Early studies show an implanted device that sends electrical signals to the brain via the vagus nerve has potential as a new therapy for rheumatoid arthritis (RA).
The vagus nerve travels from the brain stem to almost every organ in the body to keep them operating within normal, healthy levels. The vagus nerve is part of the parasympathetic, or involuntary, nervous system. Stimulating the vagus nerve can cause changes in heart rate, blood pressure, brain activity, and mood.
For more than a century, doctors have used techniques called vagal maneuvers, such as deliberate coughing, help slow a rapid heart rate. In the 1990s, they began using vagus nerve stimulators (VNS), which can be implanted into the chest wall.
Doctors currently use VNS to treat certain kinds of epilepsy as well as long-term depression that doesn’t respond to drugs. Researchers are also studying the devices to treat a host of other conditions, including headache, asthma, chronic pain, Alzheimer’s disease and, most recently, inflammatory conditions such as inflammatory bowel disease and RA.
What is a Vagus Nerve Stimulation?
The vagus nerve stimulators (VNS) used today for epilepsy and depression are about the size of a silver dollar. Neurosurgeons implant the device under the skin of the chest wall just below the collarbone, then thread a tiny wire from the device to the vagus nerve in the left side of the neck. Implantation is done under general anesthesia and takes about an hour.
Patients pass a magnet over the device to activate it, typically for seconds a day. When it is activated, the device sends signals to the brainstem, which then signals certain areas of the brain to stimulate the vagus nerve.
The devices are meant to be left in place indefinitely and activated daily. If people don’t respond as expected or have side effects they can’t manage – which is rare, most side effects are mild – the device can be deactivated or removed.
Signals Block Inflammation
An experiment that neurosurgeon Kevin Tracey, MD, conducted almost 20 years ago led to an unexpected discovery that may – in the future – give people with RA an additional treatment option.
Dr. Tracey, a professor of neurosurgery and molecular medicine at the Hofstra Northwell School of Medicine in Manhasset, New York, had been injecting rat’s brains with an anti-inflammatory drug to see if quelling inflammation there could help stroke recovery. He was surprised to find it also blocked inflammation in the spleen and other organs, but he wasn’t sure how.
After months of experimentation, he developed a theory: the brain could be sending electrical signals though the vagus nerve to the spleen, where many inflammatory proteins are produced, to regulate inflammation.
He scribbled on a napkin an idea for using VNS to block production of inflammatory proteins.
“We learned to control one of the body’s natural reflexes with electrical signals,” says Dr. Tracey.
“This reflexive action controls production of inflammatory cytokines, such as TNF, interleukins and others involved in RA and many autoimmune diseases,” he says.
Dr. Tracey mapped the molecular pathway that the vagus nerve uses to turn off production of TNF and other inflammatory proteins. He began working with Paul-Peter Tak, MD, PhD, who did much of the preclinical work confirming the theoretical promise of the therapy in his lab at the University of Amsterdam, where he was professor of medicine in the Division of Clinical Immunology & Rheumatology.
In 2011, Drs. Tracey, Tak and colleagues began a pilot study in eight people with RA. The patients activated the implanted VNS for 30 to 60 seconds a day. These eight patients had RA that hadn’t responded to traditional disease-modifying antirheumatic drugs (DMARDs), but they had never tried biologic drugs.
After 42 days, researchers measured their disease activity and markers of inflammation, such as C-reactive protein. Two patients had 25% improvement, four had 50% improvement, and two reached 75% improvement, according to the American College of Rheumatology’s RA disease activity classification system.
The next 10 patients recruited for testing had severe disease activity that had not responded to traditional DMARDs or at least two biologics that target two different inflammatory proteins.
Investigators published the second group’s results in the online edition of the Proceedings of the National Academy of Sciences in July 2016. The study was funded by SetPoint Medical, maker of the device.
“This is a very interesting study that demonstrates the presence of an inflammatory reflex in [humans] and highlights the close relationship between the nervous and immune systems,” says David Pisetsky, MD, PhD, a rheumatologist and professor of medicine at Duke University, Durham, North Carolina. Dr. Pisetsky was not involved in this study. “Future research will determine how best to stimulate this reflex and identify patients who can benefit from what has been called bioelectronic medicine.”
Research Is Ongoing
Dr. Tak stresses VNS for RA is still in very early days of testing and requires much more investigation.
“This is a fundamentally different approach to treat RA and possibly other chronic inflammatory disorders,” he says. “[These studies] show for the first time that, by interfering with the neurological system, we can reduce inflammation and basically restore balance in the human body.”
The VNS used in the studies thus far is one that was already commercially available. A device specifically for treating RA and other inflammatory disorders is being designed that will be smaller and easier to implant. If the RA-specific device proves safe, investigators will begin a larger trial to determine how well the therapy works compared with available RA treatments. That trial is expected to begin in 2018.
Author: Emily Delzell for the Arthritis Foundation