title: Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid.
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 CD25(high) 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.
  
  
  CONCLUSIONS
  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.
authors: Divisions of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA 95817, USA.
authors: Masanobu
authors: M
authors: Tsuda
authors: Yuki
authors: Y
authors: Moritoki
authors: Zhe-Xiong
authors: ZX
authors: Lian
authors: Weici
authors: W
authors: Zhang
authors: Katsunori
authors: K
authors: Yoshida
authors: Kanji
authors: K
authors: Wakabayashi
authors: Guo-Xiang
authors: GX
authors: Yang
authors: Toshio
authors: T
authors: Nakatani
authors: John
authors: J
authors: Vierling
authors: Keith
authors: K
authors: Lindor
authors: M Eric
authors: ME
authors: Gershwin
authors: Christopher L
authors: CL
authors: Bowlus
mesh_terms: D000328:Adult; D000469:Alkaline Phosphatase / Q000097:blood; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology / Q000627:therapeutic use*; D001323:Autoantibodies / Q000097:blood; D001402:B-Lymphocytes / Q000187:drug effects*; D018791:CD4 Lymphocyte Count; D002756:Cholagogues and Choleretics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D016130:Immunophenotyping; D008099:Liver / Q000201:enzymology; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D000069283:Rituximab; D013601:T-Lymphocytes / Q000378:metabolism; D017211:Treatment Failure; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D001323:Autoantibodies; D002756:Cholagogues and Choleretics; D007155:Immunologic Factors; D012333:RNA, Messenger; D000069283:Rituximab; D014580:Ursodeoxycholic Acid; D000469:Alkaline Phosphatase