Some people with rheumatoid arthritis (RA) take a disease-modifying antirheumatic drug (DMARD) and/or a biologic and reach remission. Others try drug after drug after drug and never find one that’s effective — or that treats their symptoms without causing intolerable side effects. At the same time, other patients with active disease refuse to take the most powerful and effective medications on the market or can’t take them because of their medical history or personal risk factors that would make doing so dangerous.
While many scientists are continuing to explore better drug options, some are focused on developing new treatments that aren’t medications at all. One such experimental approach that’s gaining some traction is called vagus nerve stimulation, which entails using electrical impulses to stimulate the vagus nerve — the longest of the cranial nerves that stem from the brain.
What Is the Vagus Nerve — and Why Can It Help Rheumatoid Arthritis?
The vagus nerve runs from the brain, through the face and neck, and down into the abdomen. It’s a key part of the autonomic nervous system, the division of your nervous system that controls functions you don’t have to think about, such as breathing, digesting food, and the beating of your heart. The vagus nerve is also the home of the inflammatory reflex, a pathway that appears to be crucial for detecting and modulating inflammation.
When something in your body gets injured or attacked by an invader (like a virus or bacteria), the vagus nerve helps decide how strong of an immune response the body should mount. When that response is appropriate, germs get killed off and injured tissue starts to heal. But when it’s too aggressive for the threat at hand — imagine trying to put out a small candle by holding it under a waterfall — you end up with chronic inflammation, which results in joint and tissue damage.
If you have an autoimmune condition, you already know that your immune system is far more revved up than it should be. In the case of RA, the immune system mistakenly tries to attack healthy tissue in the joints as well as in other organs. No one knows exactly what sets RA in motion, but experts do know that inflammatory substances called cytokines play an important role in causing tissue damage. Those cytokines include tumor necrosis factor (TNF) and interleukins (IL), among others.
Scientists now know that the vagus nerve has the power to reduce the production of them.
Vagus Nerve Stimulation vs. RA Medication: Same Targets, Different Approach
Many people with RA take drugs that target specific cytokines. Biologic medications such as etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade) target the ctytokine TNF, whereas anakinra (Kineret) targets IL-1 and tocilizumab (Actemra) and sarilumab (Kevzara) target IL-6.
But these drugs don’t work for everyone with RA. For these patients, stimulating the vagus nerve seems to be another way to reduce the production of cytokines that cause inflammation.
“The premise is that when you stimulate the vagus nerve it leads to the production of acetylcholine [a neurotransmitter], which binds to receptors on cells that secrete cytokines. When acetylcholine binds to those cytokine-producing cells, it inhibits them from producing TNF and interleukin-6,” says rheumatologist Mark Genovese, MD, a professor of medicine at Stanford University who conducted a pilot study on vagus nerve stimulation that was presented at the 2019 European Congress of Rheumatology (EULAR) conference.
In Genovese’s study, which was published as an abstract in the journal Annals of the Rheumatic Diseases, 14 people with RA who had tried and failed to respond to at least two medications had a small “MicroRegulator” — about the size of a nickel — implanted on the left side of the neck along the vagus nerve.
Although the primary goal of this small trial was to assess the safety of the device, half of patients who had impulses sent to the MicroRegulator once a day had significant improvements in their RA disease activity scores. A decrease in cytokine production was also measured.
A few adverse effects were reported, but all were temporary. Those included pain and swelling at the incision site as well as one patient who had temporary vocal cord paralysis.
Dr. Genovese is now helping SetPoint Medical, the company that is investigating vagus nerve science and sponsored the pilot study, design a much larger, multi-center clinical trial to learn more about whether vagus nerve stimulation can be used to treat RA, especially in people who don’t respond sufficiently to drugs.
Earlier studies, including another small trial that involved RA patients in Europe, similarly found that that implantable vagus nerve stimulator could be used to reduce TNF production and, in turn, inflammation.
A Broader Look at Bioelectronic Medicine: What Does It Mean for Patients?
While Dr. Genovese and SetPoint Medical are focused on implantable stimulators, other non-invasive approaches in this growing area of bioelectronic medicine are also being explored: One small study, published in the journal Bioelectronic Medicine this year, found that holding up a vibrational device to the ear could be used to stimulate the vagus nerve and inhibit the production of TNF, IL-1, and IL-6.
At the same time, researchers are trying to determine whether it’s possible to predict who is likely to respond well to RA medication and who’s apt to be a non-responder. One way to do that might be by testing vagal nerve tone: Low vagal tone has already been linked to more inflammation and a greater risk of autoimmune conditions.
Although more research is needed, RA patients with low vagal tone may turn out to be good candidates for vagus nerve stimulation. That’s the premise behind a medical device called ANS Neuroscan that’s being developed by Inmedix, says Vibeke Strand, MD, adjunct clinical professor in the division of immunology/rheumatology at Stanford University and a pharmaceutical and biotech consultant for companies including SetPoint Medical and Inmedix.
If ANS Neuroscan gets FDA clearance, rheumatologists might be able to use it as an in-office tool to help determine which patients are most likely to respond to biologics and who might fare better on an emerging therapy such as vagus nerve stimulation. This device provides information about vagal tone by measuring heart rate variability (as do electrocardiograms and a number of apps and gadgets like the Apple Watch).
Dr. Strand also notes that while patients who are found to have low vagal tone might very well benefit from vagus nerve stimulation, electrical impulses aren’t the only way to do it. You might be able to improve your vagal tone on your own by learning some specific breathing techniques or employing other mind-body strategies, though substantial training is likely to be involved.
“There’s a lot of stress associated with having rheumatoid arthritis, or any autoimmune disease, and that’s probably leading to some of the immune system over-activity and the autoimmune response” as modulated by the vagus nerve, says Dr. Strand.
The vagus nerve, she explains, is integral to the mind-body connection. It’s a major route by which messages travel between the brain and the gastrointestinal tract (gut-brain axis), which is why vagus nerve stimulation has also gained attention as a treatment for psychiatric and digestive disorders.
“The autonomic nervous system is part and parcel of our immune response,” says Dr. Strand. “It takes a little time for some people to wrap their heads around that.”
Looking Ahead: The Future of Vagus Nerve Stimulation
If ongoing and future studies are positive, vagus nerve stimulation might one day become a viable option for RA patients who don’t respond to medication, can’t take it, or don’t want to, says Dr. Strand. Some new research is also examining whether electrical nerve stimulators might be used in conjunction with drug therapies to boost their effectiveness, says Dr. Genovese.
While all this might sound a bit futuristic, vagus nerve stimulators are already on the market — just not yet for RA. Implantable stimulators have been FDA-approved for patients with drug treatment-resistant epilepsy and depression since 1997, and there’s an FDA-cleared non-invasive device aimed at people who get migraine attacks and cluster headaches. In addition to RA, vagus nerve stimulation is being investigated for a wide range of potential applications including inflammatory bowel disease, bipolar disorder, and Alzheimer’s disease.
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