12. Investigating Autoimmune Disorders with Jill Schofield, M.D.

Episodes have been transcribed to improve the accessibility of this information. Our best attempts have been made to ensure accuracy,  however, if you discover a possible error please notify us at info@bendybodies.org

00:00:00 

Linda Bluestein 

Welcome to bendy bodies with the hypermobility MD. This is your host, Dr. Linda Bluestein today, along with  Jennifer Milner. I have the great pleasure of speaking with Dr. Jill Schofield, founder, and director of the center  for multi-system disease after completing her internal medicine residency at Johns Hopkins, Dr. Scofield  underwent subspecialty training and multi-systemic autoimmune disease and blood clotting disorders. In 2014,  she described the association of autonomic disorders and the anti phospholipid syndrome with Dr. Graham  Hughes in London, who himself had first described the antiphospholipid syndrome. Dr. Scofield was the  recipient of the dysautonomia support network patients choice gamechanger award in 2019 for her work in the  use of immunoglobulin therapy and auto-immune dysautonomia. She also authored the chapter auto-immunity  and hypermobility for the book disjointed navigating the diagnosis and management of hypermobile Ehlers Danlos syndrome and hypermobility spectrum disorders, which is a must read for anyone interested in these  types,  

00:01:10 

Linda Bluestein 

Hello, and welcome to bendy bodies and Jennifer. Hello, and it's so great to chat with you again today. Good to  be back as always. Dr. Schofield, can you start out by giving us a general overview of auto-immune disorder?  

00:01:25 

Jill Schofield 

Sure. Autoimmune disorders, are disorders really where there's a mistake in the immune system. The, job of the  immune system is to fight off foreign invaders, and that might seem like a simple job, but actually in order to do  it right, the immune system has to distinguish between self and non-self or our body and foreign invaders. And,  

sometimes a mistake occurs where the immune system thinks a molecule or protein in the body is foreign. That's  when auto-immunity develops because the immune system is then attacking something in the body and that  leads to tissue damage. That manifests as symptoms depending on what tissue or tissues are damaged. The most common example is autoimmune thyroid disease, where the immune system is recognizing a molecule or  protein in the thyroid as foreign. And then there's damage to the thyroid. There's not always actually damage to  the thyroid. There can just be the antibodies, but the thyroid works normally, but it's still a marker that there's a  problem with the immune system that can, once there's one problem with the immune system, more problems  can arise.  

00:02:47 

Jill Schofield 

It can serve as a marker red flag that we, the person's at risk of other autoimmune issues. Also they're at risk  where their thyroid function might deteriorate over time. Thyroid autoimmune, thyroid disease, an example of  what we call a disease specific, autoimmune disease where just the thyroid might be affected, but diseases like  autoimmune diseases like lupus, rheumatoid arthritis, Sjogren's syndrome. Those are systemic autoimmune  diseases where there can be problems with multiple organ systems and depending on the individual case. Really  there a problem of, dysregulation in the immune system. And, only about 8% of the population will ever get an  autoimmune disease. You have to inherit a genetic predisposition to ever get it an autoimmune disease. There  has to be a trigger and probably there has to be more than one trigger, for the, for an auto-immune disease to  actually manifest clinically. And so it's very complex.  

00:03:57 

Jill Schofield 

We have a lot to learn about it, but that's kind of an overview.  

00:04:01 

Linda Bluestein 

Sure, sure. Overall, do you think the prevalence is increasing and if so, why might that be, or is this something  that, you mentioned 8%, is that something that's been pretty stable over time?  

00:04:13 

Jill Schofield 

The, the incidences increasing for, I think every autoimmune and immune mediated disease, except perhaps  rheumatoid arthritis, cause smoking is a big trigger for rheumatoid arthritis is incidence of smoking has gone  down and that may be why that incidents, rheumatoid arthritis hasn't risen like most or all of the rest of the auto immune diseases. Probably, mass cell activation syndrome, which is not an autoimmune disease because, but it's  an immune mediated disease where the mass cells are also part of the immune system, but in mass cell  activation syndrome, they're getting activated and they're not attacking something in the body. They're just  releasing chemicals that are then damaging the body, but there's not, they're not specifically attacking a  molecule in the body and mass cell activation syndrome seems to be increasing as well. I don't know that's been  formally published in the medical literature, but for those of us in clinical practice certainly seems to be  exploding.  

00:05:15 

Jill Schofield 

Sure, sure. Why, so why there is a tremendous change in our environment? there hasn't been time for there to be  genetic changes, because we're seeing this increase in the last one and even, two generations. It has to be a  problem with our environment and there's, as we all know, tremendous change in our environment in the last  two decades with, some of the things that have been suggested, are, all the chemicals in the environment, the  ability to, prior to COVID the ability to dart here and there, from this country to that country, which leads to a  shift in the microbiome and the microbiome we're learning has tremendous influence on the immune. There's the  hygiene hypothesis, which is probably going to be even worse now with COVID where we keep everything to  clean kids aren't playing in the dirt anymore. The immune system is kind of doesn't have anything to do.  

