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 Table of Contents  
Year : 2020  |  Volume : 15  |  Issue : 4  |  Page : 323-332

Role of neuroimmunomodulation by vagus nerve stimulation in rheumatoid arthritis: Are we heading towards a drug-free era?

Department of Rheumatology, Max Super Speciality Hospital, New Delhi, India

Date of Submission15-Apr-2020
Date of Acceptance07-Jul-2020
Date of Web Publication18-Dec-2020

Correspondence Address:
Dr. Prasan Deep Rath
Department of Rheumatology, Max Super Speciality Hospital, Ground Floor West Block, 1,2 Press Enclave Marg, Saket Institutional Area, Saket, New Delhi - 110 017
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_92_20

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Progressive clinical research in the field of neuroimmunomodulation has formed a base for the development of a new therapeutic paradigm for various inflammatory diseases, including rheumatoid arthritis (RA). One of the most common mechanisms is electrical vagus nerve stimulation of inflammation. The role of the vagal nerves in activation of various immune responses through preclinical and clinical evidence has established its role in assisting the control of inflammation and improving survival in the infectious and inflammatory disorders through efferent as well as afferent vagal pathways that regulate the peripheral inflammation via the central nervous system. Another mechanism is the neural inflammatory reflex that regulates innate and adaptive immune responses and also inhibits the production of a vital inflammatory therapeutic target molecule, known as tumor necrosis factor, for RA. This review discusses the multifactorial and multidimensional interactions between neurons and immune cells, the mechanisms of the nervous system which are responsible for the regulation of inflammation, the impact of cholinergic pathways on inflammation, and the evidence supporting the role of various bioelectronic devices in vagus nerve stimulation.

Keywords: Inflammatory disorders, neuroimmunomodulation, rheumatoid arthritis

How to cite this article:
Rath PD, Pandey S, Bisaralli R. Role of neuroimmunomodulation by vagus nerve stimulation in rheumatoid arthritis: Are we heading towards a drug-free era?. Indian J Rheumatol 2020;15:323-32

How to cite this URL:
Rath PD, Pandey S, Bisaralli R. Role of neuroimmunomodulation by vagus nerve stimulation in rheumatoid arthritis: Are we heading towards a drug-free era?. Indian J Rheumatol [serial online] 2020 [cited 2022 Jun 29];15:323-32. Available from:

  Overview of rheumatoid arthritis: what are the major hurdles in successful management of RA? Top

Rheumatoid arthritis (RA) is a chronic autoimmune condition that leads to inflammation of the joints and an increase in the proliferation of synovial tissues and subsequent erosion of bone and damage to cartilage.[1] It affects approximately 1% of the population worldwide. The prevalence of RA in India ranges from 0.3% to 0.75%.[2] It is a systemic disease that contributes to significant morbidity and mortality. Women were two times higher risk of developing RA than men. People who have family history and habit of smoking are more prone to develop RA.

Currently, available clinical treatments are categorized as conventional synthetic disease modifying anti-rheumatic drugs (DMARDs) such as methotrexate, leflunomide, and sulfasalazine; targeted synthetic DMARDs such as tofacitinib and baricitinib; and biologic DMARDs. Despite increasing options, early diagnosis and intervention remains the key to reduce joint deformities and disability. However currently available treatment options are associated with an increased risk of infections, malignancies and are limited by their tolerability and side effects. Added to this is an inherent fear of taking any medicine which is common in our society.[3] It is difficult in maintaining long-term patient compliance, leading to discontinuation and shifting the patient to alternative medicine. In India, other factors including nonavailability of expert advice and supervision also impact the use of current treatment strategies.[2] Vagal nerve stimulation (VNS) has gained attention as a novel nonpharmacological therapy as it offers a promising alternative to conventional therapy; it helps to control inflammation and prevent joint damage by modulating the local neuroimmunomodulation pathway.[4]

  Cross-Talk between the Nervous System and the Immune System Top

Since the last few decades, interactions between neurons and immune cells have received attention due to their multifactorial and multidimensional roles in various physiological mechanisms. Interaction between myeloid cells and neurons has been shown to play a vital role in the central nervous system (CNS) homeostasis along with other pathophysiological states, including autoimmunity, neurodegeneration, infection, and mechanical injury.[5] Regulation of inflammatory processes and immune surveillance of the CNS by meningeal lymphatic vessels make them a potential target for therapeutic intervention.[6] Any damage to CNS leads to the development of astrocyte-protective and -harmful phenotypes. Further, infections in the CNS are caused due to interactions between neuroprotective and damaging innate and adaptive immune responses. Evidence also suggests neuroimmune communication in the gut which responses to a wide array of dietary products and pathogens. Studies related to the association of motor and sensory neurons with the regulation of immune responses are currently at the forefront as promising observations indicate a substantial potential of afferent and efferent neurons in the modulation of immune activities and inflammation.[7]

