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

Levine, Yaakov A.; Faltys, Michael; Zitnik, Ralph

doi:10.1016/b978-0-12-805353-9.00126-1

Cited by 5 publications

(6 citation statements)

References 83 publications

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“…Higher pulse frequencies and widths may be associated with reductions in heart rate (Ardell et al 2017 ; Heck et al 2002 ). Minimizing these concerns, the device in this study for treating RA uses an extremely low duty cycle (60 s per day), a lower pulse frequency and pulse width of 10 Hz and 250 µs, respectively, that were well tolerated, safe, and did not demonstrate an impact on heart rate in several animal studies and previous human clinical studies of RA (Koopman et al 2016 ; Genovese et al 2020 ; Levine et al 2018a , b ).…”

Section: Discussionmentioning

confidence: 99%

Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study

Peterson,

Van Poppel,

Boling

et al. 2024

Bioelectron Med

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Background Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes persistent synovitis, bone damage, and progressive joint destruction. Neuroimmune modulation through electrical stimulation of the vagus nerve activates the inflammatory reflex and has been shown to inhibit the production and release of inflammatory cytokines and decrease clinical signs and symptoms in RA. The RESET-RA study was designed to determine the safety and efficacy of an active implantable device for treating RA. Methods The RESET-RA study is a randomized, double-blind, sham-controlled, multi-center, two-stage pivotal trial that enrolled patients with moderate-to-severe RA who were incomplete responders or intolerant to at least one biologic or targeted synthetic disease-modifying anti-rheumatic drug. A neuroimmune modulation device (SetPoint Medical, Valencia, CA) was implanted on the left cervical vagus nerve within the carotid sheath in all patients. Following post-surgical clearance, patients were randomly assigned (1:1) to active stimulation or non-active (control) stimulation for 1 min once per day. A predefined blinded interim analysis was performed in patients enrolled in the study’s initial stage (Stage 1) that included demographics, enrollment rates, device implantation rates, and safety of the surgical procedure, device, and stimulation over 12 weeks of treatment. Results Sixty patients were implanted during Stage 1 of the study. All device implant procedures were completed without intraoperative complications, infections, or surgical revisions. No unanticipated adverse events were reported during the perioperative period and at the end of 12 weeks of follow-up. No study discontinuations were due to adverse events, and no serious adverse events were related to the device or stimulation. Two serious adverse events were related to the implantation procedure: vocal cord paresis and prolonged hoarseness. These were reported in two patients and are known complications of surgical implantation procedures with vagus nerve stimulation devices. The adverse event of vocal cord paresis resolved after vocal cord augmentation injections with filler and speech therapy. The prolonged hoarseness had improved with speech therapy, but mild hoarseness persists. Conclusions The surgical procedures for implantation of the novel neuroimmune modulation device for the treatment of RA were safe, and the device and its use were well tolerated. Trial registration NCT04539964; August 31, 2020.

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Section: Discussionmentioning

confidence: 99%

Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study

Peterson,

Van Poppel,

Boling

et al. 2024

Bioelectron Med

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“…Numerous publications from laboratories worldwide have since provided additional details of the anatomic, cellular, and molecular pathways involved in the inflammatory reflex (Fig. 1), as well as supporting evidence of central control over aspects of inflammation through these neuroimmune pathways, reviewed elsewhere (Andersson and Tracey 2012b;Olofsson et al 2012b;Matteoli and Boeckxstaens 2013;Levine et al 2018a;Pavlov et al 2018). These abundant and varied reports have converged on two major findings.…”

Section: Inflammatory Reflexmentioning

confidence: 96%

“…Whereas the fundamental discoveries described a novel mechanism for central control over inflammation and immunity, they also established that the reflex could be harnessed by electrical stimulation of the vagus nerve to therapeutically modulate disease in animal models driven by inflammation. These included several rodent models of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) (Meregnani et al 2011;Sun et al 2013;Levine et al 2014aLevine et al , 2018a, both of which have a large unmet clinical need for new treatments that do not compromise host response to infection. The promise of developing a nonpharmacologic and potentially much safer treatment option for the millions of patients suffering from debilitating chronic conditions provided the impetus for translating these discoveries in animals to the clinical-dosing parameters and novel technologies currently under evaluation in a first-in-human bioelectronic therapy trial.…”

Section: Inflammatory Reflexmentioning

confidence: 99%

Harnessing the Inflammatory Reflex for the Treatment of Inflammation-Mediated Diseases

Levine

Faltys

Chernoff

2019

Cold Spring Harb Perspect Med

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“…There are many different animal models of IBD that recapitulate certain aspects of Crohn’s disease and ulcerative colitis, but none fully capture the complexity of either clinical disease ( Kiesler et al, 2001 ; Mizoguchi, 2012 ). An anti-inflammatory effect of vagus nerve stimulation (VNS) was observed in a number of studies of rodent colitis, such as DSS-, oxazolone-, and TNBS-colitis ( Ghia et al, 2006 ; Bai et al, 2007 ; Snoek et al, 2010 ; Meregnani et al, 2011 ; Meroni et al, 2021 ) and others previously reviewed ( Levine et al, 2018a ). However, experimental data on VNS effect on lesions in the small bowel are largely lacking.…”

Section: Introductionmentioning

confidence: 99%

Vagus Nerve Stimulation Reduces Indomethacin-Induced Small Bowel Inflammation

et al. 2022

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Crohn’s disease is a chronic, idiopathic condition characterized by intestinal inflammation and debilitating gastrointestinal symptomatology. Previous studies of inflammatory bowel disease (IBD), primarily in colitis, have shown reduced inflammation after electrical or pharmacological activation of the vagus nerve, but the scope and kinetics of this effect are incompletely understood. To investigate this, we studied the effect of electrical vagus nerve stimulation (VNS) in a rat model of indomethacin-induced small intestinal inflammation. 1 min of VNS significantly reduced small bowel total inflammatory lesion area [(mean ± SEM) sham: 124 ± 14 mm2, VNS: 62 ± 14 mm2, p = 0.002], intestinal peroxidation and chlorination rates, and intestinal and systemic pro-inflammatory cytokine levels as compared with sham-treated animals after 24 h following indomethacin administration. It was not known whether this observed reduction of inflammation after VNS in intestinal inflammation was mediated by direct innervation of the gut or if the signals are relayed through the spleen. To investigate this, we studied the VNS effect on the small bowel lesions of splenectomized rats and splenic nerve stimulation (SNS) in intact rats. We observed that VNS reduced small bowel inflammation also in splenectomized rats but SNS alone failed to significantly reduce small bowel lesion area. Interestingly, VNS significantly reduced small bowel lesion area for 48 h when indomethacin administration was delayed. Thus, 1 min of electrical activation of the vagus nerve reduced indomethacin-induced intestinal lesion area by a spleen-independent mechanism. The surprisingly long-lasting and spleen-independent effect of VNS on the intestinal response to indomethacin challenge has important implications on our understanding of neural control of intestinal inflammation and its potential translation to improved therapies for IBD.

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

Cited by 5 publications

References 83 publications

Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study

Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study

Harnessing the Inflammatory Reflex for the Treatment of Inflammation-Mediated Diseases

Vagus Nerve Stimulation Reduces Indomethacin-Induced Small Bowel Inflammation

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