00:06:11 

Jill Schofield 

I think I'm not at all anti-vaxxer, but the number, the sheer number of vaccines that are given today compared to  one or even two or even one generation ago is dramatically increased in every vaccine has an Agilent. An  Agilent is a non-specific stimulator of the immune system to make us respond to the vaccine, to the molecule of  say a virus. If you're born within everything exists on a bell shaped curve, and if your immune system is on the  kind of higher end of active, and you're getting, 25 vaccines in your first year, that could tip you over to where  you might develop an autoimmune disease where you might not have many years ago, but obviously as we're  learning with COVID, I mean, vaccines are extremely important. It's, a hundred years ago people died of infectious diseases and now, and the people with an overactive immune system were in a better position and  now, the tables have turned.  

00:07:18 

Jill Schofield 

Those are some of the reasons, that have been proposed for why we may be seeing this explosion in auto immune diseases. It's probably more complicated even than that. The immune system is extremely complicated  and its interaction, our interaction of our immune system with the environment. Very complicated.  

00:07:38 

Linda Bluestein 

Sure. What about the difference between males and females? It w I'm thinking of in terms of like pregnancy and  that kind of thing you were talking about like a triggering event, is, are there differences between males and  females?  

00:07:52 

Jill Schofield 

There's a much greater incidence of auto-immune disease in females. That's not fully understood. It's not as  simple as hormones. Certainly we think hormones play a role because it's the period of time, of the menstruation  in women, from say age 15 to 50 that's when we see the most auto-immune disease. Some of the autoimmune  diseases, the ratio is very high, like I think Sjogren's, it's nine to one lupus. It's eight to one, somewhere in that  ballpark, it's dramatically higher in women. And, people are studying that, differences in B cells and women  versus men, et cetera. It's not as simple as hormonal, but that's felt to play a role. Just another of the many areas  we have a lot to learn about. It doesn't seem like there's such a, difference in, female, male ratio and M cast  though. That's just my anecdotal experience. I don't know what others' experiences then that doesn't seem as  strongly female predominant in impasse auto immune disease.  

00:09:08 

Linda Bluestein 

That's interesting because we know that for EDS Ehlers-Danlos syndromes and for those, that probably a lot of  people know what MCAS is, but mass cell activation syndrome, we will refer to that as MCAS, a lot through  this conversation. So, so we know that, and that was the next thing I was going to ask you about was if you  could describe the relationship between autoimmune disorders, dysautonomia, EDS, and MCAS, and we know  that dysautonomia and EDS are more prevalent in females, right?  

00:09:37 

Jill Schofield 

Yeah, absolutely. I guess all of those things are, seem to be much more prevalent symptomatically in women  than males, except for, I think, except for. There seems to be this tremendous link between all of those  conditions. That those of us in the trenches are noticing. I know that some of the group, the MCAS group that  has a much more narrow definition of AMCAS is tried to refute that link. If you see patients, there's a very  strong link. I think of it as three gears, taking EDS out of it. There's the autonomic nervous system, which is the  master regulator. We're learning that it regulates along with everything else that regulates also the immune  system. There's a two arms of the immune system, the primitive arm, first responders, where the mass cells  reside and then there's this sophisticated arm or the acquired arm and immune system where auto-immunity  resides.  

00:10:34 

Jill Schofield 

I think of all these things as interacting like three gears and when one gets off and I start to see the other ones  get off and we know it has been demonstrated, in the medical literature, the link between autonomic nervous  system disorders and Ehlers-Danlos syndrome. So that link has been established. I haven't seen, you know,  official links. I mean, there's early as I, as we wrote, as I wrote in a short Disjointed chapter on the link between  EDS and auto-immunity, that's just an emerging link with preliminary kind of small studies suggesting a link. I  think that will be shown to be true, but, and then the link between EDS and M cast seems dramatically obvious  when you see patients, but I don't think that's been proven yet in the literature either, but I don't think I have an  EDS patient who I wouldn't say has some significant degree of mass cell activation clinically, whether it's  proven objectively or not. 

00:11:40 

Jill Schofield 

Because that's a whole other conversation, as the link seems incredibly strong and, there are hypotheses about,  that there may be the reason we may not have, there may not be an identifiable mutation in college and or  college and regulatory genes in hypermobile EDS, patients that at least a subset of those patients that might, it  may because they need original mutation or mutations are in mass cells. Some of the mass cell mediators are  damaging to tissues. Like if you go to the store and you buy meat tenderizer, it has one ingredient, which is  tryptase.  

