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WASHINGTON -- A small implant delivering electrical stimulation to the vagus nerve outperformed a sham treatment in relieving rheumatoid arthritis (RA) symptoms among patients who failed at least one biologic or targeted synthetic drug, a researcher reported here.

After 24 weeks, 51.5% of patients randomized to active stimulation achieved ACR20 responses (20% improvement in symptoms by American College of Rheumatology criteria), according to John Tesser, MD, of Arizona Arthritis & Rheumatology Associates in Phoenix.

As well, just over 35% of 122 patients in the intervention group achieved DAS28-CRP (Disease Activity Score in 28 joints modified by C-reactive protein level) values of 3.2 or less -- indicating low activity or remission -- at week 24, the group reported in a late-breaking poster presented at the American College of Rheumatology's annual meeting.

Patients assigned to sham treatment (n=120) received the implant but it was not turned on for the first 12 weeks. At the end of that double-blind period, 24.2% had reached ACR20, as opposed to 35.2% of the active-treatment group (P=0.02). Then the device was activated in the control group for an additional 12 weeks; by week 24, 53.1% of the control group had achieved ACR20.

While most current advanced therapies for RA have shown greater ACR20 responses in their clinical trials, they typically did not involve patients with refractory disease. In the current study, well over half had actually failed two or more biologic or targeted synthetic agents for RA.

Vagus nerve stimulation has been postulated to relieve RA symptoms through a "neuroimmune reflex," in which the nervous system senses inflammatory reactions and dials them back. "Activating this reflex with a 60-second stimulation inhibits intracellular pathways to suppress multiple inflammatory cytokines by 30%-70%, with sustained reduction for 24-48 hours post stimulation," Tesser's poster explained.

Other groups have investigated vagus nerve stimulation for RA, and highly favorable results have been reported. But those were mostly open-label, uncontrolled studies. Results were very different in a randomized, sham-controlled trial published last year, in which only 25% of patients met ACR20 criteria after 12 weeks.

That trial, however, applied stimulation to patients' ears, and enrolled only 113 patients. The stimulation device used in the current trial, developed by SetPoint Medical of Sausalito, California, is surgically inserted into the left side of the neck. It , about 3 cm in length. Patients can recharge it themselves wirelessly while implanted.

As an invasive treatment, it made sense to test the SetPoint system in patients who hadn't responded to conventional therapy. The randomized, double-blind trial, called , began in early 2021. Almost 5 years of open-label follow-up is planned.

Mean patient age was 56 and about 85% were women. Body mass index values averaged about 30. Half of the participants were seropositive for RA-related blood markers. DAS28-CRP values at baseline weren't reported, but tender and swollen joint counts averaged about 15 and 10, with mean high-sensitivity CRP levels of 8.2 mg/L. Disease duration averaged more than 12 years.

Tesser and colleagues also performed MRI scans to assess erosion progression, via RA Magnetic Resonance Imaging Scoring (RAMRIS). Participants showing a change from baseline greater than 0.5 in RAMRIS score were considered "erosion progressors."

Even though the double-blind phase lasted only 12 weeks, the researchers found significant differences between the control and active-therapy groups. Not in all patients, for which there was only a weak trend toward less progression with nerve stimulation, but among 82 patients who had failed just one previous advanced therapy, 9% of those receiving stimulation were progressors at week 12, versus 25% of sham-treated patients (P=0.010). And among 98 patients classed as "highly erosive" at baseline, 37% of controls versus 18% of stimulated patients were progressors (P=0.016).

Four patients, including three in the active-treatment group, experienced treatment-related serious adverse events. They included severe incision-site swelling, vocal cord paresis and dysphagia, significant dysphonia that diminished but never entirely resolved, and a pharyngeal injury during device placement that was repaired on the spot.

Ten patients in the active-treatment group reported adverse effects from the stimulation itself. These were not serious and were managed by adjusting the degree of stimulation. No one quit the study because of adverse effects.

Limitations to the study included the short follow-up reported thus far, and the lack of more stringent efficacy outcomes such as ACR50/70 responses (50%/70% symptom reduction).

SetPoint described the trial as "pivotal" and that it intends to submit an FDA premarket approval application on the strength of these findings. The company also to start a pilot trial of the stimulation device in patients with multiple sclerosis; inflammatory bowel disease is another potential target, SetPoint indicated.

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