The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus

J Autoimmun. 2018 Jul;91:45-54. doi: 10.1016/j.jaut.2018.03.003. Epub 2018 Apr 7.

Abstract

Objective: In systemic lupus erythematosus (SLE) patients, excessive formation of neutrophil extracellular traps (NETs) is observed and their degradation is impaired. In vitro, immune complexes (ICx) trigger NET formation while NET-derived DNA is a postulated autoantigen for anti-nuclear autoantibodies (ANAs), found in SLE. Based on these self-perpetuating mechanisms in SLE, this study investigates whether interfering with ICx formation using a combination of rituximab (RTX) and belimumab (BLM) could decrease NET formation and ameliorate disease.

Methods: A phase 2A, open-label, single arm proof-of-concept study was performed wherein 16 SLE patients with severe, refractory disease were treated with a combination of CD20-mediated B-cell depletion with rituximab and sustained inhibition of B-cell activating factor BlyS with belimumab. Besides safety, the study's endpoints were chosen to address the concept of autoantibodies in relation to excessive NET formation.

Results: We demonstrated a surge of BlyS levels upon RTX-mediated B-cell depletion which was abrogated by subsequent BLM treatment. As such, therapeutic intervention with RTX + BLM led to specific reductions in ANAs and regression of excessive NET formation. RTX + BLM appeared to be safe and achieved clinically significant responses: low lupus disease activity state was achieved in 10 patients, renal responses in 11 patients and concomitant immunosuppressive medication was tapered in 14 out of the 16 patients.

Conclusions: This study provides novel insights into clinical beneficence of reducing excessive NET formation in SLE by therapeutic targeting ANA production with RTX + BLM. Altogether putting forward a new treatment concept that specifically ameliorates underlying SLE pathophysiology.

Trial registration: ClinicalTrials.gov NCT02284984.

Keywords: Autoantibody; Belimumab; Clinical trial; Lupus nephritis; Neutrophil extracellular traps; Refractory lupus; Rituximab; Systemic lupus erythematosus.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Antigen-Antibody Complex / metabolism
  • Autoantibodies / blood*
  • Cells, Cultured
  • DNA / immunology
  • Disease Progression
  • Drug Therapy, Combination
  • Extracellular Traps / metabolism*
  • Female
  • Humans
  • Immunotherapy / methods*
  • Lupus Erythematosus, Systemic / drug therapy*
  • Male
  • Middle Aged
  • Neutrophils / immunology*
  • Rituximab / therapeutic use*
  • Young Adult

Substances

  • Antibodies, Monoclonal, Humanized
  • Antigen-Antibody Complex
  • Autoantibodies
  • Rituximab
  • belimumab
  • DNA

Associated data

  • ClinicalTrials.gov/NCT02284984