Vipul Jairath

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 Guyatts 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.

Systematic review with meta-analysis: faecal microbiota transplantation for the induction of remission for active ulcerative colitis

Faecal microbiota transplantation (FMT) is emerging as a novel therapy for ulcerative colitis (UC). Interpretation of efficacy of FMT for UC is complicated by differences among studies in blinding, FMT administration procedures, intensity of therapy and donor stool processing methods.

Systematic review: the safety of vedolizumab for the treatment of inflammatory bowel disease.

Vedolizumab specifically recognises the α4β7 integrin and selectively blocks gut lymphocyte trafficking: potentially, it offers gut‐specific immunosuppression.

Advances in Use of Endoscopy, Radiology, and Biomarkers to Monitor Inflammatory Bowel Diseases

Crohns disease and ulcerative colitis are heterogeneous inflammatory bowel diseases, and therapeutic requirements vary among patients. We have a limited capacity to predict disease progression for individual patients, therefore it is important that they are evaluated for the presence of active disease when symptoms are mild or even absent, when patients are more likely to respond to new treatment interventions. It then is important to monitor responses to treatment, to quickly identify those therapies that are ineffective, modify or change therapy, and avoid disease complications. Studies are underway to assess the effects of different monitoring strategies. Because of the heavy burden of severe inflammatory bowel disease on patients health andxa0quality of life, and the association between intestinal healing and disease progression in high-risk patients, a treat-to-target strategy (based on tissue healing) is likely to be optimal.

Review article: dose optimisation of infliximab for acute severe ulcerative colitis

Although optimal medical management of acute severe ulcerative colitis (UC) is ill‐defined, infliximab has become a standard of care. Accumulating evidence suggests an increased rate of infliximab clearance in patients with acute severe UC and a reduced colectomy rate with an intensified infliximab induction regimen.

Acute lower GI bleeding in the UK: patient characteristics, interventions and outcomes in the first nationwide audit

Objective Lower GI bleeding (LGIB) is a common reason for emergency hospital admission, although there is paucity of data on presentations, interventions and outcomes. In this nationwide UK audit, we describe patient characteristics, interventions including endoscopy, radiology and surgery as well as clinical outcomes. Design Multicentre audit of adults presenting with LGIB to UK hospitals over 2u2005months in 2015. Consecutive cases were prospectively enrolled by clinical teams and followed for 28u2005days. Results Data on 2528 cases of LGIB were provided by 143 hospitals. Most were elderly (median age 74u2005years) with major comorbidities, 29.4% taking antiplatelets and 15.9% anticoagulants. Shock was uncommon (58/2528, 2.3%), but 666 (26.3%) received a red cell transfusion. Flexible sigmoidoscopy was the most common investigation (21.5%) but only 2.1% received endoscopic haemostasis. Use of embolisation or surgery was rare, used in 19 (0.8%) and 6 (0.2%) cases, respectively. 48% patients underwent no inpatient investigations. The most common diagnoses were diverticular bleeding (26.4%) and benign anorectal conditions (16.7%). Median length of stay was 3u2005days, 13.6% patients rebled during admission and 4.4% were readmitted with bleeding within 28u2005days. In-hospital mortality was 85/2528 (3.4%) and was highest in established inpatients (17.8%, p<0.0001) and in patients experiencing rebleeding (7.1%, p<0.0001). Conclusions Patients with LGIB have a high burden of comorbidity and frequent antiplatelet or anticoagulant use. Red cell transfusion was common but most patients were not shocked and required no endoscopic, radiological or surgical treatment. Nearly half were not investigated. In-hospital mortality was related to comorbidity, not severe haemorrhage.

The expanding therapeutic armamentarium for inflammatory bowel disease: How to choose the right drug[s] for our patients?

The therapeutic landscape for inflammatory bowel disease [IBD] is rapidly evolving. Two new biologic drugs, vedolizumab and ustekinumab, have recently entered the marketplace, the first biosimilars have been introduced, and several other agents are at an advanced stage of clinical development. In parallel, therapeutic goals have shifted from symptom control towards mucosal healing and prevention of bowel damage. In the coming years, gastroenterologists will be faced with unprecedented choices when selecting the best treatment for their patients with IBD. In this article, we review existing data on the mechanisms of action, efficacy, and safety of recently approved and late-stage pipeline therapies, and use this information to speculate on the positioning of these drugs, alone or in combination, in therapeutic algorithms for Crohns disease and ulcerative colitis.

