled ozanimod trial by four blinded pathologists using the Geboes (GS) and modified Riley (MRS) scores, the Robarts Histopathology (RHI) and Nancy Histological (NHI) indices and a Visual Analogue Scale. Reliability was assessed with intraclass correlation coefficients (ICCs). Index responsiveness was evaluated by assessing longitudinal validity (Pearson correlations of changes in index scores and other disease measures), and effect size estimates (standardised effect size (SES)) using two criteria for change (treatment assignment and >2 point decrease in total Mayo Clinic score). Area under the receiver operating characteristic (AUROC) curve estimates evaluated the probability of the indices to discriminate between treatment and placebo. RESULTS: Inter-rater reliability of the histological indices was substantial to almost perfect (ICC>0.61), and responsiveness was moderate to large (SES estimates>0.5); 0.81 (0.52, 1.10), 0.87 (0.58, 1.17), 0.57 (0.30, 0.84) and 0.81 (0.52, 1.09) when treatment assignment was the criterion for change and 1.05 (0.80, 1.31), 1.13 (0.87, 1.39), 0.88 (0.64, 1.12) and 1.06 (0.80, 1.31) for the change in Mayo score criterion for the GS, MRS, RHI and NHI, respectively. The indices had similar drisciminative ability based on AUROC estimates (range 0.608-0.649). CONCLUSION: All four existing histological indices were similarly reliable and responsive based on this dataset.

Reliability among central readers in the evaluation of endoscopic disease activity in pouchitis.

BACKGROUND AND AIMS: Pouchitis is a common adverse event after proctocolectomy with ileal pouch anal anastomosis for ulcerative colitis. Evaluation of pouchitis disease activity and response to treatment requires use of validated indices. We assessed the reliability of items evaluating endoscopic pouchitis disease activity. METHODS: Twelve panelists used a modified RAND appropriateness methodology to rate the appropriateness of items evaluating endoscopic pouchitis disease activity derived from a systematic review and also identified additional potential endoscopic items based on expert opinion. Four central readers then evaluated 50 pouchoscopy videos in triplicate, in random order. Intra- and inter-rater reliability for each item was assessed by calculating and comparing intraclass correlation coefficients (ICCs). A Delphi process identified common sources of disagreement among the readers. RESULTS: Ten existing endoscopic items were identified from the systematic review and an additional 7 exploratory items from the panelists. ICCs for inter-rater reliability were highest for the existing item of pouch ulceration (.72; 95% confidence interval [CI], .60-.82) and for the exploratory item of ulcerated surface in the pouch body (.67; 95% CI, .53-.75). Inter-rater reliability for all other existing and exploratory items was "moderate" (ICC < .60). The item "ulcerated surface in the pouch body" demonstrated the best correlation with a global evaluation of lesion severity (r = .80; 95% CI, .73-.85). CONCLUSION: Substantial reliability was observed only for the endoscopic items of ulceration and ulcerated surface in the pouch body. Future studies should assess responsiveness to treatment in the next stage toward development of an endoscopic pouchitis disease activity index.

Risk Stratification of Patients with Crohn's Disease: A Retrospective Analysis of Clinical Decision Making and Its Impact on Long-Term Outcome.

