title: The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus.
abstract: OBJECTIVE
  Despite wide use of the anti-CD20 monoclonal antibody rituximab in the treatment of B cell lymphomas, the mechanism by which it causes B cell depletion remains a subject of controversy. As part of an ongoing phase I/II trial of rituximab in the treatment of systemic lupus erythematosus (SLE), we sought to determine whether the effectiveness of B cell depletion was influenced by polymorphisms of Fc receptors (FcR) on effector cells.
  
  
  METHODS
  During rituximab treatment of 12 SLE patients, B cell depletion was monitored as a function of the serum rituximab level and FcgammaRIIa and FcgammaRIIIa genotypes at baseline and at 1 month and 2 months after treatment. FcR genotypes were determined by polymerase chain reaction. Serum levels of rituximab were measured by enzyme-linked immunosorbent assay (ELISA). B lymphocyte percentages were assessed by flow cytometry.
  
  
  RESULTS
  B cell depletion was highly variable in this patient cohort, with B cell percentages at the 1-2-month posttreatment nadir ranging from undetectable (<0.1 cell/microl) to 16% ( approximately 30 cells/microl) of the total peripheral blood lymphocytes. At 2 months posttreatment, B cell percentages were highly correlated with both the serum rituximab level and the FcgammaRIIIa genotype (R(2) = 0.75, P = 0.002). The FcgammaRIIIa genotype was a significant independent predictor of the efficacy of B cell depletion (P = 0.019).
  
  
  CONCLUSIONS
  These results highlight the potential variability of B cell depletion by rituximab in the treatment of autoimmune disease and indicate that Fc receptors are an important determinant of that variability. The findings further suggest the importance of antibody-dependent cell-mediated cytotoxicity and/or apoptosis induction via FcgammaRIIIa-expressing effector cells in the mechanism of B cell depletion by this widely used monoclonal antibody.
authors.affiliation: University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Anolik
authors.forename: Debbie
authors.initials: D
authors.lastname: Campbell
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Felgar
authors.forename: Faith
authors.initials: F
authors.lastname: Young
authors.forename: Inaki
authors.initials: I
authors.lastname: Sanz
authors.forename: Joseph
authors.initials: J
authors.lastname: Rosenblatt
authors.forename: R John
authors.initials: RJ
authors.lastname: Looney
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000097:blood; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D005260:Female; D005838:Genotype; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D018655:Lymphocyte Count; D008297:Male; D017452:Receptors, IgG / Q000235:genetics*; D000069283:Rituximab
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D017452:Receptors, IgG; D000069283:Rituximab