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The BAFFling effects of rituximab in lupus: danger ahead?

Nature Reviews Rheumatology volume 12, pages 367–372 (2016)Cite this article

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Abstract

Suboptimal trial design and concurrent therapies are thought to account for the unexpected failure of two clinical trials of rituximab in patients with systemic lupus erythematosus (SLE). However, in this Opinion article we propose an alternative explanation: that rituximab can trigger a sequence of events that exacerbates disease in some patients with SLE. Post-rituximab SLE flares that are characterized by high levels of antibodies to double-stranded DNA are associated with elevated circulating BAFF (B-cell-activating factor, also known as TNF ligand superfamily member 13B or BLyS) levels, and a high proportion of plasmablasts within the B-cell pool. BAFF not only perpetuates autoreactive B cells (including plasmablasts), particularly when B-cell numbers are low, but also stimulates T follicular helper (TFH) cells. Moreover, plasmablasts and TFH cells promote each others' formation. Thus, repeated rituximab infusions can result in a feedback loop characterized by ever-rising BAFF levels, surges in autoantibody production and worsening of disease. We argue that B-cell depletion should be swiftly followed by BAFF inhibition in patients with SLE.

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Figure 1: BAFF activates and perpetuates interactions between plasmablasts and TFH cells in SLE.
Figure 2: The relationship between BAFF, anti-dsDNA antibodies and B-cell numbers in SLE, before and after rituximab therapy.
Figure 3: The effects of repeated rituximab infusions on anti-dsDNA antibody levels in a patient with SLE.

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Acknowledgements

The authors' research is funded by grants from Arthritis Research UK and University College London Hospitals Biomedical Research Centre.

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  1. Division of Medicine, Centre for Rheumatology, University College London, 5 University Street, London, WC1E 6JF, UK

    Michael R. Ehrenstein & Charlotte Wing

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Both authors contributed to all aspects of the article: researching data for the article, writing the manuscript, discussions of its content and review or editing of manuscript before submission.

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Correspondence to Michael R. Ehrenstein.

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Competing interests

M.R.E. is Chief Investigator for BEAT-LUPUS, a trial combining rituximab and belimumab for patients with SLE. This trial is jointly funded by GlaxoSmithKline, Arthritis Research UK and University College London Hospitals Biomedical Research Centre.

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Ehrenstein, M., Wing, C. The BAFFling effects of rituximab in lupus: danger ahead?. Nat Rev Rheumatol 12, 367–372 (2016). https://doi.org/10.1038/nrrheum.2016.18

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