Relationship between pruritus and sleep in participants with primary biliary cholangitis in the Phase 2b GLIMMER trial.

BACKGROUND: Cholestatic pruritus and fatigue are debilitating conditions associated with primary biliary cholangitis (PBC) and can significantly impact patients' quality of life. Pruritus in PBC often worsens at night and patients frequently report sleep disturbance, which contributes to cognitive symptoms and fatigue. Linerixibat is an ileal bile acid transporter inhibitor in clinical development for the treatment of pruritus associated with PBC and was recently assessed versus placebo in the Phase 2b GLIMMER trial. This post-hoc analysis assesses the relationship between pruritus severity and sleep disturbance in participants of GLIMMER regardless of treatment group. METHODS: GLIMMER (NCT02966834), a multicenter, double-blind, randomized, placebo-controlled trial, recruited 147 patients with PBC and moderate-to-severe pruritus. Following 4 weeks single-blind placebo, patients (randomized 3:1) received linerixibat or placebo for 12 weeks (to Week 16). Participants graded their itch (twice daily) and its interference with sleep (once daily) in an electronic diary using a 0-10 numerical rating scale (NRS). Weekly and monthly itch scores were calculated as the mean of the worst daily itch score over the respective time period. At study visits, participants completed the 5-D itch scale and the PBC-40 quality of life questionnaire, both of which contain an item specific to itch-related sleep disturbance. The impact of pruritus on sleep was assessed post hoc through correlations between the changes in NRS, 5-D itch, and PBC-40. RESULTS: Strong correlations were found between change from baseline in weekly itch and sleep NRS scores (r = 0.88 [95% confidence interval (CI): 0.83; 0.91]) at the end of treatment (Week 16), as well as in monthly itch and sleep NRS scores (r = 0.84 [95% CI: 0.80; 0.87]). Patients with improved weekly pruritus score severity category demonstrated reduced perceived sleep interference on average. Itch responders (≥2-point improvement in weekly itch score from baseline) displayed larger improvements in weekly sleep NRS score, 5-D itch, and PBC-40 sleep items, than itch non-responders (<2-point improvement). CONCLUSIONS: A strong correlation exists between changes in pruritus severity and sleep interference in patients with PBC; pruritus reduction could generate concomitant improvement in sleep.

Cholestatic Pruritus Treatments in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: A Systematic Literature Review.

BACKGROUND AND AIMS: We conducted a systematic literature review to understand the evidence supporting treatment decisions for cholestatic pruritus associated with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). METHODS: Studies that enrolled ≥ 75% participants with PBC or PSC and reported ≥ 1 endpoint(s) related to efficacy, safety, health-related quality of life (HRQoL) or other patient-reported outcomes were included. Bias was assessed using the Cochrane risk of bias tool for randomised controlled trials (RCTs) and the Quality of Cohort studies tool for non-RCTs. RESULTS: Thirty-nine publications were identified, covering 42 studies and six treatment classes (including investigational and approved products): anion-exchange resins, antibiotics (rifampicin/derivatives), opiates, selective serotonin reuptake inhibitors, fibrates, ileal bile acid transporter inhibitors and other agents not categorised in these six classes. Across studies, median sample size was small (n = 18), 20 studies were over 20 years old, 25 followed patients for ≤ 6 weeks, only 25 were RCTs. Pruritus was assessed using several different tools, with inconsistencies in their application. Cholestyramine, considered first-line therapy for moderate-severe cholestatic pruritus, was assessed in six studies (two RCTs) including 56 patients with PBC and 2 with PSC, with evidence of efficacy demonstrated in only three studies, among which, two RCTs were assessed as having a high risk of bias. Findings were similar for other drug classes. CONCLUSIONS: There is a lack of consistent and reproducible evidence available on efficacy, impact on HRQoL, and safety of cholestatic pruritus treatments, leaving physicians to rely on clinical experience rather than evidence-based medicine for treatment selection.

Prognosis of acute variceal bleeding: Is being on beta-blockers an aggravating factor? A short-term survival analysis.

