Background/Purpose: Vagus nerve stimulation (VNS) has emerged as a potential therapeutic strategy for inflammatory diseases by modulating inflammatory reflex pathways. Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive approach that may offer symptomatic relief for rheumatoid arthritis (RA). This study aims to investigate the effects of taVNS on disease activity, pain, and inflammation in RA patients.

Methods: This exploratory, open-label clinical study enrolled patients diagnosed with RA who required treatment modification. Participants received daily taVNS treatments (25Hz, 1-10mA, 1 hour/day) for 12 weeks. Clinical assessments, including swollen and tender joint counts, Visual Analogue Scale (VAS), Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index (SDAI), Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR), and DAS28-C-reactive protein (DAS28-CRP), were conducted at baseline, weeks 4, 8, and 12. Laboratory analyses included inflammatory markers and immune cell profiling. Additionally, an exploratory proteomic analysis was performed using SomaScan®︎ Assay to comprehensively measure plasma proteins in both RA patients and Collagen Antibody-Induced Arthritis (CAIA) model mice before and after VNS treatment. Proteins commonly elevated in both species following taVNS were identified.

Results: Seven RA patients (mean age: 61.9 years; 100% female) were included in this analysis. Baseline disease activity scores were as follows: CDAI median [IQR] 24 [12:49.5], SDAI 25.1 [12.4:49.8], DAS28-ESR 4.66 [3.92:5.16], DAS28-CRP 3.94 [3.16:4.62], tender joint count 5 [4:21], swollen joint count 5 [2:14], VAS 24 [12:49.5]. After 12 weeks of taVNS, disease activity scores showed a decreasing trend; however, the differences did not reach statistical significance. Proteomic analysis by using SomaScan®︎ Assay revealed that Protein X was significantly upregulated in both RA patients and CAIA mice following taVNS. Notably, plasma levels of Protein X increased significantly in CAIA mice treated with taVNS (1007.0 ± 49.4) compared to untreated CAIA mice (886.5 ± 13.5, p=0.02). In contrast, no significant changes were observed in inflammatory proteins related to RA pathogenesis (TNF-α, IL-1β, IL-6, IL-17A, GM-CSF) or pain-associated neuropeptides (Substance P, CGRP, β-Endorphin, Enkephalin, Neuropeptide Y).

Conclusion: Protein X is a protein that modulates inflammatory pathways, particularly via STAT1 signaling. Preliminary findings suggest a potential association between taVNS and disease activity in RA, possibly involving Protein X and STAT1 signaling.

Disease activity in rheumatoid arthritis during 12 weeks of transcutaneous auricular vagus-nerve stimulation. Mean (±SD) CDAI, SDAI, DAS28-ESR, and DAS28-CRP for seven patients are plotted at baseline and at weeks 4, 8, and 12; none of the observed declines reached significance (repeated-measures ANOVA, p > 0.05).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effects-of-transcutaneous-auricular-vagus-nerve-stimulation-on-disease-activity-in-patients-with-rheumatoid-arthritis-a-pilot-study/