Advances in the Management of AIH and Overlap Syndromes
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(2) Acknowledgements N. Kirstein, N. Schweitzer, A. Vogel, R. Taubert, Hardtke-Wolenski, E. Jaeckel, P. Obermayer, U.Christen, G. Dalekos, T. Philipp, M.G. Clemente, T. Sugimura, M. Cornberg, H. Wedemeyer, C. Strassburg ..
(3) Disclosure of Interest. Falk Phama GmbH, Freiburg, Germany Intercept, Novartis, Basel, Switzerland.
(4) 4. Autoimmune Liver Diseases Autoimmune hepatitis (AIH). Primary Biliary Cholangitis (PBC). Primary Sclerosing Cholangitis (PSC).
(5) Disease Associations Of Autoimmune Liver Diseases Autoimmune hepatitis: AIH. Primary biliary cholangitis: PBC. Autoimmune thyroiditis. Keratoconjunctivitis sicca. Ulcerative colitis. Grave’s disease. Xerostomia. Crohn’s disease. Ulcerative colitis. Sjögren’s syndrome. Histiocytosis X. Autoimmune hemolytic anemia. Scleroderma/CREST syndrome. Rheumatoid arthritis. Idiopathic thrombocytopenia. Rheumatoid arthritis. Colorectal cancer. Systemic lupus erythematosus. Autoimmune thyroiditis. Cholangiocarcinoma. Sjögren’s syndrome. Celiac disease. Celiac disease. Polymyositis. Mixed connective tissue. Retroperitoneal fibrosis. Mixed connective tissue disease. Renal tubular acidosis. Celiac disease Myasthenia gravis. Feld J.J, Heathcote EJ. J Gastroenterol Hepatol. 2003;18:1118-1128.. Primary sclerosing cholangitis: PSC. 5.
(6) Genetic and Epigenetic Fine-mapping Of Causal Autoimmune Disease Variants Shared Genetic Features Between Different Autoimmune Diseases. Farh K K-H, et al.Nature, Feb 19 2015;518(7539):337-343.. 6.
(7) Challenges in Overlap Syndromes • Treat dominating disease component first • Exclude autoimmune cholangitis (AIC) in pediatric patients by MRCP/ERCP • UDCA / Budesonide in non-cirrhotic PBC/AIH overlap.
(8) « Response Guided » PBC management. exclusion AIH. exclusion NAFLD. PPAR. GR FXR FXR = Farnesoid X Rezeptor (Gallensäuren Rezeptor). Modified Slide - Courtesy R. Poupon. Rabahi et al., Gastroenterol Clin Biol 2010; 34: 283 Poupon, Dig Dis 2011; 29: 85.
(9) 9. Autoimmune Hepatitis Autoimmune hepatitis (AIH). Primary Biliary Cholangitis (Cirrhosis) (PBC). Primary Sclerosing Cholangitis (PSC).
(10) DIAGNOSIS OF AUTOIMMUNE HEPATITIS. • • • • • • •. Female gender Hypergammaglobulinia (IgG) Immunsuppressive Therapy Genetics: HLA DR 3 , DR 4, AIRE Extrahepatic autoimmune syndromes Histology Autoantibodies: ANA, LKM-1, SMA, SLA/LP.
(11) MM AASLD 2011. Autoreactive cells Autoreactive TT cells. Genetic Background. Molecular Mimicry Infections Retroviruses Drugs, .... Activation of Autoreactive T cells. Organ microenvironment by undefined inflammatory processes. Autoimmune Disease.
(12) Molecular Pathogenesis Of Autoimmune Hepatitis. Manns M.P, et al. Journal of Hepatology 2015;62:S100–S111... 12.
(13) Molecular Pathogenesis Of Autoimmune Hepatitis. Manns M.P, et al. Journal of Hepatology 2015;62:S100–S111... 13.
(14) Intrahepatic accumulation of Tregs in AIH. Hamburg cohort. Hannover cohort. Peiseler et al. 2012. Taubert et al. 2014. PB LTx: protocol biopsy after liver Tx; ACR: acute cellular rejection after liver Tx (steroid sensitive portal hepatitis) Clinic for Gastroenterology, Hepatology and Endocrinology.
(15) Anti-HEV IgG Seroprevalence (MP assay). Hepatitis E – breaker of hepatic tolerance?. 33%. Wantai assay (p=0.05). 21%. • Anti-HEV T cell reactivity in all anti-HEV+ AIH patients • HEV replication only in 1/208 AIH pats. with clearance under reduced immunosuppression. Clinic for Gastroenterology, Hepatology and Endocrinology. Pischke , … Wedemeyer, 2014.
