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B cells as therapeutic targets in SLE

Abstract

The use of B-cell targeted therapies for the treatment of systemic lupus erythematosus (SLE) has generated great interest owing to the multiple pathogenic roles carried out by B cells in this disease. Strong support for targeting B cells is provided by genetic, immunological and clinical observations that place these cells at the center of SLE pathogenesis, as initiating, amplifying and effector cells. Interest in targeting B cells has also been fostered by the successful use of similar interventions to treat other autoimmune diseases such as rheumatoid arthritis, and by the initial promise shown by B-cell depletion to treat SLE in early studies. Although the initial high enthusiasm has been tempered by negative results from phase III trials of the B-cell-depleting agent rituximab in SLE, renewed vigor should be instilled in the field by the convergence of the latest results using agents that inhibit B-cell-activating factor (BAFF, also known as BLyS and tumor necrosis factor ligand superfamily, member 13b), further analysis of data from trials using rituximab and greatly improved understanding of B-cell biology. Combined, the available information identifies several new avenues for the therapeutic targeting of B cells in SLE.

Key Points

  • B cells have antibody-dependent and antibody-independent functions that can either promote or inhibit autoimmunity

  • B-cell-targeted therapies would ideally eliminate pathogenic B cells or promote the expansion and function of protective B cells, or both

  • Despite clinical observations of benefit and results from early trials, two large phase III, randomized placebo-controlled trials of rituximab have failed to meet their primary or secondary clinical endpoints

  • More-selective B-cell depletion achieved by blocking B-cell-activating factor (using belimumab) has demonstrated considerable clinical benefit

  • Improved knowledge of the biology of B cells and plasma cells opens the door to several additional strategies for the therapeutic targeting of B cells

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Figure 1: The Janus nature of B cells.
Figure 2: Strategies for B-cell targeting in SLE.
Figure 3: Phases of B-cell depletion: a working model.
Figure 4: Variable B-cell homeostasis in human SLE.

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Acknowledgements

Supported in part by NIH grants U19 AI56390 (Rochester Autoimmunity Center of Excellence) and R01 AI049660 to I. Sanz, and K23 AI67501 to F. E.-H. Lee.

Désirée Lie, Univesity of California, Orange, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

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Correspondence to Iñaki Sanz.

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Dr. Sanz has served as a paid consultant for Genentech (attendance of a B-cell summit meeting) and GlaxoSmithKline and has received research support from Biogen; research support from GlaxoSmithKline is pending. Dr. Lee declares no competing interests.

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Sanz, I., Lee, FH. B cells as therapeutic targets in SLE. Nat Rev Rheumatol 6, 326–337 (2010). https://doi.org/10.1038/nrrheum.2010.68

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