title: Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus.
abstract: OBJECTIVE
  To assess the effects of the B lymphocyte stimulator (BLyS)-specific inhibitor belimumab on immunologic biomarkers, including B cell and T cell populations, and maintenance of antibody titers to prior vaccines in autoantibody-positive systemic lupus erythematosus (SLE) patients.
  
  
  METHODS
  Pooled data from 2 phase III trials, the Study of Belimumab in Subjects with SLE 52-week (BLISS-52) and 76-week (BLISS-76) trials, comparing belimumab 1 mg/kg or 10 mg/kg versus placebo (plus standard SLE therapy for each group) were analyzed for changes in autoantibody, immunoglobulin, and complement levels. BLISS-76 patients were also analyzed for changes in B cell and T cell populations and effects on prior vaccine-induced antibody levels.
  
  
  RESULTS
  Belimumab-treated patients experienced significant sustained reductions in IgG and autoantibodies and improvement in C3/C4 levels, resulting in greater positive-to-negative conversion rates for IgG anti-double-stranded DNA (anti-dsDNA), anti-Sm, anticardiolipin, and anti-ribosomal P autoantibodies and normalization of hypergammaglobulinemia and low C3/C4 levels. Belimumab-treated patients experienced significant decreases in the numbers of naive and activated B cells, as well as plasma cells, whereas memory B cells and T cell populations did not decrease. Belimumab did not substantially affect preexisting antipneumococcal or anti-tetanus toxoid antibody levels. Post hoc analysis showed greater reductions in SLE disease activity and the risk of severe flares in patients treated with belimumab 10 mg/kg (P≤0.01) who were anti-dsDNA positive and had low C3/C4 levels at baseline. Normalization of the C3 or anti-dsDNA level by 8 weeks, irrespective of therapy, was predictive of a reduced risk of severe flare over 52 weeks.
  
  
  CONCLUSIONS
  Belimumab appears to promote normalization of serologic activity and reduce BLyS-dependent B cell subsets in serologically and clinically active SLE. Greater serologic activity may predict a better treatment response to belimumab.
authors.affiliation: Los Angeles County+University of Southern California Medical Center and University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA. stohl@usc.edu
authors.forename: William
authors.initials: W
authors.lastname: Stohl
authors.forename: Falk
authors.initials: F
authors.lastname: Hiepe
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Latinis
authors.forename: Mathew
authors.initials: M
authors.lastname: Thomas
authors.forename: Morton A
authors.initials: MA
authors.lastname: Scheinberg
authors.forename: Ann
authors.initials: A
authors.lastname: Clarke
authors.forename: Cynthia
authors.initials: C
authors.lastname: Aranow
authors.forename: Frank R
authors.initials: FR
authors.lastname: Wellborne
authors.forename: Carlos
authors.initials: C
authors.lastname: Abud-Mendoza
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Hough
authors.forename: Lilia
authors.initials: L
authors.lastname: Pineda
authors.forename: Thi-Sau
authors.initials: TS
authors.lastname: Migone
authors.forename: Z John
authors.initials: ZJ
authors.lastname: Zhong
authors.forename: William W
authors.initials: WW
authors.lastname: Freimuth
authors.forename: W Winn
authors.initials: WW
authors.lastname: Chatham
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001323:Autoantibodies; C511911:belimumab; D003165:Complement System Proteins