BACKGROUND AND AIMS: Complications such as need for bowel resections and hospitalization due to Crohn's disease (CD) occur when disease activity persists due to ineffective therapy. Certain "high-risk" features require an early introduction of anti-tumor necrosis factor-α therapy to prevent such complications. We aim to evaluate the prevalence of "high-risk" features among a cohort of patients with CD and examine the association between discordance of early therapy with baseline risk stratification and disease outcome. PATIENTS AND METHODS: All adult patients with CD were retrospectively identified and their medical records were reviewed. Clinical, endoscopic, laboratory, and radiological data were collected. Patients were divided into "low" and "high" risk groups according to the presence or absence of penetrating disease, perianal involvement, foregut involvement, extensive disease seen on endoscopy or cross-sectional imaging, young age at the time of diagnosis (<40), persistent cigarette smoking and frequent early requirements for corticosteroid therapy. Initial treatment selection and treatment approach ("step-up" vs. "accelerated step-up" vs. "top-down") within 6 months of diagnosis were recorded. Rates of CD-related bowel resections and hospitalization within 5 years of diagnosis were calculated. Logistic regression analysis was used to examine the association between "discordance" of early treatment selections and risk stratification categories with outcomes. RESULTS: Eighty-five CD patients were included. The median age and duration of disease were 25 (interquartile range [IQR] 19-32) and 5 (IQR 4-6) years, respectively. Sixty five percent were females and 66% were native Saudis. Smoking was reported in 12% of patients and perianal disease in 18%. "High-risk" features were identified in 43 (51%) patients, of which only 6 (14%) were treated with "top-down" therapy and 7 (16%) with "accelerated step-up" care. The risk of requiring a bowel resection, and hospitalization was higher for "high-risk" patients compared to "low-risk" patients (risk ratio [RR] 13.67, 95% CI 1.88-99.41; p = 0.003, and RR 1.86, 95% CI 0.03-0.43; p = 0.0312, respectively). "Discordance" occurred in 34% of cases. Bowel resection was required in 15/85 (18%) patients and 32/85 (38%) required at least one hospitalization within 5 years of diagnosis. Logistic regression analysis identified a statistically significant association between "discordance" and need for bowel resections (OR 6.50, 95% CI 1.59-26.27, p = 0.009), and hospitalizations (OR 3.01, 95% CI 1.08-8.39, p = 0.035) within 5 years of diagnosis. CONCLUSIONS: "Discordance" between patient risk-profile and treatment selection early in the course of CD has a significant impact on disease outcome, specifically need for bowel resection and hospitalization, which are more likely to occur in the presence of "high-risk" features. Early identification of "high-risk" features could help prevent long-term complications.

Endoscopic scoring indices for evaluation of disease activity in ulcerative colitis.

