Vagus nerve stimulation may tame autoimmune diseases

Tiny pulses of electricity may provide the next big advance in treating diseases like rheumatoid arthritis.

The pulses would be delivered via implanted devices that stimulate the vagus nerve, and they are showing promise in people with arthritis and other autoimmune diseases, including Crohn’s, and multiple sclerosis.

Currently, autoimmune diseases are usually treated with drugs that suppress the immune system. Some of these drugs are given by infusion, and can cost tens of thousands of dollars a year. They also increase a person’s risk of infections.

Vagus nerve stimulation might offer a way to augment or replace drug treatment, doctors say.

“Neural signals have the ability to reflexively control aspects of the immune system that frankly, nobody had thought about before,” says Dr. Kevin Tracey, president of the Feinstein Institutes for Medical Research at Northwell Health on Long Island.

Tracey co-founded SetPoint Medical, a company that hopes to market a vagus nerve stimulation system for autoimmune diseases.

It’s still not clear whether vagus nerve stimulation will be as effective as drug treatment, says Dr. Andrew Ko, a neurosurgeon at the University of Washington in Seattle who implanted SetPoint stimulators in patients with rheumatoid arthritis as part of a study.

“Drugs work, but they sometimes don’t, and you can have side effects,” Ko says. “In those cases, there are some benefits to looking at devices.”

Ko notes that implanted vagus nerve stimulators are already approved for certain patients with epilepsy and depression. Devices that stimulate the brains of people with Parkinson’s disease have proved “better than medication” at reducing symptoms, he says.

Rheumatoid arthritis, which affects about 1.5 million people in the U.S., is poised to become the first autoimmune disease treated with electrical pulses sent through the vagus nerve.

A device made by SetPoint Medical is under review by the U.S. Food and Drug Administration, which is likely to make a decision by the end of 2025.

The agency’s review will include a 2024 study of 242 patients. It found that 12 weeks of stimulation with the device significantly reduced both symptoms and progression of the disease. Also, damage to their joints occurred more slowly, and levels of inflammatory proteins fell dramatically.

A wandering nerve that links brain and body

The vagus nerve’s link to the immune system was discovered by accident more than 20 years ago.

Northwell’s Kevin Tracey and a team of researchers gave rats an experimental drug meant to prevent inflammation in the brain. To their surprise, it also suppressed inflammation in the body.

The reason turned out to be a signal sent from the brain to the body’s immune system.

“We realized that the signal was traveling down the vagus nerve and the vagus nerve was like the brake lines in your car,” Tracey says. “It was the brakes on inflammation.”

Tracey says that realization led to a question: “Can we make devices that turn on the brakes and then treat patients with excessive inflammation?”

It would take decades of research to make that happen.

The vagus nerve is actually a pair of nerves, right and left, that connect the brain with internal organs including the heart, lungs, liver, gut, and spleen.

“It’s the only nerve in your body if you cut it on both sides, you die,” Tracey says.

Much of the contemporary research on the vagus nerve has been done at the Feinstein Institute of Bioelectronic Medicine, one of the institutes Tracey supervises. Dr. Stavros Zanos is in charge of a team that has been mapping the human vagus nerve, which is often compared with a superhighway carrying signals throughout the torso.

During a tour of his lab, Zanos holds up a clear tube containing a foot or so of white cord-like tissue slightly thinner than a pencil.

“This is most of the vagus nerve from the brain to the neck to half the distance through the chest,” he says.

Next, he shows me what a cross-section looks like under a microscope.

“It’s like a slice from a cucumber,” he says. “You see all of these tiny green spots, thousands and thousands of them? Those are individual fibers.”

The right and left vagus nerve bundles each have more than 100,000 of these strands.

“A lot of the fibers inform the brain about the inflammatory state of the entire body,” Zanos says.

Researchers at Feinstein have been eavesdropping on those fibers in animals, and have even developed a system that transforms traffic along the vagus into real-time audio.

That allows them to hear how inflammation in the body changes signals going to the brain.

Sangeeta Chavan plays a recording from one experiment. At first, there is a steady thrum following the rhythm of heartbeat and respiration, but when researchers inject a substance that causes inflammation, the sound becomes like popcorn dropped into hot oil.

“When inflammation occurs, molecules activate signals that travel up the vagus nerve,” Tracey says.

And that’s just half the story.

The electrical impulses activate a reflex that causes the brain to produce another set of signals that travels back down the vagus nerve.

Those are the brake signals Tracey’s team discovered decades earlier. They tamp down the immune system so inflammation doesn’t get out of control.

The signals do this by telling certain immune cells to stop producing inflammatory proteins called cytokines.

“What we discovered is that the vagus nerve signals turn off cytokine production in the spleen,” an organ that plays a major role in immune response.

Next, Tracey’s team learned how to stimulate the vagus nerve in a way that activates the anti-inflammation reflex.

That allowed SetPoint Medical to develop an implantable stimulation device.

“It’s about the size of a large pill, a really big multivitamin,” Ko says, adding that it’s similar to the FDA-approved vagus nerve stimulators he implants in patients with epilepsy.

SetPoint is already looking beyond rheumatoid arthritis patients. The company has launched trials of its stimulation device in patients with multiple sclerosis and Crohn’s disease.