A recent University of Iowa study reveals a biological link between pain and fatigue and may help explain why more women than men are diagnosed with chronic pain and fatigue conditions like fibromyalgia and chronic fatigue syndrome.
Working with mice, the researchers, led by Kathleen Sluka, Ph.D., professor in the Graduate Program in Physical Therapy and Rehabilitation Science in the UI Roy J. and Lucille A. Carver College of Medicine, found that a protein involved in muscle pain works in conjunction with the male hormone testosterone to protect against muscle fatigue.
Chronic pain and fatigue often occur together — as many as three in four people with chronic, widespread musculoskeletal pain report having fatigue; and as many as 94 percent of people with chronic fatigue syndromes report muscle pain. Women make up the majority of patients with these conditions.
To probe the link between pain and fatigue and the influence of sex, the UI team compared exercise-induced muscle fatigue in male and female mice with and without ASIC3 — an acid-activated ion channel protein that the team has shown to be involved in musculoskeletal pain.
A task involving three one-hour runs produced different levels of fatigue in the different groups of mice as measured by the temporary loss of muscle strength caused by the exercise.
Male mice with ASIC3 were less fatigued by the task than female mice. However, male mice without the ASIC3 protein showed levels of fatigue that were similar to the female mice and were greater than for the normal males.
In addition, when female mice with ASIC3 were given testosterone, their muscles became as resistant to fatigue as the normal male mice. In contrast, the muscle strength of female mice without the protein was not boosted by testosterone.
“The differences in fatigue between males and females depends on both the presence of testosterone and the activation of ASIC3 channels, which suggests that they are interacting somehow to protect against fatigue,” Sluka said. “These differences may help explain some of the underlying differences we see in chronic pain conditions that include fatigue with respect to the predominance of women over men.”
The study, which was published in the Feb. 28 issue of the American Journal of Physiology — Regulatory, Integrative and Comparative Physiology, indicates that muscle pain and fatigue are not independent conditions and may share a common pathway that is disrupted in chronic muscle pain conditions. The team plans to continue their studies and investigate whether pain enhances fatigue more in females than males.
“Our long-term goal is to come up with better treatments for chronic musculoskeletal pain,” Sluka said. “But the fatigue that is typically associated with chronic, widespread pain is also a big clinical problem — it leaves people unable to work or engage in social activities. If we could find a way to reduce fatigue, we could really improve quality of life for these patients.”
In addition to Sluka, the UI research team included Lynn Burnes, a research assistant and lead author of the study; Sandra Kolker; Jing Danielson; and Roxanne Walder. The study was funded in part by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
An estimated nine million men and women in the United States live with myofascial pain syndrome, a condition marked by pain that permeates muscles in the neck, back and shoulders. The condition is difficult to diagnose and not entirely understood, but research studies indicate that a new imaging technology developed at Mayo Clinic holds promise for a definitive diagnosis and, perhaps eventually, new treatments for people who have the syndrome.
A Mayo Clinic study published in the November issue of the Archives of Physical Medicine and Rehabilitation shows that magnetic resonance elastography, or MRE, can provide images of the affected muscle with clarity and insight not possible with magnetic resonance imaging, or MRI. While an MRI uses a magnetic field and radio waves to create clear and detailed cross-sectional images of the body’s internal tissues and organs, an MRE measures the elasticity of tissue as it is gently vibrated.
“Additional research is necessary, but our findings in this pilot study provide a strong basis to suspect that MRE technology can identify changes in muscle tone and stiffness that could previously only be identified by physical examination by a physician or a therapist,” says Jeffrey Basford, M.D., Ph.D., a Mayo Clinic specialist in physical medicine and rehabilitation and an author of the study. “Prior to these findings, we did not have a good diagnostic test for myofascial pain syndrome.”
An MRE employs standard MRI equipment with a few modifications and works by measuring the wavelength of vibrations sent through the tissues. A vibrating metal plate is placed on the patient causing muscles to contract and stiffen. When this occurs, researchers can measure the elasticity of muscles and detect abnormal hardening of tissues, which in myofasical pain syndrome can cause pain.
