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Autoimmunity has become a huge issue in POTS (postural orthostatic tachycardia syndrome) and is becoming a major one in chronic fatigue syndrome (ME/CFS).  The autoimmunity revolution underway in POTS – few now believe the disease doesn’t have a major autoimmune component – has come fast and fierce. Although it was less than five years ago that autoimmunity began to be a serious topic in POTS, researchers are now suggesting that the autoimmune findings in POTS may be the tip of the iceberg. They believe their results may play a role in other autonomic disorders including ME/CFS.

The fact that this is happening in POTS – a condition which has received little funding from the NIH – is encouraging. It shows that even diseases without much funding can still at times make rapid strides if researchers explore the right areas.

The Autoimmunity Revolution in POTS (Postural Orthostatic Tachycardia Syndrome)

Dr. Kem has been behind a growing revolution in how to think about POTS. He believes that EBV, Lyme disease and other infections have activated enzymes that clip off loops found on the alpha/beta adrenergic receptors. He believes the damage to those receptors has so tweaked the immune system that it’s begun attacking them – triggering an autoimmune response.

This work goes back almost twenty years to a finding that α1AR autoantibodies can attack a second extracellular loop (ECL2) in the adrenergic receptors found on our blood vessels.

Redefining POTS

Autoimmunity findings are redefining how we think of POTS.

Jump forward to to 2011 when Kem and other researchers at the University of Oklahoma found autoantibodies to adrenergic and muscarinic receptors in a small cohort of patients (n=6) whose blood pressure falls dramatically upon standing (orthostatic hypotension). Most of these patients were medical mysteries – until this study; a larger, but still small study (n=20) in 2012 duplicated their findings and suggested that autoimmunity might be playing a role in other diseases characterized by problems with standing.

Then, in 2014, the Oklahoma team also found β1AR‐activating autoantibodies in all of the POTS patients it studied and β2AR-activating autoantibodies in some. At this point, the Oklahoma team suggested that POTS may very well be an autoimmune disease and laid out a model of POTS pathophysiology.

“These data support the addition of POTS to a growing number of cardiovascular entities with an autoimmune pathophysiology.” Li et. al.

This damaged adrenergic receptor made it more difficult for norepinephrine (NE) to trigger a vasoconstrictor response to standing, leaving POTS patients needing 55% more NE than normal to tighten down their blood vessels. The “catecholamine surge” that resulted was a compensatory mechanism used to override the adrenergic receptor malfunction. The increased levels of stress hormones needed to compensate would likely leave POTS patients “wired and tired”.

The problems POTS patients had maintaining their blood pressure caused their baroreceptors to become twitchy and hypersensitive. The end result of all this was the tachycardia (rapid heart beat) seen in POTS. It was clear that neither blood pressure nor heart rate regulation were working properly in POTS and the researchers’ autoantibody findings could explain why.  They stated that:

“These contrasting effects provide an appealing explanation for the cardiovascular effects associated with upright posture in those so afflicted.”

Nor did they believe their findings were only going to apply to POTS. They believed a range of autoantibodies were likely producing a spectrum of cardiovascular dysautonomias. The kind of dysautonomia you had depended on the types and levels of autoantibodies present. The autoantibodies typically didn’t turn off a receptor response; instead, in an allosteric fashion, they inhibited its functioning to various degrees. They proposed that a novel therapeutic using IVIG or “decoy peptides” could be the answer for many with POTS and related diseases.

The autoantibody work in POTS was just beginning, however. In a 2017 paper, the authors stated they believed the autoantibodies they’d identified were only in part responsible “for many of the cardiovascular manifestations” they’d seen in POTS patients. They believed that other autoantibodies were also playing a role, and in a 2018 paper in the Journal of the American Heart Association, they showed that as well.

Another Damaged System

Angiotensin II Type 1 Receptor Autoantibodies in Postural Tachycardia Syndrome
Xichun Yu, MD, 1 , † Hongliang Li, MD, PhD, 1 Taylor A. Murphy, BS, 1 Zachary Nuss, BS, 1 Jonathan Liles, BS, 1Campbell Liles, BS, 1 Christopher E. Aston, PhD, 2 Satish R. Raj, MD, 3 , 4 Artur Fedorowski, MD, PhD, 5 , 6 , † andDavid C. Kem, MD. J Am Heart Assoc. 2018 Apr 17; 7(8): e008351. Published online 2018 Apr 4. doi:  10.1161/JAHA.117.008351

It turned out that another system that helps us stand is damaged in POTS as well. The renin-angiotensin-aldosterone system helps regulate our blood pressure when we stand, and its receptor – the angiotensin II (Ang II) type I receptor (AT1R) belongs to the same family as the adrenergic receptors the Oklahoma team had found problems with. That suggested to them that these autoantibodies might also be present in POTS patients.

autoantibodies-blood pressure- POTS

Autoantibodies affecting the renin-aldosterone-angiotension system which regulates blood pressure were also found in POTS.

They were right. While none of the controls or the disease control group (vasovagal syncope) had autoantibodies to the angiotensin receptor, most of the 23 POTS patients in the study did. Further study revealed that the autoantibodies were indeed interfering with the system’s functioning.

