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

Abstract

IntroductionBone 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.MethodsActive 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.ResultsRituximab 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.ConclusionsRituximab 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.

Relationship between the type I interferon signature and the response to rituximab in rheumatoid arthritis patients

“…It is conceivable that higher inflammatory activity in patients with an IFN high signature may relatively protect B cells against the depleting effects of rituximab. Although we found similar systemic levels of BLyS and APRIL in the IFN high and IFN low groups, type I IFNs may promote the survival of pathogenic B cells in lymphoid tissue (38,39) or bone marrow (40)(41)(42). This might involve contactdependent interactions with T cells, dendritic cells, and stromal cells and membrane-bound survival factors such as CXCL12, vascular cell adhesion molecule, membrane-bound BLyS, or heparan sulfate-bound APRIL (43).…”

Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy

“…[29][30][31][32][33] However, several studies have shown that rituximab therapy effectively eliminates B cells from the peripheral blood but fails to effectively deplete all B cells within secondary lymphoid tissues. [34][35][36][37][38][39] Thus, whether PCs remaining in this setting are long-lived or dependent on replenishment by the residual B cells is unknown.…”

Robust memory responses against influenza vaccination in pemphigus patients previously treated with rituximab

“…Previous observations have suggested that some B cells survive depletion after rituximab therapy within secondary lymphoid organs (38,(57)(58)(59)(60)(61)(62). However, there are very few studies of this in humans, and it is often difficult to interpret the data from these studies due to low sample numbers and patient-to-patient variability.…”

“…To our knowledge, there is only one report of human antigen-specific MBCs surviving in the spleen after rituximab depletion (14). Several mechanisms underlying the persistence of B cells in tissues have been proposed, including resistance of activated B cells to rituximab-mediated depletion (61,63), effect of Fc glycosylation on rituximab and its resulting interaction with Fc receptors on accessory cells (64), the inflammatory or cytokine milieu allowing for B cells to survive (65,66), or possibly the inability of rituximab to fully access tissues to deplete B cells (67). It is also possible that CD20 expression is downregulated in B cells residing in tissues.…”