The MRE technique is being applied to the diagnosis of other diseases, such as liver disease and could also be used to diagnose breast cancer and other tumors, which tend to be harder than the surrounding normal tissue.
Myofascial pain syndrome is sometimes confused with fibromyalgia, but the two conditions are clinically different. Fibromyalgia is a chronic condition typically characterized by widespread pain in muscles, ligaments and tendons, as well as fatigue and multiple tender points. Myofascial pain syndrome, is a more localized pain that is associated with trigger point tenderness. A trigger point is a small lump in a band of tight muscle that, when pressed, triggers a reproducible pattern of referred pain.
“In the past, myofasical pain syndrome has been very difficult to diagnose. These new findings may be the next step for a diagnosis and in the future may help to refine treatment options,” Dr. Basford says.
In some chronic cases of myofascial pain, combinations of physical therapy and trigger point injections are needed to relieve pain. In addition, the condition is sometimes treated with the “spray and stretch” technique, which involves spraying the muscle and trigger point with a coolant and then slowly stretching the muscle.
People who have the common chronic pain condition fibromyalgia often report that they don’t respond to the types of medication that relieve other people’s pain.
New research from the University of Michigan Health System helps to explain why that might be: Patients with fibromyalgia were found to have reduced binding ability of a type of receptor in the brain that is the target of opioid painkiller drugs such as morphine.
The study included positron emission tomography (PET) scans of the brains of patients with fibromyalgia, and of an equal number of sex- and age-matched people without the often-debilitating condition. Results showed that the fibromyalgia patients had reduced mu-opioid receptor (MOR) availability within regions of the brain that normally process and dampen pain signals — specifically, the nucleus accumbens, the anterior cingulate and the amygdala.
“The reduced availability of the receptor was associated with greater pain among people with fibromyalgia,” says lead author Richard E. Harris, Ph.D., research investigator in the Division of Rheumatology at the U-M Medical School’s Department of Internal Medicine and a researcher at the U-M Chronic Pain and Fatigue Research Center.
“These findings could explain why opioids are anecdotally thought to be ineffective in people with fibromyalgia,” he notes. The findings appear in The Journal of Neuroscience. “The finding is significant because it has been difficult to determine the causes of pain in patients with fibromyalgia, to the point that acceptance of the condition by medical practitioners has been slow.”
Opioid pain killers work by binding to opioid receptors in the brain and spinal cord. In addition to morphine, they include codeine, propoxyphene-containing medications such as Darvocet, hydrocodone-containing medications such as Vicodin, and oxycodone-containing medications such as Oxycontin.
The researchers theorize based on their findings that, with the lower availability of the MORs in three regions of the brains of people with fibromyalgia, such painkillers may not be able to bind as well to the receptors as they can in the brains of people without the condition.
Put more simply: When the painkillers cannot bind to the receptors, they cannot alleviate the patient’s pain as effectively, Harris says. The reduced availability of the receptors could result from a reduced number of opioid receptors, enhanced release of endogenous opioids (opioids, such as endorphins, that are produced naturally by the body), or both, Harris says.
The research team also found a possible link with depression. The PET scans showed that the fibromyalgia patients with more depressive symptoms had reductions of MOR binding potential in the amygdala, a region of the brain thought to modulate mood and the emotional dimension of pain.
The study subjects were 17 women with fibromyalgia and 17 women without the condition.
The senior author of the paper was Jon-Kar Zubieta, M.D., Ph.D., the Phil F. Jenkins Research Professor of Depression in the U-M Department of Psychiatry and a member of U-M’s Molecular and Behavioral Neuroscience Institute, Depression Center and Department of Radiology. Other authors were Daniel J. Clauw, M.D.; David J. Scott, Ph.D.; Samuel A. McLean, M.D., MPH; and Richard H. Gracely, Ph.D.
