Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of ursodeoxycholic acid. Up to 40% of patients do not, however, respond adequately to ursodeoxycholic acid and therefore still remain at risk of disease progression to cirrhosis.

Serum miRNA profiles are altered in patients with primary sclerosing cholangitis receiving high-dose ursodeoxycholic acid.

Background & Aims: Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease that can lead to end-stage liver disease and cholangiocarcinoma. High-dose ursodeoxycholic acid (hd-UDCA, 28-30 mg/kg/day) was evaluated in a previous multicentre, randomised placebo-controlled trial; however, the study was discontinued early because of increased liver-related serious adverse events (SAEs), despite improvement in serum liver biochemical tests. We investigated longitudinal changes in serum miRNA and cytokine profiles over time among patients treated with either hd-UDCA or placebo in this trial as potential biomarkers for PSC and response to hd-UDCA, as well as to understand the toxicity associated with hd-UDCA treatment.

Optimizing therapy in primary biliary cholangitis: Alkaline phosphatase at six months identifies one-year non-responders and predicts survival.

Background And Aims: Patients with primary biliary cholangitis (PBC) and insufficient response to ursodeoxycholic acid (UDCA), currently assessed after 1 year, are candidates for second-line therapy. The aims of this study are to assess biochemical response pattern and determine the utility of alkaline phosphatase (ALP) at six months as a predictor of insufficient response.

Methods: UDCA-treated patients in the GLOBAL PBC database with available liver biochemistries at one year were included.

The power of rotation schedules on the career selection decisions of medical students.

Choosing a career pathway in medicine is a high stakes decision for both medical students and the field of medicine as a whole. While past research has examined how characteristics of the medical student or specialties influence this decision, we introduce temporal elements as novel variables influencing career selection decisions in medicine. Specifically, we investigate how timing and duration of residency options, based on a rotation schedule that medical students have limited control over, influence their career selection decisions.

Ursodeoxycholic Acid Treatment-Induced GLOBE Score Changes Are Associated With Liver Transplantation-Free Survival in Patients With Primary Biliary Cholangitis.

Introduction: Treatment of primary biliary cholangitis (PBC) can improve the GLOBE score. We aimed to assess the association between changes in the GLOBE score (ΔGLOBE) and liver transplantation (LT)-free survival in patients with PBC who were treated with ursodeoxycholic acid (UDCA).

Methods: Among UDCA-treated patients within the Global PBC cohort, the association between ΔGLOBE (ΔGLOBE 0-1 : during the first year of UDCA, ΔGLOBE 1-2 : during the second year) and the risk of LT or death was assessed through Cox regression analyses.

Geographical region and clinical outcomes of patients with primary biliary cholangitis from Western Europe.

Background And Aims: The are geographic variations in the incidence and prevalence of primary biliary cholangitis (PBC). The aim was to explore whether clinical outcomes of patients within Western Europe differ according to geographical region.

Methods: Ursodeoxycholic acid-treated patients from European centers from the Global PBC database diagnosed from 1990 onwards were included.

Greater Transplant-Free Survival in Patients Receiving Obeticholic Acid for Primary Biliary Cholangitis in a Clinical Trial Setting Compared to Real-World External Controls.

Background & Aims: The Primary Biliary Cholangitis (PBC) Obeticholic Acid (OCA) International Study of Efficacy (POISE) randomized, double-blind, placebo-controlled trial demonstrated that OCA reduced biomarkers associated with adverse clinical outcomes (ie, alkaline phosphatase, bilirubin, aspartate aminotransferase, and alanine aminotransferase) in patients with PBC. The objective of this study was to evaluate time to first occurrence of liver transplantation or death in patients with OCA in the POISE trial and open-label extension vs comparable non-OCA-treated external controls.

Methods: Propensity scores were generated for external control patients meeting POISE eligibility criteria from 2 registry studies (Global PBC and UK-PBC) using an index date selected randomly between the first and last date (inclusive) on which eligibility criteria were met.

Liver transplant-free survival according to alkaline phosphatase and GLOBE score in patients with primary biliary cholangitis treated with ursodeoxycholic acid.

Background: After 1 year of ursodeoxycholic acid (UDCA), patients with primary biliary cholangitis (PBC) may have a normal GLOBE score despite high alkaline phosphatase (ALP) levels.

Aim: To assess the association between ALP and liver transplantation (LT)-free survival according to the GLOBE score METHODS: Among patients with a normal or elevated GLOBE score in the Global PBC cohort, the association between ALP after 1 year of UDCA and the risk of LT/death was assessed. The LT-free survival was compared with that of a matched general population.

A pilot study of vidofludimus calcium for treatment of primary sclerosing cholangitis.

The purpose of this pilot study was to explore the efficacy, safety, and tolerability of vidofludimus calcium (VC) in the treatment of primary sclerosing cholangitis (PSC). This was a single-arm open-label pilot study with a cohort of 18 patients with PSC. Study patients received VC for a period of 6 months.

Machine learning in primary biliary cholangitis: A novel approach for risk stratification.

Background & Aims: Machine learning (ML) provides new approaches for prognostication through the identification of novel subgroups of patients. We explored whether ML could support disease sub-phenotyping and risk stratification in primary biliary cholangitis (PBC).

Methods: ML was applied to an international dataset of PBC patients.

Dynamic Risk Prediction of Response to Ursodeoxycholic Acid Among Patients with Primary Biliary Cholangitis in the USA.

Background: Ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC); however, inadequate treatment response (ITR) is common. The UK-PBC Consortium developed the modified UDCA Response Score (m-URS) to predict ITR (using alkaline phosphatase [ALP] > 1.67 times the upper limit of normal [*ULN]) at 12 months post-UDCA initiation).

