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Management of Recalcitrant Autoimmune Hepatitis

  • Complex Clinical Issues (SA Harrison and NS Reau, Section Editors)
  • Published:
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Abstract

Recalcitrant autoimmune hepatitis occurs in 7 % of patients treated with conventional corticosteroid regimens. High dose prednisone alone or a lower dose combined with azathioprine is the first line treatment. Doses are reduced after each month of improvement until clinical stability is achieved. Laboratory tests improve in 75 %, but histological resolution eventuates in only 20 %. Second line therapy with calcineurin inhibitors can be instituted for non-response or treatment intolerance, and mycophenolate mofetil is another option. Composite experiences indicate that 93-98 % of patients treated with cyclosporine or tacrolimus improve, whereas mycophenolate mofetil is effective in only 10 % with recalcitrant disease. Rituximab, rapamycin, non-mitogenic monoclonal antibodies to CD3, abatacept, and mesenchymal stem cell transplantation are plausible but untested rescue treatments. Problematic patients can be identified early by clinical phenotype, mathematical models, antibodies to soluble liver antigen, and rapidity of response to conventional corticosteroid treatment. Salvage therapies must not delay or supersede liver transplantation.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. •• Montano-Loza AJ, Carpenter HA, Czaja AJ. Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease. Hepatology. 2007;46:1138–45. The frequency of recalcitrant autoimmune hepatitis and the factors that may identify problematic patients early are assessed. The model of end-stage liver disease (MELD score greater than or equal to 12 points at presentation) is shown to have high sensitivity (97 %) and specificity (68 %) for treatment failure.

  2. Czaja AJ. Safety issues in the management of autoimmune hepatitis. Expert Opin Drug Saf. 2008;7:319–33.

    Article  PubMed  CAS  Google Scholar 

  3. •• Czaja AJ: Rapidity of treatment response and outcome in type 1 autoimmune hepatitis. J Hepatol. 2009;51:161–167. Patients who respond to conventional treatment within 6 months are older, have a lower frequency of HLA DRB1*03 (36 % versus 76 %), progress to cirrhosis less commonly (18 % versus 54 %), and require liver transplantation less often (2 % versus 15 %) than patients who respond after 36 months.

    Article  PubMed  CAS  Google Scholar 

  4. Czaja AJ, Menon KV, Carpenter HA. Sustained remission after corticosteroid therapy for type 1 autoimmune hepatitis: a retrospective analysis. Hepatology. 2002;35:890–7.

    Article  PubMed  CAS  Google Scholar 

  5. Czaja AJ. Treatment strategies in autoimmune hepatitis. Clin Liver Dis. 2002;6:799–824.

    Article  PubMed  Google Scholar 

  6. •• Manns MP, Czaja AJ, Gorham JD, et al.: Practice Guidelines of the American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis. Hepatology 2010;51:2193–2213. Codified guidelines for the treatment of autoimmune hepatitis endorse the preference for high dose prednisone (or prednisolone) alone or combined with high dose azathioprine as first line treatment for recalcitrant autoimmune hepatitis (treatment failure).

    Article  PubMed  CAS  Google Scholar 

  7. •• Selvarajah V, Montano-Loza AJ, Czaja AJ: Systematic review: managing suboptimal treatment responses in autoimmune hepatitis with conventional and nonstandard drugs. Aliment Pharmacol Ther. 2012;36:691–707. The suboptimal responses to conventional corticosteroid therapy are incomplete (or partial) improvement, drug toxicity, and treatment failure (worsening despite complance with therapy), and the current and promising management strategies for each of these outcomes are presented.

    Article  PubMed  CAS  Google Scholar 

  8. •• Czaja AJ: Current and future treatments of autoimmune hepatitis. Expert Rev Gastroenterol Hepatol. 2009;3:269–291. The salvage therapies for patients refractory to conventional treatment include high dose corticosteroids with or without high dose azathioprine, 6-mercaptopurine, mycophenolate mofetil, tacrolimus and cyclosporine, and liver transplantation, whereas molecular and cellular interventions are on the distant horizon.

    Article  PubMed  CAS  Google Scholar 

  9. •• Czaja AJ: Emerging opportunities for site-specific molecular and cellular interventions in autoimmune hepatitis. Dig Dis Sci. 2010;55:2712–2726. The range of possible new therapies generated by advances in molecular and cellular technologies include synthetic analog peptides, dimeric recombinant molecules, monoclonal antibodies, oral tolerization technics, T cell vaccination, and small inhibitory RNAs.