The renin-angiotensin-aldosterone system kicks in during more prolonged standing, but an animal model indicated that the effects were mostly the same as the earlier results in POTS – an inability to properly squeeze the blood vessels and stop the blood from pooling in the lower body. The end result was lower blood pressure levels in POTS patients with the ATIR antibodies than in POTS patients without them.

The authors believed that the new autoantibodies may explain a mysterious group of POTS patients who have elevated angiotensin II levels but low aldosterone levels. They also suggested that the salt loading POTS patients typically do may be an attempt to compensate for this receptor’s blockage.

In his conference talk, Kem reported that the M2 receptor in POTS patients is resistant to acetylcholine, the neurotransmitter driving the vagus nerve and the parasympathetic nervous system. Studies indicate that the M2 receptor blockage found results in a vagal withdrawal (reduced vagus nerve activity). Because the vagus nerve regulates the sympathetic nervous system, which helps control the heart rate, vagal withdrawal is yet another way to produce the heart rate increases seen in POTS. (Vagal withdrawal in POTS, ME/CFS and FM is reflected in low heart rate variability results).

By 2018, then, the University of Oklahoma group had demonstrated, in mostly small studies, the presence of four different autoantibodies (α1AR, β1/2AR) that affect cardiovascular functioning in POTS. Earlier, the same research group found autoantibodies to muscarinic receptors in another disease of orthostatic intolerance called idiopathic postural hypotension. In a small 2016 study, Dubey’s findings suggested the same was true for POTS – bringing the number of possible cardiovascular system-affecting autoantibodies in POTS to six.

“We Have A Potential For a Therapy”

The big news from Kem’s talk was the real potential for a therapy – and not just a therapy which moves the needle a bit, but one which gets at the core of the disease.  Here again, POTS researchers proved to be moving faster than ME/CFS or FM researchers.  Neither ME/CFS nor fibromyalgia has an animal model, but at the conference, Kem reported that an animal model of POTS has been created.

Kem has a novel treatment – a decoy peptide which causes the autoantibodies to bind to it instead of the damaged receptors. Using a mouse-sized tilt table, Kem tested the decoy peptide in the animal model and it worked – the mice experienced no heart rate increases when taking a tilt table test.

Roadblock

Kem proclaimed, “We now have a potential for a therapy”, but he has hit a legal roadblock. It turns out that just two sentences in another patent described a similar method of using a “peptide decoy”. Despite the fact that the other patent didn’t test the idea or fully explicate it in the patent, the patent office is, thus far, denying Kem’s patent application – which he will need to raise money for the study.

stop patent POTS

Kem’s patent application for a novel therapy for POTS hit a roadblock, but he hopes to get back on track in about 6 months.

An appeal is underway and should be complete within 6-8 months. If successful, it will take a year to test the decoy peptide in laboratory animals. If that’s successful, a Phase II safety and efficacy study in humans would probably take two years. If that works out, then come the big Phase III studies; we’re looking at a minimum of five years, if everything goes smoothly, before a drug could come to market. If it does make it, though, it could be a very effective treatment for POTS.

Kem is putting his focus on getting treatments to POTS patients first, and the antibody tests he’s using are not available commercially yet. Kem, though, appears absolutely sure that POTS is, at least in large part, an autoimmune disease. He believes all postulates needed by Witebskey’s Postulates for the presence of an autoimmune disorder have been fulfilled.

From the discovery of perhaps six autoantibodies that are whacking away at the cardiovascular systems of POTS patients, to a potential treatment that appears, at least thus far, to work in an animal model, the POTS field, small as it is (the NIH didn’t even track POTS spending until recently), has been moving fast.

Next up, a Mayo MD talked about an autoimmune disease he believes is greatly underdiagnosed in POTS, how he treats the autoimmunity he finds in POTS, the role he believes MCAS plays, and more.

Autoimmunity, Sjogren’s Syndrome, Mast Cell Activation Syndrome and POTS – Brent Goodman MD

Brent Goodman is a Mayo Clinic doctor hailing from Phoenix, Az who gets it. He came to talk about the complex situation regarding autoimmunity, MCAS, POTS and treatment.

Some clues indicating that you may have an autoimmune condition include: acute onset, infectious onset, immunization onset, family history of autoimmunity, significant and rapid weight loss, onset during pregnancy – many of which we see in POTS, ME/CFS and/or FM.

It’s a complex field. Unfortunately, most autoantibody tests lack specificity. (Ron Davis’s lab is working on better antibody tests). Plus, as Grubb noted in his earlier presentation, more than one autoantibody is usually present in an autoimmune disease. (Eight to ten are apparently present in rheumatoid arthritis. Thus far, about six have been associated with POTS, and more may be present in ME/CFS).

The presence or absence of autoantibodies may not, however, correlate with disease activity, and autoantibody treatment may not result in reduced symptoms. Major fluctuations in symptoms in diseases like Sjogren’s Syndrome can obscure treatment effects. You get the feeling that while medical science has made strides with treating some autoimmune diseases, it’s still struggling to get a handle on them.