Global incidence, prevalence and features of primary sclerosing cholangitis: A systematic review and meta-analysis.

Background & Aims: Primary sclerosing cholangitis (PSC) is an idiopathic, cholestatic liver disease with a diverse range of clinical manifestations. Inter-regional data on PSC are variable, but its global geoepidemiology has not been well-studied. We aimed to examine the worldwide incidence, prevalence and features of PSC and PSC-inflammatory bowel disease (PSC-IBD).

A Comparison of Prognostic Scores (Mayo, UK-PBC, and GLOBE) in Primary Biliary Cholangitis.

Introduction: Comparative data on scores that predict outcome in primary biliary cholangitis (PBC) are scarce. We aimed to assess and compare the prognostic value of the Mayo Risk Score (MRS, 1989 and 1994), UK-PBC score, and GLOBE score in a large international cohort of patients with PBC.

Methods: Ursodeoxycholic acid-treated patients from 7 centers participating in the GLOBAL PBC Study Group were included.

Safety of fibrates in cholestatic liver diseases.

Background And Aim: Off-label use of fibrates in patients with cholestatic liver diseases results in improved biochemical parameters and pruritus; however, their safety in this population has been a concern. This study summarizes safety data for fibrates when used for treatment of cholestatic liver diseases.

Methods: A systematic review of published studies evaluating the use of fibrates for treatment of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) was performed.

Simplified care-pathway selection for nonspecialist practice: the GLOBAL Primary Biliary Cholangitis Study Group Age, Bilirubin, Alkaline phosphatase risk assessment tool.

Background: Opportunity to redefine the care journeys for those living with primary biliary cholangitis (PBC) includes facilitating access to enhanced (PBC-dedicated) programmes by nonspecialist risk 'flagging' of patients.

Objective: To develop a nonexpert PBC stratification tool to help care pathway choices (standard vs. enhanced) choices in PBC.

Successful response of primary sclerosing cholangitis and associated ulcerative colitis to oral vancomycin may depend on brand and personalized dose: report in an adolescent.

Primary sclerosing cholangitis (PSC) is a rare, progressive liver disease characterized by cholestasis and bile duct fibrosis that has no accepted therapy known to delay or arrest its progression. We report a 23-year-old female patient who at age 14 was diagnosed with moderate pancolonic ulcerative colitis (UC) and at age 15 with small-duct PSC unresponsive to conventional therapy. The patient began single drug therapy with the antibiotic oral vancomycin (OVT) and achieved normalization of liver enzymes and resolution of UC symptoms with colonic mucosal healing.

Validity of an Automated Algorithm to Identify Cirrhosis Using Electronic Health Records in Patients with Primary Biliary Cholangitis.

Background: Biopsy remains the gold standard for determining fibrosis stage in patients with primary biliary cholangitis (PBC), but it is unavailable for most patients. We used data from the 11 US health systems in the FibrOtic Liver Disease Consortium to explore a combination of biochemical markers and electronic health record (EHR)-based diagnosis/procedure codes (DPCs) to identify the presence of cirrhosis in PBC patients.

Methods: Histological fibrosis staging data were obtained from liver biopsies.

Liver Stiffness Measured by Either Magnetic Resonance or Transient Elastography Is Associated With Liver Fibrosis and Is an Independent Predictor of Outcomes Among Patients With Primary Biliary Cholangitis.

Goals: We aimed to describe the diagnostic and prognostic performance of transient elastography (TE) and magnetic resonance elastography (MRE) in patients with primary biliary cholangitis (PBC).

Background: The diagnostic performance of TE and MRE in detecting advanced fibrosis in PBC and in predicting outcomes independent of existing serologic prognostic markers is incompletely understood.

Materials And Methods: Five hundred thirty-eight consecutive patients with PBC at 3 centers with liver stiffness (LS) measurements by TE (n=286) or MRE (n=332) were reviewed.

Early Cholangiocarcinoma Detection With Magnetic Resonance Imaging Versus Ultrasound in Primary Sclerosing Cholangitis.

Background And Aims: Early detection of perihilar cholangiocarcinoma (CCA) among patients with primary sclerosing cholangitis (PSC) is important to identify more people eligible for curative therapy. While many recommend CCA screening, there are divergent opinions and limited data regarding the use of ultrasound or magnetic resonance imaging (MRI) for early CCA detection, and it is unknown whether there is benefit in testing asymptomatic individuals. Our aims were to assess the diagnostic performances and prognostic implications of ultrasound and MRI-based CCA detection.

Measurement of Gamma Glutamyl Transferase to Determine Risk of Liver Transplantation or Death in Patients With Primary Biliary Cholangitis.

Background & Aims: Gamma-glutamyltransferase (GGT) is a serum marker of cholestasis. We investigated whether serum level of GGT is a prognostic marker for patients with primary biliary cholangitis (PBC).

Methods: We analyzed data from patients with PBC from the Global PBC Study Group, comprising 14 centers in Europe and North America.

The long-term outcomes of patients with immunoglobulin G4-related sclerosing cholangitis: the Mayo Clinic experience.

Background: The long-term outcomes of immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) are not well known.

Methods: The outcomes of patients with IgG4-SC at Mayo Clinic (1999-2018) were compared to an age- and gender-matched (1:1 ratio) group of patients with primary sclerosing cholangitis (PSC).

Results: We identified 89 patients with IgG4-SC; median age at diagnosis was 67 years, 81% were males, and the median follow-up was 5.