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.

Impact of Pruritus on Quality of Life and Current Treatment Patterns in Patients with Primary Biliary Cholangitis.

BACKGROUND AND AIMS: Patients with primary biliary cholangitis (PBC) often suffer with pruritus. We describe the impact of pruritus on quality of life and how it is managed in a real-world cohort. METHODS: TARGET-PBC is a longitudinal observational cohort of patients with PBC across the USA. Data include information from medical records for three years prior to the date of consent up to 5 years of follow-up. Enrolled patients were asked to complete patient-reported outcome surveys: PBC-40, 5-D itch, and the PROMIS fatigue survey. Kruskal-Wallis tests were used to compare differences in symptoms between groups. RESULTS: A total of 211 patients with completed PRO surveys were included in the current study. PRO respondents were compared with non-respondents in the TARGET-PBC population and were broadly similar. Pruritus was reported in 170 patients (81%), with those reporting clinically significant pruritus (30%) scoring worse across each domain of the PBC-40 and 5-D itch, more frequently having cirrhosis, and having significantly greater levels of fatigue. Patients reporting clinically significant pruritus were more likely to receive treatment, but 33% had never received treatment (no itch = 43.9%, mild itch = 38.3%). CONCLUSIONS: The prevalence of pruritus was high in this population, and those reporting clinically significant pruritus had a higher likelihood of having advanced disease and worse quality of life. However, this study found that pruritus in PBC is under-treated. This may be due in part to ineffectiveness of current treatments, poor tolerance, or the lack of FDA-approved medications for pruritus.

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.

The Vulnerability of Microbial Ecosystems in A Changing Climate: Potential Impact in Shark Bay.

The potential impact of climate change on eukaryotes, including humans, has been relatively well described. In contrast, the contribution and susceptibility of microorganisms to a changing climate have, until recently, received relatively less attention. In this review, the importance of microorganisms in the climate change discourse is highlighted. Microorganisms are responsible for approximately half of all primary production on earth, support all forms of macroscopic life whether directly or indirectly, and often persist in "extreme" environments where most other life are excluded. In short, microorganisms are the life support system of the biosphere and therefore must be included in decision making regarding climate change. Any effects climate change will have on microorganisms will inevitably impact higher eukaryotes and the activity of microbial communities in turn can contribute to or alleviate the severity of the changing climate. It is of vital importance that unique, fragile, microbial ecosystems are a focus of research efforts so that their resilience to extreme weather events and climate change are thoroughly understood and that conservation efforts can be implemented as a response. One such ecosystem under threat are the evolutionarily significant microbial mats and stromatolites, such as those present in Shark Bay, western Australia. Climate change models have suggested the duration and severity of extreme weather events in this region will increase, along with rising temperatures, sea levels, and ocean acidification. These changes could upset the delicate balance that fosters the development of microbial mats and stromatolites in Shark Bay. Thus, the challenges facing Shark Bay microbial communities will be presented here as a specific case study.

Cumulative Corticosteroid Dose Over Fifty-Two Weeks in Patients With Systemic Lupus Erythematosus: Pooled Analyses From the Phase III Belimumab Trials.

OBJECTIVE: To examine the effects of treatment with belimumab on corticosteroid dose in patients with systemic lupus erythematosus (SLE) over 52 weeks in 2 randomized, controlled trials. METHODS: Data on patients who were taking corticosteroids at baseline in the Study of Belimumab in Subjects with SLE trials were pooled post hoc to compare patients who received belimumab 10 mg/kg plus standard therapy with those who received placebo plus standard therapy. The primary end point was cumulative change from baseline in corticosteroid dose (prednisone equivalent) through week 52. Further analyses specifically examined oral corticosteroid dose. RESULTS: At baseline, 966 of 1,125 patients (86%) were receiving corticosteroids (478 belimumab 10 mg/kg and 488 placebo). Most were women (94%), their mean age was 37.1 years, mean Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index score was 9.8, and mean corticosteroid dosage was 12.5 mg/day. Over 52 weeks, there was a smaller increase in mean cumulative corticosteroid dose for the belimumab group than for the placebo group (531.2 mg versus 916.3 mg; P < 0.0001). Compared with placebo, the mean of all decreases in cumulative corticosteroid dose was higher with belimumab (P = 0.0165), and the mean of all increases was lower (P = 0.0005). More patients in the belimumab group had decreases in oral corticosteroid dose (38.5% versus 30.9%), and fewer had increases in dose (18.4% versus 30.7%), compared with placebo. Adverse events were comparable across groups. CONCLUSION: Our findings show a significantly smaller increase in cumulative corticosteroid dose over 1 year, more patients with decreases in oral corticosteroid dose, and fewer patients with increases in oral corticosteroid dose in the belimumab group compared with the placebo group. These data suggest that belimumab may be steroid sparing.

