Introduction

B cells contribute to the pathogenesis of systemic lupus erythematosus (SLE) through multiple actions, including primary autoantibody production as well as antigen presentation, T cell induction, and the secretion of proinflammatory cytokines. Therefore, the development of biologic therapies designed to target B cells in SLE has remained of great interest to researchers. This chapter will review the rationale for B cells as therapeutic targets in SLE, as well as several key trials investigating the efficacy of these biologic agents in treating SLE. Additionally, the classification, treatment, and monitoring of lupus nephritis, one of the most problematic manifestations of SLE, will be reviewed.

B Cell Roles in SLE

• Autoantibody production results in the formation of immune complexes that accumulate in tissues, inducing a type III hypersensitivity reaction that manifests clinically as nephritis, arthritis, and other disease manifestations
  
  
  
  • Autoantibody-producing cells fall into two categories: short-lived and long-lived populations which have differing CD20 expression and antibody production profiles
    
  • This separation bears important implications for our understanding of SLE pathogenesis
    
  • Rational design of therapeutic strategies must take into account the markers differentially expressed by short-lived and long-lived plasma cells, as well as the roles of different classes of autoantibodies
  
  
• Immune complexes, perhaps more powerfully those formed by anti-ribonucleoprotein antibodies, also induce disease due to their ability to co-engage stimulatory Fcγ receptors and Toll-like receptors (TLRs) in dendritic cells, thereby promoting the production of type I interferon and amplification of inflammation
  
• Additional antibody-independent functions are increasingly recognized as contributing significantly to disease pathogenesis, including:
  
  
  
  • Promotion of CD4+ and CD8+ effector T cell populations including T_H17 induction
    
  • Inhibition of T_REG cell populations
    
  • Recruitment of dendritic cells
    
  • Production of proinflammatory cytokines including TNF and IL-6
  
  
• Of note, B cells can also suppress autoimmunity through a variety of functions that often represent the mirror image of their pathogenic functions; whether this balancing act represents a competition between different B cell subsets with a committed phenotype to a given function or instead is achieved by environmental modulation of multi-functional cells remains to be elucidated
  
• B cells suppress autoimmunity through the following functions:
  
  
  
  • Induction of T cell anergy
    
  • Suppression of helper T cells
    
  • Expansion of T_REG cell populations
    
  • Inhibition of dendritic cells
    
  • Production of anti-inflammatory cytokines, predominantly IL-10
    
    
    
    • In humans, both transitional B cells and B10 cells (regulatory B cells that produce IL-10) have been shown to be able to downregulate T_H cell activation and reduce the production of proinflammatory cytokines by monocytes through the production of IL-10
      
    • Of significant interest, transitional regulatory B cells, while numerically increased, have been postulated to be functionally deficient in SLE
      
    • Similarly, B10 cells and their precursors can also be increased in active SLE, suggesting either a functional deficiency or increased resistance of their target cells

Therapies Targeting B Cells

Existing Therapies for SLE

Additional Therapies Targeting B Cells in SLE under Investigation

• Atacicept, a recombinant TACI-FC receptor fusion protein capable of binding to both BLyS as well as APRIL, a cytokine that powerfully mediates memory B cell and plasma cell survival, impacts the survival of a broader swath of B cells and plasma cells and has a more powerful effect on antibody titers
  
  
  
  • The promise of this agent has been compromised by the occurrence of serious infectious complications that led to the interruption of clinical trials both in rheumatoid arthritis and SLE (the latter when combined with mycophenolate mofetil)
  
  
• Epratuzumab is an anti-CD22 antibody that inhibits B cell activation and maturation and induces a more modest degree of B cell depletion
  
  
  
  • Early, small studies show a steroid-sparing effect at 24 weeks
  
  
• Bortezomib is a proteosome inhibitor commonly used to treat multiple myeloma
  
  
  
  • By selectively inhibiting the 26s proteasome, resulting in apoptosis, bortezomib has shown promise in triggering plasma cell apoptosis and modifying the proinflammatory response
    
  • Dramatic improvement of lupus nephritis has been demonstrated with this agent in mouse models
    
  • The unique mechanism of action of this class of agents, the importance of autoantibody-producing plasma cells (not directly affected by rituximab or belimumab) and the availability of new-generation proteasome inhibitors (such as carfilzomib) with significantly reduced incidence of painful peripheral neuropathy, all illustrate the promise of this approach for the treatment of SLE

Lupus Nephritis