Article Text

Download PDFPDF

PS7:129 Synergetic b-cell immunomodulation with rituximab and belimumab combination treatment in severe, refractory sle
  1. T Kraaij1,
  2. SWA Kamerling1,
  3. ENM de Rooij1,
  4. PLA van Daele2,
  5. OW Bredewold1,
  6. JA Bakker3,
  7. IM Bajema4,
  8. HU Scherer5,
  9. REM Toes5,
  10. TWJ Huizinga5,
  11. TJ Rabelink1,
  12. C van Kooten1 and
  13. YKO Teng1
  1. 1Department of Nephrology, LUMC, Leiden, The Netherlands
  2. 2Department of Clinical Immunology, Erasmus MC, Rotterdam, The Netherlands
  3. 3Department of Clinical Chemistry and Laboratory Medicine, LUMC, Leiden, The Netherlands
  4. 4Department of Pathology, LUMC, Leiden, The Netherlands
  5. 5Department of Rheumatology, LUMC, Leiden, The Netherlands


Background Neutrophil extracellular traps (NETs) are auto-antigenic DNA strands and potentially give rise to SLE-specific autoantibodies that can deposit in glomeruli. It has been shown that autoantibodies can induce NETs, contributing to the vicious circle of immune activation in SLE. We hypothesised that eliminating autoantibodies can lead to decreased NET induction and thereby ameliorating disease in SLE. Therefore, we designed a proof-of-concept study to eliminate autoantibodies and NET formation through synergetic B-cell immunomodulation with rituximab and belimumab (RTX+BLM) in severe refractory SLE.

Methods We treated patients with severe, refractory SLE in a phase 2 study with RTX+BLM. The primary endpoint assessed reduction of pathogenic autoantibodies and NET induction at 24 weeks. Anti-dsDNA autoantibodies were measured and high sensitivity FACS was performed to assess B-cell subsets. NET induction was measured with 3D confocal immunofluorescence microscopy.

Results We included 16 patients with severe, refractory SLE of whom 13 had a renal flare. At 24 weeks we observed significant reductions in anti-dsDNA autoantibodies (p=0.0004). CD19 +B cells were depleted throughout the study (p=0.0002) while plasma cells (PCs) temporarily decreased but returned at week 24 despite persistent depletion of transitional B-cells. Taken together with the observed reductions of autoantibodies and stable total IgG and protective antibodies, there is no reconstitution of autoreactive PCs. Further, we observed excessive NET induction in all patients at baseline which was reduced after 24 weeks (p=0.0006). In vitro studies elucidated this resulted in reduction of immune complexes by RTX+BLM. Importantly, the beneficial immunological effects translated to amelioration of clinical disease activity: SLEDAI decreased from a median of 18 to 2 (p<0.0001). Eleven out of 13 LN patients showed a response (5 complete renal responders). The response was achieved while tapering immunosuppressive medication. Treatment was generally well-tolerated.

Conclusion The SynBiose study is the first to demonstrate that RTX+BLM ameliorated disease in patients with severe SLE in association with the reduction of pathogenic autoantibodies and immune complex-mediated NET induction. Therefore, RTX+BLM represents a novel treatment concept in SLE.

  • Systemic Lupus Erythematosus
  • Biologicals
  • Neutrophil extracellular traps

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.