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J Autoimmun. 2018 Jul;91:45-54. doi: 10.1016/j.jaut.2018.03.003. Epub 2018 Apr 7.

The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus.

Author information

1
Dept of Nephrology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
2
Dept of Clinical Immunology, Erasmus MC, Rotterdam, The Netherlands.
3
Dept of Clinical Chemistry & Laboratory Medicine, LUMC, Leiden, The Netherlands.
4
Dept of Pathology, LUMC, Leiden, The Netherlands.
5
Dept of Rheumatology, LUMC, Leiden, The Netherlands.
6
Dept of Nephrology, Leiden University Medical Center (LUMC), Leiden, The Netherlands. Electronic address: y.k.o.teng@lumc.nl.

Abstract

OBJECTIVE:

In systemic lupus erythematosus (SLE) patients, excessive formation of neutrophil extracellular traps (NETs) is observed and their degradation is impaired. In vitro, immune complexes (ICx) trigger NET formation while NET-derived DNA is a postulated autoantigen for anti-nuclear autoantibodies (ANAs), found in SLE. Based on these self-perpetuating mechanisms in SLE, this study investigates whether interfering with ICx formation using a combination of rituximab (RTX) and belimumab (BLM) could decrease NET formation and ameliorate disease.

METHODS:

A phase 2A, open-label, single arm proof-of-concept study was performed wherein 16 SLE patients with severe, refractory disease were treated with a combination of CD20-mediated B-cell depletion with rituximab and sustained inhibition of B-cell activating factor BlyS with belimumab. Besides safety, the study's endpoints were chosen to address the concept of autoantibodies in relation to excessive NET formation.

RESULTS:

We demonstrated a surge of BlyS levels upon RTX-mediated B-cell depletion which was abrogated by subsequent BLM treatment. As such, therapeutic intervention with RTX + BLM led to specific reductions in ANAs and regression of excessive NET formation. RTX + BLM appeared to be safe and achieved clinically significant responses: low lupus disease activity state was achieved in 10 patients, renal responses in 11 patients and concomitant immunosuppressive medication was tapered in 14 out of the 16 patients.

CONCLUSIONS:

This study provides novel insights into clinical beneficence of reducing excessive NET formation in SLE by therapeutic targeting ANA production with RTX + BLM. Altogether putting forward a new treatment concept that specifically ameliorates underlying SLE pathophysiology.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT02284984.

KEYWORDS:

Autoantibody; Belimumab; Clinical trial; Lupus nephritis; Neutrophil extracellular traps; Refractory lupus; Rituximab; Systemic lupus erythematosus

PMID:
29636274
DOI:
10.1016/j.jaut.2018.03.003

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