Primary biliary cholangitis

Transcription

1 A guide to Primary biliary cholangitis Miss Jennifer Hayden, Autoimmune Liver Disease Clinical Nurse Specialist Professor Gideon M Hirschfield, Professor and Consultant Transplant Hepatologist Centre for Liver Research, NIHR Biomedical Research Centre, University of Birmingham, and Centre for Rare Diseases, Institute of Translational Medicine, Birmingham Health Partners, University Hospitals Birmingham, Birmingham B15 2TT Correspondence to: Professor GM Hirschfield (g.hirschfield@bham.ac.uk) This booklet was sponsored by Intercept Pharma UK & Ireland Ltd. The sponsoring company has had no editorial control over the content, except to review the document for factual accuracy. Job Code: UK-NP-PB-0222 Date of Preparation: December 2017

2 Introduction The autoimmune biliary disease primary biliary cholangitis (formerly known as primary biliary cirrhosis) is a chronic inflammatory liver disease that is characterised by persistent immunedriven biliary injury (Table 1). This results in cholestasis, progressive liver fibrosis, and for some patients end-stage liver disease. Disease is usually identified in a patient with a cholestatic pattern of serum liver tests elevated levels of alkaline phosphatase and/or gamma-glutamyltransferase and the presence of circulating anti-mitochondrial antibodies (Hirschfield and Gershwin, 2013). In contrast to other liver diseases, most patients living with primary biliary cholangitis are women and the average age at presentation is between 50 and 60 years. The estimates for prevalence in the UK suggest that at least 1 in 1000 women over the age of 40 years live with primary biliary cholangitis (Hirschfield et al, 2017). The incidence of new diagnoses of primary biliary cholangitis is around 2 3 per per year (Hirschfield et al, 2017). Paradoxically for what is considered an archetypal autoimmune disease, children do not develop primary biliary cholangitis. Men with primary biliary cholangitis have the same diagnostic characteristics but their disease course tends to be more serious, either because they present at diagnosis with more advanced disease, or because their response to first-line therapy with ursodeoxycholic acid appears reduced (Trivedi et al, 2016). At the time of diagnosis, most patients with primary biliary cholangitis report few if any symptoms. However, many patients develop symptoms that can be burdensome, and these may be specific or non-specific. Within the symptom complex associated with primary biliary cholangitis are pruritus, sicca complex, abdominal discomfort, fatigue, bone pain and restless legs. It is notable that symptom burden need not directly correlate with disease severity, albeit that patients presenting at a young age with more aggressive disease may be particularly troubled with pruritus, and patients with late stage disease are inevitably frequently more symptomatic. Pathogenesis The aetiology of primary biliary cholangitis is believed to result from a combination of genetic and Table 1. Primary biliary cholangitis: an overview Age Sex Female > male (9:1) Serology Immunoglobulin Imaging Liver histology Symptoms Licenced treatment options Follow up Usually >45 years; diagnosis <45 years associated with higher risk of progression Anti-mitochondrial antibody in ~95%, disease-specific anti-nuclear antibody in ~30 50%, antismooth muscle antibody may be present IgM typically elevated (sensitive but not specific for primary biliary cholangitis) Normal bile ducts Rarely indicated; lymphocytic infiltrate, inflammatory duct lesion, granuloma possible Pruritus, bone pain, fatigue, sicca, restless legs Ursodexycholic acid (13 15 mg/kg/day); obeticholic acid (5 10 mg/day, dose adjust for patients with Child Pugh score B/C) Ambulatory care, 6 12 months; variable burden

