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Summary: Background: Fibrotic stricture is a common complication of Crohn's disease (CD) affecting approximately half of all patients. No specific anti‐fibrotic therapies are available; however, several therapies are currently under evaluation. Drug development for the indication of stricturing CD is hampered by a lack of standardised definitions, diagnostic modalities, clinical trial eligibility criteria, endpoints and treatment targets in stricturing CD. Aim: To standardise definitions, diagnosis and treatment targets for anti‐fibrotic stricture therapies in Chron's disease. Methods: An interdisciplinary expert panel consisting of 15 gastroenterologists and radiologists was assembled. Using modified RAND/University of California Los Angeles appropriateness methodology, 109 candidate items derived from systematic review and expert opinion focusing on small intestinal strictures were anonymously rated as inappropriate, uncertain or appropriate. Survey results were discussed as a group before a second and third round of voting. Results: Fibrotic strictures are defined by the combination of luminal narrowing, wall thickening and pre‐stenotic dilation. Definitions of anastomotic (at site of prior intestinal resection with anastomosis) and naïve small bowel strictures were similar; however, there was uncertainty regarding wall thickness in anastomotic strictures. Magnetic resonance imaging is considered the optimal technique to define fibrotic strictures and assess response to therapy. Symptomatic strictures are defined by abdominal distension, cramping, dietary restrictions, nausea, vomiting, abdominal pain and post‐prandial abdominal pain. Need for intervention (endoscopic balloon dilation or surgery) within 24‐48 weeks is considered the appropriate endpoint in pharmacological trials. Conclusions: Consensus criteria for diagnosis and response to therapy in stricturing Crohn's disease should inform both clinical practice and trial design. [ABSTRACT FROM AUTHOR]

Summary: Background: Aminosalicylates are the most frequently prescribed drugs for patients with Crohn's disease (CD), yet evidence to support their efficacy as induction or maintenance therapy is controversial. Aims: To quantify aminosalicylate use in CD clinical trials, identify factors associated with use and estimate direct annual treatment costs of therapy. Methods: MEDLINE, Embase and CENTRAL were searched to April 2017 for placebo‐controlled trials in adults with CD treated with corticosteroids, immunosuppressants or biologics. The proportion of patients co‐prescribed aminosalicylates in placebo arms was pooled using a random‐effects model. Meta‐regression was used to identify factors associated with aminosalicylate use. Annual treatment costs were estimated using the 2016 Ontario Drug Benefit Program. Results: Forty‐two induction and 10 maintenance trials were included. The pooled proportion of patients co‐prescribed aminosalicylates was 44% [95% CI: 39%‐49%] in induction trials and 49% [95% CI: 35%‐64%] in maintenance trials. There was substantial to considerable heterogeneity (I2 = 86.0%, 91.8% for induction and maintenance trials, respectively). In multivariable meta‐regression, aminosalicylate use has decreased over time in induction trials (OR 0.50 [95% CI: 0.34–0.74] per 10‐year increment). While a decline has been seen over time, 35% of CD patients were still using aminosalicylates in contemporary trials from the last 5 years. The estimated annual cost for the lowest price mesalazine (mesalamine) formulation is approximately $32 million for the Canadian CD population. Conclusions: Over one‐third of CD patients entering clinical trials are still co‐prescribed aminosalicylates. A definitive trial is needed to inform the conventional practice of using aminosalicylates as CD maintenance therapy. [ABSTRACT FROM AUTHOR]