00:12:23 

Jill Schofield 

On the other hand, I had seen also MCAS in patients with Marfan syndrome. It's not going to be that simple. It's  very complicated. We have, it's going to be incredibly interesting over the next 10 years to see what shakes out  and know the people doing really good research, which hasn't really occurred yet a lot in MCAS because it's so  new.  

00:12:45 

Linda Bluestein 

Sure, sure. And, could you go into detail about what autonomic disorders are? And, I know you work a lot with  people that have dysautonomia, especially, autoimmune forms auto-immune activated dysautonomia. Could you  talk about what autonomic disorders are, just, in general and why people who are bendy, why they should know  about them?  

00:13:11 

Jill Schofield 

Well, yeah, so it has been shown, I believe the numbers around 80% in the studies, the formal studies that have  been published 80% or so of people with EDS will have symptoms and or abnormal autonomic testing,  abnormal autonomic symptoms and, or a normal autonomic testing. So it's extremely strong link. That's why  people with EDS should know about it. So, and it runs like anything. It runs from very mild to very severe and  disabling. But, dysautonomia is that is the umbrella term that we use for any dysfunction of the autonomic  nervous system, as the name says dysautonomia. It's an umbrella term that encompasses a number of different  disorders of the autonomic nervous system pots or postural orthostatic tachycardia syndrome has quickly  become the most famous. There's on a spectrum with pots as orthostatic intolerance, and there's,  neurocardiogenic syncope and there's inappropriate sinus tachycardia. These are all have very specific criteria  for how we diagnose them.  

00:14:19 

Jill Schofield 

In general, they're kind of treated all the same and they have kind of similar symptoms, multi-system symptoms,  but the most specific symptom I would say of dysautonomia is feeling lightheaded when you stand up. That's  kind of the most specific symptom, but we also see severe fatigue kind of help rotations or tachycardia, which  means a fast heart rate, exercise intolerance or any exertional intolerance, including cognitive intolerance,  cognitive exertion, thinking a lot, thinking about complicated things. Those are, Oh, and of course syncope, like  when you stand near, like near passing out or passing out, that's kind of the range of symptoms that we see most  often in people with dysautonomia. Although many of those symptoms overlap with MCAS, for example. So it  becomes complicated. That's why I say the most specific symptoms feeling lightheaded when you stand on a  regular basis. Not everybody with autonomic disorders passes out.  

00:15:29 

Jill Schofield 

So that's what dysautonomia is. The most of the time, in the formal 2015 heart rhythm society guidelines for  how we diagnose these conditions, they can be diagnosed with tilt table testing or in office stand testing, where  we look at what happens to the blood pressure and heart rate in response to standing, which is, a major stress to  the autonomic nervous system. Because if, when we stand there's this immediate displacement downward of  blood due to gravity, and if we didn't make some compensation, we would all pass out and the autonomic  nervous system is what makes that compensation. That, looking at the blood pressure and heart rate has  provided a window into looking at the autonomic nervous system, which you can imagine is extremely hard to  study. How do you study the regulation of temperature, the regulation of digestion, the regulation of response to  stress. Those things are much harder to study than like a tumor you can see on an x-ray. 

00:16:31 

Jill Schofield 

That's why I think we're so behind in learning about autonomic disorders.  

00:16:38 

Linda Bluestein 

Sure. How do you differentiate autoimmune from non auto immune dysautonomia?  

00:16:45 

Jill Schofield 

Well, audit diagnosing auto-immune disease is very complicated. There are criteria. Everything has to have  criteria or boxes that are specifically defined and in auto-immune disease, it's very complicated. Like MCAS is  similar. We have similar difficulties in coming to agreements on how to make these boxes and how to define,  but in general, it's a comp in general. Well, I guess the biggest thing would be auto antibodies. Okay. But it's  more than that. You can't just have pots and have auto antibodies. I mean, it's complicated because you have to  take into a symptom, you have to take into account the symptoms. What else might be going on? is there MCAS  is there it's complicated, very complicated, but I would say, there are auto antibodies that have been associated  in the medical literature with dysautonomia, usually small fiber or autonomic neuropathy. So, the kind of, red  flags are when I, I mean anybody who has significant dysautonomia, it, you have to consider the possibility that  it could be auto-immune.  

00:18:08 

Jill Schofield 

The red flags for me are, there's a family history of auto-immune disease. Because as we said, if there's a genetic  predisposition, we know you're, you may fall into that 8% of people you do fall. You're at risk of being in that  8% of people. So family history is really important. For me in looking at somebody, although, because there's an  increase in autoimmune disease in general, not everybody does have a family history of autoimmune disease.  Family history of auto-immune disease, a subacute or acute and progressive onset. That always makes me think  of an autoimmune cause. There, there are things like Raynauds. There are certain clinical features that make you  think about an autoimmune disease. If there's a trigger and there's not always a trigger, so you mentioned  pregnancy can be a trigger surgery, car accident, concussion, vaccine infection, those are all kind of trigger. If  someone has it, they were fine.  

