Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus.
OBJECTIVE
B lymphocyte depletion has recently emerged as a promising approach to the treatment of systemic lupus erythematosus (SLE). As part of a phase I/II dose-ranging trial of rituximab in the treatment of SLE, we evaluated the fate of discrete B cell subsets in the setting of selective depletion by anti-CD20 monoclonal antibody and during the B cell recovery phase.


METHODS
B cell depletion and phenotype were examined by flow cytometry of peripheral blood mononuclear cells for CD19, CD20, CD27, IgD, and CD38 expression. Changes in autoreactive B lymphocytes and plasma cells were assessed by determination of serum autoantibody levels (anti-double-stranded DNA and VH4.34) and by direct monitoring of a unique autoreactive B cell population bearing surface antibodies whose heavy chain is encoded by the VH4.34 gene segment.


RESULTS
Compared with normal controls, SLE patients displayed several abnormalities in peripheral B cell homeostasis at baseline, including naive lymphopenia, expansion of a CD27-,IgD- (double negative) population, and expansion of circulating plasmablasts. Remarkably, these abnormalities resolved after effective B cell depletion with rituximab and immune reconstitution. The frequency of autoreactive VH4.34 memory B cells also decreased 1 year posttreatment, despite the presence of low levels of residual memory B cells at the point of maximal B cell depletion and persistently elevated serum autoantibody titers in most patients.


CONCLUSIONS
This study is the first to show evidence that in SLE, specific B cell depletion therapy with rituximab dramatically improves abnormalities in B cell homeostasis and tolerance that are characteristic of this disease. The persistence of elevated autoantibody titers may reflect the presence of low levels of residual autoreactive memory B cells and/or long-lived autoreactive plasma cells.
Anolik
Jennifer H
JH
University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA. jennifer_anolik@urmc.rochester.edu
Barnard
Jennifer
J
Cappione
Amedeo
A
Pugh-Bernard
Aimee E
AE
Felgar
Raymond E
RE
Looney
R John
RJ
Sanz
Iñaki
I
D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D015551:Autoimmunity / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D005260:Female; D006706:Homeostasis; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D007937:Leukapheresis; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D007166:Immunosuppressive Agents; D000069283:Rituximab