Background The inflammatory reflex plays a role in regulating innate and adaptive immunity through cellular and molecular pathways1. Activation of this neuroimmune reflex by electrical vagus nerve stimulation (VNS) reduced systemic inflammation and improved disease activity in a 17 subject rheumatoid arthritis (RA) proof-of-concept study using a reprogrammed epilepsy stimulator2. A novel miniaturized neurostimulator, the “MicroRegulator” (MR), was developed for a first-in-human pilot study in multi-drug refractory RA.
Objectives To assess the safety and efficacy of the MR in a double-blind study in active RA patients.
Methods The MR was implanted 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 stable background of methotrexate. 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 of sham, QD, or QID stimulations for 12 weeks. Patients, rheumatologists, joint assessors and monitors were fully blinded to treatment arm. Subjects randomized to sham had their devices activated after the primary endpoint at 12 weeks. Clinical efficacy was measured by DAS28-CRP response and contrast-enhanced MRI (RAMRIS OMERACT). The pharmacodynamic response to VNS was assessed in blood using cytokine production in an ex-vivo bioassay (TruCulture).
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 surgery related adverse events (left vocal cord paralysis, Horner’s syndrome) that resolved without clinically significant sequelae. DAS28-CRP change at week 12 was (mean ± SEM): Open label QD= -1.44 ± 0.64, QD= -1.24 ± 0.88, QID= 0.38 ± 0.71, Sham=0.16 ± 0.21. Of QD stimulated patients, 4 of 6 had a EULAR good or moderate response. MRI measures of synovitis or osteitis did not change after 12 weeks of stimulation. RAMRIS erosion scores correlated with EULAR response (change ± SEM in erosion scores in EULAR responders = -2.2 ± 1.4 vs. 2.4 ± 0.96 in EULAR non-responders). The pharmacodynamic response to VNS was confirmed in actively stimulated groups with >30% decrease from baseline in bioassay levels of IL-1β, IL-6, and TNF-a at week 12.
Conclusion The novel MR device and stimulation was well tolerated independent of the two surgery-related events. MR associated stimulation reduced signs and symptoms of RA in a meaningful number of highly drug-refractory subjects. No clinical improvement was observed in the sham group. These initial pilot data support the use of the MR 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 and other chronic inflammatory diseases.
References  Andersson U, Tracey K, Annu. Rev. Immunol. 2012; 30:313.
 Koopman, F, et. al. PNAS. 2016; 113(29):8284
Disclosure of Interests Mark C. Genovese Grant/research support from: Sanofi/Genzyme, Genentech/Roche, RPharm, Consultant for: Sanofi/Genzyme, Genentech/Roche, RPharm, Norman Gaylis Grant/research support from: Multiple clinical research trials, BMS, AbbVie, GSK, Janssen, Amgen, Pfizer, Regeneron, UCB, Sanofi, SetPoint, ImmunPharma, Astra Zeneca, Sandoz, Novartis, Gilead, Consultant for: electroCore, David Sikes Grant/research support from: SetPoint MedicalPfizerActelionAbbvieEli Lilly, Alan Kivitz Shareholder of: Novartis, Consultant for: Abbvie, Janssen, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Boehringer Ingelheim, Sun Pharma Advanced Research, Flexion., Paid instructor for: Celgene, Horizon, Merck, Novartis, Pfizer, Genzyme, Sanofi, Regeneron, Speakers bureau: Celgene, Horizon, Merck and Genetech, Flexion, Diane M Horowitz Grant/research support from: SetPoint Medical, Charles Peterfy Shareholder of: Spire Sciences, Inc, Consultant for: AbbVie, Acerta, Amgen, AstraZeneca, Bristol-Myers Squibb, Centrexion, Daiichi Sankyu, Five Prime Therapeutics, Genentech, Hoffmann-La Roche, Janssen, Lilly USA, MedImmune, Merck, Novartis, Plexxikon, Pfizer, Sanofi, Salix-Santarus, Samsung, Employee of: Spire Sciences, Inc, Speakers bureau: Amgen, Yaakov Levine Shareholder of: SetPoint Medical, Employee of: SetPoint Medical, David Chernoff Shareholder of: SetPoint Medical, Consultant for: Crescendo BioScience, Employee of: SetPoint Medical
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