00:19:12 

Jill Schofield 

The one of these triggers occurred and then they were getting very sick quite quickly. In a progressive fashion,  that's kind of the person that I'm really worried may have an auto-immune cost. There's a number of, auto  antibodies that I test for. Then, then we see what shakes out on that. We see, we start trying to treat the person's  pots. If there seems to be MCAS, we tried to treat the MCAS and the people with auto-immune disease, they  don't seem to respond very well to those and that kind of, I repeat, I always repeat the antibodies three months  later, and if they're still positive and they're just not improving, in fact, they're getting worse, that's when I really  pursue, that diagnosis is being kind of the driving force. There is no everybody, this is a very emerging area.  Nobody does things the same, including tests, what antibodies you test for.  

00:20:14 

Jill Schofield 

For example, I really liked this panel called the novel Sjogren's panel. It hasn't been there. There's only a very  minimal publications about it in the medical literature. In fact, it might not even be published formally in the  medical literature. There was a poster presented at the international auto-immunity meetings some years ago.  And, there was another publication that maybe didn't make it into the medical literature, but it was more in a  

layman's thing, but I've been ordering that test, which has been commercially available since 2012. Ever since I  saw this just very first inkling of a link, because we know that Sjogren's is a very important cause of autonomic  neuropathy. And, but we also know that the tests that are included in the criteria for Sjogren's the SSA or used to  be SSA and SSB now it's only SSA are terribly insensitive, like terribly insensitive, and almost worthless,  especially in the population with, the young people who get severely disabling, dysautonomia.  

00:21:21 

Jill Schofield 

I liked that test, the novel Sjogren's panel. It really seems to be, correlate with people. Some of the clinical manifestations we see in Sjogren's, as an abnormal Schirmer's test, which is we have a actually test your tear  production in the office, to dry eyes, dry mouth very often goes with Sjogren's, often hair loss, significant hair  loss. Those not at all specific for that. We see that in MCAS too, but pretends to be a phenotype that you see.  And, the people who have that phenotype, I often do see the positive, novel Sjogren's panel and it's often  negative and other people, but it hasn't been officially studied. It's not in the criteria, so that's where I say, these  are not slam dunk, easy diagnosis to make. And it's very frustrating. I'm sure for patients, we all wish it were  much simpler. Like, you get an x-ray and you got a tumor and get a biopsy, you got cancer, it's not like,  

00:22:25 

Linda Bluestein 

Right, right. Which is why I say all the time it's, these conditions are just a horrible match for the way healthcare  is right now, because it's absolutely not set up for it. Yeah.  

00:22:37 

Jill Schofield 

I think what needs to happen in the healthcare system is, they have to recognize their complex patients and that  those patients, providers seeing those patients need more time period. Right now it doesn't exist like that. You  can spend an hour, you can put a really long note, you could code all, whatever you're supposed to code, and  they still don't reimburse you for your time. They'll pay unfortunately for a patient to see 10 different specialists  for an hour. Each who don't know anything about these things and don't do anything, but they won't pay one  provider who actually knows about this for four hours of time that it takes. That's my hope that's my call to  action. If any insurance people are listening, we have a definition of complex patients. Multi-system disease that  doesn't fall into the current boxes of medicine. And, and so, because right now, unfortunately, as most of those  of us who do this work have been forced, to go into a cash only practice.  

00:23:42 

Jill Schofield 

That's not because we're greedy it's because we couldn't do the work by taking insurance and people, there's a  certain level of compensation you want to have like somewhere remotely close to what you would make. If you  did some other kind of work in the field that in order to take on the stress and responsibility of that work period,  and people aren't going to do it. If they're not making anywhere, like probably I was making a quarter of what  my colleagues would make to work much harder, and that's just not sustainable. It's just, people are doing it  cause that's the only way they can providers are doing. It's the only way that we can do this work and have  enough time to spend with patients to really get to the bottom of these complicated patients. You cannot do it in  an hour period and you cannot provide the education.  

00:24:33 

Jill Schofield 

You can't try to shake out which pieces are involved. We hope, with time, I think that's the only solution is the  insurers have to recognize there are complex patients. I think they will with time, I think they'll recognize, okay,  mast cell pots EDS, these are complex conditions. But we need more work, more research. There's not any  funding in this kind of research. Those of us like spent hours and hours of our time trying to write papers  without any kind of compensation or any kind of support. It's very difficult.  

00:25:08 

Speaker 3 

Well, and we also need as much as we need insurance companies to recognize it, we need more doctors that can  work multi-systemic as well. Yeah. There's only so many patients you can see, right?  

