Safety and efficacy of neurostimulation with a miniaturised vagus nerve stimulation device in patients with multidrug-refractory rheumatoid arthritis: a two-stage multicentre, randomised pilot study

Summary 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. Methods 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 . Findings 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. Interpretation 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. Funding SetPoint Medical.