  Neuroimmune Axis Top

Neuroendocrine axis

The relationship of the immune system with nervous and endocrine systems is a two-decade-old concept that is being researched to date as it shows promising potential for targeting in the management of various autoimmune diseases. Various molecules that aid in maintaining a balance between these three systems through the communication of neurons with immune systems include cytokines, neurotransmitters, neurosteroids, neuropeptides, cyclic nucleotides, and calcium and protein kinases. Adrenocorticotropic hormone is stimulated by the inflammatory cytokines, which leads to the secretion of cortisol which inhibiting proinflammatory cytokines. Impairment of regulation of any of these systems has severe consequences due to aberrant immune, endocrine, and neurological responses.[8]

  Various Mechanisms of the Nervous System Responsible for the Regulation of Inflammation Top

Vagus nerve stimulation is the most frequently used term when we think of neuroimmunomodulation of inflammation. Intriguing observations from various studies have formed a fundamental building block for the role of the vagal nerves in the activation of various immune responses through preclinical and clinical evidence. VNS assists to control inflammation and improve survival in the experimental models of infectious and inflammatory disorders.[9],[10],[11],[12] It is a noteworthy status quo that efferent as well as afferent vagal pathways regulate the peripheral inflammation via the CNS. Another mechanism that has been proved to regulate innate and adaptive immune responses is the neural inflammatory reflex, signals traversing through vagus nerve which inhibits tumor necrosis factor (TNF) production by monocyte and macrophage.[10]

[TAG:2]Inflammatory Reflex [/TAG:2]

The inflammatory reflex [Figure 1]is a prototypical neural reflex circuit, which is composed of afferent and efferent neurons that are traversing through the vagus nerve. It helps in maintaining balance in immune response and modulates both innate and adaptive immunity. It regulates both inflammation onset and resolution. Efferent arc is composed of “cholinergic anti-inflammatory pathway” (CAP), while the mechanism for afferent pathway is still unknown.[13] Progressive clinical research has formed a base for the development of a new therapeutic paradigm; peripheral nervous system and CNS play a vital role in the downregulation of mediators of inflammation through CAP. In the CAP signaling pathway, brainstem nuclei of vagus nerve prime the signals to pass via efferent vagus nerves to the celiac ganglion; from here, neural cells project axons to the splenic nerve. Vagal nerve fibers are parasympathetic junctions that communicate with the sympathetic nervous system.[14] Splenic nerves (fibers originated in celiac ganglion) have norepinephrine as a primary neurotransmitter.[15] This stimulates acetylcholine discharge by splenic lymphocytes.[16]
Figure 1: Prototypical neural reflex circuit in a schematic diagram. Afferent and efferent arc showing cholinergic anti-inflammatory pathway which is mediated by dorsal motor nucleus of vagus through celiac ganglion and splenic nerve (explained in Figure 2), the acetyl choline released by T-lymphocytes act on the macrophages and dendritic cells and downregulates the inflammatory cytokines, thereby exerting anti-inflammatory activity. a-7nAChR: a-7 nicotinic acetylcholine receptors

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[TAG:2]Neuroimmunology Pathway in Inflammation [/TAG:2]

In rat T-cells, it has been found thatAcetylcholine (ACH) is three times more than B-cells, and CD 4(+) has more ACH than CD8(+) cells.[17] In addition to ACH-producing lymphocytes, dendritic cells, and macrophages express choline acetyl transferase, which synthesizes ACH.[18],[19],[20] Norepinephrine acts on beta-2 adrenoreceptors on CD4(+) T-cells which synthesizes and releases ACH. It has been shown that in mice devoid of functional T-cells, VNS is unable to downregulate TNFα, suggesting impairment in CAP.[16] However, choline acetyl transferase (ChAT) + B-cells only limit local neutrophil infiltration[18] [Figure 2].
Figure 2: Acetylcholine release from splenic lymphocytes, dorsal motor nucleus of vagus through celiac ganglion and splenic nerve that release norepinephrine that acts on splenic T- and B-cells via B2 adrenergic receptor and stimulates choline acetyl transferase that releases acetyl choline for its action on macrophages and dendritic cells; however, rat models have demonstrated that splenic CD4 cells secrete 4 times more Ach owing to its higher activity of choline acetyl transferase enzyme, B-lymphocytes secrete low levels of acetyl choline that acts locally to inhibit neutrophil infiltration. (A: AcH)

