A Randomized, Double‐Blind, Sham‐Controlled, Clinical Trial of Auricular Vagus Nerve Stimulation for the Treatment of Active Rheumatoid Arthritis

OBJECTIVE: Preliminary 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. METHODS: This randomized, double-blind, sham-controlled trial enrolled patients aged 18 to 75 years with active RA who had failed conventional synthetic disease-modifying antirheumatic drugs (DMARDs) 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). RESULTS: A 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 versus 26.9% for sham (difference vs. sham, -1.9; 95% CI, -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. CONCLUSION: Auricular 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.