Autoimmune Liver Disease: an Update on Treatment

1. Autoimmune Liver Disease: an Update on Treatment Gideon Hirschfield, Birmingham, UK

2. A family affair Granulomatous lymphocytic cholangitis Central vein Hepatocytes Portal triad PBC Periductal “onionskin’ fibrosis Small duct SC AIH Large duct SC Biliary strictures and dilatation Lympho-plasmacytic infiltrate Hirschfield; BMJ 2009 Sep 8;339:b3305 Duodenum

3. AIH Definition • Unresolving inflammation of the liver of unknown cause • Interface Hepatitis and portal plasma cell infiltration • Hypergammaglobulinaemia • Autoantibodies

4. Spectrum of AIH • Classical symptomatic chronic hepatitis  cirrhosis • “Burned out” cirrhosis • Asymptomatic chronic hepatitis  cirrhosis • Acute hepatitis • Fulminant liver failure • Autoimmune overlap syndromes • De Novo or recurrent AIH following transplant

5. Hepatitis- non specific

6. Plasma cell rich interface activity

7. Exclude viral, metabolic and drug induced liver disease HEPATITIS CHOLESTASIS ANA pos ANA neg AMA pos AMA neg 0.5-1% of healthy individuals are AMA pos ASMA neg ASMA pos ASMA pos ASMA neg F-actin ELISA if biopsy not classic Up to ~35% of Type 1 AIH Up to ~65% of Type 1 AIH PBC Up to ~20% of healthy individuals are ANA pos Up to ~40% of healthy individuals are ASMA pos >90% have this profile Confirm specific AMA by ELISA (AMA-M2 or MIT3) AMA pos AIH LKM-1 neg LKM-1 pos Up to ~20% of classic AIH is AMA pos, often in isolation ~90% of Type 2 AIH have this profile Consider reference laboratories for anti-SLA/LP Sero-negative autoimmune hepatitis still occurs in <5% ANA pos ANA neg Specific ANAs are seen in PBC (gp210/sp100) and most patients (>85%) with AMA neg PBC are ANA pos Non-specific ANA frequently seen in PSC Serology alone does not make a diagnosis of autoimmune liver disease MRI Cholangiography ?sclerosing cholangitis Liver biopsy (if no PSC)

8. Specific ANA patterns in PBC • Multiple nuclear dots, involves the staining of 3–20 dots distributed throughout the nucleus, but sparing the nucleoli • Sp100 and promyelocytic leukaemia antigen account for this pattern • Rim-like/membranous pattern reactivity against the structures of the nuclear pore complex • gp210 protein, nucleoporin p62 and the lamin B receptor account for this pattern Alimentary Pharmacology & Therapeutics Volume 24, Issue 11-12, Pages 1575-1583

9. Drugs Inducing an AIH-like Syndrome

10. Simplified criteria for diagnosis of AIH Maximum number of points for all autoantibodies is 2, total is 8 points *It is not clear what distinguishes “probable” and “definite”. Hennes et al. Hepatology 2008; 48:169

11. Royal Free Treatment Trials Prednisone = 15mg daily Kirk AP, Jain S, Pocock S et al. Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis. Gut 1980; 21: 78–83.

12. Azathioprine and prevention of relapse Monotherapy with azathioprine at 2mg/kg Remission for >1 year with prednisone (5-15mg/od) and azathioprine (1mg/kg)/kg) Johnson PJ et al. N Engl J Med 1995;333:958-963.

13. Response to treatment is slow – don’t rush, it’s not asthma

14. Complete biochemical remission rate at month 6 compared with the biochemical remission defined as ALT activity <2x ULN at month 6 Manns et al. Gastro 2010

15. Management of AIH

16. Overlaps • Presentations that raise the spectre of overlap span: • An immunoserological overlap: e.g. positive ANA/ASMA-titres and elevated IgG in conjunction with AMA-positive PBC; or AMA positivity in AIH; • A biochemical overlap: AST/ALT>5xULN in patients with PBC or PSC; or ALP >3xULN in patients with AIH (or gGT >5xULN in children); • A radiological overlap: clinical features of AIH with cholangiographic abnormalities indicative of a inflammatory cholangiopathy; • A histological overlap: lymphoplasmacytic infiltrate and interface hepatitis on liver biopsy with bile-duct lesions indicative of either PBC or PSC; • Varying combinations of the above including temporally i.e. consecutive vs. sequential presentations.