Exercise-based rehabilitation after hospital discharge for survivors of critical illness with intensive care unit-acquired weakness: A pilot feasibility trial.

PURPOSE: The aim of this study was to investigate feasibility of exercise-based rehabilitation delivered after hospital discharge in patients with intensive care unit-acquired weakness (ICU-AW). MATERIALS AND METHODS: Twenty adult patients, mechanically ventilated for more than 48 hours, with ICU-AW diagnosis at ICU discharge were included in a pilot feasibility randomized controlled trial receiving a 16-session exercise-based rehabilitation program. Twenty-one patients without ICU-AW participated in a nested observational cohort study. Feasibility, clinical, and patient-centered outcomes were measured at hospital discharge and at 3 months. RESULTS: Intervention feasibility was demonstrated by high adherence and patient acceptability, and absence of adverse events, but this must be offset by the low proportion of enrolment for those screened. The study was underpowered to detect effectiveness of the intervention. The use of manual muscle testing for the diagnosis of ICU-AW lacked robustness as an eligibility criterion and lacked discrimination for identifying rehabilitation requirements. Process evaluation of the trial identified methodological factors, categorized by "population," "intervention," "control group," and "outcome." CONCLUSIONS: Important data detailing the design, conduct, and implementation of a multicenter randomized controlled trial of exercise-based rehabilitation for survivors of critical illness after hospital discharge have been reported. REGISTRATION: Clinical Trials Identifier NCT00976807.

Evaluation of the migraine treatment sumatriptan/naproxen sodium on blood pressure following long-term administration.

Anti-inflammatory and pain therapies have been associated with blood pressure (BP) destabilization. Hence, the effects on BP of sumatriptan/naproxen sodium in fixed-dose combination, sumatriptan 85 mg, and naproxen sodium 500 mg administered intermittently for the acute treatment of migraine attacks were assessed. Patients with migraine with or without aura and no history of hypertension were randomized to sumatriptan/naproxen sodium (n=135), sumatriptan (n=136), or naproxen sodium (n=136) to treat migraine attacks for 6 months in a double-blind, parallel-group trial. Following a treated migraine attack, patients performed 2 consecutive days of self-measured BPs beginning ≥24 hours after the last dose of study medication and transmitted them by a transtelephonic modem. The primary end point was the change from baseline in self-measured BP at 6 months. Changes in self-measured BP from baseline to 6 months for sumatriptan/naproxen sodium were -2.1/-1.5 mm Hg (95% confidence intervals, -3.4 to -0.8 for systolic and -2.6 to -0.3 for diastolic). Mean changes from baseline in self-measured BP did not differ among the 3 treatment groups. Additional categorical analyses did not show increases from baseline with sumatriptan/naproxen sodium relative to either of the monotherapy groups. Intermittent acute migraine treatment with sumatriptan/naproxen sodium for up to 6 months was associated with clinically insignificant decreases in self-measured BP that were similar to those with sumatriptan or naproxen alone in normotensive patients with migraine.

A double-blind comparison between bupropion XL and venlafaxine XR: sexual functioning, antidepressant efficacy, and tolerability.

In this double-blind, multicenter study, bupropion XL, a norepinephrine-dopamine reuptake inhibitor, and venlafaxine XR, a serotonin-norepinephrine reuptake inhibitor, were compared with regard to sexual functioning, efficacy, and tolerability. A total of 348 sexually active adult outpatients with depression were randomized to receive bupropion XL (titrated to a target dose of 300-450 mg/d) or venlafaxine XR (titrated to a target dose of 150-225 mg/d) for 12 weeks. Total scores on the primary dependent variable, the Changes in Sexual Functioning Questionnaire (self-report), increased for subjects receiving bupropion XL and decreased for those treated with venlafaxine XR; the mean change scores differed significantly between groups from week 2 onward. Among subjects with normal pretreatment sexual functioning, Changes in Sexual Functioning Questionnaire total scores remained essentially unchanged for the bupropion XL group but were decreased significantly for the venlafaxine XR group; mean change scores also differed between groups from week 2 onward. Although the therapies resulted in similar change on the 17-item Hamilton Depression Rating Scale, remission rates were significantly higher among those treated with bupropion XL (46%) versus venlafaxine XR (33%) (odds ratio, 1.93; 95% confidence interval, 1.07-3.46). Aside from adverse effects of venlafaxine XR on sexual function, both treatments were reasonably well tolerated. In conclusion, in this patient population (ie, relatively young, sexually active outpatients), bupropion XL was at least as effective as venlafaxine XR and had a significantly more favorable sexual side effect profile.