Noninvasive auricular vagus nerve stimulation (VNS) is no more effective than placebo at controlling symptoms of rheumatoid arthritis (RA), according to a new study. But experts emphasize that these results do not mean trials of different forms of VNS will have the same fate.
VNS offers a potential additional therapy for autoimmune disease beyond disease-modifying antirheumatic drugs (DMARDs), explained first author, Matthew Baker, MD, clinical chief, division of immunology and rheumatology, Stanford University, California, and colleagues.
“The principle of VNS is based upon the inflammatory reflex, which describes a primitive connection between the nervous system and immune system,” the authors write. Signals sent down the vagus nerve to the splenic nerve stimulate immune cells in the spleen, which ultimately results in blocking production of inflammatory cytokines such as tumor necrosis factor (TNF). “It is hypothesized that this reduction in systemic inflammation can be harnessed for the treatment of diseases such as RA,” they continue, and smaller studies suggest this treatment could benefit patients.
In a previous 12-week, open-label trial, 17 patients with RA who were implanted with a VNS device on the left cervical vagus nerve saw improvement in RA symptoms as well as a decrease in TNF production. Noninvasive devices that stimulate the auricular branch of the vagus nerve have also shown some promise. A sham-controlled study of 18 patients with systemic lupus erythematosus (SLE) found that patients who received transcutaneous auricular VNS reported reduced musculoskeletal pain over just 4 days. An open-label study of 30 patients with RA showed clinically significant reductions in disease activity score of 28 joints with C-reactive protein (DAS28-CRP) and clinical improvement in American College of Rheumatology (ACR) responses over 12 weeks. Additional trials have also demonstrated this positive effect of noninvasive VNS on RA symptoms, but all studies conducted thus far have been relatively small or uncontrolled, Baker said.
Results of Latest Trial
In this new trial, researchers enrolled 113 patients with active RA who had inadequate responses or intolerance to conventional synthetic DMARDs and were naïve to biologic or targeted synthetic DMARDs. All patients were given an auricular vagus nerve stimulator via a custom-molded earpiece that was controlled by a smartphone app. Patients wore the device for 15 minutes each day. When worn and turned on, the device generated electrical signals delivered transcutaneously to the cymba concha, a region of the ear connected to the auricular branch of the vagus nerve. This stimulation is imperceptible to patients, Baker explained. “For the sham arm, we simply did not turn the device on at all,” he said. A subject in the sham arm would use the same device on a 15-minute timer, but no stimulation was given.
After 12 weeks, researchers found no statistically significant difference between the treatment and sham arms in achieving 20% improvement in ACR response criteria or mean change in DAS28-CRP. A total of 17 patients, including 12 in the treatment arm, reported adverse events during the study, and all events were categorized as mild to moderate.
The trial results were published online June 30 in Arthritis & Rheumatology.
While the research team was “obviously disappointed” about the results, Baker said, negative findings in trials also are important. “The real value of our study is pointing out the need for large controlled, sham-controlled studies,” he said, especially for potential treatments with a lot of enthusiasm behind them.
Results Don’t Seal the Fate of Other VNS Approaches
“As a properly controlled trial, the results are impressively negative,” writes Roy Fleischmann, MD, clinical professor of medicine, University of Texas Southwestern Medical Center, and codirector, Metroplex Clinical Research Center, both in Dallas, in an editorial about the study. Many of the previous studies looking at this therapy in RA were open label, which could bias the results, he argued. The biggest question, he noted, is if other blinded, sham-controlled trials looking at VNS devices will show similar results.
By itself, this finding does not imply that other VNS devices will be unsuccessful, argued Jonathan Kay, MD, the Timothy S. and Elaine L. Peterson chair in rheumatology, and professor of medicine and population and quantitative health sciences, UMass Chan Medical School and UMass Memorial Medical Center, both in Worcester, Massachusetts. He is also an investigator for the RESET-RA trial, a randomized, sham-controlled trial that will assess the safety and efficacy of an implantable VNS device in an estimated 250 patients with RA. He was not involved with Baker’s work.
“Auricular VNS is delivered more distally than cervical or splenic nerve stimulation,” Kay said, and the potential effect of these other forms of VNS may have different outcomes.
Cynthia Aranow, MD, rheumatologist and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, New York, agreed with Kay, noting that direct VNS stimulation via implantable device and transcutaneous stimulation through the skin are not comparable. She also is unaffiliated with the study.
“This group conducted a well-designed, sham-controlled study of a reasonable number of patients and over a reasonable period of time and observed no significant differences between those participants receiving true and those participants receiving sham stimulation,” she wrote in an email. “However, it’s important to point out that the stimulation settings used in this study were kHz (kilohertz) which is 1000 times greater than the settings used in multiple other studies in which transauricular VNS has been shown to be clinically effective, including studies in long COVID, tinnitus, SLE, cluster headaches, erosive hand osteoarthritis, pediatric kidney disease, among others,” she said.
The role for VNS treatment, whether direct stimulation via implantable device or transcutaneous, in autoimmune and inflammatory diseases “remains to be determined by future studies,” she said.
Arthritis Rheumatol. Published online June 30, 2023. Abstract, Editorial
The study was funded by Nesos Corporation. Baker received personal fees from Nesos during the study. Kay has received consulting fees from AbbVie, Boehringer Ingelheim, Celltrion Healthcare, and several other pharmaceutical companies. Aranow reports no relevant financial relationships.
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