BACKGROUND: Endoscopic assessment of mucosal disease activity is routinely used to determine eligibility and response to therapy in clinical trials of ulcerative colitis. The operating properties of the existing endoscopic scoring indices are unclear. OBJECTIVES: A systematic review was undertaken to evaluate the development and operating characteristics of endoscopic scoring indices for the evaluation of ulcerative colitis. SEARCH METHODS: We searched MEDLINE, Embase and CENTRAL from inception to 5 July 2016. We also searched references and conference proceedings (Digestive Disease Week, United European Gastroenterology Week, European Crohn's and Colitis Organization). SELECTION CRITERIA: Any study design (e.g. randomized controlled trials, cohort studies, case series) that evaluated endoscopic indices for evaluation of ulcerative colitis disease activity were considered for inclusion. Eligible participants were adult patients (> 16 years), diagnosed with ulcerative colitis using conventional clinical, radiologic and endoscopic criteria. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed the studies identified from the literature search. These authors also independently extracted and recorded data on the number of patients enrolled; number of patients per treatment arm; patient characteristics including age and gender distribution; endoscopic index; and outcomes such as reliability (intra-rater and inter-rater), validity (content, construct, criterion), responsiveness and feasibility. Any disagreements regarding study inclusion or data extraction were resolved by discussion and consensus with a third author. Risk of bias was assessed by determining whether assessors were blinded to clinical information and whether assessors scored the endoscopic index independently. We also assessed the methodological quality of the validation studies using the COSMIN checklist MAIN RESULTS: A total of 23 reports of 20 studies met the pre-defined inclusion criteria and were included in the review. Of the 20 included validation studies, 19 endoscopic scoring indices were assessed, including the Azzolini Classification, Baron Score, Blackstone Endoscopic Interpretation, Chinese Grading System of Ulcerative Colitis, Endoscopic Activty Index, Jeroen Score, Magnifying Colonoscopy Grade, Matts Score, Mayo Clinic Endoscopic Subscore, Modified Baron Score, Modified Mayo Clinic Endoscopic Subscore, Osada Score, Rachmilewtiz Endoscopic Score, St. Mark's Index, Ulcerative Colitis Colonoscopic Index of Serverity (UCCIS), endoscopic component of the Ulcerative Colitis Disease Activity Index (UCDAI), Ulcerative Colitis Endoscopic Index of Severity (UCEIS), Witts Sigmoidoscopic Score and Watson Grade. The individuals who performed the endoscopic scoring were blinded to clinical and/or histologic information in ten of the included studies, not blinded to clinical and/or histologic information in one of the included studies, and it was unclear whether blinding occurred in the remaining nine included studies. Independent observation was confirmed in four of the included studies, unclear in five of the included studies, and non-applicable (since inter-rater reliability was not assessed) in the remaining eleven included studies. The methodological quality (COSMIN checklist) of most of the included studies was rated as 'good' or 'excellent'. One study that assessed responsiveness was rated as 'fair'. The inter-rater reliability of nine endoscopic scoring indices including the Baron Score, Blackstone Endoscopic Interpretation, Endoscopic Activity Index, Matts Score, Mayo Clinic Endoscopic Subscore, Osada Score, UCCIS, UCEIS, Watson Grade was assessed in seven studies, with estimates of correlation, ƙ, ranging from 0.44 to 0.97. The iIntra-rater reliability of seven endoscopic scoring indices including the Baron Score, Blackstone Endoscopic Interpretation, Matts Score, Mayo Clinic Endoscopic Subscore, Osada Score, UCCIS and UCEIS was assessed in three studies, with estimates of correlation, ƙ, ranging from 0.41 to 0.86. No studies assessed content validity. Three studies evaluated the criterion validity of three endoscopic scoring indices including the Rachmilewitz Endoscopic Score, Magnifying Colonoscopy Grade and the UCCIS. These indices were correlated with objective markers of disease activity including albumin, blood leukocytes, C-reactive protein, fecal calprotectin, hemoglobin, mucosal interleukin-8 concentration and platelet count. Correlation estimates ranged from r = -0.19 to 0.83. Thirteen endoscopic scoring indices were tested for construct validity in 13 studies. Estimates of correlation between the endoscopic scoring indices and other measures of disease activity ranged from r = 0.27 to 0.93. Two studies explored the responsiveness of four endoscopic scoring indices including the Mayo Endoscopic Subscore, Modified Baron Score, Modified Mayo Endoscopic Subscore and UCEIS. One study concluded that the Modified Baron Score, Modified Mayo Endoscopic Subscore and UCEIS had similar responsiveness for detecting disease change in ulcerative colitis. The other included study concluded that the UCEIS may be the most accurate endoscopic scoring tool. None of the included studies formally assessed feasibility. AUTHORS' CONCLUSIONS: While the UCEIS, UCCIS and Mayo Clinic Endoscopic Subscore have undergone extensive validation, none of these instruments have been fully validated and only two studies assessed responsiveness. Further research on the operating properties of these indices is needed given the lack of a fully-validated endoscopic scoring instrument for the evaluation of disease activity in ulcerative colitis.

Development and validation of a histological index for UC.

OBJECTIVE: Although the Geboes score (GS) and modified Riley score (MRS) are commonly used to evaluate histological disease activity in UC, their operating properties are unknown. Accordingly, we developed an alternative instrument. DESIGN: Four pathologists scored 48 UC colon biopsies using the GS, MRS and a visual analogue scale global rating. Intra-rater and inter-rater reliability for each index and individual index items were measured using intraclass correlation coefficients (ICCs). Items with high reliability were used to develop the Robarts histopathology index (RHI). The responsiveness/validity of the RHI and multiple histological, endoscopic and clinical outcome measures were evaluated by analyses of change scores, standardised effect size (SES) and Guyatt's responsiveness statistic (GRS) using data from a clinical trial of an effective therapy. RESULTS: Inter-rater ICCs (95% CIs) for the total GS and MRS scores were 0.79 (0.63 to 0.87) and 0.80 (0.69 to 0.87). The correlation estimates between change scores in RHI and change score in GS and MRS were 0.75 (0.67 to 0.82) and 0.84 (0.79 to 0.88), respectively. The SES and GRS estimates for GS, MRS and RHI were: 1.87 (1.54 to 2.20) and 1.23 (0.97 to 1.50), 1.29 (1.02 to 1.56) and 0.88 (0.65 to 1.12), and 1.05 (0.79 to 1.30) and 0.88 (0.64 to 1.12), respectively. CONCLUSIONS: The RHI is a new histopathological index with favourable operating properties.

