Treating autoimmune hepatitis – More science, more progress, better 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 Access See Article, pages 576–585 See Article, pages 576–585 People living with autoimmune diseases frequently have impaired quality and quantity of life, and usually a chronic disease course.[1]Conrad N. Misra S. Verbakel J.Y. et al.Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK.Lancet (London, England). 2023; 401: 1878-1890Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Physicians usually focus on their own areas of interest but taking the 'patient helicopter' view is important to challenge our current management paradigms. Patients may fairly ask what do autoimmune hepatitis (AIH), rheumatoid arthritis, multiple sclerosis, psoriasis, and inflammatory bowel diseases have in common? All are immune-mediated diseases, whose exact aetiology is unknown, all may lead to acute flares that can be effectively managed by corticosteroid therapy, all require long-term maintenance immunotherapy, and all may benefit from treatment with azathioprine. However, corticosteroids and azathioprine are no longer the cornerstone of therapy for any of these diseases, except AIH! Patients living with the other autoimmune conditions are offered multiple therapeutic alternatives based on enormous progress over decades from basic and clinical immunology.2Fanouriakis A. Kostopoulou M. Andersen J. et al.EULAR recommendations for the management of systemic lupus erythematosus: 2023 update.Ann Rheum Dis. 2024; : 83https://doi.org/10.1136/ARD-2023-224762Crossref Google Scholar, 3Smolen J.S. Landewé R.B.M. Bergstra S.A. et al.EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update.Ann Rheum Dis. 2023; 82: 3-18Crossref PubMed Scopus (257) Google Scholar, 4Sorensen P.S. Magyari M. Sellebjerg F. An update on combination therapies for multiple sclerosis: where are we now?.Expert Rev Neurother. 2023; 23: 1173-1187Crossref PubMed Scopus (0) Google Scholar, 5Jakimovski D. Bittner S. Zivadinov R. et al.Multiple sclerosis.Lancet (London, England). 2023; (published online Jan 13)https://doi.org/10.1016/S0140-6736(23)01473-3Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar AIH may be more rare, more heterogeneous, and more difficult to diagnose and study, but nevertheless, as a Hepatology community, we must address concerns that we are failing our patients in not providing them access to a plethora of more specific drugs, both established and emerging. Nor are we providing the data needed to choose the right drug for the right patient at the right time, such as addressing disease presentation, disease maintenance, or disease-related symptoms.[6]Muratori L. Lohse A.W. Lenzi M. Diagnosis and management of autoimmune hepatitis.BMJ. 2023; https://doi.org/10.1136/bmj-2022-070201Crossref PubMed Scopus (19) Google Scholar,[7]Trivedi P.J. Hirschfield G.M. Recent advances in clinical practice: epidemiology of autoimmune liver diseases.Gut. 2021; 70: 1989-2003Crossref PubMed Scopus (85) Google Scholar While 50 years ago Hepatology was leading the field with the conduct of three randomised trials – indeed some of the earliest randomised trials in medical history, proving the life-saving effectiveness of corticosteroid therapy in AIH – very few trials have been performed since.8Soloway R.D. Summerskill W.H. Baggenstoss A.H. et al.Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis.Gastroenterology. 1972; 63: 820-833Abstract Full Text PDF PubMed Google Scholar, 9Manns 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 (331) Google Scholar, 10Kirk A.P. Jain S. Pocock S. Thomas H.C. Sherlock S. Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis.Gut. 1980; 21: 78-83Crossref PubMed Scopus (223) Google Scholar, 11Murray-Lyon I.M. Stern R.B. Williams R. Controlled trial of prednisone and azathioprine in active chronic hepatitis.Lancet (London, England). 1973; 1: 735-737Abstract PubMed Scopus (381) Google Scholar, 12Cook G.C. Mulligan R. Sherlock S. Controlled prospective trial of corticosteroid therapy in active chronic hepatitis.Q J Med. 1971; 40: 159-185Crossref PubMed Scopus (450) Google Scholar As we debate if one corticosteroid is better than another (budesonide vs. prednisone/prednisolone[13]Díaz-González Á. Hernández-Guerra M. Pérez-Medrano I. et al.Budesonide as first-line treatment in patients with autoimmune hepatitis seems inferior to standard predniso(lo)ne administration.Hepatology. 