Budesonide may be an acceptable second-line treatment for autoimmune hepatitis among patients who experience steroid-induced side effects or who are dependent on high doses of prednisolone, a retrospective single-center analysis suggested.
Among 60 patients who were switched to budesonide from prednisolone, 55% were considered responders after 6 months of treatment, as were 70% after 12 months, according to Christoph Schramm, MD, and colleagues from University Medical Center Hamburg-Eppendorf in Germany.
In addition, the rates of biochemical response — defined as normalization of serum levels of aminotransferases and IgG — were 68% after 24 months and 70% after 36 months, the researchers reported in Clinical Gastroenterology and Hepatology.
Autoimmune hepatitis is characterized by liver inflammation, high levels of aminotransferases and IgG, and the presence of circulating autoantibodies such as antinuclear antibodies (ANA) and smooth muscle antibodies (SMA). Standard treatment involves corticosteroids alone or with azathioprine.
Prednisolone typically has been favored because of its efficacy in controlling liver inflammation, but an estimated 44% of patients develop steroid-associated side effects with this agent, and up to 15% are refractory and require alternative treatments.
Budesonide is a synthetic steroid derived from 16α-hydroxyprednisolone that has fewer adverse effects than prednisolone because its hepatic first-pass clearance exceeds 90%. This drug is not recommended for patients with cirrhosis because of adverse events associated with portosystemic shunting.
Previous studies evaluating budesonide in autoimmune hepatitis have had conflicting results, with one randomized trial showing efficacy for both remission and maintenance after 6 and 12 months but another showing low rates of response at 6 months. Moreover, longer-term data are sparse, and autoimmune hepatitis often requires lifelong therapy.
Therefore, to explore a possible role for budesonide among patients with inadequate responses or intolerance to prednisolone, Schramm and colleagues retrospectively analyzed data that had been collected prospectively at their center from 2001 to 2016.
Among 328 patients with autoimmune hepatitis in their database, 60 (51 women) had been switched to budesonide from prednisolone — 30 because of side effects and 30 because of the inability to taper the steroid dose sufficiently. The mean age at the time of diagnosis was 42, and most patients were positive for both ANA and SMA.
Concomitant autoimmune diseases were present in some patients, such as thyroid disease in 12%, diabetes in 7%, rheumatoid arthritis in 3%, and lupus in 2%.
The mean duration of prednisolone therapy before switching was 47 months, and the mean daily dose was 8.5 mg.
In 10 patients, budesonide was given as monotherapy, while 40 also received azathioprine, six were given mycophenolate mofetil (CellCept), and two received 6-mercaptopurine.
Mean alanine aminotransferase levels were 123 U/L at the beginning of budesonide treatment, declining to 45.7 U/L at 6 months (P<0.001) and thereafter remaining stable through 36 months, when the mean level was 50.3 U/L.
The mean serum IgG levels also declined, from 14.2 g/L at budesonide initiation to 12.2 g/L at 6 months (P=0.006), and were 12.8 g/L at 36 months.
The mean dose of budesonide was 9 mg/day at baseline, and the mean maintenance dosage was 6.2 mg/day.
Among patients who had switched to budesonide because of adverse effects with prednisolone, responses at 6, 12, 24, and 36 months were seen in 50%, 65%, 70%, and 72% of patients, respectively.
Among those who switched because of the inability to taper prednisolone, responses at those time points were seen in 60%, 75%, 64%, and 69%, respectively. The mean dosages were 5.8 mg after 6 months and 5.1 mg/day after 36 months, “showing efficacy of medium doses of budesonide in the group of patients with prior prednisolone dependency,” the authors noted.
A total of 17 patients switched back to prednisolone after a mean of 17.1 months, because of side effects or lack of efficacy. In nine of these, there was a flare of aminotransferase levels, three developed cirrhosis, and one had new onset bullous pemphigoid.
Among 15 patients who had osteopenia during prednisolone treatment, six had improved T-scores and eight remained stable during budesonide therapy, while only one had T-score worsening.
The lack of bone mineral density deterioration during budesonide treatment supports the use of this treatment approach among patients who did not respond to prednisolone, the authors suggested. “However, treatment efficacy and tolerance must be monitored because efficacy of budesonide may not suffice to maintain remission or control concomitant autoimmune disease and budesonide-induced side effects may occur in patients even in the absence of cirrhosis.”
In an accompanying editorial, Michael P. Manns, MD, of Hannover Medical School in Germany, and two colleagues said there is a need for additional treatments for autoimmune hepatitis that utilize different mechanisms of action, such as calcineurin inhibitors and monoclonal antibodies including rituximab (Rituxan) and infliximab (Remicade).
“It is hoped that ongoing initiatives will lead to a consensus approach for the development of effective second-line therapies for this difficult-to-treat group of patients,” the editorialists stated.
The limitations of the study, Schramm and colleagues wrote, included the retrospective design and the single tertiary care setting.
The study was supported by the YAEL Foundation, the German Research Foundation, and the Helmut and Hannelore Greve Foundation.
The Schramm and c0-authors reported financial relationships with the Falk Foundation and Falk Pharma.
The editorialists reported financial relationships with Novartis, Basel, the Falk Foundation, and the Falk Pharma.
F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner