Background/Purpose:

Rheumatoid arthritis (RA) is a debilitating chronic disease with an unmet need for additional therapeutic approaches. Bioelectronic therapy (BET), such as electrical neurostimulation of the vagus nerve to activate innate protective neuro-immune reflexes, represents a novel means of treating diseases characterized by systemic inflammation. We performed a proof-of-concept study in RA patients using a marketed vagus nerve stimulation device at very low duty cycles (1-4 min/day), showing reduction of clinical disease activity, concomitant with reductions in TNF-α and IL-6 (PNAS 2016;113:8284). We have developed a novel advanced generation neurostimulation device, the MicroRegulator System, which is being evaluated in a first-in-man clinical study.

Methods:

The MicroRegulator System is unique in that it is implanted directly on the vagus nerve as a single unit that contains an application specific integrated circuit (ASIC), pulse generator with a wireless rechargeable battery, as well as a self-contained nerve-encapsulating cuff and electrodes that function without vagus nerve lead wires (Figure 1). Low power requirements allow for miniaturization of the device (< 2 cc). External components include an intermittently worn flexible collar that generates a radio frequency field for recharging and telemetry, as well as an iPad-based control device programming application.

Results:

The first-in-man study is a USA-based multi-centered double-blind trial, designed to look at safety and efficacy of the implanted MR system in refractory RA patients that have insufficient response to ≥ 2 biologic or targeted synthetic DMARDs of ≥ 2 modes of action. This study is unique in its use of a neurosurgical sub-investigator paired with the rheumatologist to manage the first weeks of the study period. Implanted subjects, washed off biologics and on stable background of methotrexate, are randomized to 1 min of sham, QD, or QID stimulations for 12 weeks. Efficacy outcomes include standard RA clinical disease measures as well as quantitative MRI joint scoring, validated RA-specific biomarker panels, autonomic balance measurements and immune cell bioassays.

Conclusion:

A novel neurostimulation device has been developed and deployed in a first-in-man clinical study.  BET, a non-pharmacological intervention, will potentially give rheumatologists a novel alternative means to treat RA, including those patients who have failed conventional treatments.

Figure 1. Schematic Representation of MicroRegulator System