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Efficacy and Safety of Mycophenolate Mofetil and Tacrolimus as Second-line Therapy for Patients With Autoimmune Hepatitis

      Background & Aims

      Predniso(lo)ne, alone or in combination with azathioprine, is the standard-of-care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH.

      Methods

      We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6–190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second-line therapy as a result of side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC.

      Results

      There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal.

      Conclusions

      Long-term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.

      Keywords

      Abbreviations used in this paper:

      AIH (autoimmune hepatitis), AZA (azathioprine), MMF (mycophenolate mofetil), SOC (standard-of-care)
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      References

        • Manns M.P.
        • Czaja A.J.
        • Gorham J.D.
        • et al.
        Diagnosis and management of autoimmune hepatitis.
        Hepatology. 2010; 51: 2193-2213
        • Montano-Loza A.J.
        • Thandassery R.B.
        • Czaja A.J.
        Targeting hepatic fibrosis in autoimmune hepatitis.
        Dig Dis Sci. 2016; 61: 3118-3139
        • Hübener S.
        • Oo Y.H.
        • Than N.N.
        • et al.
        Efficacy of 6-Mercaptopurine as second-line treatment for patients with autoimmune hepatitis and azathioprine intolerance.
        Clin Gastroenterol Hepatol. 2016; 14: 445-453
        • Weiler-Normann C.
        • Schramm C.
        • Quaas A.
        • et al.
        Infliximab as a rescue treatment in difficult-to-treat autoimmune hepatitis.
        J Hepatol. 2013; 58: 529-534
        • Ytting H.
        • Larsen F.S.
        Everolimus treatment for patients with autoimmune hepatitis and poor response to standard therapy and drug alternatives in use.
        Scand J Gastroenterol. 2015; 50: 1025-1031
        • Baven-Pronk A.M.C.
        • Coenraad M.J.
        • van Buuren H.R.
        • et al.
        The role of mycophenolate mofetil in the management of autoimmune hepatitis and overlap syndromes.
        Aliment Pharmacol Ther. 2011; 34: 335-343
        • Hennes E.M.
        • Oo Y.H.
        • Schramm C.
        • et al.
        Mycophenolate mofetil as second line therapy in autoimmune hepatitis?.
        Am J Gastroenterol. 2008; 103: 3063-3070
        • Inductivo-Yu I.
        • Adams A.
        • Gish R.G.
        • et al.
        Mycophenolate mofetil in autoimmune hepatitis patients not responsive or intolerant to standard immunosuppressive therapy.
        Clin Gastroenterol Hepatol. 2007; 5: 799-802
        • Hlivko J.T.
        • Shiffman M.L.
        • Stravitz R.T.
        • et al.
        A single center review of the use of mycophenolate mofetil in the treatment of autoimmune hepatitis.
        Clin Gastroenterol Hepatol. 2008; 6: 1036-1040
        • Sharzehi K.
        • Huang M.A.
        • Schreibman I.R.
        • et al.
        Mycophenolate mofetil for the treatment of autoimmune hepatitis in patients refractory or intolerant to conventional therapy.
        Can J Gastroenterol. 2010; 24: 588-592
        • 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-naïve patients.
        J Hepatol. 2011; 55: 636-646
        • Van Thiel D.H.
        • Wright H.
        • Carroll P.
        • et al.
        Tacrolimus: a potential new treatment for autoimmune chronic active hepatitis: results of an open-label preliminary trial.
        Am J Gastroenterol. 1995; 90: 771-776
        • Larsen F.S.
        • Vainer B.
        • Eefsen M.
        • et al.
        Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis.
        World J Gastroenterol. 2007; 13: 3232-3236
        • Aqel B.A.
        • Machicao V.
        • Rosser B.
        • et al.
        Efficacy of tacrolimus in the treatment of steroid refractory autoimmune hepatitis.
        J Clin Gastroenterol. 2004; 38: 805-809
        • Tannous M.M.
        • Cheng J.
        • Muniyappa K.
        • et al.
        Use of tacrolimus in the treatment of autoimmune hepatitis: a single centre experience.
        Aliment Pharmacol Ther. 2011; 34: 405-407
        • Marlaka J.R.
        • Papadogiannakis N.
        • Fischler B.
        • et al.
        Tacrolimus without or with the addition of conventional immunosuppressive treatment in juvenile autoimmune hepatitis.
        Acta Paediatr. 2012; 101: 993-999
        • Hennes E.M.
        • Zeniya M.
        • Czaja A.J.
        • et al.
        Simplified criteria for the diagnosis of autoimmune hepatitis.
        Hepatology. 2008; 48: 169-176
        • Vierling J.M.
        Autoimmune hepatitis and overlap syndromes: diagnosis and management.
        Clin Gastroenterol Hepatol. 2015; 13: 2088-2108
        • Bedossa P.
        • Poynard T.
        An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group.
        Hepatology. 1996; 24: 289-293
        • Czaja A.J.
        Late relapse of type 1 autoimmune hepatitis after corticosteroid withdrawal.
        Dig Dis Sci. 2010; 55: 1761-1769
        • Dhaliwal H.K.
        • Hoeroldt B.S.
        • Dube A.K.
        • et al.
        Long-term prognostic significance of persisting histological activity despite biochemical remission in autoimmune hepatitis.
        Am J Gastroenterol. 2015; 110: 993-999
        • Heneghan M.A.
        • Al-Chalabi T.
        • McFarlane I.G.
        Cost-effectiveness of pharmacotherapy for autoimmune hepatitis.
        Expert Opin Pharmacother. 2006; 7: 145-156
        • Devlin S.M.
        • Swain M.G.
        • Urbanski S.J.
        • et al.
        Mycophenolate mofetil for the treatment of autoimmune hepatitis in patients refractory to standard therapy.
        Can J Gastroenterol. 2004; 18: 321-326
        • Yeoman A.D.
        • Westbrook R.H.
        • Zen Y.
        • et al.
        Early predictors of corticosteroid treatment failure in icteric presentations of autoimmune hepatitis.
        Hepatology. 2011; 53: 926-934
        • Than N.N.
        • Wiegard C.
        • Weiler-Normann C.
        • et al.
        Long-term follow-up of patients with difficult to treat type 1 autoimmune hepatitis on tacrolimus therapy.
        Scand J Gastroenterol. 2016; 51: 329-336