17. Spectrum of features in AILD Trivedi and Hirschfield APT 2012 In Press

18. Chronic non-suppurative destructive cholangitis 1 in 1000 women over the age of 40 are estimated to have PBC Orphanet Journal of Rare Diseases 2008 3:1

19. What causes PBC? Non immune Genes Ethnicity Female P zzzz Environment and Xenobiotics B Bacteria and virus Age Epigenetics C Y T I L Immune Genes I B A B P O R Hirschfield and Gershwin; Annual Review of Pathology; 2013 In Press

20. Anti-mitochondrial antibodies >90% of patients have antibodies against their mitochondria Courtesy of Dr E Gershwin

21. Rational therapy for patients is needed Failure to respond to UDCA therapy is associated with poor outcome and a present unmet need for new therapy Responders (N=270) Bilirubin <ULN + AST <2 ULN + ALP <3 ULN at one year P=7.3x10-9 Non-responders (N=132) Red Line = Age Matched Healthy Females 10-year survival: 92% Hirschfield et al. CDDW 20111

22. ~ x100  FXR agonism Obeticholic Acid UDCA ursodeoxycholic acid OCA 6a-ethyl chenodeoxycholic acid CDCA chenodeoxycholic acid FXR EC50 (agonist) 0.099 mM 8.66 mM No activity • Nuclear receptor for bile acid signaling • Natural ligand: Chenodeoxycholic acid • Bile acid synthesis regulation • Feedback via FGF-19 & SHP • ↓ Hepatic Triglyceride, VLDL Synthesis • Hepatic regeneration, intestinal bacterial overgrowth/translocation protection; Modulation of insulin sensitivity & adiposity Pelliciari R. J.Med.Chem 2002

23. Intercept Phase II Trial Data Hirschfield et al. AASLD 2011

24. Fibrates Hepatology, 2008

25. The immunoregulatory skyline is striking HLA IL12RB2 IL12A IRF5 STAT4 CXCR5 SOCS1 Hirschfield et al. EASL 2012

26. Novel approaches to treating primary biliary cirrhosis Th1 Macrophage IL12 B-cell Th2 Autoreactive CD4+ Anti-IL12/23 CD8+ CD28 CD80 Activated NK(T) p40 p40 CXCR3 p35 p35 CXCL10 Anti-CD80 Anti-CXCL10 IL23 Th17 ?Stimulate CXCL10 production Antigen presenting cell Small bile ducts

27. PSC: greatest need in Hepatology Asymptomatic at presentation Symptomatic at presentation Transplantation-free survival (+95% Cl) for 211 patients with PSC Journal of Hepatology (2009) 158–164

28. Primary sclerosingcholangitis-patchy disease characterised by strictures, inflammation and malignancy risks

30. Cumulative colon cancer risk Cumulative risk (95% CI) of colorectal cancer for 211 patients with PSC with (----- ) or without (——) concurrent IBD. Journal of Hepatology (2009) 158–164

31. Cumulative cholangiocarcinoma risk Cumulative risk (+95% CI) of cholangiocarcinoma for 211 patients with PSC Journal of Hepatology (2009) 158–164

32. Rare genetic syndromes Atypical infection Autoimmune pancreatitis Biliaryischaemia MDR2 knockout DSS Colitis/CFTR knockout

33. High dose UDCA vs Placebo HEPATOLOGY, Vol. 50, No. 3, 2009

34. Take home messages • Uncommon but chronic diseases • Focus efforts on careful characterisation of the predominant disease • Focus treatment towards compliance and careful use of immunosuppressants • Recognise the new insights genetics in particular has for understanding disease