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It has been shown in studies that in splenic nephrectomized or splenectomized animals, VNS is unable to inhibit TNFα production in response to endotoxemia. Hence, proven spleen, splenic nerve, and vagus nerve are important to CAP.[14]

This acetylcholine signals splenic macrophages by binding the alpha-7 nicotinic acetylcholine receptor (α7nAChR).[14] It has been shown in studies that α7nAChRs are expressed on the endothelial cells too.[21],[22] When endothelial cells are stimulated with cholinergic agonist, this in turn reduces intercellular adhesion molecule 1 expression and interleukin 6 (IL-6)-mediated monocyte chemoattractant protein 1 release.[23] Janus kinase 2 (JAK2) signal transducer and activator of transcription 3 pathway is also activated by cholinergic agonist.[24],[25],[26]

Local proinflammatory signals trigger Acetylcholine release by T cell that binds on macrophages thereby reducing cytokine release. This inflammatory reflex can be used as a potential therapeutic target to ameliorate inflammation by electrical neurostimulation of the vagus nerve; this in turn will help regulate inflammatory response to injury and infection.[9],[13]

A study by Levine et al. was the first study to demonstrate that CAP stimulation leads to a decrease in the severity of arthritis. This evidence can be used in human inflammatory disorders.[12] Prior studies have also revealed that increasing the inflammatory reflex signaling using electrical stimulation of the vagus nerve significantly reduces cytokine production and attenuates disease severity in the experimental models of endotoxemia, sepsis, and colitis and other preclinical animal models of inflammatory syndromes.[9],[13],[14],[27],[28]

The inflammatory reflex mechanisms also inhibit the production of a vital inflammatory therapeutic target molecule, known as TNF, for RA. Despite promising observations from several animal studies supporting electrical stimulation of the vagus nerve leading to TNF inhibition, it is yet unclear with very few human studies corroborating the same. Koopman et al. were the first to assess the effect of vagus nerve stimulation in the inhibition of TNF production and reduction in disease severity in RA patients. They revealed the positive mechanistic results that indicate the role of vagus nerve stimulation in the attenuation of disease severity in RA patients.[10]

  How Cholinergic Pathways, Both Neural and Nonneural, May Impact on Inflammation and Specifically Arthritis? Top

Novel nonpharmacological strategies for control of inflammation in RA are being researched in the field of CAP. The effect of the vagus nerve on arthritis is always indirect because there is no direct connection between the vagal nerve and joints. Earlier, it was postulated that loss of control by the “cholinergic anti-inflammatory pathway” plays a role in maintaining arthritis. However, few studies could not prove any effect of unilateral vagotomy on disease severity.[29],[30] Contrary to these findings, nicotinic receptors independent of the vagus were seen to contribute to the aggravation of inflammation in collagen-induced arthritis mice deficient of α7nAChR.[31]

Preclinical studies have reported that electrical vagus nerve stimulation has the capacity to inhibit cytokine production through ligand binding to α7nAChR. Therefore, electrical vagus nerve stimulation can aid in the reduction of inflammation in the joints and have the potential to cause experimental models of RA that have shown that electrical vagus nerve stimulation can aid in the reduction of inflammation in joints.[4]

  Treatment Based on Neural Reflex Control of Inflammation by Applying Bioelectronic Medicine in Chronic Inflammatory Diseases Top

VNS potentially maintains the balance between reduced parasympathetic and increased sympathetic activity seen in chronic inflammatory diseases. Assessment of electrical vagus nerve stimulation in various clinical trials for determining the alternative therapeutic strategy in RA and Crohn's disease is underway.[10],[32],[33] Primary results support and demonstrate positive results that improve clinical symptoms with the reduction of inflammation and homeostasis of inflammatory pathways in RA.[10],[34] In a study by Bonaz et al., all patients showed improvement in Crohn's diseases with endoscopic remission at 6 months, reduced abdominal pain, and no device-related severe adverse events.[32] In another trial, the vagus nerve-stimulated patients demonstrated clinical improvement in an interim analysis.[33]

Overall, these reports indicate that electrical neurostimulation of the vagus nerve in an appropriate manner with an implantable device is emerging as a novel and potentially feasible means of treating diseases characterized by excessive and dysregulated inflammation. Vagus nerve stimulation delivered using an implantable device is a potential therapeutic intervention in various chronic inflammatory diseases. However, further clinical trials are necessary to evaluate long-term safety and efficacy of vagus nerve stimulation in suppressing inflammation through different mechanisms.

