Autoimmune hepatitis: A life-long disease
Authors: Christina Weiler-Normann, Ansgar W. Lohse
Journal: Journal of Hepatology (2012)

Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remissionJournal of HepatologyVol. 58Issue 1PreviewCurrent treatment strategies in autoimmune hepatitis (AIH) include long-term treatment with corticosteroids and/or azathioprine. Here we determined the risk of relapse after drug withdrawal in patients in long-term remission and factors associated with such a relapse. Full-Text PDF The immune system is build on the basis of genetic and epigenetic factors, and shaped by constant and repeated internal and external challenges. Autoimmune disease appears to arise as a consequence of unknown external triggers in a susceptible host. Susceptibility develops on a predetermined genetic background [[1]Lohse A.W. Mieli-Vergani G. Autoimmune hepatitis.J Hepatol. 2011; 55: 171-182Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar], and is probably influenced by multiple environmental factors and life events such as infections. Once clinically apparent autoimmune disease has developed, the predisposition is so strong that cure is very rare indeed. This applies to such diverse autoimmune diseases as multiple sclerosis [[2]Weiner H.L. The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease?.Ann Neurol. 2009; 65: 239-248Crossref PubMed Scopus (291) Google Scholar], lupus [[3]Bertsias G.K. Salmon J.E. Boumpas D.T. Therapeutic opportunities in systemic lupus erythematosus: state of the art and prospects for the new decade.Ann Rheum Dis. 2010; 69: 1603-1611Crossref PubMed Scopus (95) Google Scholar], type 1 diabetes [[4]Michels A.W. Eisenbarth G.S. Immune intervention in type 1 diabetes.Semin Immunol. 2011; 23: 214-219Crossref PubMed Scopus (39) Google Scholar] or rheumatoid arthritis [[5]Machold K.P. Prevention and cure of rheumatoid arthritis: is it possible?.Best Pract Res Clin Rheumatol. 2010; 24: 353-361Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. To an immunologist, it does therefore not come as a surprise that autoimmune hepatitis (AIH) behaves similarly, and that most patients require life-long treatment as reported in this issue of the Journal [[6]van Gerven N.M. Verwer B.J. Witte B.I. Hoek B.V. Coenraad M.J. van Erpecum K.J. et al.Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remission.J Hepatol. 2013; 58: 141-147Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar]. However, this message does come as a surprise to the patient. And it often also comes as a surprise to the treating hepatologist. Patients want diseases to disappear, and as physicians we like to share our patients' optimism. In case of autoimmune hepatitis, the mostly excellent response to immunosuppressive therapy [[7]Yoshizawa K. Matsumoto A. Ichijo T. Umemura T. Joshita S. Komatsu M. et al.Long-term outcome of Japanese patients with type 1 autoimmune hepatitis.Hepatology. 2012; 56: 668-676Crossref PubMed Scopus (89) Google Scholar] and the usually asymptomatic course of AIH in remission make it all the more tempting to try and withdraw treatment. Furthermore, the possible side effects of immunosuppressive drug treatment make a trial of treatment withdrawal even more attractive. Like in all other chronic diseases, it is difficult to know which drug schedule and which dosages should be applied and for how long. The published guidelines give only very little help in these decisions and the data on which these are based are scarce [8Gleeson D. Heneghan M.A. British Society of Gastroenterology (BSG) guidelines for management of autoimmune hepatitis.Gut. 2011; 60: 1611-1629Crossref PubMed Scopus (213) Google Scholar, 9Manns M.P. Czaja A.J. Gorham J.D. Krawitt E.L. Mieli-Vergani G. Vergani D. et al.Diagnosis and management of autoimmune hepatitis.Hepatology. 2010; 51: 2193-2213Crossref PubMed Scopus (1108) Google Scholar, 10Montano-Loza A.J. Carpenter H.A. Czaja A.J. Consequences of treatment withdrawal in type 1 autoimmune hepatitis.Liver Int. 2007; 27: 507-515Crossref PubMed Scopus (96) Google Scholar]. The study by van Gerven et al. [[6]van Gerven N.M. Verwer B.J. Witte B.I. Hoek B.V. Coenraad M.J. van Erpecum K.J. et al.Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remission.J Hepatol. 2013; 58: 141-147Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar] describing the relapse rate in a large group of patients observed in various centers in the Netherlands is therefore a very welcome addition to the literature, and the message is sobering: even when being selective in choosing patients in whom a trial of treatment withdrawal is undertaken, the vast majority relapse, and very few patients indeed maintain remission without continued therapy. Relapse is usually early, but may sometimes be late, and a longer observation period in this study might have increased this figure even further. The study is based on a retrospective analysis of a national registry, and therefore has a number of almost inevitable methodologically weak points. Most importantly, parameters considered essential before trying to stop treatment were missing in many patients. Only 51% of these patients had received measurement of their IgG levels, and only 18% had received a liver biopsy prior to reduction of immunosuppression. IgG levels in particular are essential in defining remission [[11]Lüth S. Herkel J. Kanzler S. Frenzel C. Galle P.R. Dienes H.P. et al.Serologic markers compared with liver biopsy for monitoring disease activity in autoimmune hepatitis.J Clin Gastroenterol. 