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What Dysautonomia Patients Should Know About Antiphospholipid Syndrome

Many patients have sent Dysautonomia International questions about the association between antiphospholipid syndrome and POTS, after an article appeared in the medical journal Lupus on this topic on February 25, 2014.  Dysautonomia International asked the first author of this article, Dr. Jill Schofield, to address some of the questions raised by the patient community in the following blog post.  Please note that this is not meant to replace advice given by your own physician.

What Dysautonomia Patients Should Know About Antiphospholipid Syndrome
by Jill R. Schofield, MD

We have recently published the first clinical association of postural orthostatic tachycardia syndrome (POTS), neurocardiogenic syncope (NCS) and orthostatic hypotension (OH) with antiphospholipid syndrome (APS).  APS is also known as Hughes syndrome.  I was delighted to co-author this paper with Professor Graham Hughes, who first described antiphospholipid syndrome in 1983, Professor Yehuda Shoenfeld, considered by many to be the “father of autoimmunity” and Dr. Svetlana Blitshteyn, noted autonomic expert and member of the Dysautonomia International Medical Advisory Board.  You can view the abstract of the article here: Postural tachycardia syndrome (POTS) and other autonomic disorders in antiphospholipid (Hughes) syndrome (APS).  The journal requires a paid subscription to view the full article, but your physician should be able to access it.

What is APS?
APS is a complex autoimmune disorder that is associated with several different antiphospholipid antibodies.  These antibodies may be directed against clotting factors, platelets, and/or the cells that line blood vessel walls and they cause the blood to be too sticky. This results in an increased risk of blood clots in:

1) Arteries–causing most commonly stroke or heart attack.
2) Veins–causing deep vein thrombosis (DVT) of the legs and/or pulmonary embolus (PE) of the lungs.
3) Placenta–causing recurrent miscarriage, stillbirth or low birth weight babies.

In addition to an increased risk for blood clots, a number of other manifestations may occur in APS due to “sludging” of the blood. The list of these non-clotting manifestations is long and they are less well known to most physicians.  Some of these manifestations include migraine (which may be severe and refractory to usual treatments), memory loss, seizures and stress fractures. We have now demonstrated that POTS, NCS and OH may also occur as non-clotting manifestations of APS.

How is APS diagnosed?
The Sapporo criteria for the diagnosis of definite APS requires:

1. Clinical criteria: Thrombosis (blood clot) or very specific pregnancy complications (such as three or more miscarriages).

2. Laboratory criteria: Medium to high titer antiphospholipid antibodies on more than one occasion at least 12 weeks apart.

These criteria were designed for rigorous clinical research studies, not for diagnosis. Unfortunately, most practicing physicians believe they were designed for diagnosis and this has resulted in patients with low titer antibodies and/or non-clotting manifestations not being diagnosed with APS, when they do have the syndrome. My hope is that we can change this perception, because I believe that with earlier diagnosis, we can prevent the thrombotic events!

For our study, we used the following criteria:

At least one clinical manifestation of the syndrome (including the non-clotting manifestations) along with the presence of one or more of the antiphospholipid antibodies in any titer:

1) Anticardiolipin IgG and/or IgM
2) Beta 2 glycoprotein I IgG and/or IgM
3) Lupus anticoagulant

It is common to have only one of these antibodies, but some patients have two or even all three. Occasionally various infections might cause a transient elevation in one or more of these tests, so the diagnostic criteria require you to have one or more of these antibodies on more than one occasion at least 12 weeks apart.  Notably, many of the patients in our study had low titers of the APS antibodies.

The lupus anticoagulant test has a misleading name because it is not a test for lupus and it is associated with increased clotting, not decreased clotting as the name implies. APS, however, may occur along with lupus, as well as Sjogrens syndrome or rheumatoid arthritis. It may also occur on its own. Most APS experts are either rheumatologists, hematologists or obstetricians, but most physicians are familiar with these tests, they can be ordered at any lab and they are relatively inexpensive.

Once a diagnosis of APS is made, there is no indication to repeat the antibody tests.  APS is not known to just resolve, but the antibodies are known to wax and wane over time.  There are many stories of patients who have had their levels fall into the normal range when their physicians repeatedly tested their antibodies and when told they no longer had APS and could stop their blood thinners, they went on to develop stroke or other major clotting events.

Regarding imaging tests, CT or MRI scans are used to test for stroke or other blood clots in APS patients with suspicious symptoms and clots in this syndrome can be found in any blood vessel.    Some APS patients have “white spots” on brain MRI scans; these are felt to represent very tiny clots. Ultrasound is commonly used to test for blood clots in the legs when there is new leg pain and/or swelling.

How common is APS?
APS is not rare.  It has been estimated to affect approximately 1 out of 100 people (1% of the population).  It is, however, underdiagnosed.

We do not know how many POTS, NCS or OH patients have APS, but Dysautonomia International recently funded a research project designed by Dr. Svetlana Blitshteyn to try to shed some light on the topic of autoimmune markers and autoimmune conditions in patients with POTS.  Dysautonomia International will make an announcement when Dr. Blitshetyn’s study results are released.

We also do not yet know how often autonomic disorders occur in APS patients.

Should all patients with POTS be tested for APS?
Because this is a newly described clinical association, we have a lot to learn.  At this time, I believe all POTS patients should be tested for APS; other physicians might disagree.  At the very least, I believe all POTS patients with any of the following should be tested for APS: migraine, memory loss, balance trouble, livedo reticularis, Raynaud’s phenomenon, history of miscarriage, another autoimmune condition, a family history of blood clots or a family history of autoimmune disease. These were the most common findings in the patients in our study.  Also, of note, three of the 15 APS patients included our study also had Joint Hypermobility Syndrome (JHS).

Raynaud-hand2                               Screen Shot 2014-03-04 at 7.34.04 PM
Raynaud’s Phenomenon                                               Livedo Reticularis

The reason I believe all POTS patients without an apparent cause should be tested for APS is that POTS caused by APS might improve with a trial of aspirin, clopidogrel, heparin, warfarin and/or IVIG.  Many of these agents increase the risk of bleeding, however, which makes many physicians not experienced with APS nervous about using them in APS patients who have not had a clotting episode.  Because APS is a very hypercoagulable condition, however, APS patients (even those on high doses of blood thinners) have a much greater risk of clotting than bleeding. Despite this, Professor Hughes believes that many APS patients have been under-treated due to physician concerns about bleeding.

Additionally, APS is a serious medical condition and early diagnosis can help reduce the risk of major complications.  If you have one or more of the APS antibodies, you are at an increased risk for blood clots. If you are aware you have one or more of these antibodies, you can reduce your risk of blood clots by avoiding cigarettes, birth control pills or hormone replacement therapy.  You can also be sure that if you have other vascular risk factors, such as high blood pressure, high cholesterol or diabetes, they are treated aggressively.  Aspirin has also been shown to reduce the risk of arterial events in patients with APS antibodies.  Additionally, Professor Yehuda Shoenfeld’s research has shown that vitamin D levels are low (less than 15 ng/ml) in half of patients with APS and that low levels are associated with an increased risk for clotting and non-clotting manifestations of the syndrome.  So it makes sense for these patients to also be treated with vitamin D.

How is APS treated?
In addition to the points made above, APS patients who have had an arterial or venous clotting event are generally treated with blood thinners (usually warfarin or heparin) for life.  There are also several newer oral anticoagulants, one of which is presently being studied in APS patients in London.  Until this data is available, these drugs are generally not recommended for most APS patients.  APS patients with recurrent miscarriages are treated with aspirin and usually heparin (warfarin is contraindicated in pregnancy) throughout their pregnancy and for at least 6 weeks after delivery.

Importantly, Professor Hughes has found over the years that many of the non-clotting manifestations of APS often improve significantly or may even be completely aborted with anti-platelet agents such as aspirin or clopidogrel, and/or warfarin or heparin.  He has also found this to be true for autonomic symptoms in some APS patients.  Two patients in our study with POTS that did not improve with standard APS treatments (despite improvement of other APS manifestations) improved significantly with regular intravenous immunoglobulin (IVIG) therapy.  Unfortunately, IVIG is very expensive and many insurance companies require more data than two case reports before approving its use for a specific indication.

Where can you find additional resources on APS?
Dysautonomia International has a brief explanation of APS on its website, as well as some links to APS related journal articles and non-profit organizations. You can find a physician experienced in APS by going to APSAction.org, an international organization started in 2010 to improve collaboration amongst APS experts and to facilitate APS research.  An excellent patient forum on APS is HealthUnlocked Hughes syndrome and Professor Hughes has written a great book for patients entitled, Understanding Hughes Syndrome: Case Studies for Patients.

