Hepatitis Autoinmune: Terapias Emergentes

Transcription

1 Hepatitis Autoinmune: Terapias Emergentes Jorge Rakela, MD, MACP, FAASLD Getz Family Research Professor Mayo Clinic Arizona Phoenix, AZ Santiago, 29 de septiembre, MFMER slide-1

2 Objetivos: Describir manifestaciones clínicas de la HAI y su manejo actual Identificar estrategias terapéuticas emergentes 2013 MFMER slide-2

3 Autoimmune Hepatitis (AIH) Definition Syndrome of progressive hepatitis characterized by loss of tolerance for hepatic autoantigens that results in: Hepatocellular necroinflammation Autoantibodies: non-organ, non-species-specific Hypergammaglobulinemia and/or IgG Well defined histopathology, although not pathognomic Responsiveness to immunosuppressive medications 2013 MFMER slide-3

4 Autoimmune Hepatitis Demographics and Epidemiology Uncommon Incidence 1.9 per 100,000 per year Prevalence 16.9 per 100,000 Female to male ratio, 4:1 Afflicts both children and adults Bimodal age distribution, y/o vs y/o 6% of liver transplants in US 40% mortality in untreated, symptomatic patients 6 months 2013 MFMER slide-4

5 Autoimmune Hepatitis Classification Based on Autoantibodies Types 1 (95-97%) 2 (3-5%) Auto Abs ANA &/or SMA panca ASGR SLA/LP LKM1/3 LC-1 SLA/LP Initial Testing for AIH: ANA, SMA, LKM1 and SLA/LP consensus: 2 types 2013 MFMER slide-5

6 Simplified Diagnostic Criteria for AIH. Hennes et al 2008 Variable Cutoff Points ANA or SMA 1:40 1 ANA or SMA 1:80 or LKM 1:40 or SLA Positive 2* IgG >ULN 1 Liver histology Absence of viral hepatitis >1.10 ULN 2 Compatible with AIH 1 Typical AIH 2 Yes 2 6: probable AIH 7: definite AIH Needs validation * Addition of points for autoabs, max. 2 points 2013 MFMER slide-6

7 Interface hepatitis Czaja AJ, Carpenter HA: Gastroenterology 105:1824, 1993 Czaja AJ, Carpenter HA: Clin Gastroenterol Hepatol 5:898, MFMER slide-7

8 Plasma Cells May or May Not Be Present Czaja AJ, Carpenter HA: Gastroenterology 105:1824, 1993 Czaja AJ, Carpenter HA: Clin Gastroenterol Hepatol 5:898, 2007 CP MFMER slide-8

9 Coincidental bile duct injury Czaja AJ, Carpenter HA: Hepatology 34:659, MFMER slide-9

10 Autoimmune Hepatitis Clinical Spectrum Chronic hepatitis, insidious clinical course ~50% Acute hepatitis 25-30% Usually younger Icteric acute viral hepatitis-like picture Asymptomatic 15-20% Extrahepatic manifestations may present Acute hepatic failure ~5%, potentially reversible without OLT 2013 MFMER slide-10

11 Prognoses Associated with Disease Severity in Untreated AIH 100 Survival (%) Kings Copenhagen Severe activity AST 10-fold normal AST 5-fold normal and GG 2-fold normal Bridging necrosis or multiacinar necrosis Czaja AJ, Freese DK: Hepatology 36:479, 2002 Royal Free Stanford Mayo Mild activity AST <10-fold normal AST <5-fold normal and GG <2-fold normal Inactive cirrhosis Focal interface hepatitis Follow-up (years) Belgian CP MFMER slide-11

12 Autoimmune Hepatitis Conventional Immunosuppression Week 1 Week 2 Week 3 Week 4 Maintenance until end point Reasons for Preference Monotherapy Prednisone only* (mg/day) Cytopenia -TPMT deficiency -Pregnancy -Malignancy Combination Therapy Prednisone* (mg/day) Azathioprine USA (mg/ day) Postmenopausal state -Osteoporosis -Brittle diabetes -Obesity -Acne -Emotional lability -Hypertension EU (mg/ kg/ day) * Prednisolone can be used in place of prednisone in equivalent doses. AASLD Practice Guidelines AIH, MFMER slide-12

13 Autoimmune Hepatitis Adverse Effects of Chronic Immunosuppression Corticosteroids Fluid-electrolyte Hypertension Cataracts Osteoporosis Acne Poor wound healing Glucose intolerance Psychiatric Azathioprine Bone marrow suppression Gastrointestinal upset Rash Secondary infection Hepatotoxicity Hematologic malignancies: lymphoma, AML, etc.

