Mycophenolate for the treatment of autoimmune hepatitis: Prospective assessment of its efficacy and safety for induction and maintenance of remission in a large cohort of treatment-naïve patients

Background & Aims

Standard therapy for autoimmune hepatitis (AIH) is corticosteroids with or without azathioprine. However, 20% of patients do not respond or are intolerant to conventional treatment. Therefore, we evaluated prospectively the efficacy and safety of mycophenolate mofetil (MMF) in inducing and/or maintaining remission in treatment-naïve AIH patients.

Methods

Fifty-nine treatment-naïve patients with well defined AIH were treated with prednisolone plus 1.5–2 g/d of MMF. Patients were candidates for MMF withdrawal after at least 4 years. Treatment outcomes were defined according to the International Autoimmune Hepatitis Group report.

Results

Treatment duration with MMF was 26 months (range 3–92). Eighty-eight percent (52/59) of patients responded initially clinically and biochemically (normalization of transaminases and γ-globulins) most of them within 3 months. The remaining 7 patients (12%) had partial response. In total, 59.3% (35/59) of patients had complete response (CR) with 37% (22/59) of them having achieved CR off prednisolone, while 28.8% (17/59) had initial CR with relapses. No patient was non-responder. Prednisolone withdrew in 57.6% (34/59) of patients in 8 months. The only independent predictor of treatment outcome, was γ-GT (baseline γ-GT, p = 0.008 and γ-GT on month 24, p <0.05). Severe side effects leading to MMF discontinuation occurred in only 3.4% (2/59) of patients. Six patients (2 according to protocol and 4 for personal reasons), stopped treatment with MMF, but 3 relapsed.

Conclusions

MMF seems safe and effective as first-line therapy in inducing and maintaining remission in treatment-naive patients with AIH, having a significant and rapid steroid sparing effect as attested by the fact that so far, 37% (22/59) of AIH patients achieved CR off prednisolone.

Introduction

Autoimmune hepatitis (AIH) is an unresolving, progressive liver disease characterized by hypergammaglobulinaemia, circulating autoantibodies, and interface hepatitis [1], [2], [3]. The prognosis of untreated patients is poor, and 10-year-survival has been reported to be as low as 10% [4], [5].

Since the early 1970s, corticosteroids, often in combination with azathioprine (AZT), have been the standard therapy for AIH established by four classic randomized controlled trials [4], [6], [7], [8]. Many patients can be maintained in remission for variable periods, but a true cure is rare. Furthermore, over 20% of patients do not respond to or are intolerant of conventional corticosteroid therapy [9], [10] and 50–86% relapse when treatment is withdrawn. Repeated re-treatments and relapses are associated with an increasing cumulative frequency of cirrhosis and liver failure, and prolonged or indefinite immunosuppressive therapy may be required [11], [12], [13].

Side effects associated with standard corticosteroid therapy are well described and include cosmetic changes, osteoporosis, diabetes, cataract formation, and hypertension [9], [10]. AZT, a non-selective immunosuppressant that acts by inhibition of several enzymes involved in purine synthesis, can also contribute to the toxicity of standard therapy by inducing nausea, vomiting, rash, cytopenia, pancreatitis, and cholestasis in at least 10% of patients [14]. In addition, the measurement of AZT metabolites neither provides a foolproof way of avoiding toxicity nor predicts response, and it is time consuming and not widely available [15], [16].

The pathogenic mechanisms for the loss of self-tolerance in AIH have not been fully elucidated, but a defect in homeostatic processes leading to both autoantibody production and induction of autoreactive CD4 and CD8 T-cells has been implicated [17]. Alternative immunosuppressive agents, such as cyclosporine, tacrolimus, and mycophenolate mofetil (MMF) constitute a core repertoire of regimens with selective actions that target critical pathogenic pathways in AIH [9], [10], [18]. Cyclosporine and tacrolimus have been used as salvage therapy in AIH but they proved to have significant side effects hampering their use as maintenance therapy [19], [20], [21]. MMF inhibits selectively the activated T and B lymphocyte, with minimal side effects [22].

MMF has largely supplanted AZT as an agent in multi-drug post-transplant immunosuppressant regimens in organ transplantation. Furthermore, MMF has recently passed from the transplantation field to the armamentarium in the treatment of autoimmune rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), and vasculitis [23]. Multiple small single-center studies have also indicated that MMF can be useful in patients with AIH who are either intolerant of AZT or who have disease refractory to standard treatment with corticosteroids and AZT [24], [25], [26], [27], [28], [29], [30], [31]. However, the small number of patients included in these studies has led to limited conclusions about the tolerability and efficacy of MMF in AIH. Furthermore, the studies focused on the use of MMF as salvage therapy and only a few small studies have assessed MMF as front-line treatment [31], [32].

The objective of this study was to evaluate the effectiveness, tolerability, and safety of MMF in inducing and/or maintaining remission of AIH in a large number of treatment naïve AIH patients studied prospectively in a non-controlled setting.