Summary: Background: In Phase 3 studies of ustekinumab, a fully human monoclonal IL‐12/23p40 antibody approved for moderate‐to‐severe Crohn's disease, patients entered a long‐term extension after completing 8 weeks of induction and 44 weeks of maintenance treatment. Efficacy through 92 weeks and safety through 96 weeks of IM‐UNITI maintenance are reported. Methods: UNITI‐1 (TNF‐antagonist failures) and UNITI‐2 (conventional therapy failures) patients (N = 1281) entered IM‐UNITI, including 397 ustekinumab intravenous induction responders randomised to subcutaneous ustekinumab 90 mg every 12 weeks, every 8 weeks, or placebo and 884 nonrandomised patients. Dose‐adjustment to 90 mg every 8 weeks occurred in patients randomised to 90 mg every 12 weeks and placebo patients with loss of response (Weeks 8–32). All Week 44 completers could enter the long‐term extension without further dose adjustment. Placebo patients discontinued following study unblinding. Results: A total of 718 patients (all treated) entered the long‐term extension (298 randomised and 420 not randomised). Overall, 86.5% (621/718) completed Week 96. The proportions of randomised patients in clinical remission were generally maintained from Week 44 through 92 in ustekinumab 90 mg every 12 weeks (77.4% to 72.6%), every 8 weeks (84.1% to 74.4%), and prior dose adjustment groups (63.4% to 53.5%). At Week 92, the proportions of patients in clinical remission were similar in the ustekinumab 90 mg every 12 weeks and every 8 weeks groups and lower in patients with prior dose adjustment. Proportions of patients in clinical remission at Week 92 for all treated every 8 weeks (64.4%) and every 12 weeks (64.3%) groups were lower than randomised every 8 weeks (74.4%) and every 12 weeks (72.6%) groups, but similarly maintained. Safety events (per hundred patient‐years) were similar among all placebo and ustekinumab patients (Week 0‐96), including adverse events (484.39 vs 447.76), serious adverse events (19.24 vs 18.82), and serious infections (4.09 vs 4.02). No dose effect was observed. Conclusions: Subcutaneous ustekinumab maintained clinical response and remission through Week 92. No new safety signals were observed. ClinicalTrials.gov number NCT01369355. [ABSTRACT FROM AUTHOR]

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 (RCTs) 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 (I2 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 RCTs but are highly heterogeneous. Outcome standardisation may reduce heterogeneity and is needed in this field. [ABSTRACT FROM AUTHOR]

Summary: Background: The validity of the eosinophilic oesophagitis (EoE) histologic scoring system (EoEHSS) has been demonstrated, but only preliminary reliability data exist. Aim: Formally assess the reliability of the EoEHSS and additional histologic features. Methods: Four expert gastrointestinal pathologists independently reviewed slides from adult patients with EoE (N = 45) twice, in random order, using standardised training materials and scoring conventions for the EoEHSS and additional histologic features agreed upon during a modified Delphi process. Intra‐ and inter‐rater reliability for scoring the EoEHSS, a visual analogue scale (VAS) of overall histopathologic disease severity, and additional histologic features were assessed using intra‐class correlation coefficients (ICCs). Results: Almost perfect intra‐rater reliability was observed for the composite EoEHSS scores and the VAS. Inter‐rater reliability was also almost perfect for the composite EoEHSS scores and substantial for the VAS. Of the EoEHSS items, eosinophilic inflammation was associated with the highest ICC estimates and consistent with almost perfect intra‐ and inter‐rater reliability. With the exception of dyskeratotic epithelial cells and surface epithelial alteration, ICC estimates for the remaining EoEHSS items were above the benchmarks for substantial intra‐rater, and moderate inter‐rater reliability. Estimation of peak eosinophil count and number of lamina propria eosinophils were associated with the highest ICC estimates among the exploratory items. Conclusion: The composite EoEHSS and most component items are associated with substantial reliability when assessed by central pathologists. Future studies should assess responsiveness of the score to change after a therapeutic intervention to facilitate its use in clinical trials. [ABSTRACT FROM AUTHOR]

Background Magnetic resonance imaging ( MRI) is the gold standard for assessment of perianal fistulising Crohn's disease ( CD). The Van Assche index is the most commonly used MRI fistula index. Aims To assess the reliability of the Van Assche index, and to modify the instrument to improve reliability and create a novel index for fistulising CD. Methods A consensus process developed scoring conventions for existing Van Assche index component items and new items. Four experienced radiologists evaluated 50 MRI images in random order on three occasions. Reliability was assessed by estimates of intraclass correlation coefficients ( ICCs). Common sources of disagreement were identified and recommendations made to minimise disagreement. A mixed effects model used a 100 mm visual anologue scale ( VAS) for global severity as outcome and component items as predictors to create a modified Van Assche index. Results Intraclass correlation coefficients (95% confidence intervals) for intra-rater reliability of the original and modified Van Assche indices and the VAS were 0.86 (0.81-0.90), 0.90 (0.86-0.93) and 0.86 (0.82-0.89). Corresponding ICCs for inter-rater reliability were 0.66 (0.52-0.76), 0.67 (0.55-0.75) and 0.58 (0.47-0.66). Sources of disagreement included number, location, and extension of fistula tracts, and rectal wall involvement. A modified Van Assche index (range 0-24) was created that included seven component items. Conclusions Although 'almost perfect' intra-rater reliability was observed for the assessment of MRI images for fistulising CD using the Van Assche index, inter-rater reliability was considerably lower. Our modification of this index should result in a more optimal instrument. [ABSTRACT FROM AUTHOR]