    Article  PubMed  Google Scholar 

  10. •• Czaja AJ: Promising pharmacological, molecular and cellular treatments of autoimmune hepatitis. Curr Pharm Des. 2011;17:3120–3140. The promising nonstandard drug therapies are the calcineurin inhibitors (cyclosporine, tacrolimus), mycophenolate mofetil, and rapamycin, whereas cytotoxic T lymphocyte antigen-4 fused with immunoglobulin, monoclonal antibodies to CD3 and CD20, adoptive transfer of regulatory T lymphocytes, mesenchymal stem cell transplantation, gene silencing, and gene replacement therapies are feasible interventions that deserve investigation as salvage therapies.

    Article  PubMed  CAS  Google Scholar 

  11. •• Czaja AJ: Autoimmune hepatitis: focusing on treatments other than steroids. Can J Gastroenterol. 2012;26:615–620. The success of cyclosporine and tacrolimus as salvage agents ranges from 82-92 % in the compilation of published reports, whereas salvage with mycophenolate is 47 % and mainly in patients with azathioprine intolerance. Non-mitogenic monoclonal antibodies to CD3 and recombinant cytotoxic T lymphocyte antigen 4 fused with immunoglobulin constitute feasible molecular interventions for study in autoimmune hepatitis.

    PubMed  Google Scholar 

  12. •• Czaja AJ: Advances in the current treatment of autoimmune hepatitis. Dig Dis Sci. 2012;57:1996–2010. Problematic patients are identified early by mathematical models, clinical phenotype (age≤ 30 years and HLA DRB1*03), rapidity of treatment response (≤24 months), presence of antibodies to soluble liver antigen, and non-white ethnicity, and the calcineurin inhibitors (cyclosporine and tacrolimus) are preferred to mycophenolate mofetil in steroid-refractory disease.

    Article  PubMed  CAS  Google Scholar 

  13. •• Czaja AJ: Nonstandard drugs and feasible new interventions for autoimmune hepatitis. Part- I. Inflamm Allergy Drug Targets. 2012;11:337–350. The promising pharmcological agents for autoimmune hepatitis are the calcineurin inhibitors, mycophenolate mofetil, budesonide, and rapamycin, and the results of treatment with these drugs in animal models of human immune-mediated diseases and patients with autoimmune hepatitis or other autoimmune conditions are presented.

    Article  PubMed  CAS  Google Scholar 

  14. •• Czaja AJ: Nonstandard drugs and feasible new interventions for autoimmune hepatitis. Part-II. Inflamm Allergy Drug Targets. 2012;11:351–363. Feasible new molecular and cellular interventions directed at critical sites in the pathogenic pathways of autoimmune hepatitis include monoclonal antibodies to CD3 and CD20, recombinant molecules of cytotoxic T lymphocyte antigen 4, adoptive transfer of regulatory T cells, and manipulation of natural killer T cells with disease-specific glycolipid antigens.

    Article  PubMed  CAS  Google Scholar 

  15. •• Manns MP: Autoimmune hepatitis: the dilemma of rare diseases. Gastroenterology 2011;140:1874–1876. The difficulty in developing new therapies relate in part to the rarity of the disease, complacency with current therapy, absence of a collaborative network of investigators, and lack of funding. Progress will require strong societal support.

    Article  PubMed  Google Scholar 

  16. Neuberger J. Transplantation for autoimmune hepatitis. Semin Liver Dis. 2002;22:379–86.

    Article  PubMed  Google Scholar 

  17. Nunez-Martinez O, De la Cruz G, Salcedo M, et al. Liver transplantation for autoimmune hepatitis: fulminant versus chronic hepatitis presentation. Transplant Proc. 2003;35:1857–8.

    Article  PubMed  CAS  Google Scholar 

  18. Cross TJ, Antoniades CG, Muiesan P, et al. Liver transplantation in patients over 60 and 65 years: an evaluation of long-term outcomes and survival. Liver Transpl. 2007;13:1382–8.

    Article  PubMed  Google Scholar 

  19. •• Tripathi D, Neuberger J: Autoimmune hepatitis and liver transplantation: indications, results, and management of recurrent disease. Semin Liver Dis. 2009;29:286–296. End stage liver failure reflected in a MELD score >16, intractable symptoms, newly diagnosed hepatocellular cancer, and acute severe (fulminant) hepatic failure are indications for liver transplant, and the procedure has a 10-year survival exceeding 70 %.

    Article  PubMed  Google Scholar 

  20. •• Schramm C, Bubenheim M, Adam R, et al.: Primary liver transplantation for autoimmune hepatitis: a comparative analysis of the European Liver Transplant Registry. Liver Transpl. 2010;16:461–469. The 5-year survival after liver transplantation is 73 %, but it is worse in patients older than 50 years (61 %) and worse than the 5-year survival of primary biliary cirrhosis (83 %), possibly because of increased fatal infections in older patients with autoimmune hepatitis.

