Systemic lupus erythematosus (SLE) is characterized by multisystem immune-mediated injury in the setting of autoimmunity to
nuclear antigens. The clinical heterogeneity of SLE, the absence of universally agreed clinical trial end points, and the paucity of validated therapeutic targets have, historically, contributed to a lack of novel treatments for SLE. However, in 2011, a therapeutic
monoclonal antibody that neutralizes the
cytokine TNF
ligand superfamily member 13B (also known as
B-cell-activating factor of the TNF family [BAFF]),
belimumab, became the first targeted
therapy for SLE to have efficacy in a randomized clinical trial. Because of its specificity, the efficacy of
belimumab provides an opportunity to increase understanding of SLE pathophysiology. Although
belimumab depletes B cells, this effect is not as powerful as that of other B-cell-directed
therapies that have not been proven efficacious in randomized clinical trials. In this article, therefore, we review results suggesting that neutralizing BAFF can have effects on the immune system other than depletion of B cells. We also identify aspects of the BAFF system for which data in relation to SLE are still missing, and we suggest studies to investigate the pathogenesis of SLE and ways to refine anti-BAFF
therapies. The role of a related
cytokine, TNF
ligand superfamily member 13 (also known as a proliferation-inducing
ligand [APRIL]) in SLE is much less well understood, and hence this review focuses on BAFF.