Use of mycophenolate in the treatment of autoimmune hepatitis

Autoimmune hepatitis (AIH) is a chronic progressive liver disease of unknown aetiology. It is thought to be caused by the dysregulation of the immune system. A number of possible triggering factors have been identified these include viruses, xenobiotics and drugs. The syndrome is characterized by elevated serum transaminase activity, hypergammaglobulinemia, high titre circulating organ non-specific auto-antibodies and interface hepatitis (1, 2). In those of northern European ethnicity, AIH is associated with the HLA haplotype DRB1*0301 and DRB1*0401, with other susceptibility alleles sharing a similar or identical motif in the DR.ß71 of the HLA class II molecule (3, 4). A working classification for the diagnosis of AIH was developed by the International Autoimmune Hepatitis working group who generated a scoring system, based on a combination of clinical, serological and histological criteria: a definite diagnosis was given when an aggregate scores >15 before treatment and >17 after treatment was achieved and probable AIH was defined as aggregate scores of 10–15 before treatment and 12–17 after treatment (1). This is useful both in clinical practice and in research but has some practical limitations. Several sub-types of AIH have been identified and the classification depends primarily on the pattern of auto-antibodies (5, 6). Type 1 AIH is seen most commonly and is characterized by anti-nuclear antibodies, anti-smooth muscle antibodies and perinuclear antineutrophil cytoplasmic antibodies; type 2, occurs in a younger age group and is associated with positive anti-liver kidney microsomal antibodies type 1 (1). The standard treatment for AIH is well-established and is based on treatment with corticosteroids and azathioprine and although prednisolone doses could be reduced, only a minority were able to be withdrawn completely (7-10). Of note, AIH was the first chronic liver disease where a significant improvement in patient survival was noted following drug treatment (11). Most, if not all, patients require long-term treatment with corticosteroids and azathioprine. Some can be maintained on monotherapy. For those patients who develop decompensated liver disease despite therapy, orthotopic liver transplantation is the treatment of choice (12). After transplantation, the patients are at risk of recurrent disease, which develops despite the use of immunosuppressive agents and may not respond to introduction or increased doses of corticosteroids (13-15). Remission will be achieved in over 80% of cases of those on prednisolone and azathioprine (16); thus, in up to 20%, alternative treatments must be considered. Alternative therapy may be required because of failure to achieve remission This may be because of an incorrect diagnosis, non-compliance and a few will fail to respond or require very high doses of corticosteroids to maintain remission. Intolerance of side effects is another reason for consideration of alternative therapy. Long-term use of glucocorticoids is complicated by many side effects including diabetes, osteoporosis and hypertension. There is also a small number of patients who cannot tolerate azathioprine because of side effects that may be symptomatic (such as nausea, vomiting, abdominal discomfort) or severe (such as pancreatitis, hepatotoxicity and bone marrow suppression) (16). A variety of alternative treatments have been tried for those who fail to respond fully to standard treatment (prednisolone and azathioprine) or who are intolerant of the side effects. Mostly, evidence of benefit is based on a very small series of patients, often heterogeneous; there have been very few large-scale prospective studies. There are several reasons for the lack of well conducted studies: the efficacy of standard treatment means that it is unlikely that any one centre has sufficient patients who have failed to respond who can be entered in a study; there are potential ethical dilemmas in undertaking a prospective randomized study comparing standard treatment with a novel therapy. Furthermore, such a study would need to overcome many hurdles, practical, regulatory and financial, thus making a prospective study comparing novel treatments with standard treatment unlikely to be achievable. Of the agents that may be used as alternatives to standard treatments, some are listed below: Budesonide, this is a second-generation glucocorticoid with high (90%) first-pass clearance by the liver and its metabolites exhibit no glucocorticoid activity (17). A major potential advantage over prednisolone is preservation of bone density. There were two previous reports of budesonide use in AIH, which showed conflicting results (18, 19). Deflazacort is an oxazoline derivative of prednisolone with both anti-inflammatory and immunosuppressive activities and a lower incidence of steroid-induced complications than prednisolone (20). One study in 15 patients showed that replacement of prednisolone by deflazacort resulted in maintained remission in all (21). Cyclosporine, is a calcineurin inhibitor that has been successfully used in patients with AIH as salvage therapy (22, 23). It binds to cyclophilin and inhibits the phosphatase activity of calcineurin thus impairing the transcription of IL-2. Side effects include nephrotoxicity, neurotoxicity, hypertension and hyperlipidemia. Tacrolimus (TAC) is another calcineurin inhibitor, with a mechanism of action and side-effect profile broadly similar to cyclosporine. It has shown to improve biochemical profile in AIH patients when given for 3 months (24). Cyclophosphamide is a cytotoxic agent and its use in AIH has been limited. One report showed induction of histological remission in three patients with severe AIH (25). 