The research was supported by grants from the Department of the Army; the National Center for Research Resources, a component of the National Institutes of Health; and the NIH. Harris was supported by an NIH–National Center for Complementary and Alternative Medicine Grant. McLean was supported by an NIH grant.
Pregnant women with fibromyalgia (FM) experience significant pain, fatigue and psychological stress, symptoms that are often misdiagnosed or undertreated as a normal part of pregnancy, according to a pilot study by Karen M. Schaefer, D.N.Sc., R.N., assistant professor of nursing at Temple University’s College of Health Professions. Her research, the first to look at the impact of pregnancy on women with FM, was recently presented at the 2006 Association of Women’s Health, Obstetrics and Neonatal Nurses’ convention in Baltimore.
Fibromyalgia is a chronic condition commonly found in women that causes pain in the muscles and soft tissues of the body. Many sufferers feel weak from fatigue, and the condition, at its worst, can lead to disability.
“Until now, there was only anecdotal evidence suggesting that women with FM had a rougher time during pregnancy,” said Schaefer. “This data is the first step toward gathering hard evidence of FM effects on this group and will hopefully help us identify ways to reduce the impact of fibromyalgia during pregnancy.”
For this study, Schaefer recruited pregnant women with and without FM through an Internet announcement on a fibromyalgia Web site. Study subjects were between the ages of 29 and 31, in their third trimester, with no history of stillbirth and free of chronic illnesses other than FM.
The women were then mailed a questionnaire about fatigue, depression, pain and ability to function. A demographic form was also used to assess the number of painful areas in the body as well as age, marital status, education, hours slept and use of medication.
Schaefer’s results revealed that the pregnant women with fibromyalgia had a hard time functioning, felt more stiff and tired, and experienced pain in more body areas than women without FM.
“Most women with FM have trouble getting this condition properly diagnosed, let alone knowing where to turn for help once their condition is identified. We need to start looking at how FM affects all areas of these women’s lives and come up with ways to provide as much comfort and support as possible,” she said.
Schaefer, whose research focuses on women with chronic illness (fibromyalgia, lupus, ovarian cancer) is currently expanding her study to include a larger group of subjects.
GAINESVILLE, Fla.—The millions of Americans who suffer from fibromyalgia live with a two-edged sword: excruciating pain, accompanied by the doubts of many who dismiss it as a made-up illness invented by a troubled mind.
But researchers at the University of Florida and elsewhere are beginning to piece together clues that reveal the physical basis of the puzzling syndrome that causes severe fatigue and aches, and has defied easy diagnosis.
UF scientists have found an abnormal central nervous system reaction in those with fibromyalgia-the body magnifies ordinary repetitive stimulation into an experience of crippling pain.
“This is particularly important because it has been unclear if fibromyalgia was just an imagined illness or a real syndrome,” said Dr. Roland Staud, an associate professor of medicine at UF’s College of Medicine who also is affiliated with the UF Brain Institute. “We now have good evidence that shows that it’s not a psychological abnormality, butthat there is a neurological abnormality present.”
Staud, who presented his research findings at the annual meeting of the American College of Rheumatology last November, recently was awarded a National Institutes of Health grant worth nearly $800,000 to continue his studies for the next four years. Donald Price, a UFprofessor of oral and maxillofacial surgery, and Charles Vierck, a UF professor of neuroscience, are collaborating on the research. Their goal is to develop a better understanding of the condition, with an eye toward improving diagnostic tests and treatments.
An estimated 3.7 million people in the United States – primarily women who are diagnosed during their 30s and 40s – have fibromyalgia, according to the NIH. A chronic illness with no known cure, its cause also is not known. Researchers have theorized that an injury to the central nervous system or an infectious agent might be responsible for triggeringit in people who have inherited susceptibility. Symptoms include persistent and widespread musculoskeletal pain, fatigue and tenderness in the neck, spine, shoulders and hips.