Background High concentration mesalazine formulations are more convenient than conventional low concentration formulations for the treatment of ulcerative colitis ( UC). Aim To compare the efficacy and safety of 1600 mg and 400 mg tablet mesalazine formulations. Methods Patients with mild-to-moderate active UC (Mayo Clinic Score >5; N=817) were randomised to 3.2 g of oral mesalazine, administered as two 1600 mg tablets once, or four 400 mg tablets twice daily. We hypothesised that treatment with the 1600 mg tablet was non-inferior (within a 10% margin) to the 400 mg tablet for induction of clinical and endoscopic remission at week 8. Open-label treatment with the 1600 mg tablet continued for 26-30 weeks based on induction response. Predictors of treatment response were also explored. Results At week 8, remission occurred in 22.4% and 24.6% of patients receiving the 1600 mg and 400 mg tablets, respectively (absolute difference −2.2%, 95% CI: −8.1% to 3.8%, non-inferiority P=.005). Endoscopic and histopathologic disease activity, leucocyte concentration and age were significantly associated with clinical remission ( P=.022, .042, .014 and .023, respectively). At week 38, 43.9% (296/675) of patients who continued treatment with the 1600 mg formulation were in remission, including 70.3% (142/202) of patients who received a reduced dose of mesalazine (1.6 g/d). The overall incidence of serious adverse events was low. Conclusions Induction therapy with 3.2 mg mesalazine using two 1600 mg tablets once-daily was statistically and clinically non-inferior to a twice-daily regimen using four 400 mg tablets ( NCT01903252). [ABSTRACT FROM AUTHOR]

Background: Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn's disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy.Methods: We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn's Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150).Results: The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups.Conclusions: Among patients with moderately to severely active Crohn's disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .). [ABSTRACT FROM AUTHOR]

Background Matrix metalloproteinase-9 is a proteolytic enzyme whose expression is increased in ulcerative colitis. Aim To evaluate the safety and efficacy of GS-5745, a fully humanised anti-matrix metalloproteinase-9 monoclonal antibody, in moderately-to-severely active ulcerative colitis. Methods We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS-5745 or placebo. Multiple-dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS-5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS-5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS-5745. Exploratory analyses in the multiple-dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS-5745 were explored using histological and molecular approaches. Results Twenty-three of the 42 patients (55%) receiving multiple doses of GS-5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS-5745 showed target-mediated drug disposition, approximately dose-proportional increases in maximum plasma concentration and more than dose-proportional increases in the area under the plasma drug concentration-time curve. Clinical response occurred in 18/42 patients (43%) receiving GS-5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS-5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS-5745 had reductions in matrix metalloproteinase-9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation. Conclusion This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS-5745 in the treatment of ulcerative colitis. [ABSTRACT FROM AUTHOR]

Crohn's disease and ulcerative colitis are chronic inflammatory disorders resulting from immune dysregulation. Patients who fail conventional medical therapy require biological treatment with monoclonal antibodies (mAbs). Although mAbs are highly effective for induction and maintenance of clinical remission, not all patients respond, and a high proportion of patients lose response over time. One factor associated with loss of response is immunogenicity, whereby the production of antidrug antibodies accelerates mAb clearance. However, other factors related to patient and disease characteristics also influence the pharmacokinetics of mAbs. These factors include gender, body size, concomitant use of immunosuppressive agents, disease type, serum albumin concentration, and the degree of systemic inflammation. Because it is important to maintain clinically effective concentrations to provide optimal clinical response and drug exposure is affected by patient factors, a better understanding of the pharmacology of mAbs will ultimately result in better patient care. [ABSTRACT FROM AUTHOR]

