MADRID –
A minimal clinically important difference in the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) and the Clinical Disease Activity Index (CDAI) at 12 weeks was achieved or exceeded by 5 out of 10 patients; with 2 patients achieving DAS28-CRP–defined remission.
The disease activity scores also were paired with MRI scans and showed, in a handful of individuals, that there was improvement in erosions in those with a clinical response. Greater reductions in proinflammatory cytokines – interleukin (IL)-1-beta, IL-6, IL-17, IL-23, and tumor necrosis factor – were seen with neurostimulation, compared with a sham control group.
“The goal here was to use electrical stimulation to modify or modulate, and improve the treatment of active rheumatoid arthritis,” Mark C. Genovese, MD, said in an interview at the European Congress of Rheumatology.
“The reason for choosing refractory patients is, one, there’s a clear unmet need, but two, because this was a first-in-human study using a novel microregulatory device stimulating the vagus nerve, we thought the benefits-to-risk ratio was most appropriate for its first trial in patients with refractory disease,” explained Dr. Genovese, professor of medicine and director of the rheumatology clinic in the division of immunology and rheumatology at Stanford (Calif.) University.
He added: “Over time, if the device proves successful for modulating disease, one can see it potentially being used earlier in the disease. Whether it is developed as a stand-alone or used as an adjunct on additional therapy will have to be determined based on both its efficacy and its safety.”
Neurostimulation is a novel concept in rheumatology but has been used with success in other areas of medicine – including epilepsy and depression – using electrical pulses instead of drugs. The idea behind it is that it stimulates the inflammatory reflex that modulates multiple the inflammatory pathways. Essentially, it’s thought that electrically stimulating the vagus nerve sends signals to the spleen where T-lymphocytes then signal to other immune cells, such as macrophages and monocytes, to temper their production of proinflammatory cytokines and other mediators.
“Unlike traditional immunosuppressive biologics that may be specifically targeting one inflammatory process, by suppressing the inflammatory reflex we believe we can suppress a variety of inflammatory cytokines in the region of between 30% and 70%,” Dr. Genovese said at a press briefing.
Data from a 12-week, open-label study (Proc Natl Acad Sci U S A. 2016;113:8284-9) have already shown that the approach works in patients with refractory RA (n = 17). Once-daily electrical vagus nerve stimulation using an existing device made for treating epilepsy showed that clinically meaningful changes in DAS28-CRP could be achieved through TNF suppression. The effects on systemic TNF release lasted for around 24-48 hours after stimulation.
For the current study, a much smaller, leadless, investigational neurostimulation device was used. Called a MicroRegulator (SetPoint Medical), it is about 1 inch long, less than 2 cc in total volume, and is surgically implanted by a neurosurgeon at the top of the vagus nerve. When activated through an iPad app by the health care professional, it sends electrical impulses down the vagus nerve. The device’s battery is charged externally and wirelessly a few minutes each week. Dr. Genovese noted that the device needs to be turned on for only 60 seconds at a time to have an effect and that patients may feel a vibration but this was not reported in the study as an adverse event.
Results of the first in-human study with the device were presented by Dr. Genovese during the late-breaking clinical trials session at the meeting. He described how a total of 14 patients had the device implanted, the first 3 of whom received once-daily, open-label neurostimulation. The remaining 11 patients were randomized to either once-daily or four-times-daily neurostimulation via the device, or to receive sham therapy in which the device was implanted but not switched on. The patients had moderate to severe RA, defined as four or more tender joints, four or more swollen joints, and a CDAI score greater than 10, plus they had radiologically active disease and an insufficient response to at least two biologic or targeted synthetic disease-modifying antirheumatic drugs with differing mechanisms of action.
All patients went through the same schedule of device charging and they did not know if they were in the active or sham groups. At the end of the study, patients had the option to continue in a long-term safety extension phase, have the device switched off, or could have it surgically removed.
“This trial was specifically a pilot trial to assess the MicroRegulator from a safety standpoint,” Dr. Genovese noted, but it also was designed to “help understand whether or not there was going to be clinical efficacy and applicability.”
While “there were no device or treatment-related serious adverse events,” there were some “surgical complications associated with the initial procedure.” One patient experienced paralysis of the left vocal cord during implantation that later resolved, and others experienced the following: Horner’s syndrome, tenderness and swelling at the surgical site, acute postoperative pain, and rash and pruritus. That said, there were no withdrawals from the study due to adverse events.
Commenting in a press release issued by the European League Against Rheumatism, Thomas Dörner, MD, of Charité Universitätsmedizin Berlin, said, “This is a really exciting development. For many patients suffering from rheumatoid arthritis, current treatments don’t work, or aren’t tolerated. These results open the door to a novel approach to treating not only rheumatoid arthritis, but other chronic inflammatory diseases. This is certainly an area for further study.”
The study was sponsored by SetPoint Medical. Dr. Genovese disclosed receiving consulting fees from and having contracts with/grants with the company and acting as a consultant to Galvani and Vorso. He has also received research support from and served as a consultant to Sanofi/Genzyme, Genentech/Roche, and R-Pharm. Dr. Dörner was not involved in the study and commented as part of his role as the chairperson of the EULAR Scientific Program Committee.
SOURCE: Genovese M et al. Ann Rheum Dis. Jun 2019; 78(Suppl 2):264. Abstract LB0009, doi: 10.1136/annrheumdis-2019-eular.8716