Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
Galvani Bioelectronics, Stevenage, UK.
J Intern Med. 2017 Jul;282(1):64-75. doi: 10.1111/joim.12626. Epub 2017 May 26.
Imbalance in the autonomic nervous system (ANS) has been observed in many established chronic autoimmune diseases, including rheumatoid arthritis (RA), which is a prototypic immune-mediated inflammatory disease (IMID). We recently discovered that autonomic dysfunction precedes and predicts arthritis development in subjects at risk of developing seropositive RA. In addition, RA patients with relatively high vagus nerve tone (higher parasympathetic parameters, measured by heart rate variability) respond better to antirheumatic therapies. Together, these data suggest that the ANS may control inflammation in humans. This notion is supported by experimental studies in animal models of RA. We have found that stimulation of the so-called cholinergic anti-inflammatory pathway by efferent electrical vagus nerve stimulation (VNS) or pharmacological activation of the alpha7 subunit of nicotinic acetylcholine receptors (α7nAChR) improves clinical signs and symptoms of arthritis, reduces cytokine production and protects against progressive joint destruction. Conversely, increased arthritis activity was observed in alpha7nAChR knockout mice. These studies together with previous work in animal models of sepsis and other forms of inflammation provided the rationale for an experimental clinical trial in patients with RA. We could for the first time show that an implantable vagus nerve stimulator inhibits peripheral blood cytokine production in humans. VNS significantly inhibited TNF and IL-6 production and improved RA disease severity, even in some patients with therapy-resistant disease. This work strongly supports further studies using a bioelectronic approach to treat RA and other IMIDs.
自主神经系统（ANS）失衡在许多已确立的慢性自身免疫性疾病中都有观察到，包括类风湿关节炎（RA），这是一种典型的免疫介导的炎症性疾病（IMID）。我们最近发现，自主神经功能障碍在易发生血清阳性 RA 的患者中先于关节炎的发生，并可预测关节炎的发生。此外，RA 患者的迷走神经张力相对较高（通过心率变异性测量的较高副交感神经参数）对抗风湿治疗的反应更好。这些数据共同表明，ANS 可能在人类中控制炎症。这一观点得到了 RA 动物模型的实验研究的支持。我们发现，通过传出电迷走神经刺激（VNS）或烟碱型乙酰胆碱受体（α7nAChR）的药理学激活刺激所谓的胆碱能抗炎途径，可改善关节炎的临床症状和体征，减少细胞因子的产生并预防进行性关节破坏。相反，在α7nAChR 敲除小鼠中观察到关节炎活动增加。这些研究以及之前在败血症和其他形式的炎症的动物模型中的工作为 RA 患者的实验性临床试验提供了依据。我们首次证明，植入式迷走神经刺激器可抑制人类外周血细胞因子的产生。VNS 可显著抑制 TNF 和 IL-6 的产生，并改善 RA 的严重程度，甚至对一些治疗抵抗性疾病的患者也有效。这项工作强烈支持使用生物电子方法治疗 RA 和其他 IMID 的进一步研究。
