Vagus Nerve Stimulation Wanders into Mainstream Rheumatology

The word “vagus” comes from the Latin “to wander.” Accordingly, the vagus nerve takes a meandering path through the body, impacting everything from digestion to immunity. As understanding of this pathway grew, clinicians and researchers saw it as a potential therapeutic target. The mental health community capitalized first, using vagus nerve stimulation as a staple of epilepsy and depression treatment for decades.

During that time, research into this approach in rheumatic diseases wandered along, so to speak, in relative obscurity, gaining minimal attention. That changed at EULAR 2019.

Mark C. Genovese, MD, James W. Raitt Endowed Professor of Medicine, and clinical chief of the division of immunology and rheumatology at Stanford University, stepped onto the dais in Madrid and showed the startling efficacy of vagus nerve stimulation in a cohort of 14 refractory patients with rheumatoid arthritis. He reported positive changes in DAS28 and EULAR responses, along with encouraging RAMRIS erosion scores, in patients treated with active stimulation compared with those implanted with a sham device.

Although the rheumatology community took notice, Genovese was cautious in his assessment of the results. “The program remains quite early in development,” he told Healio Rheumatology. “The first trial was designed to assess the safety of this new device, and we were fortunate to have seen some efficacy in this 14-patient trial of patients with refractory disease.”

The “new device” Genovese referenced is a proprietary implantable vagus nerve stimulator from SetPoint Medical that was created for the specific purpose of treating RA. In the mid-2010s, a landmark proof-of-concept study was conducted in patients with RA using a vagus nerve stimulator that was repurposed from use in epilepsy. After the success of this trial, research and development continued forward, culminating, at least for now, in ongoing trials of the SetPoint product.

The Genovese study represents what may turn out to be a significant leap forward in a body of research largely conducted by Kevin Tracey, MD, president and CEO of the Feinstein Institute for Medical Research and professor of neurosurgery and molecular medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell. “For the past 2 decades, Kevin Tracey and those who have trained under him have elegantly mapped out how the brain and the immune system communicate with each other via the vagus nerve, and how we can use that information to provide alternative therapies for the treatment of autoimmune diseases, David N. Chernoff, MD, chief medical officer at SetPoint Medical, told Healio Rheumatology.

Rheumatologists worldwide have begun to see the potential in vagus nerve stimulation. “This represents a completely new approach to managing inflammatory disease by capitalizing on an evolutionary relationship between the immune system and the nervous system,” Iain McInnes, MD, professor of experimental medicine and director of the institute of infection, immunity and inflammation at the University of Glasgow, in Scotland, said in an interview.

With the roadmap in place, a device to target RA gaining steam, and trials underway investigating the use of this treatment method in Crohn’s disease, Sjögren’s syndrome and systemic lupus erythematosus, among other conditions, vagus nerve stimulation may be poised to wander into the limelight of rheumatology. But, like the path of the vagus itself, the road is likely to be winding, with many stops along the way.

Understanding the Vagus Nerve

As with any journey from basic science to clinical application, the published literature from Tracey and colleagues involves literally dozens of studies. They ultimately demonstrated that stimulating the vagus nerve could control the immune system, alert the brain to the presence of inflammation, and down-tune TNF production.

In one key data set in that body of work, Borovikova and colleagues described a parasympathetic anti-inflammatory pathway that allows the brain to modulate systemic inflammatory responses to endotoxin. Their results showed that electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxemia in murine models inhibited TNF synthesis in the liver, attenuated peak serum TNF levels, and prevented the onset of shock, according to the findings.

“It is important to understand what nature has built into humans, primates and rodents in terms of the endogenous reflex that controls inflammation,” Chernoff said. “When there is systemic inflammation, the nervous system, particularly the vagus nerve, can act as a neural sensor.”

McInnes added that the nervous system and the immune system communicate at least in part via the cholinergic nervous system, which is mediated in part by the vagus nerve. “Murine model studies showed that manipulation of the vagus nerve would deliver an anti-inflammatory signal to the immune system and, as a result, reduce articular inflammation,” he said.

Chernoff likened the activity of the vagus nerve in inflammation to the coagulation cascade: Meaning, when a blood vessel is injured, through a complex series of communications, the body knows when to form a clot, and when to take that clot away after the injury is healed.

