1. Primary Sclerosing Cholangitis - Clinical Studies - Oslo 14.6.2010 U. Beuers Academic Medical Center, Univerity of Amsterdam, NL

2. Primary Sclerosing Cholangitis Bile duct stenoses Aggravation of injury by BA Cholestasis with retention of hydrophobic bile acids in liver Liver cell damage, apoptosis, necrosis, fibrosis, cirrhosis Liver failure Immunologic bile duct injury (Cytokine-mediated) Pathogenetic model m, 42 J.

3. Study design, inclusion criteria, endpoints Medical approaches (3 min Christoph Schramm) Endoscopic approaches (3 min Cyriel Ponsioen) Surgical approaches (3 min Martti Faerkkila) Primary Sclerosing Cholangitis

4. Study design, inclusion criteria, endpoints Medical approaches Endoscopic approaches Surgical approaches Primary Sclerosing Cholangitis

5. Treatment of Primary Sclerosing Cholangitis Bile duct stenoses Aggravation of injury by BA Cholestasis with retention of hydrophobic bile acids in liver Liver cell damage, apoptosis, necrosis, fibrosis, cirrhosis Liver failure Immunologic bile duct injury (Cytokine- mediated) Pathogenetic model Placebo-contr.Studies Pilot studies Cyclosporine Methotrexate Infliximab D-Penicillamine Colchicin Budesonide Cladribin Etanercept MMF Nicotine Pentoxifylline Prednisone Tacrolimus Pirfenidone

6. Treatment of Primary Sclerosing Cholangitis Bile duct stenoses Aggravation of injury by BA Cholestasis with retention of hydrophobic bile acids in liver Liver cell damage, apoptosis, necrosis, fibrosis, cirrhosis Liver failure Immunologic bile duct injury (Cytokine- mediated) Placebo-contr.Studies Pilot studies Cyclosporine Methotrexate Infliximab D-Penicillamine Colchicin Budesonide Cladribin Etanercept MMF Nicotine Pentoxifylline Prednisone Tacrolimus Pirfenidone Pathogenetic model

7. Bile duct stenoses Aggravation of injury by BA Cholestasis with retention of hydrophobic bile acids in liver Liver cell damage, apoptosis, necrosis, fibrosis, cirrhosis Liver failure PSC : Therapy Immunologic bile duct injury (Cytokine- mediated) Pathogenetic model Ursodeoxycholic acid (15-20 mg/kg/d) ?

8. Treatment of Primary Sclerosing Cholangitis with UDCA - Serum liver tests - Beuers et al., Hepatology 1992;16:707 Change [%] Bilirubin Placebo UDCA Gamma - GT Alk. Phosphatase Months P<0.05 P<0.01 n=14

9. Treatment of Primary Sclerosing Cholangitis with UDCA - Placebo-controlled studies - München Mayo Oxford ScandinaviaMayo (1992) (1997)(2001) (2005) (2009) Dose [mg/kg/d]13-15 13-15 20 17-2328-30 (n=14) (n=105) (n=24) (n=219) (n=150) Duration [years] 1 2.2 2 5 5 Symptoms - - - - - Serum liver tests + + + - + Histology + + - - Beuers et al., Hepatology 1992;16:707 Lindor et al., New Engl J Med 1997;336:691 Mitchell et al., Gastroenterology 2001;121:900 Olsson et al. Gastroenterology 2005;129:1464 Lindor et al., Hepatology 2009;50:1

10. Olsson et al., Gastroenterology 2005;129:1464 [%] Placebo (n=101) UDCA (n=97) Survival without liver trans- plantation Study days Power analysis a priori: n = 346 p = 0.37 Treatment of Primary Sclerosing Cholangitis with UDCA - Transplant-free survival -

11. Cullen et al., J Hepatol 2008;48:792 Treatment of Primary Sclerosing Cholangitis with UDCA Doubleblind, randomized, placebo-controlled dose finding study: Oxford/Munich - Serum Alkaline Phosphatase - * p<0.05

12. Lindor et al., Hepatology 2009;50:1n=150 Treatment of Primary Sclerosing Cholangitis with UDCA Double blind, randomized, placebo-controlled trial - High dose UDCA (30 mg/kg/d) for 5 years -

13. Treeprasertsuk et al., Hepatology 2010:51:1302 n=150 Treatment of Primary Sclerosing Cholangitis with UDCA Double blind, randomized, placebo-controlled trial - High dose UDCA (30 mg/kg/d) for 5 years - Patient population: 41.3% (62)Advanced liver fibrosis / cirrhosis 58.7% (88)Mild liver fibrosis

