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Abstract: FR-PO1047

The Effect of B Cell Targeted Therapies on Autoantibodies and Excessive Neutrophil Extracellular Trap Formation in Systemic Lupus Erythematosus Patients

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • van Dam, Laura Sophie, LUMC, Leiden, Netherlands
  • Osmani, Zgjim, LUMC, Leiden, Netherlands
  • Kraaij, Tineke, LUMC, Leiden, Netherlands
  • Kamerling, Sylvia, LUMC, Leiden, Netherlands
  • Bakker, Jaap A., LUMC, Leiden, Netherlands
  • Scherer, Hans Ulrich, LUMC, Leiden, Netherlands
  • Rabelink, Ton J., LUMC, Leiden, Netherlands
  • Voll, Reinhard E., University Medical Center Freiburg, Freiburg, Germany
  • Isenberg, David, University College London, London, United Kingdom
  • van Kooten, Cees, LUMC, Leiden, Netherlands
  • Teng, Yoe Kie Onno, LUMC, Leiden, Netherlands
Background

Systemic lupus erythematosus (SLE) is a severe systemic autoimmune disease characterized by immune-complexes (ICx) which cause inflammation and damage. Effective targeting of autoantibody secreting cells could be key to reset autoimmunity. Functionally, SLE-specific ICx are important triggers of neutrophil extracellular trap (NET) formation. A consortium was formed to study B-cell targeted therapies, including RTX, Bortezomib (BTZ) or combination of RTX + Belimumab (BLM). The present study aimed to investigate the effects of these therapies on relevant autoantibody levels and excessive NET formation.

Methods

This study involved three cohorts of severe SLE patients that were eligible to experimental treatment with RTX (n=16), BTZ (n=12) or RTX+BLM (n=16). A cross-sectional cohort of 35 SLE patients served as a control cohort. A panel of SLE relevant autoantibodies against dsDNA, histones, nucleosomes and C1q were measured by ELISA. NET formation was quantified by a novel highly-sensitive assay using 3D confocal microscopy (Kraaij et al. 2016).

Results

Comparing three regimens, RTX+BLM resulted in the strongest significant reduction on anti-dsDNA, anti-Histone and anti-Nucleosomes antibodies compared to a smaller decrease by RTX and BTZ. Interestingly, RTX+BLM specifically decreased anti-C1q antibodies, which were not targeted by RTX or BTZ. ICx-mediated NET formation was only significantly decreased with a median of 75% [53 – 85%] after RTX+BLM (p=0.0002). Successful seroconversion of autoantibodies associated with decreased NET formation (p=0.02). The latter phenomenon was further corroborated in an independent cohort of SLE patients, where excessive NET formation associated with the presence of three or more autoantibody specificities (p=0.02), and specifically with the presence of anti-C1q antibodies (p=0.03).

Conclusion

In this reverse, translational study of B-cell targeted therapies, we demonstrate that anti-C1q autoantibodies were derived from Blys-dependent proliferating plasmablasts because they were only susceptible to RTX+BLM therapy. Moreover, therapeutically narrowing of the autoantibody repertoire decreased immune-complex mediated NET formation.