PRIMARY BILIARY CHOLANGITIS: DIAGNOSIS AND MANAGEMENT Project ID:

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1 ACCREDITATION STATEMENT This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint providership of the Purdue University College of Pharmacy and the Chronic Liver Disease Foundation (CLDF). Purdue University College of Pharmacy, an equal access/equal opportunity institution, is accredited by the ACCME to provide continuing medical education for physicians. Purdue University College of Pharmacy designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NURSING STATEMENT Purdue University Continuing Nursing Education is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center s Commission on Accreditation. Release: January 19, 2018 Expiration: January 19, 2019 DISCLOSURE OF CONFLICTS OF INTEREST All faculty, staff, and reviewers involved in the planning, review, or presentation of continuing education activities sponsored/provided by Purdue University College of Pharmacy are required to disclose to the audience any relevant commercial financial affiliations related to the content of the presentation or enduring material. Full disclosure of all commercial relationships must be made in writing to the audience prior to the activity. All additional planning committee members, staff, and reviewers of the Chronic Liver Disease Foundation and Purdue University College of Pharmacy have no relationships to disclose. The opinions expressed in this enduring material are those of the faculty and do not necessarily represent the views of the Purdue University College of Pharmacy. The information is presented for the purpose of advancing the attendees professional development. LEARNER ASSURANCE STATEMENT The Purdue University College of Pharmacy is committed to resolving all conflicts of interest issues that could arise as a result of prospective faculty members significant relationships with drug or device manufacturer(s). OBJECTIVES After reading and studying this newsletter, the participant should be able to: Describe evolving patient management strategies for primary biliary cholangitis (PBC) Discuss the latest treatment algorithms for PBC and apply them to clinical practice AUTHORS Ira M. Jacobson, MD Professor of Medicine Director of Hepatology NYU School of Medicine New York, New York Andres F. Carrion, MD Director of Hepatology Assistant Professor of Medicine Division of Gastroenterology and Hepatology Texas Tech University Health Sciences Center El Paso El Paso, Texas Cynthia Levy, MD Associate Professor of Medicine Division of Hepatology University of Miami Miller School of Medicine Miami, Florida REVIEWED BY Zobair M. Younossi, MD, MPH, FACG Member, Board of Trustee of Chronic Liver Disease Foundation (CLDF) Co-chair of International Coalition of Hepatology Educators (IC-HEP) Board Member, ACG Institute AUTHOR DISCLOSURES Ira Jacobson, MD Research Support: Genfit, Gilead, Merck Consultant: AbbVie, Bristol-Myers Squibb, Gilead, Intercept, Merck, Trek Speakers Bureau: Gilead, Intercept, Merck Andres Carrion, MD Consultant/Speakers Bureau: Alexion, Bristol-Myers Squibb, Intercept, Merck Advisory Board Membership: Gilead, Intercept Cynthia Levy, MD Grants/Research Support: CymaBay, Gilead, GlaxoSmithKline, Intercept, Novartis, NGM, Shionogi, Shire, Tobira Consultant: Intercept Advisory Board Membership: Intercept, Novartis Honorarium Recipient: UpToDate royalties Editorial Board Involvement: Liver Transplantation 1

2 Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is the most common chronic cholestatic liver disease in adults in the United States. The disease disproportionately affects middle-aged women (9:1 female-to-male ratio). In September 2015, a multi-societal position paper established the change in the disease s nomenclature while maintaining the commonly used acronym PBC. 1 Without pharmacological treatment, progressive fibrosis characterizes the natural history of PBC. Characterized by progressive immune-mediated inflammatory destruction of septal and interlobular bile ductules, the fundamental pathophysiological mechanism for PBC is likely related to a complex interaction between unidentified environmental triggers and genetic susceptiblility. Molecular mimicry, loss of tolerance, and dysregulated immune attacks directed against the E2 subunit of pyruvate dehydrogenase complex (PDC-E2) appear to be the cornerstone of PBC pathogenesis. 