    PubMed  Google Scholar 

  21. Lim KN, Casanova RL, Boyer TD, Bruno CJ. Autoimmune hepatitis in African Americans: presenting features and response to therapy. Am J Gastroenterol. 2001;96:3390–4.

    Article  PubMed  CAS  Google Scholar 

  22. Zolfino T, Heneghan MA, Norris S, et al. Characteristics of autoimmune hepatitis in patients who are not of European Caucasoid ethnic origin. Gut. 2002;50:713–7.

    Article  PubMed  CAS  Google Scholar 

  23. Verma S, Torbenson M, Thuluvath PJ. The impact of ethnicity on the natural history of autoimmune hepatitis. Hepatology. 2007;46:1828–35.

    Article  PubMed  Google Scholar 

  24. •• Czaja AJ: Autoimmune hepatitis in special patient populations. Best Pract Res Clin Gastroenterol. 2011;25:689–700. Different ethnic groups commonly have advanced hepatic fibrosis, rapidly progressive disease, or cholestatic features, and these special populations must be recognized and treated with tailored therapy.

    Article  PubMed  Google Scholar 

  25. •• Wong RJ, Gish R, Frederick T, et al.: The impact of race/ethnicity on the clinical epidemiology of autoimmune hepatitis. J Clin Gastroenterol. 2012;46:155–161. African-American patients with autoimmune hepatitis present with advanced disease and respond less well to conventional corticosteroid treatment than white patients ; Hispanic American patients respond well to corticosteroid therapy; and Asian American patients have the highest mortality.

    Article  PubMed  Google Scholar 

  26. Czaja AJ, Souto EO, Bittencourt PL, et al. Clinical distinctions and pathogenic implications of type 1 autoimmune hepatitis in Brazil and the United States. J Hepatol. 2002;37:302–8.

    Article  PubMed  Google Scholar 

  27. Nguyen GC, Thuluvath PJ. Racial disparity in liver disease: Biological, cultural, or socioeconomic factors. Hepatology. 2008;47:1058–66.

    Article  PubMed  Google Scholar 

  28. Czaja AJ, Carpenter HA. Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly. Hepatology. 2006;43:532–8.

    Article  PubMed  Google Scholar 

  29. Czaja AJ, Strettell MD, Thomson LJ, et al. Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis. Hepatology. 1997;25:317–23.

    Article  PubMed  CAS  Google Scholar 

  30. Czaja AJ, Carpenter HA. Autoimmune hepatitis with incidental histologic features of bile duct injury. Hepatology. 2001;34:659–65.

    Article  PubMed  CAS  Google Scholar 

  31. Czaja AJ. Frequency and nature of the variant syndromes of autoimmune liver disease. Hepatology. 1998;28:360–5.

    Article  PubMed  CAS  Google Scholar 

  32. •• Yeoman AD, Westbrook RH, Zen Y, et al.: Early predictors of corticosteroid treatment failure in icteric presentations of autoimmune hepatitis. Hepatology 2011;53:926–934. Treatment failure can be predicted in treatment-naïve, jaundiced patients at presentation by the MELD score, MELD plus sodium score, and the United Kingdom end stage liver disease score (UKELD), and failure to decrease the UKELD score by 2 or more points within 7 days of treatment has a sensitivity of 85 % and specificity of 68 % for treatment failure.

    Article  PubMed  Google Scholar 

  33. Ma Y, Okamoto M, Thomas MG, et al. Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease. Hepatology. 2002;35:658–64.

    Article  PubMed  CAS  Google Scholar 

  34. Czaja AJ, Donaldson PT, Lohse AW. Antibodies to soluble liver antigen/liver pancreas and HLA risk factors for type 1 autoimmune hepatitis. Am J Gastroenterol. 2002;97:413–9.

    Article  PubMed  Google Scholar 

  35. •• Montano-Loza AJ, Shums Z, Norman GL, Czaja AJ: Prognostic implications of antibodies to Ro/SSA and soluble liver antigen in type 1 autoimmune hepatitis. Liver Int. 2012;32:85–92. Ninety-six percent of patients with antibodies to soluble liver antigen have antibodies to Ro52, and antibodies to Ro52 alone or in conjunction with antibodies to soluble liver antigen are independently associated with the development of cirrhosis and death from hepatic failure or need for liver transplantation.

    Article  PubMed  CAS  Google Scholar 

  36. •• Czaja AJ: Autoantibodies as prognostic markers in autoimmune liver disease. Dig Dis Sci. 2010;55:2144–2161. Antibodies to soluble liver antigen, actin, liver cytosol type 1, asialoglycoprotein receptor, chromatin, cyclic citrullinated peptide, and uridine glucuronosyltransferases are associated with the occurrence, severity and progression of autoimmune hepatitis, but antibodies to soluble liver antigen are the best indicators of severity, treatment dependence, relapse, treatment failure and presence of HLA DRB1*03.

