Treatment of Rheumatoid Arthritis via Electroacupuncture

treatment of rheumatoid arthritis via electroacupuncture

If you suffer from Rheumatoid Arthritis, or know someone who does, chances are you’re aware of the high financial, physical, and emotional costs of the condition. Recent medical breakthroughs are finding success with the experimental implantation of an electric stimulator on the vagus nerve, which sends a message to the spleen, turning off proteins which lead to systemic inflammation responsible for autoimmune conditions such as Rheumatoid Arthritis. While this fascinating development very well may usher in a new line of care for RA patients in the future, electroacupuncture can produce this effect utilizing the same technology today.

Even more fascinating is the fact that the point on the body we can painlessly stimulate via electroacupuncture to send impulses through the vagus nerve to the spleen is located on the neck (at the same location researchers are implanting their electric stimulators) at Renying, or “Stomach 9.” Stomach 9 is classified as a “Window of Sky” and “Sea of Qi” point that strongly regulates both qi and blood. And qi, as we’re now learning, may very well be synonymous with gasotransmitters, which affect the function of all cells that express target proteins. The same target proteins we’re trying to down-regulate in RA! Chinese medicine also teaches that the stomach and the spleen are internally and externally related, which is beautifully illustrated by the fact that stimulation of this point on the stomach channel directly affects proteins manufactured in the spleen!

This modality of treatment for RA fascinated me so much that I wrote a research proposal on the subject for one of my doctoral classes. If you’re interested in diving deep into the science of the treatment of RA with bioelectric medicine, keep reading on as I’ve attached an excerpt from my proposal below:

Electroacupuncture plus Methotrexate for the Treatment of Rheumatoid Arthritis: 
A Pragmatic Randomized Controlled Trial

Abstract

Rheumatoid Arthritis (RA) is a painful autoimmune disease that primarily causes chronic swelling within the synovial tissues of the joints that can lead to permanent disability. It affects approximately 1.3 million Americans, with women being diagnosed at a rate of 2 to 3 times more than men (Vandever, 2017). Studies estimate RA costs $5,720 per person affected (Cooper, 2000), and annual medication costs of biologics can top $15,000-$30,000 per person (Chauhari, 2008). Objectives: The proposed pragmatic randomized controlled trail is designed to explore whether the addition of biweekly electroacupuncture treatment, targeting the vagus nerve, to the standard of care pharmaceutical, Methotrexate, versus standard of care alone will result in decreased biomarkers of inflammation and self-reported pain in patients with RA. Methods: Subjects will be randomly assigned to either the Methotrexate alone group (control) or Methotrexate plus electroacupuncture group (intervention). The intervention group will receive electroacupuncture twice weekly, bilaterally at acupuncture point ST9, for a total of six weeks. Results: Results are expected to show a statistically significant decrease in inflammatory biomarkers and self-reported pain in the intervention group compared to the control group, leading to better quality of life for RA sufferers. Conclusions: A significant reduction in inflammatory biomarkers in the intervention group compared to the control group could decrease the future likelihood of cardiovascular disease and stroke in RA patients, increase quality of life, and decrease the prescription of cost-prohibitive, potentially dangerous Anti-TNFa drugs (Vandever, 2017).

Keywords:  Rheumatoid Arthritis, Methotrexate, electroacupuncture, vagus nerve, TNF-a, Anti-TNFa, MTX

Introduction

Research Problem

Rheumatoid Arthritis (RA) is a painful, often permanently debilitating autoimmune disease that affects approximately 1.3 million Americans, with women age 30-60 being 2 to 3 times more likely than men to receive a diagnosis. Although the disease primarily attacks the synovial tissues within the joints, it can negatively impact additional areas of the body such as the heart, lungs, muscles, cartilage, and ligaments (Vandever, 2017). Those who suffer from RA are 60% more likely to experience a heart attack one year after being diagnosed than those in the general population, are twice as likely to suffer from depression, and are at high risk of developing infections which may cause death (Dunkin, 2015). 