Staud and colleagues found the central nervous system abnormality byconducting a series of repetitive stimulation tests on people with thesyndrome as well as healthy research participants. The tests involved repeatedly placing warm plates on their hands and arms. The healthy participants felt the sensation but did not report it as pain.
For those with fibromyalgia, however, the sensation would magnify with each repetition into an experience of crippling and unbearable pain.
“When a sensation signal reaches the spinal cord, the signal can be omitted, changed or augmented,” Staud said. “If it is augmented, then something that is innocuous, such as pressure on the skin, can then be perceived as a painful stimulus.”
Jessica LeMay, one of Staud’s patients, has been battling fibromyalgia since 1993. The 30-year-old Lake City resident said the pain starts in one area and usually spreads, sometimes becoming overwhelming.
“I imagine if someone had taken a baseball bat and beaten me with it,that’s got to be what it feels like,” she said. “Depending on the day, I’ll just move out of the way if someone tries to touch me.”
The pain of fibromyalgia often interferes with a person’s working life.
“These are people who are diagnosed in their productive years. Many have personal or professional problems adjusting to the pain experience,” Staud said. “The illness makes some people feel dysfunctional because they can’t do the activities they once did.”
The condition can worsen from stress and inadequate sleep, Staud said. Because living with fibromyalgia often causes stress, and pain makes sleeping difficult, a vicious cycle develops.
LeMay said many people dismiss her condition, not understanding the “huge difference” between her severe fatigue and the healthy person’s occasional tiredness.
“When this fatigue would come about, it’s almost like a weight being dropped on you, and you can’t function anymore,” she said.
LeMay said she is hopeful that Staud’s research will lead to more effective treatment for fibromyalgia patients and better understanding by the general public.
“In our society, you either get better or you die, and fibromyalgiapatients don’t do that,” she said. “We don’t fit in the mold, so people don’t know what to do with us.”
Researchers in the U.K. report that non-restorative sleep is the strongest, independent predictor of widespread pain onset among adults over the age of 50. According to the study published in Arthritis & Rheumatology (formerly Arthritis & Rheumatism), a journal of the American College of Rheumatology (ACR), anxiety, memory impairment, and poor physical health among older adults may also increase the risk of developing widespread pain.
Muscle, bone and nerve (musculoskeletal) pain is more prevalent as people age, with up to 80% of people 65 years of age and older experiencing daily pain. Widespread pain that affects multiple areas of the body — the hallmark feature of fibromyalgia — affects 15% of women and 10% of men over age 50 according to previous studies.
Led by Dr. John McBeth from the Arthritis Research UK Primary Care Centre, Keele University in Staffordshire, this newly published population-based prospective study identified factors that increase the risk of the development of widespread pain in older adults. The team collected data on pain, psychological and physical health, lifestyle and demographic information from 4326 adults over the age of 50 who were free of widespread pain at the start of the study (1562 subjects reported no pain and 2764 had some pain). These participants were followed up three years later for the development of widespread pain.
Results show that at follow-up, 800 (19%) reported new widespread pain. The development of new widespread pain was greater in those with some pain at the start of the study; 679 (25%) of those with some pain and 121 (8%) of those with no pain at the start developed new widespread pain at three year follow-up.
Analyses determined that pain status, anxiety, physical health-related quality of life, cognitive complaint and non-restorative sleep were associated with increased risk of widespread pain development, after adjusting for osteoarthritis (OA). Increasing age was associated with a decreased likelihood of the development of widespread pain.
“While OA is linked to new onset of widespread pain, our findings also found that poor sleep, cognition, and physical and psychological health may increase pain risk,” concludes Dr. McBeth. “Combined interventions that treat both site-specific and widespread pain are needed for older adults.”
Lupus patients have been waiting a while for some good news. Only one drug, belimumab (Benlysta), has been FDA-approved for lupus in more than 50 years — and that happened back in 2011. Since then, scientists have been trying to develop additional therapeutic agents (and failing for various reasons). But research presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals (ACR/ARP) Annual Meeting in Atlanta suggests that a new lupus medication, anifrolumab, might have the potential to get approved and make its way to market.