In chronic inflammatory disease, the symptoms can aggravate or be mild over the course of diseases with no particular pattern. Hence, it is vital to monitor these sudden changes in symptom occurrence in the individual and subsequent optimizing of dosage to prevent further disease progression with keeping side effects at the minimal level. Taking into consideration the limitations of current technologies to adapt to variations in disease severity, the development of novel technologies is a necessity. Recent reports from two studies revealed that specific electrical activity in the vagus nerve can be simplified to provide information on the tissue levels of inflammatory cytokines and even distinguish between different cytokines.[35],[36] Therefore, real-time monitoring of disease through advancement in the already available technologies that will assist in providing continuous information to patients, physicians, as well as devices, about the need for anti-inflammatory therapy, would significantly benefit in paving a new pathway toward better individualization of the treatment of inflammatory diseases.[37]

[TAG:2]Types of Vagus Nerve Stimulation Devices [/TAG:2]

  • Food and Drug Administration (FDA) has approved various invasive devices [Figure 3] such as Aspire VNS[38],[39] and Sentiva VNS,[40] while other devices such as ViVistim system,[41],[42] CardioFit VNS,[43],[44],[45] SET point medical,[46] and Miniaturized neurostimulator–Microregulator (MR)[47] are under investigation for stroke rehabilitation, chronic heart failure, and RA
  • Non-invasive devices such as transcutaneous VNS[48],[49],[50] and repeated vagus nerve stimulation[51],[52],[53] are approved for epilepsy and cluster headaches. Non-invasive ultrasound using the high-intensity focused ultrasound[54] probe is only studied in rats. Their advantages and safety concerns are discussed in [Table 1]
  • Currently, there are no FDA-approved devices available for arthritis. More studies needed to know the efficacy and side effects of devices available for arthritis. Exact time frame for commercial availability cannot be commented.
Figure 3: Schematic diagram showing a typical vagal nerve stimulation showing an impulse generator which delivers the electrical stimuli to vagus through electrodes

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Table 1: Types of vagal nerve stimulation devices

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[TAG:2]Vagus Nerve Stimulation Clinical and Preclinical Evidence [/TAG:2]

As discussed above, immune response regulation via the nervous system is the novel and potential treatment strategy that is being assessed in various clinical trials all over the globe [Table 2]. Vagus nerve stimulation has received attention in the field of bioelectronic medicines as several reports indicate its potential to alleviate inflammation and improve survival in experimental models of infectious and inflammatory disorders.[9],[10],[11],[12] Evidence corroborates the hypothesis that states the role of electrical vagus nerve stimulation in the regulation of peripheral inflammation through an efferent peripheral pathway mediated by the sympathetic splenic nerve, splenic lymphocytes producing acetylcholine, and α7nAChR modulating macrophages.[55] On the other hand, few studies demonstrated a new direction of vagal stimulation that may trigger afferent signals toward the brain and contribute to modulate the immune system.[56],[57],[58],[59],[60],[61]
Table 2: Clinical trials in patients with rheumatoid arthritis (completed and ongoing)