            Low-dose Methotrexate (MTX), has become the most widely prescribed standard of care drug worldwide for the treatment of RA (Weinblatt, 2013). Methotrexate is not without its side effects, and may result in gastrointestinal, hepatic, immunologic, and nervous system complications in greater than 10% of patients. Although uncommon, lymphomas and leukemias have been reported (“Methotrexate Side Effects”, 2019). There are no universally effective therapies for RA, but symptomatic relief can be achieved in up to 50% of patients using biological agents that inhibit tumor necrosis factor (TNF) (Koopman, et al., 2016). There are 5 licensed drugs in this class of anti-TNF monoclonal antibodies, including etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab (Choy, 2016), which come with a high cost of $15,000-$30,000 per year per patient and may cause dangerous, even lethal side effects. However, studies have shown that the combination of MTX plus anti-TNF therapy is significantly better than monotherapy with MTX or monotherapy with anti-TNF therapy at improving clinical response of RA (Weinblatt, 2013).

            The purpose of this proposal is to study if the addition of biweekly electroacupuncture over the course of 6 weeks, to the standard of care, MTX, can significantly reduce the levels of inflammatory cytokines in RA patients, compared to MTX as monotherapy. Much research is currently being conducted throughout the scientific community to explore alternatives to costly, potentially dangerous monoclonal antibody therapy, and provide better quality of life to RA patients. A majority of this research is centered around vagus nerve stimulation.

Previous Research

            A 2019 pilot study by Genovese, et. al. involved direct vagus nerve stimulation by implanting a novel miniaturized neurotransmitter called a MicroRegulator into the necks of 14 patients with RA who had failed to respond previously to monoclonal antibody therapy. Patients were randomized into three groups which consisted of placebo, stimulated once daily, or stimulated four times daily for a duration of 12 weeks (Genovese, et al., 2019). The conclusion of the study showed that those who were stimulated once daily had the greatest reduction in symptoms of RA, but both stimulation groups had a distinct, greater than 30% reduction of cytokines (Beyer, 2019). There were two surgery-related adverse events of vocal cord paralysis, known as Horner’s syndrome, that resolved without sequelae of clinical significance (Genovese, et al., 2019).

Proposed Research

This proposal is for a pragmatic randomized controlled study of RA patients utilizing MTX as monotherapy. The goal of the study is to prove the addition of elctroacupuncture at the site of the neck that directly stimulates the vagus nerve will reduce the symptoms of RA and levels of circulating cytokines in the blood. The significance of this study would be to provide a safer, more cost-effective alternative to monoclonal antibody therapy for patients with RA.

Hypothesis

            This study would disprove the null hypothesis that there is no difference in outcome measures in levels of cytokines in the blood and patient-reported symptoms of RA in the standard of care group versus the standard of care plus electroacupuncture group.

Background and Significance

Literature Review

            The knowledge that the body’s inflammatory response is regulated by the nervous system in a reflexive manner has opened the door to research exploring the treatment of inflammation through selective and reversible hard-wired neural systems (Tracey, 2002). The malfunctioning of the inflammatory reflex causes an increase in cytokine production, which in turn leads to the complications that occur in autoimmune diseases such as RA (Tracey, 2015). An excessive amount of TNF-ais present in the blood and joints of patients with RA (Choy, 2016), and recent research has shown that reflex neural circuits can inhibit TNF-aproduction via signals from the vagus nerve, allowing immune system modulation without abolishing it or producing immunosuppression (Andersson & Tracey, 2012). Many studies have examined the spleen as a target, as it is a major site for production of TNF, and action potentials descend down the vagus nerve to directly influence the organ’s production of cytokines (Tracey, 2015). 

