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. 2009;11(4):R131.
doi: 10.1186/ar2798. Epub 2009 Aug 28.

Rituximab therapy reduces activated B cells in both the peripheral blood and bone marrow of patients with rheumatoid arthritis: depletion of memory B cells correlates with clinical response

Magda Nakou  1 , Georgios Katsikas, Prodromos Sidiropoulos, George Bertsias, Eva Papadimitraki, Amalia Raptopoulou, Helen Koutala, Helen A Papadaki, Herakles Kritikos, Dimitrios T Boumpas
Affiliations

Rituximab therapy reduces activated B cells in both the peripheral blood and bone marrow of patients with rheumatoid arthritis: depletion of memory B cells correlates with clinical response

Magda Nakou et al. Arthritis Res Ther. 2009.

Abstract

Introduction: Bone marrow (BM) is an immunologically privileged site where activated autoantibody-producing B cells may survive for prolonged periods. We investigated the effect of rituximab (anti-CD20 mAb) in peripheral blood (PB) and BM B-cell and T-cell populations in active rheumatoid arthritis (RA) patients.

Methods: Active RA patients received rituximab (1,000 mg) on days 1 and 15. PB (n = 11) and BM (n = 8) aspirates were collected at baseline and at 3 months. We assessed B-cell and T-cell populations using triple-color flow cytometry.

Results: Rituximab therapy decreased PB (from a mean 2% to 0.9%, P = 0.022) but not BM (from 4.6% to 3.8%, P = 0.273) CD19+ B cells, associated with a significant reduction in the activated CD19+HLA-DR+ subset both in PB (from 55% to 19%, P = 0.007) and in BM (from 68% to 19%, P = 0.007). Response to rituximab was preceded by a significant decrease in PB and BM CD19+CD27+ memory B cells (P = 0.022). These effects were specific to rituximab since anti-TNF therapy did not reduce total or activated B cells. Rituximab therapy did not alter the number of activated CD4+HLA-DR+ and CD4+CD25+ T cells.

Conclusions: Rituximab therapy preferentially depletes activated CD19+HLA-DR+ B cells in the PB and BM of active RA patients. Clinical response to rituximab is associated with depletion of CD19+CD27+ memory B cells in PB and BM of RA patients.

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Figures

Figure 1
Figure 1
Effect of rituximab on B cells in rheumatoid arthritis peripheral blood and bone marrow. Rituximab preferentially depletes B cells in peripheral blood (PB) and reduces activated B cells in the PB and the bone marrow (BM) of rheumatoid arthritis (RA) patients. (a) The percentage of PB (n = 11) CD19+ B cells was significantly reduced following 3 months of treatment with rituximab. A nonsignificant reduction in B cells was also observed in the BM (n = 8) of RA patients. (b) Representative flow cytometry analysis of PB CD19+ B cells in a RA patient at baseline (left) and after 12 weeks of rituximab treatment (right). (c) Rituximab depletes activated CD19+HLA-DR+ B cells both in the PB and in the BM of RA patients. (d) Representative flow cytometry histograms of HLA-DR expression in PB and BM CD19+-gated cells of a RA patient at baseline and after treatment with rituximab. *P < 0.05 for paired analysis, **P < 0.05.
Figure 2
Figure 2
Correlation of clinical response to rituximab with depletion of CD19+CD27+ memory B cells. Clinical response to rituximab correlates with depletion of CD19+CD27+ memory B cells in peripheral blood (PB) and in the bone marrow (BM) of rheumatoid arthritis (RA) patients. PB CD19+CD27+ cells increased by 29 ± 16% in nonresponders (NR) (n = 5), compared with a reduction by 26 ± 10% in responders (R) (P = 0.023) (n = 4). Similarly, BM CD19+CD27+ cells increased by 31 ± 13% in NR (n = 4), whereas they decreased by 26 ± 13% in R (n = 2). *P < 0.05 for paired analysis between baseline and 3 months.
Figure 3
Figure 3
Effect of anti-TNF treatment on peripheral blood B cells in rheumatoid arthritis patients. (a) No effect of anti-TNF treatment on peripheral blood (PB) CD19+ cells, CD19+HLA-DR+ cells, and CD19+CD27+ cells in rheumatoid arthritis (RA) patients (n = 7). B-cell depletion is specific to rituximab therapy. (b) Treatment with rituximab does not affect the proportion of total CD4+ T cells, activated CD4+HLA-DR+ T cells and CD4+CD25+ T cells in the PB of RA patients.
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