Novel Bioelectronic Medicine for Rheumatoid Arthritis: A Review

Monday, April 14, 2025

Abstract

Arthritis is a common medical condition that affects millions of people worldwide. It is characterized by joint inflammation, pain, stiffness, and swelling, which can lead to reduced mobility and quality of life. There are several treatment options available that can help manage symptoms and improve overall quality of life. Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) are often used to reduce pain, while Disease Modifying Anti-Rheumatic Drugs (DMARDS) are used to slow or stop the progression of rheumatoid arthritis. Corticosteroids can also be used to reduce inflammation in joints. There is no cure for the disease, and the existing treatments have certain drawbacks. Bioelectronic medicine is a novel approach to treating Rheumatoid Arthritis by using electrical signals to modulate the immune system and reduce inflammation in joints. This is achieved through the use of small electronic devices that are implanted near the affected joints. It involves the use of Vagus Nerve Stimulation (VNS) to modulate the immune system, thereby reducing inflammation. VNS has been shown to reduce inflammation in animal models of RA and human clinical trials.

Keywords: Bioelectronics Medicine, Rheumatoid Arthritis, Electrical Signals

Introduction

Rheumatoid Arthritis is a chronic autoimmune disease that affects the joints, causing pain, inflammation, and stiffness. While there is no cure, conventional treatments involve using drugs such as NSAIDS, corticosteroids, DMARDS, and biological agents.1 However, these treatments come with side effects and may not work for everyone. Bioelectronic medicine is a new and promising approach to treating Rheumatoid Arthritis that uses electrical impulses to modulate the nervous system and reduce inflammation.2,3 Preclinical and clinical studies have shown great potential in this field, offering a potentially safer and more effective treatment option for RA patients.

Autoimmune diseases are conditions in which the immune system mistakenly attacks healthy cells and tissues in the body, as if they were foreign or harmful. This can lead to inflammation and damage in various organs and systems, and cause a range of symptoms and complications, depending on the specific disease and affected areas. Some examples of autoimmune diseases include rheumatoid arthritis, lupus, type 1 diabetes, multiple sclerosis, and psoriasis.4

Autoimmune diseases occur when the immune system, which normally defends the body against infections and foreign substances, mistakenly targets and attacks the body’s cells, tissues, and organs. This can happen due to various factors, such as genetic predisposition, environmental triggers (such as infections, drugs, or toxins), or dysregulation of immune cells and molecules 5,6

In autoimmune diseases, the immune system produces antibodies and immune cells that recognize and attack specific self-antigens (proteins or other molecules that are normally present in the body), leading to inflammation, tissue damage, and loss of function.7 This can affect different organs and systems, depending on the specific disease and the location and extent of the immune response. The mechanisms underlying autoimmune diseases are complex and involve interactions between various components of the immune system, such as T and B lymphocytes, cytokines, chemokines, complement proteins, and antigen-presenting cells.8 The exact mechanisms may differ between different diseases and are still being studied to develop better treatments and preventions.

Some autoimmune diseases are:

Rheumatoid arthritis, Type 1 diabetes, Multiple sclerosis, Lupus, Celiac disease, Psoriasis, Graves’ disease, Hashimoto’s thyroiditis, Sjögren’s syndrome, Inflammatory bowel disease (IBD)5, including Crohn’s disease and ulcerative colitis Myasthenia gravis, Guillain Barré syndrome, Polymyositis, Dermatomyositis, Scleroderma, Addison’s disease, Vitiligo, Pernicious anaemia, Autoimmune hepatitis, Goodpasture’s syndrome.9,10

Rheumatoid Arthritis

Figure 1. RA Inflamed Joint

An autoimmune condition of the joints known as rheumatoid arthritis (RA) is characterized by extra-articular involvement in addition to inflammatory arthritis. 11 It frequently affects several joints in both hands, causing morning stiffness that could continue for many hours.12

It is a chronic inflammatory condition with no known cause that mostly affects synovial joints. If left untreated, it often begins in tiny peripheral joints, progresses to involve proximal joints, and is frequently symmetric.13,14 Joint deterioration caused by cartilage and bone loss over time as a result of joint inflammation. Early RA is described as having symptoms that have been present for less than six months, while established RA is defined as having symptoms that have been present for more than six months.15

Rheumatoid arthritis patients need both pharmacological and nonpharmacological treatments to be treated. Early treatment with disease-modifying anti-rheumatic medications is now considered standard of care.16 Despite receiving treatment, a significant percentage of people eventually become disabled and experience serious morbidity. To improve therapeutic outcomes, a thorough pharmacological and non-pharmacological support (physiotherapy, counselling, and patient education) is needed.

