Emerging Approaches to PBC and PSC

Transcription

1 Emerging Approaches to PBC and PSC Keith D. Lindor, MD, FACG Dean, College of Health Solutions Arizona State University OUTLINE PBC Epidemiology Diagnosis Treatment PSC Natural History Treatment Cancer Copyright 2015 American College of Gastroenterology 1

2 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. Copyright 2015 American College of Gastroenterology 2

3 Predictors of Prognosis Yang W, Yu JH, Nakajima,et al. Clin Gastroenterol Hepatol 2004;2(12): Nakamura M, Shimizu-Yoshida Y, Takii Y, et al. J Hepatol 2005;42(3): 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): Copyright 2015 American College of Gastroenterology 3

4 Survival Rates, Elastography & PBC Corpechot C, Carrat F, Poujol-Robert A, et al. Hepatology. 2012; 56 (1): Copyright 2015 American College of Gastroenterology 4

5 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 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): Copyright 2015 American College of Gastroenterology 5

6 Medical Approaches to PBC UDCA Survival Free of Transplantation Combined Data Probability of survival % UDCA Placebo & UDCA 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: Survival in PBC Treated vs. Untreated Treated vs. Population 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): Copyright 2015 American College of Gastroenterology 6

7 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): Combination Therapy for PBC Ursodiol Alone Biochemical normalization in ~1/3 Risk scores or alkaline phosphatase response predictive* Various drugs tried in combination 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): Copyright 2015 American College of Gastroenterology 7

8 Biochemical Endpoints for Predicting Outcomes Percentage of patients reaching endpoints ALP <1.5 <1.67 <2 >2 >3 Newer Therapies for PBC Bezafibrate/Fenofibrate Silymarin B cell antibodies FXR agonists Copyright 2015 American College of Gastroenterology 8

9 OCA Treatment in Patients with PBC Decreases in ALP Values during DB Phase Change in ALP Values in Completer Population Decreases in ALP Values during Open-Label Extension Change in ALP Values during Open-Label Extension Hirschfield GM, Mason A, Luketic V et al. Efficacy of Obeticholic Acid in Patients with primary biliary cirrhosis and inadequate response to ursodexycholic. Gastroenterology. 2015;148:4. Pruritus Severity in PBC Patients with OCA Pruritus Severity in the Double-Blind Phase Pruritus Severity in the Open- Label OCA Therapy Extension Hirschfield GM, Mason A, Luketic V et al. Efficacy of Obeticholic Acid in Patients with primary biliary cirrhosis and inadequate response to ursodexycholic. Gastroenterology. 2015;148:4. Copyright 2015 American College of Gastroenterology 9

10 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 18 Patients over 25 years Multivariate Analysis O.R P_ Age 1.6 <.02 Male 5.6 <.05 Hx Transfusion 4.7 <.07 Mayo Risk 1.3 <.02 Copyright 2015 American College of Gastroenterology 10

11 Hepatocellular Carcinoma in PBC Survival probability 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): Conclusions About PBC Becoming more common Slowly progressive, even if asymptomatic Prognostic markers helpful UDCA improves natural history Cancer risk is present Copyright 2015 American College of Gastroenterology 11

12 Histologic Features of PSC Eaton JE, Talwalkar JA, Lazaridis KN, et al. Pathogenesis of Primary Sclerosing Cholangitis and Advances in Diagnosis and Management. Gastroenterology. 2013; 145: Copyright 2015 American College of Gastroenterology 12

13 Liver Transplantation for PBC & PSC Lee J, Belanger A, Doucette JT, et al. Transplantation Trends in Primary Biliary Cirrhosis. Clin Gastroenterol Hepatol 2007;5(11): PSC Survival in Olmsted County Minnesota Bambha K, Kim WR, Talwalkar, et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastro 2003;125(5): Copyright 2015 American College of Gastroenterology 13

14 Ursodiol in PSC High-dose Urso for PSC Results Primary Endpoints UDCA Placebo Death 5 3 Liver Transplant 11 5 Minimal Listing Criteria for Liver Transplant Development of Cirrhosis 6 4 Esophageal and/or Gastric Varices 15 5 Cholangiocarcinoma 2 2 Total Endpoints Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009;50(3): Copyright 2015 American College of Gastroenterology 14

