Background/Purpose: The inflammatory reflex regulates innate and adaptive immunity (Andersson O, Tracey K, Annu. Rev. Immunol. 2012; 30:313). Activation of its efferent arm (the Cholinergic Anti-inflammatory Pathway (CAP)), by electrical vagus nerve stimulation (VNS) reduces systemic inflammation and ameliorates disease in many acute and chronic animal models. We determined whether VNS could similarly improve clinical manifestations of rheumatoid arthritis (RA).

Methods: This is an open label study of patients with active RA (>/= 4 tender and 4 swollen joints (28 joint scoring), and CRP of at least 7 mg/L) despite stable methotrexate dose for 3 months. Patients failing TNF antagonists (only for safety or tolerability reasons) could also be enrolled after washout.  After a pre-implantation baseline visit, patients were surgically implanted with a Cyberonics VNS system. The device delivered the first VNS during its standard intraoperative diagnostic check sequence. Two weeks following implantation patients returned for initial in-clinic VNS. One week after the first clinic visit (day 7), patients began self-delivery of 60 second, once daily home stimulations, escalated in output current intensity as tolerated, through day 28. At day 28 patients without a EULAR good or moderate response were increased to four times daily VNS. Primary endpoint results at day 42 are reported. 

Results: 8 patients (4 female, 7/8 RF+, 6/8 ACPA+, mean age 56 [range 39-70], mean disease duration 8 yrs [range 0.5-13]) were enrolled and implanted. Implantation and stimulation were generally well tolerated. Moderate postoperative hoarseness occurred in one patient. Pre implantation baseline values (mean, SD) were: DAS28-CRP: 6.06 (0.87), CRP: 17.5 mg/L (9.9), HAQ-DI: 1.63 (0.90). Changes at day 42 visit from pre-implantation values were: DAS28-CRP: -2.28 (1.65), CRP: -3.46 (17.95) mg/L , HAQ-DI: -0.44 (0.48). Similar levels of improvement were seen across all ACR core set assessments. ACR 20/50/70 response rates from pre-implantation baseline to day 42 were 75% (6/8), 50% (4/8), and 25% (2/8), respectively. 

Conclusion: In this pilot study VNS was generally well tolerated and improved signs and symptoms of RA. This is the first demonstration in humans that stimulation of the CAP can favorably impact clinical manifestations of systemic inflammation. If efficacy and safety are confirmed in larger controlled studies, implantable medical devices may offer a feasible alternative approach to the treatment of RA and other chronic inflammatory diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pilot-study-of-stimulation-of-the-cholinergic-anti-inflammatory-pathway-with-an-implantable-vagus-nerve-stimulation-device-in-patients-with-rheumatoid-arthritis/