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Future directions in PSC research

PSC Partners Seeking a Cure. Future directions in PSC research. New Haven June 25, 2016 U. Beuers Department of Gastroenterology & Hepatology Tytgat Institute of Liver and Intestinal Research Academic Medical Center University of Amsterdam The Netherlands. Primary sclerosing cholangitis.

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Future directions in PSC research

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  1. PSC Partners Seeking a Cure Future directions in PSC research New Haven June 25, 2016 U. Beuers Department of Gastroenterology & Hepatology Tytgat Institute of Liver and Intestinal Research Academic Medical Center University of Amsterdam The Netherlands

  2. Primary sclerosing cholangitis Hirschfield et al. Lancet 2013;382:1587

  3. Future Directions in PSC Research • Epidemiology • Diagnosis & Screening • Pathophysiology • Treatment

  4. Primary sclerosing cholangitis The typical patient in the Netherlands Point prevalence (per 100.000)6.0 Age at manifestation (yrs, mean)38.9 Male gender 64% Inflammatory bowel disease68% UDCA treatment 92% LTx-free survival (yrs, mean) 21.2 (LTx-free survival of 450 patients at 3 LTx centres 13.2) Cholangiocarcinoma 7% Colorectal carcinoma 3% m, 42 years Boonstra, Ponsioen et al., Hepatology 2013;58:2045 population-based cohort [n=590, follow-up 92 months] covering the Northern half of the Netherlands)

  5. Future Directions in PSC Research • Epidemiology • Diagnosis & Screening • Pathophysiology • Treatment

  6. Diagnosis of PSC A diagnosis of PSC is made in patients with biochemical markers of cholestasis not otherwise explained, when MRCP shows typical findings and causes of secondary sclerosing cholangitis are excluded. EASL Clinical Practice Guidelines, J Hepatol 2009;51:237

  7. A male patient with cholestasis and sclerosing cholangitis 71 yrs, m

  8. The Patient with Sclerosing Cholangitis Diagnostic Algorithm Sclerosing Cholangitis History, additional diagnostic procedures: Causes of secondary sclerosing cholangitis ? • Bile duct surgery • Abdominal trauma • Choledocholithiasis * • Cholangiocarcinoma * • Recurrent pancreatitis • Ischemic cholangitis • Eosinophilic cholangitis • Mastcel cholangiopathy • AIDS cholangiopathy • Recurrent pyogenic cholangitis • Portal hypertensive biliopathy • IgG4-assoc. cholangitis (IAC) • ABCB4 deficiency • others no yes Primary sclerosing cholangitis Secondary sclerosing cholangitis * may be consequence of PSC EASL Clinical Practice Guidelines, J Hepatol 2009;51:237

  9. The Patient with Sclerosing Cholangitis Diagnostic Algorithm Sclerosing Cholangitis History, additional diagnostic procedures: Causes of secondary sclerosing cholangitis ? • Bileductsurgery • Abdominal trauma • Choledocholithiasis * • Cholangiocarcinoma * • Recurrent pancreatitis • Ischemic cholangitis • Eosinophilic cholangitis • Mastcelcholangiopathy • AIDS cholangiopathy • Recurrentpyogenic cholangitis • Portal hypertensivebiliopathy • IgG4-assoc. cholangitis (IAC) • ABCB4deficiency • others no yes Primary sclerosing cholangitis Secondarysclerosing cholangitis * may be consequence of PSC EASL Clinical Practice Guidelines, J Hepatol 2009;51:237

  10. IgG4-Associated Cholangitis (IAC) The typical patient • Male (80%) • Middle aged / elderly (> 60 yrs) • Jaundice, weight loss, abdominal compl. • Localized organ swelling / tumor • Elevated serum / tissue IgG4 • Other organ manifestations of IgG4-RD 71 yrs, m; IgG4 11.9 g/L (n < 1.4) Stone et al N Engl J Med 2012;366:539 Hubers et al. Clin Rev Allerg Immunol 2015;48:198 Alderlieste et al., Digestion 2009;79:220

  11. Diagnostic value of serum IgG4 is limited Sensitivity = 86% Specificity = 75% 1.4 Doorenspleet, Hubers et al. Hepatology. 2016: epub ahead of print n=125 CA: Biliary and pancreatic malignancies

  12. Distinguishing PSC and IgG4-associated cholangitis The most prominent IgG4+ BCR clone ranks higher in IgG4-RD than PSC Sensitivity = 100% Specificity = 100% Rank of themost prominent IgG4+ BCR clone among all IgGclones 63 n=34 n=17 n=17 Doorenspleet, Hubers et al. Hepatology. 2016: epub ahead of print BCR: B-cell receptor CA: Biliary and pancreatic malignancies