“When systemic inflammation occurs, the brain and the vagus nerve serve the role of down-tuning the immune system and turning back inflammatory responses by down-regulating the ability to secrete inflammatory responses,” he said. “It is a system of checks and balances. A certain amount of inflammation is necessary, but if you had too much inflammation, you would not survive.”

Groups like Serhan and colleagues picked up the ball from Tracey’s work, recently showing that electrical stimulation of the vagus nerve in humans “reduces both prostaglandins and leukotrienes and enhances resolvins and the other [specialized pro-resolving mediators].” The findings demonstrate that vagus stimulation coupled with releases of SPMs provides another mechanism that augments myeloid antimicrobial functions and resolution of infection and inflammation. “Moreover, they define a new pro-resolution of inflammation reflex operative in mice and human tissue that involves a vagus [specialized pro-resolving mediators] circuit,” they wrote.

The genius of modern medical science is in the ability to take information like this and put it into clinical practice. It is here that technology steps in. In the context of autoimmune diseases, there is an imbalance in the systems described by Serhan and colleagues, according to Chernoff.

“In patients with autoimmune diseases, there is too little parasympathetic response, so by giving a digital dose of electricity, we can restore that sympathetic balance,” he said.

With all of this information in hand, the stage was set to test vagus nerve stimulation in humans with rheumatic diseases.

Proving the Concept, Changing the Game?

The stepping stone trial that came shortly before the Genovese trial was conducted by Koopman and colleagues, who observed that vagus nerve stimulation as many as four times per day significantly reduced TNF production for up to 84 days in a cohort of patients with RA. Disease severity also improved for these patients.

“The original proof of concept study for RA was conducted in the Netherlands starting in 2013 and was published in 2016,” Chernoff said. “It used a commercially available Cyberonics anti-seizure device because the SetPoint Medical microregulator device was still in development at that time. Given that it is nearly 2020, the U.S. rheumatology community may be forgiven for not remembering these findings.”

Apart from the use of a device specifically targeting RA, the other notable component of the Genovese study was the patient population itself. Participants had failed on an average of six different therapies, with nine members of the cohort failing on tofacitinib (Xeljanz, Pfizer). “The fact that we saw any clinical improvement was somewhat of a surprise given how advanced and multidrug-refractory these patients were at baseline,” Chernoff said. “They basically had failed everything, so had no therapeutic options left.”

Ronald van Vollenhoven, MD, PhD, chair of the department of rheumatology and clinical immunology at Amsterdam University Medical Center, offered some perspective on the Genovese data set. “The study was rather small in numbers and of short duration,” he said. “Encouragingly, there were modest clinical improvements in the treated patients and none in the sham-treated patients, but statistical significance was not achieved. An ex vivo study on leukocytes from the patients did support the idea that a biological effect is induced by the vagal nerve stimulation.”

The results were not quite paradigm-changing, but they were encouraging enough to warrant further exploration. Rheumatology is finally catching up to the mental health field in terms of how to exploit the brain and vagus nerve for therapeutic benefit. “Other fields understand and have shown us how electrical stimulation can work,” Chernoff said. “Rheumatology is finally getting up to speed to where the epilepsy community was 25 years ago. Crazy ideas sometimes work.”

Fulfilling Unmet Needs

The unmet needs in rheumatology are well documented: better drugs, cheaper drugs, new approaches. “The reality is that despite the really nice clinical trials that have been done, the bar for getting a drug approved is pretty low — if you make about half of the patients get 20% better, with a safety profile that is acceptable, the FDA approves the drug,” Chernoff said. “Very few patients experience remarkable effects from what is available now.”

Although vagus nerve stimulation has yet to show any broad or meaningful efficacy outcomes that improve on those produced by current therapies, its success in epilepsy and depression — combined with the encouraging Genovese and Koopman findings — is enough to offer hope to many in the rheumatology community.

Improved efficacy is not the only gap that vagus nerve stimulation may fill. Due to the chronic nature of most rheumatic diseases, patients often have to take drugs daily for years or decades, making adherence problematic. “The key advance would be allowing short-term electro stimulation under the control of the patient or remotely by their doctor to modify the degree of immune suppression and thus disease control,” McInnes said. In short — assuming this was their only anti-arthritis therapeutic — patients will not have to remember to take their pills.