Reliability of EUS indices to detect inflammation in ulcerative colitis.

BACKGROUND AND AIMS: EUS is a potentially useful modality to assess severity of inflammation in ulcerative colitis (UC). We assessed the reliability of existing EUS indices and correlated them with endoscopic and histologic scores. METHODS: Four blinded endosonographers assessed 58 endoscopic and EUS videos in triplicate, from patients with UC. Intrarater and interrater reliability of the hyperemia and Tsuga scores were estimated by using intra-class correlation coefficients (ICCs). Correlation with the Mayo endoscopy score, modified Baron score (MBS), Ulcerative Colitis Endoscopic Index of Severity (UCEIS), and Geboes histopathology score (GHS) were calculated by using bootstrapping methods. A RAND consensus process led to development of standardized definitions and a revised EUS-UC score. RESULTS: ICCs for intrarater reliability were 0.76 (95% confidence interval [CI], 0.71-0.80) for the hyperemia score and 0.85 (95% CI, 0.79-0.89) for the Tsuga score. Corresponding values for interrater reliability were 0.34 (95% CI, 0.25-0.42) and 0.36 (95% CI, 0.24-0.46). Correlation between hyperemia and Tsuga scores to Mayo scoring system, MBS, UCEIS, and the GHS were 0.39 (95% CI, 0.15-0.61) and 0.28 (95% CI, 0.04-0.51), 0.38 (95% CI, 0.16-0.57) and 0.25 (95% CI, -0.01-0.48), 0.41 (95% CI, 0.16-0.62) and 0.27 (95% CI, 0.01-0.50), 0.37 (95% CI, -0.01-0.48) and 0.24 (95% CI, 0.13-0.57), respectively. The revised EUS-UC score included bowel wall thickening, depth of inflammation, and hyperemia. CONCLUSIONS: Although substantial to almost perfect intrarater agreement existed for EUS indices in UC, interrater agreement was fair. Standardization of item definitions with development of a revised evaluative instrument has potential application as an evaluative and prognostic tool for UC. (Clinical trial registration number: NCT01852760.).

The utility of fecal calprotectin in predicting the need for escalation of therapy in inflammatory bowel disease.

BACKGROUND AND AIMS: Fecal calprotectin is an important biomarker used in the evaluation of inflammatory bowel disease. It has proven to be an effective tool in initial screening as well monitoring response to therapy. The aim of this study is to examine the utility of fecal calprotectin both as a predictor for the escalation of therapy in established inflammatory bowel disease and as a predictor of de novo diagnosis. METHODS: Patients with signs and symptoms concerning for inflammatory bowel disease presenting to outpatient clinics were recruited to provide fecal calprotectin stool samples prior to endoscopic evaluation. Patients were followed up for at least one year and monitored clinically for any change in symptomatology, escalation of therapy or development of IBD, confirmed endoscopically. RESULTS: A total of 126 patients, of whom 72 were known to have underlying inflammatory bowel disease, were included in the final analysis. Among the patients with elevated fecal calprotectin levels and known inflammatory bowel disease, 66% (33/50) went on to have escalation of therapy within 12 months compared to 18% (4/22) if the fecal calprotectin levels were in the normal range (p < .0001). For the remaining patients who at baseline did not have inflammatory bowel disease and a normal endoscopic evaluation, elevated fecal calprotectin resulted in no cases (0/17) of a new diagnosis in the next 12 months. CONCLUSIONS: Fecal calprotectin is a useful test for predicting escalation of therapy in established inflammatory bowel disease.

Histologic scoring indices for evaluation of disease activity in ulcerative colitis.