6-Mercaptopurine (6-MP) is an anti-proliferative agent and is the major metabolite of Azathioprine. Of three patients treated with 6-MP, improvement in biochemical and histological remission was noted in one patient and two patients were able to reduce the steroid dose (26). D-Penicillamine is a modified amino acid with anti-inflammatory activity and metal chelating properties. Toxicity requires discontinuation of therapy in up to 45% of patients and side effects include mucocutaneous, gastrointestinal, renal, haematological, pulmonary and autoimmune complications. Two controlled trials have shown sustaining remission in AIH patients but both found that there were significant side effects even at relatively low doses. The availability of less toxic agents argues against its use over standard therapy (27, 28). Methotrexate has been reported to be effective in normalization of liver enzymes, improved liver histology, maintain in remission with steroid sparing effect in previous case reports (29, 30). Ursodeoxycholic acid (UDCA), which in cholestatic liver diseases has a variety of effects on immune parameters as well as other effects such as inhibition of apoptosis and increase in bile flow, has been used as adjunctive therapy patients with in type 1 AIH; although there has been reported improvement in the liver enzymes over the short term (6 months), however, use of UDCA was not associated with a reduction in the dose of steroids, and did not affect clinical outcome or reduce histology activity (31). Although one study from Japan with eight patients has shown that clinical, biological and histological features of inflammation, but not those of fibrosis were improved if ursodeoxycholic was used for 2 years (32). MPA was first isolated and described in 1946 (33): mycophenolate is now used extensively in the management of liver; heart and kidney transplant recipients without reported hepatotoxicity (34-38). Indeed, in the USA, mycophenolate has largely replaced azathioprine in the maintenance regime of liver allograft recipients. Currently two formulations are available: an enteric formulation and an ester. Mycophenolate mofetyl (MMF) is an ester prodrug of MPA and is converted into MPA after oral absorption. MPA is a non-competitive inhibitor of inosine monophosphate dehydrogenase, which blocks the rate limiting enzymatic steps in de novo purine nucleotide synthesis thereby arresting DNA replication in T and B lymphocytes that are unable to use alternative salvage pathway (39, 40). Mycophenolate is well tolerated: leucopenia and diarrhoea are the main side effects. Unlike the calcineurin inhibitors, mycophenolate does not have neurotoxic or nephrotoxic side effects (34-36). Although mycophenolate is an effective immunosuppressive agent, it is expensive, especially in comparison with corticosteroids, azathioprine and many of the other agents that have been shown to be effective in AIH. Furthermore, it is potentially teratogenic and this may be a major factor in choice of treatment for a disease that often affects women of child-bearing years. Mycophenolate has been used in several other autoimmune diseases, such as rheumatoid arthritis and ulcerative colitis, but with limited effect. With regards to MMF, there were only few retrospective studies using it in refractory AIH or those who could not tolerate azathioprine. Richardson et al. (41) studied seven patients with type 1 AIH who were intolerant of azathioprine (three patients) or refractory to it (four patients). Patients received MMF (2 g/day) in addition to prednisolone over a median follow up of 46 months. Five of seven patients had normal transaminase after 3 months of treatment. Prednisolone requirement was reduced from a median of 20 to 2 mg/day after 9 months, with significant improvement in histology. One patient required MMF dose reduction because of fall in white cell count but no other adverse effects were noted. Devlin has reported five patients unresponsive or unable to take azathioprine, 6-mercaptourine or corticosteroid who were treated with MMF dose ranging from 500 mg to 2 g daily. It was noted that while on MMF, serum transaminases normalized in all patients. Histological remission was noted in one patient after 7 months of MMF. Use of MMF was associated with a steroid-sparing effect: the mean dose of prednisolone fell from 21.25 mg/day before MMF to 8.4 mg/day 1 year after starting MMF (42). Previously Schuppan also reported the use of MMF for therapy-refractory AIH (43). Chatur et al. in this issue of Liver International report their experience with the use of MMF in Canadian patients with AIH who were refractory or resistant to corticosteroids and/or azathioprine. Patients were identified by members of the Canadian Association for the Study of Liver (CASL). A total of 16 patients (three males, mean age at diagnosis 45 years, AIH score ranging from 12 to 17) were identified. These patients were followed up for an average of 26.5 months. Three were treated with TAC, 11 with MMF and two with combination of MMF and TAC. Complete response (CR), defined as sustained normalization of serum transaminase, was observed in 50%; a partial response (PR), defined as improvement in transaminase by greater than 50% from pretreatment level, was noted in 12.5%. Relapse was noted in 25% and non-response occurred in 12.5%. The CR to MMF without TAC was approximately 64%. The mean time to normalization of transaminases was 4.2 months; the mean dose of prednisolone fell from 20 mg/day pretreatment prednisolone dose to 4.7 mg in those with a CR or PR. Adverse effects were noted in five patients: three patients with gastrointestinal symptoms (one required dose reduction) one with leucopenia and thrombocytopenia and one (on TAC) with intractable abdominal pain required discontinuation of TAC. The group has concluded that MMF is effective and well tolerated in patients with AIH who do not respond to, or are intolerant of, conventional immunosuppressive agents (44). However, there are limitations to this study, which the authors acknowledge. The number of patients in the study is small. That this report is the result of a survey means that the patients included may be biased and unrepresentative; there was no common protocol for either the selection or the management of these patients, and this leads to variation in treatment regimes. There was a lack of histopathologic correlation before and after the mycophenolate treatment. Thus, the conclusions have to be drawn with caution. There are a small number of patients with AIH who need treatment other than prednisolone and azathioprine. A number of agents have been suggested to be effective but mostly in the context of small, uncontrolled and often retrospective studies. There is little evidence to show that any one agent is superior to another. Mycophenolate appears relatively safe and effective for those in whom standard therapy is not indicated, although it is expensive and should not be used in those who wish to become pregnant. Although mycophenolate is widely used and well tolerated, there is no strong evidence to show that it should be the first of the second-line therapies in those with AIH who require second-line therapies.

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