(16) Potential viral triggers for pediatric and adult autoimmune hepatitis. •. Hepatitis E infections seem to be an external AIH risk factor in middle aged and older adults. •. Hepatitis E seems to trigger only hepatocellular but not biliary autoimmune liver diseases. •. Parvovirus B19 infections seem to be an external AIH risk factor in children. •. Hepatitis A may be an AIH risk factors in children and middle aged adults, but our study is underpowered so far. •. Different external and genetic risk factors in pediatric and adult AIH. Taubert, …,Jaeckel, EASL 2017. 16.
(17) MM AASLD 2011. • Variant infectious strains • MHC polymorphism • TCR repertoire of the immune system. Initiation. Trigger of worsening. Percent of beta cells. 100 %. Precipitation. 20 %. Lag period of decades Years.
(18) Why do we need animal models for AIH ?. Better understanding of the pathophysiology. Developing novel therapeutic strategies. Clinic for Gastroenterology, Hepatology and Endocrinology.
(19) Limits of animal models of AIH • Acute but not chronic and not self perpetuating disease. • No spontaneous disease process. • Autoantigen unknown or not relevant for human AIH. Clinic for Gastroenterology, Hepatology and Endocrinology.
(20) AIH models: chronic autoimmune hepatitis in mice Genetic background: . Wild type FVB/N vs CYP2D6 mice (Holdener, Christen) NOD mice (Hardtke-Wolenski, Jaeckel) AIRE knock ouc mice (Hardtke-Wolenski, Jaeckel) C57BL/6 (Lapierre, Alvarez). Antigen stimulus: Ad5-2D6 FTCD CYP2D6-FTCD. Vector: Adenovirus Plasmid Clinic for Gastroenterology, Hepatology and Endocrinology.
(21) Model of AIH:. • CYP2D6 humanized mouse AIH model.
(22) CYP2D6 humanized mouse Animal model for AIH. MM AASLD 2011. months. 1. 2. No Hepatitis. Ad-2D6. No Hepatitis. Immunerepertoire. 3. 4. No Hepatitis. Autoimmune liver disease Expansion of antigen-specific cells. Antigen-specific (precursor) cells 2D6 2D6 Hepatocyte. 2D6. Tolerance Ignorance. Ad-2D6 2D6. 2D6 2D6 Inflammation Cellular attraction (non-specific / innate). 2D6 2D6 2D6 Virus elimination (antigen specific adaptive). 2D6. 2D6. 2D6. Liver damage (antigen specific adaptive). Holdener,.…,Johnson, Manns, von Herrath, Christen et al, J EXP MED, 2008.
(23) LKM-1 sera recognizing WDPAQPPRD: Gueguen et al (1991) Yamamoto et al (1993) Kitazawa et al (2001). 85% 100% 93% 71%. Type 1/3 AIH. Manns et al (1991). Type 2 AIH (LKM-1). SPOTs membrane 12aa peptides with a 3aa offset – linear epitopes. CYP-2D6 mouse. CYP2D6 mouse and LKM-1 sera recognize identical epitopes. PAQPPRD found in IE175 of HSV-1 100. Holdener, et al, J EXP MED, 2008. 200. 300. 400.
(24) Threedimensional Structure of CYP2D6 Major Linear Epitope Novel Epitope. Manns et al, JCI, 1989. HSV 175 !!!!. Minor Epitope Minor Epitope. Sugimura et al. Autoimmunity December 2002.
(25) What animal models can tell us about AIH: Better understanding of the pathophysiology Disease process from environmental trigger to chronic hepatitis Genetic predisposition: MHC, non-MHC, AIRE (ex2 vs ex8), NOD, BALB/c, FVB, …. Environmental factors: Viruses, …... Developing novel therapeutic strategies: e.g. T reg therapies Clinic for Gastroenterology, Hepatology and Endocrinology.
(26) Model of AIH:. • FTCD/LC1 as an autoantigen in chronic AIH.
(27) Tolerance to hepatic antigens is difficult to break. – Danger signal (non replicating adenovirus) plus – heterologeous (human) antigens: -Formiminotransferase-cyclodeaminase (FTCD/LC1) -GFP control – 1x109 to 1x1010 ifu/mouse (NOD/Ltj) Hardtke – Wolenski et al, Hepatology, 2013 Department of Gastroenterology, Hepatology and Endocrinology.
(28) Ad-hFTCD mice develop chronic hepatitis. Elevation of gamma globulins !. Department of Gastroenterology, Hepatology and Endocrinology, MHH.
(29) Treatment of emAIH. Department of. Hardtke – Wolenski et al, Hepatology, 2013.
