Cholestatic Pruritus Research Articles

Ditch the Itch: Propofol in the Management of Cholestatic Pruritus.

Ditch the Itch: Propofol in the Management of Cholestatic Pruritus.

WED-257 - Impact of maralixibat on cholestatic pruritus in adults aged 16 years and older with Alagille syndrome

WED-257 - Impact of maralixibat on cholestatic pruritus in adults aged 16 years and older with Alagille syndrome

WED-283 - Investigating the cholestatic pruritus of primary sclerosing cholangitis (ItCh-PSC): a study of patients participating in the consortium for autoimmune liver disease (CALiD)

WED-283 - Investigating the cholestatic pruritus of primary sclerosing cholangitis (ItCh-PSC): a study of patients participating in the consortium for autoimmune liver disease (CALiD)

Cholestatic Pruritus in Children: Conventional Therapies and Beyond.

Pruritus in the setting of cholestatic liver disease is difficult to treat and occurs in patients ranging in age from infancy to adulthood. Likely multifactorial in etiology, this symptom often involves multimodal therapy targeting several pathways and mechanisms proposed in the underlying etiology of cholestatic pruritus. Many patients in both the pediatric and adult populations continue to experience unrelenting pruritus despite maximal conventional therapy. Options are further limited in treating pediatric patients due to sparse data regarding medication safety and efficacy in younger patients. Conventional therapies for the treatment of cholestatic pruritus in children include ursodeoxycholic acid, cholestyramine, hydroxyzine, and rifampin. Certain therapies are more routinely used in the adult populations but with limited data available for use in child and adolescent patients, including opioid antagonists and selective serotonin reuptake inhibitors. Recently, ileal bile acid transport inhibitors have been shown to alleviate pruritus in many children with Alagille syndrome and progressive familial intrahepatic cholestasis and is an additional therapy available for consideration for these patients. Ultimately, surgical options such as biliary diversion or liver transplantation are considered in specific circumstances when medical therapies have been exhausted and pruritus remains debilitating. While further investigation regarding underlying etiologies and effective therapies are needed to better understand itch pathogenesis and treatment in pediatric cholestasis, current considerations beyond conventional management include the use of opioid antagonists, selective serotonin reuptake inhibitors, ileal bile acid transport inhibitors, and surgical intervention.

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

Background and AimsWe 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).MethodsStudies 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.ResultsThirty-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.ConclusionsThere 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.

Japanese subgroup analysis of GLIMMER: A global Phase IIb study of linerixibat for the treatment of cholestatic pruritus in patients with primary biliary cholangitis.

To compare patient characteristics and outcomes between the overall and Japanese populations of GLIMMER. GLIMMER was a multicenter, double-blind, randomized, placebo-controlled, Phase IIb study evaluating linerixibat for the treatment of pruritus in patients with primary biliary cholangitis. In total, 147 patients were randomized in the GLIMMER overall population with 38 patients comprising the Japanese population. Demographics and baseline clinical characteristics were similar across treatment groups and between both populations. A reduction in mean worst daily itch score from baseline to week 16 (primary endpoint) was seen in all groups, with the largest reduction observed with linerixibat 40mg twice daily (BID; -2.92 [95% confidence interval: -5.07, -0.76] and -2.86 [95% confidence interval: -3.76, -1.95] for Japanese and overall populations, respectively). The highest proportion of responders was generally in the 40mg BID group in both populations regardless of the responder definition applied. Improvements in health-related quality of life were generally consistent in both populations. In the Japanese and overall populations, on-treatment drug-related adverse events were reported in 25% and 19% of patients in the placebo group and 0%-86% and 31%-78% of patients in the linerixibat groups, respectively. Consistent with the mechanism of action, the most common events were gastrointestinal in nature. The effects of linerixibat on pharmacodynamic biomarkers favored BID dosing. Therapeutic responses and safety of linerixibat were consistent between the Japanese and overall populations of GLIMMER. Linerixibat may provide an effective treatment option for cholestatic pruritus in patients with primary biliary cholangitis. NCT02966834.

The Investigation of Therapeutic Implications of Mast Cell Stabilizer Cromolyn Sodium on Cholestasis and Cholestatic Pruritus in Experimental Cholestasis.

