The Management of Autoimmune Hepatitis
The Management of Autoimmune Hepatitis
The guidelines of the AASLD and the BSG strongly endorse corticosteroid therapy as the front-line treatment of autoimmune hepatitis, but budesonide and mycophenolate mofetil have also been tested in this role. Neither drug has supplanted conventional corticosteroid therapy as initial treatment in autoimmune hepatitis, but their availability and supporting clinical experiences can complicate management decisions in certain patients.
Budesonide is a next-generation corticosteroid, and it has a 90% first-pass hepatic clearance and rapid degradation of activity to its metabolites (16 α-hydroxy prednisolone and 6 β-hydroxy budesonide). Budesonide (3 mg thrice daily) in combination with azathioprine (1–2 mg/kg daily) has normalised serum aminotransferase levels more commonly (47% vs. 18%) and with fewer side effects (28% vs. 53%) than prednisone (40 mg daily tapered to 10 mg daily) in combination with azathioprine (1–2 mg/kg daily) when used as a front-line therapy in a large randomised clinical trial for 6 months. Other small, nonrandomised, clinical experiences have documented similar results. The frequency of histological resolution and the durability of the response to budesonide are unknown. Furthermore, the low frequency of response (18%) and high frequency of side effects (53%) in patients randomised to standard therapy in the clinical trial are unexplained. These factors must be carefully weighed when formulating a decision regarding front-line therapy with budesonide.
The major justification for considering treatment with budesonide is to avoid corticosteroid-induced complications. The decision point must balance the frequency and severity of these drug-induced complications against uncertainties regarding the strength and extent of the immunosuppressive actions of budesonide compared to prednisone ( Table 5 ). Budesonide in combination with azathioprine did normalise serum aminotransferase levels more frequently than standard combination therapy with prednisone after 6 months. This experience, however, contrasts with that in other studies in which 91% of patients treated with conventional corticosteroid regimens normalised laboratory tests within 3 months. Furthermore, differences in the strength of anti-inflammatory, anti-proliferative, and anti-apoptotic properties have been recognised between the various corticosteroids in cell lines and animal models and the impact of these differences on human outcomes is uncertain.
Other considerations that must influence the decision to institute front-line therapy with budesonide are the stage of the liver disease at presentation and the presence of concurrent extrahepatic immune-mediated diseases. Typical corticosteroid-induced side effects are common in budesonide-treated patients with cirrhosis, presumably because of decreased first-pass hepatic clearance of the drug and increased systemic bioavailability. In other patients, exacerbations of extrahepatic immune-mediated diseases, such as vasculitis or synovitis, are possible, presumably because of high first-pass hepatic clearance of the drug and low systemic bioavailability. Budesonide is not effective as a salvage therapy for steroid-refractory disease, nor can it be easily switched with prednisone without incurring severe withdrawal symptoms. These limitations should counter any temptation to extend budesonide therapy beyond its front-line role in selected patients.
Treatment-naïve, noncirrhotic patients with uncomplicated autoimmune hepatitis seem to be the most appropriate candidates for therapy with budesonide in combination with azathioprine. Asymptomatic patients with mild or early-stage disease fit this profile, and other patients in whom there is reluctance to treat with prednisone or prednisolone (individuals with diabetes, hypertension, osteopenia or obesity) can also be considered.
Mycophenolate mofetil (starting dose, 1 g daily; final dose, 1.5–2 g daily) has also been used in combination with prednisolone (0.5–1 mg/kg daily) as a front-line therapy. Of 59 previously untreated individuals who received mycophenolate mofetil for up to 92 months (range, 3–92 months; mean, 26 months), 88% normalised serum aminotransferase and c-globulin levels (usually within 3 months) and 12% had a partial response. Corticosteroids were withdrawn in 58% (usually within 8 months), and serious side effects occurred in 3%. These findings proved the principle that mycophenolate mofetil could be used safely and effectively as front-line therapy for autoimmune hepatitis, but they did not establish a preference of this regimen over standard therapy.
The principal reason for considering mycophenolate mofetil as front-line treatment is the prospect of corticosteroid withdrawal. The frequency of laboratory improvement is comparable to that obtained by a standard combination regimen using azathioprine, and the expense of achieving this result is greater. Histological resolution is uncertain, and the ability to terminate therapy with mycophenolate mofetil is unknown. The side effects are similar to those associated with standard combination therapy with azathioprine, and the risk of teratogenicity in humans is established. The decision point must balance the uncertain prospect of complete corticosteroid withdrawal against well-defined disadvantages and salient uncertainties about treatment with this drug. The counterweight against front-line treatment with mycophenolate mofetil is heavy ( Table 5 ).