(30) What are we still missing ?. The ideal animal model resembling human AIH !. Clinic for Gastroenterology, Hepatology and Endocrinology.
(31) 31. Management of Autoimmune Hepatitis. 2010. October 2015. AASLD Practice Guidelines: Manns et al., Hepatology 2010; www.EASL.eu.
(32) Advances and Challenges in AIH • Diagnosis: Role of Autoantibodies • Differential Diagnosis: APECED Syndrome • Treatment: Whom and whom not to treat ? • Role of Budesonide • Management failures to standard of care.
(33) Variability of antinuclear Antibodies. nucleus Cytoplasm. homogenous Immunfluorescence. Nucleus: Immunfluorescence. “nuclear dots” Immunfluorescence.
(34) Autoantibodies in Liver Diseases Autoantibodies. Target. Disease association. ANA. multiple nuclear antigens. AIH, SLE, MTCD etc.. AMA. 2-oxo-acid-dehydrogenase complex. PBC. pANCA. h-Lamp-2, proteinase 3,. AIH, PSC, PBC. SMA. Actin, troponin, tropomysin. AIH 1. LKM 1. CYP 2D6. AIH 2, HCV. LKM 2. CYP 2C9. Tienilic acid-induced hepatitis. LKM 3. UGT1A. AIH 2, hepatitis D. LKM. CYP 2A6. APS-1, hepatitis C. LC1. FTCD. AIH 2. SLA/LP. tRNP(Ser)Sec. AIH 3. LM. CYP 1A2. Dihydralzine-induced hepatitis, APS-1. ASGP-R. Asialoglycoproteinrezeptor. Autoimmune liver disease, HCV.
(35) LIVER KIDNEY MIKROSOMAL Antibodies: LKM. LIVER. Kidney.
(36) Threedimensional Structure of CYP2D6: LKM-1 Major Linear Epitope Novel Epitope. Manns et al, JCI, 1989. HSV 175 !!!!. Minor Epitope Minor Epitope. Sugimura et al. Autoimmunity December 2002.
(37) Autoantibodies in Liver Diseases Autoantibodies. Target. Disease association. ANA. multiple nuclear antigens. AIH, SLE, MTCD etc.. AMA. 2-oxo-acid-dehydrogenase complex. PBC. pANCA. h-Lamp-2, proteinase 3,. AIH, PSC, PBC. SMA. Actin, troponin, tropomysin. AIH 1. LKM 1. CYP 2D6. AIH 2, HCV. LKM 2. CYP 2C9. Tienilic acid-induced hepatitis. LKM 3. UGT1A. AIH 2, hepatitis D. LKM. CYP 2A6. APS-1, hepatitis C. LC1. FTCD. AIH 2. SLA/LP. tRNP(Ser)Sec. AIH 3. LM. CYP 1A2. Dihydralzine-induced hepatitis, APS-1. ASGP-R. Asialoglycoproteinrezeptor. Autoimmune liver disease, HCV.
(38) CYPs and UGTs : Targets for Immune Reactions ?. Chronic Hepatitis C Autoimmune Hepatitis Chronic Hepatitis D. Hepatitis in APS1. in APS1. Dihydralazine Hepatitis CYP2A6 CYP2D6 UGT1. P450s & UGTs. CYP21 Addison Disease Adrenal Failure in APS1. Alcoholic Cirrhosis. CYP1A2. CYP11β CYP17. Gonadal Failure in APS1 Manns and Obermayer, Hepatology, 2002. CYP2E1 rCYP3A1 rCYP2C11. Halothane Hepatitis. CYP2C9 Anticonvulsant Hepatitis. Tienilic Acid Hepatitis.
(39) The SLA Story SLA Manns et al. Lancet 1987 Wächter et al. J Hepatol 1990 Wesierska-Gadek et al. Gastro 1996 Ma et al. Hepatol 2002. LP Berg et al. DGIM 1981 Stechemesser et al. Hepatology1993. Anti SLA/LP antibodies recognize a serine tRNA associated 48-50 kD protein. Molecular Cloning of SLA/LP antigen Wies et al. Lancet 2000 Volkmann et al. J Hepatol 2000 Costa et al. Clin Exp Immunol 2000 Kernebeck 2001 Hepatol 2001. Antibodies against Serine tRNA-associated protein in a subgroup of severe AIH Gelpi et al. PNAS 1992.
(40) Classification Of Autoimmune Hepatitis Based On Autoantibodies. Autoimmune hepatitis Type 1 Autoimmune hepatitis Type 2. Autoimmune hepatitis Type 3. ANA, SMA. LKM-1, LKM-3, LC-1. SLA/LP. AASLD Clinical Practice Guidelines: Hepatology 2010. • 80% of cases • age: 16-30 years • slow onset • 20% of cases • age: around 10 • also fulminant cases • similar to type 1 • more relapse, • more difficult to treat.
