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 .

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Publication Details

Journal
Nature Medicine
Published
2025-12-22
DOI
https://doi.org/10.1038/s41591-025-04114-7
Citations
3
Primary Topic
Vagus Nerve Stimulation Research
Type
article
Field-Weighted Citation Impact
2.53
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article

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

Jeffrey R. Curtis, Stuart Novack, David Chernoff, Victoria D. Vuong et al.
3 citations
Nature Medicine
Vagus Nerve Stimulation Research
2.53
article

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

Jeffrey R. Curtis, Stuart Novack, David Chernoff, Victoria D. Vuong, Melissa Evangelista, A Crowley, Minna J. Kohler, Norman Gaylis, Gineth Paola Pinto-Patarroyo, Yaakov A. Levine, Jeff Peterson, G. Lam, Atul K. Singhal, Melvin A. Churchill, Pendleton Brewster Wickersham, Emily Jane Box, Eric C. Lee, Glenn R. Parris, Joshua P. June, Amy A. Derosier, Jose A. Pando, Tina Shah, R. Mark Richardson, Leroy A. Pacheco, John R. P. Tesser, David J. Ridley, Guillermo J. Valenzuela
article en
3 citations

Abstract

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 .

Nature MedicineVol. 32(1)
University of North Carolina at Charlotte (US), University of Nebraska–Lincoln (US), Southwest Research Institute (US), Feinstein Institute for Medical Research (US), Arthritis Foundation (US), Karolinska University Hospital (SE), Harvard University (US), Inova Fairfax Hospital (US), Stamford Hospital (US), Karolinska Institutet (SE), University of Alabama at Birmingham (US), Massachusetts General Hospital (US), Arthritis and Rheumatic Disease Specialties (US), Clinical Trials of Texas (US), Donald & Barbara Zucker School of Medicine at Hofstra/Northwell (US), Healthpoint (AE), Ecolab (United States) (US), Arthritis and Rheumatism Associates (US), Willow Wood (United States) (US), Atlanta Gastroenterology Associates (US), University of Washington Bothell (US), Los Angeles Clinical Trials (US), Rheumatology Consultants (US), Radiology Associates of Albuquerque (US), Bone Health and Osteoporosis Foundation (US), Institute of Medicinal Plant Development (CN), Kansas City VA Medical Center (US), Alta Bates Summit Medical Center (US), Altoona Arthritis and Osteoporosis Center (US)
Openalex Percentile: Top 9%
Vagus Nerve Stimulation Research
2.53
DOIOpen Access PDFOpenAlex
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