JillSchofieldDr. Schofield is a Johns Hopkins trained internist who has developed an interest in APS over the last few years. She currently practices in Denver, Colorado but plans to develop a multi-disciplinary (i.e. involving physicians from many specialties) APS clinic in an academic environment and is currently exploring options for where best to do this.

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New evidence of autoimmunity in POTS!

IS POTS AN AUTOIMMUNE DISEASE?

Big news this week in POTS research! Researchers from the University of Oklahoma and Vanderbilt University have identified evidence of adrenergic receptor autoantibodies in a small group of POTS patients, suggesting that POTS may be an autoimmune condition in these patients. The study was published in the Journal of the American Heart Association (JAHA). JAHA is an official journal of the American Heart Association, so this is great news for POTS awareness!

To help patients better understand what this means, Dr. David Kem from the University of Oklahoma Health Sciences Center has kindly provided Dysautonomia International with a patient friendly explanation of this complex research. Before we get to Dr. Kem’s explanation, let’s go over the basics of adrenergic receptors and autoantibodies.

Adrenergic receptors are present on the surface of cells in many different parts of the body, including the heart, blood vessels, nerves, brain, lungs, bladder, gastrointestinal tract and elsewhere. There are two main types of adrenergic receptors in the body – alpha adrenergic receptors and beta adrenergic receptors. Within the alpha and beta types, there are many different subtypes (alpha-1, alpha-2A, alpha-2B, alpha-2C, beta-1, beta-2, etc.)

Think of adrenergic receptors like a TV antenna (if you are old enough to remember when TVs had antennas!). If the TV antenna picks up a signal, it transmits a message across the screen. In adrenergic receptors the “signals” are chemicals present in the body called catecholamines (primarily epinephrine and norepinephrine). The “message” is what the catecholamine tells the receptor to do. For example, constrict a blood vessel or make the heart beat faster.

adrenergic receptor

 

Image of an adrenergic receptor, which is stimulated by catecholamines.

 

 

Antibodies are proteins created by your own immune system to protect you from pathogens, like bacteria and viruses. The human immune system can make more than 1 trillion different antibodies, each one meant to protect us from a different pathogen. Unfortunately, sometimes the antibody formation process goes awry, and the antibodies created by your immune system can turn against your own cells. These trouble-making antibodies are called autoantibodies. Autoantibodies can attack, damage or interfere with the functioning of healthy tissues and cells in your body.

Now that we all know what adrenergic receptors and autoantibodies are, here is what Dr. Kem has to say about the adrenergic receptor autoantibodies recently found in POTS patients:

POTS occurs frequently, but not exclusively, in younger females and its onset is occasionally preceded by or associated with a viral-like illness. It is more than a minor annoyance for most patients and leads to significant life changes and limitations in normal life. Our present study (Autoimmune Basis for Postural Tachycardia Syndrome) has produced data supporting the idea that production of autoantibodies, circulating proteins that normally fight such infections, have instead interacted with critical site(s) on specialized cell membrane proteins which alter their normal cell function.

These autoantibodies interfere with the system which controls the ability of blood vessels to constrict, which is needed to prevent a drop of blood pressure as a person stands. In POTS patients, this inadequate response to standing leads to a generalized increase of activity in the body’s sympathetic nerve system, which frequently normalizes the blood pressure. This increased nerve activity, however, increases the heart rate which is a prominent symptom in POTS.

We have also discovered a second group of autoantibodies in some POTS patients which directly increase the heart rate.

The combination of these two autoantibodies appears to cause the abnormal heart rate response observed in all 14 POTS patients we have tested to date for these autoantibodies.  We have previously identified similar autoantibodies in individuals diagnosed with idiopathic orthostatic hypotension (Editor’s note: see Agnostic Autoantobodies as Vasodilators in Orthostatic Hypotension: A New Mechanism and Autoantibody Activation of Beta-Adrenergic and Muscarinic Receptors Contributes to an “Autoimmune” Orthostatic Hypotension).

These autoantibodies may explain why beta blockers aren’t always effective in treating the tachycardia seen in POTS, since beta blockers fail to completely block autoantibody activity on their protein receptor and they fail to alter the partial blockade of the autoantibodies on the arteriole blood vessels that initiate the orthostatic problem.

Confirmation of our findings will require testing a larger group of POTS patients for these autoantibodies. We hope to eventually develop treatments to block these autoantibodies, without blocking the target receptor proteins at the cell surface at the same time. Such agents are in development and within a few years may be applicable in POTS. This approach may prove useful in several other diseases which are caused by similar autoantibodies.

