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Rituximab and other B cell targeted therapies for rheumatoid arthritis

Maria J Leandro, MD, PhD
Section Editor
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Deputy Editor
Paul L Romain, MD


B cell targeted therapy for rheumatoid arthritis (RA) was developed with the objective of removing B cell clones responsible for the production of pathogenic autoantibodies. A specific objective was to induce sustained remission from short-term B cell depletion, based on the hypothesis that autoantibodies could not only produce tissue pathology but might be expected to drive their own production through a vicious cycle [1]. Although this has yet to be achieved, B cell depletion therapy has been found to have a major impact on RA in the short term.

Interest in B cell depletion was fueled by new evidence for the potential pathogenic role of immune complexes in RA. The beneficial effects of anti-tumor necrosis factor (TNF) agents highlighted the importance of the production of TNF by macrophages within the joint. The association of RA with major histocompatibility complex (MHC) class II allotype implicated a CD4-T cell dependent process, but it was not clear whether this involved T cell help for antibody production or a direct effect of T cells on macrophages. Work on macrophage Fc-gamma receptors showed that TNF production in synovium might be explained by the binding of small IgG-based immune complexes to these receptors rather than by the action of cytokines from antigen–stimulated T cells [2]. The evidence for this remains conflicting.

Central to the concept of B cell depletion therapy was the idea that pathogenic B cell clones and their autoantibody products might be engaged in a vicious cycle of self-perpetuation that does not require T cell autoreactivity. The interruption of such a cycle would restore immune tolerance and, therefore, might allow sustained benefit. This objective has been partially achieved. Although the majority of patients relapse within the first eighteen months after treatment, a small number of patients remain well for longer (occasionally up to four years) after a single course of treatment [3].

B cell depletion has been associated with clinical improvement in many (but not all) conditions associated with autoantibody production. In contrast, a variety of conditions that are seronegative conditions (eg, psoriasis) does not appear to respond to this intervention. Nevertheless, modest improvement has been reported in seronegative RA, and there remains a possibility that, in at least some cases, a therapeutic effect is achieved through B cell functions involved in supporting T cell effector mechanisms.

Antigen presentation by B cells and cytokine-mediated interactions with stromal and accessory cells could potentially activate autoreactive T cells, although there is some doubt as to whether this is consistent with the behavior of synovial T cells in RA [4]. B cells are very efficient at presenting soluble antigen that has been bound by their antigen receptor (surface immunoglobulin) during the acquisition of T cell help.


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Literature review current through: Sep 2016. | This topic last updated: Nov 28, 2015.
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