ObjectivePreliminary evidence suggests that vagus nerve stimulation (VNS) may have some benefit in patients with rheumatoid arthritis (RA), however prior studies have been small and/or uncontrolled; this study aimed to address that gap.MethodsThis randomized, double‐blind, sham‐controlled trial enrolled patients aged 18‐75 years with active RA who had failed conventional synthetic disease‐modifying antirheumatic drugs (csDMARDs) and were naïve to biologic and/or targeted synthetic DMARDs. All patients received an auricular vagus nerve stimulator and were randomized 1:1 to active stimulation or sham. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Secondary endpoints included mean changes in disease activity score of 28 joints with C‐reactive protein (DAS28‐CRP) and Health Assessment Questionnaire‐Disability Index (HAQ‐DI).ResultsA total of 113 patients (mean age 54 years; 82% female) enrolled, and 101 patients (89.4%) completed week 12. ACR20 response at week 12 was 25.0% for active stimulation vs 26.9% for sham (difference vs sham [95% CI]: ‐1.9 [‐18.8‐14.9], p=0.823). The least square mean (SE) change in DAS28‐CRP was –0.95 (0.16) for active stimulation and –0.66 (0.16) for sham (p=0.201); in HAQ‐DI it was –0.19 (0.06) for active stimulation and –0.02 (0.06) for sham (p=0.044). Adverse events occurred in 17 patients (15%); all were mild or moderate.ConclusionAuricular VNS did not meaningfully improve RA disease activity. If VNS with other modalities is pursued in the future for the treatment of RA, larger, controlled studies will be needed to understand its utility.This article is protected by copyright. All rights reserved.
Transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive alternative to vagus nerve stimulation (VNS) with implantable devices, has shown promise in treating disorders such as depression, migraine, and insomnia. Studies of these disorders with resting-state functional magnetic resonance imaging (MRI) (rsfMRI) have found sustained changes in resting-state functional connectivity (rsFC) in patients treated with low frequency (1–20 Hz) taVNS. A recent study has reported reductions in pain scores in patients with rheumatoid arthritis after a 12-week treatment of high-frequency (20 kHz) sub-threshold taVNS. However, no studies to date have examined the effects of high-frequency sub-threshold taVNS on rsFC. The objective of this study was to determine whether high-frequency sub-threshold taVNS induces changes in rsFC using seed regions from the cingulate cortex and insula, brain regions that play a key role in interoception and processing of pain. With a single-blind placebo-controlled repeated measures experimental design, rsfMRI scans were acquired before and after 15 min of either sub-threshold taVNS treatment or a sham control. Significant taVNS-related changes in functional connections to the cingulate cortex were detected between the anterior cingulate cortex and right superior temporal gyrus and between the midcingulate cortex and right inferior parietal lobule. In addition, significant changes in functional connections to the insula were detected between the posterior insula and right precuneus and between the anterior insula and right cuneus gyrus. These results suggest that high-frequency sub-threshold taVNS can lead to sustained effects on the rsFC of brain regions involved in interoception and processing of pain in a cohort of healthy subjects. This study lays the foundation for future rsfMRI studies of high-frequency sub-threshold taVNS in clinical populations.
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