2023; 77: 1095-1105Crossref PubMed Scopus (8) Google Scholar), all other disciplines are spoiled for choice with a surfeit of immune-modulating drugs – admittedly with varying efficacy and varying side-effect profiles, but with real options and impressive advances in care for diseases that were previously much harder to manage than AIH. It is therefore most welcome that this issue of the Journal of Hepatology includes what is so clearly needed to provide some progress in the field, a randomized-controlled trial on the treatment of AIH.[14]Snijders R. Stoelinga A. et al.An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitis.J Hepatol. 2024; 80: 576-585Abstract Full Text Full Text PDF Google Scholar Romée Snijders, Anna Stoelinga and Joost Drenth, on behalf of their co-authors, and the Dutch Autoimmune Hepatitis Working Group, therefore deserve much credit for designing, recruiting, analysing, and publishing an investigator initiated open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil (MMF) for the induction of remission in treatment-naive AIH. In what is clearly a pragmatic trial, the data supports a role for MMF in managing AIH, extending clinical experience by providing trial evidence. MMF with prednisolone achieved a higher rate of biochemical remission at 24 weeks compared to azathioprine combined with prednisolone. Azathioprine use was associated with more adverse events leading to cessation of treatment (8 of the 31 patients in the azathioprine arm). Thus, the difference between the two drugs was primarily due to this difference in their tolerability profile – if analysis is restricted to the patients taking the investigational drug, i.e. the per protocol analysis, the effectiveness (or lack of effectiveness, considering the relatively low biochemical remission rate) of the two drugs was very much comparable. It is interesting to note that the use of MMF was evaluated in untreated patients, a very heterogeneous group generally, and in this study, we are unable to evaluate how representative the enrolled participants are because the denominator for new patients with AIH requiring treatment across the study sites is not available to us. The primary endpoint was biochemical remission defined as normalisation of serum values of alanine aminotransferase and immunoglobulin G after 24 weeks of treatment. The trialists report on seventy consenting patients (mean age 57.9 years; 72.9% female). More patients were randomly assigned to the MMF plus prednisolone (n = 39) arm than the azathioprine plus prednisolone (n = 31) arm. The primary endpoint was met in 56.4% and 29.0% of patients assigned to the MMF group and the azathioprine group, respectively (p = 0.022). The MMF group exhibited higher complete biochemical response rates at 6 months (72.2% vs. 32.3%) but it is notable that baseline characteristics were not matched between groups. No serious adverse events occurred in patients who received MMF, but serious adverse events were reported in four patients who received azathioprine. Two patients in the MMF group and eight patients in the azathioprine group discontinued treatment. Whether treatment optimisation for azathioprine was ideal is unclear, albeit a counter argument could be made that if MMF is simply easier to use, then that itself is an important practice point. For clinicians appraising this trial, context is important. Whilst the findings are helpful, many will interpret this study with some caution based on their overall treatment experience of AIH. Firstly, MMF has for a long time been a treatment consideration in AIH. It is a drug familiar to many, used in systemic lupus erythematosus, post-transplant, and other autoimmune conditions. Prior evidence has shown it has a role in AIH (as does in fact nearly any immunosuppressant with some potency), but drawbacks include higher cost than azathioprine, inability to use in women wishing to conceive, and variation in gastrointestinal tolerability depending on brand formulation. MMF is also a twice daily drug, unlike azathioprine which can usually be taken once daily. Azathioprine is ubiquitously used, cheap, and can be dose adjusted based on drug levels. Secondly, the trial is not really asking the right question: guidelines universally recommend corticosteroids as the drug of choice to induce remission and azathioprine or MMF, usually as a second-line drug if azathioprine is not tolerated, as maintenance therapy, but this trial is studying remission induction. We knew in advance that MMF is a good alternative to azathioprine in AIH, and patients who are intolerant to azathioprine should be switched to MMF according to all guidelines. In this trial, presumably for reasons of trial design, patients were not switched to MMF as recommended in the guidelines, and as is usual medical practice. More importantly, patients are much more interested in the long-term