New insights in pathogenesis and therapy of primary biliary cholangitis Keith D. Lindor Dean Professor of Medicine
OUTLINE PBC Epidemiology Diagnosis Treatment
Incidence of PBC and PSC Trends Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: A systematic review. Journal of Hepatology. 2012; 56(5): 1181-1188.
Prevalence of PBC and PSC Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: A systematic review. Journal of Hepatology. 2012; 56(5): 1181-1188.
PBC Prevalence Boonstra K, Kunst A, Stadhouders P, et al. Rising incidence and prevalence of primary biliary cirrhosis: a large population-base study. Liver International. 2014;34:e35.
PBC Incidence Boonstra K, Kunst A, Stadhouders P, et al. Rising incidence and prevalence of primary biliary cirrhosis: a large population-base study. Liver International. 2014;34:e35.
Liver Transplantation for PBC and PSC Lee J, Belanger A, Doucette JT, et al. Transplantation Trends in Primary Biliary Cirrhosis. Clin Gastroenterol Hepatol 2007;5(11):1313-5
Predictors of Prognosis ANA Anti-Centromere Antibodies ANA/gp210 Years Years Yang W, Yu JH, Nakajima,et al. Clin Gastroenterol Hepatol 2004;2(12):1116-22. and Nakamura M, Shimizu-Yoshida Y, Takii Y, et al. J Hepatol 2005;42(3):386-92.
Higher APRI is Associated with Poorer Transplant-Free/Overall Survival in PBC Trivedi PJ, Bruns T, Cheung A, et al. Optimizing risk stratification in primary biliary cirrhosis: AST/platelet ratio index predicts outcome independent of ursodeoxycholic acid response. J Hepatol. 2014;60(6):1249-58.
Survival Rates, Elastography and PBC Corpechot C, Carrat F, Poujol-Robert A, et al. Hepatology. 2012; 56 (1): 198-208.
Role of Liver Biopsy in PBC If: AMA Alk Phos > 1.5 times nl AST < 5 times normal Then: Positive predictive value for PBC > 98% (sensitivity 80%, specificity 92%) Zein CO, Angulo P, Lindor K. When is liver biopsy needed in the diagnosis of primary biliary cirrhosis? Clin Gastro and Hepatol 2003;1(2):89-95
Predictors of Esophageal Varices in PBC Odds Ratio Platelet Count <140,000 7.6 Mayo Risk Score >4.5 10.6 Levy C, Zein CO, Gomez J, et al. Prevelence and Predictors of Esophageal Varices in Patients with Primary Biliary Cirrhosis. Clin Gastro Hepatol 2007;5(7):803-808.
Potential Therapeutic Agents Carey EJ, Ali AH, Lindor KD. Primary Biliary Cirrhosis. The Lancet. 2015 Oct.; 386(10003):1565-1575.
Probability of survival % Poupon RE, Lindor KD, Cauch-Dudek K, et al. Combined Analysis of Randomized Controlled Trials of Ursodeoxycholic Acid in Primary Biliary Cirrhosis. Gastroenterology. 1997; 113:884-890 Medical Approaches to PBC UDCA Survival Free of Transplantation Combined Data UDCA 273 236 116 Placebo & UDCA 275 220 87
Poupon RE, Bonnand AM, Chretien Y, et al. Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. The UDCA-PBC Study Group. Hepatology1999; 29(6):1668-1671 Survival in PBC Treated vs. Untreated Treated vs. Population
Natural History of PBC Effects of UDCA Poupon RE, Bonnand AM, Chretien Y, et al. Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. The UDCA-PBC Study Group. Hepatology. 1999; 29(6):1668-1671
Angulo P, Lindor KD, Therneau TM, et al. Utilization of the Mayo risk score in patients with primary biliary cirrhosis receiving ursodeoxycholic acid. Liver. 1999; 19(2): 119-121. Combination Therapy for PBC Ursodiol Alone Biochemical normalization in ~ 1/3 Risk scores or alkaline phosphatase response predictive* Various drugs tried in combination
Biochemical Endpoints for Predicting Outcomes 25 20 Percentage of patients reaching endpoints 15 10 5 0 ALP <1.5 <1.67 <2 >2 >3
Criteria to Define Biochemical Response to UDCA Carey EJ, Ali AH, Lindor KD. Primary Biliary Cirrhosis. The Lancet. 2015 Oct.; 386(10003):1565-1575.