Please note that Dr. Kem and the other researchers involved are not able to test patient blood samples for these autoantibodies outside of a research setting at this time. There are very strict federal laws that prohibit them from doing so. If such a test becomes available to the public, Dysautonomia International will be shouting it from the roof tops. Imagine that – a blood test to help diagnose POTS ? We’re looking forward to it, but there is much work to be done.

Dysautonomia International is committed to funding additional research in this area as quickly as possible. We are optimistic that this will lead to a better understanding of POTS, better ways to diagnose it, and most importantly, better ways to treat it.

If you would like to support the next phase of this exciting new research, please consider making a donation to Dysautonomia International today.  You can make a difference in the lives of millions of people around the world living with POTS!

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How to Find Accurate Scientific Information on the Web

As both a POTS patient and a researcher, my goal in writing this blog post is to help all POTS patients find reliable information on their illness and become a refined connoisseur of scientific literature. By doing this, you can generate intelligent hypotheses and engage in meaningful discussions with doctors and scientists – because we need your help. You don’t need a doctorate degree to contribute to science.

When I first started researching POTS in a laboratory setting, I thought I knew a lot about the disorder since I had done my own online research for years. I had no idea how much of what I “knew” about POTS was based on speculation or even incorrect information.

For instance, I thought that POTS involved an overstimulation of the sympathetic nervous system that led to symptoms, because I read about it on so many blogs, websites, and Wikipedia. Talking with my mentors and digging deep into the existing scientific literature, I found out that it’s not that simple. In fact, I learned that most POTS patients actually have a blunted increase in sympathetic nerve activity upon standing.

Published scientific papers are much more reliable than other sources of information because they are peer-reviewed. This means that before a paper is accepted and published by a journal, it is sent to at least two experts in the field who either approve, suggest revisions be made, or reject the paper. The peer-review process helps ensure that the research is meaningful and that the paper is a valid representation of the study.

There are three main types of research papers:

1.     Case Reports and Case Series
Case reports and  series are detailed reports of an individual or a small series of patients. Case reports and series are often used to describe a rare disease, or an unusual presentation of a common disease. The report includes patient demographic information, as well as symptoms, diagnosis, and treatment of the disease. However, case reports and series only contain anecdotal information about one patient or a small number of patients; they are not science and most are not peer-reviewed. Case reports are given the least weight and credibility by medical professionals and researchers.

2.     Original Research Articles
Original research articles contain a detailed report from the researchers about the study they conducted. Original research articles are usually divided into five parts: (1) the abstract which summarizes the study; (2) the introduction, which gives you some background and states the objective and hypothesis for the study; (3) the methods that explain how the study was conducted; (4) the results; and (5) the discussion or conclusion which puts the results in the context of the field of research and explains the study’s significance and implications. Original research articles are a primary source and there is no better way to gather information than directly from the researchers themselves.

There are many different types of original research articles, and the study design is the major factor in determining how much weight to give a study. Observational studies, such as questionnaires, study research subjects at one or more time points, but no intervention is given. An interventional study looks at the effect of a certain treatment (a drug, exercise, diet, etc.) on a group of subjects and either compares the subjects to themselves before the intervention or to a control group. When reading interventional studies look for keywords in the methods like “control,” “placebo-control”, “blind” and “double-blind,” “crossover,” and “randomized.” A control group is a group of subjects that did not receive treatment, which is compared to a treatment group. A placebo-control means that one group received a placebo treatment instead of the active treatment. A placebo is a “fake” treatment, like a sugar pill or an injection that doesn’t contain any drug. In blinded studies the subjects don’t know what treatment they receive and in double-blinded studies neither the subjects nor the researchers are aware of the treatment (usually a nurse or lab technician knows the treatments for safety reasons). In a crossover study, each subject receives more than one treatment during the study duration and randomized means that the order that the treatments are given varies across subjects. All of these design features strengthen the study and make the results more compelling.

3.     Review Articles
Review articles are papers that summarize a certain topic by discussing results from numerous original research articles. There are pros and cons to review articles. They are great for getting a broad overview of a topic. Journals invite experts on certain topics to write review articles and they are also peer-reviewed so the information is very reliable. The downside is that review articles do not go into the methods of every study they cite and the authors can sometimes misinterpret the primary literature in the review article. Therefore, if you read a review article I would suggest that you look at the references and find the original review articles that correspond to the sections that interested you and skim those as well.