(41) 41. Severity Of Autoimmune Hepatitis Overall and LT-free Survival, n=354. Association of liver-related death or transplantation, n=240. 1. 1. No cirrhosis n=122. 0,8. % survival. Cirrhosis at diagnosis N=89. 0,6. 0,4. Cirrhosis ? Time N=5. Cirrhosis subsequently N=24. 0,2. Cumulative survival. 0,8. No cirrhosis. 0,6 Cirrhosis. 0,4. Independent Risk Factor Anti-SLA. 0,2. P=0.000; log rank. x2=24, P<0.001. 0. 0 0. 5. 10. 15 20 Years. 25. 30. Hoeroldt B, et al. Gastroenterology. 2011 Jun;140(7): 1980-9.. 0. 5. 10. 15 20 Years. 25. 30. Kirstein MM, et al. Hepatology. 2015 Nov;62(5): 1524-35..
(42) 42. Autoantibodies In The Diagnosis Of AIH Liver disease of unknown origin. ANA. SMA, LMK-1, AMA. ANA+. SMA+. LKM1+. AIH. Atypical pANA+. AIH. F-actin +. AMA+. Conventional tests negative. PBC. F-actin, SLA/LP, LC1, LKM3, PDH-E2, pANCA. SLA/LP +. PSC. AIH. LC1+ LKM3+. PDH-E2+. Negative. PBC. Cryptogenic chronic hepatitis. Manns MP, et al. Hepatology. 2010 Jun;51(6):2193-213..
(43) Advances and Challenges in AIH • Diagnosis: Role of Autoantibodies • Differential Diagnosis: APECED Syndrome • Treatment: Whom and whom not to treat ? • Role of Budesonide • Management failures to standard of care.
(44) Autoimmune Polyendocrinopathy Syndrome Type 1 (APS-1, APECED) Endocrine Components Testicular Failure Ovarian Failure Hypothyroidism Parietal-Cell Atrophy IDDM Adrenal Failure Hypoparathyroidism. Nonendocrine Components Candidiasis Alopecia Vitiligo Keratopathy Hepatitis Malabsorption Enamel Hypoplasia Tympanic Membrane Calcification Nail dystrophy. 0. 20. 40. 60. % Patients Ahonen et al. New Engl J Med 1999. 80. 100.
(45) Autoimmune Regulator AIRE • Identified by positional cloning in 1997 • Chromosome 21q22.3, 13kb in length, 14 exons • Expression mainly in thymus and to lesser extent in other lymphoid organs • not detectable in target cells • Transcriptional transactivator • More than 50 mutations identified in APS-1 patients. Nagami et al., Nature Genetics 1997 Finnish-German Consortium, Nature Genetics 1997. Kumar et al. Journal of Biological Chemistry 2001 Heino et al., European Journal of Immunology 2000.
(46) Frequency of Mutations in the AIRE Gene in Patients with AIH, PBS and PSC. Patients [%]. 100 80 60 40 20 0. Hepatitis in APS1. AIH. PBC. PSC. Vogel et al., Hepatology 2001 Djilali-Saiah et al., Journal of Hepatology 2004.
(47) Overlap in Targets of Autoimmunity: Idiopathic Autoimmune Diseases versus APECED/APS Idiopathic. APECED/APS-1 related. Adrenal Insufficiency. CYP 21. CYP 21. Hypoparathyroidism. Ca2+-sensing receptor. Ca2+-sensing receptor. Diabetes. GAD 65. GAD 65. Hepatitis. CYP 2D6, UGT1A, LC-1 CYP1A2, CYP1A6, AADC. CYP17. CYP11A. Obermayer et al, Gastroenterology, 2002.
(48) AIRE Mutations May Account for a More Severe Clinical Course in Children with Autoimmune Liver Diseases Patient 1 Autoantibodies. Extrahepatic manifestation. Anti LKM-1 Anti CYP450 SCC Anti CYP450 C17 Hypoparathyroidism Addison‘s disease Gastric atrophy. Patient 2. Patient 3. Patient 4. Patient 5. Anti-LC-1. Anti LKM-1 Anti CYP-450 SCC Anti CYP450 C17. Anti LKM-1. Anti LC-1. None. None. Autoimmune Enteropathy. Autoimmune Enteropathy Autoimmune Nephropathy (before ALF). (after OLT). (after ALF). AIRE analysis. Homozygous Deletion P398fsX448, Exon 10. Homozygous Finnish major mutation R257X, Exon 6. Heterozygous Polymorphism R441C, Exon 12. None. None. Clinical course. ALF- 3 y, Azathioprin + Steroids. ALF- 6 m, OLT, azathioprin, Steroids, Tacrolimus AIH recurrence Exitus letalis at 3.5 y. ALF- 2 y, Azathioprin, Steroids, Cyclosporin A Remission. ALF- 8 m, OLT, Chronic rejection OLT n° 2 hepatic artery thrombosis Exitus letalis 3.5 y. ALF- 1 y Azathioprin, Steroids, Cyclosporin A Remission. Remission. Lankisch, Jaquemin et al., Journal of Pediatrics 2005.
