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

Laura van Dam¹, Zgjim Osmani¹, Tineke Kraaij¹, Sylvia W.A. Kamerling¹, Jaap A. Bakker², Hans U. Scherer³, Ton Rabelink¹, Reinhard Voll⁴, David A. Isenberg⁵, Cees van Kooten¹ and Y.K. Onno Teng¹, ¹Nephrology, Leiden University Medical Center, Leiden, Netherlands, ²Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, Netherlands, ³Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands, ⁴Clinic for Rheumatology and Clinical Immunology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany, ⁵University College London, London, United Kingdom

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: autoantibodies and plasma cells, B cell targeting, NETosis, SLE

Session Information

Date: Tuesday, October 23, 2018

Title: 5T085 ACR Abstract: B Cell Biology & Targets in Autoimmune & Inflammatory Disease (2791–2796)

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: 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.

Disclosure: L. van Dam, None; Z. Osmani, None; T. Kraaij, None; S. W. A. Kamerling, None; J. A. Bakker, None; H. U. Scherer, None; T. Rabelink, None; R. Voll, None; D. A. Isenberg, None; C. van Kooten, None; Y. K. O. Teng, None.

To cite this abstract in AMA style:

van Dam L, Osmani Z, Kraaij T, Kamerling SWA, Bakker JA, Scherer HU, Rabelink T, Voll R, Isenberg DA, van Kooten C, Teng YKO. The Effect of B Cell Targeted Therapies on Autoantibodies and Excessive Neutrophil Extracellular Trap Formation in Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/the-effect-of-b-cell-targeted-therapies-on-autoantibodies-and-excessive-neutrophil-extracellular-trap-formation-in-systemic-lupus-erythematosus/. Accessed .

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