Electrical stimulation of the vagus nerve may offer a novel method of treating rheumatoid arthritis (RA) by blocking the production of inflammatory cytokines and thereby decreasing disease activity -- even among patients who had failed to respond to biologic therapies.

In a study that included 17 patients with active RA, the production of tumor necrosis factor (TNF) decreased from 2,900 pg/mL on day −21 to 1,776 pg/mL on day 42 (P<0.05), according to Paul-Peter Tak, MD, PhD, of the University of Amsterdam, and colleagues.

And at those two time points, mean Disease Activity Scores in 28 joints (DAS28) fell from 6.05 to 4.16 (P<0.001), the researchers reported in Proceedings of the National Academy of Sciences.

Linear regression analysis comparing the changes in TNF levels and DAS28 scores showed a "highly significant correlation" (r = 0.384, P<0.0001), they found.

"Recent advances at the intersection of immunology and neuroscience reveal reflex neural circuit mechanisms regulating innate and adaptive immunity. One well characterized reflex circuit, termed the 'inflammatory reflex,' is defined by signals that travel in the vagus nerve to inhibit monocyte and macrophage production of TNF and other cytokines," Tak and colleagues explained.



The Inflammatory Reflex
In the early days of immunology, the immune system was considered unique in being autonomous. Unlike other systems such as the cardiovascular and gastrointestinal systems that were regulated by neural mechanisms, the immune system was considered self-regulating, according to Kevin J. Tracey, MD, who is president and CEO of the Feinstein Institute for Medical Research in Manhasset, N.Y.

"Immunity was viewed as autonomous to the immune system, mediated by interactions between immune cells in a largely self-regulated system that could be influenced by external factors, humoral mediators, and products of immunocompetent cells," Tracey and colleagues wrote in the Journal of Experimental Medicine.

That view began to change with findings in immunology and neuroscience identifying mechanisms for anatomic and functional links between the immune system and neural circuits.

"We discovered quite by accident that when we put a certain molecule in the brain, it blocked TNF and IL-1 and other cytokines, not only in the brain but also in the spleen and many other body organs. This was a real surprise," Tracey told MedPage Today.

"We expected to see blocking of the cytokines in the brain, but we didn't expect to find this throughout the body. We discovered that the molecule in the brain was turning on a signal transmission in the vagus nerve, which goes from the brainstem to the liver, spleen, and other organs. We then spent 15-plus years mapping the molecular mechanisms by which the nervous system through these neural signals can block the immune system," said Tracey, who is also professor of neurosurgery and molecular medicine at Hofstra Northwell School of Medicine in Hempstead, N.Y.

"We proposed that afferent and efferent signals transmitted in the vagus nerve are components of an inflammatory reflex, a neural circuit that modulates innate immune responses. This became the founding, prototypical member of an expanding family of reflex neural circuits that maintain immunological homeostasis," his group wrote.

Experimental animal models have demonstrated that electrical stimulation of the vagus nerve can block cytokine release and decrease disease activity for various inflammatory conditions, including sepsis and colitis. In addition, the use of an implanted device that stimulated the vagus nerve in a rat model of arthritis was associated with decreased synovitis, joint swelling, and erosions.

Testing the Concept
Devices that provide vagus nerve electrical stimulation have long been used for difficult-to-manage epilepsy, having been implanted in more than 100,000 patients, and have generally been tolerated well.

Therefore, to see if this type of device could be helpful in RA, the researchers first enrolled seven patients with epilepsy who had no history of autoimmune disease, implanting a device on the left cervical vagus nerve. While under anesthesia, the patients were given single 30-second stimulation at 1 mA output current, 20 Hz pulse frequency, and 500 µs pulse duration.

In peripheral blood, the stimulation was associated with a decrease in production of TNF, IL-6, and IL-1β, which could not have been a placebo effect because the patients were under anesthesia, according to the authors.

They then recruited patients with RA who had at least four tender and swollen joints despite methotrexate treatment. Mean age was 51, more than three-quarters were women, and mean duration of disease was 11 years.

The patients were divided into two cohorts. Cohort I consisted of seven patients who had not previously received a TNF inhibitor or had failed TNF inhibition because of toxicity, while cohort II included 10 patients who had been treated unsuccessfully with at least two different types of biologic agents.

Surgical implantation of the device took place on day −14, and from that day to day 0, the device was turned off. Then, on the first day of the study (day 0), patients received a single 60-second electric current pulse of 250 µs duraton, 10 Hz, output current of 0.25 to 2 mA, as tolerated. No additional stimulations were given for the next 7 days.

On day 7, the current was then adjusted to the highest level tolerated up to 2 mA, delivered once per day for 60 seconds, with 250 µs pulse widths and at 10 Hz. At day 28, patients who had not achieved a good or moderate response according to the criteria of the European League Against Rheumatism could have the stimulation frequency increased up to four times per day.

On day 42, the stimulator was turned off for 14 days, and by day 56, TNF levels had increased to 2,617 pg/mL. At day 56 it was turned on again and patients were followed until day 84, at which time TNF levels again had fallen, to 1,975 pg/mL (P<0.01).

A similar pattern was seen for DAS28. After the device was turned off on day 42, DAS28 increased from 4.16 to 4.96 by day 56 (P=0.001), but then decreased after stimulation was reinstated.

Other efficacy endpoints echoed the DAS28 results. At day 42, the 20%, 50%, and 70% improvements in the criteria of the American College of Rheumatology were achieved by 71.4%, 57.1%, and 28.6% of patients in cohort I and by 70%, 30%, and 0%, respectively, in cohort II.

DAS28 remission, defined as a score below 2.6, was seen in 28.6% of cohort I but none of the patients in cohort II. Improvements also were seen in the individual components of the DAS28, including tender and swollen joint counts, patient's pain rating, and patient and physician global assessments.

These were "very significant clinical responses," Tracey commented.
"To our knowledge, this study is the first to assess whether stimulating the inflammatory reflex by directly implanting an electronic device modulates TNF and other cytokines in humans," Tak and colleagues wrote.
They noted that the protocol followed in this study was quite different to that used in epilepsy, with a maximum of 4 minutes stimulation per day, whereas epilepsy patients can be given electrical stimulation for up to 4 hours per day.

"I think the story of the current trial was the demonstration that in patients it works, which is significant," Tracey said.

"But the larger story is what it means, which is that if you understand the mechanisms for a particular molecular target, you can develop devices that use electrons to replace drugs," he said in an interview.

Towards Bioelectronic Medicine
"This first-in-class study supports a conceptual framework for further studies of electronic medical devices in diseases currently treated with drugs, an approach termed 'bioelectronic medicine'," the researchers stated.

"We are building a major new center for bioelectronic medicine here in New York, which will be an intellectual home for research in bioelectronic medicine for the next decades," Tracey said.

"The idea of bioelectronic medicine is based on the convergence of molecular biology with neurophysiology or neuroscience and with neurotechnology or biomedical engineering. The convergence of those three things is a very powerful scientific mechanism-based approach for developing new therapies," he said.