The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus
The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus
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DOI：
10.1016/j.jaut.2018.03.003
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发表时间：
2018-07-01
影响因子：
12.8
通讯作者：
Teng, Y. K. Onno
中科院分区：
文献类型：
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作者：
Kraaij, Tineke;Kamerling, Sylvia W. A.;Teng, Y. K. Onno
目的：在系统性红斑狼疮（SLE）患者中，观察到中性粒细胞胞外陷阱（NET）的过度形成，并且它们的降解受损。在体外，免疫复合物（ICx）触发NET形成，而NET衍生的DNA是SLE中发现的抗核自身抗体（ANA）的假定自身抗原。基于SLE的这些自我维持机制，本研究调查了使用利妥昔单抗（RTX）和贝利木单抗（BLM）的组合干扰ICx形成是否可以减少NET形成并改善疾病。进行了2A期、开放标签、单臂概念验证研究，其中16名患有重度、重度或重度SLE的SLE患者，用利妥昔单抗联合CD20介导的B细胞耗竭和贝利木单抗持续抑制B细胞活化因子BIyS治疗难治性疾病。除了安全性，该研究的终点被选择来解决的概念，自身抗体过度NET formation.Results的关系：我们证明了一个激增的BIyS水平RTX介导的B细胞耗竭后，这是废除了随后的BLM治疗。因此，RTX + BLM的治疗干预导致ANA的特异性减少和过度NET形成的消退。RTX + BLM似乎是安全的，并取得了临床显着的反应：低狼疮疾病活动状态达到10例，肾反应11例，伴随免疫抑制药物逐渐减少14的16 patients.Conclusions：这项研究提供了新的见解，减少过多的NET形成在SLE的治疗靶向ANA生产与RTX + BLM的临床效益。总之，提出了一个新的治疗概念，特别是改善潜在的SLE病理生理学。(C)2018爱思唯尔有限公司版权所有
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.