Epidemiology

The frequency of RA is 0.24 percent worldwide. In the United States and other western countries of northern Europe, the annual incidence of RA is roughly 40 per 100,000 people. Epidemiologic data show that women are more likely than males to have RA, with a mortality risk of 3.6% for women and 1.7% for men. RA risk rises with age as well, reaching its peak occurrence between the ages of 65 and 80.17

In the entire world, RA occurs 0.24 percent of the time. The prevalence rate of RA is around 40 per 100,000 people in the US and other western nations of northern Europe. According to epidemiologic data, women are more likely than men to develop RA, with a 3.6% mortality risk for women compared to a 1.7% risk for men. The risk of developing RA increases with aging as well, peaking between the ages of 65 and 80.18,19

The biggest relationship between modifiable risk factors and RA is cigarette smoking. Diet and nutrition have also been demonstrated to be essential ecological triggers for RA. The normal “western” diet, which is calorie-dense, heavy in fat, and poor in fiber, raises the risk of RA. Long-chain omega-3 polyunsaturated fatty acid consumption is linked to a lower risk of RA. Another recognized potential risk for RA is obesity. Patients with a body mass index (BMI) of more than 30 kg/m2 have a 30% higher risk of developing RA, while those with a BMI between 25 and 29.9 kg/m2 had a 15% higher risk.20,21

ProQuest Central, MEDLINE, Web of Science, and EMBASE were the four electronic databases that were searched for peer-reviewed English papers that provide prevalence estimates of RA between 1980 and 2019. In our search technique, we used case-control studies, cross-sectional studies, and prospective or retrospective cohort studies. The pooled prevalence estimates were created using a random-effect meta-analysis approach. Sensitivity analysis, sub-group, and meta-regression analyses were used to find the potential between-study heterogeneity. The meta-analysis comprised 67 studies in total, with 742,246 RA patients and 211,592,925 healthy controls during the research period. With a 95% prediction interval, the estimated global prevalence of RA was 0.46% (95% confidence interval [CI] 0.39 0.54; I2 = 99.9%). (0.06-1.27). Between 1986 and 2014, the RA point prevalence was 0.45% (95% CI 0.38-0.53%), but from 1955 to 2015, the pooled period-prevalence was 0.46% (95% CI 0.36% and 0.57%). The most significant increase in RA pooled prevalence (0.69%; 95% CI 0.47-0.95) was found in studies using connected data sources. According to meta-regression, sample size, geographic location, and risk assessment of studies are among the variables that account for the studies’ variability of RA prevalence. Between 1980 and 2019, the prevalence of RA was 460 per 100,000 people worldwide, with variations due to study design and geographic region.

Preparations

Table 1. Preparations for treatment of RA.
Figure 2. Formulations for Management of R
Figure 3. Topical formulations used in the management of Rheumatoid Arthritis

Introduction to Bioelectronic Medicine for Treatment of Rheumatoid Arthritis

To regulate organ function and restore physiological balance during illness, nerve stimulation and bioelectronic therapy are growing fields in modern medicine. Recent research on neuromodulation showed that during sickness, the nervous system can restore physiological balance and regulate organ function. These findings prompted researchers to consider the potential of neuromodulation in the management of inflammatory and viral diseases. The enteric, sympathetic, and parasympathetic divisions of the autonomic nervous system regulate the urogenital, cardiovascular, and gastrointestinal systems as well as physiological homeostasis9. Similar to this, the nervous system alters immune function to restore immune homeostasis following infections, trauma, and other immunological challenges.23,24

The major nerve that connects the brain and viscera, the vagus nerve, is a bidirectional nerve that sends signals in both directions, one to the brain and the other to the viscera. In an initial study, it was discovered that efferent vagal projections reduce inflammation in endotoxemic mice, but afferent vagal fibers stimulate the hypothalamic-pituitary-adrenal (HPA) axis. These findings prompted numerous researchers to explore the potential of vagal stimulation in a variety of inflammatory diseases, including RA.25,26

In the case of rheumatoid arthritis (RA), bioelectronic medicine has several potential advantages over current therapies:

  1. Targeted therapy: Bioelectronic medicine allows for more precise and targeted therapy, as it can deliver electrical impulses to specific nerves that are involved in the inflammatory process of RA.
  2. Non-invasive: Unlike some current therapies for RA, such as joint injections or infusions, bioelectronic medicine can be delivered non-invasively through a small, implanted device or external devices such as patches or cuffs.
  3. Reduced side effects: Bioelectronic medicine may have fewer side effects than current RA therapies, which can have systemic effects throughout the body. Because bioelectronic medicine acts locally, it may be able to reduce inflammation in the joint without affecting other parts of the body.
  4. Personalized treatment: Bioelectronic medicine can be personalized to each patient, as the electrical impulses can be tailored to target the specific nerves involved in the inflammatory process in that patient.

While bioelectronic medicine is still a developing field and more research is needed to fully understand its potential benefits for RA, it has the potential to offer a promising new approach to treating these chronic autoimmune diseases.

Bioelectronic Medicine

A recent medical discipline called “bioelectronic medicine” combines electrical engineering, neurophysiology, and molecular biology to develop novel treatments and diagnostics that interface with the body via electronic devices. Targeting specific nerves and brain networks in bioelectronics medicine has also been presented as a novel approach to manage organ function and inflammation. For the treatment of refractive epilepsy, the use of a pulse generator implanted behind the clavicle to cause electrical vagal stimulation was given FDA approval in 1997. These therapies are risk-free and without serious side effects, and the FDA also approved a similar stimulation method for drug-resistant depression in 2005.

