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B-cell-directed therapies for autoimmune disease

Nature Reviews Rheumatology volume 5, pages 433–441 (2009)Cite this article

Abstract

Approval of the anti-CD20 antibody rituximab for the treatment of moderate-to-severe rheumatoid arthritis in patients who fail to respond to anti-tumor-necrosis-factor agents has raised interest in B-cell-directed therapy for this disease. A number of direct and indirect modalities with distinct mechanisms of action are being investigated, including anti-CD20 and anti-CD22 therapies, and new approaches for blocking members of the tumor necrosis factor cytokine family including B cell activating factor (BAFF) and a proliferation ligand (APRIL), which are at late stages of clinical development. Clinical experience is most extensive with rituximab, and suggests that targeting 'autoimmune' memory B cells is a feasible approach for treating autoimmune disease. Although anti-CD20 therapy has only been approved for rheumatoid arthritis thus far, data suggest this approach could be valid for other autoimmune diseases, including systemic lupus erythematosus, Sjögren's syndrome, vasculitides, autoimmune cytopenias, and neurologic and dermatologic autoimmune diseases. Additional studies of direct and indirect B-cell-directed treatments are needed before we can draw conclusions as to the value of this approach in patients with various autoimmune diseases and whether more precisely defined techniques than these are required to target the complex humoral system effectively.

Key Points

  • Approval of rituximab as a B-cell-directed therapy for rheumatoid arthritis has raised interest in B-cell-directed therapies for other autoimmune diseases

  • Studies of B-cell-depletion approaches have shown that peripheral immunoglobulins are probably generated by plasma cells with different lifespans

  • Short-lived plasma cells produce an important array of activity-related autoantibodies, whereas long-lived plasma cells are mainly responsible for protective immunoglobulin titers

  • Approaches that target adaptive immunity, such as B-cell depletion with anti-CD20 antibodies, involve a longer time to clinical response than do approaches that preferentially target innate immunity

  • Anti-CD20 therapy selectively depletes reactive memory B cells that are otherwise refractory to conventional therapy

  • Despite reports of rituximab being effective in patients with treatment-refractory autoimmune diseases other than rheumatoid arthritis, randomized controlled clinical trials are needed to assess the value of this approach

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Figure 1: A schematic of B-cell development.
Figure 2: Mechanisms adopted by the immune system to prevent emergence of autoimmune B cells.
Figure 3: Targets of anti-CD20 antibody therapy.

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Acknowledgements

The work was supported in part by SFB 650 and Deutsche Forschungsgemeinschaft grants Do492/5–5 and Do492/7–1.

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  1. Charité Center 12 and 14, Charité University Hospital & Deutsches Rheuma-forschungszentrum Berlin, Berlin, Germany

    Thomas Dörner, Andreas Radbruch & Gerd R. Burmester

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Correspondence to Thomas Dörner.

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T. Dörner declares that he has acted as a consultant for Genentech, he has received grant or research support (including clinical trials) from Immunomedics and has acted as a consultant, been involved in speakers' bureaux (honoraria) and received grant or research support (including clinical trials) from Roche.

Gerd R. Burmester declares that he has received grant or research support (including clinical trials) from Medimmune, and has acted as a consultant, been involved in speakers' bureaux (honoraria) and received grant or research support (including clinical trials) from Roche and UCB.

Andreas Radbruch declares no competing interests.

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Dörner, T., Radbruch, A. & Burmester, G. B-cell-directed therapies for autoimmune disease. Nat Rev Rheumatol 5, 433–441 (2009). https://doi.org/10.1038/nrrheum.2009.141

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