BACKGROUND: Disease activity can be determined using clinical, endoscopic or histologic criteria in patients with ulcerative colitis (UC). Persistent disease activity is associated with poor outcomes. Histologic disease activity has been shown to be associated with relapse, colectomy and colorectal cancer. The ability to objectively evaluate microscopic disease activity using histology is important for both clinical practice and clinical trials. However, the operating properties of the currently available histologic indices remain unclear. OBJECTIVES: A systematic review was undertaken to identify and evaluate the development and operating characteristics of histologic disease activity indices used to assess disease activity in people with ulcerative colitis. SEARCH METHODS: We searched MEDLINE, EMBASE, PubMed, CENTRAL and the Cochrane IBD Review Group Specialized Trials Register from inception to 2 December 2016 for applicable studies. There were no language or document type restrictions. SELECTION CRITERIA: Any study design (e.g. randomized controlled trials, cohort studies, case series) that evaluated a histologic index in patients with UC were considered for inclusion. Eligible patients were adults (> 18 years), diagnosed with UC using conventional clinical, radiographic, endoscopic and histologic criteria. DATA COLLECTION AND ANALYSIS: Two authors (MHM and CEP) independently reviewed the titles and abstracts of the studies identified from the literature search. A standardized form was used to assess eligibility of trials for inclusion and for data extraction.Two authors (MHM and CEP) independently extracted and recorded data, which included the number of patients enrolled, number of patients per treatment arm, patient characteristics including age and gender distribution, and the name of the histologic index. Outcomes (i.e. intra-rater reliability, inter-rater reliability, internal consistency, content validity, criterion validity, construct validity, responsiveness, and feasibility) were recorded for each trial. MAIN RESULTS: In total, 126 reports describing 30 scoring indices were identified through the screening process. Eleven of the 30 scoring indices have undergone some form of index validation. Intra-rater reliability was assessed for eight scoring indices. Inter-rater reliability was evaluated for all 11 of the scoring indices. Three of the indices underwent content validation. Two of the included scoring indices assessed criterion validity. Six of the included scoring indices explored content validity. Two of the included scoring indices were tested for responsiveness. AUTHORS' CONCLUSIONS: The Nancy Index and the Robarts Histopathology Index have undergone the most validation in that four operating properties including reliability, content validity, construct validity (hypothesis testing) and criterion validity have been tested. However, none of the currently available histologic scoring indices have been fully validated. In order to determine the optimal endpoint for histologic healing in UC, more research is required. The optimal index would need to be fully validated.

Placebo response and remission rates in randomised trials of induction and maintenance therapy for ulcerative colitis.

