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<h2>Abstract</h2><h3>Background:</h3> Activation of vagus nerve-mediated neuroimmune reflex by electrical stimulation can downregulate multiple inflammatory cytokines, providing a novel treatment approach for managing autoimmune conditions like Rheumatoid Arthritis (RA).[1,2] Vagus nerve stimulation also increases specialized pro-resolving mediators to promote the resolution of inflammation by multiple mechanisms, including increasing clearance of cellular debris and mineralization of bone. Activating this reflex with a 60-second electrical stimulation inhibits intracellular pathways, resulting in suppression of multiple pro-inflammatory cytokines by 30-70%, with sustained reduction for up to 24-48 hours post-stimulation.[2,3] The implantable neurostimulator designed to activate these neuroimmune pathways is placed on the left cervical vagus nerve during an outpatient procedure and programmed to deliver automatic stimulation for one minute, daily. <h3>Objectives:</h3> The objective of the RESET-RA study is to assess the safety and efficacy of an implantable cervical neurostimulation device for treatment of adults with moderately to severely active RA with inadequate response or intolerance to at least 1 prior biological DMARD (bDMARD) or targeted-synthetic DMARD (tsDMARD). <h3>Methods:</h3> This randomized, double-blind, sham-controlled study enrolled 242 patients at 41 US sites. All patients remained on stable background conventional DMARDs and were washed off their b/tsDMARD prior to implant procedure. Patients were randomized 1:1 to active (treatment) or non-active (control) stimulation. The primary endpoint was the proportion of patients achieving the American College of Rheumatology 20% response (ACR20) at Week 12 compared to baseline on the day of informed consent, prior to device implantation. Secondary and exploratory endpoints included DAS28-CRP good/moderate EULAR response rate, low disease activity (LDA) and remission rates, and proportion of subjects with progression in erosions (>0.5 increase in erosion score) as measured by MRI (RAMRIS). Patients were imputed as non-responders if rescued with additional RA treatment prior to Week 12 or if missing ACR response data at Week 12. After Week 12, the study became open-label, with one-way crossover of control to active stimulation and efficacy assessments repeated at Week 24. Augmentation of RA treatment was allowed after Week 12 at the investigator's discretion. <h3>Results:</h3> Baseline demographics and characteristics were well-balanced and representative of the RA population in the US, with mean age 56 years, 86% female, RA duration 12 years, BMI 30, 15 tender joints, and 10 swollen joints (28 joint count). On average, patients had inadequate response or intolerance to 2.6 prior b/tsDMARDs before entering the study, with 40% having failed 1 prior, 21% with 2 prior, and 39% with ≥3 prior b/tsDMARDs. 53% were seropositive (RF and/or anti-CCP) and the mean hsCRP was 8.2mg/L. ACR20 response at Week 12 showed a statistically significant difference between treatment and control groups (p-value=0.0209, 95% CI 0.6 to 23.1). At Week 24, ACR20 response increased after crossover to 51.5% in treatment and 53.1% in control to crossover group. ACR20 response at Week 12 for patients with 1 prior bDMARD exposure (prespecified analysis) was higher, with 45.5% for treatment and 19.0% for control (p-value=0.0037, 95% CI 8.6 to 44.3) (Table 1). All secondary and several exploratory endpoints trended in favor of the treatment group. Proportion of patients with DAS28-CRP moderate to good EULAR response at Week 12 was statistically significant and higher for the treatment group at 60.7% compared to control group at 41.7% (p-value=0.0012, 95% CI 7.3 to 31.7). DAS28-CRP LDA/remission at Week 12 also showed a statistically significant difference between treatment and control groups and improved further through Week 24. The proportion of erosion progressors by RAMRIS was lower in the treatment vs. control group. At Week 24, 81% of patients remained free of added high-dose steroids or b/tsDMARDs. Overall, the implant procedure and stimulation were safe and well-tolerated both acutely and through long-term follow-up. Related serious adverse event (SAE)-rate was low (1.7%) (Table 2). AE with the highest frequency related to treatment was mild to moderate hoarseness or vocal cord dysfunction. There were no deaths in the study. <h3>Conclusion:</h3> Neuroimmune modulation using vagus nerve stimulation represents a novel potential treatment modality for patients with RA who have failed at least one bDMARD or tsDMARD. The RESET-RA study met its primary endpoint with significant improvement in actively stimulated patients. The implant procedure, device, and stimulation were well-tolerated with low and anticipated rates of adverse events, and notably, no related cases of serious infections, major cardiovascular events, or malignancies. Activating neural pathways with this implantable neurostimulator can regulate inflammation and potentially provide an alternative to currently available pharmaceutical RA therapies. (ClinicalTrials.gov, NCT04539964). <h3>REFERENCES:</h3> [1] Lancet Rheumatol. 2020; 2:e527-538. [2] PNAS 2016; 113:8284-89. [3] Immunity. 2017; 46(1): 92–105. <h3>Acknowledgements:</h3> <b>NIL</b>. <h3>Disclosure of Interests:</h3> John Tesser AbbVie/Abbott, AstraZeneca, Bristol-Myers Squibb (BMS), Eli Lilly, GSK, Janseen, Pfizer, UCB, AbbVie/Abbott, AstraZeneca, Behringer-Ingelhaim, Eli Lilly, GSK, Janssen, Novartis, SetPoint, UCB, AstraZeneca, Boehringer-Ingelhaim, Bristol-Myers Squibb (BMS), Celgene, Eli Lilly, Genentech, Gilead, GSK, IGMBiosciences, Janssen, Merck,MSD, Novartis, Pfizer, Roche, SetPoimt, UCB, Angela Crowley Abbvie/Abbott, Amgen, GSK, Janssen, UCB, Kiowa Kirin, Abbvie/Abbott, Amgen, GSK, Janssen, Novartis, UCB, SetPoint, Abbvie/Abbott, Amgen, Eli Lilly, GSK, Janssen, Novartis, UCB, Pendleton Wickersham AbbVie, Amgen, Astrazeneca, Aurinia, Eli Lilly, Janssen, Novartis, AbbVie, AstraZeneca, Eli Lilly, Janssen, UCB, AbbVie, Horizon, LG Chem, Paraxel, SetPoint, SunPharma, Joshua June Janssen, Jane Box SetPoint Medical, Guillermo Valenzuela AbbVie, Amgen, AstraZeneca, Celgene, GSK, Janssen, Eli Lilly, Malinkrodt, Radius, Sanofi, Taked, UCB, GSK, Nikila Kumar: None declared, Norman Gaylis: None declared, Gordon Lam AbbVie/Abbott, Janssen, Pfizer, Sanofi, UCB, AbbVie/Abbott, Janssen, Sanofi, SetPoint Medical, UCB, David Ridley: None declared, Gineth Pinto-Patarroyo: None declared, David Chernoff SetPoint Medical, SetPoint Medical. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.