The manufacturer, AstraZeneca, is expected to file for FDAapproval in 2020. It’s hardly a slam dunk: The company conducted two phase 3 trials on anifrolumab, and one of them did not hit its primary endpoint, though secondary endpoints suggested that the drug had benefits. The second phase 3 study, which was presented for the first time at the recent ACR/ARP meeting, yielded more consistently positive results.
“I’m optimistic and hopeful that this drug will be approved,” says Chronicwoman medical advisor Vinicius Domingues, MD. “We have one [phase 3] study that was technically negative but with a lot of positives because of the secondary endpoints, plus a second [phase 3] study that was all positive. Patients should know that this is promising.”
The first phase 3 trial was called TULIP 1 (Treatment of Uncontrolled Lupus via the Interferon Pathway). Last August, AstraZeneca reported that anifrolumab failed to meet its primary target in TULIP 1, which was a “statistically-significant reduction in disease activity… as measured by the SLE Responder Index 4 (SRI4) at 12 months.”
SRI4 is a composite score that is often used to measure disease activity in patients with systemic lupus during clinical trials. According to SRI4, anifrolumab was as flop: Patients who added the drug to their treatment regimen did not, on average, fare better than those who added a placebo.
However, secondary endpoints in TULIP 1 found that anifrolumab beat the placebo. Those secondary endpoints included a different composite score of disease activity, called BICLA (British Isles Lupus Assessment Group-Based Composite Lupus Assessment), as well as reduced reliance on corticosteroid drugs.
The results of TULIP 1 appear in the journal Lancet Rheumatology and were discussed at the 2019 ACR/ARP meeting.
TULIP 2, the second phase III study of anifrolumab, used BICLA as its primary endpoint — and met it. TULIP 2, which was also presented at the 2019 ACR/ARP meeting, found that the drug beat the placebo as far as BICLA was concerned. It also determined that patients using it had greater improvements in skin disease and decreased use of corticosteroids.
While it’s true that researchers deliberately switched to a primary endpoint that they were likely to meet when moving from TULIP 1 to TULIP 2, there’s no clear consensus among rheumatologists that SRI4 is “better” than BICLA. In fact, a 2014 study compared these two outcome measures and determined that either one could “likely be an optimal primary endpoint” in a given clinical trial.
According to Northwestern University rheumatologist Michael Putman, MD, reporting on the trials for RheumNow, the SRI4 requires 100 percent improvement in some domains, “whereas with the BICLA you can get a little better across the board.” That might be part of why one endpoint seemed to work and the other didn’t, he said.
Anifrolumab is a monoclonal antibody that inhibits type 1 interferons, proteins that are involved in inflammation. Some lupus patients (but not all) have a “high interferon gene signature.” Scientists are simultaneously developing a test that can be used to identify those individuals. “It can be used to help predict who may or may not respond to this drug,” says Dr. Domingues. “This is an example of precision medicine, and it’s how cancer is being treated nowadays.”
“There has been a case building for many years about the importance of interferons in the pathogenesis of lupus,” Timothy Niewold, MD, Judith and Stewart Colton Professor of Medicine and Pathology and Director of the Colton Center for Autoimmunity at the New York University School of Medicine, told the ACR Daily News. “One of the most exciting recent developments is that drug companies have created agents to target the interferon pathway. It’s been a rocky road, but there have been some positive results.”
If anifrolumab gets the green light from the FDA, patients who haven’t responded well to other lupus treatments — especially those who have a high interferon gene signature — might benefit by including it in their current drug regimen, says Dr. Domingues. (The drug would be an add-on, not a replacement.)