2 The result, at least microscopically, reflects the new terminology and can be identified by nonsuppurative cholangitis manifesting biochemically as cholestasis. Without pharmacological treatment, progressive fibrosis characterizes the natural history of PBC. Clinical features are nonspecific and include fatigue, pruritus, right upper quadrant abdominal pain, dyslipidemia, bone mineral density loss, xanthelasmas and, rarely, xanthomas. PBC diagnosis may be established by two of the following three criteria in the absence of a cholestatic drug reaction or biliary obstruction: a) biochemical evidence of cholestasis (otherwise unexplained elevation of serum alkaline phosphatase); b) presence of autoantibodies, typically anti-mitochondrial antibodies (AMA); and, c) histological findings of non-suppurative destructive cholangitis. 3 Characteristic histological features, previously thought to be necessary for establishing a PBC diagnosis, are not mandatory if the other two diagnostic criteria are satisfied. Furthermore, the pathognomonic florid duct lesion is only present in a minority of PBC patients, particularly during early stages. 4 Even when seen, this lesion, characterized by intraepithelial lymphocyte infiltration with visible bile duct injury, may be present in only one portal tract out of whatever number was obtained in the biopsy specimen. Among many hepatologists, the trend has been to rely upon noninvasive assessment of fibrosis, especially when the diagnosis of PBC can be established the first two criteria outlined above. Vibration-controlled transient elastography (Fibroscan ) has been shown to be reliable and may have particular utility for monitoring fibrosis progression. 5 Vibration-controlled transient elastography (Fibroscan ) has been shown to be reliable and may have particular utility for monitoring fibrosis progression. 5 It is important to recognize that AMA, the hallmark autoantibody of PBC, may not be detectable in approximately 5 to 10% of patients with the disease (the so-called AMA-negative PBC), in which histology is mandatory to establish the diagnosis. Most patients with AMA-negative PBC have antinuclear antibodies (ANA). Among these, two subtypes of ANA, nuclear pore membrane protein gp210, and nuclear body protein sp100, are relatively insensitive but highly specific (>95%) markers of PBC (PLOS One article below), and may help corroborate the diagnosis. 6 Ursodeoxycholic acid (UDCA), the first pharmacological agent licensed for PBC treatment, has proven to alter the natural history of the disease significantly when administered orally at a 2

3 dose of mg/kg/day. Important outcomes associated with UDCA therapy in PBC include reduced fibrosis progression, diminished need for liver transplantation (LT), and improved LT-free survival. Nevertheless, up to 40% of PBC patients who are treated with UDCA for at least a year have an inadequate biochemical response and experience lesser benefits on long-term outcomes. 7 Response to pharmacologic therapy is assessed predominantly by reductions in serum alkaline phosphatase and bilirubin levels, two biochemical markers that accurately predict long-term outcomes in PBC. 8 Incomplete responders are at higher risk for progression towards biliary cirrhosis and end-stage liver disease and are more likely to develop hepatocellular carcinoma compared to those who respond to UDCA. 9 Other recommendations in the management of patients with PBC are listed in Table 2. The PBC GLOBE score (available at is a newly validated non-invasive assessment tool that uses readily available and objective variables (age, bilirubin, albumin, alkaline phosphatase, and platelet count) for accurately identifying patients at risk for clinically important outcomes, such as the need for LT and mortality within the next three, five, and 10 years. 10 An online calculator can be used to derive this score rapidly in any patient for whom recent laboratory parameters are available. It may be particularly useful as an aid to monitoring the course of a patient s response to UDCA treatment and thereby assess the need for additional therapies. Obeticholic acid (OCA) was licensed on May 27, 2016 by the Food and Drug Administration. OCA is currently indicated for treating PBC, in combination with UDCA, in adults with an inadequate biochemical response to UDCA for at least 12 months, or as monotherapy in adults who cannot tolerate UDCA. OCA is a selective farnesoid X receptor (FXR) agonist derived from the naturally occurring chenodeoxycholic acid, an endogenous FXR ligand. FXR is a member of the nuclear bile acid receptor superfamily expressed in high levels in hepatocytes and enterocytes in the terminal ileum and its activation results in suppression of cholesterol 7 alpha-hydroxylase (CYP7A1) and transcription of fibroblast growth factor (FGF) 19. CYP7A1 is the rate-limiting enzyme in bile acid synthesis from cholesterol. Accordingly, FXR activation markedly reduces the bile acid pool. Similarly, increased levels of FGF19 inhibit de novo synthesis of bile acids; nevertheless, this hormone also regulates several metabolic pathways, including insulin sensitivity and lipid metabolism. Furthermore, in animal models, FXR activation has proven to result in fibrosis regression. 