Abstract
BackgroundRheumatoid arthritis (RA) is a chronic and debilitating inflammatory disease characterized by extensive joint tissue inflammation. Implantable bioelectronic devices targeting the inflammatory reflex reduce TNF production and inflammation in preclinical models of inflammatory disease, and in patients with RA and Crohn’s disease. Here, we assessed the effect of applying a vibrotactile device to the cymba concha of the external ear on inflammatory responses in healthy subjects, as well as its effect on disease activity in RA patients.MethodsSix healthy subjects received vibrotactile treatment at the cymba concha, and TNF production was analyzed at different time points post-stimulation. In a separate study, nineteen healthy subjects were enrolled in a randomized cross-over study, and effects of vibrotactile treatment at either the cymba concha or gastrocnemius on cytokine levels were assessed. In addition, the clinical efficacy of vibrotactile treatment on disease activity in RA was assessed in nine patients with RA in a prospective interventional study.ResultsVibrotactile treatment at the cymba concha reduced TNF levels, and the suppressive effect persisted up to 24 h. In the cross-over study with 19 healthy subjects, vibrotactile treatment at the cymba concha but not at the gastrocnemius significantly reduced TNF, IL-1β, and IL-6 levels compared to pre-treatment baseline (TNF p < 0.05, IL-6 p < 0.01, IL-1β p < 0.001). In healthy subjects, vibrotactile treatment at the cymba concha inhibited TNF by 80%, IL-6 by 73%, and IL-1β by 50% as compared to pre-treatment baseline levels. In RA patients, a significant decrease in DAS28-CRP scores was observed two days post-vibrotactile stimulation at the cymba concha (DAS28-CRP score pre-treatment = 4.19 ± 0.33 vs post-treatment = 3.12 ± 0.25, p < 0.05). Disease activity remained significantly reduced 7 days following vibrotactile treatment (DAS28-CRP score 7 days post-treatment = 2.79 ± 0.21, p < 0.01). In addition, a persistent improvement in visual analogue scale scores, a patient derived measure of global health assessment, was observed in RA patients following vibrotactile treatment.ConclusionApplication of a vibrotactile device to the cymba concha inhibits peripheral blood production of TNF, IL-1β, and IL-6 in healthy subjects, and attenuates systemic inflammatory responses in RA patients.Trial registrationsClinicalTrials.gov Identifier: NCT01569789 and NCT00859859. The AMC trial conducted in The Netherlands does not have a ClinicalTrials.gov Identifier.
Highlights
Rheumatoid arthritis (RA) is a progressive and debilitating disease characterized by an inflammatory pannus whose growth is stimulated by Tumor necrosis factor (TNF) and IL-6 (Smolen et al 2016)
Application of a vibrotactile device at the cymba concha decreases TNF in a pilot study of healthy subjects To assess the effect of vibrotactile treatment on modulating inflammatory cytokines in healthy subjects, we conducted a pilot study at the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
We observed that vibrotactile stimulation at the cymba concha in healthy subjects significantly attenuated endotoxin induced TNF by 56, 55, 69% (p < 0.01, Repeated measures analysis of variance (RMANOVA)- Friedman test), and 42% at 30 min, 2 h, 4 h and 24 h post-stimulation respectively (Fig. 3)
Summary
Rheumatoid arthritis (RA) is a progressive and debilitating disease characterized by an inflammatory pannus whose growth is stimulated by TNF and IL-6 (Smolen et al 2016). Anti-TNF biologics are widely-prescribed and efficacious in rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and psoriasis. Despite their clinical efficacy, these agents are costly (>$25,000 per patient annually), and render patients susceptible to serious infections as a direct result of TNF blockade (Monaco et al 2015). Bioelectronic devices targeting the inflammatory reflex reduce TNF and inflammation in preclinical models of inflammatory disease, and in patients with rheumatoid arthritis and Crohn’s disease (Chavan et al 2017; Andersson and Tracey 2012a; Levine et al 2014; Koopman et al 2016; Bonaz et al 2016). We assessed the effect of applying a vibrotactile device to the cymba concha of the external ear on inflammatory responses in healthy subjects, as well as its effect on disease activity in RA patients
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