3 environmental triggers, although precise causation continues to be evasive, and as such there are no treatments that cure patients (Hirschfield and Gershwin, 2013; Webb and Hirschfield, 2017). Studies have shown many genetic variations which predispose an individual to developing primary biliary cholangitis, and the genes highlighted appear relevant to immune regulation; an exemplar of this is the interleukin-12 signalling pathway. Geo-epidemiological studies in patients with primary biliary cholangitis repeatedly support the likely involvement of environmental triggers, with immunological studies demonstrating potential pathogenic mechanisms through xenobiotics and molecular mimicry that relate environmental triggers to loss of immune tolerance to the key auto-antigen, pyruvate dehydrogenase. Other insights into disease have also arisen from population studies which demonstrate how patients with primary biliary cholangitis are more likely to have smoked cigarettes than those without disease, and to have a higher rate of recurrent urinary tract infections. The striking gender imbalance and late onset of disease for the majority of cases support added epigenetic mechanisms relevant to disease expression. Diagnosis Of the three autoimmune liver diseases, primary biliary cholangitis is the most straightforward to diagnose, and for the majority of patients a confident diagnosis can be made in the correct clinical context, based on a combination of cholestatic liver biochemistry and the presence of anti-mitochondrial antibodies. Liver biopsy is therefore an infrequent investigation in the diagnostic pathway, although a role persists in the absence of characteristic serological reactivity, where features of autoimmune hepatitis are also present, or in cases where it is unclear if there could be an added liver injury such as nonalcoholic fatty liver disease. The predominant pattern recognised by serum liver tests in patients with primary biliary cholangitis is a rise in alkaline phosphatase levels. A concomitant rise in gamma-glutamyltransferase levels is consistent with a biliary origin for the increased alkaline phosphatase levels. There may also be elevations in aminotransferase levels, but these are usually not as marked; values above five times the upper limit of normal are uncommon in classically presenting primary biliary cholangitis (Hirschfield et al, 2017). The purpose of arranging a baseline ultrasound is not to visualise primary biliary cholangitis (it being a small bile duct disease) but to exclude biliary obstruction as an aetiology for cholestatic liver tests, as well as to look for features of cirrhosis and portal hypertension. No additional imaging is normally needed. With disease progression, particularly in those with baseline risk factors for high-risk disease, or those who fail to respond adequately to therapy, patients may show features of advanced liver disease such as jaundice, hepatomegaly and splenomegaly. Immuno-serology, which critically must always be interpreted in the context of a patient s overall clinical presentation, is key to diagnosing autoimmune liver disease, and in particular primary biliary cholangitis. Over 90% of patients will be anti-mitochondrial antibody-positive. This is often accompanied by a non-specific rise in IgM concentrations. A small percentage of patients with primary biliary cholangitis are negative for anti-mitochondrial antibodies. In this setting immunofluorescence patterns of anti-nuclear antibodies may help, notably multi-nuclear dot and peri-nuclear rim reactivity, as well as centromere reactivity. Specific immunoassays related to anti-nuclear reactivities may reveal anti-gp210 or antisp100 reactivity which are both very specific for primary biliary cholangitis.

4 Clinical consequence of disease With current treatment, and in contrast to previous eras, the overwhelming majority of patients are diagnosed early in their disease course and treated proactively; all should be offered ursodeoxycholic acid first line. A licenced secondline therapy in the form of obeticholic acid became available in the UK in Transplant rates for primary biliary cholangitis have subsequently fallen over time (Webb et al, 2017). Nevertheless morbidity and mortality remains real and survival in primary biliary cholangitis is associated with baseline and on-treatment risk factors. Those patients who are male, are diagnosed at a younger age (<45 years) and/or present with advanced disease have greater risk of disease progression. Furthermore, patients with biochemical disease activity (i.e. elevations in alkaline phosphatase and/or serum aminotransferase activity values) despite therapy with ursodeoxycholic acid have greater likelihood of progressive disease (Lammers et al, 2014; Trivedi et al, 2016). The development of progressive biliary disease is associated with portal hypertension, liver failure and hepatocellular carcinoma risk. Stratification of risk The goal of treatment is to ensure each individual is managed in a way that reflects the disease course of primary biliary cholangitis for that person, including symptoms. Therefore therapeutic strategies for primary biliary cholangitis should evaluate a patient s risk of disease progression, together with an assessment of the present disease stage and the patient s symptom burden. To stage liver disease in primary biliary cholangitis, attention is given to markers of disease severity bilirubin values and platelet count in particular as well as imaging findings, encompassing evidence of cirrhotic liver morphology and/or presence of splenomegaly on ultrasound, as well as interpretation of serial transient elastography. Staging is important as those with advanced liver disease have a higher risk of future disease progression. With effective interventions predicted to be most beneficial if offered before late stage disease, patients are evaluated for risk of progressive liver disease from the point of diagnosis and treatment (Trivedi et al, 2016). This process needs to account for both baseline risk factors (e.g. young age at diagnosis (<45 years) and advanced stage at presentation, particularly cirrhosis and elevated bilirubin levels), as well as on-treatment (biochemical response) predictors of future risk. Multiple studies (Lammers et al, 2014; Trivedi et al, 2016) demonstrate a high risk of adverse events for patients with inadequate response to ursodeoxycholic acid treatment usually judged 1 year after initiation. The definitions of inadequate biochemical response to ursodeoxycholic acid vary, but all encompass an evaluation of serum liver tests, in particular bilirubin and alkaline phosphatase levels. Interface hepatitis is a histological marker of poor prognosis and persistent serum aminotransferase elevations are also identifiable as risk markers. There are a variety of reported tools (Trivedi et al, 2016), some dichotomous, others continuous, such as the GLOBE score and UK-PBC score. Of these, one simple, widely applied criterion used in clinical trials of new therapies is to define high-risk disease as those patients having elevated bilirubin levels and/or an alkaline phosphatase level greater than 1.67 times the upper limit of normal (Nevens et al, 2016). Treatment Management of primary biliary cholangitis focuses on: 1. Confirming the diagnosis clearly to the patient 2. Recognising the severity of liver disease at presentation and during follow up 3. Identifying the patients at greatest risk of disease progression based on baseline presenting

