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

被引：101

作者：

Kraaij, Tineke ^{[1
]}

Kamerling, Sylvia W. A. ^{[1
]}

de Rooij, Esther N. M. ^{[1
]}

van Daele, Paul L. A. ^{[2
]}

Bredewold, Obbo W. ^{[1
]}

Bakker, Jaap A. ^{[3
]}

Bajema, Ingeborg M. ^{[4
]}

Scherer, Hans U. ^{[5
]}

Toes, Rene E. M. ^{[5
]}

Huizinga, Tom J. W. ^{[5
]}

Rabelink, Ton J. ^{[1
]}

van Kooten, Cees ^{[1
]}

Teng, Y. K. Onno ^{[1
]}

机构：

[1] LUMC, Dept Nephrol, POB 9600, NL-2300 RC Leiden, Netherlands

[2] Erasmus MC, Dept Clin Immunol, Rotterdam, Netherlands

[3] LUMC, Dept Clin Chem & Lab Med, Leiden, Netherlands

[4] LUMC, Dept Pathol, Leiden, Netherlands

[5] LUMC, Dept Rheumatol, Leiden, Netherlands

来源：

JOURNAL OF AUTOIMMUNITY | 2018年 / 91卷

关键词：

Systemic lupus erythematosus; Lupus nephritis; Refractory lupus; Rituximab; Belimumab; Neutrophil extracellular traps; Autoantibody; Clinical trial; B-LYMPHOCYTE STIMULATOR; NEUTROPHIL EXTRACELLULAR TRAPS; LOW-DENSITY GRANULOCYTES; DISEASE-ACTIVITY; NETTING NEUTROPHILS; DOUBLE-BLIND; NEPHRITIS; AUTOIMMUNE; EFFICACY; VASCULITIS;

D O I：

10.1016/j.jaut.2018.03.003

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 BIyS 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 BIyS 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. (C) 2018 Elsevier Ltd. All rights reserved.

引用

页码：45 / 54

页数：10

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