Abstract / Summary
Abstract Background: Preclinical studies have demonstrated that splenic nerve stimulation (SpNS) can effectively modulate immune responses and reduce inflammation. This open-label single arm study was conducted to evaluate the safety and feasibility of SpNS with an active implantable neuromodulation device in patients with rheumatoid arthritis (RA).
Methods: RA patients who had inadequate responses to two or more biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/ts)DMARDS were laparoscopically implanted with the device. Prior to implantation, a washout of b/tsDMARDs was performed, but participants were allowed to stay on a stable dose of conventional synthetic (cs)DMARD or low dose oral prednisone. After a recovery for a period of approximately 28 days, SpNS was initiated for 12 weeks, followed by continued stimulation during the long-term follow-up period with or without a b/tsDMARD. The primary outcome measures were the safety and tolerability of the device, its implantation, and chronic SpNS. Secondary and exploratory outcome measures included changes in disease activity and in blood biomarkers. In addition, stimulation dose ranging was evaluated.
Results: Five patients were enrolled in the study. The device was successfully implanted in all participants and subsequently programmed to deliver SpNS. No serious or unanticipated adverse effects related to the implantation, stimulation or device were observed. In one participant, the stimulation was stopped after 12 weeks due to a Device Deficiency (DD). Stimulation was generally well tolerated in all participants, when delivered 6 or 12 times per day, as well as during day and night. One participant demonstrated a marked reduction of DAS28-CRP of -2.34 at week 12, which was accompanied by a drug free remission of a pre-existing refractory complex regional pain syndrome type 1 (CRPS-1). In this participant a reduction in pro-inflammatory cytokines was observed, especially IL-17A. This was accompanied by a reduced STAT3 phosphorylation in Th17 cells.
Conclusion: This first single arm open-label clinical trial evaluating a new investigational implantable neuromodulation device demonstrated that implantation and SpNS was feasible, demonstrated a favourable safety profile, and was well tolerated. Additionally, a reduction in RA disease activity was observed in one participant receiving stimulation in combination with a csDMARD for more than 1.5 years and this was accompanied by a remarkable reduction in pain caused by CRPS-1. In addition, one participant receiving a combination of a tsDMARD and stimulation in Period 2 exhibited clinically meaningful reductions in disease activity. Together, these findings warrant future studies in larger patient groups to determine if SpNS is a valuable novel treatment option for patients with RA. Trial registration Clinicaltrial.gov NCT04955899, 5th of July 2021