Citations

Abstract Background Regulatory guidance for Crohn’s disease trials recommends coprimary efficacy end points that evaluate both symptoms and mucosal inflammation. We aimed to characterize the operating properties of commonly used disease activity assessments alone and in combination. Methods Endoscopic and clinical data were available for 129 participants from the Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease trial. Readers scored the Simple Endoscopic Score for Crohn’s Disease and the Crohn’s Disease Endoscopic Index of Severity using standardized conventions. Index reliability was determined using intraclass correlation coefficients. Index responsiveness was assessed using standardized effect sizes based upon treatment assignment. Outcomes were evaluated for optimal sensitivity to treatment effect. Results Substantial inter-rater reliability was observed when the Simple Endoscopic Score for Crohn’s Disease and Crohn’s Disease Endoscopic Index of Severity were used as continuous measures (intraclass correlation coefficient, 0.64; 95% confidence interval [CI], 0.50-0.73; and 0.62 95% CI, 0.36-0.77) compared with moderate reliability when dichotomized (0.46; 95% CI, 0.26-0.65; and 0.51; 95% CI, 0.00-0.78). The Simple Endoscopic Score for Crohn’s Disease, Crohn’s Disease Endoscopic Index of Severity, patient-reported outcome-2, and Crohn’s Disease Activity Index were similarly responsive (standardized effect size, 0.43, 95% CI, 0.05-0.81; 0.38, 95% CI, 0.0-0.76; 0.53, 95% CI, 0.15-0.91). A composite outcome of Crohn’s Disease Activity Index score <150 and Crohn’s Disease Endoscopic Index of Severity score <6 was most sensitive to treatment effect (28.9%; 95% CI, 11.0%-46.8%; P = .003). Conclusion Endoscopic indices were more reliable as continuous measures. Composite outcomes including endoscopy improved sensitivity to treatment effect.

Abstract Background & Aims Crohn’s disease (CD) is a lifelong illness with substantial morbidity, although new therapies and treatment paradigms have been developed. We provide guidance for treatment of ambulatory patients with mild to severe active luminal CD. Methods We performed a systematic review to identify published studies of the management of CD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a group of specialists. Results The consensus includes 41 statements focused on 6 main drug classes: antibiotics, 5-aminosalicylate, corticosteroids, immunosuppressants, biologic therapies, and other therapies. The group suggested against the use of antibiotics or 5-aminosalicylate as induction or maintenance therapies. Corticosteroid therapies (including budesonide) can be used as induction, but not maintenance therapies. Among immunosuppressants, thiopurines should not be used for induction, but can be used for maintenance therapy for selected low-risk patients. Parenteral methotrexate was proposed for induction and maintenance therapy in patients with corticosteroid-dependent CD. Biologic agents, including tumor necrosis factor antagonists, vedolizumab, and ustekinumab, were recommended for patients failed by conventional induction therapies and as maintenance therapy. The consensus group was unable to clearly define the role of concomitant immunosuppressant therapies in initiation of treatment with a biologic agent. Conclusions Optimal management of CD requires careful patient assessment, acknowledgement of patient preferences, evidence-based use of existing therapies, and thorough assessment to define treatment success.

SummaryBackgroundThe appropriate location for biopsy procurement relative to an ulcer in active Crohn's disease is unknown.AimTo explore the relationship between biopsy location, histological disease activity, proinflammatory gene expression and the presence of inflammatory cells.MethodsFifty‐one patients with Crohn's disease and ulcers >0.5 cm diameter in the colon and/or ileum were prospectively enrolled at three centres. Biopsies were obtained from 0 mm, 7 to 8 mm and 21 to 24 mm from the edge of the largest ulcer. Histological activity was blindly assessed with the Global Histological Disease Activity Score, the Robarts Histopathology and Nancy Histological indices. Messenger ribonucleic acid (mRNA) levels for interleukins‐6, ‐8 and ‐23 (p19 and p40 subunits), CD31 and S100A9 were measured using quantitative polymerase chain reaction. The number of CD3+, CD68+ and myeloperoxidase‐positive cells was quantified by immunohistochemistry. Data were analysed using mixed models with location and segment as fixed effects and patients as random effect to account for correlation among segments within a patient.ResultsHistological disease activity scores (P < 0.0001), proinflammatory gene expression levels (P < 0.005) and numbers of myeloperoxidase‐positive cells (P < 0.0001) were highest in biopsies from the ulcer edge in the colon and ileum, with decreasing gradients observed with distance from the edge (P < 0.05). No differences between colonic and ileal samples were detected for the parameters measured at any location.ConclusionsBiopsies from the ulcer edge in patients with Crohn's disease yielded the greatest histological disease activity and mRNA levels and had similar readouts in the colon and ileum. Research is needed to confirm this conclusion for other measures.