Looking at other needs, while many more safety trials are sure to come, early signs indicate that the implantable device may come with fewer adverse effects than pharmacotherapeutic options. “This is essentially a well-tolerated procedure that may offer benefit with few adverse events, other than surgical complications with the SetPoint device,” Vibeke Strand, MD, adjunct clinical professor in the division of immunology/rheumatology at Stanford University, added in an interview. “It could offer an alternative therapy with a good benefit/risk profile, provided there are fewer surgical complications.”

For van Vollenhoven, the novelty of the approach is important in filling gaps in the current treatment paradigm. “It would be exciting to have a treatment that builds on a completely different insight into the immune system,” he said. “From the practical perspective, to have something to offer the highly-refractory patient would be very positive.”

Beyond RA

Studies in RA have gained the most attention; however, vagus nerve stimulation is also being tested in a number of other conditions.

Aranow and colleagues studied 18 patients with SLE, randomizing them in a 2:1 ratio to active vagus nerve stimulation or sham stimulation. Safety data showed that both types of stimulation were well tolerated. Efficacy results indicated that participants in the active therapy group experienced a significant decrease in pain and fatigue compared with controls. Moreover, a clinically significant reduction in pain also was reported (OR = 25; P = .02).

“This was an interesting controlled trial, using a noninvasive stimulator, in patients with SLE who had pain and fatigue,” van Vollenhoven said. “The clinical parameters did seem to improve with the stimulation but not with the sham stimulation. However, in this trial the biomarkers did not change. There is a question in this trial whether the patients were not really blinded, that the ones who were stimulated may have felt it.”

In their EULAR 2019 abstract, Tarn and colleagues looked at vagus nerve stimulation in 40 patients with primary Sjögren’s syndrome, assigning 20 to an active device and 20 to a sham device. Results showed a 30% reduction in physical fatigue symptoms in participants in the active treatment group, compared with just 6% of those in the sham group (P = .047). However, there were no significant differences between the two groups in mental fatigue or neuropsychological test scores.

“This study was published as an abstract, but it was not selected for presentation at the EULAR Congress, so we do not know more than what is written in the abstract,” van Vollenhoven said. He added that fatigue is a “big problem” in patients with Sjögren’s syndrome.

“Although this looks promising, there are two main concerns: was this the only positive finding, in which case it may have been just chance?” van Vollenhoven continued. “And again, is it not possible that the stimulated individuals had a placebo effect, because they did feel the electrical stimulus?”

Bonaz and colleagues investigated vagus nerve stimulation in inflammatory bowel disease, including seven patients with Crohn’s disease and ulcerative colitis. Results showed that two of the patients failed to show any improvement at 3 months, but five of them demonstrated clinical, biological and endoscopic remission at 6 months. The researchers observed no major adverse events.

“SetPoint conducted this trial in Crohn’s that involved refractory patients,” Chernoff said. “As we expand and continue to look at these devices in different conditions, we are going to be looking at different devices, including external devices and those that can be implanted in the ears.”

Potential Bumps in the Road

For Strand, there is just one obstacle to uptake of the vagus nerve approach. “The main issue is really only insurance issues regarding cost,” she said, noting that there are other approaches that do not require an implantable device.

Cost indeed remains a question, as current devices are not yet close enough to market to have prices attached to them. But Chernoff pointed out that ICD-9 codes for implantable vagus nerve devices are already in place for epilepsy and depression indications, which may streamline certain decisions in the payer/insurance coverage arena. However, ironing out the kinks between its use in the U.S. and use in the EU remains a regulatory challenge on the horizon that will have implications in the insurance realm.

Another consideration is whether the cost of an implantable device would be higher or lower than the price tag on a biologic or biosimilar therapy. It seems likely that a single procedure and a single device would ultimately be cheaper than a lifetime of prescriptions, but questions surrounding durability of the devices must be answered. Moreover, as technology advances and improves, it may be necessary for patients to be implanted with a new or updated device.

To that point, McInnes sees “lots of potential challenges,” including safety. “What are the risks of having electric implants in a person for life?” he said. “What happens if there is a side effect of surgical complication? There are so many unanswered questions at this stage, but it is still an interesting possibility.”