  13. Distinguishing PSC and IgG4-associated cholangitis The most prominent IgG4+ BCR clone ranks higher in IgG4-RD than PSC Sensitivity = 100% Specificity = 100% Rank of themost prominent IgG4+ BCR clone among all IgGclones 63 n=34 n=17 n=17 Doorenspleet, Hubers et al. Hepatology. 2016: epub ahead of printCA: Biliary and pancreatic malignancies

  14. Distinguishing PSC and IgG4-Related Disease An affordable IgG4/IgG RNA qPCR is almost as accurate as NGS technology Sensitivity = 94% Specificity = 99% 5% Doorenspleet, Hubers et al. Hepatology. 2016: epub ahead of print n=125 CA: Biliary and pancreatic malignancies

  15. Distinguishing PSC and IgG4-Related Disease An affordable IgG4/IgG RNA qPCR is almost as accurate as NGS technology Sensitivity = 94% Specificity = 99% 5% Supportedby PSC Partners – THANKS ! Doorenspleet, Hubers et al. Hepatology. 2016: epub ahead of print n=125 CA: Biliary and pancreatic malignancies

  16. The Patient with Sclerosing Cholangitis Diagnostic Algorithm Sclerosing Cholangitis History, additional diagnostic procedures: Causes of secondary sclerosing cholangitis ? • Bileductsurgery • Abdominal trauma • Choledocholithiasis * • Cholangiocarcinoma * • Recurrent pancreatitis • Ischemic cholangitis • Eosinophilic cholangitis • Mastcelcholangiopathy • AIDS cholangiopathy • Recurrentpyogenic cholangitis • Portal hypertensivebiliopathy • IgG4-assoc. cholangitis (IAC) • ABCB4deficiency • others no yes Primary sclerosing cholangitis Secondary sclerosing cholangitis * maybeconsequence of PSC EASL Clinical Practice Guidelines, J Hepatol 2009;51:237

  17. Primary sclerosing cholangitis - Enhanced risk of cholangiocarcinoma - Diagnosis of cholangiocarcinoma in PSC • Jaundice, itch, abdominal pain, weight loss • CA 19-9 > 100 U/ml • CT • MRCP / MRI • ERC: Brush / Biopsy • To further evaluate: • Fluorescence-in situ-hybridisation (FISH) in brushes • Bile and urine marker analysis (lipidomics, proteomics) • Cholangioscopy • Positron emission tomography (PET) / CT

  18. Primary sclerosing cholangitis - Enhanced risk of colon carcinoma and galbladder carcinoma - • Annual (or biennial) colonoscopy in the presence of IBD • Annual ultrasound for galbladder and liver

  19. Follow-up of patients with PSC: Elastography Ficus Study Corpechot et al. Gastroenterology 2014;146:970.

  20. Future Directions in PSC Research • Epidemiology • Diagnosis & Screening • Pathophysiology • Treatment

  21. Pathogenesis of primary sclerosing cholangitis Hepatocyte Genetic predisposition Microbiota (bacterial pathogens) Bile ducts Aberrant homing of intest.T-cells Association with IBD >70%

  22. Cholangiocyte senescence is a characteristic of PSC Tabibian, LaRusso et al., Hepatology 2014; 59: 2263 SASP: Senescence-associated secretory phenotype

  23. The cholangiocyte secretes HCO3- upon various stimuli Bile Minagawa et al., Gastroenterology 2007;133:1592 (modified)

  24. Hypothesis: The biliary HCO3-umbrella Bile Apoptosis Senescence Fibrosing cholangiopathy Beuers et al., Hepatology 2010;52:1489 Hohenester, Wenniger et al. Hepatology 2012;55:173 Chang et al. Hepatology 2016; epub

  25. Pathogenesis of primary sclerosing cholangitis Defects in the “Biliary HCO3- Umbrella“? PSC “risk genes” FUT2 Karlsen et al., Gastroenterology 2010;138:1102 Folseraas et al., J Hepatol 2012; 57: 366 FUT2: Fucosyltransferase 2

  26. Future Directions in PSC Research • Epidemiology • Diagnosis & Screening • Pathophysiology • Treatment

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

  28. Potential mechanisms and sites of action of UDCA in cholestatic liver diseases Bile acids Stimulation of hepatocellular secretion Apoptosis Necrosis Antiapoptotic effects Stimulation of cholangiocellular secretion Reduction of bile toxicity Biliary HCO3- umbrella Hepatology 2010;52:1489 Hepatology 2012;55:173 Beuers. Trauner, Jansen, Poupon. J Hepatol 2015;62:S35

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

  30. Treatment of primary sclerosing cholangitis with UDCA - Transplant-free survival - Survival without liver trans- plantation UDCA (n=97) Placebo (n=101) [%] n.s. Study days Power analysis a priori: n = 346 Olsson et al., Gastroenterology 2005;129:1464

