Vagus Nerve Stimulation Shows Sustained RA Responses at 24 Months

Patients with rheumatoid arthritis (RA) who have had inadequate responses to multiple biologic or targeted synthetic therapies face fewer remaining treatment options. In 24-month open-label follow-up from the RESET-RA trial, 62.7% of patients receiving vagus nerve stimulation without a concomitant biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) achieved an ACR20 response.¹

John Tesser, MD, FACP, FACR, MACR, a rheumatologist at Arizona Arthritis & Rheumatology Associates in Phoenix and national rheumatology principal investigator of RESET-RA, presented the long-term results at the American College of Rheumatology (ACR) Convergence 2026 in Orlando, Florida. In an interview with HCPLive, he discussed the evidence behind the SetPoint System, the trial findings, and the potential role of neuroimmune modulation in RA treatment.

Vagus Nerve Stimulation and the Inflammatory Reflex in Rheumatoid Arthritis

The SetPoint System delivers electrical stimulation to the vagus nerve, targeting neural pathways involved in regulating inflammatory responses. The approach is based on research into the inflammatory reflex, a mechanism through which neural signaling can influence immune activity and cytokine production.

Tesser discussed the work of neurosurgeon Kevin Tracey, MD, whose research beginning in the 1990s helped establish the role of vagus nerve signaling in inflammatory regulation.

The stimulation parameters, including current, voltage, and frequency, were developed to activate pathways associated with reduced production of proinflammatory cytokines. This mechanism provides the rationale for investigating vagus nerve stimulation as a treatment for inflammatory diseases, including RA.

Unlike conventional RA therapies, which target specific immune mediators or signaling pathways pharmacologically, the SetPoint System uses electrical stimulation to modulate neuroimmune signaling.

RESET-RA Trial Design and ACR20 Response With the SetPoint System

RESET-RA enrolled 242 patients at 41 US sites. Participants had moderately to severely active RA and an inadequate response or intolerance to at least 1 b/tsDMARD.²

All participants underwent implantation of the device on the left cervical vagus nerve before randomization in a 1:1 ratio to active or sham stimulation for 3 months. Following the double-blind period, participants were eligible to receive open-label stimulation.

The trial met its primary endpoint at 3 months. An ACR20 response was achieved by 35.2% of patients assigned to active stimulation compared with 24.2% receiving sham stimulation (P = .0209).²

Based on the pivotal trial results, the US Food and Drug Administration (FDA) approved the SetPoint System in July 2025 for adults with moderately to severely active RA who have had an inadequate response, loss of response, or intolerance to at least 1 b/tsDMARD.³

Tesser also discussed patient interest in the trial and the potential influence of requiring a surgical procedure on treatment acceptance. According to Tesser, more than 20,000 individuals expressed interest after recruitment was announced. This figure reflects reported interest rather than enrollment or demonstrated acceptance of implantation.

24-Month ACR50 and ACR70 Responses in Biologic-Experienced RA

The RESET-RA population included patients with substantial prior treatment exposure. Participants had a mean age of approximately 56 years, 86% were women, and the mean duration of RA was approximately 12 years. More than 60% had previously received at least 2 b/tsDMARDs.²

“That’s a very difficult group to treat because the more advanced therapies that have failed a patient, the more difficult it is for them to achieve better responses on the next therapy that’s chosen,” Tesser said.

In the open-label follow-up through 24 months, patients receiving vagus nerve stimulation without a concomitant b/tsDMARD achieved ACR20, ACR50, and ACR70 response rates of 62.7%, 38.7%, and 18.7%, respectively.¹

Among patients in this subgroup, 77.7% achieved a good or moderate European Alliance of Associations for Rheumatology (EULAR) response. Approximately half achieved low disease activity or remission according to the Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) and Clinical Disease Activity Index (CDAI).¹

At the 24-month assessment, investigators reported 91.7% of patients were continuing stimulation, while 29.3% were receiving a concomitant b/tsDMARD. Device removal was reported in 14 patients (5.8%), most commonly because of perceived lack of effectiveness.¹

Although the findings describe clinical responses during longer-term treatment, the open-label follow-up did not include a concurrent sham-stimulation control group. Consequently, the 24-month results cannot establish comparative long-term efficacy or determine the extent to which observed responses were attributable to stimulation alone.

SetPoint System Safety Through 24 Months

Safety findings from the randomized trial and subsequent open-label follow-up provide information about adverse events associated with implantation and ongoing stimulation.

During the initial randomized period, the most notable treatment-related events were associated with implantation. Reported events included swelling, redness, dysphonia, and dysphagia. In the published pivotal trial, device- or procedure-related serious adverse events occurred in 1.6% of participants. All occurred during the perioperative period and resolved.²

From the 3-month crossover through 24 months, investigators reported no serious adverse events attributed to the device or stimulation.¹ Mild to moderate implant-site pain was the most frequently reported device-related event during this period, affecting fewer than 5% of patients.¹

Investigators also evaluated adverse events of particular interest in RA treatment, including serious infections, malignancies, major adverse cardiovascular events, and venous thromboembolism. The absence of reported device-related events in these categories during the follow-up period should not be interpreted as evidence of no associated risk.

Tesser contrasted the SetPoint System with earlier vagus nerve stimulation devices used for neurologic conditions, including epilepsy and depression. Conventional systems generally involve a pulse generator implanted in the chest and leads extending to the vagus nerve.

The SetPoint System instead incorporates the battery, pulse generator, and electrodes into a single implant positioned around the cervical vagus nerve. Its leadless design eliminates complications specifically associated with separate connecting leads, although implantation and device-related risks remain relevant.

Combining Neuroimmune Modulation With Biologics and JAK Inhibitors

RESET-RA also permitted the addition of advanced RA therapies for patients requiring rescue treatment during the double-blind period. During longer-term follow-up, some participants received vagus nerve stimulation alongside b/tsDMARDs.

At 24 months, 29.3% of patients were receiving a concomitant b/tsDMARD.¹ These findings document the use of combination treatment within the study population but do not independently establish the efficacy or comparative safety of specific combinations.

Tesser discussed the possibility of integrating neuroimmune modulation into existing RA treatment strategies, including its use alongside biologics and Janus kinase (JAK) inhibitors. He also raised the potential for reducing concomitant medication use in patients achieving adequate disease control, although medication tapering requires further prospective evaluation.

Beyond RA, neuroimmune modulation is being investigated in other immune-mediated diseases. Tesser described ongoing development in multiple sclerosis and potential future research in inflammatory bowel disease (IBD) and other autoimmune conditions.

“This device is the first and only device that’s been approved by the FDA for use in autoimmune disease, and specifically in rheumatoid arthritis,” Tesser said.

The 24-month RESET-RA findings extend the available evidence for vagus nerve stimulation in treatment-experienced RA. Further controlled studies and longer-term follow-up will be important for characterizing response durability, treatment combinations, and safety in broader patient populations.

Editor’s Note: Tesser reports relevant disclosures with SetPoint Medical.

References

1. SetPoint Medical. SetPoint Medical Presents 24-Month Data Demonstrating Sustained Clinical Benefit and Favorable Long-Term Safety of the SetPoint System for Rheumatoid Arthritis. News release. Published November 9, 2026.

2. Tesser JRP, Crowley AR, Box EJ, et al. Vagus Nerve-Mediated Neuroimmune Modulation for Rheumatoid Arthritis: A Pivotal Randomized Controlled Trial. Nat Med. 2026;32(1):369-378. doi:10.1038/s41591-025-04114-7

3. US Food and Drug Administration. SetPoint System (P240039). Approved July 30, 2025.