Vagus nerve stimulation: A promising alternative for RA
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Research continues to suggest that vagus nerve stimulation may become an “exciting alternative” treatment for those with rheumatoid arthritis, according to Mark C. Genovese, MD.
Although early in its move toward the market, vagus nerve stimulation (VNS) appears to have the potential to benefit a number of patients with RA, such as those with refractory disease. However, Genovese, who is the James W. Raitt Endowed Professor of Medicine Emeritus-Active and Emeritus clinical chief of the division of immunology and rheumatology at Stanford University, emphasized that further studies are necessary.
During an interview with Healio, Genovese discussed the studies supporting the use of VNS in RA, the potential benefits and side effects of this treatment approach and clinical considerations for its use in this patient population.
Healio: What are the physiological underpinnings of use of VNS for RA?
Genovese: The underlying pathogenesis here is that we believe that the autonomic nervous system, through the delivery of components of the parasympathetic system, can result in down-modulation of inflammatory mediators through various cell types in the spleen.
Healio: Why is VNS an attractive treatment option compared with medication for RA?
Genovese: VNS is fundamentally different in the delivery of the signal to the body than, let's say, using a small-molecule medication or biologic. Through electrical stimulation of the vagus nerve, you can attempt to modulate inflammation using the body's own regulatory system to downregulate those inflammatory mediators.
VNS might be an attractive treatment option to patients who have tried traditional medications and have not had an adequate response, or individuals who have had a response to traditional medications but lost it over time. Additionally, there are patients who have tried traditional medications but have developed tolerability or safety concerns while on them. For the most part, that is how this approach is being studied: for those who have tried and failed traditional medications or biologics.
Healio: The devices studied have largely been repurposed from those used for other conditions. In what ways have they been modified so they would be better suited for RA?
Genovese: In the original study that was published in 2016 from colleagues in the Netherlands, the researchers used a repurposed device. It was implanted the same way that you would implant a pacemaker. It had leads that went from that device into the neck and wrapped around the vagus nerve. However, in the second study that we published in 2020 in The Lancet Rheumatology, we used a new device, which was designed specifically for this purpose (SetPoint Medical). Rather than looking like a pacemaker, it is about the size of a nickel. It is a self-contained device that is designed to sit and overlie the vagus nerve on the left side of the neck and provide stimulation to the vagus nerve. So, again this study was designed to assess the safety of a brand-new device, a microregulator, to provide VNS for RA, and maybe in the future for other diseases. I do want to highlight the fact that there are other ways of stimulating the vagus nerve, including transcutaneous stimulation, for which there are data in both RA and, more recently, in systemic lupus.
Healio: The studies in this area have been promising but small. Do we have sufficient evidence to move to larger clinical trials?
Genovese: The first studies demonstrated proof-of-concept that, in humans with active disease, VNS — whether through a repurposed epilepsy device or through a uniquely designed small microregulator —could result in potential improvement of symptoms, and the stimulation itself could be done safely. Based on that, larger studies are warranted for several reasons: to address the potential efficacy of the approach in larger populations, to define what populations are best served by VNS, to assess the durability of this response, to show whether or not long-term stimulation of the vagus nerve can be effective and safe and to demonstrate that you do not develop desensitization of the nerve.
Healio: For which patients would this treatment be best?
Genovese: The honest answer is that I do not think we know. The original study in 2016 looked at the original device in patients who were unresponsive or intolerant to methotrexate. The second study in 2020, looked at the new device in individuals who had tried and failed conventional drugs, and more specifically, those who had tried and failed at least two biologics or targeted synthetic drugs, like janus kinase inhibitors, with at least two different mechanisms of action. Thus, this study involved a much, much more refractory population. That was probably the most appropriate thing to do, given the fact you are implanting a novel microregulator on the vagus nerve.
Now, over time, there will be other important questions. What's the best population in which to use this device? What should this approach be used with? Can it be used with conventional drugs? Can you also use it in patients who are taking biologics or JAK inhibitors? Should it be a stand-alone approach? Or should it be an adjunct therapy in those who are getting some response from traditional medications? Could you then use VNS to get an additional response and get patients closer to remission? All those questions need to be worked out.
Healio: One concern has been the fact that VNS is an invasive procedure. Who would implant these devices?
Genovese: To date, these implantations have been done by neurosurgeons who are specially trained for implantation of the device. This is to make sure that there is no injury to the carotid artery or to the vagus nerve during the procedure and implantation.
Healio: What are the potential risks or adverse events associated with VNS?
Genovese: These can probably broken down into two separate buckets. One is the potential risks of the surgical procedure — the implantation itself. Notably, in our study in 2020, there were some adverse events associated with the surgical implantation, including an individual who developed vocal cord paralysis and another individual who developed Horner’s syndrome. Those were related specifically to the procedure. Over time those side effects were self-limited, but nonetheless, those are real potential risks.
Now, in terms of side effects associated with the VNS itself, there were relatively few in the small population studied to date.
Healio: Additionally, noninvasive VNS options are being explored. Are there data on how these noninvasive approaches perform?
Genovese: Yes. There was a paper published in The Lancet Rheumatology with a separate device that provided transcutaneous auricular branch stimulation to the vagus nerve. In a 30-patient open-label study, the researchers were able to demonstrate improvement in RA as well, although in a much less refractory patient population. That device is currently in another round of clinical trials.
Healio: Should VNS become an approved therapy for RA, would cost be prohibitive? Would this change as technology evolved?
Genovese: That is difficult to predict at this point. There are going to be the obvious costs associated with general anesthesia and the neurosurgical procedure to implant the device in addition to the cost of the device itself. The real question, though, is: If the device is effective and safe and is used long-term, how does that cost compare with the cost of using biologic or targeted synthetic drugs in the long run? One would have to carefully weigh those two costs. However, if this is being used in refractory patients for which other medications have not worked, then it is probably easier to justify that one-time cost.
Healio: What are the next steps in bringing this technology to patients?
Genovese: Coming back to one of your earlier questions, this has to do with the size of the populations that have been studied to date. The first study only included 17 patients and the second study included14 patients. What we really need is a much larger patient population to be appropriately studied for a much longer duration of time to assess safety but also to assess the durability of the response. Once we have that sort of information, then one could proceed to regulators and talk about whether or not an approach like this might ultimately come to market, but certainly not before that data is available
Healio: Are there any larger studies in the works right now?
Genovese: Yes. The small device that we used in 2020 and was designed by SetPoint is in its next round of clinical studies right now. I believe they are recruiting patients. I also know that the transcutaneous auricular stimulator is also enrolling patients in clinical trials, but there also might be more devices out there that I am unaware of.
Healio: Do you have a final message for our readers?
Genovese: This is an exciting alternative approach. There are already some proof-of-concept data, but much more robust longer-term studies will be necessary to truly assess the safety and durability of this approach and to understand the patient populations for which it is best suited.
References:
Genovese MC, et al. Lancet Rheumatol. 2020;doi:10.1016/S2665-9913(20)30172-7.
Marsal S, et al. Lancet Rheumatol. 2021;doi:10.1016/S2665-9913(20)30425-2.
For more information:
Mark C. Genovese, MD, can be reached at genovese@stanford.edu.
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