Reading peer-reviewed research and review articles is a good start, but keep in mind that not all journals carry the same weight. A journal’s impact factor is a good indicator of how important the information it publishes is. A study that will change the face of medicine can get into a high impact journal like The Journal of the American Medical Association or JAMA (impact factor = 30) or for groundbreaking cardiovascular research, Circulation (impact factor = 15). Other studies with less powerful data may be published in lower impact journals like Clinical Autonomic Research (impact factor = 1.5). This doesn’t mean that a journal with a low impact factor contains false information, articles in these journals are peer-reviewed as well, yet the data may not be as compelling or noteworthy. Low impact journals often focus on more specific topics for a targeted audience, which can be a good thing. For example, Circulation is read by most cardiologists, but it does not publish many papers on POTS. On the other hand, Clinical Autonomic Research publishes on POTS often and is read by most who study disorders of the autonomic nervous system.

However, just because something is published in a good peer-reviewed journal doesn’t mean it’s a proven fact. For example, we have all heard that “500,000 Americans have POTS.” This factoid has been published in dozens of credible journal articles which all cited to one paper for this estimate. Yet the “original” paper had no discussion to how this estimate was made. This “fact” was an educated guess made by experts in the field, which I found out by contacting the author directly. This experience taught me to be a critical reader and get to the source of a fact to see how accurate and precise it is.

If I’ve learned anything from being involved in medical research for the past three years, it’s to not believe everything I read. I encourage you all to become informed patients. Search for papers from credible peer-review journals and become a critical reader of scientific literature. Below are some tips to get you started.

How to find a credible journal article
1.     Search for primary literature on databases like PubMed.gov and Google Scholar. Don’t believe everything you read on Facebook groups, blogs, Wikipedia or commercial websites. You can also find links to many primary sources on POTS and other autonomic disorders on the Dysautonomia International website.

2.     Review articles on Medscape, Up to Date, and in most journals are good for a broad overview of a topic, but check the articles they cite before accepting anything as fact.

3.     When you find a paper, look at the journal’s name and impact factor. The higher the impact factor, the more highly regarded the journal. This is usually available on the journal’s website.

4.     Look at the author affiliations – are they from a well-known school/hospital with a reputable autonomic lab?

5.     Look at the senior author (last author on the list). He or she is the one that oversaw the study. Do you recognize his or her name as an autonomic expert?

6.     Look at the author(s) prior publications. If you click on the authors name on PubMed.gov, there is usually a link to other studies they have published. Have they published other studies on POTS or other autonomic disorders? If you can’t find this on PubMed.gov, the researcher may have a list of publications on his or her biography page, which can often be found on the website of the university he or she is affiliated with.

How to critically read an original research paper
1.  Start with the abstract – this is the summary. See if this article is interesting to you and worth reading.

2.  Read the introduction. Look for the purpose of this study. Read about what was known and unknown prior to this study to give yourself some context. Sometimes the background for a study can lead you to another fascinating paper to read later.

3.   Glance at the methods. See what was actually done in the study. You don’t have to understand all the details of the methods, but make sure the methods make sense for the topic. Some methods are more reliable and valuable than others and you will learn this over time.

4.   Look at the results and figures. Check what is statistically significant (if P < 0.05, it’s significant). If it’s not statistically significant, it’s not a solid finding.

5.   Ask yourself, do the conclusions make sense based on the results? The conclusions can sometimes be much broader than what the results actually warrant.

6.   If this study involves human subjects and you are trying to decide if these findings apply to your circumstance, check the inclusion criteria in the methods section. Also look at subjects’ demographic data (ie. age, gender, race, etc.) in the results to see if the study subjects are similar to you.

7.  Do not be afraid to get to the source. If you have questions about the research paper, send a respectful and concise email the corresponding author. Usually their email is listed on the first page of the paper.

 

735619_10200497815672835_1483624716_oGuest contributor Amanda Ross graduated from Johns Hopkins University with a B.A. in Behavioral Biology. Working with noted POTS researchers, Dr. Julian Stewart and Dr. Peter Rowe, Amanda has published two peer-reviewed research papers on POTS. She also gave a presentation on one of her studies to fellow researchers at the 24th International Symposium on the Autonomic Nervous System. She is currently pursuing a Ph.D. in Neuroscience at Pennsylvania State University College of Medicine and looks forward to conducting additional research on POTS and the autonomic nervous system. Amanda is a founding member of the Dysautonomia International Patient Advisory Board.

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