(49) Advances and Challenges in AIH • Diagnosis: Role of Autoantibodies • Differential Diagnosis: APECED Syndrome • Treatment: Whom and whom not to treat ? • Role of Budesonide • Management failures to standard of care.
(50) Autoimmune Liver Diseases. October 2015. AASLD Practice Guidelines: Manns et al., Hepatology 2010; www.EASL.eu. 50.
(51) Treatment of AIH: Endpoints Endpoints. Criteria. Recommendations. Remission. Disappearance of clinical symptoms, Normalization of aminotransferases, Bilirubin und γ-Globulins Normal liver histology or inactive liver cirrhosis. Slow Reduction of steroids within 6 weeks Control of serum AST, ALT, totalbilirubin, and γ-Globulins in 3-week intervals during and 3 months after withdrawal, then every 6 months for 2 years, then every year. Manns et al, AIH AASLD Practice Guidelines, Hepatology, 2010.
(52) Application of the 2010 AASLD criteria of remission to a cohort of Italian patients with autoimmune hepatitis. AIH (n=163). TREATMENT. Remission n=119 (73%). [AASLD 2002]. Remission n=42 (26%). [AASLD 2010]. Remission AIH (>60 months). Criteria of remission. methyilprednisolone 2-4 mg/daily or every other day. N=89. 23 (25,8%) Normal ALT [AASLD 2010]. 1 (4%). 65 (73%) ALT<2xULN [AASLD 2002]. Histological worsening of the disease. Muratori L et al, Hepatology (correspondence), 2010 Muratori P et al, Journal of Hepatology, 2009. 36 (54.5%).
(53) Treatment of AIH (Adults): How ? Monotherapy Prednisone (mg/ Tag). Combination Therapy Prednisone (mg/ Tag). Azathioprin. Week 1. 60. 30. USA (mg/ day) 50. Week 2. 40. 20. 50. 1-2. Week 3. 30. 15. 50. 1–2. Week 4. 30. 15. 50. 1–2. 20 and less. 10. 50. 1-2. MaintenanceTherapy Reasons for Choice of Therapy. Cytopenia Thiopurinmethyltra nsferase-Deficiency Pregnancy Tumors Therapy <6 Mo. EU (mg/ kg/ day) 1-2. Postmenopausal Osteoporosis uncontrolled Diabetes, Hypertension, Obesity Acne Emotional Instability. Manns et al, AIH AASLD Practice Guidelines, Hepatology, 2010.
(54) 54. Therapeutic Strategy In Autoimmune Hepatitis AIH 0.5-1 mg/kg/d predniso(lo)ne Good response. Insufficient response. Add azathioprine gradually up to 1-2 mg/kg/d. Consider non-compliance alternative diagnosis No. Azathioprineintolerance. Second-line therapy (usually MMF). Yes. Increase to 100 mg prednisolone i.v. Taper steroids (ideally trial of steroid withdrawal). Individualize doses (consider checking 6-TG levels) to achieve and maintain normal ALT and IgG. Response. Manage alternative disease. Insufficient response. Refer to specialist center for confirmation of diagnosis, LTX-evaluation and/or alternative immunosuppressives. EASL Clinical Practice Guidelines: Autoimmune hepatitis. Journal of Hepatology 2015;63:971-1004..
(55) Advances and Challenges in AIH • Diagnosis: Role of Autoantibodies • Differential Diagnosis: APECED Syndrome • Treatment: Whom and whom not to treat ? • Role of Budesonide • Management failures to standard of care.
(56) Autoimmune Hepatitis Options for Immunosuppression. Vierling JM: Curr Gastroenterol Reports. 2011.
(57) 57. Alternative Drugs:. Efficacy versus Safety.
