Should MMF treatment be the first-line therapy in autoimmune hepatitis?
Authors: Laurent Alric
Journal: Journal of Hepatology (2024)

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 The trial recently published in Journal of Hepatology by Romée Snijders et al.1Snijder R. Stoelinga A. Gevers J.G. et al.An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatement-naïve autoimmune hepatitis.J Hepatol. 2023; https://doi.org/10.1016/j.jhep.2023.11.032Abstract Full Text Full Text PDF Scopus (2) Google Scholar is very interesting because it raises a good question about the first-line treatment of autoimmune hepatitis, which is currently AZA therapy. Until now, MMF has been used as a 2nd-line treatment when AZA was ineffective or in cases of intolerance. This study shows that MMF treatment in naive patients is superior to AZA in terms of both efficacy and tolerability. This study raises a number of questions. Firstly, only 48% of patients in both groups had a compatible but non-typical diagnosis of autoimmune hepatitis. The primary objective was normalization of ALT and IgG levels at 24 weeks. A complete biochemical response based on these two parameters was achieved in 56.4% of patients treated with MMF and only 29% with AZA. The low response rate in the AZA + prednisone group contradicts previous studies, where the biochemical response was 83% in the landmark study by Johnson et al.2Johnson P.J. McFarlane I.G. Williams R. Azathioprine for long term remission in autoimmune hepatitis.New Engl J Med. 1995; 333: 958-963Crossref PubMed Scopus (356) Google Scholar or 60% in the patients given budesonide + AZA and 38.8% in those given prednisone + AZA in a more recent study.3Manns M.P. 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: 1198-1206Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar In a large real-life study4Zachou K. Gatselis K. 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 Phamarcol Ther. 2016; 43: 1035-1047Crossref PubMed Scopus (74) Google Scholar of 299 patients, the response rate was 45.5% with AZA + prednisone vs. 71.6 % with MMF + prednisone. Moreover, in the present study, if we now consider IgG normalization separately from ALT normalization, we surprisingly find that 74% of patients on MMF vs. 45% on AZA normalize their IgG levels at 24 weeks, which is far higher than the percentage achieving the primary objective (IgG and ALT normalization). Tolerability also differed between the two groups. AZA induced more side-effects, such as vomiting and nausea, as well as greater hematological toxicity than MMF. We are surprised, however, that no predictive assay of AZA metabolism was performed in this study. Before AZA is introduced, many teams around the world carry out a genetic study of the TPMT polymorphism to identify patients at risk of overdosing. When this technique is not available, during AZA treatment, blood levels of the 6-thioguanine nucleotides in red blood cells can be determined, using published thresholds to define the most effective and least 6 TGNs toxic target.5Dhaliwal H. Anderson R. Thornhill E. et al.Clinical significance of azathioprine metabolites for the maintenance of remission in autoimmune hepatitis.Hepatology. 2012; 56: 1401-1408Crossref PubMed Scopus (69) Google Scholar Regrettably, this was not done in this study. As discussed by the authors, MMF cannot be used during pregnancy, unlike AZA. Given the largely female predominance of AIH, this criterion must be taken into account. The place of MMF as a first-line replacement for AZA needs to be confirmed by larger studies in autoimmune hepatitis of definite diagnosis, and with a prior search for factors enabling AZA dosage to be adapted. The choice of treatment should be adapted to the age and profile of each patient. The author received no financial support to produce this manuscript. The author declares no conflicts of interest related to this manuscript. Please refer to the accompanying ICMJE disclosure form for further details. The following are the supplementary data to this article: Download .pdf (.19 MB) Help with pdf files Multimedia component 1