Entering the market in a disease such as RA for which there are already many treatments could also prove challenging, according to van Vollenhoven. “This approach will need to be tested in very refractory patients,” he said. “This makes the clinical/regulatory development even more difficult.”

Another obstacle highlighted by van Vollenhoven is that only a small subset of patients may ultimately end up using this particular product. Researchers must tackle questions about which patients with which diseases are optimal candidates for vagus nerve stimulation, and an already short-handed rheumatology community must figure out how to train its practitioners in both the surgical procedure and the monitoring of the device.

“A noninvasive device would, of course, have a better acceptance than an invasive device,” van Vollenhoven added.

It is possible that the external or ear-based devices discussed by Chernoff could be additional options for patients and thereby improve uptake.

Because Chernoff views the issue through the research and development lens, he knows there is work to be done. “First of all, the studies about this have to be done meticulously,” he said. “They have to be done with sham controls at centers of excellence around the country, with everything blinded, even the MRIs.”

If the trials are conducted in this way, Chernoff and his colleagues at SetPoint Medical are willing to let the results speak for themselves, positive, negative or otherwise. From there, whether doctors and patients ultimately decide that an implantable vagus nerve stimulatory device is the best option remains to be seen.

Looking to the Future

Despite these concerns, rheumatologists who have been wrestling with these hard-to-treat chronic diseases are wont to get caught up in the possibilities when presented with a novel approach that shows efficacy, even in early, proof-of-concept trials. More options are a good thing.

“If this approach reaches its potential, you could imagine that it could be a nonchemical, nonbiological approach to modulating the immune system and treating RA,” Genovese said. “It could be an adjunctive treatment for those who are failing to get a sufficient response on their current therapies, particularly those who might have already failed one or more agents.”

But there is work to be done, according to Strand. “Based on small pilot studies, there is evidence of efficacy,” she said. “But it will require larger scale randomized controlled trials to prove this.”

Even Chernoff encouraged the rheumatology community “not to expect miracles” with implantable vagus nerve devices, at least not yet. “But having another option beyond TNF or JAK inhibitors that does not put patients at risk for infectious complications is a good thing,” he said. – by Rob Volansky

• References:
• Aranow C, et al. Abstract #2652. Presented at ACR/ARHP Annual Meeting, Oct. 20-24, 2018; Chicago.
• Bonaz B, et al. J Intern Med. 2017;doi:10.1111/joim.12611
• Borovikova LV, et al. Nature. 2000;405:458-462.
• Genovese MC, et al. Abstract #LB0009. Presented at: EULAR Annual Congress; June 12-15, 2019; Madrid.
• Koopman FA, et al. Proc Natl Acad Sci U S A. 2016; doi:10.1073/pnas.1605635113.
• Serhan CN, et al. J Intern Med. 2019;doi:10.1111/joim.12871.
• Tarn J, et al. Abstract #AB0193. Presented at: EULAR Annual Congress; June 12-15, 2019; Madrid.

• For more information:
• David N. Chernoff, MD, can be reached at 25101 Rye Canyon Loop, Valencia, CA 91355; email: dchernoff@setpointmedical.com.
• Mark C. Genovese, MD, can be reached at 1000 Welch Rd. #203, Palo Alto, CA 94087; email: genovese@stanford.edu.
• Iain McInnes, MD, can be reached at B4/13, Iii - Gbrc, University Place, Glasgow G12 8TA, Scotland; email: ali.howard@glasgow.ac.uk.
• Vibeke Strand, MD, can be reached at 306 Ramona Rd., Portola Valley, CA 94028; email: vstrand@stanford.edu.
• Ronald van Vollenhoven, MD, PhD, can be reached at PO Box 22660, 1100 DD Amsterdam, The Netherlands; email: r.vanvollenhoven@amsterdamumc.nl.

Disclosure: Chernoff reports being an employee of SetPoint Medical. Genovese reports grants and consulting for Setpoint, and consulting for Valvani and Vorso. McInnes reports consulting for Galvani Bioelectronics. van Vollenhoven reports receiving research support and grants from BMS, GSK, Lilly, Pfizer, and UCB Pharma; and consultancy or honoraria from AbbVie, AstraZeneca, Biogen, Biotest, Celgene, GSK, Janssen, Lilly, Pfizer, Servier, and UCB Pharma.