Role of mycophenolate mofetil in the treatment of autoimmune hepatitis

Abstract

More than 30 years ago controlled clinical trials demonstrated that treatment with steroids improves the outcome of patients with autoimmune hepatitis (AIH) decisively. Azathioprine was soon found to add benefit in the therapy of AIH and was shown to be the drug of choice for maintenance therapy. Since then, corticosteroid monotherapy and the combination of steroids with azathioprine have become the standard of treatment for AIH [1,2]. The excellent response rates and the fact thatAIH is a raredisease requiringmulticenter efforts on theonehandand limitedcommercial benefit on the other hand have led to a lack of larger controlled clinical trials evaluating alternative first line treatment options thereafter. Using high dose prednisolone initially (0.5–1 mg/kg/d) in combination with azathioprine at a dose of 1–1.5 mg/kg/d in patients not severely jaundiced leads to complete and partial biochemical response rates in over 90% of patients within the first year of treatment and to an excellent long term survival [3,4]. This regimen is frequently used in European countries. One could, therefore, argue that there is no need for alternative first line treatments of AIH. However, up to 10% of patients do not respond sufficiently to the combination of prednisolone and azathioprine and another 5–10% experience side effects requiring treatment modification [1,5]. Side effects include the more frequent gastrointestinal complaints induced by azathioprine but also serious toxicity such as pancreatitis, cholestatic hepatitis, and neutropenia. Steroid related side effects include the multiple short term effects of high dose steroid therapy such as weight gain, diabetes, and psychosis and the long term effects on bone, eyes, and skin among others [1]. Budesonide has recently been demonstrated as a potential alternative for prednisolone with possibly less steroid side-effects in the so far largest controlled clinical trial of AIH [6], but the clinical value of budesonide remains controversial [2]. In this context, the study by Zachou et al. reported in this issue of the Journal [7] evaluated mycophenolate mofetil (MMF) in combination with prednisolone as an alternative to azathioprine in the first line treatment of AIH. MMF is a prodrug of mycophenolic acid, which is an inhibitor of inosine monophosphate dehydrogenase, the rate limiting enzyme in the de novo purine synthesis which is required for the proliferation of Band T-lym-