BACKGROUND: It is important to minimize placebo rates in randomised controlled trials (RCTs) to efficiently detect treatment differences between interventions. Historically, high placebo rates have been observed in clinical trials of ulcerative colitis (UC). A better understanding of factors influencing placebo rates may lead to more informed clinical trial design. OBJECTIVES: A systematic review and meta-analysis was conducted to evaluate placebo response and remission rates in RCTs evaluating UC treatments in adult patients. SEARCH METHODS: Electronic databases (i.e. MEDLINE, EMBASE, and CENTRAL) were searched from inception to 1 March 2017 with no language restrictions applied. Reference lists and conference proceedings of major gastroenterology meetings were also handsearched to identify additional studies. SELECTION CRITERIA: Placebo-controlled RCTs of adult patients with UC treated with corticosteroids, aminosalicylates, immunosuppressives or biologics were eligible, provided enrolment and outcome assessment was conducted using the Ulcerative Colitis Disease Activity Index (UCDAI) or the Mayo Clinic Score. The minimum trial duration was two weeks for induction trials and four months maintenance trials. DATA COLLECTION AND ANALYSIS: Pairs of authors independently determined study eligibility and extracted data with any disagreements resolved through consensus. Outcomes of interest included the proportion of patients with clinical response and remission. Trial characteristics such as the design, participant demographics and disease history, interventions, and enrolment and assessment criteria were also recorded. The methodological quality of the included studies was evaluated using the Cochrane risk of bias tool. Pooled placebo response and remission rates and 95% confidence intervals (95% CI) were calculated using a binomial normal model for proportions. Induction of remission and maintenance studies were pooled separately. The impact of study-level characteristics on placebo response and remission rates was investigated using mixed-effects meta-regression analyses with logits of event rates as the outcome variables. An assessment of pooled placebo rates over time was conducted using a cumulative meta-analysis based on date of publication. Publication bias was examined using funnel plots. MAIN RESULTS: The screening process identified 61 included studies which encompass 58 induction phases (5111 patients randomised to placebo) and 12 maintenance phases (1579 patients randomised to placebo). For induction trials, the pooled estimate of placebo response was 33% (95% CI 30% to 36%) while the pooled estimate of placebo remission was 12% (95% CI 9% to 15%). For maintenance trials, the pooled estimate of placebo response was 23% (95% CI 19% to 28%) while the pooled estimate of placebo remission was 17% (95% CI 10% to 27%).Studies enrolling patients with more active disease confirmed objectively by endoscopy were associated with significantly lower placebo remission and response rates than trials enrolling patients with less active disease (27% versus 4%, OR 2.60, 95% CI 1.25 to 5.42, P = 0.01 for UCDAI endoscopy sub score ≥1 versus ≥ 2 for remission; and 27% versus 4%, OR 1.70, 95% CI 1.02 to 2.82, P = 0.02 for UCDAI endoscopy sub score greater than or equal to one versus greater than or equal to two for response). With respect to drug class, the lowest placebo response and remission rates were observed in trials evaluating corticosteroids (23%; 95% CI 19 to 29%, and 5%; 95% CI 2 to 11%, respectively). Trials of biologics had the highest placebo response rate (35%; 95% CI 30 to 41%), while trials evaluating aminosalicylates had the highest placebo remission rate (18%; 95% CI 12 to 24%). Disease duration of greater than five years prior to enrolment was associated with a significantly lower placebo response rate compared to disease duration of less than or equal to five years (29% versus 47%, respectively; OR 0.54, 95% CI 0.32 to 0.92, P = 0.02). The requirement of a minimum rectal bleeding score for study eligibility was associated with an increased placebo response rate compared to studies that did not use rectal bleeding for trial eligibility (37% versus 32%, respectively; OR 1.70, 95% CI 1.02 to 2.82, P = 0.02). Finally, the time point of primary outcome assessment was found to be significantly associated with placebo remission rates such that every one week increment in endpoint assessment was associated with a 6% increase in the placebo remission rate (OR 1.06, 95% CI 1.02 to 1.10, P = 0.01).Cumulative meta-analysis indicated a consistent increase in the placebo response rate from 1987 to 2007 (from 13% to 33%), although rates have remained constant from 2008 to 2015 (32% to 34%). Similarly, placebo remission rates increased from 1987 to 2007 (5% to 14%) but have remained constant from 2008 to 2015 (12 to 14%). On meta-regression, there were no statistically significant differences between the 1987-2007 and 2008-2015 point estimates for both response (P = 0.81) and remission (P = 0.32). AUTHORS' CONCLUSIONS: Placebo response and remission rates vary according to endoscopic disease severity and rectal bleeding score at trial entry, class of agent, disease duration, and the time point at which the primary outcome was measured. These observations have important implications for the design and conduct of future clinical trials in UC and will help researchers design trials, determine required sample sizes and also provide useful information about trial design features which should be considered when planning new trials.

Anti-Integrins in Ulcerative Colitis and Crohn's Disease: What Is Their Place?

BACKGROUND: Inflammatory bowel diseases (IBD) are a group of heterogeneous conditions, characterized by immune-mediated inflammation of the gastrointestinal tract. Traditionally, medical management of these disorders has been based on use of systemic immunosuppressives. The development of new drugs that selectively inhibit leukocyte trafficking to the gut has the potential to reduce inflammation and minimize systemic toxicities. KEY MESSAGES: In this article, we review the immunology of the gut and the mechanism of action these emerging therapies for IBD. Natalizumab, a monoclonal antibody to the α4 integrin, was approved for the treatment of multiple sclerosis and showed promise in Crohn's disease (CD), however it is encumbered by the risk of progressive multifocal leukoencephalopathy. Vedolizumab inhibits the α4ß7 integrin to induce clinical remission in patients with both ulcerative colitis and CD. Long-term safety data on this agent is not yet available. We also review agents in the pipeline. Finally, we discuss the positioning of therapies and potential alterations to therapeutic algorithms as new medications emerge. CONCLUSIONS: New therapies are emerging for IBD; however, long-term data are pending. The positioning of these agents in algorithms will evolve.