5 features and importantly ongoing response to treatment 4. Ensuring that, beyond effective disease-specific therapy, attention is focused on managing the complications of chronic cholestatic liver disease and understanding and intervening as able with the varied symptom complex of patients. Patient management usually spans primary and secondary care settings, with tertiary programmes focusing on those at greatest risk or with greatest symptom burden. Furthermore nurse specialist care is valuable, and a means to both attending to the need for patient education, but also timely input and guidance for symptom control, as well as safe monitoring of therapies such as obeticholic acid and rifampicin. The important pathophysiological processes underlying primary biliary cholangitis are inflammation, cholestasis and fibrosis. No therapy to date has been able to cure disease; rather they modify these underlying consequences of persistent immune-mediated biliary-driven injury. Across this spectrum of targets biologic-based therapies have been disappointing and therapy to date has focused on bile acid-based drugs, which modify cholestasis and associated inflammation, and subsequent fibrogenesis. Ursodeoxycholic acid is a naturally occurring secondary bile acid (an epimer of chenodeoxycholic acid) that, in gram quantities, is choleretic and anti-inflammatory. Obeticholic acid is a semi-synthetic bile acid (6α-ethyl-chenodeoxycholic acid) that, in miligram quantities, is a selective farnesoid X receptor agonist, with anti-inflammatory, antifibrotic and choleretic properties (Beuers et al, 2015). Once a patient has been diagnosed with primary biliary cholangitis, guidelines from Europe (Hirschfield et al, 2017) and the USA (Lindor et al, 2009) both suggest that all patients should be offered treatment with weight-based ursodeoxycholic acid (13 15 mg/kg/day) with the intention that treatment will be for life. For a majority of patients, ursodeoxycholic acid (safely taken once, twice or three times/day as per patient choice) is well tolerated, side effects being limited to bloating, weight gain and thinning of hair. Biochemical response to treatment with ursodeoxycholic acid is an important marker of treatment success, and it is associated with prolonged survival. For those patients with noncirrhotic liver disease who achieve a complete response to therapy biochemically, survival is excellent, and in some series, no different to an age-matched healthy control population. If patients are either intolerant of ursodeoxycholic acid therapy, or biochemically do not achieve a sufficient response, accounting for their baseline risk, then second-line licenced therapy in the form of added obeticholic acid should be considered (Hirschfield et al, 2017). In the UK, obeticholic acid is started at 5 mg daily, and titrated if tolerated at 6 months to 10 mg daily. In a phase 3 clinical trial of obeticholic acid, nearly half of high-risk patients were deemed biochemical responders to therapy (Nevens et al, 2016). In using obeticholic acid it is important to assess the likelihood of benefit. In those patients with advanced disease dose adjustment is important. As per the drug label, obeticholic acid is dose adjusted to 5 mg weekly initially (with a maximum dose of 10 mg twice weekly) in those with liver disease with a Child Pugh B or C score. The authors practice when initiating therapy in a patient with a Child Pugh A score is to also dose adjust in the presence of portal hypertension. Cirrhotic patients should have intensified early safety evaluation in particular, and in the context of development of decompensation for a patient on obeticholic acid, dose adjustment or treatment cessation may be indicated. Pruritus is a side effect of obeticholic acid, but in clinical trial settings, treatment discontinuation

