Session Type: Abstract Submissions (ACR)
Background/Purpose: Cholinergic anti-inflammatory pathway (CAP) activation by electrical vagus nerve stimulation (VNS) is being studied in rheumatoid arthritis (RA) trials (NCT01552941). CAP signaling proceeds sequentially through vagus and splenic nerves to splenic acetylcholine-secreting T cells, which in turn signal adjacent macrophages to diminish cytokine secretion after proinflammatory stilmuli(1). VNS devices depolarize nerves by application of charge, modulated by varying output current (OC), pulse width (PW), and pulse frequency (F). Stimulation duration (D), and daily stimulation interval (SI) can also be varied. Optimally activating this complex neural-immune pathway created unique translational medicine challenges. Herein we report preclinical data guiding stimulation parameter selection for RA trials.
Methods: VNS stimulation parameter effect on cytokine production and tissue inflammation was studied in 5 models: 1) TNF production in rat systemic endotoxemia with VNS delivered by cervical vagus hook electrodes (HE); 2) morphometric measurement of ulceration in rat indomethacin-induced inflammatory enteritis using cervical vagus cuff electrodes (CE); 3) reduction in in vitro LPS-induced whole blood TNF release using VNS delivered chronically by implanted CE in normal canines; 4) improvement in endoscopic ulceration score after dextran sulfate sodium (DSS) colitis in rats using implanted CE; and 5) improvement in ankle swelling, joint histology and systemic cytokines in rat CIA using implanted CE.
Results: Selection of PW (200-250usec) and F (10Hz) was guided by prior clinical tolerability experience with VNS in epilepsy(2). OC titration experiments in rat endotoxemia/HE showed optimal CAP activation at 0.5-1.0mA, and was confirmed in canine CE. The implanted CE used in rodent experiments surrounded the entire carotid sheath rather than only the vagus, so correlation experiments in rat endotoxemia with CE vs. HE verified 3.0 mA as optimal OC for chronic rodent models using this peri-carotid CE. D variation experiments in rat endotoxemia/HE confirmed prior findings(3) that 60 seconds sufficiently activated the CAP. SI experiments in indomethacin enteritis also confirmed prior findings(3) that a 60 second stimulus caused anti-inflammatory effects persisting for at least 24 hours. Efficacy in rodent subacute DSS colitis and CIA using peri-carotid CE was achieved using 3.0mA OC, 10Hz F, 200usec PW, 60 second D, and once daily SI. For RA trials using peri-vagus CE these same parameters were selected with exception of targeted OC of >1.0mA and 250usec PW.
Conclusion: Preclinical pharmacokinetic-pharmacodynamic-efficacy relationships are typically used to understand dose-response and guide dose selection for drug trials. CAP activation involves complex interactions between neuronal cell depolarization and immune effector cell function, complicating study of analogous stimulation parameter-response relationships. These experiments show that despite these hurdles, rational optimization of therapy delivery with “bioelectronic medicines” can be achieved. 1. Science 2011; 334:98 2. Neurology 2002; 59:S31 3. Crit Care Med 2007; 35:2762
F. A. Koopman,
P. P. Tak,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/selection-of-vagus-nerve-stimulation-parameters-for-a-first-in-human-study-in-rheumatoid-arthritis-a-unique-translational-medicine-challenge/