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Background & Aims Lysyl oxidase-like 2 contributes to fibrogenesis by catalyzing cross-linkage of collagen. We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody against lysyl oxidase-like 2, in two phase 2b trials of patients with advanced fibrosis caused by nonalcoholic steatohepatitis. Methods We performed a double-blind study of 219 patients with bridging fibrosis caused by nonalcoholic steatohepatitis who were randomly assigned (1:1:1) to groups given weekly subcutaneous injections of simtuzumab (75 or 125 mg) or placebo for a planned duration of 240 weeks. We performed a separate study of 258 patients with compensated cirrhosis randomly assigned (1:1:1) to groups given intravenous infusions of simtuzumab (200 or 700 mg) or placebo every other week. The studies were performed from January 2013 through July 2014 at 80 sites in North America and Europe. Biopsy specimens were collected and analyzed at screening and at weeks 48 and 96; clinical information and serum levels of fibrosis biomarkers were collected throughout the study. The primary end point was change from baseline to week 96 in hepatic collagen content, measured by morphometry of liver specimens, in patients with bridging fibrosis; for patients with cirrhosis, the primary end point was change in hepatic venous pressure gradient from baseline to week 96. Results The 2 studies were stopped after week 96 because of lack of efficacy. All 3 groups of patients with bridging fibrosis—including those given placebo—had significant decreases in hepatic collagen content, but there was no statistically significant difference in decrease between patients receiving simtuzumab 75 mg and those receiving placebo (−0.2%, 95% confidence interval [CI] −1.3 to 1.0, P = .77) or between patients receiving simtuzumab 125 mg and those receiving placebo (−0.4%, 95% CI −1.5 to 0.8, P = .52). In patients with cirrhosis, the mean difference in hepatic venous pressure gradient between the 2 simtuzumab groups and the placebo group was 0.1 mm Hg (95% CI −1.2 to 1.5, P = .84 for 200 mg; 95% CI −1.2 to 1.4, P = .88 for 700 mg). Simtuzumab did not significantly decrease fibrosis stage, progression to cirrhosis in patients with bridging fibrosis, or liver-related clinical events in patients with cirrhosis. Rates of adverse events were similar among groups. Conclusion In two phase 2b trials of patients with bridging fibrosis or compensated cirrhosis associated with nonalcoholic steatohepatitis, simtuzumab was ineffective in decreasing hepatic collagen content or hepatic venous pressure gradient, respectively. Clinicaltrials.gov NCT01672866 and NCT01672879.

Fibrosis is an independent predictor of death in nonalcoholic steatohepatitis (NASH). We assessed the associations between histologic and noninvasive tests (NITs) for fibrosis with clinical and patient-reported outcomes (PROs) in advanced NASH.Patients with advanced NASH (NASH Clinical Research Network stage F3 or F4) were enrolled in 4 multinational clinical trials of simtuzumab and selonsertib. Liver biopsy samples, NIT results, and PROs (Short Form-36, Chronic Liver Disease Questionnaire-NASH, EuroQol-5D, and Work Productivity and Activity Impairment) were prospectively collected.A total of 2154 patients with advanced NASH were included: 52.5% with F4 NASH, 40% male, 72% with type 2 diabetes, baseline liver stiffness of 24.1 ± 14.2 kPa in F4 disease and 14.6 ± 8.0 kPa in F3 disease, baseline mean Enhanced Liver Fibrosis score of 11.4 ± 1.2 in F4 disease and 10.3 ± 1.0 in F3 disease, and a median follow-up of 16 months. Of those with baseline F3 disease, 16.7% experienced disease progression to cirrhosis, whereas for those with F4 disease, 7.3% experienced clinical events (39% ascites, 24% hepatic encephalopathy); patients who progressed had higher baseline NIT scores (all P.0001). Adjusted for baseline levels, increases in NIT scores were also associated with increased risk of disease progression in both the F3 and F4 groups (P.01 for all NITs in F3 and for ELF, NAFLD Fibrosis Score, Fibrosis-4 (FIB-4), and liver stiffness in F4). Higher NIT scores were found to be associated with impairment in PROs: ELF, ≥10.43; Nonalcoholic Fatty Liver Disease Fibrosis Score, ≥1.80; Fibrotest score, ≥0.54; liver stiffness, ≥23.4 kPa. During treatment, patients with decreases in NIT scores experienced improvement of their PRO scores, whereas those with increase in NIT scores had their PRO scores worsen (P.05).Baseline NIT scores and their changes over time are predictors of adverse clinical and PROs in patients with advanced NASH. (ClinicalTrials.gov, Numbers NCT01672866, NCT01672879, NCT03053050, and NCT03053063).