(58) Treatment-Related Side Effects. Frequency and Nature of Side Effects (Adults) Prednisone-Related Side Effects. Azathioprine-Related Side Effects. Type. Type. Cosmetic (usually mild) Facial rounding, Weight gain, Dorsal hump striae, Hirsutism, Alopecia Somatic (usually mild) Emotional Instability, Glukose intolerance, Cataract Somatic (severe) Osteopenia, Vertebral compression, Diabetes (brittle), Psychosis, Hypertension (labile) Inflammatory/Neoplastic Pancreatitis, Opportunistic infection, Malignancy. Frequency. 80% (after 2 years). 13% (Treatment ending). Rare. Hematologic (mild) Cytopenia. Hematologic (severe) Leukopenia Thrombocytopenia Somatic (mild) Nausea, Emesis, Rash, Fever, Arthralgias Neoplastic Hämatologic /enteric Bone marrow failure, villous atrophy, Malabsorption Teratogenic. Manns et al, AIH AASLD Practice Guidelines, Hepatology, 2010. Frequency. 46% (especially with cirrhosis). 6% (Treatment ending). 5% 3% (after 10 years) Rare Rare (theoretical).
(59) 59. Bioavailability Of Various Corticosteroids. Budesonide. Dexamethasone. Methylprednisolone. Prednisolone. Hydrocortisone 0. Brattsand R, 1990. 10. 20. 30 40 50 60 Absolute bioavailability [%]. 70. 80. 90.
(60) Complete Response Rates at 6 Months. %. P = 0.00004*. p = 0.00001*. Budesonide Prednisone. 50 40 30. 46.1. 47.0. 20 10. 18.4. 17.1. 0 ITT - FAS. PP. *one-sided asymptotic χ²-test for comparing two rates. anns et al, GASTROENTEROLOGY 2010; 139: 1198 - 1206.
(61) Decrease Of Steroid Specific Side Effects In Patients Switched From Prednisone To Budesonide (n=87) P<0.0001*. 50. Percent. 40. 40.2% N=35. 30 18.4% n=16. 20. 10. 0 Month 6 *McNemar’s test for paired proportions Manns MP, et al. Gastroenterology 2010;139:1198-1206. Month 12. 61.
(62) European AIH-BUC Pediatric Subanalysis Mean weight change at Months 6 and 12 6. *P=0.006. 5,1. #P<0.001*. BUD PRED BUD PRED Month 1-6). Weight change, kg. 4. 2. 1,2 0,5. 0. -2 -2,8 -4 Month 6 #. *Two sample t-test (two-sided). Paired t-test Woynarowski et al. J. Pediatrics 2013. Month 12 46 pts in 5 Pediatric Centers. 62.
(63) Role Of Budesonide • Instead of Predniso(lo)ne to reduce side effects in combination with Azathioprine – Induction of remission in risk patients for steroid specific side effects (SSSE) – Long-term maintenance of remission. • Approved for AIH in 23 European and 13 Non-European countries. 63.
(64) Budesonide Versus Prednisone: Limitations. • Budesonide should not be given to cirrhotic patients due to – Portal hypertension and loss of „topical effects“ – Potential safety issues (Hempfling et al). • Long term benefits, i.e. on bone disease, are pending, long term studies are needed • Limited if any benefit for patients not responding or dependent to predniso(lo)ne. 64.
(65) 65. OC 1. EFFICACY OF BUDESONIDE FOR THE LONG-TERM TREATMENT OF AUTOIMMUNE HEPATITIS IN A SINGLE CENTRE EXPERIENCE 10%. • •. Single Center Study (Hamburg/Germany) 83 Patients – 66 AIH, 17 AIH-Overlap. Initial Tx.. 35% Prednisolone dependency Steroid sp. side effects. 38% 100 25. 60. 40. 20. 80 20 60 Return to prednisolone On budesonide. 40. # of patients. 80. Budesonide adherence. % normalization of transaminases. 100. 15 Worsened Stable. 10. Improved. 20 5. 0. 0 6 months. 24 months. Peiseler et al, EASL AIH MTC, abstract book, p 70. Last follow-up. 0. 24 mths. budesonide.
(66) OC 2. BUDESONIDE IN THE TREATMENT OF EXPERIENCED AUTOIMMUNE HEPATITIS PATIENTS WHO RELAPSED WHILE ON PREDNISONE AND/OR AZATHIOPRINE: FROM TRIALS TO EVERYDAY PRACTICE. •. Retrospective Single Center Study (Bologna/Italy). •. AIH reactivation under Prednisolone +/- Azathioprine with side effects contraindicated an increase of dose (19 out of 327 patients). •. Regimen: •. 14/19 patients: 9mg Budesonide + 50mg Azathioprine until remission, then taper to 6mg. •. 5/19 patients: Budesonide monotherapy due to Azathioprine intolerance/side effects. Treatment response (Transaminases and IgG) No predictive factors of therapeutic success could be identified in these difficult to treat AIH cases. Remission 37%. Incomplete/non Response 63%. Nonresponders: Switched to Prednisolone within 7 month (1-60). Lalanne et al, EASL AIH MTC, London, 2015 , abstract book, p 71 - 72.