2008; 42: 926-930Crossref PubMed Scopus (115) Google Scholar], and only patients with repeatedly normal IgG can be considered to be in stable remission [[12]Montano-Loza A.J. Carpenter H.A. Czaja A.J. Improving the end point of corticosteroid therapy in type 1 autoimmune hepatitis to reduce the frequency of relapse.Am J Gastroenterol. 2007; 102: 1005-1012Crossref PubMed Scopus (132) Google Scholar], thus potentially qualifying for a trial of drug withdrawal. Furthermore, the time in remission of patients withdrawn from treatment was in some patients shorter than generally recommended. In addition, almost half of these patients still had dual therapy (steroids plus azathioprine) when treatment withdrawal was started, while most textbooks and treatment guidelines [[8]Gleeson D. Heneghan M.A. British Society of Gastroenterology (BSG) guidelines for management of autoimmune hepatitis.Gut. 2011; 60: 1611-1629Crossref PubMed Scopus (213) Google Scholar] recommend stable remission on monotherapy (usually azathioprine) before trying to taper out all treatment. Finally, autoantibody testing was incomplete, and the given information limited: patients were apparently not tested for SLA/LP antibodies, and the number of LKM-positive patients is not shown. Both autoantibodies have been described as predictors of relapse [[13]Kanzler S. Gerken G. Lohr H. Galle P.R. Meyer zum Buschenfelde K.H. Lohse A.W. Duration of immunosuppressive therapy in autoimmune hepatitis.J Hepatol. 2001; 34: 354-355Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar], and most specialists would recommend life-long treatment in patients positive for either of these two characteristic autoantibodies. At the same time, the study has some important strengths not to be found in earlier reports on this subject. The study is based on a large patient population of altogether 844 AIH cases collected from 21 Dutch treatment centers, mostly not highly specialized referral centers, and therefore is likely to reflect everyday practice quite well. It is therefore particularly sobering to see that out of this large group of patients so few could safely been withdrawn of all treatment: treatment withdrawal was only attempted in a selected 16% of the whole group; almost half of these developed a flare while still on a reduced dose of drugs and only 1.7% of the overall patient group ended up without drugs. The conclusion that with very few exceptions AIH is a chronic disease requiring long-term and mostly life-long treatment is thus very convincing. Can we predict in whom withdrawal of immunosuppressive treatment might be successful? There are hints in this study, and there are hints in the literature [13Kanzler S. Gerken G. Lohr H. Galle P.R. Meyer zum Buschenfelde K.H. Lohse A.W. Duration of immunosuppressive therapy in autoimmune hepatitis.J Hepatol. 2001; 34: 354-355Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 14Yokokawa J. Kanno Y. Saito H. Abe K. Takahashi A. Yokokawa H. et al.Risk factors associated with relapse of type 1 autoimmune hepatitis in Japan.Hepatol Res. 2011; 41: 641-646Crossref PubMed Scopus (20) Google Scholar, 15Czaja A.J. Menon K.V. Carpenter H.A. Sustained remission after corticosteroid therapy for type 1 autoimmune hepatitis: a retrospective analysis.Hepatology. 2002; 35: 890-897Crossref PubMed Scopus (145) Google Scholar, 16Al-Chalabi T. Heneghan M.A. Remission in autoimmune hepatitis: what is it, and can it ever be achieved?.Am J Gastroenterol. 2007; 102: 1013-1015Crossref PubMed Scopus (27) Google Scholar, 17Kanzler S. Lohr H. Gerken G. Galle P.R. Lohse A.W. Long-term management and prognosis of autoimmune hepatitis (AIH): a single center experience.Z Gastroenterol. 2001; 39 (344–348): 339-341Crossref PubMed Scopus (112) Google Scholar]. New in the present study is that younger age correlated with relapse, as did the presence of extra-hepatic autoimmune disease. Both findings are not surprising. Pediatric hepatologists have always recommended that immunosuppression should not be stopped in children with AIH [[18]Mieli-Vergani G. Vergani D. Autoimmune liver diseases in children – what is different from adulthood?.Best Pract Res Clin Gastroenterol. 2011; 25: 783-795Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar], and that first manifestation of the disease in childhood usually requires life-long therapy. The co-existence of other autoimmune diseases in the same patient is likely to indicate a stronger susceptibility for autoimmunity. Scientifically, these findings may not come as a surprise, but clinically, they can be very helpful in the daily management of AIH patients, as they warn us to be particularly hesitant with a trial of drug withdrawal in these two patient groups. It should also warrant an active search for concomitant autoimmune diseases. Even if drug withdrawal appears to be successful and the patient is in biochemical remission more than 1 year later, the patient remains an AIH patient: late relapse can occur. Relapse more than 20 years after successful drug withdrawal has been described in the literature [[19]Czaja A.J. Late relapse of type 1 autoimmune hepatitis after corticosteroid withdrawal.Dig Dis Sci. 2010; 55: 1761-1769Crossref PubMed Scopus (25) Google Scholar], and we have observed similar cases. Frequent laboratory controls will be necessary in the first years after treatment withdrawal [[1]Lohse A.W. Mieli-Vergani G. Autoimmune hepatitis.J Hepatol. 