BACKGROUND: Ischemic colitis has been associated with significant morbidity and mortality; however, prior studies have been limited by inconsistent definitions of the study population. Further, population-based studies on the incidence of ischemic colitis are lacking. We assessed the incidence andmortality associatedwith ischemic colitis. METHODS:We used the Data Integration, Measurement & Reporting emergency department and hospital discharge abstract administrative database to identify all patients presenting to the emergency department and/or admitted to hospital in the Calgary Health Zone (CHZ) for acute vascular insufficiency of the intestine (ICD-10 K55.1) between January 1, 2008 and December 31, 2009. Chart review confirmed the diagnosis of ischemic colitis in 210 patients. We described the ageand sex-stratified incidence of ischemic colitis. Poisson regression evaluated the adjusted incidence rate ratios (IRR) for age and sex with 95% confidence intervals (CI). We present the proportion of patients who underwent surgery and mortality. RESULTS: The median age was 68 years (IQR: 60 77) and 64.8% (95% CI: 58.3 71.2) were women. The overall incidence of ischemic colitis was 10.4 per 100,000 persons (95% CI: 9.04 11.92). Patients older than 65 years were significantly more likely to be diagnosed with ischemic colitis than younger patients (IRR=12.9; 95% CI: 9.7 17.1). Women were significantly more likely than men to be diagnosed with ischemic colitis (IRR=1.61; 95% CI: 1.21 2.14, p-value = 0.001), whereas men were more likely to die from ischemic colitis (11.8% of women versus 20.3% of men; p-value = 0.001). In-hospital mortality was 14.8% (95% CI: 10.0 19.6) and an intestinal resection was performed in 29.5% (95% CI: 22.5 34.7) of patients with ischemic colitis. The overall mortality rate of ischemic colitis was 1.54 per 100,000 persons (95% CI: 1.04 2.18). Co-existing small bowel ischemia was observed in 14.3%. Among patients with co-existing small bowel ischemia, 73.3% underwent intestinal surgery and 63.3% died. In contrast, patients with ischemic colitis isolated to the colon had fewer operations (21.7%) and reduced mortality (6.7%). CONCLUSIONS: Ischemic colitis is a common condition of the elderly that carries a significant burden to the patient and the healthcare system. Intestinal resection occurs commonly and mortality is high.

The progression of fibrosis in chronic hepatitis C infection (HCV) is related to host factors including age, gender and alcohol consumption. Due to the morbidity and potential mortality of liver biopsy, a noninvasive method of assessing hepatic fibrosis is needed. The aim of this study was to assess the utility of historical features in predicting fibrosis using published rates of fibrosis progression. The charts of 239 untreated patients with HCV were reviewed; patients who had a liver biopsy and whose duration of infection could be estimated (n=106) were categorized according to gender, age at infection ( 40 years) and peak alcohol consumption ( or = 50 g/day). Estimates of fibrosis were calculated using the product of the interval between infection and biopsy and published rates of fibrosis progression. Estimates were compared with liver biopsies staged according to the Metavir system (F0-F4; F0=no fibrosis; F4= cirrhosis). The mean age of patients was 42 +/- 8 years, 61% were male and 36% consumed > 50 g of alcohol daily. The mean duration of infection was 19 +/- 9 years (range, 1-40) and ALT was elevated > 1.5 times upper normal in 63%. When patients were classified into those with mild (F0-F2) and severe (F3-F4) fibrosis, the sensitivity, specificity, positive predictive value and negative predictive value of an estimate of mild fibrosis was 60%, 55%, 78% and 34%, respectively. An estimate of severe fibrosis had a sensitivity of 55%, specificity of 60%, positive predictive value of 34% and negative predictive value of 78%. Agreement between fibrosis estimates and actual histological stages was poor (kappa = 0.13, P=0.08). The prediction of hepatic fibrosis in HCV infection using historical features and published rates of fibrosis progression is poor in a Canadian clinical practice setting. Alternate noninvasive methods of predicting hepatic fibrosis are needed.