Elsevier

The Lancet Rheumatology

Volume 3, Issue 4, April 2021, Pages e262-e269
The Lancet Rheumatology

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

https://doi.org/10.1016/S2665-9913(20)30425-2Get rights and content

Summary

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

Nēsos.

Introduction

Rheumatoid arthritis is a chronic inflammatory disease characterised by joint pain, cartilage damage, and bone erosion, leading to considerable disability.1 Conventional synthetic disease-modifying antirheumatic drugs (DMARDs) like methotrexate are considered first-line therapy for rheumatoid arthritis treatment. In many cases, a targeted synthetic DMARD, such as a Janus kinase inhibitor, or a biological DMARD is added to the treatment regimen to attain lower disease activity. This combination has been shown to result in meaningful symptomatic relief in about 50% of patients.2, 3, 4, 5 Only a minority of patients reach the treatment goal of remission or low disease activity with the current pharmaceutical treatment options.6, 7, 8 Therefore, there is still an unmet need for effective and safe therapies for the treatment of rheumatoid arthritis, and alternative approaches are warranted.

The autonomic nervous system (ANS) plays an important role in the regulation of inflammation in both animal models and humans.9, 10, 11 Dysregulation of the ANS has been observed in patients with chronic autoimmune diseases, including rheumatoid arthritis. Recent evidence by Koopman and colleagues12 supports the notion that decreased autonomic control precedes the development of rheumatoid arthritis. The vagus nerve, which is a main component of the autonomic nervous system, might offer a way to therapeutically intervene.10, 13

Research in context

Evidence before this study

We searched PubMed for articles in English published from database inception until Aug 1, 2020, using the terms “rheumatoid arthritis”, “treatment”, and “vagus nerve”. We reviewed previous clinical trials and investigational treatments in rheumatoid arthritis. Two studies have been done with implantable devices to investigate vagus nerve stimulation as a potential treatment for rheumatoid arthritis. A single-arm, open-label, proof-of-concept study used a commercially available vagus nerve stimulation device indicated for epilepsy, which was reprogrammed and used in patients with rheumatoid arthritis. The device consisted of a pulse generator implanted in a subcutaneous subclavicular pocket, with a lead running from the generator to the neck and with electrodes that were surgically applied to the vagus nerve. This study included patients with early-stage rheumatoid arthritis and an insufficient response to methotrexate, and a second group of patients with an insufficient response to at least two biological drugs. The study showed improvements in systemic inflammation and disease activity in the 17 patients with rheumatoid arthritis who were analysed. A second pilot study further assessed the safety and efficacy of vagus nerve stimulation in a sham-controlled study of patients with multidrug-refractory rheumatoid arthritis. A custom designed, wireless, rechargeable neurostimulator was surgically placed directly on the vagus nerve and powered by an external coil, obviating the need for an implantable pulse generator. The adverse events related to surgery included Horner's syndrome and vocal cord paralysis, which resolved without clinically significant sequelae. Five (50%) of ten patients who received active stimulation had clinical improvement, based on the Disease Activity Score of 28 joints with C-reactive protein (DAS28-CRP) and clinical disease activity index.

Added value of this study

To our knowledge, this is the first report of a non-invasive, wearable vagus nerve stimulation device for the treatment of patients with rheumatoid arthritis. The Nēsos device delivers electrical stimulation sequences to the auricular branch of the vagus nerve, which supplies the cutaneous regions of the external ear with afferent innervation. This proof-of-concept study of patients with moderately to severely active rheumatoid arthritis found that there were no serious adverse events and that daily use of the wearable device produced an average reduction of 1·4 in DAS28-CRP and significant improvements in American College of Rheumatology responses.

Implications of all the available evidence

Despite the use of conventional synthetic disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis, many patients do not achieve remission or low disease activity, showing an unmet need for novel treatments. Despite the small sample size of this open-label study, the results indicate a potential therapeutic effect and offer a possible non-pharmacological alternative for the treatment of rheumatoid arthritis. Further evaluation in larger controlled studies is needed.

Vagal tone and parasympathetic signaling, which are regulated by the CNS, are decreased in patients with rheumatoid arthritis.14 Vagus nerve stimulation can potentially offer a way to restore normal signaling. In the past 5 years, an implantable vagus nerve stimulation device was investigated for the effects of vagus nerve stimulation in patients with rheumatoid arthritis.15, 16 6 weeks of daily stimulation led to reduced production of tumour necrosis factor (TNF) and interleukin (IL)-6 in lipopolysaccharide-stimulated whole blood, and this correlated with improvements in the Disease Activity Score of 28 joints with C-reactive protein (DAS28-CRP). Withdrawal of the vagus nerve stimulation resulted in worsening of rheumatoid arthritis disease activity, whereas restoration of stimulation again led to improvement.15 In a second 12-week, 2-stage, randomised, sham-controlled trial,16 active electrical stimulation of the vagus nerve with a miniaturised, implanted neurostimulator was safe and well tolerated, and signs and symptoms of rheumatoid arthritis were reduced in patients with multidrug-refractory disease. This work supports the notion that electrical stimulation therapy has the potential to modulate pro-inflammatory cytokine production, reduce inflammation, and reduce rheumatoid arthritis disease activity by affecting the functioning of the autonomic nervous system. Although this preliminary work is promising, concerns exist about the need for surgical implantation of the device and the potential for serious surgery-related adverse events.16

A novel, non-invasive, wearable vagus nerve stimulation device (Nēsos [formerly Vorso], Redwood City, CA, USA) has been created for the treatment of rheumatoid arthritis. This device is designed to deliver electrical stimulation pulses to the auricular branch of the vagus nerve, which supplies the cutaneous regions of the external ear with afferent innervation.17, 18 This study aimed to investigate the safety and efficacy of the electrical pulse sequences delivered non-invasively by the device in patients with moderately to severely active rheumatoid arthritis.

Section snippets

Study design and participants

In this prospective, multicentre, open-label, single-arm proof-of-concept study, patients aged 18–80 years with a diagnosis of rheumatoid arthritis (on the basis of the 2010 American College of Rheumatology (ACR) and European League Against Rheumatism classification criteria) for at least 6 months were enrolled. Eligible patients had active disease at screening (DAS28-CRP >3·8, with four or more tender joints and four or more swollen joints on the 28 joint count), and any active osteitis or

Results

Of 35 patients screened for eligibility, 30 (86%) were enrolled at six centres in Spain between Dec 27, 2018, and Oct 24, 2019 (figure 1). Three patients withdrew from the study before week 12: two decided to seek alternative treatment options due to a perceived absence of clinical benefit, and one moved outside of the country. 27 (90%) patients completed the week 12 visit, with the last patient's final visit occurring on Jan 21, 2020.

The mean age of patients was 54·4 years (SD 10·0), most

Discussion

Despite the notable advances in pharmacological treatments for rheumatoid arthritis during the past several decades, a meaningful proportion of patients are still unable to achieve low disease activity or remission, highlighting an unmet need for novel therapeutic approaches. This study showed a significant and clinically meaningful reduction in rheumatoid arthritis disease severity as measured by the DAS28-CRP and ACR response criteria after 12 weeks of device use.22, 26 Previous work using an

Data sharing

The datasets generated and analysed during this study are not publicly available. Nēsos is committed to sharing with qualified external researchers the access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved on the basis of scientific merit. All data provided is anonymised to respect the privacy of patients who have participated in the trial, in line with applicable laws and regulations. For more information on the process,

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