Efficacy and safety of chloroquine plus prednisone for the treatment of autoimmune hepatitis in a randomized trial

Lydia T de Moraes Falcão, Debora R B Terrabuio, Marcio A Diniz, Andreia da Silva Evangelista, Fabricio G Souza, Eduardo L R Cancado, Lydia T de Moraes Falcão, Debora R B Terrabuio, Marcio A Diniz, Andreia da Silva Evangelista, Fabricio G Souza, Eduardo L R Cancado

Abstract

Background and aim: Standard treatment for autoimmune hepatitis (AIH) consists of predniso(lo)ne and azathioprine. However, alternative therapy is required for non- or partial responders and in cases of side effects. The aim of this study was to evaluate the treatment outcomes associated with chloroquine plus prednisone in AIH patients.

Methods: Fifty-seven patients were recruited to receive either azathioprine or chloroquine, both with prednisone, in a randomized trial. The primary end-point was complete remission, based on normalization of aminotransferase levels in the first 6 months of treatment plus maintenance for at least 18 months, with minimal or no inflammatory activity in the liver biopsy. Secondary end-points were partial and nonresponse, severe side effects, and treatment withdrawal.

Results: There were no differences between groups regarding clinical, serological, histological, and treatment characteristics at baseline. There were no significant differences in the biochemical response rate (67.7 vs 53.8%, P = 0.41) or the complete remission rate (32.26 vs 15.38%, P = 0.217). However, despite the long study period, the sample size was smaller than that required for a noninferiority study. The mean prednisone dose was similar in both groups. There was a nonsignificantly higher rate of adverse effects and a tendency toward improvement in glycemic and cholesterol profiles in the chloroquine group (P = 0.09 and P = 0.07, respectively).

Conclusions: The combination of chloroquine and prednisone exhibited potentially beneficial effects in AIH patients (https://ClinicalTrials.gov: NCT02463331).

Keywords: antimalarial drug; autoimmune hepatitis; chloroquine; remission.

© 2019 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Figures

Figure 1
Figure 1
Flow chart of patients followed up.
Figure 2
Figure 2
Comparison of biochemical response and complete remission rates between treatment‐naive patients and relapsers. The percentages of each response in the azathioprine and chloroquine groups are given in the columns. (), Treatment‐naive (n = 32/57); (), relapsers (n = 25/57).
Figure 3
Figure 3
Patients' metabolic comorbidities during the follow‐up. Groups: (), AZA+PD; (), CQ+PD. AZA, azathioprine; CQ, chloroquine; PD, prednisone.

References

    1. Manns MP, Czaja AJ, Gorham JD et al Diagnosis and management of autoimmune hepatitis. Hepatology. 2010; 51: 2193–213.
    1. European Association for the Study of the Liver . EASL clinical practice guidelines: autoimmune hepatitis. J. Hepatol. 2015; 63: 971–1004.
    1. Johnson PJ, McFarlane IG, Williams R. Azathioprine for long‐term maintenance of remission in autoimmune hepatitis. N. Engl. J. Med. 1995; 333: 958–63.
    1. Czaja AJ. Review article: permanent drug withdrawal is desirable and achievable for autoimmune hepatitis. Aliment. Pharmacol. Ther. 2014; 39: 1043–58.
    1. Manns MP, Woynarowski M, Kreisel W et al Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology. 2010; 139: 1198–206.
    1. Zachou K, Gatselis NK, Arvaniti P et al A real‐world study focused on the long‐term efficacy of mycophenolate mofetil as first‐line treatment of autoimmune hepatitis. Aliment. Pharmacol. Ther. 2016; 43: 1035–47.
    1. Rubin JN, Te HS. Refractory autoimmune hepatitis: beyond standard therapy. Dig. Dis. Sci. 2016; 61: 1–6.
    1. Beretta‐Piccoli BT, Mieli‐Vergani G, Vergani D. Autoimmune hepatitis: standard treatment and systematic review of alternative treatments. World J. Gastroenterol. 2017; 23: 6030–48.
    1. Solomon VR, Lee H. Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies. Eur. J. Pharmacol. 2009; 625: 220–33.
    1. Wallace DJ, Gudsoorkar VS, Weisman MH, Venuturupalli SR. New insights into mechanisms of therapeutic effects of antimalarial agents in SLE. Nat. Rev. Rheumatol. 2012; 8: 522–33.
    1. Van Vollenhoven RF, Mosca M, Bertsias G et al Treat‐to‐target in systemic lupus erythematosus: recommendations from an international task force. Ann. Rheum. Dis. 2014; 73: 958–67.
    1. Da Silva JC, Mariz HA, Da Rocha LF et al Hydroxychloroquine decreases Th17‐related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients. Clinics (Sao Paulo). 2013; 68: 766–71.
    1. Mucenic M, De Mello ES, Cançado ELR. Chloroquine for the maintenance of remission of autoimmune hepatitis: results of a pilot study. Arq. Gastroenterol. 2005; 42: 249–55.
    1. Terrabuio DRB, Diniz MA, Falcão LTM et al Chloroquine is effective for maintenance of remission in autoimmune hepatitis: controlled, double‐blind, randomized trial. Hepatol. Commun. 2018; 3: 116–28.
    1. Alvarez F, Berg PA, Bianchi FB et al International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J. Hepatol. 1999; 31: 929–38.
    1. Trotti A, Colevas AD, Setser A et al CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin. Radiat. Oncol. 2003; 13: 176–81.
    1. 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.
    1. Chen Z‐X, Shao J‐G, Shen Y et al Prognostic implications of antibodies to soluble liver antigen in autoimmune hepatitis. Medicine (Baltimore). 2015; 94: e953.
    1. Kirstein MM, Metzler F, Geiger E et al Prediction of short‐ and long‐term outcome in patients with autoimmune hepatitis. Hepatology. 2015; 62: 1524–35.
    1. Czaja AJ, Carpenter HA, Moore SB. Clinical and HLA phenotypes of type 1 autoimmune hepatitis in North American patients outside DR3 and DR4. Liver Int. 2006; 26: 552–8.
    1. Lamers MMH, van Oijen MGH, Pronk M, Drenth JPH. Treatment options for autoimmune hepatitis: a systematic review of randomized controlled trials. J. Hepatol. 2010; 53: 191–8.
    1. Czaja AJ. Current and prospective pharmacotherapy for autoimmune hepatitis. Expert Opin. Pharmacother. 2014; 15: 1715–36.
    1. Hage MP, Al‐Badri MR, Azar ST. A favorable effect of hydroxychloroquine on glucose and lipid metabolism beyond its anti‐inflammatory role. Ther. Adv. Endocrinol. Metab. 2014; 5: 77–85.
    1. Borba EF, Bonfá E. Longterm beneficial effect of chloroquine diphosphate on lipoprotein profile in lupus patients with and without steroid therapy. J. Rheumatol. 2001; 28: 780–5.
    1. Kavanaugh A, Adams‐Huet B, Jain R, Denke M, McFarlin J. Hydroxychloroquine effects on lipoprotein profiles (the HELP trial): a double‐blind, randomized, placebo‐controlled, pilot study in patients with systemic lupus erythematosus. J. Clin. Rheumatol. 1997; 3: 3–8.
    1. Ruiz‐Irastorza G, Ramos‐Casals M, Brito‐Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann. Rheum. Dis. 2010; 69: 20–8.
    1. Marmor MF, Kellner U, Lai TYY, Melles RB, Mieler WF. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016; 123: 1386–94.

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