(67) Advances and Challenges in AIH • Diagnosis: Role of Autoantibodies • Differential Diagnosis: APECED Syndrome • Treatment: Whom and whom not to treat ? • Role of Budesonide • Management failures to standard of care.
(68) Alternative Therapies for Treatment Failures. Medication Cyclosporine A. Dose 3-5 KG/qd. mg/kg hypertension renal insuffiency. Tacrolimus. 3 mg bid. Mycophenolate Mofetil. 750-1000 bid. Klinik Gastroenterologie, Hepatologie & Endokrinologie. Side effects. hypertension renal insuffiency diabetes mg Diarrhea, leucopenia.
(69) Mycophenolate Mofetil (MMF) as Second Line Therapy – Retrospective Analysis • 61 % (22/36) of patients fail MMF • Patients with prior nonresponse to azathioprine have an even lower response rate to MMF as second line therapy !!!!!!!!!! • MMF should be considered in AZA intolerant patients. Hennes et al, Am J Gastro, 2008.
(70) 6-thioguanine in autoimmune hepatitis. 6-TG was effective and clinically well tolerated as rescue treatment in 25 pts with AIH, previously non-responsive or intolerant to thiopurins (AZA, 6-MP) Van den Brand, de Boer, ….Drenth, Bouma, EASL 2017.
(71) Clinical Challenges in AIH • Management failures to standard of care – Biologicals • Anti TNF • Anti CD 20 (Rituximab).
(72) Treatment Of Refractory AIH With Anti-TNF AST. ALT. IgG 45. 1000. 1000. 100. IgG**,mg/dL. ALT, U/L. AST, U/L. 30. 100. 15. 10. 10 Before treatment. After 3 infusions with IFX. 0 Before treatment. Weiler-Norman C, et al. J Hepatol. 2013 Mar;58(3):529-34.. After 3 infusions with IFX. Before treatment. After 3 infusions with IFX. 72.
(73) 73. Treatment Of Refractory AIH With Anti-TNF Patient. Cause of iFX Tx. Complications of tx. Response to Tx. Duration of Tx. No. of infusions. Prednisolone dose. 1*. Cirrhosis, cyclophosphamide hepatitis, flare under ongoing standard treatment. Multiple infectious complications. Repeated prompt full remission. Treatment ongoing (on/off) since 2001. >40 infusions. 20mg/d. 2. Azathioprine intolerance, MMF intolerance, aggravated depression under steroids. Shingles. Initial remission, flare under ongoing treatment. Treatment stopped after 18 months due to flare under treatment. 14. 5 mg/d. 3. Azathioprine intolerance, MMF intolerance, cyclophosphamide cumulative dose reached. Pneumonia, recurrent urinary tract infections. Full remission. Treatment ongoing for 31 months. 22. 5 mg/d. 4. Steroid-induced diabetes and weight gain, uncontrolled disease with cirrhosis. Pneumonia. Incomplete remission with elevated IgG. Treatment stopped after 8 months after pneumonia. 9. 10 mg/d. 5. Steroid-aggravated depression, weight gain. Recurrent herpes labialis. Repeated full remission. Treatment ongoing (on/off) for 24 months. 10. 10 mg/d. 6. Steroid-refractory flare under treatment. Full remission. Stopped after 8 months due to full remission. 6. Steroids tapered out. 7. Steroid-induced diabetes, weight gain. Full remission. Treatment ongoing for 15 months. 14. 10 mg/d. 8. Azathioprine intolerance. Full remission. Treatment ongoing for 12 months. 7. 10 mg/d. 9. Azathioprine intolerance. Full remission. Treatment ongoing for 15 months. 10. 10 mg/d. 10. Azathioprine induced pancreatitis. Partial response. Treatment stopped after 6 months due to allergic reaction and incomplete response. 6. 15 mg/d. 11. Azathioprine intolerance. Full remission. Treatment ongoing for 13 months. 10. 10 mg/d. Ocular Herpes simplex infection, recurrent urinary tract infections. Weiler-Norman C, et al. J Hepatol 2013;58(3):529-534..
(74) TNF as therapeutic target in Autoimmune Hepatitis. Peripheral blood mononuclear cells (PBMC) and liver-infiltrating lymphocytes (LIL) of AIH patients exhibit an increased TNF expression. Bovensiepen et al, EASL 2017. Nr. 74.