    Article  PubMed  CAS  Google Scholar 

  37. Baeres M, Herkel J, Czaja AJ, et al. Establishment of standardised SLA/LP immunoassays: specificity for autoimmune hepatitis, worldwide occurrence, and clinical characteristics. Gut. 2002;51:259–64.

    Article  PubMed  CAS  Google Scholar 

  38. Czaja AJ, Rakela J, Ludwig J. Features reflective of early prognosis in corticosteroid-treated severe autoimmune chronic active hepatitis. Gastroenterology. 1988;95:448–53.

    PubMed  CAS  Google Scholar 

  39. •• Czaja AJ: Drug choices in autoimmune hepatitis: Part A - steroids. Expert Rev. Gastroenterol Hepatol. 2012;6:603–615. Prednisone, prednisolone, and budesonide are compared for efficacy, safety, pharmacokinetics, and expense, and the bases for preferring one steroidal drug over another are provided.

    Article  PubMed  CAS  Google Scholar 

  40. •• Czaja AJ: Acute and acute severe (fulminant) autoimmune hepatitis. Dig Dis Sci. 2012. doi:10.1007/s10620-012-2445-4. Autoimmune hepatitis may have an acute severe (fulminant) presentation, have normal serum immunoglobulin G concentration, absent or low titers of antinuclear antibodies, low scores by the international diagnostic scoring systems, and responsiveness to conventional corticosteroid therapy (preferably prednisolone).

  41. Worns MA, Teufel A, Kanzler S, et al. Incidence of HAV and HBV infections and vaccination rates in patients with autoimmune liver diseases. Am J Gastroenterol. 2008;103:138–46.

    Article  PubMed  Google Scholar 

  42. Czaja AJ, Carpenter HA. Empiric therapy of autoimmune hepatitis with mycophenolate mofetil: comparison with conventional treatment for refractory disease. J Clin Gastroenterol. 2005;39:819–25.

    Article  PubMed  CAS  Google Scholar 

  43. Martinez-Martinez S, Redondo JM. Inhibitors of the calcineurin/NFAT pathway. Curr Med Chem. 2004;11:997–1007.

    Article  PubMed  CAS  Google Scholar 

  44. •• Czaja AJ: Drug choices in autoimmune hepatitis: Part B - nonsteroids. Expert Rev Gastroenterol Hepatol. 2012;6:617–635. Azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, and rapamycin are compared for efficacy, safety, pharmacokinetics, and expense, and the bases for preferring one nonsteroidal drug over another are provided.

    Article  PubMed  CAS  Google Scholar 

  45. Jorgensen KA, Koefoed-Nielsen PB, Karamperis N. Calcineurin phosphatase activity and immunosuppression. A review on the role of calcineurin phosphatase activity and the immunosuppressive effect of cyclosporin A and tacrolimus. Scand J Immunol. 2003;57:93–8.

    Article  PubMed  CAS  Google Scholar 

  46. •• Pissaia A, Jr., Aoudjehane L, Ben Othman S, et al.: Cyclosporine inhibits profibrotic effects of interleukin-4 and transforming growth factor beta on human intrahepatic fibroblasts cultured in vitro. Transplant Proc. 2010;42:4343–4346. Cyclosporine decreases the expression of messenger RNAs encoding for collagens by inhibiting the profibrotic effects of transforming growth factor-beta and interleukin-4, and it may decrease the activation of fibroblasts and collagen accumulation.

    Article  PubMed  CAS  Google Scholar 

  47. Malekzadeh R, Nasseri-Moghaddam S, Kaviani MJ, et al. Cyclosporin A is a promising alternative to corticosteroids in autoimmune hepatitis. Dig Dis Sci. 2001;46:1321–7.

    Article  PubMed  CAS  Google Scholar 

  48. Aqel BA, Machicao V, Rosser B, et al. Efficacy of tacrolimus in the treatment of steroid refractory autoimmune hepatitis. J Clin Gastroenterol. 2004;38:805–9.

    Article  PubMed  CAS  Google Scholar 

  49. Larsen FS, Vainer B, Eefsen M, et al. Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis. World J Gastroenterol. 2007;13:3232–6.

    PubMed  CAS  Google Scholar 

  50. Winkler M, Christians U. A risk-benefit assessment of tacrolimus in transplantation. Drug Saf. 1995;12:348–57.

    Article  PubMed  CAS  Google Scholar 

  51. Lohse AW, Weiler-Norman C, Burdelski M. De novo autoimmune hepatitis after liver transplantation. Hepatol Res. 2007;37 Suppl 3:S462.