11 The recommended OCA dosing is summarized in Table 1. Table 2. General recommendations for management of patients with PBC. 3 Complication Pruritus Fatigue Dyslipidemia Sicca syndrome Osteopenia / osteoporosis Gastroesophageal varices Recommendation First line: bile acid sequestrants (i.e., cholestyramine or cholestipol) Second line: rifampicin, naltrexone, sertraline Evaluate for potential causes including comorbidities, medications, depression, itching. May use modafinil (off label) Statins if needed, based on individual risk factors for cardiovascular disease First line: artificial tears/ artificial saliva Second line: pilocarpine or cevimeline for dry eyes/ mouth, cyclosporine ophthalmic for dry eyes Baseline and regular screening every 2 3 years with bone mineral density scan Calcium 1500 mg/day and vitamin D 1000 IU/ day supplementation for peri- and post-menopausal women Bisphosphonates for patients with osteoporosis Initiate screening with upper endoscopy once cirrhosis is diagnosed or Mayo risk score >4.1 or platelets <140,000 In the randomized, placebo-controlled POISE trial, the primary composite end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range (the inclusion criteria included alkaline phosphatase above this level), with a reduction of at least 15% from baseline, and a total bilirubin level at or below the upper limit of the normal range at 12 months. In the trial OCA, Hepatocellular carcinoma Screening with liver ultrasonography every 6 12 months for individuals with cirrhosis or Mayo risk score >4.1. Males and UDCAnonresponders appear to be at increased risk. 3

4 administered with UDCA or as monotherapy for 12 months, resulted in attainment of the primary endpoint in 47% of individuals treated with 10 mg/day, 46% of those started at 5 mg/day with uptitration to 10 mg, and 10% of those that received the placebo. 12 The findings of this trial, which compared two different dosing strategies for OCA, led to the approval of a starting dose of 5 mg/ day with upward titration to 10 mg/day after at least 3 months as needed to improve upon the biochemical response, provided the drug is being tolerated well. Table 1. Recommended doses for UDCA and OCA for treating PBC. No cirrhosis and compensated cirrhosis Decompensated cirrhosis UDCA mg/kg/day mg/kg/day The main side effect of OCA is pruritus, which occurred in 56% of patients who started on 5 mg/ day in the POISE trial, 68% in patients who received an initial dose of 10 mg/day, and 38% in placebo recipients. Discontinuation rates due to pruritus occurred in 10% of the 10 mg group, 1% of the 5 mg group, and 0% of the placebo recipients. Importantly, the package insert for OCA stipulates a dose reduction to 5 mg once weekly in patients with moderate to severe hepatic dysfunction, as OCA is predominantly excreted by the liver (87%). A recent safety report to providers described 19 patients OCA 5 mg/day, titrate up to 10 mg/day after three months if tolerated 5 mg/week, titrate up to 5 mg twice weekly after three months and subsequently to 10 mg twice weekly if tolerated with fatal outcomes, and an additional 11 cases of serious liver injury, associated with OCA therapy. Where details were available, a large number of these cases (including most of the fatalities) were associated with daily instead of the required weekly dosing in PBC patients with moderate to severe hepatic dysfunction at baseline. 13 Although a causal relationship between mortality and OCA has not yet been established and is under evaluation, this development underscores the need for providers to be familiar with the guidelines for dosing outlined in the product s package insert. Several other drugs are currently under evaluation for treating patients with PBC and inadequate response to UDCA. Fenofibrate, a PPAR-alpha agonist, and bezafibrate, an agonist of all three major PPAR receptors (alpha, delta and gamma), have been shown to have beneficial biochemical effects 14,15. A recent clinical trial of bezafibrate given for 24 months demonstrated normalization of alkaline phosphatase in 67% and normal levels of all biochemical parameters (bilirubin, ALT, AST, alkaline phosophatase, albumin and prothrombin time) in 30%. 