Novel Therapies in Autoimmune Hepatitis

Transcription

1 Novel Therapies in Autoimmune Hepatitis Paul W. Rassam,MD Ass. Clinical Professor of Medicine Div. of Gastroenterology and Hepatology St George Hospital University Medical Center University of Balamand

2 Approaches to Treatment of AIH Need for Alternative Drugs

3 Background 40% of patients with untreated severe disease die within 6 mos of dx and if they survive the first 2 years of illness typically survive long term 10 yrs survival rate < 30% in mild untreated cases without treatment An acute onset of illness is seen in 40% patients Prednisone and azathioprine are mainstay of treatment

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5 AIH simplified score Autoantibodies ANA or SMA ANA or SMA Antibodies to liver kidney microsome type 1 Antibodies to soluble liver antigen Absent autoantibodies +1:40 +1:80 +1:40 Positive None Immunoglobulin level Immunoglobulin G Histological Findings Morphological features of AIH Viral Disease Absence of viral hepatitis Score pre- treatment +=7 Dg certain +UNL +1.1 ULN Normal Compatible Typical Incompatible No viral markers Viral markers present Score pre- treatment 6 Dg probable Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EL, et al. Simplified diagnostic criteria for autoimmune hepatitis. HEPATOLOGY 2008;48:

6 HAI Comparaison of scores Simplified score not valid in overlap syndromes Both scores are equally sensitive but simplified score more specific

7 Indications for Treatment Absolute Serum AST>10x uln Serum AST>5x uln and globulin >2x nl Bridging necrosis or multiacinar necrosis Relative Symptoms (fatigue, arthralgia, jaundice) Serum AST and globulin less than absolute criteria Interface hepatitis No symptoms None Inactive cirrhosis Porta hepatitis

8 Pitfalls in therapy of AIH Inadequate initial therapy (histological remission lags behind biochemical remission) Failure to consider steroid sparing/free regimens Initiation of therapy without approriate indications (mild hepatitis, inactive cirrhosis) Persistent life long therapy in first complete remission with benign follow up liver biopsies Failure to recognize overalp syndromes

9 Prognostic Indices before Treatment Laboratory findings at presentation AST>10x nl: 50%, 3-year mortality AST>5x nl + GG>2x nl; 90%, 10-yr mortality AST<10x nl + GG<2x nl; 49%, cirrhosis at 15 yr; 10% 10-yr mortality Initial histolopathologic findings at presentation Interface hepatitis: 17% progression to cirrhosis in 5 yrs Bridging necrosis: 82% cirrhosis at 5 yrs; 45% 5-yr mortality Cirrhosis: 58%, 5 yr-mortality

10 Prognostic Indices after Treatment HLA B8, DR3 (onset at young age, severe disease at presentation, frequent relapse, need for OLT) HLA DR4 (onset in old age, women, response to steroids, concurrent immunological diseases) Multilobular necrosis with failure to respond, persistent hyperbilirubinemia after 2 weeks Failure to enter remission after 4 years and any occurrence of first sign of decompensation

11 Treatment Regimens Prednisone only Combination (Pred + AZA) Week 1 60 mg 30 mg+50 mg Week 2 40 mg 20 mg+50 mg Week 3 30 mg 15 mg+50 mg Week 4 30 mg 15 mg+50 mg Maintenance until endpoint 20 mg 10mg+50 mg

12 Therapy Autoimmune Hepatitis Remission following Prednisone +/-Azathioprine Absence of symptoms Absent or minimal piecemeal necrosis AST < twice normal value & normal bilirubin + gamma globulin % response to 6 months therapy symptoms biochemistry histology

13 Reasons for Preference Prednisone Severe cytopenia TPMT deficiency Pregnancy Malignancy Short course <6 mos Prior AZA intolerance Acute fulminant onset Prednisone and AZA Postmenopausal state Osteoporosis Brittle diabetes Obesity Acne Emotional lability Hypertension Prolonged therapy Elderly

14 Treatment Outcomes Remission (65-80%) Treatment Failure (9%) Incomplete Response (13%) Drug Toxicity/Intolerance (10%) Relapse off therapy Acute severe fulminant presentation

15 Remission Criteria Disappearance of symptoms for 2 yrs Normal bilirubin + globulin levels Transaminases normal or less than 2x Normal histology or minimal inflammation No interface hepatitis Histology lags 6 months Action Gradual withdrawal of prednisone over 6 wks Discontinuation of azathioprine Regular monitoring of AST/ALT/IgG at 3 wks intervals during and 3 months after drug withdrawal

16 Acute Severe Fulminant Prompt therapy with steroids monotherapy (?IV) AZA 50 mg/d added if therapy beyond 3 months OLT evaluation if: -worsening of condition with liver failure -worsening of biochemical parameters -progressive hyperbilirubinemia -no improvement in 2 weeks of intensive treatment -overall 5 yrs survival rates 50-80% Increased frequency of acute allograft rejection AIH recurrence 30-40% if inadequate immunosuppression

17 Incomplete Response Criteria Some or no improvement in clinical,and histology during therapy Failure to achieve remission after 3 years No worsening of condition Improvement in AST/ALT within twice ULN or normal AST/ALT without complete normalization IgG Action Reduction of pred dose 2.5 mg/month to lowest levels possible (< 10 mg/d) to prevent worsening AST/ALT Indefinite AZA 2 mg/kg if steroid intolerant Other immunosuppression (MMF/Cyclo/Tacrolimus) Check compliance Consider liver bx (exclude other diseases, HAI score)