(75) Anti-TNFα. Induction of AIH following TNF alpha antagonists:. Promising Therapies. Harada K et al. Clin Rheumatol 2008 AIH Exacerbation following Etanercept in patients with rheumatoid arthritis Ozorio G et al. Med J Aust 2007 AIH following infliximab therapy of ankylosing spondylitis. Cravo M. BioDrugs 2010: AIH induced by Infliximab in a patient with Crohn‘s disease, no relapse after switch to adalimumab.
(76) Treatment of AIH Rituximab. Rituximab. Chimeric monoclonal antibody against B cell marker CD20. PLoS ONE 6(10): e26358. 76.
(77) Rituximab in AIH • Benefits single cases of B cell disease and co-existent AIH – – – –. ITP Cryoglobulinemic glomerulonephritis Previous B cell lymphoma Evans syndrome (AHA plus ITP).
(78) D'Agostino et al. Pediatrics 2013.
(79) Rituximab in AIH • AIH without co-existent B cell disease, N = 6 • Intolerant or failure to Prednisone + AZA • 1000 mg i.v. at days 1 and 15; 72 week FU • AST 90 +/- 23 U/L vs. 31 +/- 4 U/L; p = 0.03 • IgG 16.4 +/- 2.0 vs. 11.5 +/-1.1 g/l; p=0.056 • No SAEs. Burak et al. Can J Gastroenterol. 2013; 27: 272 – 80.. 79.
(80) Rituximab in AIH IMMUNOHISTOCHEMISTRY. A: anti CD 3 staining B: Fox P3 + staining at baseline C: Fox P3 + staining 48 weeks after starting rituximab. Burak et al, Can J Gastroenterol. 2013; 27: 272 - 80.
(81) Rituximab – Complications and Adverse Events. • Usually mild, infrequent: – Infusion reactions, bacterial infections, neutropenia, anemia, rash, fever, diarrhea, reactivation of viral infections. • But include: – Late onset neutropenia, rheumatic disease, HBV reactivation, activation of a latent polyoma virus (JC virus) with multifocal leucoencephalopathy.
(82) Rituximab For AIH Patients Who Are Refractory Or Intolerant To Standard Therapy. Rituximab was safe, well tolerated and resulted in biochemical improvement in subjects with refractory AIH. These results support further investigation of rituximab or other anti B cell agents as a treatment for AIH.. 82.
(83) Future Therapies in AIH: Immunoregulation ?. Regulatory T cells.
(84) Intrahepatic Tregs under therapy Selective Treg depletion. Higher intrahepatic Treg in remission. BR: biochemical remission; IR: incomplete response; HC: healthy control. Clinic for Gastroenterology, Hepatology and Endocrinology. Taubert et al. 2014.
(85) Unmet Needs In AIH • Unknown etiology • SOC without significant side effects since ~80 % require long term therapy • Therapies for SOC non responders or intolerant pts: – CyA, TAC, MMF, Myfortic, 6-TG ? – Biologicals: anti TNF?, anti CD 20?, other anti B cell TX, anti CD 3? – Other signal transduction pathways as in other immune mediated diseases (rheumatology, IBD, psoriasis, etc…..) – Therapeutic targets derived from GWAS analyses ? – Specific therapies for acute onset or even fulminant AIH. • No more liver transplantation for AIH in the future. 85.
(86) Liver transplantation in Europe European Liver Transplant Registry (ELTR) 01/1988 - 12/2003. 12%. Cirrhosis 59%. 9% 3% 6%. 11%. Patient survival following OLT. PBC PSC AIH 12% 8% 4%. ( ) 1985 60%. other 76%. Patient survival (%). Liver transplantaion. 100 90. 85 81 78. 80. 82 73 69. 74. 70. 69 64. 60. 58. PBC PSC AIH viral alcohol. 50 0. 2. 4. 6. 8. 10 12 Years after OLT.
(87) Clinical Challenges in AIH • Diagnosis: Role of Autoantibodies • Differential Diagnosis: APECED Syndrome • Treatment: Whom and whom not to treat ? • Role of Budesonide • Management failures to standard of care • Acute or Fulminant autoimmune hepatitis.
(88) EARLY PREDICTIVE FACTORS OF CORTICOSTEROID RESPONSE IN PATIENTS WITH SEVERE/ACTUTE OR FULMINANT AUTOIMMUNE HEPATITIS. MC Londono, ….., A Pares, EASL 2017. 88.
(89) EARLY PREDICTIVE FACTORS OF CORTICOSTEROID RESPONSE IN PATIENTS WITH SEVERE/ACTUTE OR FULMINANT AUTOIMMUNE HEPATITIS. MC Londono, ….., A Pares, EASL 2017. 89.
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(91) THANK YOU FOR YOUR ATTENTION.
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