Relevant studies have indicated that hepatic mast cells may have potential roles in the progression of cholestasis and cholestasis-induced itch. We aimed to compare the effects of cromolyn sodium and other medications on cholestatic pruritus, serum biochemistry, histamine, total bile acids, autotaxin, liver histopathology, and mast cell distribution in tissues in an experimental cholestasis model conducted by bile duct ligation. Rats received the determined treatment consecutively for 10 days in addition to bile duct ligation. On the 5th and 10th days of the experiment, the rats' itching behaviors were observed for 5 minutes. After 10 days, blood and tissue samples were taken. Significant decreases in serum histamine and autotaxin levels, plasma total bile acids, total bilirubin, and biliary enzymes were reported only in cromolyn sodium-treated rats compared to the control group. In immunohistochemistry of the liver samples, the peribiliary mast cells stained positive for autotaxin. Except for bile duct infarctus, all histopathological findings of cholestasis significantly improved only in cromolyn sodium-treated and sertraline-treated rats. The liver and peritoneal mast cells significantly decreased only in cromolyn sodium-treated rats compared to the control group. On the 10th day of the experiment, the mean duration of itching was significantly lower in all groups, except for naloxone- and ondansetron-treated rats. Cromolyn sodium has promising antipruritic efficacy and provides biochemical and histopathological recovery of the relevant parameters of cholestasis induced by bile duct ligation. For the first time in the literature, we showed that peribiliary mast cells can produce autotaxin, which is a very important pruritogenic signal in the setting of cholestasis.

Maralixibat is an alternative to liver transplantation in children with Alagille syndrome

Alagille syndrome is a genetic multisystem disease in which one of the key symptoms that significantly impairs quality of life is cholestatic pruritus. Until recently the only treatment opportunity was liver transplantation. In 2021 the new drug maralixibat (Marixibat) was approved and registered in the United States. This article presents the first experience of using this medication in Russia. The patient stopped itching, significantly reduced the serum bile acids and also improved physical development within 7 months of therapy. Our first experience of using maralixibat in Russia, as well as the available literature data indicates a significant improvement in the quality of life of patients and allows us to consider this drug as an alternative to liver transplantation.

Systematic review: efficacy of therapies for cholestatic pruritus.

Pruritus is a symptom of several cholestatic liver diseases (CLDs) that can impair health-related quality of life (HRQoL). Despite evidence-based guideline therapy, managing cholestatic pruritus (CP) remains challenging, thus making the need for newer, more effective therapeutic agents more evident. Our study evaluated the efficacy of existing CP therapies. Systematic review. From inception until March 2023, we conducted a comprehensive search of MEDLINE, Cochrane, EMBASE, Scopus, ClinicalTrial.gov, and other sources, including pharmaceutical webpages and conference proceedings published in English that reported on CP interventions. Two reviewers independently conducted screening and full-text review of articles with extraction conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The methodological quality of studies included in our qualitative synthesis was assessed by using the Cochrane ROBINS-I and ROBINS-II tools for interventional studies and the National Heart, Lung, and Blood Institute Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. The primary outcome assessed in our systematic review was the severity of CP after therapy. Of 3293 screened articles, 92 studies were eligible for inclusion in the qualitative synthesis. Some patients' HRQoL improved with evidence-based standard therapy. Others, particularly those with severe and refractory CP, often required conversion to or addition of experimental noninvasive (e.g., ondansetron) or extracorporeal liver support to alleviate CP. In addition, studies investigating a newer class drug, the ileal bile acid transporter inhibitor (IBATi), demonstrate its effectiveness in reducing serum bile acid and alleviating CP with sustained improvement noted in patients with the inherited childhood cholestatic disorders - progressive familial intrahepatic cholestasis and Alagille syndrome. Our findings consolidate data on the efficacy of guideline-based approaches and newer therapies for CP. While the initial findings are promising, additional clinical trials will be needed to determine the full extent of IBATi's efficacy and potential use in treating other common CLDs. These results provide a foundation for future research and highlight the need for continued investigation into the management and treatment of CLDs.

GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus

GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid transporter inhibitor in development for cholestatic pruritus associated with primary biliary cholangitis (PBC). GLIMMER was a Phase 2b, multicenter, randomized, parallel-group study in adults with PBC and moderate-to-severe pruritus (≥4 on 0-10 numerical rating scale [NRS]). After 4 weeks of single-blind placebo, patients with NRS ≥3 were randomized (3:1) to double-blind linerixibat/placebo for 12 weeks (to week 16), followed by single-blind placebo (to week 20). The primary objective was to investigate dose-related changes in mean worst daily itch (MWDI) score. One hundred forty-seven patients received placebo (n= 36) or linerixibat (once daily: 20 mg, n= 16; 90 mg, n= 23; 180 mg, n= 27; twice daily: 40 mg, n= 23; 90 mg, n= 22). Linerixibat groups exhibited ≥2-point mean reductions in MWDI from baseline at week 16; however, differences from placebo were not significant. Post hoc analysis of change from baseline in monthly itch score over the treatment period (Phase 3 endpoint) showed significant differences between placebo and linerixibat 180 mg once daily (P= .0424), 40 mg twice daily (P= .0105), and 90 mg twice daily (P= .0370). A significant relationship between total daily dose and response was observed post hoc in the per protocol population (P= .0542). Consistent with mechanism of action, diarrhea was the most frequent adverse event, and incidence increased with dose. Linerixibat effect on itch was not significantly different versus placebo in the primary intent-to-treat analysis but was associated with a significant dose-dependent reduction in itch in the per protocol population. A well-tolerated dose was identified for Phase 3 investigation for cholestatic pruritus in PBC. gov ID: NCT02966834.

