Dr Chernoff Discusses the Promise of Vagus Nerve Stimulation for RA

Electrical stimulation of the vagus nerve could be a potential therapeutic option for patients with drug-refractory rheumatoid arthritis (RA), said David Chernoff, MD, chief medical officer of SetPoint Medical in Valencia, California, during his presentation “Bioelectronic Medicine for Treatment of Rheumatoid Arthritis” at the virtual Interdisciplinary Autoimmune Summit 2020.

In his presentation, Dr Chernoff reviewed the inflammatory reflex pathway and its role in autoimmune diseases. He discussed how the vagus nerve, through afferent and efferent signaling, can activate a loop within the brain to decrease inflammation. Animal models and preclinical studies showed that when the vagus nerve is transected, there are increases in inflammatory markers and inflammation.

From a therapeutic perspective, stimulation of the vagus nerve can activate the inflammatory reflex pathway and reduce inflammation. In many diseases, such as RA, there seems to be an imbalance in the cholinergic and sympathetic pathways, noted Dr Chernoff. In animal models, stimulating the vagus nerve using electricity can decrease inflammatory burden. In one preclinical model, Dr Chernoff reviewed how mice with collagen-induced arthritis experienced worsening inflammation after a vagotomy. In another animal model, Dr Chernoff discussed how placing a stimulator on the vagus nerve had no impact on inflammatory burden, but when the vagus nerve was stimulated with electricity, there was a reduction in burden and other aspects of inflammatory response in RA.

“It is interesting to note that it does not take much energy to activate the inflammatory reflex,” said Dr Chernoff. As little as a 30-second stimulation of the vagus nerve once per day can result in up to 48 hours of inflammatory cytokine inhibition in animal models, he added.

This benefit has been observed in humans as well. Researchers demonstrated that the vagus nerve controls the proresolution pathway, which resolves inflammation through mediators (eg, resolvin 1). Essentially, stimulating the vagus nerve activates the proresolution circuit and decreases inflammation.

In a proof of concept study, 17 patients with both drug-refractory RA and epilepsy received an implanted antiseizure device and underwent 6 weeks of stimulation, followed by a deactivation period, followed by another period of stimulation. “This is the first proof of concept study that shows active vagus stimulation reduces disease burden in an autoimmune disease,” said Dr Chernoff. Patients experienced reductions in clinical disease activity and inflammatory mediators, such as tumor necrosis factor alpha. A long-term study showed patients had low disease activity as far out as 2 years and they did not appear to lose response to stimulation.

He also discussed a new, smaller device that is currently under development. It was studied in 12 patients with drug refractory RA, including patients who failed Janus kinase inhibitors. Patients underwent one stimulation per day for 12 weeks, and all patients tolerated the device and had no adverse events. In addition, there was documented reduction in proinflammatory cytokines and five of 10 patients had a clinically meaningful response.

Based on these observations, a randomized, controlled trial will be conducted in the next year to examine the impact of this type of stimulation among drug-refractory patients, concluded Dr Chernoff. 

Dr Chernoff addressed several questions from the audience on whether other kinds of energy could be used to stimulate the vagus nerve and adverse events. Ultrasound, as well as other types of energy, are currently being investigated, said Dr Chernoff. A rare adverse effect associated with vagus nerve stimulation is bradycardia, but Dr Chernoff noted that the device to stimulate the nerve is implanted on the left vagus, which has minimal effects on the heart.

For more coverage of IAS 2020, visit the newsroom.

—Melissa Weiss

Reference

Chernoff D. Bioelectronic medicine for treatment of rheumatoid arthritis. Presented virtually at: Interdisciplinary Autoimmune Summit 2020; July 10, 2020.