14. Treatment of PSC EASL Clinical Practice Guidelines The available data base shows that UDCA (15-20 mg/kg/d) improves serum liver tests and surrogate markers of prognosis (I/B1), but does not reveal a proven benefit on survival (III/C2). The limited data base does not yet allow a specific recommendation for the general use of UDCA in PSC. I : Randomized, placebo-controlled trials, meta-analyses III : Opinion of respected authorities B1 : Moderate evidence – strong recommendation (GRADE) C2 : Weak evidence - weak recommendation (GRADE) EASL Clinical Practice Guidelines, J Hepatol 2009;51:237

15. Treatment of PSC AASLD Clinical Practice Guidelines In adult patients with PSC, we recommend against the use of UDCA as medical therapy (IA). In adult patients with PSC and overlap syndrome,we recommend the use of corticosteroids and other immunosuppressive agents for medical therapy (IC) I A : Strong recommendation – strong evidence I C : Strong recommendation – weak evidence Chapman et al., AASLD PG PSC. Hepatology 2010;51:660

16. Bile duct stenoses Aggravation of injury by BA Cholestasis with retention of hydrophobic bile acids in liver Liver cell damage, apoptosis, necrosis, fibrosis, cirrhosis Liver failure PSC : Future Therapy Immunologic bile duct injury (Cytokine- mediated) Pathogenetic model Antibiotics ? Docahexanoic acid ? Immunosuppresive agents ? Nor-Ursodeoxycholic acid ? ACE Inhibitors ? Nuclear receptor agonists ? - PXR - FXR - VDR - PPAR 

17. Study design, inclusion criteria, endpoints Medical approaches Endoscopic approaches Surgical approaches Primary Sclerosing Cholangitis

18. Bile duct stenoses Aggravation of injury by BA Cholestasis with retention of hydrophobic bile acids in liver Liver cell damage, apoptosis, necrosis, fibrosis, cirrhosis Liver failure PSC : Therapy Immunologic bile duct injury (Cytokine- mediated) Pathogenetic model Endoscopic dilatation

19. Treatment of PSC EASL Clinical Practice Guidelines Dominant bile duct strictures with significant cholestasis should be treated with biliary dilatation (II-2/B1). Biliary stent insertion should be reserved for cases where stricture dilatation and biliary drainage are unsatisfactory (III/C2). Prophylactic antibiotic coverage is recommended in this setting (III/C1). II-2 : Cohort- and case-control studies III : Opinion of respected authorities B1 : Moderate evidence – strong recommendation (GRADE) C1/2 : Weak evidence - strong/weak recommendation (GRADE) EASL Clinical Practice Guidelines, J Hepatol 2009;51:237

20. Treatment of PSC AASLD Practice Guidelines In patients with increases in serum bilirubin and/or worsening pruritus progressive bile duct dilatation on imaging studies, and/or cholangitis, we recommend performing an ERC promptly to exclude a dominant stricture (IB). In patients with dominant strictures from PSC, we recommend initial management with endoscopic dilatation with or without stenting (IB). We recommend antimicrobial therapy with correction of bile duct obstruction in dominant strictures to effectively resolve cholangitis (IA). IA : Strong recommendation – strong evidence (GRADE) IB : Strong recommendation – moderate evidence (GRADE) Chapman et al., AASLD PG PSC. Hepatology 2010;51:660

21. Study design, inclusion criteria, endpoints Medical approaches Endoscopic approaches Surgical approaches Primary Sclerosing Cholangitis

22. Bile duct stenoses Aggravation of injury by BA Cholestasis with retention of hydrophobic bile acids in liver Liver cell damage, apoptosis, necrosis, fibrosis, cirrhosis Liver failure PSC : Therapy Immunologic bile duct injury (Cytokine- mediated) Pathogenetic model Liver transplantation

23. Recurrence of PSC after Liver Transplantation Protection by Colectomy? Alabraba et al., Liver Transpl 2009; 15: 330

24. Bile duct stenoses Aggravation of injury by BA Cholestasis with retention of hydrophobic bile acids in liver Liver cell damage, apoptosis, necrosis, fibrosis, cirrhosis Liver failure PSC : Therapy Immunologic bile duct injury (Cytokine- mediated) Pathogenetic model Liver transplantation Endoscopic dilatation Ursodeoxycholic acid (15-20 mg/kg/d)