outcome of their treatment, and less so in the time to reach biochemical remission. Unfortunately, the long-term questions that patients ask us are almost impossible to answer in a clinical trial, and thus in addition to more innovative, and better-funded trials, we need good prospective and comprehensive long-term registry data. What then are the take-home messages after this trial for the clinical gastroenterologist and hepatologist? MMF clearly is an alternative in early treatment of AIH and has some advantages in comparison to azathioprine, which are better tolerability, at least in the short-term, and probably a faster mode of action. Thus, our therapeutic armamentarium is somewhat enlarged, albeit by a well-established old-fashioned drug with its own considerable risk profile. The second message is that azathioprine is quite frequently poorly tolerated in early treatment of AIH and care needs to be taken when using this well-weathered drug to improve tolerability – for example by starting with lower doses, by giving the drug in the first weeks only on a full stomach, and by measuring drug metabolites (6-thioguanine and 6-methyl mercaptopurine). The third and very sobering message is that even if the recommended or alternative drugs are well-tolerated, just over half of patients with AIH reach biochemical remission. We need to improve on that, and we need to know if biochemical remission is really required, or if mild disease activity may be preferred to possible drug side-effects in difficult to treat patients. More importantly, we need to know which treatments help to improve not just life-expectancy but also quality of life. In summary, both azathioprine and MMF are helpful tools for our patients, but perhaps the greater point is why indeed are we still using either drug in an era of biologics and small molecules? In AIH we need to agree on what we are seeking to achieve. We recognise from real-world studies that management is patchy in quality and heterogeneous in approach, and that despite good treatment guidelines[15]Lohse A.W. Chazouillères O. Dalekos G. et al.EASL clinical practice guidelines: autoimmune hepatitis.J Hepatol. 2015; 63: 971-1004Abstract Full Text Full Text PDF PubMed Scopus (825) Google Scholar,[16]Mack C.L. Adams D. Assis D.N. et al.Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American association for the study of liver diseases.Hepatology. 2020; 72: 671-722Crossref PubMed Scopus (410) Google Scholar from both EASL and AASLD very many patients are not receiving the recommended standard of care. Much of this problem is due to care structures and the inherent problem of rare complex illnesses, that require access to expert centres to optimise treatment of such a heterogeneous disease, with an even more heterogeneous patient population of all age groups, varying co-morbidities and varying health priorities. However, a lack of clinical research and clinical trials is just as bigger problem. We desperately need more clinical trials, brave pilot studies with new agents and new drug combinations, systematic case series reporting unconventional approaches in difficult to treat patients – and we need a closer cooperation with both the pharmaceutical industry and the regulatory authorities: hurdles for trials have to be lowered, we have to design and allow more pragmatic trials that move away from histology as gold standard, that include patient-centred outcome measures (such as quality of life), and we have to work more carefully with prospectively collected registry data. All of this speaks to a need for more science[17]Trivedi P.J. Hirschfield G.M. Adams D.H. et al.Immunopathogenesis of primary biliary cholangitis, primary sclerosing cholangitis and autoimmune hepatitis: themes and concepts.Gastroenterology. 2024; https://doi.org/10.1053/j.gastro.2024.01.0149Crossref PubMed Google Scholar that encompasses many approaches and many stakeholders. But team science such as this will surely reap the reward of better therapies in the future. The authors did not receive any financial support to produce this manuscript. GMH has consulted for Intercept, Advanz, Ipsen, Cymabay, Pliant, Mirum, GSK, Kowa; AWL occasional lecture fees from Falk Pharma; consulting for investigational drugs and trial design for Genfit, Merck and Roche. Coordinator of the European Reference Network for Hepatological Diseases (ERN RARE-LIVER). Please refer to the accompanying ICMJE disclosure forms for further details. The authors contributed equally to the production of this manuscript. The following are the supplementary data to this article: Download .pdf (.21 MB) Help with pdf files Multimedia component 1