  31. Treatment of primary sclerosing cholangitis with UDCA Summary • The available data base shows that UDCA at therapeutic doses (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). • In adult patients with PSC, we recommend against the use of UDCA as medical therapy (IA). • UDCA in doses > 28 mg/kg/d should not be used for the management of patients with PSC (IA). • I : Randomized, placebo-controlled trials, meta-analyses • III : Opinion of respected authorities • A : Strong recommendation – strong evidence • B1 : Moderate evidence – strong recommendation (GRADE) • C2 : Weak evidence - weak recommendation (GRADE) EASL Clinical Practice Guidelines, J Hepatol 2009;51:237 AASLD Practice Guidelines PSC. Hepatology 2010;51:660 ACG Clinical Guideline PSC. AJG 2015;110:646

  32. PSC : Therapy Pathogenetic model norUDCA ? Nuclear receptor agonists ? - PPARa Immunologic bile duct injury (Cytokine- mediated) RCT (Phase 2) Bile duct stenoses Aggravation of injury by BA Endoscopic dilatation RCT (Phase 3) Cholestasis with retention of hydrophobic bile acids in liver Ursodeoxycholic acid (15-20 mg/kg/d) Fibrosis, cirrhosis RCT (Phase 2) Liver failure Liver transplantation

  33. norUDCA: potent stimulus of biliary HCO3- secretion norUDCA Bile Apoptosis Senescence Fibrosing cholangiopathy Hofmann et al., Hepatology 2005;42:1391 Fickert et al., Gastroenterology 2006;130:465 Denk et al., Hepatology 2010;52:1758

  34. PPARa agonists stimulate biliary phospholipid secretion in rodents Mixed micel formation Phospholipids PPARa agonist Bile Apoptosis Senescence Fibrosing cholangiopathy Ghonem et al. Hepatology 2014;59:1030

  35. PSC : Therapy Pathogenetic model Vedolizumab norUDCA ? Nuclear receptor agonists ? - PPARa FGF19 homologues ? Immunologic bile duct injury (Cytokine- mediated) RCT (Phase 2) Bile duct stenoses Aggravation of injury by BA Endoscopic dilatation RCT (Phase 3) Cholestasis with retention of hydrophobic bile acids in liver Ursodeoxycholic acid (15-20 mg/kg/d) Fibrosis, cirrhosis RCT (Phase 2) Liver failure Liver transplantation

  36. Itch in PSC: potential pruritogens… accumulate in the systemic circulation are (biotrans-)formed in the liver and/or gut affect the endogenous serotonergic and opioidergic system Hepatocyte Cholangiocytee are secreted into bile Intestine Beuers, Kremer, Bolier, Oude-Elferink, Hepatology 2014;60:399

  37. Itch in PSC: potential pruritogens… accumulate in the systemic circulation are (biotrans-)formed in the liver and/or gut affect the endogenous serotonergic and opioidergic system Hepatocyte Cholangiocytee Autotaxin LPA X are secreted into bile Intestine Beuers, Kremer, Bolier, Oude-Elferink, Hepatology 2014;60:399 LPA: Lysophosphatidic acid

  38. Itch in PSC: targets for interventional therapies Pruritogens… accumulate in the systemic circulation are (biotrans-)formed in the liver and/or gut Albumin dialysis etc. Rifampicin affect the endogenous serotonergic and opioidergic system Autotaxin LPA Naltrexone Sertraline X are secreted into bile Rifampicin Cholestyramine Beuers, Kremer, Bolier, Oude-Elferink, Hepatology 2014;60:399

  39. Itch in PSC: targets for interventional therapies Pruritogens… accumulate in the systemic circulation are (biotrans-)formed in the liver and/or gut Albumin dialysis etc. Rifampicin affect the endogenous serotonergic and opioidergic system FITCH trial 2015 Autotaxin LPA Naltrexone Sertraline X are secreted into bile Rifampicin Cholestyramine Beuers, Kremer, Bolier, Oude-Elferink, Hepatology 2014;60:399

  40. Thank you Germany Christian Rust Tytgat Institute for Liver and Intestinal Research & AMC, Amsterdam Andreas Kremer, Simon Hohenester, Lucas Maillette de Buy Wenniger, Ruth Bollier, Dagmar Toolenaars, Remco van Dijk, Luca Maroni, Jung-Chin Chang, Coen Paulusma, Stan van de Graaf, Peter Jansen, Ronald Oude Elferink United Kingdom Carherine Williamson Rajiv Jalan Roger Chapman Spain Albert Pares Lithuania Jurate Kondrackiene Belgium Tania Roskams Mina Komura USA Ananth Menanthanarian Michael Nathanson NKI, Amsterdam Wouter Moolenaar UMC, Utrecht Karel J. van Erpecum Sektion PSC Erasmus MC, Rotterdam Edith M. Kuiper Henk R. van Buuren

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