    Article  PubMed  Google Scholar 

  52. •• Liberal R, Longhi MS, Grant CR, et al.: Autoimmune hepatitis after liver transplantation. Clin Gastroenterol Hepatol. 2012;10:346–353. Recurrent and de novo autoimmune hepatitis occur after liver transplantation, and they should be treated with conventional corticosteroid regimens and not with anti-rejection protocols.

    Article  PubMed  Google Scholar 

  53. •• Czaja AJ: Diagnosis, pathogenesis, and treatment of autoimmune hepatitis after liver transplantation. Dig Dis Sci. 2012;57:2248–2266. Autoimmune hepatitis recurs in 8-12 % at one year and 36-68 % at 5 years, and de novo autoimmune hepatitis develops in 1-7 % at 0.1-9 years, especially in children. Treatment should be appropriate for autoimmune hepatitis, and re-transplantation is necessary in 8-23 %.

    Article  PubMed  CAS  Google Scholar 

  54. Hess AD, Fischer AC, Horwitz LR, Laulis MK. Cyclosporine-induced autoimmunity: critical role of autoregulation in the prevention of major histocompatibility class II-dependent autoaggression. Transplant Proc. 1993;25:2811–3.

    PubMed  CAS  Google Scholar 

  55. Scott LJ, McKeage K, Keam SJ, Plosker GL. Tacrolimus: a further update of its use in the management of organ transplantation. Drugs. 2003;63:1247–97.

    Article  PubMed  CAS  Google Scholar 

  56. •• Wu Q, Marescaux C, Wolff V, et al.: Tacrolimus-associated posterior reversible encephalopathy syndrome after solid organ transplantation. Eur Neurol. 2010;64:169–177. Posterior reversible encephalopathy after transplantation is characterized by altered mental status, headache, focal neurological deficits, disturbed vision, and seizures in association with changes in the posterior gray and white matter and cortex of the brain by magnaetic resonance imaging.

    Article  PubMed  CAS  Google Scholar 

  57. •• Villarroel MC, Hidalgo M, Jimeno A: Mycophenolate mofetil: An update. Drugs Today (Barc) 2009;45:521–532. Mycophenolic acid is the active metabolite of mycophenolate mofetil, and it blocks inosine-5'-monophosphate dehydrogenase and prevents the formation of purine based nucleotides and the proliferation of lymphocytes.

    CAS  Google Scholar 

  58. •• Shin M, Moon JI, Kim JM, et al.: Pharmacokinetics of mycophenolic acid in living donor liver transplantation. Transplant Proc. 2010;42:846–853. Plasma concentrations of mycophenolic acid determined before dosing (C0) of mycophenolate mofetil (750 mg twice daily with tacrolimus) were the most reliable results for monitoring active drug exposure (area under the curve).

    Article  PubMed  CAS  Google Scholar 

  59. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. 2000;47:85–118.

    Article  PubMed  CAS  Google Scholar 

  60. Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus. 2005;14 Suppl 1:s2–8.

    Article  PubMed  CAS  Google Scholar 

  61. Hennes EM, Oo YH, Schramm C, et al. Mycophenolate mofetil as second line therapy in autoimmune hepatitis? Am J Gastroenterol. 2008;103:3063–70.

    Article  PubMed  CAS  Google Scholar 

  62. •• Sharzehi K, Huang MA, Schreibman IR, Brown KA: Mycophenolate mofetil for the treatment of autoimmune hepatitis in patients refractory or intolerant to conventional therapy. Can J Gastroenterol. 2010;24:588–592. Mycophenolate mofetil improved 8 of 9 patients treated for azathioprine intolerance (88 %), whereas none of 12 patients treated for refractory disease (0 %) achieved complete remission.

    PubMed  Google Scholar 

  63. •• Baven-Pronk AM, Coenraad MJ, van Buuren HR, et al.: The role of mycophenolate mofetil in the management of autoimmune hepatitis and overlap syndromes. Aliment Pharmacol Ther. 2011;34:335–343. Mycophenolate mofetil induced remission more often in patients with azathioprine intolerance than in those refractory to azathioprine therapy (67 % versus 13 %), and treatment was associated with side effects in 33 % and required premature drug withdrawal in 13 %.

    Article  PubMed  CAS  Google Scholar 

  64. Inductivo-Yu I, Adams A, Gish RG, et al. Mycophenolate mofetil in autoimmune hepatitis patients not responsive or intolerant to standard immunosuppressive therapy. Clin Gastroenterol Hepatol. 2007;5:799–802.

    Article  PubMed  CAS  Google Scholar 

  65. Hlivko JT, Shiffman ML, Stravitz RT, et al. A single center review of the use of mycophenolate mofetil in the treatment of autoimmune hepatitis. Clin Gastroenterol Hepatol. 2008;6:1036–40.

