Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid

Authors

  • Masanobu Tsuda,

    1. Divisions of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA
    2. Department of Emergency and Critical Care Medicine, Kansai Medical University, Osaka, Japan
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    • *

      These authors contributed equally to this work.

  • Yuki Moritoki,

    1. Divisions of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA
    2. Department of Infection, Allergy, Clinical Immunology, and Laboratory Medicine, Akita University Graduate School of Medicine, Akita, Japan
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    • *

      These authors contributed equally to this work.

  • Zhe-Xiong Lian,

    1. Divisions of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA
    2. Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei, China
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  • Weici Zhang,

    1. Divisions of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA
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  • Katsunori Yoshida,

    1. Divisions of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA
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  • Kanji Wakabayashi,

    1. Divisions of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA
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  • Guo-Xiang Yang,

    1. Divisions of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA
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  • Toshio Nakatani,

    1. Department of Emergency and Critical Care Medicine, Kansai Medical University, Osaka, Japan
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  • John Vierling,

    1. Baylor Liver Health, Baylor College of Medicine, Houston, TX
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  • Keith Lindor,

    1. Division of Gastroenterology & Hepatology, Mayo Clinic and Foundation, Rochester, MN
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  • M. Eric Gershwin,

    1. Divisions of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA
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  • Christopher L. Bowlus

    Corresponding author
    1. Division of Gastroenterology and Hepatology, University of California, Davis, CA
    • Internal Medicine, University of California at Davis, Sacramento, CA 95817
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    • *

      These authors contributed equally to this work.

    • fax: 530-752-3604.


  • Potential conflict of interest: Dr. Bowlus consults for, advises, and is on the speakers' bureau of Gilead. He advises and received grants from Genentech. He is on the speakers' bureau of Bristol-Myers Squib. Dr. Vierling consults for and received grants from Abbott, Bristol-Myers Squibb, Excalenz, Globeimmune, Gilead, Roche, Sundise, Vertex, and Ocera. He consults for Schering-Plough, Salix, HepaLife Technologies, and Herbalife. He received grants from Conatus, Hyperion, Idenix, Ikaria, Intercept, Merck, Mochida, Novartis, Pfizer, Pharmasset, and Zymogenetics.

  • Supported by a grant from Genentech, Inc. to M.E.G.

Abstract

The aim of this study was to determine the safety and potential efficacy of B-cell depletion with the anti-CD20 monoclonal antibody rituximab in patients with primary biliary cirrhosis (PBC) and an incomplete response to ursodeoxycholic acid (UDCA). This open-label study enrolled six patients with PBC and incomplete responses to UDCA to be treated with 2 doses of 1000 mg rituximab separated by 2 weeks and followed for 52 weeks. The primary endpoints were safety and changes in B-cell function. Two patients received only 1 dose of rituximab, one due to activation of latent varicella and the other due to a viral upper respiratory infection. Serum levels of total IgG, IgM, and IgA as well as anti-mitochondrial autoantibodies (AMAs) IgA and IgM decreased significantly from baseline by 16 weeks and returned to baseline levels by 36 weeks. Stimulation of B cells with CpG produced significantly less IgM at 52 weeks after treatment compared with B cells at baseline. In addition, transient decreases in memory B-cell and T-cell frequencies and an increase in CD25high CD4+ T cells were observed after treatment. These changes were associated with significant increases in mRNA levels of FoxP3 and transforming growth factor-β (TGF-β) and a decrease in tumor necrosis factor-α (TNF-α) in CD4+ T cells. Notably, serum alkaline phosphatase levels were significantly reduced up to 36 weeks following rituximab treatment. Conclusion: These data suggest that depletion of B cells influences the induction, maintenance, and activation of both B and T cells and provides a potential mechanism for treatment of patients with PBC with an incomplete response to UDCA. (HEPATOLOGY 2012)

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