Dept of Nephrology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
Dept of Clinical Immunology, Erasmus MC, Rotterdam, The Netherlands.
J Autoimmun. 2018 Jul;91:45-54. doi: 10.1016/j.jaut.2018.03.003. Epub 2018 Apr 7.
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.
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.
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.
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.
ClinicalTrials.gov NCT02284984.
在系统性红斑狼疮（SLE）患者中，观察到中性粒细胞胞外诱捕网（NETs）的过度形成，并且其降解受损。在体外，免疫复合物（ICx）触发 NET 的形成，而 NET 衍生的 DNA 被认为是抗核自身抗体（ANAs）的自身抗原，在 SLE 中发现。基于 SLE 中的这些自我延续机制，本研究探讨了使用利妥昔单抗（RTX）和贝利木单抗（BLM）联合抑制 ICx 形成是否可以减少 NET 形成并改善疾病。
进行了一项 2A 期、开放性、单臂概念验证研究，其中 16 例患有严重、难治性疾病的 SLE 患者接受了 CD20 介导的 B 细胞耗竭联合利妥昔单抗和 BlyS 持续抑制联合贝立木单抗治疗。除了安全性外，该研究的终点选择旨在解决与过度 NET 形成相关的自身抗体概念。
我们发现在 RTX 介导的 B 细胞耗竭时 BlyS 水平激增，随后 BLM 治疗可消除这种激增。因此，RTX+BLM 的治疗干预导致了 ANAs 的特异性减少和过度 NET 形成的消退。RTX+BLM 似乎是安全的，并实现了临床显著的反应：10 例患者达到低狼疮疾病活动状态，11 例患者出现肾脏反应，16 例患者中的 14 例同时减少了免疫抑制药物的使用。
本研究提供了新的见解，通过 RTX+BLM 治疗性靶向产生 ANA 减少 SLE 中的过度 NET 形成具有临床益处。总之，提出了一种新的治疗概念，专门改善潜在的 SLE 病理生理学。
ClinicalTrials.gov NCT02284984。
