Adverse Events Related to Low Dose Corticosteroids in Autoimmune Hepatitis

Floris F. van den Brand; Koen S. van der Veen; Birgit I. Lissenberg-Witte; Ynto S. de Boer; Bart van Hoek; Joost P. H. Drenth; Robert C. Verdonk; Jan M. Vrolijk; Carin M. J. van Nieuwkerk; Gerd Bouma

Disclosures

Aliment Pharmacol Ther. 2019;50(10):1120-1126. 

In This Article

Abstract and Introduction

Abstract

Background: Autoimmune hepatitis requires long-term therapy, and systemic corticosteroids are the backbone of therapeutic management. Prolonged use of corticosteroids may lead to adverse events but data from long-term studies are mainly derived from studies in rheumatic diseases.

Aim: To assess cataract, diabetes and fractures in relation to corticosteroid doses in the long-term maintenance treatment of patients with autoimmune hepatitis.

Methods: We retrospectively collected data on 476 patients (77% women) with an established diagnosis of autoimmune hepatitis. Binary logistic regression with a generalised estimating equation was used to analyse the association between current corticosteroid use and the incidence of cataract, diabetes and fractures with onset after autoimmune hepatitis diagnosis. We corrected for sex, age, cirrhosis at diagnosis and predniso(lo)ne use in the prior 3 years to account for possible ongoing effects.

Results: A total of 6634 years, with a median of 13 (range 1–40) per patient were recorded. The median age at diagnosis was 44 years (range 2–88). Adverse events were documented in 120 (25%) patients. Low-dose predniso(lo)ne (0.1–5.0 mg/d) increased the odds of fractures whereas higher doses (>5.0 mg/d) increased the odds of cataracts and diabetes. Budesonide increased the odds of cataract and fractures; this effect was independent of predniso(lo)ne use in the prior 1, 2 or 3 years.

Conclusions: Even low doses of corticosteroids frequently lead to substantial adverse events refuting the assumption that adverse events are prevented by administering low doses.

Introduction

Autoimmune hepatitis is a severe immune-mediated inflammation of unknown aetiology that primarily targets hepatocytes. Treatment is aimed to prevent disease relapse, relieve symptoms and achieve full biochemical and histological normalisation in order to prevent progression to fibrosis, cirrhosis and end-stage liver failure requiring liver transplantation. Since the introduction of prednisone, survival has improved dramatically.[1] Unfortunately, most patients require life-long immunosuppressive therapy, as relapse after cessation of therapy has been shown in up to 90% of patients.[2] In early clinical trials, it was found that the addition of azathioprine decreased steroid-related side effects and that this combination was as effective as prednisone alone. Currently, treatment regimens for autoimmune hepatitis are based on these trials and 44%-75% of patients require a glucocorticosteroid-based maintenance therapy, with or without azathioprine.[3,4] Up to 30% of these patients may suffer from corticosteroid-related side effects, including diabetes, osteoporotic fractures, cataract, hypertension, cushingoid appearance and weight gain.[5] Corticosteroid-specific side effects are thought to arise in autoimmune hepatitis patients on doses exceeding 7.5–10 mg/d predniso(lo)ne when administered over several months and it is advocated to reduce the dose below this threshold to prevent adverse events.[6] However, studies on dose-related side effects of corticosteroids supporting this assumption have predominantly been performed in rheumatic diseases, and data on the prevalence of side effects in patients with autoimmune hepatitis on long-term corticosteroids are scarce.[7]

In this study, we focused on three frequently occurring and documented adverse events. We aimed to assess the incidence of cataract, diabetes and osteoporotic fractures in relation to corticosteroid doses in the long-term maintenance treatment of patients with autoimmune hepatitis.[8]

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