Vagus nerve-mediated neuroimmune modulation for rheumatoid arthritis: a pivotal randomized controlled trial.

The inflammatory reflex, in which vagus nerve signaling modulates cytokine production, is dysregulated in rheumatoid arthritis (RA). RESET-RA, a pivotal, double-blind, randomized, sham-controlled trial, evaluated a vagus nerve-targeted neuromodulation system for RA in 242 patients with inadequate response/intolerance to biological/targeted synthetic disease-modifying antirheumatic drugs. Patients were randomized to active or sham stimulation for 3 months, and then all received open-label stimulation with results reported to 12 months. The primary end point was 3-month American College of Rheumatology 20% (ACR20) response. ACR20 rates were higher with active simulation than with sham at 3 months (35.2% versus 24.2%, P = 0.0209), which further improved in open-label to 50.0% at 6 months and 52.8% at 12 months (all-completers). Adverse events occurred in a similar proportion of patients in both arms. Related serious adverse events (rate = 1.6%) were all perioperative, and resolved. Vagus nerve-mediated neuroimmune modulation for RA achieved its primary efficacy end point and produced durable clinical benefits with a favorable safety profile. ClinicalTrials.gov registration: NCT04539964 .