Abstract: FR-PO695

Synergetic B-Cell Immunomodulation with Rituximab and Belimumab Combination Treatment in Severe, Refractory SLE: The SynBiose Proof-of-Concept Study

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Kraaij, Tineke, Leiden University Medical Center, Leiden, Netherlands
  • Huizinga, Tom, Leiden University Medical Center, Leiden, Netherlands
  • Rabelink, Ton J., Leiden University Medical Center, Leiden, Netherlands
  • van Kooten, Cees, Leiden University Medical Center, Leiden, Netherlands
  • Teng, Yoe Kie Onno, Leiden University Medical Center, Leiden, Netherlands
  • Kamerling, Sylvia, Leiden University Medical Center, Leiden, Netherlands
  • de Rooij, Esther, Leiden University Medical Center, Leiden, Netherlands
  • Van daele, Paul L.a., Erasmus MC, Rotterdam, Netherlands
  • Bredewold, Edwin, Leiden University Medical Center, Leiden, Netherlands
  • Bakker, Jaap A., Leiden University Medical Center, Leiden, Netherlands
  • Bajema, Ingeborg M., Leiden University Medical Center, Leiden, Netherlands
  • Scherer, Hans Ulrich, Leiden University Medical Center, Leiden, Netherlands
  • Toes, Rene, Leiden University Medical Center, Leiden, Netherlands
Background

Neutrophil extracellular traps (NETs) are auto-antigenic DNA strands and could give rise to SLE-specific autoantibodies that can deposit in glomeruli. It has been shown that autoantibodies can induce NETs, contributing to a vicious circle of immune activation in SLE. We hypothesized that eliminating autoantibodies can lead to decreased NET induction and thereby ameliorating disease in SLE. 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 week 24. Anti-dsDNA autoantibodies were measured and high sensitivity FACS was performed to assess B-cell subsets. NET induction was measured with 3D confocal microscopy.

Results

We included 14 patients with severe, refractory SLE of whom 11 had a renal flare. At 24 weeks we observed significant reductions in anti-dsDNA autoantibodies (p=0.0015). CD19+ B-cells were depleted throughout the study (p=0.0005) while plasma cells (PCs) temporarily decreased but returned at week 24 despite persistent depletion of transitional B-cells. Taken together with reductions of autoantibodies and stable total IgG, there is no reconstitution of autoreactive PCs. We observed significant decrease in NET reduction (p=0.0017). In vitro studies elucidated this resulted in reduction of immune complexes by RTX+BLM. Importantly, beneficial immunological effects translated to amelioration of clinical disease activity: SLEDAI decreased from a median of 18 to 2 (p=0.0002). Ten out of 11 LN patients showed a response (4 complete renal responders). The response was achieved while tapering immunosuppressive drugs. Treatment was well-tolerated.

Conclusion

The SynBiose study is the first to demonstrate that RTX+BLM ameliorated disease in 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. ClinicalTrials.gov NCT02284984