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An initial preclinical study demonstrated that cervical vagal stimulation with implantable electrodes reduced inflammation, articular bone loss, and the clinical score of collagen-induced arthritis in rats.[12] Electrical vagal stimulation with an implanted device (Cyberonics®/LivaNova) in epilepsy patients (n = 7) decreased the levels of TNF, IL-1β, and IL-6 production in the whole blood incubated with lipopolysaccharide.[10] Further, vagus nerve stimulation for a short period (maximum time: 4 min/day for 84 days) inhibited cytokine production and improved the clinical score in 12 of 17 RA patients in two cohorts (total n = 17; cohort I: RA patients in the early stage of disease refractory to methotrexate treatment; cohort II: RA patients in the late stages of disease refractory to biological therapy).[10],[62] Implanted device delivering vagus nerve stimulation was used once daily for 60 s; this in turn showed significant improvement in synovitis, significant bone erosions, and cytokine production.[12],[63] Inoue et al. showed the role of the vagus nerve stimulation in the prevention of kidneys against inflammation-induced injury even when the contralateral vagus nerve was blocked by local anesthetic-inhibiting efferent signals.[58] A recent study by Bassi et al. reported a new central neuroimmune pathway that induces local control of articular inflammation. Specific sympathoexcitatory brain structures regulating local sympathetic components are involved in the control of arthritic joint inflammation. In this, a central inflammatory processing network is activated through afferent vagal stimulation and cortical electrical stimulation. Afferent vagus nerve stimulation activates specific brain cortical areas, such as the parietal and cingulated cortex. Cortical electrical stimulation directed to the parietal cortex activates the paraventricular nucleus and the locus coeruleus. The activation of the locus coeruleus increases the sympathetic activity to the knee joint to control the synovial inflammatory process.[3]

A possibility of the impact of vagus nerve stimulation on metabolic adaptation cannot be ignored as the literature suggests the role of the vagus nerve in neuroendocrine adaptation. However, Tang et al. demonstrated that in response to vagal nerve stimulation, pituitary hormone levels, metabolic activity and post prandial metabolism is not affected (even if vagus nerve stimulation is used up to eight times a day). The authors demonstrated that single vagus nerve stimulation did not affect these parameters even if vagus nerve stimulation is used up to eight times a day. In RA patients, vagus nerve stimulation has shown to have no major interaction with metabolic or endocrinologic targets or other vagal nerve functions. Therefore, vagus nerve stimulation can be used as a safe and effective intervention for the management of RA patients. To validate these observations, in a detailed assessment of the effects of different vagus nerve stimulation, durations, frequencies, and intensities are needed.[64]

Another recently published study by Addorisio et al. evaluated the stimulation of cymba conchae by a vibrotactile device on RA patients and healthy subjects; disease activity was assessed in RA patients. They revealed that this application inhibits the production of TNF, IL-1β, and IL-6 in healthy subjects, and in RA patients, inflammatory response was decreased.[65]

Another important study to mention here is the first-in-human pilot study that evaluated a novel miniaturized neurostimulator, the “MR,” in multi-drug refractory RA (two biological DMARDs or JAK inhibitors). All patients continued methotrexate. Subjects were randomized to 1-min stimulation once a day versus 1-min stimulation 4 times a day. Mean disease activity score in 28 joints-C-reactive protein (DAS28-CRP) before treatment was 5.94, and the change in DAS28-CRP after 12 weeks was 1.24 ± 0.88 in once a day patient group, 0.38 ± 0.71 in four times a day patient group, and was 0.16 ± 0.21 in the sham group. The correlation was seen between EUlAR response and RAMRIS. Bioassay levels of IL-1β, IL-6, and TNFα decreased by > 30% compared to baseline at 12 weeks. The results reported that the device and stimulation were well tolerated independent of the two surgery-related events. These data support the use of the MR as a novel approach for the treatment of RA and other chronic inflammatory diseases.[47] Other trials discussing use of VNS devices in Rheumatoid arthritis patients have been discussed in [Table 2].[66],[67],[68],[69]

This review has potential limitations. Very few devices are available for vagus nerve stimulation, especially for arthritis. A limited number of human studies have been done till now for the use of vagus nerve stimulation in RA. More number of trials are needed to know the duration, frequency of VNS in Rheumatoid arthritis, and subsequently also how to modify them as per the disease activity. More research in this area would help to fill in the gaps in safety and efficacy of vagus nerve stimulation in population.

  Conclusion Top

Despite significant advancement in RA, search for the Holy Grail (long-term drug remission) remains elusive. Recent advances in understanding various neuroimmunomodulatory pathways have opened the possibility of nonpharmacological management. Vagus nerve stimulation offers nonpharmacological alternatives through methods shown to decrease cytokine production and inflammation in the experimental animal models. In human studies, however, few have shown promise in attenuating joint inflammation and thereby controlling disease activity. Acute vagus nerve stimulation treatment in RA patients has no major interactions or side effects. To validate these observations, in a detailed assessment of the effects of different vagus nerve stimulation, durations, frequencies, and intensities are needed, and the ongoing trials in RA patients will help elucidate how neuroimmunomodulation will help in heralding a drug-free era.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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