    Article  PubMed  CAS  Google Scholar 

  66. •• Aw MM, Dhawan A, Samyn M, et al.: Mycophenolate mofetil as rescue treatment for autoimmune liver disease in children: a 5-year follow-up. J Hepatol 2009;51:156–160. Mycophenolate mofetil (20 mg/kg daily increased to a maximum of 40 mg/kg daily) in 26 children induced laboratory improvement in 18 (69 %), including normalization of aspartate aminotransferase in 14 (54 %), whereas children with concurrent sclerosing cholangitis did not respond. Leukopenia developed in 7 children (27 %), and it was the most common side effect.

    Article  PubMed  CAS  Google Scholar 

  67. •• Zachou K, Gatselis N, Papadamou G, et al.: Mycophenolate for the treatment of autoimmune hepatitis: prospective assessment of its efficacy and safety for induction and maintenance of remission in a large cohort of treatment-naive patients. J Hepatol. 2011;55:636–646. Front line therapy with mycophenolate mofetil in 59 treatment-naïve patients normalized laboratory tests in 88 %, and severe treatment ending side effects developed in only 3 %. The results prove the principle that mycophenolate mofetil can be safe and effective in treatment naïve patients, but they do not establish a preference for this treatment.

    Article  PubMed  CAS  Google Scholar 

  68. Perez-Aytes A, Ledo A, Boso V, et al. In utero exposure to mycophenolate mofetil: a characteristic phenotype? Am J Med Genet A. 2008;146A:1–7.

    Article  PubMed  Google Scholar 

  69. •• Klieger-Grossmann C, Chitayat D, Lavign S, et al.: Prenatal exposure to mycophenolate mofetil: an updated estimate. J Obstet Gynaecol Can. 2010;32:794–797. Ten patients exposed to mycophenolate mofetil (500–1500 mg daily) during pregnancy had 4 miscarriages and one elective abortion but no malformations in the five live births.

    PubMed  Google Scholar 

  70. Seikaly MG. Mycophenolate mofetil–is it worth the cost? The in-favor opinion. Pediatr Transplant. 1999;3:79–82.

    Article  PubMed  CAS  Google Scholar 

  71. •• Czaja AJ: Mycophenolate mofetil to the rescue in autoimmune hepatitis: a fresh sprout on the decision tree. J Hepatol. 2009;51:8–10. The composite experience of treatment with mycophenolate mofetil indicates that the effectiveness of the drug relates to its use in the proper target population and that it is more successful in rescuing patients from azathioprine intolerance than refractory liver disease.

    Article  PubMed  CAS  Google Scholar 

  72. •• Weiner GJ: Rituximab: mechanism of action. Semin Hematol. 2010;47:115–123. Rituximab has actions that influence intracellular signaling, complement-mediated cytotoxicity, and antibody-dependent cellular cytotoxicity, but much is still unknown about the range and the complexity of its actions.

    Article  PubMed  CAS  Google Scholar 

  73. •• Amoroso A, Hafsi S, Militello L, et al.: Understanding rituximab function and resistance: implications for tailored therapy. Front Biosci. 2011;16:770–782. The binding of rituximab to CD20 induces cell death and inhibits cell proliferation, but there are indirect actions on intracellular signaling, complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity which are incompletely understood as are the mechanisms of resistance to the agent.

    Article  PubMed  CAS  Google Scholar 

  74. Liossis SN, Sfikakis PP. Rituximab-induced B cell depletion in autoimmune diseases: potential effects on T cells. Clin Immunol. 2008;127:280–5.

    Article  PubMed  CAS  Google Scholar 

  75. Santos ES, Arosemena LR, Raez LE, et al. Successful treatment of autoimmune hepatitis and idiopathic thrombocytopenic purpura with the monoclonal antibody, rituximab: case report and review of literature. Liver Int. 2006;26:625–9.

    Article  PubMed  CAS  Google Scholar 

  76. Evans JT, Shepard MM, Oates JC, et al. Rituximab-responsive cryoglobulinemic glomerulonephritis in a patient with autoimmune hepatitis. J Clin Gastroenterol. 2008;42:862–3.

    Article  PubMed  Google Scholar 

  77. •• Barth E, Clawson J: A Case of Autoimmune Hepatitis Treated with Rituximab. Case Rep Gastroenterol. 2010;4:502–509. Steroid-refractory autoimmune hepatitis in a 34 year old woman with a past history of B cell lymphoma underwent laboratory and histological improvement after 8 weeks of treatment with rituximab.