Background: The optimum regimen of epoetin alfa for prevention of allogeneic blood transfusion is unknown.Objective: To determine whether a modified regimen of epoetin alfa reduces allogeneic blood transfusion in patients undergoing hip arthroplasty.Design: Randomized, double-blind, multicenter trial comparing two modified dose regimens of epoetin alfa with placebo.Setting: 13 teaching hospitals and 4 community hospitals in Canada.Patients: 201 patients undergoing primary hip arthroplasty who had a hemoglobin concentration of 98 to 137 g/L and did not predonate blood.Intervention: Patients were assigned in a 3:5:5 ratio to receive four weekly doses of epoetin alfa, 40 000 U (high-dose; n = 44) or 20 000 U (low-dose; n = 79), or placebo (n = 78), starting 4 weeks before surgery. All patients received oral iron supplementation, 450 mg/d, for 42 or more days before surgery.Measurements: The primary end point was allogeneic transfusion. Secondary end points were thromboembolic events and change in reticulocyte count and hemoglobin concentration.Results: Both modified epoetin alfa regimens significantly reduced the need for allogeneic transfusion: Five (11.4%) patients in the high-dose group (P = 0.001) and 18 (22. 8%) patients in the low-dose group (P = 0.003) had transfusion, compared with 35 (44.9%) patients in the placebo group. The hematologic response was substantial in patients who received epoetin alfa. In the high-dose group, low-dose group, and placebo group, the preoperative increase in reticulocyte count was 58.8, 37. 0 and 1.8 x 10(9) cells/L (P < 0.001), respectively, and the increase in hemoglobin concentration was 19.5, 17.2, and 1.2 g/L (P < 0.001). The incidence of thromboembolic events did not differ among groups.Conclusions: Both modified epoetin alfa regimens were effective compared with placebo in reducing allogeneic transfusion in patients undergoing hip arthroplasty. Patients who received high-dose epoetin alfa had the lowest transfusion rate. [ABSTRACT FROM AUTHOR]

Context: Large variations exist among hospitals in the use of treatment resources for community-acquired pneumonia (CAP). Lack of a common approach to the diagnosis and treatment of CAP has been cited as an explanation for these variations.Objective: To determine if use of a critical pathway improves the efficiency of treatment for CAP without compromising the well-being of patients.Design: Multicenter controlled clinical trial with cluster randomization and up to 6 weeks of follow-up.Setting: Nineteen teaching and community hospitals in Canada.Patients: A total of 1743 patients with CAP presenting to the emergency department at 1 of the participating institutions between January 1 and July 31, 1998.Intervention: Hospitals were assigned to continue conventional management (n = 10) or implement the critical pathway (n = 9), which consisted of a clinical prediction rule to guide the admission decision, levofloxacin therapy, and practice guidelines.Main Outcome Measures: Effectiveness of the critical pathway, as measured by health-related quality of life on the Short-Form 36 Physical Component Summary (SF-36 PCS) scale at 6 weeks; and resource utilization, as measured by the number of bed days per patient managed (BDPM).Results: Quality of life and the occurrence of complications, readmission, and mortality were not different for the 2 strategies; the 1-sided 95% confidence limit of the between-group difference in the SF-36 PCS change score was 2.4 points, which was within a predefined 3-point boundary for equivalence. Pathway use was associated with a 1.7-day reduction in BDPM (4.4 vs 6.1 days; P = .04) and an 18% decrease in the admission of low-risk patients (31% vs 49%; P = .01). Although inpatients at critical pathway hospitals had more severe disease, they required 1.7 fewer days of intravenous therapy (4.6 vs 6.3 days; P = .01) and were more likely to receive treatment with a single class of antibiotic (64% vs 27%; P<.001).Conclusion: In this study, implementation of a critical pathway reduced the use of institutional resources without causing adverse effects on the well-being of patients. [ABSTRACT FROM AUTHOR]

The authors respond to an editorial which highlighted challenges in the investigation of eosinophilic oesophagitis (EoE). They cite two treatment objectives for EoE patients, including a significant reduction in symptoms and prevention of remodeling and stricture formation. They also emphasize the need to further establish the clinical validity of the EoE histological scoring system (EoEHSS).

Linked Content This article is linked to Jairath et al and Bernstein papers. To view these articles visit https://doi.org/10.1111/apt.13973 and https://doi.org/10.1111/apt.14036. [ABSTRACT FROM AUTHOR]

The article reports on the results of research which was conducted in an effort to determine whether arthroscopic surgery provided any additional benefit to optimized physical and medical therapy in patients with osteoarthritis of the knee. Researchers conducted a randomized, blinded controlled trial. They found that in patients with osteoarthritis of the knee, arthroscopic surgery did not confer any additional benefit to optimized physical and medical therapy.