Reproducibility of histological assessments of disease activity in UC.

OBJECTIVE: Histopathology is potentially an important outcome measure in UC. Multiple histological disease activity (HA) indices, including the Geboes score (GS) and modified Riley score (MRS), have been developed; however, the operating properties of these instruments are not clearly defined. We assessed the reproducibility of existing measures of HA. DESIGN: Five experienced pathologists with GI pathology fellowship training and expertise in IBD evaluated, on three separate occasions at least two weeks apart, 49 UC colon biopsies and scored the GS, MRS and a global rating of histological severity using a 100 mm visual analogue scale (VAS). The reproducibility of each grading system and for individual instrument items was quantified by estimates of intraclass correlation coefficients (ICCs) based on two-way random effects models. Uncertainty of estimates was quantified by 95% two-sided CIs obtained using the non-parametric cluster bootstrap method. Biopsies responsible for the greatest disagreement based on the ICC estimates were identified. A consensus process was used to determine the most common sources of measurement disagreement. Recommendations for minimising disagreement were subsequently generated. RESULTS: Intrarater ICCs (95% CIs) for the total GS, MRS and VAS scores were 0.82 (0.73 to 0.88), 0.71 (0.63 to 0.80) and 0.79 (0.72 to 0.85), respectively. Corresponding inter-rater ICCs were substantially lower: 0.56 (0.39 to 0.67), 0.48 (0.35 to 0.66) and 0.61 (0.47 to 0.72). Correlation between the GS and VAS was 0.62 and between the MRS and VAS was 0.61. CONCLUSIONS: Although 'substantial' to 'almost perfect' ICCs for intrarater agreement were found in the assessment of HA in UC, ICCs for inter-rater agreement were considerably lower. According to the consensus process results, standardisation of item definitions and modification of the existing indices is required to create an optimal UC histological instrument.

C-Reactive Protein, Fecal Calprotectin, and Stool Lactoferrin for Detection of Endoscopic Activity in Symptomatic Inflammatory Bowel Disease Patients: A Systematic Review and Meta-Analysis.

OBJECTIVES: Persistent disease activity is associated with a poor prognosis in inflammatory bowel disease (IBD). Therefore, monitoring of patients with intent to suppress subclinical inflammation has emerged as a treatment concept. As endoscopic monitoring is invasive and resource intensive, identification of valid markers of disease activity is a priority. The objective was to evaluate the diagnostic accuracy of C-reactive protein (CRP), fecal calprotectin (FC), and stool lactoferrin (SL) for assessment of endoscopically defined disease activity in IBD. METHODS: Databases were searched from inception to November 6, 2014 for relevant cohort and case-control studies that evaluated the diagnostic accuracy of CRP, FC, or SL and used endoscopy as a gold standard in patients with symptoms consistent with active IBD. Sensitivities and specificities were pooled to generate operating property estimates for each test using a bivariate diagnostic meta-analysis. RESULTS: Nineteen studies (n=2499 patients) were eligible. The pooled sensitivity and specificity estimates for CRP, FC, and SL were 0.49 (95% confidence interval (CI) 0.34-0.64) and 0.92 (95% CI 0.72-0.96), 0.88 (95% CI 0.84-0.90) and 0.73 (95% CI 0.66-0.79), and 0.82 (95% CI 0.73-0.88) and 0.79 (95% CI 0.62-0.89), respectively. FC was more sensitive than CRP in both diseases and was more sensitive in ulcerative colitis than Crohn's disease. CONCLUSIONS: Although CRP, FC, and SL are useful biomarkers, their value in managing individual patients must be considered in specific clinical contexts.