Serum Bile Acid Profiling and Mixed Model Analysis Reveal Biomarkers Associated with Pruritus Reduction in Maralixibat-Treated Patients with BSEP Deficiency.

Progressive familial intrahepatic cholestasis (PFIC) is a debilitating disease manifest by severe cholestasis, intractable pruritus and growth delay that ultimately leads to liver failure or transplantation. Maralixibat (MRX) was recently approved for the treatment of cholestatic pruritus in patients with Alagille syndrome. The aim of this study was to determine whether specific changes in the composition of the serum bile acid metabolome could predict pruritus response to treatment. Serum BAs (sBA) and 7α-hydroxy-4-cholesten-3-one (7α-C4), a surrogate marker of BA synthesis, were monitored by ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry over 72 weeks in PFIC patients with mild to moderate non-truncating bile salt export pump (BSEP) mutations (n = 19) treated with MRX. The weekly itch reported outcome observer (ItchRO[Obs]) score measured pruritus severity. Linear mixed models (LMM) were applied to explore the effects of individual sBA profiles and their relationship to pruritus response. Changes in the composition of sBA correlated with pruritus improvement. Notably, the trajectory of serum total and individual BA species and 7α-C4 were significantly associated with ItchRO[Obs] score (p < 0.05). These results reveal that beyond simple total sBA concentrations, specific changes to the BA metabolome are associated with pruritus reduction in patients with BSEP deficiency, thus providing further insight into causal relationship of bile acids and pruritus.

S1780 Immunoglobulin G4-Associated Cholangitis Mimicking Cholangiocarcinoma in Elderly

Introduction: Sclerosing cholangitis is a diffuse inflammation and fibrosis that progressively leads to stenosis and destruction of the bile ducts. It includes 3 types: primary sclerosing cholangitis (PSC), secondary cholangitis, and IgG4 sclerosing cholangitis (IgG4-SC). Usually they all present with cholestatic symptoms like pruritus and abdominal pain along with elevated ALP and GGT as well as bilirubin, however IgG4-SC has better outcomes, treatment response to steroids and less recurrence. We hereby presenting a case of IgG4-SC presenting as cholangiocarcinoma. Case Description/Methods: An 80 year-old male with a past medical history of bladder cancer was referred to the gastroenterology for EUS after blood work showed (ALT 320, AST 297, Bilirubin 1.4, GGT 2032), and CT abdomen with IV contrast revealed intra and extrahepatic biliary dilatation with an abrupt cutoff in mid CBD, suspicious for either a primary CBD mass or pancreatic mass (Figure). EUS showed an irregular mass in the CBD wall, suspicious for cholangiocarcinoma (Figure). The ERCP showed malignant appearing stricture of the extrahepatic bile duct consistent with cholangiocarcinoma, Bismuth 2 vs early 3B (Figure). Exploratory laparotomy was done and portal node biopsy came back benign; for which a repeat ERCP/Spyglass with direct visualization cholangioscopy, was done and showed diffusely dilated main bile duct with sludge and pus, single diffuse stenosis in right hepatic duct sludge with lining malignant appearing abnormal mucosa (nodularity and dilated vessels). IgG4 was elevated (931) consistent with IgG4 cholangitis (Figure). Biopsy and cytology brush showed no signs of dysplasia or neoplasia. Patient was then started on prednisone for a month and scheduled to repeat ERCP/Spyglass after. Discussion: IgG4-RD is a fibrous-inflammatory process related to immunomodulation, therefore IgG4-SC often co-presents with auto-immune pancreatitis, dacryoadenitis and sialadenitis. IgG4-SC is extremely challenging, as it’s frequently misdiagnosed on imaging as a pseudotumor, and can progress to liver cirrhosis if left untreated, however it comes with great response to steroids. In 2021, Mendoza criteria (tortuous vessels, irregular nodulations, raised intraductal lesions, irregular surface, and friability) was published and found to be accurate to differentiate malignant and benign causes of biliary stricture, with overall diagnostic accuracy of 77%. Our case didn’t meet the 5 criterias of Mendoza, which is consistent with IgG4-SC.Figure 1.: Top: CT of abdomen and ERCP. Bottom: Exploratory laparotomy.

