The relationship of FcγRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus

Jennifer H. Anolik, Debbie Campbell, Raymond E. Felgar, Faith Young, Inaki Sanz, Joseph D Rosenblatt, R. John Looney

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
Pages (from-to)455-459
Number of pages5
JournalArthritis and Rheumatism
Volume48
Issue number2
DOIs
StatePublished - Feb 1 2003

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Systemic Lupus Erythematosus
B-Lymphocytes
Genotype
Fc Receptors
Therapeutics
Serum
Monoclonal Antibodies
Rituximab
Antibody-Dependent Cell Cytotoxicity
B-Cell Lymphoma
Autoimmune Diseases
Flow Cytometry
Enzyme-Linked Immunosorbent Assay
Lymphocytes
Apoptosis
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

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The relationship of FcγRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. / Anolik, Jennifer H.; Campbell, Debbie; Felgar, Raymond E.; Young, Faith; Sanz, Inaki; Rosenblatt, Joseph D; Looney, R. John.

In: Arthritis and Rheumatism, Vol. 48, No. 2, 01.02.2003, p. 455-459.

Research output: Contribution to journalArticle

Anolik, Jennifer H. ; Campbell, Debbie ; Felgar, Raymond E. ; Young, Faith ; Sanz, Inaki ; Rosenblatt, Joseph D ; Looney, R. John. / The relationship of FcγRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. In: Arthritis and Rheumatism. 2003 ; Vol. 48, No. 2. pp. 455-459.
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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 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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N2 - 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.

AB - 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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