Newer Therapies for PBC Bezafibrate/Fenofibrate Silymarin B cell antibodies FXR agonists Ustekinumab
OCA in PBC: Total Alkaline Phosphatase by Treatment Group Results from Obeticholic Acid in Primary Biliary Cholangitis/Cirrhosis: A Phase 3 Trial. Clinical Trials.gov ID: NCT01473524.
OCA in PBC: Total Bilirubin by Treatment Group Results from Obeticholic Acid in Primary Biliary Cholangitis/Cirrhosis: A Phase 3 Trial. Clinical Trials.gov ID: NCT01473524.
Transplant-free Survival in PBC Patients who had Inadequate Response to UDCA Banken R, Chapman R, Emond S, et al. Obeticholic Acid for the Treatment of Primary Biliary Cholangitis: Comparative Clinical Effectiveness and Value. Institute for Clinical and Economic Review. 2016.
Banken R, Chapman R, Emond S, et al. Obeticholic Acid for the Treatment of Primary Biliary Cholangitis: Comparative Clinical Effectiveness and Value. Institute for Clinical and Economic Review. 2016. Cost-effectiveness of OCA for Treating PBC When the annual cost of OCA is $65,000 per year UCDA* OCA + UDCA Undiscounted Life Years 19.28 22.20 Discounted QALYs 10.42 11.73 Discounted Total Cost ($) 97,208 587,707 ICER ($/QALY) 374,220 *Results correspond to inadequate response to UDCA, as observed in POISE study
Banken R, Chapman R, Emond S, et al. Obeticholic Acid for the Treatment of Primary Biliary Cholangitis: Comparative Clinical Effectiveness and Value. Institute for Clinical and Economic Review. 2016. Cost-effectiveness of OCA for Treating PBC When the annual cost of OCA is $15,000 per year UCDA* OCA + UDCA Undiscounted Life Years 19.28 22.20 Discounted QALYs 10.42 11.73 Discounted Total Cost $97,208 $205,280 ICER ($/QALY) $82,596 *Results correspond to inadequate response to UDCA, as observed in POISE study
Fenofibrate for PBC Levy C, Peter JA, Nelson DR, et al. Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Alimentary Pharmacology Therapeutics. 2011;33(2):235:42
Angulo, et al. Hepatol 2000;32:897-900. Silymarin in PBC 27 patients with suboptimal response to UDCA (13-15 mg/kg/day) No change in Alk Phos, AST, Bilirubin, Albumin, or Mayo Risk Score Alk Phos AST Bili Albumin MRS Baseline 897 + 84 58 + 5 0.9 + 0.1 4.0 +.06 3.82 + 0.2 End of Tx 876 + 95 56 + 6 1.0 + 0.1 4.1 +.06 3.88 + 0.2
Serum ALP Levels among 20 Ustekinumab Treated Patients Hirschfield GM, Gershwin ME, Strauss R, et al. Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid: A proof-of-concept study. Hepatology. 2016;64(1):189-99.
Conclusion Regarding Drug Therapy When UDCA is not adequate: Doubling dose is not helpful No clear, proven choices Many promising adjuncts being investigated
Hepatocellular Cancer Risk in PBC 17 Patients over 25 years Multivariate Analysis O.R (95% CI) Age 1.7 1.1-2.5 Male 9.7 1.4-68.3 Hx Transfusion 5.0 1.0-24.3 Portal Hypertension 22.9 3.4-155.3 Suzuki A, Lymp J, Donlinger J, et al. Clinical Predicotrs for Hepatocellular Carcinoma in Patients with Primary Biliary Cirrhosis. Clin Gastro Hep. 2007;5(2):259-264
Kaplan-Meier Estimates of HCC Incidence According to Gender Trivedi PJ, Lammers WJ, Van buuren HR, et al. Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study. Gut. 2016;65(2):321-9.
Kaplan-Meier Estimates of HCC Incidence According to Baseline PBC Disease Severity Trivedi PJ, Lammers WJ, Van buuren HR, et al. Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study. Gut. 2016;65(2):321-9.
Survival probability Hepatocellular Carcinoma in PBC P=0.002 (log-rank) Time (months) Silveira MG, Suzuki A, Lindor KD. Surveillance for Hepatocellular Carcinoma in Patients with Primary Biliary Cirrhosis. Hepatology 2008;48(4):1149-57
Conclusions About PBC Becoming more common Slowly progressive, even if asymptomatic Prognostic markers helpful UDCA improves natural history Cancer risk is present Obeticholic acid recently approved