            Vagus nerve stimulation (VNS) attenuates inflammatory responses in the body, and electroacupuncture (EA) signals are transmitted directly to the vagal efferent nerves, thus vagal activity caused by EA and VNS may both act on target organs such as the spleen (Park & Namgung, 2018). Neurons within the spleen release the neurotransmitter norepinephrine, which causes T cells to secrete acetylcholine, which interacts with macrophages to diminish the production of TNF (Tracey, 2015). Electroacupunture has been found to be effective in regulating the levels of Interleukin (IL) 1b, IL-6, and TNF-ain animal models of ulcerative colitis and acute arthritis (Park & Namgung, 2018). Additionally, EA at the acupuncture point ST36 (zusanli) has been found to activate the vagal pathway connected to the spleen and attenuates the production of TNF-ain the spleen (Lim, Kim, Lee, & Namgung, 2016).

            Electroacupuncture studies focusing on its efficacy in treatment of RA and inflammation are plentiful. A 2011 study highlighted acupuncture as an emerging alternative therapy for RA. Electroacupuncture at points Zusanli (ST36), Xuanzhong (GB39), and Shenshu (UB23) were performed on rats in an adjuvant-induced arthritis model, which resulted in markedly decreased paw swelling and histologic scores of inflammation in the synovial tissue, and a reduction in body weight loss (He, et al., 2011). 

A 2016 study looked at the efficacy of EA compared to Prednisone in a Rheumatoid Arthritis-induced rat model. Electroacupuncture was applied to points Zusanli (ST36) and Kunlun (BL60) for 30 minutes, once daily, for 10 days. Results showed that in both the EA and Prednisone groups, inflammatory reactions were relieved and serum cytokines downregulated by evidence of reduced ankle diameter and serum IL-1b, ICAM-1 and TNF-a. However, there was no significant difference in outcomes between the medication and EA groups, proving they were equally efficacious (Zhang, Guo, Chen & Ma, 2016). 

An additional study in 2016 compared the effects between EA plus methotrexate and leflunomide to methotrexate and leflunomide alone in improving clinical symptoms and local joint function in RA patients. Electroacupuncture was applied to points Ganshu (BL18), Shenshu (BL23), Xuanzhong (GB39), Zusanli (ST36), Taichong (PR3) and Hegu (LI4) 3 times per week for 12 weeks. Results showed the effects of the EA plus medication group were superior to those of the medication group alone in reducing resting pain, swollen joint count, tender joint count, and improving patient’s global assessment, physician’s global assessment, and traditional Chinese medicine symptom scoring (Zhou, et al., 2016).

There is a gap in the literature that remains, in which the study of electroacupuncture in combination with MTX compared to MTX as a monotherapy in the treatment of RA patients is investigated. Additionally, a review of the literature did not provide evidence of RA studies that specifically utilized electroacupuncture at the point Renying (ST9), which is located on the neck, lateral to the Adam’s apple, on the anterior border of the sternocleidomastoid muscle, where the common carotid artery pulsates (“Stomach 9”). 

Relevance

            The combination of MTX with monoclonal antibody therapy (anti-TNF) in the treatment of RA is a common model of western medical intervention, as MTX as a monotherapy is regarded to be inferior to that of the additive effect of MTX in combination with anti-TNF. However, because of the cost issues regarding use of anti-TNF therapies, topping $15,000-30,000 per patient per year, most rheumatologists now initiate treatment with MTX as a first-line therapy (Weinblatt, 2013). The dangerous, even lethal side effects of monoclonal antibody therapy, such as infections, blood disorders, tuberculosis, and Multiple Sclerosis, are an additional deterrent to their use (Choy, 2016). The further exploration of the efficacy of EA in combination with MTX, with a hypothesized additive effect, offers a safer alternative to anti-TNF therapy for RA patients who are not receiving maximum relief from MTX as a monotherapy, and would also result in significant cost savings. Additionally, the exploration of electroacupuncture applied to the point ST9 may offer superior downregulation of TNF-ain the spleen via the vagus nerve, as this point is analogous to the site of insertion of the MicroStimulator in Genovese’s study (2019). 

Proposed Intervention

            In the proposed pragmatic randomized control study, patients with RA would receive either standard of care MTX (control) or standard of care MTX plus electroacupuncture at point ST9 bilaterally (intervention). This protocol would be administered twice weekly for 6 weeks. At both the beginning and the end of the study, the Numeric Pain Rating Scale (NPRS) would be used to assess pain levels, and serum levels of Interleukin (IL) 1b, IL-6, and TNF-awould be tested to objectively measure inflammation in both the control and intervention groups. 

