The combination of budesonide plus azathioprine achieves and maintains remission of autoimmune hepatitis as well as standard prednisone therapy does, while sparing patients many of the adverse effects of steroids, Dr. Michael P. Manns and his colleagues said in an article appearing in the October issue of Gastroenterology.
The drug combination may well become “a new standard of care for noncirrhotic patients with autoimmune hepatitis,” wrote Dr. Manns of Hannover (Germany) Medical School and his associates in the journal Gastroenterology (Oct. 2010 [doi: 10.1053/j.gastro.2010.06.046]).
They compared the safety and efficacy of the budesonide combination with the standard therapy of prednisone with azathioprine. The researchers described the study as the largest prospective, randomized, multicenter trial published to date for the treatment of autoimmune hepatitis.
In the first phase of the study, 208 patients aged 10-70 years were randomly assigned to receive budesonide (103 subjects) or prednisone (105 subjects) with azathioprine for 6 months. Budesonide was given in 3-mg oral doses three times daily, a regimen that was decreased to twice daily if remission occurred. Prednisone was started at 40 mg/day and tapered to 10 mg/day.
Azathioprine was administered at a dose of 1-2 mg/kg per day, according to the clinician’s judgment. None of the study subjects had any evidence of cirrhosis.
A total of 176 subjects completed this phase. Reasons for withdrawal included lack of efficacy (3 patients taking budesonide and 12 taking prednisone), adverse events (3 patients taking budesonide, 3 taking prednisone), and lack of compliance with the study protocol (4 patients taking budesonide, 2 taking prednisone).
In the second, open-label phase of the study, all 176 subjects received budesonide plus azathioprine for a further 6 months.
The primary end point was complete biochemical remission of autoimmune hepatitis and the absence of steroid-related adverse effects such as moon face, acne, buffalo hump, hirsutism, striae, diabetes, glaucoma, or increased intraocular pressure.
At the conclusion of the first phase of the study, 47% of the budesonide group achieved this end point, compared with only 18% of the prednisone group.
At the conclusion of the second phase, 55% of the study subjects achieved complete biochemical remission.
The incidence of steroid-related adverse effects was significantly lower after 6 months of budesonide therapy than after 6 months of prednisone therapy. After the second phase of the study, when all the subjects were taking budesonide, there was a reduction of approximately 40% in the incidence of common steroid-related adverse effects.
A post hoc analysis of the data from the first phase of the study showed that budesonide was more effective than prednisone regardless of a patient’s sex, body weight, or HLA type status (DR3 or DR4).
“The potential influence of inflammatory activity was investigated by comparing patients showing high or low aminotransferase levels. Significantly higher rates of complete biochemical response were observed in the budesonide treatment arm vs. prednisone in both subpopulations,” Dr. Manns and his colleagues said.
When adult patients were analyzed separately, the rate of complete remission remained significantly higher with budesonide (67%) than with prednisone (41%). This indicates that “the inclusion of children does not [affect] the overall results of this study,” the researchers noted.
Both study medications were well tolerated. Adverse effects included weight gain (6% of patients taking budesonide and 19% of those taking prednisone), headache (12% and 8%, respectively), mood alterations (10% and 8%), muscular weakness (5% and 8%), hypertension (3% and 7%), and insomnia (1% and 5%).
Further studies are needed to clarify the long-term effects of budesonide therapy, particularly with regard to steroid-specific effects such as an adverse impact on bone metabolism, Dr. Manns and his associates said.
This study was supported by Dr. Falk Pharma GmbH. The investigators reported ties to GlaxoSmithKline, Novartis, Abbott Labs, Essex Pharma GmbH, Roche, and Boehringer Ingelheim GmbH.