2011; 55: 171-182Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar], and regular (at least yearly) testing of both transaminases and IgG levels thereafter is essential. The threshold to reinstitute immunosuppression should be low. In particular so, because AIH may run a subclinical course, and cirrhosis may progress without symptoms [[1]Lohse A.W. Mieli-Vergani G. Autoimmune hepatitis.J Hepatol. 2011; 55: 171-182Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar] – this preventable complication should not occur. Attention should be paid to rising IgG levels even within the normal limit, as a clear increase for example from low normal to high normal values is likely to indicate renewed disease activity. What are the scientific questions arising from this study? We should try to understand better the underlying susceptibility factors that cause AIH, and that might predict who has a chance of a stable drug-free remission. We should try to identify predictors beyond those discussed in this study: disease presentation, time to remission, drug-dosage required for remission induction, autoantibody profiles and titres, IgG levels and ALT levels, including variations in the normal range, histological features at presentation and during treatment, remission duration, etc. In addition to these more biological factors, we need to address the psychological features of managing this chronic disease: compliance with the recommended treatment was recently shown to be an important factor [[20]Sockalingam S. Blank D. Abdelhamid N. Abbey S.E. Hirschfield G.M. Identifying opportunities to improve management of autoimmune hepatitis: evaluation of drug adherence and psychosocial factors.J Hepatol. 2012; 57: 1299-1304Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar], and treatment adherence in a chronic disease requiring daily medication with potentially toxic drugs may be very difficult. In managing patients wishing to withdraw treatment, different approaches may be appropriate and should be adapted to the individual wishes and fears of the patient (Fig. 1). Textbooks and guidelines [6van Gerven N.M. Verwer B.J. Witte B.I. Hoek B.V. Coenraad M.J. van Erpecum K.J. et al.Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remission.J Hepatol. 2013; 58: 141-147Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 8Gleeson D. Heneghan M.A. British Society of Gastroenterology (BSG) guidelines for management of autoimmune hepatitis.Gut. 2011; 60: 1611-1629Crossref PubMed Scopus (213) Google Scholar, 9Manns M.P. Czaja A.J. Gorham J.D. Krawitt E.L. Mieli-Vergani G. Vergani D. et al.Diagnosis and management of autoimmune hepatitis.Hepatology. 2010; 51: 2193-2213Crossref PubMed Scopus (1108) Google Scholar, 10Montano-Loza A.J. Carpenter H.A. Czaja A.J. Consequences of treatment withdrawal in type 1 autoimmune hepatitis.Liver Int. 2007; 27: 507-515Crossref PubMed Scopus (96) Google Scholar] recommend liver biopsy prior to a trial of treatment withdrawal, and no such trial if the biopsy shows relevant inflammatory activity (usually a hepatitis activity index (HAI-Score) of 3 or more). However, in daily practice we often take another approach after careful discussion with the patient: as most patients strongly wish to try treatment withdrawal, and as we prefer to undertake such a trial under our supervision rather than the patient doing it secretly (or not coming back), we discuss such a trial after a minimum of 3 years of stable remission. We strongly discourage such a trial in patients requiring dual immunosuppression or experiencing flares during maintenance therapy, as failure is certain. In all other patients, we discuss the option of biopsy or a trial of treatment withdrawal without biopsy, and insist on close monitoring. The majority of patients opt for a trial of treatment withdrawal without biopsy. In most patients, relapse tends to occur early, and if treatment withdrawal in undertaken slowly and stepwise, relapse occurs gradually. As soon as a relapse is definite (in some patients this may require biopsy to demonstrate relapse beyond doubt), immunosuppression is reinstituted, usually with a short course of dual therapy, going back to monotherapy within 3 months. The approach may be less scientific, but very effective: we find that patient compliance is greatly improved by such a trial, and the acceptance for a long-term, usually life-long immunosuppression at the lowest effective dose is greatly enhanced after such a failure of treatment withdrawal. The most important message is, as clearly shown by the present study: AIH is a chronic disease, no matter how acute the first presentation, close medical supervision is essential, and the vast majority of patients require permanent treatment. Communicating the high probability of a long-term, perhaps life-long need for immunosuppressive medication early on when diagnosis is established may not please the patient but ultimately will help develop a trusting relationship between patient and physician [[21]Weiler-Normann C. Lohse A.W. Treatment adherence – room for improvement, not only in autoimmune hepatitis.J Hepatol. 2012; 57: 1168-1170Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. Assisting the patient to accept this need, finding the lowest effective dose of the drugs tolerated best by this individual patient and motivation for the necessary drug-adherence will improve life expectancy, long-term outcome and patient satisfaction. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.