15 Results Model Of All Primary Endpoints Adjusted For Mayo Risk Score, Presence of Varices, and Stage Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for treatment of primary sclerosing cholangitis. Hepatology 2009;50(3): Kaplan-Meier Analysis of Endpoint Free Survival in all PSC Patients with UDCA Treatment Lindstrom L, Hultcrantz R, Boberg KM,, et al. Assoc. btwen reduced levels of ALK and Survival Times of Patients with PSC. Clin Gastro Hep. 2013;11(7): Copyright 2015 American College of Gastroenterology 15

16 Immunosuppressive and Other Agents Azathioprine Budesonide Docosahexaenoic acid Methotrexate Metronidazole Minocycline Mycophenolate mofetil Nicotine Pentoxifylline Pirfenodone Prednisolone Tacrolimus Vancomycin Vancomycin & Metronidazole in PSC VANCOMYCIN High dose Low dose METRONIDAZOLE Low dose High dose Tabibian JH, Weeding E, Jorgensen RA, et al. Randomized clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis a pilot study. Aliment Pharmacol Ther. 2013; 37(6): Copyright 2015 American College of Gastroenterology 16

17 Autoimmune Pancreatitis/Cholangitis in PSC IgG4 elevated in 9% PSC patients These patients have more aggressive disease These patients may be more steroid responsive. Natural History PSC & IgG4 Proportion without OLT Time (yrs) Mendes F, Jorgensen R, Keach J, et al. Elevated Serum IgG4 Concentration in Patients with Primary Sclerosing Cholangitis. Am J Gastroenterol 2006;101: Copyright 2015 American College of Gastroenterology 17

18 Association of IgG4 and Colectomy Navaneethan U, Venkatesh PGK, Choudhary M, et al. Elevated immunoglobulin G4 level is associated with reduced colectromy-free survival in patients with primary sclerosing cholangitis and ulcerative colitis. Journal of Crohn s and Colitis. 2013; 7: e35 e41. Incidence of Cholangiocarcinoma Cumulative incidence of Cholangiocarcinoma (%) Years since PSC diagnosis Copyright 2015 American College of Gastroenterology 18

19 Elevated CA 19-9 Values in PSC *T bars represent interquartile range of the values Sinakos E, Saenger AK, Keach J, et al. Many Patients with Primary Sclerosing Cholangitis and Increased Serum Levels of Carbohydrate Antigen 19-9 Do Not Have Cholangiocarinoma. Clin Gastroenterol Hepatol 2011;9(5): Colon Cancer/IBD/PSC 50% PSC/CUC CUC Risk % 31% 9% 2% 5% 10% 10 Years 20 Years 25 Years Broome U, Lofberg R, Veress B, et al. Primary sclerosing cholangitis and ulcerative colitis: Evidence for increased neoplastic potential. Hepatology. 1995;22(5): Copyright 2015 American College of Gastroenterology 19

20 High-Dose Urso in UC & PSC Patients Eaton J, Silveira MG, Pardi DS, et al. High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Am J Gastroenterol 2011;106(9): UDCA and Risk of Colorectal Neoplasia in Patients with PSC - IBD Singh S, Khanna S, Pardi DS,, et al. Effect of UDCA on the Risk of Colorectal Neoplasia in Patients with PSC and IBD: A Systematic Review and Meta-analysis. Inflamm Bowel Dis. 2013;19(8): Copyright 2015 American College of Gastroenterology 20

21 UDCA and Risk of Advanced Colorectal Neoplasia in Patients with PSC - IBD Singh S, Khanna S, Pardi DS,, et al. Effect of UDCA on the Risk of Colorectal Neoplasia in Patients with PSC and IBD: A Systematic Review and Meta-analysis. Inflamm Bowel Dis. 2013;19(8): Take Home Points PBC Ursodiol is treatment Obeticholic acid promising Liver cancer risk present PSC No established therapy Ursodiol role being defined High does UDCA (28 30 mg/kg/day) to be avoided Risk of bile duct and colon cancer Copyright 2015 American College of Gastroenterology 21