If the drug eventually gets approved, label specifics such as recommended dosing and warnings about side effects would be revealed at that time. In the TULIP 2 study, participants in the treatment group used 300 mg of anifrolumab via infusion every four weeks. Serious adverse events were rare and occurred more frequently among those in the placebo group. The most common side effect experienced by those using anifrolumab was shingles, which occurred in 7 percent of anifrolumab users.
“Giant cell arteritis requires ongoing management, but it does not necessarily require continuous treatment.”
In 2017, tocilizumab (Actemra), a biologic drug that inhibits interleukin-6 (IL-6), was FDA-approved for giant cell arteritis — an inflammation of the lining of the arteries. At the time there was sufficient research showing that tocilizumab was better than prednisone (a steroid) for helping many patients reach remission in GCA. Yet it was unclear whether those who had reached remission should stop taking the drug or if they needed to continue using it.
Now a new study, presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals Annual Meeting in Atlanta, offers good news: A sizeable group of those who reached remission with tocilizumab were still in remission two years after stopping the drug.
The new study was an extension of an earlier 52-week study that led to tocilizumab’s FDA approval for giant cell arteritis. The drug is also approved for rheumatoid arthritis, juvenile idiopathic arthritis, and severe cytokine release syndrome.
More than 200 patients who had reached remission by using tocilizumab either once a week or every other week entered the post-marketing arm and were instructed to stop using the drug. According to their findings, 47 percent of those who had been previously taking tocilizumab weekly and 36 percent of those who had previously been taking it every other week remained in remission two years later.
Those who did experience flares were restarted on tocilizumab and/or given steroids. Those who resumed using tocilizumab (with or without a steroid) were once again able to reach remission.
“Giant cell arteritis requires ongoing management, but it does not necessarily require continuous treatment,” lead author John H. Stone, MD, MPH, told the ACR/ARP Daily News. “Patients should be started on tocilizumab as soon as they are diagnosed. The goal should be to get them off steroids as quickly as possible and maintain their response with tocilizumab.”
Some people with rheumatoid arthritis (RA) take a disease-modifying antirheumatic drug (DMARD) and/or a biologic and reach remission. Others try drug after drug after drug and never find one that’s effective — or that treats their symptoms without causing intolerable side effects. At the same time, other patients with active disease refuse to take the most powerful and effective medications on the market or can’t take them because of their medical history or personal risk factors that would make doing so dangerous.
While many scientists are continuing to explore better drug options, some are focused on developing new treatments that aren’t medications at all. One such experimental approach that’s gaining some traction is called vagus nerve stimulation, which entails using electrical impulses to stimulate the vagus nerve — the longest of the cranial nerves that stem from the brain.
The vagus nerve runs from the brain, through the face and neck, and down into the abdomen. It’s a key part of the autonomic nervous system, the division of your nervous system that controls functions you don’t have to think about, such as breathing, digesting food, and the beating of your heart. The vagus nerve is also the home of the inflammatory reflex, a pathway that appears to be crucial for detecting and modulating inflammation.
When something in your body gets injured or attacked by an invader (like a virus or bacteria), the vagus nerve helps decide how strong of an immune response the body should mount. When that response is appropriate, germs get killed off and injured tissue starts to heal. But when it’s too aggressive for the threat at hand — imagine trying to put out a small candle by holding it under a waterfall — you end up with chronic inflammation, which results in joint and tissue damage.
If you have an autoimmune condition, you already know that your immune system is far more revved up than it should be. In the case of RA, the immune system mistakenly tries to attack healthy tissue in the joints as well as in other organs. No one knows exactly what sets RA in motion, but experts do know that inflammatory substances called cytokines play an important role in causing tissue damage. Those cytokines include tumor necrosis factor (TNF) and interleukins (IL), among others.
Scientists now know that the vagus nerve has the power to reduce the production of them.
Vagus Nerve Stimulation vs. RA Medication: Same Targets, Different Approach
Many people with RA take drugs that target specific cytokines. Biologic medications such as etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade) target the ctytokine TNF, whereas anakinra (Kineret) targets IL-1 and tocilizumab (Actemra) and sarilumab (Kevzara) target IL-6.
