Neurostimulation to Target the Inflammatory Reflex in Rheumatoid Arthritis

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Investigators tested whether direct stimulation of the inflammatory reflex would inhibit TNF production in humans.
Investigators tested whether direct stimulation of the inflammatory reflex would inhibit TNF production in humans.

While anti-inflammatory therapies provide symptomatic relief in many patients with rheumatoid arthritis (RA), they are ineffective in subsets of patients. In those individuals, there is a clear need for alternative treatments to stem the poor health outcomes, impaired quality of life, and reduced lifespan associated with the chronic disease. Neurostimulation is one promising approach that is supported by recent research.

Previously, animal studies found that reflex neural circuits inhibit cytokine production and reduce inflammation, including the inflammatory reflex, which has been shown to inhibit cytokine production via vagus nerve stimulation in experimental models of arthritis.1  Based on these findings, researchers at SetPoint Medical Corporation and several international universities decided to test whether direct stimulation of the inflammatory reflex would inhibit tumor necrosis factor (TNF) production in humans.2

First, they implanted a vagus nerve-stimulating device in 7 patients with epilepsy and no history of inflammatory or autoimmune disease. Electrical pulses were then transmitted to the vagus nerve while patients received general anesthesia. This significantly inhibited endotoxin-induced peripheral blood production of TNF, interleukin (IL)-1β, and IL-6, which could not be explained by a placebo effect since the patients were unconscious.

Next, they tested the device in 2 cohorts of RA patients with active disease despite at least 3 months of methotrexate therapy. Cohort I consisted of 7 patients who had never been treated with a TNF antagonist or had not experienced response to such treatment due to drug toxicity. Cohort II consisted of 10 patients for whom treatment with methotrexate or 2 different types of biological agents yielded no response.

Vagus nerve stimulation up to 4 times per day led to significant inhibition of TNF production for up to 84 days; disease severity also improved significantly. No serious adverse events, infections, or deaths were reported in either cohort.

During the 84-day period, the device was turned off on day 42 and restarted on day 56. There was a significant increase in TNF production and disease activity during that interval, followed by a significant reduction in both parameters after the device was turned on again (1776 ±342 pg/mL on day 42 vs 2617 ±342 pg/mL on day 56 and 1975 ±407 pg/mL on day 84, P <.01 for both).

“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,” wrote the investigators. “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,” they concluded. An extension study of the participants is ongoing through May 2018 and aims to assess the long-term efficacy and safety of the approach.3

The researchers in a new study published in Scientific Reports explored a method of further refining the technique in rats by selectively activating the efferent vs afferent pathway.4 Though this approach is ideal for anti-inflammatory therapy, current techniques activate both pathways. 

“Efferent activation of the cervical vagus nerve (cVN) dampens systemic inflammatory processes, potentially modulating a wide range of inflammatory pathological conditions,” they explained in the article. 

Afferent cVN activation, however, has counterproductive effects: It “amplifies systemic inflammatory processes, leading to activation of the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic nervous system through the greater splanchnic nerve (GSN), and elevation of pro-inflammatory cytokines.”

To achieve selective activation of the efferent pathways while blocking the afferent pathways, the researchers combined cVN stimulation with kilohertz electrical stimulation (KES), which their previous research found to provide a “virtual vagotomy” in blocking nerve activity in the cVNS.5 The results of the present study show that pairing the techniques increased the anti-inflammatory effects of cVN stimulation.

“Our results suggest a way to optimize clinical work on vagus nerve stimulation for reducing systemic inflammation,” said Yogi A. Patel, from the department of bioengineering at the Georgia Institute of Technology in Atlanta. “Most importantly, they suggest that stimulating both the efferent and afferent pathways may lead to mixed activation of proinflammatory and anti-inflammatory pathways, which may not be ideal for clinical applications,” he told Rheumatology Advisor.

SetPoint also recently announced positive results in a trial of vagus nerve stimulation in patients with Crohn's disease, and similar devices made by other companies have demonstrated promising results in treating conditions such as hypertension and heart failure.6

Additional, larger trials will be needed before SetPoint's device for RA could be released to market, and it is also unclear when the use of KES might be available. This would “require additional work and evaluation to determine safety and efficacy in studies lasting weeks to months,” said Mr Patel. “This makes it difficult to state an anticipated timeline to market.”

These recent findings can help guide future investigations in the use of “bioelectronic medicine” in diseases that are currently treated with medications.

Summary and Clinical Applicability

Vagus nerve stimulation has shown promise in animal and human studies in reducing inflammation and disease severity in rheumatoid arthritis. 

Limitations and Disclosures

Additional human trials and larger studies are needed.

Several authors of the SetPoint study are employed by the company.

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References

  1. Levine YA, Koopman FA, Faltys M, et al. Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis. PLoS One. 2014;9(8):e104530.

  2. Koopman FA, Chavan SS, Miliko S, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proceed Natl Acad Sci. 2016;113(29):8284-8289.

  3. ClinicalTrials.gov. Long term extension study for SPM-005 participants. www.clinicaltrials.gov/ct2/show/NCT01552538?term=NCT01552538&rank=1. Accessed January 19, 2017.

  4. Patel YA, Saxena T, Bellamkonda RV, Butera RJ. Kilohertz frequency nerve block enhances anti-inflammatory effects of vagus nerve stimulation. Sci Rep. 2017;7:39810. 

  5. Patel YA, Butera RJ. Differential fiber-specific block of nerve conduction in mammalian peripheral nerves using kilohertz electrical stimulation. J Neurophysiol. 2015;113(10):3923-3929. 

  6. Med Device Online. Electronic Implant Could Ease Hypertension; Nerve Stimulation in Neck May Reduce Heart Failure Symptoms.  www.meddeviceonline.com/doc/electronic-implant-could-ease-hypertension-0001 and www.meddeviceonline.com/doc/nerve-stimulation-in-neck-may-reduce-heart-failure-symptoms-0001.  Accessed January 19, 2017.

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