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• Response
  Gianfranco Ferraccioli
  Published on: 9 January 2014
• Reply to: Which B-cell subset should we target in lupus?
  Gururaj Arumugakani
  Published on: 20 December 2013

• Published on: 9 January 2014

  Response

  • Gianfranco Ferraccioli, Professor
  • Other Contributors:
    • Frederic A Houssiau

  Dear Editor,

  We thank Aramugakani et al. for their critical reading of our Editorial (1) accompanying Cheng et al. paper on the role of long-lived plasma cells (PC) in driving murine lupus nephritis (LN) (2). First, we obviously share - and explicitely mentioned - the safety issues related to long-lived PC depletion, in particular a possible high infection rate. Second, our purpose was not to question the effe...

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  Dear Editor,

  We thank Aramugakani et al. for their critical reading of our Editorial (1) accompanying Cheng et al. paper on the role of long-lived plasma cells (PC) in driving murine lupus nephritis (LN) (2). First, we obviously share - and explicitely mentioned - the safety issues related to long-lived PC depletion, in particular a possible high infection rate. Second, our purpose was not to question the effects of rituximab on anti- dsDNA production in active lupus patients, in particular when complete B- cell depletion is achieved (3), nor the importance of targeting plasmablasts and short-lived PC in acute lupus. Rather, we stressed that long-lived PC, including those homed in previously injured tissues, may well be responsible for relapses (sometimes after long periods of clinical and serological inactivity). In this respect, successful targeting of these cells may potentially offer a cure, as could be the case with haematopoietic stem cell transplantation.
  Finally, we agree that combination (or sequential) therapy with agents targeting both plasmablasts/short-lived PCs and long-lived PCs would make sense from a theoretical viewpoint, with the obvious caveats regarding infections.

  References

  1. Ferraccioli G, Houssiau FA. Which B-cell subset should we target in lupus. Ann Rheum Dis 2013;72:1891-1892.

  2. Cheng Q, Mumtaz IM, Khodadadi L, et al. Autoantibodies from long- lived 'memory' plasma cells of NZB/W mice drive immune complex nephritis. Ann Rheum Dis 2013;72 :2011-7.

  3. Vital EM, Dass S, Buch MH, et al. B cell biomarkers of rituximab responses in systemic lupus erythematosus. Arthritis Rheum 2011;63:3038-47.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 20 December 2013

  Reply to: Which B-cell subset should we target in lupus?

  • Gururaj Arumugakani, Clinical Research Fellow
  • Other Contributors:
    • Dr.Edward Vital, Dr.Yuzaiful Yusof, Prof.Dennis McGonagle, Prof.Paul Emery

  Dear Editor,

  We read with interest the editorial by Ferraccioli and Houssiau proposing the specific targeting of long lived plasma cells (PCs) in human lupus nephritis (LN) [1]. The authors present a cogent summary of experiments showing that long-lived PCs alone are sufficient to induce murine LN, and that targeting of PCs in these models is successful. However, we believe that clinical experience with the treatme...

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  Dear Editor,

  We read with interest the editorial by Ferraccioli and Houssiau proposing the specific targeting of long lived plasma cells (PCs) in human lupus nephritis (LN) [1]. The authors present a cogent summary of experiments showing that long-lived PCs alone are sufficient to induce murine LN, and that targeting of PCs in these models is successful. However, we believe that clinical experience with the treatment of human SLE indicates that plasmablasts and short-lived PCs, recently derived from autoreactive B-cells, are more important in the generation of autoantibody and clinical disease activity.

  The literature on antibody secreting cell subsets are in some cases difficult to interpret due to the use of the terms plasmablast and plasma cell interchangeably, and different surface phenotypes in mouse and human [2]. Human plasmablasts and PCs (latter labelled CD27-ve in article) both express CD27.

  Adoptive transfer of plasmablasts alone that mature into long-lived PCs is sufficient to cause LN in Rag-/- mice, which have no B-cells [3]. This situation is analogous to therapeutic B cell depletion in human SLE, with continued plasma cell activity in the absence of B cells. Rituximab therapy profoundly depletes B-cells, but does not directly affect long- lived PCs - demonstrated by the maintenance of total IgG including anti- microbial antibodies [4,5]. Evidence of clinical efficacy of B cell depletion in human SLE is controversial with contradictory RCTs [6,7] and open label studies [8]. However, there is abundant evidence that anti- dsDNA titre falls after rituximab [4-7]. We have previously shown that reduction in anti-dsDNA was only observed in patients with complete depletion of both B-cells and plasmablasts [5]. We also found that clinical relapse following rituximab was strongly associated with plasmablast repopulation [5]. Collectively, the effects of B cell depletion therapy in SLE suggest that autoantibodies are secreted by shorter-lived antibody secreting cells compared to those that maintain steady state antimicrobial immunoglobulin levels. This selective effect of B cell depletion on the antibody secreting cell pool may be crucial to its safety.

  We therefore believe that targeting of PCs in isolation would have limited efficacy since these cells would be replenished from autoreactive memory B-cells. It is possible that, in a subset of SLE patients resistant to rituximab, combined targeting of long-lived plasma cells is required. However, there would be important safety considerations for such indiscriminate complete ablation of autoreactive and antimicrobial antibody production.

  References

  1. Ferraccioli G, Houssiau FA. Which B-cell subset should we target in lupus? Ann Rheum Dis 2013;72(12):1891-2.

  2. Gordon CJ, Grafton G, Wood PM, et al. Modelling the human immune response: can mice be trusted? Commentary. Curr Opin Pharmacol 2001;1(4):431-5.

  3. Cheng Q, Mumtaz IM, Khodadadi L, et al. Autoantibodies from long-lived 'memory' plasma cells of NZB/W mice drive immune complex nephritis. Ann Rheum Dis 2013;72(12):2011-7.

  4. Cambridge G, Leandro MJ, Teodorescu M, et al. B cell depletion therapy in systemic lupus erythematosus: effect on autoantibody and antimicrobial antibody profiles. Arthritis Rheum 2006;54(11):3612 -22.

  5. Vital EM, Dass S, Buch MH, et al. B cell biomarkers of rituximab responses in systemic lupus erythematosus. Arthritis Rheum 2011;63(10):3038-47.

  6. Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010;62(1):222-33.

  7. Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012;64(4):1215-26.

  8. Ramos-Casals M, Soto MJ, Cuadrado MJ, et al. Rituximab in systemic lupus erythematosus: A systematic review of off-label use in 188 cases. Lupus 2009;18(9):767-76.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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