00:25:21 

Jill Schofield 

Yeah. There was no training program. That exactly there's no protocol program for multi-system disease. That's  where I kind of did my own. I kind of made up my own training program and it has no names, so I can't call it a  fellowship, but multi-system autoimmune disease. I spent two years working with various people that I wanted  

to learn from. And, I hope a fellowship like that will eventually be developed, but there's not a lot of people  doing the work. So, and the people doing the work are overburdened because there's too many patients in the air  and most of them are not in academia because academia hasn't supported it because they don't have that box.  They don't have the department of multi-system disease. So you don't fit into their world. Right. So, but it'll  happen one day. It just, it's going to take time. Yeah. The right person, the right person will come along and  make it happen. 

00:26:25 

Linda Bluestein 

I hope so too. I've gotten patients that have been turned down from academic centers, with the academic centers  saying we have nothing to offer you. Right. I think it's because, they need to be thinking about their bottom line  and they know that they're not going to get compensated, like they would for doing a surgery or procedure. They  

know that these patients, that's not what they need is and surgeries, like you said, they need time. They need  that. Right.  

00:26:46 

Jill Schofield 

That's good. At least that they told patients, we have nothing to offer them because for the most part they're  right. Rather than having the person go and go to this appointment and then get, they do nothing refer you to that  doctor and that's exhausting, stressful leads to medical PTSD. In a way, I don't think that's necessarily a bad  thing. The med yeah. The academic centers in my experience have not embraced these conditions either for  patients or for physicians trying to do the work.  

00:27:18 

Linda Bluestein 

I agree. I think that's actually a good message though, for us to get out through this podcast. That, that doesn't  mean that there isn't somebody out there that can help you because I think that's what people get discouraged  when I won't name where the letters have come from, but patients have brought me these letters and they've  shown me, ? but that can be very discouraging. Wow. If that academic Sandra center can't help me then is there  really somebody out there who can,  

00:27:46 

Jill Schofield 

Right. Yeah. Everybody's ended up for the most part outside of academia, even though it would best if we could  be in academia because we need to do research in these fields and we need to have support to do good research.  You have to have support, right. You have to have clinical research coordinators and people who can help you  submit the protocol. It's very complicated and painful subject as somebody who's tried to do the research. I spent  like so much of my time with no support, and it's just exhausting. And, but we still forge ahead and try to do it  on the side, and try to write papers that share our experience with treating these patients and hope that they'll  have some impact somebody else who's in a better position to do better research can use it as some kind of  framework kind of preliminary information.  

00:28:50 

Linda Bluestein 

You mentioned small fiber neuropathy, briefly, could you explain about what that is? Why people who are  bendy should know about it, how you work that up.  

00:29:00 

Jill Schofield 

Yeah. Well, there's two kinds of nerves. There's large fiber nerves that are involved with moving your limbs and  telling you where in space your limbs are and touch. There are the small fiber nerves, which as their definition  says are very small and they are not picked up on the test that is used to test large fiber neuropathy, which is the  EMG and nerve conduction testing because the small fiber nerves are so small and their electrical activity is so  weak. They're not picked up on that test. They, until the last two years, there is a small, there is a skin biopsy  where you kind of look at the small fiber nerves and you can actually say, are there abnormal, but to go back the  small fiber nerves, they are kind of have two functions there they're autonomic ones which control all of these  autonomic functions we're talking about.  

00:29:51 

Jill Schofield 

They also control pain, temperature sense and itch. There can be autonomic small, there are autonomic small  fiber nerves and there are sensory small fiber nerves. Those can be diagnosed by biopsy a skin biopsy. There are  because they, these nerves or they go to every gland, organ and blood vessel in the body. The easiest place to  look at that would be the skin. There is a test called the Qsart or the Q sweat, which is looking at the functional  sweating function in my experience, it's a terribly insensitive test. Yeah, but so if you have a negative Qsart or Q  sweat, in my opinion, that does not even remotely begin to go out, that you might have a small fiber neuropathy 

Page 7 of 16 

Episodes have been transcribed to improve accessibility of this information. Our best attempts have been made to ensure accuracy,  however, if you discover a possible error please notify us as soon as possible. 

Transcript for Bendy Bodies Podcast, Episode 12: Investigation Autoimmune Disorders with Jill Schofield, MD 

or autonomic neuropathy. The reason EDS patients should know about it is actually it hasn't been published in  the literature that almost everybody who has EDS has small fiber neuropathy, however, having small, there are  many causes of small fiber neuropathy, including, diabetes is number one.  

