Non-invasive vagus nerve stimulation for rheumatoid arthritis: a proof-of-concept study.

ABSTRACT

BACKGROUND: Vagus nerve stimulation delivered with an implanted device has been shown to improve rheumatoid arthritis severity. We aimed to investigate the safety and efficacy of non-invasive stimulation of the auricular branch of the vagus nerve for the treatment of patients with moderately to severely active rheumatoid arthritis. METHODS: This prospective, multicentre, open-label, single-arm proof-of-concept study enrolled patients aged 18-80 years with active rheumatoid arthritis who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and up to one biological DMARD. Biological DMARDs were stopped at least 4 weeks before enrolment and concomitant use was not allowed during the study. All eligible participants were assigned to use a non-invasive, wearable vagus nerve stimulation device for up to 30 min per day, which delivered pulses of 20 kHz. Follow-up visits occurred at week 1, week 2, week 4, week 8, and week 12 after the baseline visit. The primary endpoint was the mean change in Disease Activity Score of 28 joints with C-reactive protein (DAS28-CRP) at week 12 compared with baseline. Secondary endpoints included the mean change in the Health Assessment Questionnaire-Disability Index (HAQ-DI), the proportion of patients with a minimal clinically important difference of 0·22 on HAQ-DI, the proportion achieving American College of Rheumatology (ACR) 20, ACR50, and ACR70 response, and safety analysis. This study is registered with ClinicalTrials.gov (NCT04116866). FINDINGS: Of 35 patients screened for eligibility, 30 (86%) were enrolled at six centres in Spain between Dec 27, 2018, and Oct 24, 2019, of whom 27 (90%) completed the week 12 visit. The mean change in DAS28-CRP at 12 weeks was -1·4 (95%CI -1·9 to -0·9; p<0·0001) from a mean baseline of 5·3 (SD 1·0). 11 (37%) of 30 patients reached DAS28-CRP of 3·2 or less, and seven (23%) patients reached DAS28-CRP of less than 2·6 at week 12. The mean HAQ-DI change was -0·5 (95%CI -0·7 to -0·2; p<0·0001) from a mean baseline of 1·6 (SD 0·7), and 17 (57%) patients reached a minimal clinically important difference of 0·22 or more. ACR20 responses were reached by 16 (53%) patients, ACR50 responses by 10 (33%) patients, and ACR70 by five (17%) patients. Four adverse events were reported, none of which were serious and all of which resolved without intervention. INTERPRETATION: Use of the device was well tolerated, and patients had clinically meaningful reductions in DAS28-CRP. This was an uncontrolled, open-label study, and the results must be interpreted in this context. Further evaluation in larger, controlled studies is needed to confirm whether this non-invasive approach might offer an alternative treatment for rheumatoid arthritis. FUNDING: Nesos.