6 overall is less than 10% at labelled doses of obeticholic acid; dose titration is important in this respect. The pruritus associated with obeticholic acid should be treated by either cholestyramine or rifampicin or by adjusting the dose of obeticholic acid. Treatment efficacy is evaluated by followup serum liver tests, with the therapeutic goal of improving markers of liver injury namely a fall in alkaline phosphatase level and stabilisation of bilirubin level. Other agents used globally for primary biliary cholangitis include fibrates (a non-labelled indication) and there remain many clinical trial agents in development (Beuers et al, 2015). Symptoms should also be sought and actively managed. Medical treatments for itch can be very successful, and patients are usually started on the bile acid resin cholestyramine first. Rifampicin is used second line, but its use does require blood test monitoring, as there is a small risk of hepatotoxicity in particular. Other agents for itch include sertraline and naltrexone. Fatigue does not have a specific medical treatment, but exercise is frequently anecdotally reported as helpful. Managing complications The management of cirrhosis in the context of primary biliary cholangitis is akin to that of any patient with chronic liver disease, with priority given to diagnosing hepatocellular carcinoma early, preventing variceal haemorrhage and reducing the risk of osteoporotic fracture. Nuances include a potential for non-cirrhotic portal hypertension rarely in patients with primary biliary cholangitis, and a recognition that hepatocellular carcinoma risk is skewed in patients with primary biliary cholangitis to those with advanced liver disease, treatment non-responders and male patients. As liver disease progresses patients are followed by repeated serum liver tests, imaging and elastography, all of which help define the pattern of disease progression, as well as identifying surveillance needs, including timing of endoscopy for varices. In patients who develop persistent jaundice (>50 mmol/litre), decompensated liver disease or intractable pruritus, liver transplantation should be considered, as it is a highly effective intervention. Listing for transplantation usually requires a disease severity score consistent with accepting the risk of surgery alongside an overt indication (Hirschfield et al, 2017). Other features associated with primary biliary cholangitis are low bone-mass from osteoporosis and hyperlipidaemia associated with cholestasis. Patients are usually recommended to take calcium and vitamin D supplements and to have a bone-density evaluation, as well as a general bone-fracture risk evaluation. The cholestasis of primary biliary cholangitis is also associated with a lipogenic, non-atherogenic profile characterised by high levels of cholesterol and high-density lipoproteins and tissue deposits of lipids (referred to as xanthelasma) (Hirschfield et al, 2017). The hyperlipidaemia of primary biliary cholangitis is usually not a concern, only requiring intervention if there are added metabolic or cardiac risks. Standard pharmacological approaches to managing the hyperlipidaemia can be offered, if indicated. Routine screening for associated autoimmune diseases in patients with primary biliary cholangitis is not evidence based, but consideration should be given to the higher rate of thyroid disease and coeliac disease in this cohort of patients in particular. Conclusions Patients with primary biliary cholangitis live with the consequences of a chronic persistent biliary injury that, if untreated, progresses to end-stage liver disease. Therapies are increasingly effective, and licenced options for care now include, beyond ursodexoycholic acid, therapy with a selective bile acid-based farnesoid X receptor agonist, obeticholic acid. Overall care is thus more sophisticated

7 and attention to appropriate risk stratification and early access to additional disease-modifying therapy is important. This rests alongside the need to tackle the associated symptom burden that patients with primary biliary cholangitis have, in a way that is proactive and directed. Conflict of interest: Miss J Hayden and Professor GM Hirschfield have received speaker fees from Falk Pharma and Intercept Pharmaceuticals. This guide presents independent research supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Cover image from Adobe Stock/PIC4U Beuers U, Trauner M, Jansen P, Poupon R (2015) New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. J Hepatol 62(1): S25 S37. Hirschfield GM, Gershwin ME (2013) The immunobiology and pathophysiology of primary biliary cirrhosis. Annu Rev Pathol 8: Hirschfield GM, Beuers U, Corpechot C et al (2017) EASL clinical practice guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol 67(1): jhep Lammers WJ, van Buuren HR, Hirschfield GM et al (2014) Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology 147(6): e5. gastro Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ; American Association for Study of Liver Diseases (2009) Primary biliary cirrhosis. Hepatology 50(1): Nevens F, Andreone P, Mazzella G et al (2016) A placebocontrolled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 375(7): org/ /nejmoa Trivedi PJ, Corpechot C, Pares A, Hirschfield GM (2016) Risk stratification in autoimmune cholestatic liver diseases: opportunities for clinicians and trialists. Hepatology 63(2): Webb GJ, Hirschfield GM (2017) Primary biliary cholangitis in 2016: High-definition PBC: biology, models and therapeutic advances. Nat Rev Gastroenterol Hepatol 14(2): Webb GJ, Rana A, Hodson J et al (2017) Twenty-year comparative analysis of patients with autoimmune liver diseases on transplant waitlists. Clin Gastroenterol Hepatol