But these drugs don’t work for everyone with RA. For these patients, stimulating the vagus nerve seems to be another way to reduce the production of cytokines that cause inflammation.
“The premise is that when you stimulate the vagus nerve it leads to the production of acetylcholine [a neurotransmitter], which binds to receptors on cells that secrete cytokines. When acetylcholine binds to those cytokine-producing cells, it inhibits them from producing TNF and interleukin-6,” says rheumatologist Mark Genovese, MD, a professor of medicine at Stanford University who conducted a pilot study on vagus nerve stimulation that was presented at the 2019 European Congress of Rheumatology (EULAR) conference.
In Genovese’s study, which was published as an abstract in the journal Annals of the Rheumatic Diseases, 14 people with RA who had tried and failed to respond to at least two medications had a small “MicroRegulator” — about the size of a nickel — implanted on the left side of the neck along the vagus nerve.
Although the primary goal of this small trial was to assess the safety of the device, half of patients who had impulses sent to the MicroRegulator once a day had significant improvements in their RA disease activity scores. A decrease in cytokine production was also measured.
A few adverse effects were reported, but all were temporary. Those included pain and swelling at the incision site as well as one patient who had temporary vocal cord paralysis.
Dr. Genovese is now helping SetPoint Medical, the company that is investigating vagus nerve science and sponsored the pilot study, design a much larger, multi-center clinical trial to learn more about whether vagus nerve stimulation can be used to treat RA, especially in people who don’t respond sufficiently to drugs.
Earlier studies, including another small trial that involved RA patients in Europe, similarly found that that implantable vagus nerve stimulator could be used to reduce TNF production and, in turn, inflammation.
While Dr. Genovese and SetPoint Medical are focused on implantable stimulators, other non-invasive approaches in this growing area of bioelectronic medicine are also being explored: One small study, published in the journal Bioelectronic Medicine this year, found that holding up a vibrational device to the ear could be used to stimulate the vagus nerve and inhibit the production of TNF, IL-1, and IL-6.
At the same time, researchers are trying to determine whether it’s possible to predict who is likely to respond well to RA medication and who’s apt to be a non-responder. One way to do that might be by testing vagal nerve tone: Low vagal tone has already been linked to more inflammation and a greater risk of autoimmune conditions.
Although more research is needed, RA patients with low vagal tone may turn out to be good candidates for vagus nerve stimulation. That’s the premise behind a medical device called ANS Neuroscan that’s being developed by Inmedix, says Vibeke Strand, MD, adjunct clinical professor in the division of immunology/rheumatology at Stanford University and a pharmaceutical and biotech consultant for companies including SetPoint Medical and Inmedix.
If ANS Neuroscan gets FDA clearance, rheumatologists might be able to use it as an in-office tool to help determine which patients are most likely to respond to biologics and who might fare better on an emerging therapy such as vagus nerve stimulation. This device provides information about vagal tone by measuring heart rate variability (as do electrocardiograms and a number of apps and gadgets like the Apple Watch).
Dr. Strand also notes that while patients who are found to have low vagal tone might very well benefit from vagus nerve stimulation, electrical impulses aren’t the only way to do it. You might be able to improve your vagal tone on your own by learning some specific breathing techniques or employing other mind-body strategies, though substantial training is likely to be involved.
“There’s a lot of stress associated with having rheumatoid arthritis, or any autoimmune disease, and that’s probably leading to some of the immune system over-activity and the autoimmune response” as modulated by the vagus nerve, says Dr. Strand.
The vagus nerve, she explains, is integral to the mind-body connection. It’s a major route by which messages travel between the brain and the gastrointestinal tract (gut-brain axis), which is why vagus nerve stimulation has also gained attention as a treatment for psychiatric and digestive disorders.
“The autonomic nervous system is part and parcel of our immune response,” says Dr. Strand. “It takes a little time for some people to wrap their heads around that.”