S19 Investigation of Linerixibat 40 Mg BID for Cholestatic Pruritus of Primary Biliary Cholangitis; Further Data From the Phase 2b GLIMMER Study to Support the Phase 3 GLISTEN Study

S19 Investigation of Linerixibat 40 Mg BID for Cholestatic Pruritus of Primary Biliary Cholangitis; Further Data From the Phase 2b GLIMMER Study to Support the Phase 3 GLISTEN Study

S107 More Than Just an Itch: Impact of Cholestatic Pruritus in Primary Biliary Cholangitis (PBC) on Health-Related Quality of Life (HRQoL)

S107 More Than Just an Itch: Impact of Cholestatic Pruritus in Primary Biliary Cholangitis (PBC) on Health-Related Quality of Life (HRQoL)

Development of the Patient- and Observer-Reported PRUCISION Instruments to Assess Pruritus and Sleep Disturbance in Pediatric Patients with Cholestatic Liver Diseases.

IntroductionUnderstanding how patients experience their disease is a vital step in optimal disease management, and patient- and observer-reported outcome (PRO and ObsRO, respectively) measures can add important details to clinical information that is obtained as novel treatments are developed. Instruments that measure meaningful symptoms and impacts from the perspective of pediatric patients with cholestatic liver disease or their caregivers are needed. This study aimed to identify salient concepts in pediatric cholestatic liver disease, develop novel PRO and ObsRO instruments, and establish the instruments’ content validity.MethodsRelevant signs, symptoms, and impacts of cholestatic liver disease were identified through a literature review, interviews with expert clinicians, and concept elicitation interviews with children and caregivers of children who had progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome, biliary atresia, or primary sclerosing cholangitis. Additional cognitive debriefing interviews with patients and caregivers were performed to ensure that participants could understand the instructions, questions, and response scales of the PRO and ObsRO instruments, with modifications made as necessary to improve comprehension and/or usability.ResultsA total of 36 interviews with patients and caregivers were conducted. Pruritus and sleep disturbance (e.g., difficulty falling or staying asleep due to itch) were identified as the most problematic symptom and significant impact, respectively, of the pediatric cholestatic liver diseases assessed. The ObsRO and PRO instruments, called PRUCISION, focus on these key disease features in the morning and evening. Several modifications were made to the draft instruments following cognitive interviews. The final PRUCISION PRO and ObsRO measures are designed as an electronic diary to be completed twice daily. The response scales include pictorial, verbal, and numeric scales.ConclusionNovel PRO and ObsRO PRUCISION instruments were created that evaluate the patient experience of cholestatic pruritus in children with PFIC and other cholestatic liver diseases. The content validity of the PRUCISION instruments is established.

Disease burden of primary biliary cholangitis and associated pruritus based on a cross-sectional US claims analysis

ObjectiveIn order to identify areas of unmet need in patients with primary biliary cholangitis (PBC), this study sought to use real-world observational healthcare data to characterise the burden in patients...

Cholestatic Itch: Our Current Understanding of Pathophysiology and Treatments.

Hepatic pruritus is common in liver conditions, including cholestasis and nonalcoholic fatty liver disease. The pruritus can be severe enough to diminish sleep and decrease quality of life. The pathophysiology likely involves many molecules and receptors, including bile acids, bilirubin, lysophosphatidic acid (LPA), endogenous opioids, and serotonin. Recent advances suggest a significant role of Mas-related G protein-coupled receptor X4 (MRGPRX4) and autotaxin/LPA as key players in cholestatic pruritus. Further research is needed to develop increasingly targeted therapies with greater efficacy, especially given that many patients report itch refractory to various treatments. Cholestyramine was the only US FDA-approved drug for cholestatic pruritus until recent approval of ileal bile acid transporter (IBAT) inhibitors for use in the pediatric cholestatic conditions, progressive familial intrahepatic cholestasis and Alagille syndrome. Both medications decrease the bile acid pool. IBAT inhibitors are under investigation for broader use, and targeting LPA receptors and MRGPR4 are additional attractive options.

THU470 - More than just an itch: impact of cholestatic pruritus in primary biliary cholangitis (PBC) on health-related quality of life (HRQoL)

THU470 - More than just an itch: impact of cholestatic pruritus in primary biliary cholangitis (PBC) on health-related quality of life (HRQoL)

THU485 - Investigation of linerixibat 40mg BID for cholestatic pruritus of primary biliary cholangitis (PBC); further data from the phase 2b GLIMMER study to support the phase 3 GLISTEN study

THU485 - Investigation of linerixibat 40mg BID for cholestatic pruritus of primary biliary cholangitis (PBC); further data from the phase 2b GLIMMER study to support the phase 3 GLISTEN study

FRI274 - Experience of cholestatic pruritus emphasized by patients with PBC: results from the PBC Foundation app survey

FRI274 - Experience of cholestatic pruritus emphasized by patients with PBC: results from the PBC Foundation app survey