Vagus Nerve Stimulation Shows Promising Clinical Response in Rheumatoid Arthritis, Study Finds
USA: Researchers have found in an open-label RESET-RA trial that vagus nerve stimulation was a promising nonpharmacologic therapeutic option for rheumatoid arthritis.
The trial provides real-world evidence on the use of implantable vagus nerve stimulation in rheumatoid arthritis. Clinical efficacy was sustained, with approximately 50% of patients achieving an ACR20 response at 6 months. At 12 months, the ACR20 response rate exceeded 52%, supporting the role of vagus nerve stimulation in rheumatoid arthritis.
Rheumatoid arthritis is a chronic inflammatory disease driven by immune dysregulation and progressive joint damage. Despite advances with biologic and targeted synthetic DMARDs, many patients respond poorly or cannot tolerate these therapies, underscoring the need for nonpharmacologic options.
The pivotal RESET-RA trial, published in Nature Medicine, was led by John R. P. Tesser of Arizona Arthritis & Rheumatology Research, USA. The study evaluated an implantable vagus nerve neuromodulation system designed to regulate the inflammatory reflex, a vagus nerve–mediated pathway involved in cytokine control and disrupted in rheumatoid arthritis.
RESET-RA was a double-blind, randomized, sham-controlled trial including 242 patients with moderate-to-severe rheumatoid arthritis and inadequate response or intolerance to advanced DMARDs. Patients received active or sham stimulation for three months, followed by open-label active treatment in all participants, with outcomes assessed up to 12 months. The primary endpoint was the achievement of an ACR20 response at three months.
The study revealed the following findings:
- ACR20 response rates at three months were significantly higher with active vagus nerve stimulation than with sham stimulation.
- Clinical responses continued to improve during the open-label phase.
- Approximately 50% of patients achieved an ACR20 response at six months.
- The ACR20 response rate increased further to 52.8% at 12 months among patients who completed follow-up.
- The progressive improvement suggests a gradual and sustained therapeutic effect rather than a rapid onset typical of pharmacologic treatments.
- Adverse events occurred at similar frequencies in the active and sham groups.
- Serious device-related adverse events were rare, confined to perioperative complications, and resolved without lasting issues.
- The low requirement for additional drug therapy during follow-up supported the durability of the treatment effect.
The investigators noted that the three-month duration of the controlled phase was a limitation, reflecting regulatory requirements to minimize prolonged placebo exposure. However, unlike drug trials where maximal responses are often seen early, vagus nerve stimulation appeared to require a longer period to achieve peak benefit, likely due to its mechanism of modulating innate neuroimmune pathways rather than directly suppressing inflammatory mediators.
Overall, the RESET-RA trial demonstrates that vagus nerve–mediated neuroimmune modulation can deliver sustained improvements in disease activity with a favorable safety profile. These findings position implantable vagus nerve stimulation as a first-in-class, nonpharmacologic therapeutic option for patients with difficult-to-treat rheumatoid arthritis.
Reference:
Tesser, J. R., Crowley, A. R., Box, E. J., June, J. P., Wickersham, P. B., Valenzuela, G. J., Gaylis, N. B., Lam, G. K., Pacheco, L. A., Ridley, D. J., Pinto-Patarroyo, G. P., Novack, S. N., Churchill, M. A., Kohler, M., Lee, E. C., Pando, J. A., Parris, G. R., Peterson, J. R., Shah, T., . . . Chernoff, D. (2025). Vagus nerve-mediated neuroimmune modulation for rheumatoid arthritis: A pivotal randomized controlled trial. Nature Medicine, 32(1), 369-378. https://doi.org/10.1038/s41591-025-04114-7
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