Systematic Review: Disease Activity Indices in Eosinophilic Esophagitis

Objectives:There is no clear consensus regarding the most appropriate measure(s) of eosinophilic esophagitis (EoE) disease activity. We aimed to identify all scoring indices used for the measurement of disease activity in EoE, appraise their operating properties, and discuss their value as outcome measures.Methods:MEDLINE, EMBASE, and CENTRAL (The Cochrane library) were searched from inception to 11 May 2016. Randomized controlled trials (RCTs), cohort, case–control, and cross-sectional studies that reported outcomes to measure EoE disease activity or response to treatment were eligible. Operating properties of histologic, endoscopic, and patient reported/symptomatic and health-related quality of life measures were critically appraised according to guidelines proposed by the United States Food and Drug Administration.Results:Of 4,373 citations, 130 studies were eligible, of which 20 were RCTs. Although no index met all evaluative criteria, we found that: (1) the EoE histologic scoring system (EoEHSS) is the most valid histologic measure; (2) the Endoscopic Reference Score (EREFS) is the most reliable and responsive endoscopy measure; and (3) the Eosinophilic Esophagitis Activity Index (EEsAI) or the Dysphagia Symptoms Questionnaire (DSQ) had superior construct validity and responsiveness in adults. The Pediatric Quality of Life Inventory EoE was the most valid pediatric symptomatic measure.Conclusions:Current evidence supports the use of the EoEHSS and EREFS as measures of histologic and endoscopic EoE disease activity, respectively, and the EEsAI, DSQ, or Pediatric Quality of Life Inventory EoE as measures of adult and pediatric symptoms. Additional research is needed to optimize endpoint configuration to facilitate development of new therapies.

Responsiveness of Endoscopic Indices of Disease Activity for Crohn’s Disease

Objectives:The Crohn’s Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score for Crohn’s Disease (SES-CD) are commonly used to assess Crohn’s disease (CD) activity; however neither instrument is fully validated. We evaluated the responsiveness to change of the SES-CD and CDEIS using data from a trial of adalimumab, a drug therapy of known efficacy.Methods:Paired video recordings (N=112) of colonoscopies (baseline and week 8–12) obtained from patients with CD who participated in a trial of adalimumab therapy were reviewed in random order, in duplicate, by four central readers (56 pairs of videos by 2 groups of readers). Responsiveness of the SES-CD and the CDEIS was evaluated by comparing correlations between the observed and pre-specified predictions of change scores for these endoscopic indices with a global endoscopic evaluation of severity (GELS), a patient reported outcome (PRO2), and the Crohn’s disease activity index (CDAI), and by calculation of the standardized effect size, and Guyatt’s Responsiveness statistic (GRS) using 2 definitions of change; (1) treatment assignment and (2) an absolute change in total PRO2 of 50. The potential application of effect size estimates was demonstrated by calculating hypothetical sample sizes for comparing two independent groups. The impact of removing stenosis as an index item and adjusting for the number of segments observed was also assessed.Results:Changes in both endoscopic instruments and the GELS were highly correlated. The SES-CD displayed numerically higher effect sizes for both definitions of change. The standardized effect size and GRS estimates (95% confidence interval) for the SES-CD based on treatment assignment were 0.84 (0.53, 1.15) and 0.79 (0.48, 1.09). Corresponding values for the CDEIS were 0.72 (0.42, 1.02) and 0.75 (0.45, 1.06). The standardized effect size and GRS estimates for the SES-CD based on an absolute change in total PRO2 of 50 points or greater were 0.76 (0.49, 1.02) and 0.93 (0.64, 1.21). Corresponding values for CDEIS were 0.70 (0.44, 0.97), 0.83 (0.55, 1.10). Removal of stenosis as an index item and adjusting for observed segments did not improve responsiveness estimates.Conclusions:Although both the SES-CD and CDEIS are valid measures of endoscopic disease activity that are moderately responsive to changes in endoscopic disease activity, the SES-CD displayed numerically greater responsiveness in this data set.

Evolving Concepts in Phases I and II Drug Development for Crohn's Disease.

The highest attrition rates during drug development programmes occur at the proof of concept stage. Given the large number of molecules under development for Crohn’s disease, a need exists to improve the efficiency of early drug development by fast-tracking promising agents and terminating ineffective ones. Multiple opportunities are available to achieve these goals, including the use of more responsive outcome measures, and the incorporation of sophisticated pharmacokinetic modelling and/or highly specific pharmacodynamic markers into exposure-based dosing regimens and novel trial designs. In this article we review these strategies and propose an integrated paradigm of early drug development in Crohn’s disease.