Uncertainties in Managing Treatment-naïve Patients With Nonstandard Drugs
The guidelines of the AASLD and the BSG strongly endorse corticosteroid therapy as the front-line treatment of autoimmune hepatitis, but budesonide and mycophenolate mofetil have also been tested in this role. Neither drug has supplanted conventional corticosteroid therapy as initial treatment in autoimmune hepatitis, but their availability and supporting clinical experiences can complicate management decisions in certain patients.
Budesonide as Front-line Therapy
Budesonide is a next-generation corticosteroid, and it has a 90% first-pass hepatic clearance and rapid degradation of activity to its metabolites (16 α-hydroxy prednisolone and 6 β-hydroxy budesonide). Budesonide (3 mg thrice daily) in combination with azathioprine (1–2 mg/kg daily) has normalised serum aminotransferase levels more commonly (47% vs. 18%) and with fewer side effects (28% vs. 53%) than prednisone (40 mg daily tapered to 10 mg daily) in combination with azathioprine (1–2 mg/kg daily) when used as a front-line therapy in a large randomised clinical trial for 6 months. Other small, nonrandomised, clinical experiences have documented similar results. The frequency of histological resolution and the durability of the response to budesonide are unknown. Furthermore, the low frequency of response (18%) and high frequency of side effects (53%) in patients randomised to standard therapy in the clinical trial are unexplained. These factors must be carefully weighed when formulating a decision regarding front-line therapy with budesonide.
The major justification for considering treatment with budesonide is to avoid corticosteroid-induced complications. The decision point must balance the frequency and severity of these drug-induced complications against uncertainties regarding the strength and extent of the immunosuppressive actions of budesonide compared to prednisone ( Table 5 ). Budesonide in combination with azathioprine did normalise serum aminotransferase levels more frequently than standard combination therapy with prednisone after 6 months. This experience, however, contrasts with that in other studies in which 91% of patients treated with conventional corticosteroid regimens normalised laboratory tests within 3 months. Furthermore, differences in the strength of anti-inflammatory, anti-proliferative, and anti-apoptotic properties have been recognised between the various corticosteroids in cell lines and animal models and the impact of these differences on human outcomes is uncertain.
Other considerations that must influence the decision to institute front-line therapy with budesonide are the stage of the liver disease at presentation and the presence of concurrent extrahepatic immune-mediated diseases. Typical corticosteroid-induced side effects are common in budesonide-treated patients with cirrhosis, presumably because of decreased first-pass hepatic clearance of the drug and increased systemic bioavailability. In other patients, exacerbations of extrahepatic immune-mediated diseases, such as vasculitis or synovitis, are possible, presumably because of high first-pass hepatic clearance of the drug and low systemic bioavailability. Budesonide is not effective as a salvage therapy for steroid-refractory disease, nor can it be easily switched with prednisone without incurring severe withdrawal symptoms. These limitations should counter any temptation to extend budesonide therapy beyond its front-line role in selected patients.
Treatment-naïve, noncirrhotic patients with uncomplicated autoimmune hepatitis seem to be the most appropriate candidates for therapy with budesonide in combination with azathioprine. Asymptomatic patients with mild or early-stage disease fit this profile, and other patients in whom there is reluctance to treat with prednisone or prednisolone (individuals with diabetes, hypertension, osteopenia or obesity) can also be considered.
Mycophenolate Mofetil as Front-line Therapy
Mycophenolate mofetil (starting dose, 1 g daily; final dose, 1.5–2 g daily) has also been used in combination with prednisolone (0.5–1 mg/kg daily) as a front-line therapy. Of 59 previously untreated individuals who received mycophenolate mofetil for up to 92 months (range, 3–92 months; mean, 26 months), 88% normalised serum aminotransferase and c-globulin levels (usually within 3 months) and 12% had a partial response. Corticosteroids were withdrawn in 58% (usually within 8 months), and serious side effects occurred in 3%. These findings proved the principle that mycophenolate mofetil could be used safely and effectively as front-line therapy for autoimmune hepatitis, but they did not establish a preference of this regimen over standard therapy.
The principal reason for considering mycophenolate mofetil as front-line treatment is the prospect of corticosteroid withdrawal. The frequency of laboratory improvement is comparable to that obtained by a standard combination regimen using azathioprine, and the expense of achieving this result is greater. Histological resolution is uncertain, and the ability to terminate therapy with mycophenolate mofetil is unknown. The side effects are similar to those associated with standard combination therapy with azathioprine, and the risk of teratogenicity in humans is established. The decision point must balance the uncertain prospect of complete corticosteroid withdrawal against well-defined disadvantages and salient uncertainties about treatment with this drug. The counterweight against front-line treatment with mycophenolate mofetil is heavy ( Table 5 ).