OBJECTIVES: Prokinetics are recommended for the treatment of functional dyspepsia (FD) but systematic reviews give conflicting results on the efficacy of these agents. We have therefore conducted an updated systematic review to support the 2017 joint ACG/CAG dyspepsia guidelines. METHODS: Electronic databases, including MEDLINE, EMBASE, and CENTRAL, were searched until September 2017 for randomized controlled trials (RCTs) comparing either prokinetics and placebo or two types of prokinetics to improve FD symptoms. The primary outcome was absence or improvement of dyspeptic symptoms at the end of treatment. Double-blind eligibility assessment and data extraction was performed. Pooled risk ratios of symptoms persisting or adverse events occurring, and standardized mean difference of quality-of-life (QoL) scores with 95% CI, using a random effects model, were calculated. Quality of evidence was assessed using GRADE. RESULTS: The search identified 1388 citations; 38 studies in 35 papers were included. Of these, 29 trials comparing prokinetics with placebo were found. There was a statistically significant effect of prokinetic treatment in reducing global symptoms of FD (RR 0.81, 95% CI 0.74 to 0.89; I 2 91%; NNT 7), regardless of FD subtype or ethnicity. When comparing two types of prokinetic, the most commonly used comparator was domperidone. There was no difference in reducing global symptoms (RR 0.94, 95% CI 0.83 to 1.07). QoL was not improved with prokinetic treatment. The adverse events with individual prokinetics were not different from placebo, except for cisapride. The GRADE assessment rated the quality of the evidence in each outcome as very low. CONCLUSIONS: From the current evidence, prokinetics may be effective for the treatment in all subtypes of FD, with very low quality of evidence. There was no difference between prokinetics for dyspeptic symptom improvement. High-quality RCTs with large sample sizes of FD patients are needed to verify the efficacy of prokinetics.

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.

Summary Background Regulatory requirements for claims of mucosal healing in ulcerative colitis ( UC ) will require demonstration of both endoscopic and histologic healing. Quantifying these rates is essential for future drug development. Aims To meta‐analyse endoscopic and histologic placebo response and remission rates in UC randomised controlled trials ( RCT s) and identify factors influencing these rates. Methods MEDLINE , EMBASE and the Cochrane Library were searched from inception to March 2017 for placebo‐controlled trials of pharmacological interventions for UC . Endoscopic and histologic placebo rates were pooled by random effects. Mixed effects univariable and multivariable meta‐regression was used to evaluate the influence of patient, intervention and trial‐related study‐level covariates on these rates. Results Fifty‐six induction (placebo n = 4171) and 8 maintenance trials (placebo n = 1011) were included. Pooled placebo endoscopic remission and response rates for induction trials were 23% [95 confidence interval ( CI ) 19‐28%] and 35% [95% CI 27‐42%] respectively, and 20% [95% CI 16‐24%] for maintenance of remission. The pooled histologic placebo remission rate was 14% [95% CI 8‐22%] for induction trials. High heterogeneity was observed for all outcomes ( I 2 56.2%‐88.3%). On multivariable meta‐regression, central endoscopy reading was associated with significantly lower endoscopic placebo remission rates (16% vs 25%; OR = 0.52, [95% CI 0.29‐0.92], P = 0.03). On univariable meta‐regression, higher histologic placebo remission was associated with concomitant corticosteroids ( OR = 1.17 [95% CI 1.08‐1.26], P < 0.0001, per 10% increase in corticosteroid use). Conclusions Placebo endoscopic and histologic rates range from 14% to 35% in UC RCT s but are highly heterogeneous. Outcome standardisation may reduce heterogeneity and is needed in this field.