Michael A. Faltys

Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis

Significance Rheumatoid arthritis (RA) is a chronic, prevalent, and disabling autoimmune disease that occurs when inflammation damages joints. Recent advances in neuroscience and immunology have mapped neural circuits that regulate the onset and resolution of inflammation. In one circuit, termed “the inflammatory reflex,” action potentials transmitted in the vagus nerve inhibit the production of tumor necrosis factor (TNF), an inflammatory molecule that is a major therapeutic target in RA. Although studied in animal models of arthritis and other inflammatory diseases, whether electrical stimulation of the vagus nerve can inhibit TNF production in humans has remained unknown. The positive mechanistic results reported here extend the preclinical data to the clinic and reveal that vagus nerve stimulation inhibits TNF and attenuates disease severity in RA patients. Rheumatoid arthritis (RA) is a heterogeneous, prevalent, chronic autoimmune disease characterized by painful swollen joints and significant disabilities. Symptomatic relief can be achieved in up to 50% of patients using biological agents that inhibit tumor necrosis factor (TNF) or other mechanisms of action, but there are no universally effective therapies. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in animal models. One well-characterized cytokine-inhibiting mechanism, termed the “inflammatory reflex,” is dependent upon vagus nerve signals that inhibit cytokine production and attenuate experimental arthritis severity in mice and rats. It previously was unknown whether directly stimulating the inflammatory reflex in humans inhibits TNF production. Here we show that an implantable vagus nerve-stimulating device in epilepsy patients inhibits peripheral blood production of TNF, IL-1β, and IL-6. Vagus nerve stimulation (up to four times daily) in RA patients significantly inhibited TNF production for up to 84 d. Moreover, RA disease severity, as measured by standardized clinical composite scores, improved significantly. Together, these results establish that vagus nerve stimulation targeting the inflammatory reflex modulates TNF production and reduces inflammation in humans. These findings suggest that it is possible to use mechanism-based neuromodulating devices in the experimental therapy of RA and possibly other autoimmune and autoinflammatory diseases.

Neurostimulation of the Cholinergic Antiinflammatory Pathway in Rheumatoid Arthritis and Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) cause significant morbidity and mortality. Despite significant therapeutic advances, the medical need for patients with these disorders remains high. An important neural-immune regulatory mechanism termed the “inflammatory reflex,” and its efferent arm, the “cholinergic antiinflammatory pathway” regulate innate and adaptive immunity. An emerging body of evidence indicates that stimulation of this pathway with implantable medical devices is a feasible therapeutic approach in disorders of dysregulated inflammation. Herein we describe the underlying biology and the preclinical experiments done in standard animal models that provided the rationale for testing in clinical trials. The preclinical development approach comprised elements of classic drug and medical device development, yet had unique features and challenges. “Bioelectronic medicines” having ideal characteristics of both drugs and medical devices hold great conceptual promise for treatment of systemic diseases in the future. However studies being done today will help determine whether neurostimulation of the cholinergic antiinflammatory pathway (NCAP) has the potential in the nearer term to fulfill the needs of patients, caregivers and payers for an additional potential treatment option for inflammatory disorders, and might thus become one of the first feasible examples of a bioelectronic medicine.

VNS for Treatment of Inflammatory Joint Diseases

The cholinergic anti-inflammatory pathway regulates innate and adaptive immunity during normal physiological function, and activation of the pathway by electrical stimulation of the vagus nerve (VNS) can reduce pathological levels of inflammation in animal models of autoimmune disorders. A proof-of-concept human study of VNS in rheumatoid arthritis (RA) has shown that VNS can ameliorate inflammation in humans. Future clinical studies will employ a novel, application-specific investigational stimulation system. In concept, this system is capable of being evolved to function in a closed-loop manner, adjusting therapy delivery to the patient’s level of disease activity.

Activation of the Inflammatory Reflex in Rheumatoid Arthritis and Inflammatory Bowel Disease; Preclinical Evidence

Abstract The “inflammatory reflex” is an important neural-immune mechanism that can be activated by electrical vagus nerve stimulation (VNS) to drive pleiotropic antiinflammatory effects in the periphery. It has therefore been posited that chronic inflammatory diseases, such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), may be treated by targeted neuromodulation of the vagus nerve. Here we present wide preclinical evidence of ameliorating inflammatory disease through activation of the inflammatory reflex, providing the rationale and framework in which to study VNS as a putative treatment in clinical IBD and RA.

Bioelectronic Therapy for the Treatment of Rheumatoid Arthritis and Inflammatory Bowel Disease

Abstract Inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) cause significant morbidity and mortality despite significant advances in treatment. A large body of preclinical work has shown that vagus nerve stimulation (VNS) can activate an important neural-immune mechanism, termed the “inflammatory reflex,” which regulates innate and adaptive immunity. Here we present the first clinical evidence of ameliorating IBD and RA with a bioelectronic therapy using VNS as well as describe the development of application-specific neuromodulation device for future studies.