SetPoint VNS for Rheumatoid Arthritis: For Rheumatologists

SetPoint VNS for rheumatoid arthritis: information for rheumatologists.

The FDA approved the SetPoint System (PMA P240039) on July 30, 2025 for adults with moderately to severely active RA who have had an inadequate response, loss of response, or intolerance to one or more biologic or targeted synthetic DMARDs (b/tsDMARDs). The implant is a restricted device sold only to surgeons trained by SetPoint Medical. We place the implant. The rheumatologist programs the device after recovery and continues to manage the patient's RA.

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Mechanism.

SetPoint stimulates the left cervical vagus nerve to activate the inflammatory reflex, a neural circuit that regulates cytokine production. In earlier studies, one minute of vagus nerve stimulation reduced several proinflammatory cytokines by 30 to 70% (Koopman 2016; Genovese 2020).

The device.

• The implant is an integrated neurostimulator about 1 inch (2.5 cm) long and 3 g in weight, seated in a silicone pod on the left cervical vagus nerve. It has no leads and no chest battery pack.

• Stimulation is delivered automatically for 60 seconds once daily. The rheumatologist sets and adjusts therapy with a Bluetooth Programmer.

• The patient recharges the implant with a wireless charger worn around the neck for a few minutes about once a week. The battery is designed to last up to 10 years.

• The implant is MRI conditional. A patient must wait at least two weeks after implantation before an MRI, and MRI personnel must follow the SetPoint MRI safety manual.

RESET-RA.

RESET-RA was a randomized, double blind, sham controlled, multicenter pivotal study at 41 US sites. All 242 patients were implanted and randomized to stimulation (122) or sham (120). The primary endpoint was ACR20 response at week 12. After week 12 the sham group crossed over to stimulation, and all patients entered open label follow-up for 252 weeks. Patients had to remain on a stable csDMARD through week 12. b/tsDMARDs were withdrawn before implantation and not permitted through week 12.

Baseline characteristics: mean age 55.7 years, 86% women, mean RA duration 12.4 years, 53% seropositive, mean DAS28-CRP 5.3, mean CDAI 37.1, mean 14.6 tender and 10.0 swollen joints. Patients had a mean of 2.6 prior b/tsDMARDs (39% had three or more). Prior exposure was 93% anti-TNF, 28% CTLA4-Ig, 23% anti-IL-6, 20% JAK inhibitor, and 14% B cell depleting agents.

Week 12 results (intention to treat).

Open label ACR20 response (patients completing follow-up, both groups on stimulation).

Non augmented patients received no added b/tsDMARD or high dose steroid. Secondary endpoints were not powered for significance. The open label phase has no control group. Benefit accrued slowly over the first 24 weeks, especially in patients with several prior b/tsDMARDs. From week 12 on, adding a b/tsDMARD was permitted for worsening disease.

Safety.

• Serious adverse events related to the implant procedure or device through week 12 occurred in 4 of 242 patients (1.65%): incision site swelling evaluated in hospital (infection excluded), vocal cord paresis with dysphagia requiring hospitalization, dysphonia that impaired daily activities (mild sequelae), and a pharyngeal perforation during an explant procedure that was repaired intraoperatively. All were reported as resolved.

• Non serious procedure related events through week 12 occurred in 16% of patients. Vocal cord paresis occurred in 4.1% of the stimulation group and 5.0% of the sham group, dysphonia in 3.3% and 2.5%, and dysphagia in 0.8% and 1.7%. Wound infection and stitch abscess each occurred in one patient.

• Stimulation related events through week 12 occurred in 8.2% of the stimulation group, all mild or moderate. The most common was device pain (3.3%).

• In long term follow up to March 10, 2025, 5.0% and 4.2% of the two groups had a related, non serious event, mostly related to stimulation and managed by changing stimulation strength or timing. One patient had a moderate vocal cord paresis after week 12. Two patients discontinued treatment for related, non serious events.

• The implant had been explanted in 14 of 242 patients (5.8%) at the time of FDA review, at a mean of 469 days after implantation.

• No deaths, no unanticipated adverse device effects, and no related serious events occurred in long term follow up.

Patient selection.

Label contraindications. Bilateral or left cervical vagotomy, splenectomy, a pacemaker or defibrillator, neck spine disease that makes intubation unsafe, inability to tolerate anesthesia, and a neck too large to wear the charger.

RESET-RA entry criteria. Age 22 to 75 years, at least 4 of 28 tender and 4 of 28 swollen joints, inadequate response, loss of response, or intolerance to one or more b/tsDMARDs, and a stable csDMARD for at least 4 weeks. Exclusions included current nicotine use, untreated or poorly controlled psychiatric illness, history of substance abuse, significant immunodeficiency, stroke or TIA, clinically significant cardiovascular disease, multiple sclerosis, Alzheimer disease, Parkinson disease, uncontrolled fibromyalgia, prior carotid surgery, recurrent vasovagal syncope, and inability to have an MRI.

What happens after you refer.

1. Referral. Submit the referral form with the patient’s RA history. Patients can also refer themselves.

2. Surgical consultation. We review the history, examine the neck and document baseline voice quality by video, and confirm eligibility.

3. Surgery. The operation is outpatient, takes about 60 to 90 minutes under general anesthesia, and uses a single left neck incision. The closure uses absorbable sutures and skin glue.

4. Recovery and programming. Programming begins 2 to 3 weeks after surgery and takes 3 to 4 weekly visits with the rheumatology team.

5. Follow up. Patients continue their current RA medications. Clinical benefit is expected over 12 weeks to 6 months or longer.

What to include with a referral.

• RA diagnosis date, serostatus, and current disease activity (DAS28-CRP or CDAI, tender and swollen joint counts)

• Current csDMARD, glucocorticoid, and NSAID doses

• Each prior b/tsDMARD and the reason it was stopped

• Function (HAQ-DI if available) and current symptoms

• Medical and surgical history, especially head and neck surgery or radiation

• Any pacemaker or defibrillator

• Baseline voice and swallowing

• Allergies, tobacco use, and support at home on the day of surgery

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References.

1. Tesser J, et al. RESET-RA. Nature Medicine 2026.
2. SetPoint System Surgeon Instructions for Use, 65154-01 Rev A.
3. US Food and Drug Administration. Premarket approval letter P240039, July 30, 2025.
4. Koopman FA, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci USA 2016;113:8284-8289.
5. Genovese MC, et al. Safety and efficacy of neurostimulation with a miniaturised vagus nerve stimulation device in patients with multidrug-refractory rheumatoid arthritis. Lancet Rheumatol 2020;2:e527-e538.
6. Peterson D, et al. Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis. Bioelectron Med 2024;10:8.