UNLABELLED: Nonselective beta-blockers (NSBB) are widely used because they have been proved effective in the prophylaxis of acute variceal bleeding (AVB). However, a significant proportion of patients still experience AVB while on treatment with NSBB, and its impact on prognosis of AVB is unknown. The present study was aimed at assessing the effect of being on prophylactic therapy with NSBB on 5-day failure and 6-week mortality of patients with cirrhosis admitted with AVB. Included were 142 patients: 49 were receiving prophylactic therapy with NSBB (NSBB group) and 93 were not (control group). There were some differences in the baseline characteristics between the groups: higher proportion of alcoholic etiology and active alcoholism (37% versus 10%), higher platelet count, and lower hematocrit at admission in the control group. However, the severity of AVB and initial treatment were similar. Five-day failure occurred in 20% of patients (14% in NSBB versus 24% in controls, P = 0.27). The adjusted odds ratio for 5-day failure under NSBB was 2.46 (95% confidence interval 0.53-11.37, P = 0.25). Nineteen patients (13%) died, and two had liver transplantation within 6 weeks. The probability of survival at 6 weeks was 96% in the NSBB group and 82% in the control group (P = 0.02). After adjusting by propensity score and Model for End-Stage Liver Disease score, the NSBB adjusted odds ratio for 6-week mortality was 0.38 (95% confidence interval 0.05-2.63, P = 0.32). The estimated association between NSBB with both 5-day failure and 6-week mortality was homogenous across all Model for End-Stage Liver Disease spectrums. CONCLUSION: Prophylactic NSBB treatment is not a negative prognostic indicator for the short-term survival of patients with cirrhosis admitted with AVB.

Patients whose first episode of bleeding occurs while taking a ß-blocker have high long-term risks of rebleeding and death.

BACKGROUND & AIMS: Patients who have their first episode of variceal bleeding despite primary prophylaxis with a nonselective ß-adrenergic receptor antagonist (also called a nonselective ß-blocker [NSBB]) receive additional treatment by endoscopic band ligation to prevent further bleeding. However, little is known about their long-term outcomes. METHODS: We collected data on 89 consecutive patients with cirrhosis who were admitted to the Liver Unit of Hospital Clínic, Barcelona, with acute esophageal variceal bleeding between June 2007 and February 2011. Thirty-four patients were receiving primary prophylaxis with NSBBs when they had their first episode of variceal bleeding, whereas 55 were not receiving NSBBs (controls). All patients were subsequently treated with a combination of endoscopic band ligation and NSBBs. Patients were examined after 1, 3, and 6 months and every 6 months thereafter until 2 years. RESULTS: After 2 years, a greater proportion of patients who had their first episode of bleeding while on NSBBs had further bleeding, compared with controls (48% vs 24%; P = .01). Primary prophylaxis with NSBBs and serum levels of bilirubin were independent predictors of rebleeding. Overall, 11 patients died, and 5 underwent liver transplantation. Liver transplantation-free survival was lower among patients who had their first episode of bleeding while taking NSBBs (66% vs 88% for controls; P = .02). Primary prophylaxis with NSBBs and Child-Pugh class were independently associated with liver transplantation-free survival. CONCLUSIONS: Patients who have their first episode of variceal bleeding while on primary prophylaxis with a ß-blocking agent have an increased risk of further bleeding and death, despite adding endoscopic band ligation. These patients possibly require alternative treatment approaches.

Short segment Barrett's esophagus and distal gastric intestinal metaplasia.

BACKGROUND: Short segment Barrett's esophagus is defined by the presence of <3 cm of columnar-appearing mucosa in the distal esophagus with intestinal metaplasia on histophatological examination. Barrett's esophagus is a risk factor to develop adenocarcinoma of the esophagus. While Barrett's esophagus develops as a result of chronic gastroesophageal reflux disease, intestinal metaplasia in the gastric cardia is a consequence of chronic Helicobacter pylori infection and is associated with distal gastric intestinal metaplasia. It can be difficult to determine whether short-segment columnar epithelium with intestinal metaplasia are lining the esophagus (a condition called short segment Barrett's esophagus) or the proximal stomach (a condition called intestinal metaplasia of the gastric cardia). AIMS: To study the association of short segment Barrett's esophagus (length <3 cm) with gastric intestinal metaplasia (antrum or body) and infection by H. pylori. PATIENTS AND METHODS: Eight-nine patients with short segment columnar-appearing mucosa in the esophagus, length <3 cm, were studied. Symptoms of gastroesophageal reflux disease were recorded. Biopsies were obtained immediately below the squamous-columnar lining, from gastric antrum and gastric corpus for investigation of intestinal metaplasia and H. pylori. RESULTS: Forty-two from 89 (47.2%) patients were diagnosed with esophageal intestinal metaplasia by histopathology. The mean-age was significantly higher in the group with esophageal intestinal metaplasia. The two groups were similar in terms of gender (male: female), gastroesophageal reflux disease symptoms and H. pylori infection. Gastric intestinal metaplasia (antrum or body) was diagnosed in 21 from 42 (50.0%) patients in the group with esophageal intestinal metaplasia and 7 from 47 (14.9%) patients in the group with esophageal columnar appearing mucosa but without intestinal metaplasia. CONCLUSION: Intestinal metaplasia is a frequent finding in patients with <3 cm of columnar-appearing mucosa in the distal esophagus. In the present study, short segment intestinal metaplasia in the esophagus is associated with distal gastric intestinal metaplasia. Gastroesophageal reflux disease symptoms and H. pylori infection did not differ among the two groups studied.