14 Autoimmune Hepatitis Clinical, Biochemical, and Histologic Resolution on Therapy (Soloway R et al, 1972) % clinical biochemical histologic Months

15 2012 AIH Treatment Goals New Concept of Remission Prevent progression and LT Relieve symptoms Biochemical: normalize ALT: <19 U/L for women, <30 U/L for men; normal γ-globulin and IgG levels Histology: eliminate portal lymphocytic infiltrates, eliminate interface hepatitis; prevent progression to cirrhosis Use combinations of immunosuppressive drugs to inhibit immunopathogenic mechanisms at multiple sites, less adverse events

16 Autoimmune Hepatitis Remission Rate Using 2002 versus 2010 AASLD Guidelines (Muratori L. et al. Hepatology 2011) Remission 73% Remission 26% 2002 AASLD AIH Guideline 2010 AASLD AIH Guideline

17 Autoimmune Hepatitis Progression Rate after Remission, 2010 AASLD Guideline (Muratori L. et al. Hepatology 2011) 4% No progression during remission 96%

18 Consequences of treatment withdrawal in type 1 autoimmune hepatitis (Montano-Loza et al. 2007)

19 Autoimmune Hepatitis Risk Factors for Progression and Need for LT Presentation as ALF Non-response to treatment HLA haplotype DR3>DR4; TNF G308A polymorphism Onset of decompensation in cirrhotics Younger age, type 2 Male

20 Promising New Drugs New steroids: budesonide Calcineurin inhibitors: cyclosporine, tacrolimus Purine antagonist: mycophenolate mofetil 2013 MFMER slide-20

21 Autoimmune Hepatitis Prospective, Double-Blind, Randomized, Controlled Trial Budesonide/AZA versus Prednisone/AZA Manns MP, et al. Gastroenterology 2010; 139:

22 Budesonide Caveats Not salvage for refractory disease Difficult switch with prednisone Concurrent immune disease flare; preferably without extrahepatic manifestations Steroid effect in cirrhosis Best for treatment of naïve, non-cirrhotic patients with uncomplicated disease 2013 MFMER slide-22

23 Azathioprine Intolerance or Lack of Response Allopurinol to Optimize Thiopurine Metabolites in AIH 6-methylmercaptopurine 6-methylthioinosine NTs Immunosuppressant and anti-inflammatory allopurinol 6-thiouric acid Inactive metabolites 6-thioguanine NTs

24 Azathioprine Intolerance or Lack of Response Allopurinol to Optimize Thiopurine Metabolites in AIH De Boer YS et al Aliment Pharmacol Ther 2013; 37:

25 Allopurinol Safely and Effectively Optimizes Thiopurine Metabolites in Patients with AIH Nonresponsive or intolerance to AZA due to skewed thiopurine metabolism with low 6- TGN and high 6-MMP levels Allopurinol 100 mg and low-dose AZA increased 6-TGN and decreased 6- MMP All 8 patients showed ALT improvement Conclusion: allopurinol optimizes thiopurine therapy De Boer YS et al Aliment Pharmacol Ther 2013; 37:

26 Immunosuppression in AIH: Identification of Drugs Active at Multiple Sites Antigen-Specific T Cell Activation & Costimulation Production of T Cell IL-2 Activation of mtor by IL- 2R Effector T Cell Clonal Proliferation Corticosteroids Sirolimus Everolimus Sirolimus Everolimus Azathioprine (6-MP) T Cell Rituximab Rituximab APC T Cell T Cell T Cell B7-CD28 IL-2R IL-2 Autoantigen Cyclosporine Tacrolimus Cyclosporine Tacrolimus Mycophenolate mofetil T Cell T Cell T Cell Mycophenolate mofetil Transendothelial Migration and Tissue Injury Infliximab Adalimumab Rituximab?

27 Cyclosporine 10 reports in 133 patients in 28 yrs. Experiences Positive response Negative response (3 studies) 3/3 (100%) 0/3 (0%) (2 studies) 6/7 (86%) 1/7 (14%) (3 studies) 36/39 (92%) 3/39 (8%) (2 studies) 79/84 (94%) 5/84 (6%) Total 124/133 (93%) 9/133 (7%) Mistilis et al 1985; Sherman et al 1994; Alvarez et al MFMER slide-27

28 Tacrolimus 3 reports in 41 patients in 18 years Study Positive response Negative response Van Thiel (1995) 21/21 (100%) 0/21 (0%) Aqel (2004) 10/11 (91%) 1/11 (9%) Larsen (2007) 9/9 (100%) 0/9 (0%) Total 40/41 (98%) 1/41 (2%) Van Thiel et al 1995; Aqel et al 2004; Larsen et al MFMER slide-28

29 Concerns about Calcineurin Inhibitors Paradoxical autoimmune effects Unable to prevent or treat AIH after transplantation Expensive, long-term, significant AEs Emergence of other drug options with antiinflammatory actions as well Lohse et al 2007; Czaja et al MFMER slide-29

30 Experiences with Mycophenolate Mofetil (11 reports) Study Positive Response Negative Response Czaja (2005) 5/8 (62%) 3/8 (38%) Hlivko (2008) 16/29 (55%) 13/29 (45%) Hennes (2008) 14/36 (39%) 22/36 (61%) Wolf (2009) 5/16 (31%) 11/16 (69%) Total 40/89 (45%) 49/89 (55%) 2013 MFMER slide-30

31 Factors Influencing MMF Response Clinical Experience AZA Intolerance Refractory Disease Hennes (2008) 12/28 (45%) 2/8 (24%) Sharzehi (2010) 8/9 (88%) 0/12 (0%) Baven (2011) 10/15 (67%) 6 /15 (40%) Total Response 30/52 (58%) 8/35 (23%) 2013 MFMER slide-31