00:30:56 

Jill Schofield 

There's, HIV, hepatitis C certain vitamin deficiencies and Lyme disease auto-immune disease. It doesn't tell us  in any way what the causes. The way that I diagnose autoimmune small fiber neuropathy is you have first of all,  consistent clinical picture of the right kind of symptoms. You have auto ant, persistent positivity of, and more  auto antibodies that have been associated with it. You have a skin biopsy that shows you have it. I only do a skin  biopsy personally. I can clinically out pretty much tell if someone has small fiber neuropathy. Cause they're,  there are exam findings that suggest it. If you're trying to get it, if I'm trying to get a trial of IVG, I like to have  an abnormal skin biopsy because then the insurance company, people can wrap their head around, okay, there's  these auto antibodies, these nerves are damaged. We think they're linked. Otherwise I don't usually do a skin  biopsy.  

00:31:51 

Jill Schofield 

I just clinically suspect it based on the nature of their physical exam.  

00:31:57 

Linda Bluestein 

That's a perfect lead into my next question, which is what criteria do you use for determining if someone is a  candidate for IVG?  

00:32:05 

Jill Schofield 

My, so the things I just said, plus they're severely disabled. They can't work or, and, or they can't go to school  because IVG is extremely expensive. It's burdensome by that. I mean, it requires a lot of time getting an IV  infusions and, it's not like any what we call parenteral therapy, non oral therapy has higher risks. Although I  consider the risk relatively, but there are risks to it. So those are the criteria I use.  

00:32:47 

Linda Bluestein 

Okay. And, and can you tell us about anti-phospholipid syndrome? I know this is another area of expertise of  yours. Yes.  

00:32:57 

Jill Schofield 

That's one of my goals in life to try to increase awareness about this link, because I think it's a really, it will be  shown, I believe with time to be a very important association with small fiber neuropathy. The reason it's  important is, well it's auto-immune and we have treatments for it. It's also very important because these patients  are at risk for blood clots, which can be very severe. What clots of the arteries and blood clots of the vein. What  co clots of the artery you would most commonly stroke, but it kind of mean a heart attack and rarely it can mean  it can, there can be a clot to, the artery perfusing your leg and you lose your leg. So these are very serious issues.  Then, and the veins, artery, blood clots of the veins most commonly is a blood clot in the leg or arm, or the  lungs is a pulmonary embolus.  

00:33:55 

Jill Schofield 

Those can be fatal or extremely disabling event. So, that's why I think this link is so important and, it's just very  confusing and complicated because the cry, again, we come back to the problem with criteria and the criteria for  antiphospholipid syndrome were intended to be used for research purposes, to capture a uniform population of  patients with this very heterogeneous or mixed syndrome that have the blood clots, because blood clots are a big  deal. So, but there are no diagnostic criteria. The research criteria get used for diagnosis and they focus on blood  clots. If there's a doctor doesn't really know much about the same quickly re Google it and they see these criteria  and it says, Oh yeah, there's no link with pots. Antiphospholipid, so those antibodies you have don't mean  anything and there, they don't pay any attention to it and tell her, unless you've had a blood clot, which to me is  a failure, because if you've had a blood clot, that's a big deal, especially if it was a massive stroke or it was a  fatal pulmonary embolus. 

00:35:10 

Jill Schofield 

That's why I'm very passionate about this. Yeah. Also, another thing in the criteria that's problematic in my  opinion, is that it has been shown that the higher the antibody levels and the more antibodies you have, the more  likely you are to have a blood clot. I have people have very minimally elevated antibodies who have had a blood  clot. The criteria actually call for you to have a high titer antibody significantly higher than what the people who  designed the essay said a positive is that, a lot of my patients, some of my worst patients have minimally  elevated antibodies, but they are out there are positive and they have clinical features. They're the people who  have antiphospholipid syndrome, or we don't call it syndrome, unfortunately, unless you have a blood clot. We  have to just say, there is an ICD 10 code for antiphospholipid antibody positive. You don't really have anything  unless you've got a blood clot, but you just have, anti-fossil live antibody positive, but there's a very specific  phenotype, of the people who, have antiphospholipid syndrome or antiphospholipid antibody positive.  

00:36:29 

Jill Schofield 

That is, first of all, like the clues that might suggest you might be at risk for this would be first of all, frequent  migraine, often refractory often with aura, like a visual kind of changes that come on before the migraine, Ray  nodes, memory loss more than just brain fog. Like, and that can be hard to tease out because everybody with  pots has brain fog. Right. It's often a bigger complaint and people with anti-fossil lipid, many people in their  twenties or thirties, they're worried they have dementia. They're worried they have Alzheimer's they're blank  spells. You're thinking where, they can't remember the name of their best friend from 30 years, or, just more  prominent memory loss. There's, skin finding called livedo reticularis, which is like the a lacey pattern of the  skin. You can Google it. If you Google anything, you get the worst possible picture, but it's usually not as bad as  the pictures that you'll see on most of the pictures you see on the internet, but it's most often present kind of on  the, this part, the inner part of the arm and around the knees or the thighs.  