References

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Beyer, M. (2019, June 24). Vagus nerve stimulation may reduce the symptoms of rheumatoid arthritis. Retrieved from https://www.medicalnewstoday.com/articles/325532.php#1.

Chaudhari, P. (2008). The Impact of Rheumatoid Arthritis And Biologics on Employers and Payers. Biotechnology Healthcare, 5(2), 37–44. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706169/

Choy, E. (2016, January 14). Anti-TNFa Treatment in Rheumatoid Arthritis. Retrieved from https://www.nras.org.uk/anti-tnfa-treatment-in-rheumatoid-arthritis.

Cooper, N. J. (2000). Economic burden of rheumatoid arthritis: a systematic review. Rheumatology, 39(1), 28–33. doi: 10.1093/rheumatology/39.1.28

Dunkin, M. A. (2015, April). More Than Just Joints: How Rheumatoid Arthritis Affects the Rest of Your Body. Retrieved from https://www.arthritis.org/about-arthritis/types/rheumatoid-arthritis/articles/rhemuatoid-arthritis-affects-body.php.

Genovese, M. C., Gaylis, N., Sikes, D., Kivitz, A., Horowitz, D. M., Peterfy, C., … Chernoff, D. (2019). Lb0009  First-In-Human Study Of Novel Implanted Vagus Nerve Stimulation Device To Treat Rheumatoid Arthritis. Oral Presentations. doi: 10.1136/annrheumdis-2019-eular.8716

He, T.-F., Yang, W.-J., Zhang, S.-H., Zhang, C.-Y., Li, L.-B., & Chen, Y.-F. (2011). Electroacupuncture Inhibits Inflammation Reaction by Upregulating Vasoactive Intestinal Peptide in Rats with Adjuvant-Induced Arthritis. Evidence-Based Complementary and Alternative Medicine, 2011, 1–8. doi: 10.1155/2011/290489

Koopman, F. A., Chavan, S. S., Miljko, S., Grazio, S., Sokolovic, S., Schuurman, P. R., … Tak, P. P. (2016). Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proceedings of the National Academy of Sciences, 113(29), 8284–8289. doi: 10.1073/pnas.1605635113

Lim, H.-D., Kim, M.-H., Lee, C.-Y., & Namgung, U. (2016). Anti-Inflammatory Effects of Acupuncture Stimulation via the Vagus Nerve. Plos One, 11(3). doi: 10.1371/journal.pone.0151882

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Park, J.-Y., & Namgung, U. (2018). Electroacupuncture therapy in inflammation regulation: current perspectives. Journal of Inflammation Research, 2018(11), 227–237. doi: 10.2147/jir.s141198

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Tracey, K. (2015, March). Stimulation of the nervous system could replace drugs for inflammatory and autoimmune conditions. Scientific American, 28–35. Retrieved from https://www.scientificamerican.com/index.cfm/_api/render/file/?method=inline&fileID=CA2FBE84-2294-46D8-825FBE2644ADE81C

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Zhang, R., Guo, L. H., Chen, T. W., & Ma, W. Z. (2016). Effect of Electroacupuncture on Serum TNF-α, IL-1β and Intercellular adhesion molecule 1 Levels in Rheumatoid Arthritis Rats. Zhen Ci Yan Jiu, 41(1), 51–54. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27141621

Zhou, Y., Zhu, J., Li, L. B., He, T. F., Chen, X. Y., & Chen, Y. F. (2016). Effects of Electroacupuncture on Joint Function in Rheumatoid Arthritis Patients of Liver- and Kidney-Yin Deficiency Type. Effects of Electroacupuncture on Joint Function in Rheumatoid Arthritis Patients of Liver- and Kidney-Yin Deficiency Type, 41(5), 440–446. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29071946

Image Source: "Paint the Pain" by Avita Flit is licensed under CC BY-NC-ND 4.0