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The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus
  1. Tobias Alexander1,2,
  2. Ramona Sarfert3,
  3. Jens Klotsche2,
  4. Anja A Kühl4,
  5. Andrea Rubbert-Roth5,
  6. Hannes-Martin Lorenz6,
  7. Jürgen Rech3,
  8. Bimba F Hoyer1,2,
  9. Qingyu Cheng1,2,
  10. Aderajew Waka1,2,
  11. Adriano Taddeo1,2,
  12. Michael Wiesener7,
  13. Georg Schett3,
  14. Gerd-Rüdiger Burmester1,
  15. Andreas Radbruch2,
  16. Falk Hiepe1,2,
  17. Reinhard E Voll3,8
  1. 1Department of Rheumatology and Clinical Immunology, Charité - University Medicine, Berlin, Germany
  2. 2German Rheumatism Research Center (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany
  3. 3Department of Internal Medicine 3 (Rheumatology), University Erlangen-Nurnberg, Erlangen, Germany
  4. 4Department of Gastroenterology, Infectiology and Rheumatology, Charité - University Medicine, Berlin, Germany
  5. 5Medical Clinical I, University of Cologne, Cologne, Germany
  6. 6Division of Rheumatology, Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany
  7. 7Department of Nephrology and Hypertension, University Erlangen-Nuremberg, Erlangen, Germany
  8. 8Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany
  1. Correspondence to Dr Falk Hiepe, Department of Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, Charitéplatz 1, Berlin 10117, Germany; falk.hiepe{at}charite.de

Abstract

Objectives To investigate whether bortezomib, a proteasome inhibitor approved for treatment of multiple myeloma, induces clinically relevant plasma cell (PC) depletion in patients with active, refractory systemic lupus erythematosus (SLE).

Methods Twelve patients received a median of two (range 1–4) 21-day cycles of intravenous bortezomib (1.3 mg/m2) with the coadministration of dexamethasone (20 mg) for active SLE. Disease activity was assessed using the SLEDAI-2K score. Serum concentrations of anti–double-stranded DNA (anti-dsDNA) and vaccine-induced protective antibodies were monitored. Flow cytometry was performed to analyse peripheral blood B-cells, PCs and Siglec-1 expression on monocytes as surrogate marker for type-I interferon (IFN) activity.

Results Upon proteasome inhibition, disease activity significantly declined and remained stable for 6 months on maintenance therapies. Nineteen treatment-emergent adverse events occurred and, although mostly mild to moderate, resulted in treatment discontinuation in seven patients. Serum antibody levels significantly declined, with greater reductions in anti-dsDNA (∼60%) than vaccine-induced protective antibody titres (∼30%). Bortezomib significantly reduced the numbers of peripheral blood and bone marrow PCs (∼50%), but their numbers increased between cycles. Siglec-1 expression on monocytes significantly declined.

Conclusions These findings identify proteasome inhibitors as a putative therapeutic option for patients with refractory SLE by targeting PCs and type-I IFN activity, but our results must be confirmed in controlled trials.

  • Systemic Lupus Erythematosus
  • Autoimmune Diseases
  • B cells
  • Treatment
  • Autoimmunity

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