Autoimmune hepatitis: Mycophenolate mofetil vs. azathioprine as first-line therapy

An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitisJournal of HepatologyVol. 80Issue 4PreviewPatients with autoimmune hepatitis (AIH) almost invariably require lifelong immunosuppressive treatment. There is genuine concern about the efficacy and tolerability of the current standard combination therapy of prednisolone and azathioprine. Mycophenolate mofetil (MMF) has emerged as an alternative option. The aim of this study was to compare MMF to azathioprine as induction therapy for AIH. Full-Text PDF Open AccessReply to: Comments on "An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitis"Journal of HepatologyPreviewWe express our appreciation to our colleagues for their invaluable feedback1–5 on our recent publication,6 which has garnered considerable interest. Full-Text PDF A recent open label, multicenter, randomized, controlled trial by Snijders et al.1Snijders R.J.A.L.M. Stoelinga A.E.C. Gevers T.J.G. et al.Dutch Autoimmune Hepatitis Working Group. An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitis.J Hepatol. 2023; https://doi.org/10.1016/j.jhep.2023.11.032Google Scholar compared the efficacy and safety of mycophenolate mofetil (MMF) and azathioprine (AZA) as first-line induction therapy in treatment-naive autoimmune hepatitis (AIH). The main findings were that MMF showed better tolerability and led to a higher rate of biochemical response at 24 weeks. The study is a welcome addition to the limited number of randomized-controlled trials in AIH. The authors present clear data, but we think that several issues need further clarification. Adverse events leading to cessation of treatment were surprisingly common in the AZA group (25.8%) compared to patients who received MMF (5.1%). For comparison, we noted AZA discontinuation rates of 5.6% (4/71) and 4.9% (3/61) in two of our previously published studies.2Purnak T. Efe C. Kav T. et al.Treatment response and outcome with two different prednisolone regimens in autoimmune hepatitis.Dig Dis Sci. 2017; 62: 2900-2907Google Scholar,3Yüksekyayla O. Kına N. Ulaba A. et al.The frequency and clinical significance of anti-SLA/LP in Autoimmune Hepatitis: a prospective single center study.Eur J Gastroenterol Hepatol. 2024 May 1; 36: 652-656https://doi.org/10.1097/MEG.0000000000002747Google Scholar The high rate of side effects and the significant response difference between the AZA and MMF group may reflect differences in baseline patient characteristics. The data presented by Snijders et al. do not permit detailed evaluation of the representativity and comparability of the two patient groups. The AZA group had higher MELD and lower albumin levels suggestive of a more impaired baseline liver function. Of note, the MELD score was not available in 46% of MMF-treated patients and 26% of AZA-treated patients, which is surprising for a such well-planned study. Four patients (Table S9) had severe (life-threating) side effects that were considered to be AZA-related. One patient presented with general malaise and skin abnormalities after 35 days of therapy, which are known side effects of AZA. However, we have some concerns about the other three patients. As per study protocol, all three patients received prednisolone 40-60 mg/day. High dose prednisolone predisposes to the development of systemic bacterial or fungal infections, especially in patients with baseline cirrhosis or in acute severe AIH.4Téllez L. Sánchez Rodríguez E. Rodríguez de Santiago E. et al.Early predictors of corticosteroid response in acute severe autoimmune hepatitis: a nationwide multicenter study.Aliment Pharmacol Ther. 2022 Jul; 56: 131-143https://doi.org/10.1111/apt.16926Google Scholar,5Yeoman A.D. Westbrook R.H. Zen Y. et al.Prognosis of acute severe autoimmune hepatitis (AS-AIH): the role of corticosteroids in modifying outcome.J Hepatol. 2014; 61: 876-882Google Scholar Due to steroid effects or natural disease behavior, such subgroups of patients with AIH may clinically worsen during induction therapy.4Téllez L. Sánchez Rodríguez E. Rodríguez de Santiago E. et al.Early predictors of corticosteroid response in acute severe autoimmune hepatitis: a nationwide multicenter study.Aliment Pharmacol Ther. 2022 Jul; 56: 131-143https://doi.org/10.1111/apt.16926Google Scholar In the present study, AZA was given to two patients (patient 3 and 4, Table S9) for only 3-5 days, which may be too short to observe its immunosuppressive effects. For patient 3, the development of liver failure and thrombocytopenia may be explained by systemic features of septicemia. Two other patients developed liver failure and pneumonia even before initiation of treatment with AZA or MMF. These findings suggest that steroid therapy and advanced clinical baseline features may explain the most severe outcomes, rather than AZA- or MMF-related adverse effects. We question whether it is proper to include patients with acute severe AIH in a study like this. Such patients are usually treated with steroid monotherapy. Limited data suggest efficacy of tacrolimus or MMF, but no place for AZA in the treatment of acute severe AIH.5Yeoman A.D. Westbrook R.H. Zen Y. et al.Prognosis of acute severe autoimmune hepatitis (AS-AIH): the role of corticosteroids in modifying outcome.J Hepatol. 2014; 61: 876-882Google Scholar,6Efe C. Tacrolimus as second-line therapy in acute severe autoimmune hepatitis.Scand J Gastroenterol. 2021; 56: 298Google Scholar In this study, steroid-related side effects were observed in about 15% of patients in both the AZA and MMF arms. For comparison, about 50% of patients with AIH developed at least one steroid-specific side effect in the prednisolone arm of the budesonide vs. prednisone trial by Manns et al.,7Manns M.P. Woynarowski M. Kreisel W. et al.European AIH-BUC-Study GroupBudesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis.Gastroenterology. 2010; 139: 1198-1206Google Scholar but AZA-related severe side effects were not mentioned. The considerable differences between studies may suggest bias. One study focuses on only AZA/MMF-induced side effects while another on steroid-related adverse events. It is important to note that the included patients showed heterogeneous features, and that the study groups were not identical. The authors however reported similar 4-week therapy response rates in both groups despite biochemical resolution potentially taking longer in patients with AIH and higher MELD scores.8Montano-Loza A.J. Carpenter H.A. Czaja A.J. Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease.Hepatology. 2007; 46: 1138-1145Google Scholar,9Özaslan E. Günşar F. Çiftçibaşı Örmeci A. et al.Diagnosis and treatment of autoimmune hepatitis: questions, answers, and illustrative cases: endorsed by autoimmune liver diseases special interest group, Turkish association for the study of liver.Turk J Gastroenterol. 2023 Nov; 34: S1-S33Google Scholar The short 24-week follow-up favors MMF over AZA by study design, as the immunosuppressive action of MMF is quicker than that of AZA in the transplant setting.10Allison A.C. Mechanisms of action of mycophenolate mofetil in preventing chronic rejection.Transpl Proc. 2002; 34: 2863-2866Google Scholar We agree with the authors that 12-month follow-up data will enable more robust conclusions. AIH is a very heterogenous disease and therapy should be individualized according to age, co-morbidities and clinical manifestations of AIH. Beyond current guidelines, we also believe that MMF or tacrolimus may be more suitable than AZA for some patients with AIH. The study by Snijders et al. paves the way for designing additional prospective studies that compare the efficacy and safety of the standard regimen (AZA + prednisolone) to other immunosuppressives drugs, and even to biologic agents. The authors did not receive any financial support to produce this manuscript. The authors of this study declare that they do not have any conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details. CŞ, SW and CE interpreted data and prepared manuscript. CE, EB and SW approved the final version of the manuscript. The following are the supplementary data to this article: Download .pdf (.09 MB) Help with pdf files Multimedia component 1