Background/Purpose:

RA is a debilitating chronic disease with an unmet need for additional therapeutic approaches. Modulating innate neuro-immune reflex pathways by stimulation of the vagus nerve (VNS) could represent a novel means of treating RA (van Maanen MA et al. Nat Rev Rheumatol. 2009; 5:229-32). We recently reported a 12-week proof of concept study using a VNS device, approved for drug-resistant epilepsy, showing reductions in the DAS28-CRP and in TNF-α and IL-6 levels (Koopman FA et al. PNAS 2016;113:8284). To understand the long term safety and efficacy of this novel treatment approach, we followed the patients in a 24 months long-term extension study and report on the safety and clinical efficacy data.

Methods:

In the primary study, VNS devices were implanted into 17 RA patients, mostly with insufficient response to multiple conventional and biologic DMARDs, on stable background of methotrexate (≤25 mg weekly) therapy. The devices electrically stimulated the vagus nerve, 1-4 min/day, over a 12 week open label period. On completion, subjects were offered to enroll into a follow-up study, where the study physicians were given flexibility to alter VNS dosing parameters and/or to add a biologic DMARD to the treatment regimen. DAS28-CRP and Health Assessment Questionnaire-Disability Index (HAQ-DI) were collected over 2 years.

Results:

All subjects electively continued on VNS treatment through 24 months of the long term follow-up study. Biologic DMARDs were started in 1 and restarted in 8 of 17 subjects; of these, 4 were non-responders to VNS in the primary study, and 5 had stable improvement but had not yet achieved disease remission on VNS alone (Table 1). At the start of the follow-up study, the mean DAS28-28 and HAQ-DI were significantly reduced compared to the pre-implant baseline (mean difference± SE in DAS28-CRP = -1.60± 0.37, p<0.0001; mean difference± SE in HAQ-DI = -0.44± 0.21, p<0.037), and the depth of effect was retained through 24 months. No association between DAS28-CRP and stimulation frequency (Range= 1X-8X/day) was observed.  At 24 months, both the subjects using VNS monotherapy and those using a combination of VNS and biologic DMARDs exhibited stable improvements in DAS28-CRP and HAQ-DI. No difference in the adverse events profile between the two groups was observed.

Conclusion:

The data presented here demonstrate that VNS in subjects with RA is associated with a substantial reduction in disease activity that is sustained for 24 months without untoward safety signals. Further, the data suggest that biological DMARDs may be initiated safely in combination with VNS treatment, though this requires validation in larger cohorts. These results support additional development of VNS devices as an alternative therapeutic approach for RA treatment, which potentially can safely be combined with biologic DMARDs.