Synergetic B-Cell Immunomodulation with Rituximab and Belimumab Combination Treatment in Severe, Refractory SLE

Tineke Kraaij¹, Sylvia W.A. Kamerling¹, Esther N.M. de Rooij¹, Paul L. van Daele², O.W. Bredewold¹, Jaap A. Bakker³, Ingeborg Bajema⁴, Hans U. Scherer⁵, Rene E.M. Toes⁵, Tom W.J. Huizinga⁵, Ton Rabelink¹, Cees van Kooten¹ and Y.K. Onno Teng¹, ¹Nephrology, Leiden University Medical Center, Leiden, Netherlands, ²Immunology, Erasmus Medical Center, Rotterdam, Netherlands, ³Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, Netherlands, ⁴Pathology, Leiden University Medical Center, Leiden, Netherlands, ⁵Rheumatology, Leiden University Medical Center, Leiden, Netherlands

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: B cell targeting, belimumab, Neutrophil Extracellular Traps, rituximab and systemic lupus erythematosus (SLE)

Session Information

Date: Sunday, November 5, 2017

Title: Systemic Lupus Erythematosus – Clinical Aspects and Treatment I: Novel and Current Therapies

Session Type: ACR Concurrent Abstract Session

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

Background/Purpose:

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 hypothesized 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 (SynBiose) 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 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 the observed reductions of autoantibodies and stable total IgG, there is no reconstitution of autoreactive PCs. We also observed significant decrease in NET reduction (p=0.0017). 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=0.0002). Ten out of 11 LN patients showed a response (4 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 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.

Disclosure: T. Kraaij, None; S. W. A. Kamerling, None; E. N. M. de Rooij, None; P. L. V. Daele, None; O. W. Bredewold, None; J. A. Bakker, None; I. Bajema, None; H. U. Scherer, None; R. E. M. Toes, None; T. W. J. Huizinga, None; T. Rabelink, None; C. van Kooten, None; Y. K. O. Teng, Aurinia Pharmaceuticals, 5.

To cite this abstract in AMA style:

Kraaij T, Kamerling SWA, de Rooij ENM, Daele PLV, Bredewold OW, Bakker JA, Bajema I, Scherer HU, Toes REM, Huizinga TWJ, Rabelink T, van Kooten C, Teng YKO. Synergetic B-Cell Immunomodulation with Rituximab and Belimumab Combination Treatment in Severe, Refractory SLE [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/synergetic-b-cell-immunomodulation-with-rituximab-and-belimumab-combination-treatment-in-severe-refractory-sle/. Accessed .

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