If ongoing and future studies are positive, vagus nerve stimulation might one day become a viable option for RA patients who don’t respond to medication, can’t take it, or don’t want to, says Dr. Strand. Some new research is also examining whether electrical nerve stimulators might be used in conjunction with drug therapies to boost their effectiveness, says Dr. Genovese.
While all this might sound a bit futuristic, vagus nerve stimulators are already on the market — just not yet for RA. Implantable stimulators have been FDA-approved for patients with drug treatment-resistant epilepsy and depression since 1997, and there’s an FDA-cleared non-invasive device aimed at people who get migraine attacks and cluster headaches. In addition to RA, vagus nerve stimulation is being investigated for a wide range of potential applications including inflammatory bowel disease, bipolar disorder, and Alzheimer’s disease.
Will rheumatoid arthritis patients soon be able to make use of a similarly FDA–approved implant or non-invasive device? Stay tuned, as the results of upcoming trials are expected in the near future.
The anti-malarial drug lowers cholesterol and blood sugar makes blood less sticky, which is good for reducing blood clots and heart attack risk.
If you take the anti-malarial drug hydroxychloroquine (Plaquenil) as part of your treatment for lupus or rheumatoid arthritis (RA), you may be getting cardiovascular protection as an added bonus.
That’s welcome news because it’s estimated that about half of lupus patients experience heart complications, and heart attacks occur at younger ages in lupus patients than in the general population. Even as young adults, black and Hispanic women with lupus often have plaque build-up in their arteries that hikes their risk of heart attack. And experts have long known that people with RA are more likely to develop heart disease, even if they don’t show signs of clogged arteries: inflammation from arthritis disease activity is thought to be the link.
Because hydroxychloroquine (HCQ) has been associated with lower levels of cholesterol, blood sugar, and the tendency of blood to clot — all cardiovascular risk factors — researchers looked at the association between HCQ use and the occurrence of heart attacks, strokes, and blood clots (in lungs or deep veins). The results were presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals annual meeting in Atlanta.
Using a health database that covers the entire population of British Columbia in Canada, researchers compared lupus and rheumatoid arthritis patients who had experienced a cardiovascular event with up to three matched patients who did not have a cardiovascular incident. Most of the patients were female (64 percent) and their average age was 74. In total, researchers studied 532 lupus cardiovascular cases and 1,249 controls, as well as 9,736 RA cardiovascular cases and 28,720 controls.
HCQ use was categorized by the most recent date covered by a prescription and divided into those currently using the medication (within last month), those who recently stopped using it (used within 30 to 365 days), those who stopped using HCQ more than a year previously, and those who had never taken it.
After controlling for such other factors as kidney disease and the use of glucocorticoids, disease-modifying anti-rheumatic drugs, and heart disease medication, lupus and RA patients currently using HCQ were 17 percent less likely to have a heart, stroke, or blood clot.
In contrast, those who had discontinued HCQ within the last year were 8 percent more likely to have one of the cardiovascular events.
When people stopped using HCQ more than a year ago, the risk of cardiovascular events was no different than those who had never been prescribed HCQ.
In another hydroxychloroquine study presented at the meeting, Johns Hopkins researchers looked at blood levels of HCQ in lupus patients who developed a blood clot (including heart attacks and clot-caused strokes). They found that patients with the highest levels of HCQ in their bloodstreams were the least likely to have developed a clot.
The researchers cautioned that following the suggestion of the American Academy of Ophthalmologists to reduce HCQ doses in an effort to prevent damage to the retina (which occurs in about one out of 5,000 patients taking HCQ for more than five years, according to Johns Hopkins), may also reduce or eliminate the benefit of HCQ in preventing blood clots.
If you’re taking hydroxychloroquine and are concerned about your dosage and how it may affect your heart disease risk or the odds of vision problems, talk to your rheumatologist and ophthalmologist to understand your risk factors and make the right decision for you.