    Article  PubMed  Google Scholar 

  78. •• Cooper N, Arnold DM: The effect of rituximab on humoral and cell mediated immunity and infection in the treatment of autoimmune diseases. Br J Haematol. 2010;149:3–13. Rituximab has a minimal effect on mature plasma cells since most do not express CD20, and there may be an increase in infection associated with hypogammaglobulinemia associated with B cell depeletion and in reactivation of latent JC virus and hepatitis B virus.

    Article  PubMed  CAS  Google Scholar 

  79. •• Berger JR: Progressive multifocal leukoencephalopathy and newer biological agents. Drug Saf. 2010;33:969–983. Progressive multifocal leukoencephalopathy due to the JC virus can occur in patients treated with monoclonal antibodies and other drugs, including rituximab and mycophenolate mofetil, and both drugs carry "black box" warnings.

    Article  PubMed  CAS  Google Scholar 

  80. •• Chakravarty EF, Murray ER, Kelman A, Farmer P: Pregnancy outcomes after maternal exposure to rituximab. Blood 2011;117:1499–1506. The results of 153 pregnancies in women exposed to rituximab included 22 premature births (14 %), one neonatal death, 11 infants with hematological abnormalities (7 %), four infants with neonatal infections (3 %), and two infants with congenital malformations (1 %). These findings justified the admonition that pregnancy be avoided for 12 months after exposure to rituximab.

    Article  PubMed  CAS  Google Scholar 

  81. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471–84.

    Article  PubMed  CAS  Google Scholar 

  82. •• Zhang Y, Zhang JW, Lv GY, et al.: Effects of STAT3 gene silencing and rapamycin on apoptosis in hepatocarcinoma cells. Int J Med Sci. 2012;9:216–224. The silencing of the JAK/STAT3 signaling pathway by small inhibitory RNA and the mTOR pathway by rapamycin each increased apoptosis in cell lines, especially if both signaling pathways were targeted simultaneously.

  83. Strauss L, Whiteside TL, Knights A, et al. Selective survival of naturally occurring human CD4+CD25+Foxp3+ regulatory T cells cultured with rapamycin. J Immunol. 2007;178:320–9.

    PubMed  CAS  Google Scholar 

  84. Nikolaeva N, Bemelman FJ, Yong SL, et al. Rapamycin does not induce anergy but inhibits expansion and differentiation of alloreactive human T cells. Transplantation. 2006;81:445–54.

    Article  PubMed  CAS  Google Scholar 

  85. Kerkar N, Dugan C, Rumbo C, et al. Rapamycin successfully treats post-transplant autoimmune hepatitis. Am J Transplant. 2005;5:1085–9.

    Article  PubMed  Google Scholar 

  86. Chatenoud L. CD3 antibody treatment stimulates the functional capability of regulatory T cells. Novartis Found Symp. 2003;252:279–86. discussion 286–290.

    Article  PubMed  CAS  Google Scholar 

  87. Chatenoud L. CD3-specific antibodies restore self-tolerance: mechanisms and clinical applications. Curr Opin Immunol. 2005;17:632–7.

    Article  PubMed  CAS  Google Scholar 

  88. Chatenoud L, Thervet E, Primo J, Bach JF. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci USA. 1994;91:123–7.

    Article  PubMed  CAS  Google Scholar 

  89. Ochi H, Abraham M, Ishikawa H, et al. New immunosuppressive approaches: oral administration of CD3-specific antibody to treat autoimmunity. J Neurol Sci. 2008;274:9–12.

    Article  PubMed  CAS  Google Scholar 

  90. Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346:1692–8.

    Article  PubMed  CAS  Google Scholar 

  91. Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med. 2005;352:2598–608.

    Article  PubMed  CAS  Google Scholar 

  92. Chatenoud L, Bluestone JA. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol. 2007;7:622–32.

    Article  PubMed  CAS  Google Scholar 

  93. •• Czaja AJ, Manns MP: Advances in the diagnosis, pathogenesis and management of autoimmune hepatitis. Gastroenterology 2010;139:58–72. The recommended improvements in the routine management of autoimmune hepatitis (treatment until laboratory and histological resolution, long-term azathioprine therapy after the first relapse) and the prospects for treating recalcitrant disease with antibodies to CD3 and recombinant cytotoxic lymphocyte antigen 4 are reviewed.

    Article  PubMed  CAS  Google Scholar 

  94. •• Korhonen R, Moilanen E: Abatacept, a novel CD80/86-CD28 T cell co-stimulation modulator, in the treatment of rheumatoid arthritis. Basic Clin Pharmacol Toxicol. 2009;104:276–284. The CTLA-4 Ig fusion protein, Abatacept, interferes with the activation of T cells in rheumatoid arthritis, and this action in turn inhibits the production of proinflammatory cytokines, neovascularization in synovial tissue, autoantibody production, and activation of synoviocytes and osteoclasts.

