title: The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus.
abstract: OBJECTIVE
  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/m(2)) 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.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité - University Medicine, Berlin, Germany German Rheumatism Research Center (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Alexander
authors.affiliation: Department of Internal Medicine 3 (Rheumatology), University Erlangen-Nurnberg, Erlangen, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Sarfert
authors.affiliation: German Rheumatism Research Center (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany.
authors.forename: Jens
authors.identifier: http://orcid.org/0000-0002-2954-5755
authors.initials: J
authors.lastname: Klotsche
authors.affiliation: Department of Gastroenterology, Infectiology and Rheumatology, Charité - University Medicine, Berlin, Germany.
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.affiliation: Medical Clinical I, University of Cologne, Cologne, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rubbert-Roth
authors.affiliation: Division of Rheumatology, Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Hannes-Martin
authors.initials: HM
authors.lastname: Lorenz
authors.affiliation: Department of Internal Medicine 3 (Rheumatology), University Erlangen-Nurnberg, Erlangen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Rech
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité - University Medicine, Berlin, Germany German Rheumatism Research Center (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany.
authors.forename: Bimba F
authors.initials: BF
authors.lastname: Hoyer
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité - University Medicine, Berlin, Germany German Rheumatism Research Center (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité - University Medicine, Berlin, Germany German Rheumatism Research Center (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany.
authors.forename: Aderajew
authors.initials: A
authors.lastname: Waka
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité - University Medicine, Berlin, Germany German Rheumatism Research Center (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany.
authors.forename: Adriano
authors.initials: A
authors.lastname: Taddeo
authors.affiliation: Department of Nephrology and Hypertension, University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wiesener
authors.affiliation: Department of Internal Medicine 3 (Rheumatology), University Erlangen-Nurnberg, Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité - University Medicine, Berlin, Germany.
authors.forename: Gerd-Rüdiger
authors.initials: GR
authors.lastname: Burmester
authors.affiliation: German Rheumatism Research Center (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité - University Medicine, Berlin, Germany German Rheumatism Research Center (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Hiepe
authors.affiliation: Department of Internal Medicine 3 (Rheumatology), University Erlangen-Nurnberg, Erlangen, Germany Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Voll
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000906:Antibodies / Q000097:blood; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D000069286:Bortezomib; D004247:DNA / Q000276:immunology; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D005858:Germany; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008297:Male; D010950:Plasma Cells / Q000187:drug effects* / Q000473:pathology; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D001897:Boronic Acids; D007370:Interferon Type I; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone; D004247:DNA
keywords: Autoimmune Diseases; Autoimmunity; B cells; Systemic Lupus Erythematosus; Treatment