THE ARISING · Longevity & Healthspan
Implanted Vagus Nerve Stimulator Linked to Sustained Responses in Rheumatoid Arthritis at Two Years
A small device wrapped around a nerve in the neck, switched on for one minute a day, produced more improvement in rheumatoid arthritis than a sham device in a randomized trial, and most patients were still using it two years later.
The trial, called RESET-RA, was published in Nature Medicine in 2026. It was a double-blind, sham-controlled randomized trial of 242 adults with moderately to severely active rheumatoid arthritis. All had failed to respond to, or could not tolerate, at least one biologic or targeted synthetic disease-modifying drug. These are the advanced drugs used after standard treatments such as methotrexate.
The idea rests on what the authors call the inflammatory reflex. The vagus nerve carries signals between the brain and the body's organs. In this reflex, vagus nerve activity prompts immune cells to release less of the chemical messengers that drive inflammation, including TNF, IL-6 and IL-1β. The paper reports that in rheumatoid arthritis this nerve activity is diminished, and that the drop precedes the onset of clinical disease.
The implant is placed on the left vagus nerve in the neck. Active stimulation was set to the patient's upper comfort level, up to 2.5 mA, and delivered a one-minute train of pulses once daily at 10 Hz. Patients had lived with the disease for an average of 12.4 years. They had tried a median of two advanced drugs before enrolling.
After surgery, patients were randomized to active or sham stimulation for three months. The primary measure was ACR20, a standard score meaning at least a 20% improvement in tender and swollen joints and in several other measures, such as pain and disability. ACR20 was reached by 35.2% of the active group and 24.2% of the sham group (one-sided P = 0.0209). The adjusted difference was 11.8 percentage points, with a confidence interval of 0.6 to 23.1.
A secondary measure showed a larger gap. A good or moderate response by European rheumatology criteria occurred in 60.7% with stimulation and 41.7% with sham. Other secondary measures also favored stimulation, but did not reach statistical significance after adjustment for multiple comparisons.
After three months, everyone received stimulation in an open-label phase. ACR20 rates in the original stimulation group rose to 50.0% at six months and 52.8% at 12 months among all completers. Across both groups at 12 months, 57.6% reached ACR20 in an analysis that excluded patients given added drug therapy. During the open-label year, 32.2% of patients received added drug treatment by month 12, and 75.2% remained free of added biologic or targeted drugs.
On safety, adverse events occurred in a similar share of patients in both arms. Related serious adverse events occurred in 1.6% of patients. All happened around the time of surgery, and all resolved.
Longer follow-up was presented at the American College of Rheumatology's Convergence 2026 meeting, according to SetPoint Medical’s conference announcement. John Tesser, the trial's national rheumatology principal investigator, reported the 24-month results. Among patients not taking a concomitant biologic or targeted drug, 62.7% reached ACR20, 38.7% reached ACR50 and 18.7% reached ACR70. About half reached low disease activity or remission. At 24 months, 91.7% were still using stimulation and 29.3% were also taking an advanced drug. Fourteen patients (5.8%) had the device removed, most often because of perceived lack of effectiveness. The company reported no serious adverse events attributed to the device or stimulation from month three to month 24.
The 24-month figures come from open-label follow-up with no sham group, so only the three-month comparison isolates the effect of stimulation.
The US Food and Drug Administration approved the SetPoint System in July 2025 for adults with moderately to severely active rheumatoid arthritis after inadequate response, loss of response or intolerance to at least one biologic or targeted synthetic disease-modifying drug, according to the company. What to watch next is whether longer controlled comparisons confirm that the benefits seen in open-label use hold up against sham, and how the device fits alongside biologic and JAK inhibitor drugs.