18 Drug Toxicity/Intolerance Reduce dose or stop offending agent Maintenance on tolerated drug in adjustred dose MMF? as an empiric option for AZ intolerance with a response rate around 70% Consider other immunosuppressives

19 Drug Toxicity

20 Treatment Failure Criteria Worsening clinical, labs and histology despite compliance Inc transaminasis by 67% Development of jaundice, ascites or hepatic encephalopathy Common in cirrhotics, disease onset at young age, long time before diagnosis, HLA B8 and/or HLA DR3 Action Pred 60 mg/d or pred 30 mg/d with AZA 150 mg/d x 1 mo (? 2mg/kg) Reduction of the dose each month of improvement until maintenance levels MMF 1 gm BID Prograf 4 mg BID Cyclosporin 2-3 mg/kg/d OLT as last option

21 Relapse Criteria: -Occurs in 20-80% who enter remission -Depends on histology at end point (presence of portal plasma cells, interface hepatitis, inactive cirrhosis)- -Increase AST>3folds -Increase IgG >2g/dl Action: (after 2 relapses) Retreat with same original regimen than taper Indefinite low dose prednisone (<10 mg/d) if AZA intolerant Indefinite low dose AZA 2 mg/kg/d Enforce compliance Does not need to be life-long? Role for combination

22 Maintenance Therapy Lowest effective dose for Prednisone 10mg/d or AZA mg/kg/d or Prednisosone 10 mg/d plus AZA 50 mg/d

23 Withdrawal of Therapy Withdrawal of therapy more successful if total duration of therapy at least 4 years Do not attempt in AIH type 2 (LKM+) Biopsy useful to assess histologic activity - wean prednisone by 2.5 mg q 3 months - wean AZA by 25 mg q 3 months - check ALT/AST/IgG monthly - if reactivation occurs, prednisone 0.5 mg/kg will suffice

24 Methotrexate Methotrexate Immunosuppressive effects due to inhibition of enzyme involved in the metabolism of folic acid MTX can be used as a second-line therapy in pediatric patients with AIH type I in whom traditional therapy with steroids and AZA/6-MP has failed or if the patient was to become intolerant to this regimen Relatively rapid onset of action (4-6 weeks) Side effects Stomatitis Oral ulcers GI upset Teratogenic in women of child bearing age

25 MMF Mycophenolate mofetil (MMF) is an alternative option for patients intolerant or incomplete responders to prior AZA therapy However a majority of patients fail MMF Patients with prior nonresponse to AZA have an even lower response rate to MMF as second line therapy with exceedingly SE (31%)

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27 Cyclosporine Cyclosporine 3rd immunosuppressant identified Cyclic nonribosomal peptide Site of action- calcineurin (inhibits phosphatase activity) Side effects Interacts with a wide variety of other drugs and substances hyperplasia, convulsions, peptic ulcers, fever, vomiting, diarrhea, confusion, breathing difficulties, numbness and tingling, high blood pressure, kidney and liver dysfunction

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29 Budesonide Corticosteroid with the highest affinity to glucocorticoid receptor and with a high 90% first pass in the liver (thus less steroid related SE ) Several controversial studies in the last decade as for it s role in inducing remission however it appears to be recommended in steroid dependant or steroid and AZA intolerant AIH patients Budesonide in combination with AZA induces and maintain remission in non cirrhotics patients with AIH

30 compared the effects of budesonide and prednisone, both in combination with azathioprine. 6-month, prospective, double-blind multicenter RCT in patients with AIH without evidence of cirrhosis budesonide (3 mg, TID or BID) or Prednisone (40 mg/d, tapered to 10 mg/d) PLUS azathioprine (1 2 mg/kg/d) Primary end point: complete biochemical remission, (normalast and ALT,, at 6 months.

31 Results The primary end point was achieved in 47/100 patients given budesonide (47.0%) and in 19/103 patients given prednisone (18.4%). At 6 months, complete biochemical remission occurred in 60% of the patients given budesonide versus 38.8% of those given prednisone 72.0% of those in the budesonide group did not develop steroid-specific side effects versus 46.6% in the prednisone Among 87 patients who were initially given prednisone and then received budesonide after 6 months, steroid-specific side effects decreased from 44.8% to 26.4% at month 12

32 Immunosupressants in AIH

33 Algorithm for Treatment of AIH

34 Overlap Syndromes

35 AIH and Pregnancy If AIH in remission pregnancy tolerated unless evidence for PHTN Increased frequency of stillbirth and prematurity Many reports of AIH de novo or flares during pregnancy or post partum Consider increasing steroid dose shortly before the expected date of delivery Standard immunosuppression appears to be safe

36 Take Home Messages 1. The major factor of successful management of autoimmune hepatitis is the timely establishment of the correct diagnosis 2- Standard treatment is not ideal and characterized mainly by steroid side effects that affect compliance 3- Remisssion endpoints should aim at normalization of ALT/IgG and histology preferable with AZA monotherapy for 3-4 yrs 4- Steroids are drug of choice for remission induction and in noncirrhotic patients budesonide may offer an attractive alternative 5- Consider MMF (preferably), cyclosporin, or tacrolimus for treatment failures or when AZA not tolerated 6- OLT represents the ultimate treatment in true non responders with signs of pending liver failure with good survival rates but also a significant risk of graft loss because of disease recurrence