A systematic review and meta-analysis of second-line immunosuppressants for autoimmune hepatitis treatment Michele De Lemos-Bonotto, Cristiane Valle-Tovo, Ane M. Costabeber, Angelo A. Mattos and André L.F. Azeredo-da-Silva Introduction The gold-standard treatment for autoimmune hepatitis (AIH) is a prednisone/azathioprine combination. However, subgroups of patients may be unresponsive to this treatment. The aim of this study is to evaluate the efficacy of second-line immunosuppressive therapies for AIH through a systematic review and meta-analysis in adult patients. Patients and methods The systematic review was registered at the PROSPERO platform under number 42015019831. Databases MEDLINE (PubMed), Lilacs, Cochrane, and Scielo were searched. The keywords used were ‘Hepatitis, Autoimmune’ and descriptors terms (MeSH and DeCS). These terms were linked with each immunosuppressant of interest. Results A total of 1532 studies were identified. Of these, 1492 were excluded on the basis of title and abstract reading. Among the 40 studies retrieved for detailed full-text analysis, a total of 15 fulfilled the inclusion criteria for the analysis. The most studied second-line immunosuppressive was mycophenolate mofetil (MM). The mean reduction of aminotransferases was observed in 94.3% with tacrolimus/prednisone, 91.3% for cyclosporine/prednisone, 85.5% for budesonide, and 78.7% MM/prednisone. For MM/prednisone, the mean rate of histological remission was 88.6%, liver transplantation was indicated in 11.4%, and the mortality rate was 7.2%. Limitations were also present, such as the lack of randomized-controlled trials and prospective studies, the small number of patients, and the heterogeneity between remission criteria. Conclusion This is the first systematic review and meta-analysis to compare the second-line imunossupressant therapy for AIH. The most studied second-line immunosuppressive is the MM, with a reasonable histological remission. The use of combined tacrolimus/prednisone was the most effective for the normalization of aminotransferases. Eur J Gastroenterol Hepatol 00:000– 000 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Introduction Autoimmune hepatitis (AIH) is a chronic disease of mul- tifactorial etiology, characterized by hypergammaglobuli- nemia, specific autoantibodies, and interface hepatitis on histologic study [1]. The clinical presentation is hetero- geneous, and varies from subclinical disease to acute liver failure and end-stage liver disease. The current standard treatment recommended is a prednisone and azathioprine combination that is effective in 80–90% of cases [2]. However, 10–20% of patients seem to be refractory to standard treatment, which could be a result of non- compliance, partial compliance, or true nonresponse. Furthermore, there are patients who do not respond and may develop side effects related to the treatment. To treat this group of patients, several alternative immunosup- pressive regimens are used; however, there is still no clear definition of what is the most effective second-line therapy for AIH treatment [2,3]. The aim of this study is to com- pare the efficacy of second-line immunosuppressive therapies for hepatitis autoimmune through a systematic review and meta-analysis in adult patients. Patients and methods A systematic review of the literature was performed to iden- tify randomized-controlled trials (RCTs) and observational studies reporting the frequency of AIH remission and other outcomes of interest among patients intolerant or refractory to therapy with azathioprine and prednisone. Databases MEDLINE (PubMed), Lilacs, Cochrane, and Scielo were searched to carry out a systematic review and meta-analysis. The keywords used were ‘Hepatitis, Autoimmune’ and descriptor terms (MeSH and DeCS). These terms were linked with each immunosuppressant of interest, including ‘Cyclosporin’ [MeSH], ‘Tacrolimus’ [MeSH], ‘Budesonide’ [MeSH], ‘Azathioprine’ [MeSH], ‘Prednisone’ [MeSH], ‘Methotrexate’ [MeSH], ‘Cyclophosphamide’ [MeSH], and ‘Mycophenolate mofetil’ [MeSH]. The full search strategy is presented in Supplementary Material (Supplemental digital content 1, http://links.lww.com/EJGH/A244). Department of Hepatology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil Correspondence to Michele De Lemos-Bonotto, MD, Department of Gastroenterology and Endoscopy of Santa Casa de Porto Alegre, Poty Medeiros Street, 110/503, Porto Alegre 90570030, Rio Grande do Sul, Brazil Tel: + 55 51 981418522; fax : + 55 51 32148585; e-mail: mime.b@icloud.com Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website, www.eurojgh.com. Received 12 June 2017 Accepted 7 October 2017 European Journal of Gastroenterology & Hepatology 2017, 00:000–000 Keywords: budesonide, mycophenolate mofetil, prednisone, tacrolimus ’ Original article 0954-691X Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MEG.0000000000001019 1 Copyright r 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.