The relationship of FcγRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus
JH Anolik, D Campbell, RE Felgar… - Arthritis & …, 2003 - Wiley Online Library
Arthritis & Rheumatism, 2003•Wiley Online Library
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 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 …
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 FcγRIIa and FcγRIIIa 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/μl) to 16% (∼30 cells/μl) of the total peripheral blood lymphocytes. At 2 months posttreatment, B cell percentages were highly correlated with both the serum rituximab level and the FcγRIIIa genotype (R2 = 0.75, P = 0.002). The FcγRIIIa genotype was a significant independent predictor of the efficacy of B cell depletion (P = 0.019).
Conclusion
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 FcγRIIIa‐expressing effector cells in the mechanism of B cell depletion by this widely used monoclonal antibody.
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