32 Mycophenolate Mofetil as Frontline Treatment with Prednisone Type of Response (n=59) * Frequency (%) Normal ALT and γ-globulin (most 3 mo) Improved tests but not normal (partial response) Steroid withdrawal (most 8 mo) DC Treatment due to drug intolerance *Treatment duration, 3-92 mo (mean, 26 mo) dose g daily Starting dose 1g daily; final Zachau et al, J Hepatol MFMER slide-32

33 Mycophenolate Drawbacks 6-7 times more expensive Corticosteroids needed in 60% Treatment indefinite Side effects in 3-34% Category D drug Effective mainly for AZA intolerance 2013 MFMER slide-33

34 AIH Non-Response or Intolerance to Steroids ± AZA mtor Inhibition: Everolimus (Ytting & Larsen, 2015) 7 patients Everolimus trough levels 3-6 ng/ml Aminotransferases improvement within 2 weeks Sustained remission after 1 year of treatment in 3 patients

35 Empiric Therapy with Nonstandard Drugs Treatment-naïve AIH Mild AIH Obesity Osteopenia Diabetes Hypertension Refractory Disease or Drug Intolerance Prednisone± Azathioprine Budenoside+ Azathioprine Refractory Disease Azathioprine Intolerance Calcineurin Inhibitor or Mycophenolate (23% response) Mycophenolate (58% response) 2013 MFMER slide-35

36 Immunosuppression in AIH: Identification of Drugs Active at Multiple Sites Antigen-Specific T Cell Activation & Costimulation Production of T Cell Mitogen IL-2 Activation of mtor by IL-2R Effector T Cell Clonal Proliferation Corticosteroids UDCA Sirolimus Everolimus Sirolimus Everolimus Azathioprine (6-MP) T Cell Rituximab Rituximab APC T Cell T Cell T Cell B7-CD28 IL-2R IL-2 Autoantigen Cyclosporine Tacrolimus Cyclosporine Tacrolimus Mycophenolate mofetil T Cell T Cell T Cell Mycophenolate mofetil Transendothelial Migration and Tissue Injury Infliximab Adalimumab Rituximab?

37 Site-specific Molecular and Cellular Interventions Anti-TNF infliximab Monoclonal antibodies anti-cd20 (rituximab) 2013 MFMER slide-37

38 Infliximab as a rescue treatment in difficultto treat AIH. Weiler-Normann et al Patients:11 patients with AIH, poor response or intolerance; 7 with cirrhosis. 10/11 patients also received prednisone 5-20 mg/day. Number of infusions: 6->40 In 3/11, infliximab was discontinued due to pneumonia, allergic reaction, and lack of response, respectively MFMER slide-38

39 Succesful Rituximab Therapy in Refractory AIH and Evans Syndrome (Carey, Somaratne and Rakela, Rev Med Chile 2011) 44 y/o woman with AIH initially responded to prednisone,and AZA. Subsequently AST/ALT >10xULN, refractory to prednisone, AZA/MMF. Also presented with sudden onset of anemia and thrombocytopenia (Evans syndrome). Rituximab 375 mg/m 2 once a week, total doses:4. Anemia, thrombocytopenia, AST/ALT resolved. A year later, serum aminotransferases remain less than 2xULN.

40 AIH Non-Response or Intolerance to Steroids ± AZA Anti-B Cell Therapy: Rituximab 6 patients 2 infusions of rituximab 1000 mg 2 wks apart ALT normalized by 12 weeks Regulatory T cells improved Safe, well-tolerated Burak et al Can J Gastroenterol MFMER slide-40

41 Clinical Management of AIH in the Real World: Second-Line Drugs (Liberal et al. EASL Barcelona 2016) 2013 MFMER slide-41

42 Repressing Immunity in Autoimmune DiseaseTr1 Cell. Bayry J. N Engl J Med 2016;374: Central tolerance in thymus and bone marrow during ontogeny Regulatory T cells: CD4, CD25, FOXP3+, and type 1 regulatory T cell (Tr1) Tr1 are CD49b, LAG3, FOXP3- Expansion of single antigen-specific Tr1 cells Nanoparticles (NP) coated with autoimmune disease-relevant peptides bound to major histocompatibility complex (MHC) class II molecules (pmhcii-nps)

43 Autoimmune Hepatitis Summary Exclude Wilson disease, DILI, HCV infection without positive anti-hcv Convert to budenoside if non-cirrhotic If intolerant to AZA, consider 6-MP, MMF If remission not achieved with P/A, conversion to MMF is futile Alternative therapy: cyclosporine, tacrolimus, sirolimus, anti-tnf-α agent, anti-cd20 If remission achieved, indefinite maintenance therapy

44 Conclusions. Emergent Therapies AZA metabolites? Allopurinol? New steroidal option in non-cirrhotic patients budenoside + AZA Non-steroidal treatment options expanded calcineurin inhibitors, MMF, sirolimus, everolimus Molecular and cellular interventions rituximab, infliximab 2013 MFMER slide-44