    Article  PubMed  CAS  Google Scholar 

  95. •• Ben-Shoshan M: CTLA-4Ig: uses and future directions. Recent Pat Inflamm Allergy Drug Discov. 2009;3:132–142. CTLA-4 Ig is approved for use in rheumatoid arthritis, but its ability to block CD28 interactions indicates that it may have value in treating other autoimmune and allergic diseases.

    Article  PubMed  CAS  Google Scholar 

  96. Boden E, Tang Q, Bour-Jordan H, Bluestone JA. The role of CD28 and CTLA4 in the function and homeostasis of CD4+CD25+ regulatory T cells. Novartis Found Symp. 2003;252:55–63. discussion 63–56, 106–114.

    Article  PubMed  CAS  Google Scholar 

  97. Alegre ML, Fallarino F. Mechanisms of CTLA-4-Ig in tolerance induction. Curr Pharm Des. 2006;12:149–60.

    Article  PubMed  CAS  Google Scholar 

  98. •• Maxwell L, Singh JA: Abatacept for rheumatoid arthritis. Cochrane Database Syst Rev. 2009:CD007277. Analysis of 7 human trials involving 2908 patients with rheumatoid arthritis indicated that individuals treated with Abatacept were twice as likely to improve than those treated with placebo, and the treatment was judged to be moderately efficacious and safe when not used in combination with other biologic agents.

  99. •• Pham T, Claudepierre P, Constantin A, et al.: Abatacept therapy and safety management. Joint Bone Spine. 2009;76 Suppl 1:S3-S55. Clinical guidelines are proposed based on reported evidence and expert opinion to assist in the use of abatacept, and these guidelines are online and regularly updated.

  100. •• Szodoray P, Varoczy L, Papp G, et al.: Immunological reconstitution after autologous stem cell transplantation in patients with refractory systemic autoimmune diseases. Scand J Rheumatol. 2012;41:110–115. High dose chemotherapy followed by autologous hematopoietic stem cell transplantation can salvage patients with severe refractory systemic autoimmune diseases by reconstituting the peripheral immune system within 5–6 months with a transplantation-related mortality of 17 % and transplantation-related toxicity of 33 %.

    Article  PubMed  CAS  Google Scholar 

  101. •• Duffy MM, Ritter T, Ceredig R, Griffin MD: Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Res Ther. 2011;2:34. Mesenchymal stem cells modulate the functions of T and B lymphocytes, natural killer cells, macrophages, dendritic cells, and neutrophils by mediators that generally suppress activation and inhibit disease-associated cellular immune responses.

    Article  PubMed  CAS  Google Scholar 

  102. Kuo TK, Hung SP, Chuang CH, et al. Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology. 2008;134:2111–21. 2121 e2111-2113.

    Article  PubMed  Google Scholar 

  103. Vogel A, Heinrich E, Bahr MJ, et al. Long-term outcome of liver transplantation for autoimmune hepatitis. Clin Transplant. 2004;18:62–9.

    Article  PubMed  Google Scholar 

  104. •• Martin SR, Alvarez F, Anand R, et al.: Outcomes in children who underwent transplantation for autoimmune hepatitis. Liver Transpl. 2011;17:393–401. Liver transplantation in 113 children with autoimmune hepatitis had a 5-year survival of 86 %, and the patient and graft survivals, retransplantation rates, and frequencies of infectious or metabolic complications were similar to those of children transplanted for other conditions. African-American and Hispanic ethnicities were more common in the transplanted population with autoimmune hepatitis than in the overall transplanted population.

  105. Hayashi M, Keeffe EB, Krams SM, et al. Allograft rejection after liver transplantation for autoimmune liver diseases. Liver Transpl Surg. 1998;4:208–14.

    Article  PubMed  CAS  Google Scholar 

  106. Birnbaum AH, Benkov KJ, Pittman NS, et al. Recurrence of autoimmune hepatitis in children after liver transplantation. J Pediatr Gastroenterol Nutr. 1997;25:20–5.

    Article  PubMed  CAS  Google Scholar 

  107. Ratziu V, Samuel D, Sebagh M, et al. Long-term follow-up after liver transplantation for autoimmune hepatitis: evidence of recurrence of primary disease. J Hepatol. 1999;30:131–41.

    Article  PubMed  CAS  Google Scholar 

  108. Yusoff IF, House AK, De Boer WB, et al. Disease recurrence after liver transplantation in Western Australia. J Gastroenterol Hepatol. 2002;17:203–7.

    Article  PubMed  Google Scholar 

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Czaja, A.J. Management of Recalcitrant Autoimmune Hepatitis. Curr Hepatitis Rep 12, 66–77 (2013). https://doi.org/10.1007/s11901-012-0161-3

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