Numerous preclinical and clinical investigations have shown that vagal stimulation can lower inflammation in arthritic conditions. A preliminary investigation in rats with collagen-induced arthritis showed that cervical vagal stimulation with implantable electrodes reduced inflammation, articular bone loss, and clinical score of collagen.

Twelve of 17 RA patients in two cohorts (total n = 17; cohort I: RA patients in the early stage of the disease refractory to methotrexate treatment; cohort II: RA patients in the late stages of the disease refractory to biological therapy) showed clinical improvement after receiving vagus nerve stimulation for a brief period (maximum time: 4 min/day for 84 days) that reduced the production of cytokines.

In RA patients, transcutaneous noninvasive vagus nerve stimulation with gammaCore (a cervical vagus nerve stimulator approved for the treatment of various types of primary headaches, including migraine and cluster headaches) and Nemos® (an auricular branch vagal stimulation device used to reduce seizure frequency in drug resistant patients) has recently become an alternative to permanent device implants. In a preliminary, randomized, and blinded pilot study of 20 healthy volunteers, gammaCore reduced the release of proinflammatory cytokines and chemokines while increasing the release of the anti-inflammatory cytokine IL-10 when compared to sham stimulation. In healthy subjects (n = 20), bilateral cervical vagal nerve stimulation with gammaCore increases cardiac vagal tone and decreases TNF blood levels [156]. Similarly, transcutaneous auricular vagus nerve stimulation can reduce the amount of proinflammatory cytokines in the blood in endotoxemic rats.

Figure 3. Topical formulations used in the management of Rheumatoid Arthritis

Market Size and Trends in the Future

The market for bioelectric medicines has been expanding steadily over the past few years and is expected to continue expanding over the forecast period (2020-2027). The report provides a thorough analysis of the market and includes future trends, current growth drivers, thoughtful opinions, facts, historical data, and market data that has been statistically supported and verified by the industry.

The Bioelectric Medicine Market study provides a comprehensive analysis of the parent market based on leading companies, recent history, and forecasted future developments. This information will be useful to all competitors in the market. Secondary research has been used to identify major market players in the field of bioelectric medicine, and primary and secondary research have been used to estimate their market shares. Utilizing both confirmed secondary sources and primary sources, all measurement shares, splits, and breakdowns have been precisely determined. The Bioelectric Medicine Market report starts with a fundamental overview of the industry lifecycle, definitions, classifications, applications, and industry chain structure; taken together, these will aid leading players in understanding the market’s scope, the qualities it offers, and how it will satisfy customers’ needs.27

Barriers to Bioelectronic Medicine

Bioelectronic medicine is a relatively new field that aims to use electrical signals to treat various diseases and conditions. Despite its potential, several barriers have hindered its widespread adoption and development. Some of the main barriers to bioelectronic medicine include:

  1. Technical Challenges: Bioelectronic medicine requires a deep understanding of the complex interplay between biology, electronics, and signal processing. This requires the development of highly sophisticated and miniaturized devices that can be implanted or administered to patients.
  2. Regulatory Hurdles: The development and approval of bioelectronic devices are subject to rigorous regulatory standards. This can be a time-consuming and expensive process, and the high risk associated with implanting devices into patients adds to the regulatory burden.
  3. Cost: Bioelectronic devices are often expensive to develop and manufacture, and this cost is passed on to patients. In many cases, the benefits of these devices may not be immediately apparent, which can make them difficult to justify from a financial perspective.
  4. Limited Clinical Evidence: Although there have been some promising results in early clinical trials, there is still a need for more robust clinical evidence to demonstrate the safety and efficacy of bioelectronic devices.
  5. Lack of Expertise: Bioelectronic medicine requires a multi-disciplinary approach, combining expertise from fields such as biology, electronics, and computer science. There is a need for more scientists and engineers with the relevant training and skills to work in this field.

Overall, the barriers to bioelectronic medicine highlight the need for ongoing research and development to overcome these challenges and advance the field.

Conclusion

The use of bioelectronic medicine offers a promising approach to treating chronic autoimmune diseases. The ability to modulate inflammatory response through the use of electronic devices provides a safe and effective alternative to traditional treatments such as DMARDS, NSAIDS, corticosteroids, and biological agents. Nonetheless, Bioelectronic medicine offers a potentially transformative treatment option for RA, and its continued development and exploration are warranted.

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Author Details 

Ruchi Keswani, Muizz Kachhi, and Chandrashekar Bobade, School of Health Science and Technology,Dr. Vishwanath Karad MIT World Peace University, Kothrud, Pune, 411038

Corresponding Author: Chandrashekhar Bobade, PhD,  Asst. Prof. School of Health Science and Technology, Dr. Vishwanath Karad, MIT World Peace University, Kothrud, Pune, 411038, chandrashekhar.bobade@mitwpu.edu.in

Publication Details

This article appeared in American Pharmaceutical Review:
Vol. 28, No. 3
April 2025
Pages: 52-56

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