Belimumab in systemic lupus erythematosus: an update for clinicians

Abstract

Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder that is driven by autoantibodies that target multiple organ systems. B-lymphocyte stimulator (BLyS) and its receptors on B-cell subsets play an important role in autoimmune B-cell development and SLE pathogenesis. Targeted therapy with belimumab, the monoclonal antibody against BLyS, has shown clinical benefit in two large-scale, multicenter phase III trials leading to US Food and Drug Administration approval for patients with serologically positive SLE who have active disease despite standard therapy. This review will discuss the challenges in lupus drug development and clinical trials, the basics of B-cell pathogenesis in SLE, the recent lupus clinical trials of B-cell targeted treatments, and other potential targeted therapies under investigation for patients with lupus.

Keywords: B-lymphocyte stimulator; belimumab; systemic lupus erythematosus.

Figure 1.

Phases of B-cell development and activation (adapted from [Cancro et al. 2009]).***, High-affinity binding; *, low-affinity binding, relatively; , increased dependence; , decreased dependence, relatively. (A/B) Pre-B cells originate from mesenchymal stem cells in bone marrow. Immature B cells leave bone marrow and enter into circulation as transitional B cells. B cells complete maturation in the spleen. In the periphery, signals from antigen activation and co-stimulation from T cells, help transition mature, preimmune B cells to form germinal centers, ultimately leading to memory and plasma cell development. (C) Three B-lymphocyte stimulator (BLyS) family receptors (BR3, BAFF-receptor 3; TACI, transmembrane activator and calcium modulator and cyclophylin ligand interactor; and BCMA, B-cell maturation antigen) vary in their expression patterns and levels across stages of B-cell development. (D) BLyS binding affinity is dominant in the immature, pre-B cell phase in the bone marrow, and continues to increase onto the transitional cell phase. BR3 expression is highest in the follicular and marginal zone subsets of B cells in the spleen. After antigen activation, BLyS/APRIL receptor expression on mature B-cells transitions from BR3 expression to TACI and/or BCMA expression in the memory/plasma cell population. APRIL-TACI and APRIL-BCMA interactions have been shown to influence plasma cell survival and Ig class-switching.

Figure 2.

Systemic Lupus Erythematosus Responder Index (SRI) for BLISS-52, BLISS 76, and BLISS 52/76 combined results at week 52 [Navarra et al. 2011; van Vollenhoven et al. 2011; Furie et al. 2010]. *Statistically significant difference from placebo.