Background/Purpose: The inflammatory reflex is an endogenous neuroimmune circuit that helps regulate innate and adaptive immunity (Annu. Rev. Immunol. 2012; 30:313). Activation of this reflex by electrical vagus nerve stimulation (VNS) reduced systemic inflammation and disease activity in a 17 patient rheumatoid arthritis (RA) proof-of-concept study using a reprogrammed epilepsy stimulator (PNAS 2016; 113(29):8284). Here we report on the safety and efficacy of a novel miniaturized neurostimulator, the “MicroRegulator” (MR), in a first-in-human, double-blind pilot study of VNS in multi-drug refractory RA patients. 

Methods: The MR was implanted on the left vagus nerve in 14 patients with active RA and prior insufficient response to ≥2 bDMARDS or JAK inhibitors with ≥2 different modes of action; all patients remained on a stable background of MTX (n=12) or HCQ. Three weeks after implantation, the first 3 subjects were stimulated 1 min QD and, following safety review board approval, the remaining 11 patients were implanted with the MR and randomized to 1 min: sham, QD, or QID VNS for 12 weeks (primary endpoint; PE). Patients, rheumatologists, joint assessors and monitors were fully blinded to treatment arm. Patients randomized to sham had their devices activated after the PE was reached. The pharmacodynamic response to VNS was assessed in blood using cytokine production in an ex-vivo bioassay (TruCulture). Clinical efficacy was measured by DAS28-CRP and CDAI responses and by wrist MRI (RAMRIS OMERACT).  Vagus nerve activity (tone) was extracted from heart rate variability assessments of Holter-captured ECG.

Results: 14 patients were enrolled (mean prior bDMARDs = 4.8, mean DAS28-CRP= 5.94). Implantation and stimulation were generally well tolerated. There were no device or treatment-related SAEs and 2 notable surgery related adverse events (left vocal cord paralysis, Horner’s syndrome) that resolved without clinically significant sequelae. Confirming activation of the inflammatory reflex, the pharmacodynamic response of VNS was observed in both actively stimulated groups with >30% decrease from baseline in bioassay levels of IL-1β, IL-6, and TNF-α at PE, with minimal change in the sham group. Mean DAS28-CRP change at PE was: combined QD= -1.34, QID= 0.38, Sham= 0.16. Of QD stimulated patients, 4/6 had a EULAR good or moderate response vs. 1/4 QID and 0/4 shams. Both DAS28 and CDAI response was achieved by 5/10 actively stimulated patients at PE, with 2 in DAS28 remission. MRI inflammation measures did not change by PE. RAMRIS erosion scores correlated with EULAR response (change in responders = -2.2 vs. 2.4 in non-responders). Mean vagal tone in the stimulated patients was increased 2.75-fold relative to sham stimulated patients.

Conclusion:

The novel MR device and stimulation was well tolerated independent of the two surgery-related events. MR associated VNS reduced signs and symptoms of RA in a meaningful number of highly drug-refractory patients. No clinical improvement was observed in the sham group. These initial pilot data support the use of the MR for QD VNS in a larger blinded sham-controlled study in patients who have failed biologics or targeted oral therapies as a novel approach for treatment of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/neurostimulation-for-treatment-of-drug-refractory-rheumatoid-arthritis-a-first-in-human-study-using-a-novel-vagus-nerve-stimulator/