B cell therapies for rheumatoid arthritis: beyond B cell depletion.

Initially suggested by the presence of rheumatoid factor autoantibodies, multiple pathogenic roles for B cells (both antibody-mediated and antibody-independent) in rheumatoid arthritis (RA) now are supported by a growing body of experimental observations and human studies. The pathogenic significance of B cells in this disease also has been established conclusively by the proven benefit of Rituximab-induced B cell depletion in RA patients refractory to tumor necrosis factor (TNF) blockade. This article reviews the rationale for the use of B cell-targeting therapies in RA and discusses the caveats and limitations of indiscriminate B cell depletion as currently applied, ncluding incomplete depletion of pathogenic B cells and elimination of protective B cells. Finally, it presents alternative therapeutic strategies that exploit current knowledge of B cell activation, survival, and differentiation to provide more selective B cell and plasma cell targeting.