00:37:44 

Jill Schofield 

It often comes out the most common time. People might notice it as when they get out of the shower. They're  going from hot to cold, or if they're just in the cold, it tends to come out or tends to be more prominent for some  people at Sarah all the time. Other people that is more fleeting and that's a really important clinical clue that  somebody might be, somebody should, that diagnosis should be, considered. Obviously if someone's had a  blood clot and they have pots, you better start thinking about, and I possible live in, and then the other one is,  pregnancy complications. Recurrent miscarriage, especially late miscarriage, after 10 weeks, stillbirth,  preeclampsia, or eclampsia, seizures we see in patients with antiphospholipid syndrome. Those are, then there's  some other more subtle ones like thickening of the heart valves. I always look very carefully at the echoes of  my, all of my patients with pots.  

00:38:50 

Jill Schofield 

I'm looking to see if the cardiologist said their aortic or mitral valve are thickened because they almost never put  that in the impression. I don't know why, because it is at normal. And, Oh, the other thing is white matter change  on brain MRI. That's another thing a lot of neurologists say, Oh, that's nothing it's just due to your migraines. It's  another thing that I think if a study were formally done, the people with migraine who actually have white  

matter change are probably much more likely to have antiphospholipid antibodies. So that's sort of the clinical  phenotype. It's almost always women, but I have a few men and they often have a more prominent, they don't  often fit that phenotype quite as well, but they are more likely to have memory loss and less likely to have  migraine, but that's just, there aren't enough patients to really kind of characterize it.  

00:39:45 

Jill Schofield 

It's much more, very female predominant like lupus. Sjogren's interesting are men who get it.  

00:39:53 

Linda Bluestein 

I saw in one of your papers that there was a, it was even a relationship between antiphospholipid antibody  syndrome and CRPS or complex regional pain syndrome and EDS, which is fascinating. 

00:40:07 

Jill Schofield 

Yeah. Thanks for asking about that. Yeah. We saw that the people, usually the people have, I mean, CRPS  complex, regional pain syndrome is another way in which this autonomic neuropathy can look clinically. It's  very complicated with some people have pots, some people have severe gastro-paresis or other GI dysmotility.  Some people have this complex regional pain syndrome. Some people have all of them, so it can have, different,  it can look differently in different patients. Yeah, the other thing that all of the patients that I have had with  complex regional pain syndrome, which is a very severe pain syndrome that develops most commonly after like  a fracture or someone other injury to an extremity, they have all had either MCAS and, or anti-fossil lipid  syndrome. You can kind of tell which one, I, I can almost always tell which one they're going to have because  the APS people, they got the migraines, they got the Raynauds, they got the white matter change in the mast cell  people.  

00:41:16 

Jill Schofield 

They got hives, they got, abdominal pain, diarrhea. They, they, you can tell, but they can have both too, but I've  never had a patient with CRPS who didn't have one or the other of those. This is also a super emerging concept  too, that they're even beginning to think about what might be the cause of CRPS. We're, we're just happy if  somebody has actually gotten a diagnosis. Cause that is very difficult for people to get diagnosed with that.  CRPS is, the most painful condition there is period. The Montreal pain, well, you can probably comment, Dr.  Bluestein as anesthesiology pain specialist, but so correct me if I'm wrong, but there's Montreal pain scale that  goes up to 55, right? So instead of going from zero to 10, they were trying to characterize, people who are at a  10 and make kind of spread them out and see who is worse.  

00:42:19 

Jill Schofield 

The very most painful condition to CRPS has been more painful than a childbirth without anesthesia or  amputation without anesthesia. So it's extremely painful. These patients get just written off and told they're  crazy too. Very tragic.  

00:42:37 

Linda Bluestein 

Yeah, it is. It definitely is. Yeah. Among the many painful conditions of which our, EDS population is at higher  risk for, also like adhesive arachnoiditis, which is another, super painful condition. It's, it's, especially important  to recognize these things since there are so many other comorbid conditions that we can at least, try to be doing  something about. So, right.  

00:43:03 

Jill Schofield 

Yeah. There is treatment for CRPS and mean people who get into physical therapy right away. If there is M cast  or there is an auto-immune cause the patients who have my patients who've had antiphospholipid syndrome,  they respond to it. The biggest thing is to get the pain under controlled with, things like Gabapentin and getting  into therapy and trying to avoid opiates if possible, and then looking for an underlying cause. The clinical clues,  there is just the aid. If you've had, you had a recent fracture or pain is just way out of proportion, to what they're  expecting you to have, it's getting worse. It's not getting better. There are these autonomic findings, cause it is a  disorder of these autonomic nerves are small fiber nerves. There's temperature change on the affected limb.  There can be color change on the affected limb. There can be swelling of the affected limb because the  autonomic nerves actually go to the tiny blood vessels.  

