Genovese Mark C, Gaylis Norman B, Sikes David, Kivitz Alan, Lewis Horowitz Diane, Peterfy Charles, Glass Emmett V, Levine Yaakov A, Chernoff David
Division of Immunology and Rheumatology, Stanford University, Palo Alto, CA, USA.
Arthritis and Rheumatic Disease Specialties, Aventura, FL, USA.
Lancet Rheumatol. 2020 Sep;2(9):e527-e538. doi: 10.1016/S2665-9913(20)30172-7. Epub 2020 Jul 28.
Background The inflammatory reflex plays a role in regulating innate and adaptive immunity by modulating cellular and molecular inflammatory pathways. The vagus nerve is a major constituent of the inflammatory reflex and studies have shown that the reflex can be activated by electrical stimulation of the vagus nerve. In this first in-human pilot study, we assessed the safety and efficacy of a novel miniaturised vagus nerve stimulation (VNS) device for the treatment of multidrug-refractory rheumatoid arthritis.
Participants with moderately to severely active rheumatoid arthritis and prior insufficient response to two or more biological disease-modifying anti-rheumatic drugs or Janus kinase inhibitors with at least two different modes of action were enrolled in a two-stage study done at five clinical research sites in the USA. Stage 1 was open label; participants were implanted with a miniaturised VNS device, which was activated for 1 min once a day. In stage 2, participants were randomly assigned (1:1:1) to receive active stimulation (1 min once a day or 1 min four times a day) or sham stimulation (device implanted but not activated), with the sites and participants masked to treatment assignment. The primary outcome was incidence of treatment-emergent adverse events. Clinical efficacy was assessed as a key secondary outcome. The study was registered with ClinicalTrials.gov, NCT03437473.
14 patients were enrolled between March 13 and Aug 8, 2018. Three patients received stimulation in stage 1 and, following safety review board approval, the remaining 11 patients were implanted during stage 2 and randomly assigned to receive 1 min of stimulation once daily (n=3), 1 min of stimulation four times daily (n=4), or no stimulation (n=4) for 12 weeks. There were no device-related or treatment-related serious adverse events. Surgery-related adverse events were Horner's syndrome and vocal cord paralysis (in one patient each), which resolved without clinically significant sequelae. No deaths were recorded.
VNS with a miniaturised neurostimulator was safe and well tolerated and reduced signs and symptoms of rheumatoid arthritis in patients with multidrug-refractory disease. These results support further evaluation in a larger randomised sham-controlled study.
SetPoint Medical.
背景 炎症反射通过调节细胞和分子炎症途径在调节固有免疫和适应性免疫中发挥作用。迷走神经是炎症反射的主要组成部分，研究表明该反射可通过迷走神经电刺激激活。在这项首次人体试验研究中，我们评估了一种新型小型化迷走神经刺激（VNS）装置治疗多药难治性类风湿关节炎的安全性和有效性。
患有中度至重度活动性类风湿关节炎且先前对两种或更多种具有至少两种不同作用方式的生物性改善病情抗风湿药物或Janus激酶抑制剂反应不足的参与者，参加了在美国五个临床研究地点进行的两阶段研究。第1阶段为开放标签；参与者植入了小型化VNS装置，每天激活1分钟。在第2阶段，参与者被随机分配（1:1:1）接受主动刺激（每天1次，每次1分钟或每天4次，每次1分钟）或假刺激（植入装置但未激活），研究地点和参与者对治疗分配不知情。主要结局是治疗中出现的不良事件的发生率。临床疗效作为关键次要结局进行评估。该研究已在ClinicalTrials.gov注册，注册号为NCT03437473。
2018年3月13日至8月8日期间招募了14名患者。3名患者在第1阶段接受了刺激，经安全审查委员会批准后，其余11名患者在第2阶段植入装置并随机分配接受每日1次1分钟刺激（n = 3）、每日4次1分钟刺激（n = 4）或不接受刺激（n = 4），为期12周。没有与装置相关或与治疗相关的严重不良事件。与手术相关的不良事件为霍纳综合征和声带麻痹（各1例患者），均自行缓解，无临床显著后遗症。未记录到死亡病例。
使用小型化神经刺激器的VNS安全且耐受性良好，并减轻了多药难治性疾病患者类风湿关节炎的体征和症状。这些结果支持在更大规模的随机假对照研究中进行进一步评估。
SetPoint Medical公司。