Sjogren’s Syndrome – The All Purpose Disorder

Goodman highlighted Sjogren’s Syndrome (SS). When you look for SS in POTS, he said, you will find it. He believes it’s an important part of POTS.

Sjogren Syndrome (SS) is a subject that’s near and dear to my heart – my mother didn’t have ME/CFS, but she eventually died of complications from Sjogren’s in her fifties.

SS is known for the dry eyes and mouth it often – but not always – produces, but it also has a predilection for affecting the autonomic nervous system. In fact, Goodman is so taken with the autonomic nervous system symptoms SS produces that he and his co-authors wrote in a recent study that: “A diagnosis of Sjögren Syndrome should be aggressively pursued in patients with signs and symptoms suggestive of autonomic nervous system impairment.”

That small study suggested that autonomic problems run rampant in Sjogren’s Syndrome. All the participants reported lightheadedness, fainting or near fainting upon standing. Over half of his patients displayed exaggerated heart rates or increased blood pressure upon standing. Plus, the gastrointestinal and/or urinary symptoms so often present in POTS and ME/CFS were found in almost all the participants, and gut motility was impaired in 5/6 patients who underwent testing.

Sjogren's diagnosis

If your symptoms fit Sjogren’s and you have a negative antibody test, you still need a lip biopsy to rule Sjogren’s Syndrome in or out.

Goodman is not the only one to notice the Sjogren’s autonomic nervous system connection. A larger Korean study found that autonomic problems were common in Sjogren’s and were associated with increased fatigue. An even larger 2012 UK study and a 2008 Swedish study suggested the same.

Sjogren’s Syndrome – which was mentioned again and again at the conference – could be causing your POTS or ME/CFS-like symptoms. In fact, Goodman, who called Sjogren’s an all-purpose disorder, said that if you can think of a neurological condition, Sjogren’s can cause it.

The good news is that if you do happen to have Sjogren’s Syndrome – instead of or in addition to POTS or ME/CFS – treatment possibilities are available: Goodman reported that three Sjogren’s Syndrome patients in his study who received immune therapy (IVIG or IVIG+Rituximab) improved significantly. After treatment, two of them no longer experienced any autonomic nervous system symptoms such as problems standing.

Getting Tested

Getting diagnosed with SS requires either positive antibody blood tests OR a positive minor salivary gland biopsy. Doctors who rely on antibody tests in combination with dry eyes/mouth to diagnose SS are behind.  About 40% of Sjogren’s patients don’t have the SS-A or SS-B antibodies, Some never experience dry eyes or mouth.  Dysautonomia International notes that younger SS patients with neurological symptoms may be more likely to have negative antibody tests. SS can affect the autonomic nervous system without producing either.

Mast Cell Activation Syndrome (MCAS)

Goodman was another presenter at the conference who was very high on mast cell activation syndrome (MCAS). He believes MCAS is a common downstream consequence of Sjogren’s Syndrome. He gave another twist to the autoantibody findings in POTS when he reported that the adrenergic antibodies found in POTS can also activate mast cells.

Lauren Stiles (Dysautonomia International founder), whose tortured path to her SS diagnosis can be found below, noted that her mast cells were going bananas until she got IVIG and then they quieted down.

From Chronic Fatigue Syndrome to Fibromyalgia To POTS To Success: One Woman’s Journey Through the Medical Profession

Goodman recommends MCAS treatment whether testing is positive or not if the symptoms fit the bill. (He treats the patients – not the lab results).

Goodman noted that GI dsymotility (movement issues – either slowed or increased) are greatly underappreciated and can be severe in POTS. They can affect the gut (digestive problems) and/or the esophagus (swallowing problems) and require feeding tubes, resulting in hospitalization. He’s also finding that Cromolyn works great for gastrointestinal symptoms.

Autoimmune diseases can produce so many symptoms that diagnosis can take a while. Goodman remembered a 36 year old woman diagnosed by a Mayo doctor with “adjustment disorder”, whom he, another Mayo doctor, later found to have POTS. She had indications of autoimmunity and he treated her with IVIG and methylprednisone and she quickly recovered. He wondered if early treatment (which rarely happens) could make a big difference. In people with Sjogren’s Syndrome and POTS, he reported that IVIG has an 83% success rate (!).

Treatment can be tricky, though. Goodman described a Sjogren’s Syndrome patient who responded to IVIG, recovered, played sports again, and then developed a bad case of dry eyes/mouth and started producing antibodies to Sjogren’s.

Goodman usually uses subQ immunoglobulin (SCIG, 0.4 grams/kg weekly) instead of IVIG in chronic conditions because of the risk of developing aseptic meningitis and because of headache problems.

Goodman also uses methylprednisolone (1 g IV x 1-2 d.) instead of prednisone. The potential for the chronic side effects associated with prednisone use are minimal with methylprednisone. He also uses Rituximab a fair bit.

Conference Overviews

Thanks to Dysautonomia International for their support attending the conference.

Next Up – An Entirely Different Kind of POTS – Hyperadrenergic POTS

 

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