8 Abbreviated Prescribing Information OCALIVA (obeticholic acid) (Please refer to the Full Summary of Product Characteristics (SmPC) before prescribing) Presentation: OCALIVA supplied as film-coated tablets containing 5 mg and 10 mg obeticholic acid. Indication: For the treatment of primary biliary cholangitis (also known as primary biliary cirrhosis) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA. Dosage and administration: Oral administration. The starting dose is 5 mg once daily. Based on an assessment of tolerability after 6 months, the dose should be increased to 10 mg once daily to achieve optimal response. No dose adjustment of concomitant UDCA is required in patients receiving obeticholic acid. For cases of severe pruritus, dose management includes dose adjustment such as reduced dosage, temporal interruption or discontinuation for persistent intolerable pruritus; use of bile acid binding agents or antihistamines (see SmPC). No dosage adjustment for elderly. Renal impairment: No dose adjustments are required. Hepatic impairment: No dose adjustment for mild hepatic impairment (Child-Pugh Class A). The recommended starting dosage for moderate/ and severe (Child-Pugh Class B/C) hepatic impairment is 5 mg once weekly. Titrate to 5 mg and subsequently to 10 mg twice weekly (at least 3 days between doses) if patient does not achieve adequate reductions in alkaline phosphatase and/or total bilirubin after 3 months, depending on response and tolerability. Paediatric population: No data. Contraindications: Hypersensitivity to the active substance or any excipients. Complete biliary obstruction. Special warnings and precautions for use: Liver-related adverse events occurring as early as within the first month of treatment; elevations in alanine amino transferase (ALT), aspartate aminotransferase (AST) and hepatic decompensation have been observed and patients should be monitored during treatment with OCALIVA. Severe pruritus; see recommendations for dosage reduction and use of bile acid binding resins or antihistamines. Interactions: Following co-administration of warfarin and obeticholic acid. International normalised ratio (INR) should be monitored and the dose of warfarin adjusted, if needed, to maintain the target INR range. Therapeutic monitoring of CYP1A2 substrates with narrow therapeutic index (e.g. theophylline and tizanidine) is recommended. Obeticholic acid should be taken at least 4-6 hours before or after taking a bile acid binding resin, or at as great an interval as possible. Fertility, pregnancy and lactation: Avoid use in pregnancy. Either discontinue breast-feeding or discontinue/abstain from obeticholic acid therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. No clinical data on fertility effects. Undesirable effects: Very common ( 1/10) adverse reactions were pruritus, fatigue, and abdominal pain and discomfort. The most common adverse reaction leading to discontinuation was pruritus. The majority of pruritus occurred within the first month of treatment and tended to resolve over time with continued dosing. Other commonly ( 1/100 to < 1/10) reported adverse reactions are, thyroid function abnormality, dizziness, palpitations, oropharyngeal pain, constipation, eczema, rash, arthralgia, peripheral oedema, and pyrexia. Please refer to the SmPC for a full list of undesirable effects. Overdose: Liver-related adverse reactions were reported with higher than recommended doses of obeticholic acid. Patients should be carefully observed and supportive care administered, as appropriate. Legal category: POM Marketing authorisation numbers: EU/1/16/1139/001 & 002 Marketing authorisation holder: Intercept Pharma Ltd, 2 Pancras Square, London, N1C 4AG, United Kingdom Package Quantities and Basic NHS cost: OCALIVA 5 mg and 10 mg 2, per bottle of 30 tablets. Date of revision: 20/DEC/2016 Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Intercept Pharma Ltd on +44 (0) or drugsafety@interceptpharma.com