15 Another recent agent, seladelpar (MBX-8025), a PPAR-delta agonist, effected substantial reductions or even normalization of alkaline phosphatase in a phase 2 trial, but were associated with grade 3 transaminase elevations at doses of mg/day. 16 At reduced doses of 5-10 mg given for 12 weeks, reductions in alkaline phosphatase were 39-45% without grade 2 or 3 transaminase elevations and phase 3 studies are planned. 17 At the present time, however, only OCA remains approved for patients with an inadequate response to ursodeoxycholic acid. PBC is the sixth leading indication for LT in the United States; pharmacological therapy has resulted in a steady decline in the number of individuals requiring LT since UDCA approval. 18 Outcomes following LT for PBC are excellent and have been considered the benchmark for patient and allograft survival to which other indications for LT are compared. Although recurrence post-lt is relatively common, it has no significant impact on survival. Recent data from a retrospective study suggest that preventive administration of UDCA may markedly diminish recurrence of PBC 10 years post- LT. 19 These data need to be corroborated by prospective studies and there are currently no data on the role of OCA and prevention of recurrent PBC post-lt. In Summary: PBC is a heterogeneous disease and not all patients respond to firstline therapy with UDCA. Secondline therapy with OCA is available for nonresponders and for those who are intolerant to UDCA. Care for PBC patients must be individualized based on staging and appropriate risk stratification. 4

5 REFERENCES 1. Meglasson MD, Smith KM, Nelson D, Erecinska M. alpha-glycerophosphate shuttle in a clonal beta-cell line. The American Journal of Physiology 1989;256:E Shigematsu H, Shimoda S, Nakamura M, et al. Fine specificity of T cells reactive to human PDC-E peptide, the immunodominant autoantigen in primary biliary cirrhosis: implications for molecular mimicry and cross-recognition among mitochondrial autoantigens. Hepatology 2000;32: Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. Hepatology 2009;50: Kaplan MM, Gershwin ME. Primary biliary cirrhosis. The New England Journal of Medicine 2005;353: Poupon R. Non-Invasive Assessment of Liver Fibrosis Progression and Prognosis in Primary Biliary Cholangitis. Dig Dis 2015;33(suppl 2): Zhao FR, Hu Q, Chen WX. Meta-analysis Assessment of GP210 and SP100 for the diagnosis of primary biliary cirrhosis. Shi-Ling Hu. PLOS One 2014;9: Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 2008;48: Lammers WJ, van Buuren HR, Hirschfield GM, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology 2014;147: e5; quiz e Kuiper EM, Hansen BE, Adang RP, et al. Relatively high risk for hepatocellular carcinoma in patients with primary biliary cirrhosis not responding to ursodeoxycholic acid. European Journal of Gastroenterology & Hepatology 2010;22: Lammers WJ, Hirschfield GM, Corpechot C, et al. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology 2015;149: e Fausther M, Dranoff JA. New insights on the pathogenesis of biliary cirrhosis provided by studies in FXR knockout mice. Journal of Hepatology 2011;55: Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. The New England Journal of Medicine 2016;375: Cheung AC, Lapointe-Shaw L, Kowgier M, et al. Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes. Aliment Pharmacol Ther Jan;43(2): Corpechot C, Chazouilleres O, Rousseau A et al. A 2-year multicenter, double-blind, randomized, placebo-controlled study of bezafibrate for the treatment of primary biliary cholangitis in patients with inadequate biochemical response to ursodeoxycholic acid therapy (Bezurso). J. Hepatology 2017;66:S Jones D, Boudes PF, Swain MG et al. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-ofconcept study. Lancet Gastro and Hepatol 2017;2, No 10: Hirschfield G., Bowlus C., Harrison S. et al. Treatment Efficacy and Safety of Low Dose Seladelpar a Selective PPAR-δ Agonist, in Patients with Primary Biliary Cholangitis: 12-week Interim Analysis of an International, Randomized, Dose Ranging, Phase 2 Study. Annual Meeting of the American Association for the Study of Liver Diseases, Washington D.C. October 21, 2017, abstract LB Lee J, Belanger A, Doucette JT, Stanca C, Friedman S, Bach N. Transplantation trends in primary biliary cirrhosis. Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association 2007;5: Bosch A, Dumortier J, Maucort-Boulch D, et al. Preventive administration of UDCA after liver transplantation for primary biliary cirrhosis is associated with a lower risk of disease recurrence. Journal of Hepatology 2015;63: If you wish to receive acknowledgement of participation for this activity, please complete the posttest, evaluation form, and request for credit by clicking the link below ACCREDITATION 5