Case–Control Study on Prednisolone Combined With Ursodeoxycholic Acid and Azathioprine in Pure Primary Biliary Cirrhosis With High Levels of Immunoglobulin G and Transaminases

To the best of our knowledge, this is the first study to address the use of glucocorticoids in the comparatively special population of pure primary biliary cirrhosis (PBC) patients who have high levels of immunoglobulin G (IgG) and transaminases but do not have PBC-autoimmune hepatitis overlap syndrome. Ursodeoxycholic acid (UDCA) is now assumed to be the standard therapy for PBC patients. However, patients treated with UDCA still have a risk of progression to cirrhosis and end-stage liver disease. The most recent European Association for the Study of the Liver guidelines of 2009 declared that further studies on glucocorticoid therapy in this disease should be a priority. Therefore, we designed this 3-year longitudinal retrospective study, which might provide deep insight into the treatment for PBC. The aim of this study was to assess whether the combination of prednisolone, UDCA, and azathioprine was superior to UDCA alone in these PBC patients. Sixty patients were enrolled in this study. Thirty-one patients underwent UDCA monotherapy, and 29 patients were treated with prednisolone, UDCA, and azathioprine. We analyzed their biochemistries, immune parameters, liver synthetic function, and noninvasive assessments of liver fibrosis, as well as treatment efficacy and adverse effects at baseline and at 1, 3, 6, 12, 24, and 36 months. Alkaline phosphatase (ALP), γ-glutamyl transpeptidase, alanine aminotransferase, and aspartate aminotransferase levels and the aspartate aminotransferase-to-platelet ratio index (APRI) and S-index improved dramatically in both groups, whereas IgG levels only decreased in the combination group (all P< 0.05). Albumin (ALB) levels decreased in the UDCA group but increased with the combination treatment at 36 months. Significant differences between the 2 groups were observed at 36 months in ALP (P1⁄4 0.005), IgG (P1⁄4 0.002), ALB (P1⁄4 0.002), APRI (P1⁄4 0.015), and S-index (P1⁄4 0.020). Prednisolone combined with UDCA and azathioprine showed a higher efficacy based on our new criteria. The combination of prednisolone, UDCA, and azathioprine is superior to UDCA alone for the treatment of pure PBC patients with high levels of IgG and transaminases. Side effects were minimal or absent. (Medicine 93(20):e104) Abbreviations: AIH = autoimmune hepatitis, ALB = albumin, ALP = alkaline phosphatase, ALT = alanine aminotransferase, APRI = aminotransferase-to-platelet ratio index, AST = aspartate aminotransferase, BMI = body mass index, EASL = European Association for the Study of the Liver, GGT = γ-glutamyl transpeptidase, GLO = globulin, IgG = immunoglobulin G, IgM = immunoglobulin M, PBC = primary biliary cirrhosis, UDCA = ursodeoxycholic acid. INTRODUCTION Primary biliary cirrhosis (PBC) is an agnogenic, chronic cholestatic autoimmune liver disease characterized by a high specificity of antimitochondrial antibody and small bileduct destruction. PBC leads to portal area inflammation, intrahepatic cholestasis, and fibrosis and can progress to cirrhosis and eventually liver failure. Ursodeoxycholic acid (UDCA) has been considered the standard therapy for improving the biochemical indexes of PBC patients. Although previous meta-analyses have suggested that UDCA has a beneficial effect in significantly decreasing liver biochemistry, UDCA has no effect on liver disease related mortality despite the observed reduction in the incidence of liver transplantations. A proportion of patients treated with UDCA in the early stages still have a risk of progression to cirrhosis and end-stage liver disease. Many studies have revealed that the use of glucocorticoids to suppress inflammation is considered an attractive approach among PBC patients. Glucocorticoids also appeared to be Editor: Mostafa Mohamed Sira. Received: June 5, 2014; revised: August 8, 2014; accepted: August 10, 2014. From the Centre for Liver Diseases and Department of Infectious Diseases (Y-QF, WJ, JL, Y-QD, YW, MY, G-QW), Peking University First Hospital, Xicheng District, Beijing; and Department of Infectious Diseases (D-XL), Sixth Hospital of Shenyang, Heping District, Shenyang, Liaoning, China. Correspondence: Gui-Qiang Wang, Centre for Liver Diseases and Department of Infectious Diseases, Peking University First Hospital, No.8 Xishiku Street, Xicheng District, Beijing, China (e-mail: [email protected]). This study was funded by the key disciplines of Beijing and the key clinical medical disciplines of China. It was also funded by the special fund project for technological innovation of Shenyang city. The authors have no conflicts of interest to disclose. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.md-journal.com). Copyright © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. ISSN: 0025-7974 DOI: 10.1097/MD.0000000000000104 Medicine • Volume 93, Number 20, October 2014 www.md-journal.com | 1 more effective among nonresponders to UDCA. In clinical practice, we have found that some patients who do not respond to UDCA still have disease progression, even if additional glucocorticoids are added later. Thus, the prognosis of PBC patients might be improved if we combine UDCA and glucocorticoids earlier and take measures to prevent their side effects; this hypothesis must be further confirmed. Wolfhagen et al showed that the short-term administration of prednisolone (a large dose at the beginning that is tapered rapidly) could improve biochemical parameters and liver histology with no obvious side effects. Patients might be more adaptive to glucocorticoids if we initiate their treatment with a megadose and then taper to a low-maintenance dose rapidly, assuming the necessary prophylaxis is provided. PBC and autoimmune hepatitis (AIH) are chronic autoimmune liver diseases. Increasingly, studies have agreed that either of these diseases can develop into an overlap syndrome that has features of both PBC and AIH. PBC-AIH overlap syndrome typically has a high level of immunoglobulin G (IgG) and is an indication for the use of glucocorticoids. However, the appropriateness of glucocorticoids remains unclear in the severe PBC patients who have high levels of IgG and transaminase but do not have definite PBC-AIH overlap syndrome. Poupon et al reported that, in patients with PBC, increased levels of IgG and γ-globulin are related to the severity of lymphocytic hepatocellular piecemeal necrosis and lobular inflammation. This relationship between IgG levels and fibrosis reveals that IgG might play an important role in the development of liver fibrosis. An in vitro test showed that prednisolone could reduce the proliferation of IgG-producing cells in combination with Con A. PBC patients with high levels of IgG and transaminases might have more severe necrosis and inflammation of the hepatic lobule than patients with normal levels. The latest European Association for the Study of the Liver (EASL) guidelines of 2009 declared that further studies regarding glucocorticoid therapy in PBC patients should be a priority. This is the first study to address the use of glucocorticoids in a comparatively special pure PBC population who have high IgG and transaminase levels but do not have PBC-AIH overlap syndrome (all patients included did not meet the criteria for PBC-AIH overlap syndrome). We designed this 3-year longitudinal retrospective study to observe the efficacy and safety of a combination therapy with prednisolone, UDCA, and azathioprine for the treatment of these PBC patients.