00:44:03 

Jill Schofield 

When they're dysregulated, there can be a DMR swelling, and there can be changed in the growth of, hair and  nails, which is also another thing, the autonomic nervous system regulates. There can be probably there can be  itch too, because although I guess I haven't seen that. I take that back, but small fiber neuropathy patients can  show up with itch.  

00:44:27 

Linda Bluestein 

Yeah. I've definitely seen the itch, not so much, with the Sierra yeah. The pain, the pain. 

00:44:32 

Jill Schofield 

Predominates, they might have itch, but it would just be drowned out by that.  

00:44:36 

Linda Bluestein 

Right, right. Yeah. Yeah, definitely. And, and you studied, 22 patients in your 2017 paper autonomic neuropathy  and its many guises as the initial manifestation of anti-fossil lipid syndrome. I found this really fascinating  reading about this paper because you talked about a subset of people with joint hypermobility that actually had a  lower incidence of arterial thrombosis, but a higher incidence of small fiber sensory neuropathy. And, and you  also talked about like the, high percentage of, auto-immune disease, most commonly thyroiditis. Do you have  any thoughts about that paper in particular?  

00:45:20 

Jill Schofield 

Not really because there weren't really enough patients that was just, it wasn't a statistical significant statistically  significant thing, but, and it's also very confusing in EDS because, and when I say, when you say the sensory, I  actually, all of my patients in that paper had the skin biopsy that was analyzed both for the autonomic nerves,  which is quantitated as the what's called the sweat gland nerve fiber density. They had what's called the sensory  nerves, which are quantitative by the epidermal nerve fiber density. They were, the people without EDS were  more likely just to have the autonomic rather than the autonomic and the sensory. But, so I don't know what that  means. Like I said, there weren't enough patients, but as I already said before, we don't know why almost every  patient with EDS, if you do a skin biopsy on them, they have small fiber neuropathy. 

00:46:17 

Jill Schofield 

We don't know why that is. I think if you asked me why, like my hypothesis is, there's a super strong link with  mass cell and I, and the muscles lineup along these autonomic small fiber nerves. And they interact intimately,  anatomically and functionally. I think if the muscles are overactive and they're dumping these toxic mediators  

on those nerves, that they're not going to look normal or act normal, they're not going to look normal on the skin  biopsy. They're not going to act normal in that. In other words, that the patient's going to have, they eat  something with red dye and they get this burning pain all over their body. There's a link with math skills in  small fiber neuropathy. If you're in the trenches, seeing these patients, but hasn't been published yet. I hope  somebody is publishing it right now as I speak, because I know it is a cause of small fiber neuropathy.  

00:47:01 

Jill Schofield 

Every, since everybody seems to have small fiber neuropathy and everybody with EDS seems to have muscle, I  think that's the reason. There are the people who get the auto-immunity and I, do the skin biopsy to try to prove  my case that I think it's auto-immune as I mentioned to get a trial of IVF, but I could pretty much know that the  person's going to have it, even if it wasn't auto-immune because it doesn't the presence of it doesn't improve. It.  Doesn't tell us the cause. It's very complicated and it, and that's where it gets back again to you. Can't just look  

at, you have to look at the whole person's whole clinical picture. You can't just look at the biopsy and the  antibody, do you have to look at their whole clinical picture, which includes the fact that they are not responding  to treatment for pots, like salt and foods and exercise and the pharmacologic medications we have that helped  pods.  

00:47:57 

Jill Schofield 

They're not responding to the mass cell therapy and they're just getting worse and worse. They, they have the  auto antibodies that, and they have clinical, like say that, say they have antiphospholipid antibodies. Well, they  have livedo reticularis and they have Raynauds and they have this white matter change then you're like, okay,  they should get a trial of IVG. Cause I think this is auto-immune. It becomes, it's a very complicated, you'd  really have to spend a lot of time going through all of these pieces and you have to, it also takes time when  somebody, if I see somebody in the middle getting I'm worried about an autoimmune, cause I have a family  history of auto-immunity in our run antibodies and they have antibodies. I don't just pull out IVG tomorrow. I  only save it for the people who weren't responding to the other things, because people do respond to the other  things, even if they have the auto antibodies. 

00:48:43 

Jill Schofield 

Sure. What are the things do you treat antiphospholipid syndrome with? Oh yeah. Good question. I think of  antiphospholipid syndrome as having two components. Okay. There's the sticky blood piece, which is the  layman's term for antiphospholipid syndrome, sticky blood. There's the immune auto immune piece. One of the  areas, my areas of interest, and I just submitted a paper about this, 17, the eight patients with antiphospholipid  antibodies and migraines, severe migraine, who I gave a trial of antithrombotic therapy for, which would include  either medications that target the platelets like aspirin or Plavix or in some people anticoagulation. This is  something that this is a phenomenon that's been described by Dr. Hughes in the early days that he noted when  he treated patients with antiphospholipid syndrome, who had a blood clot with blood thinners. Many patients, all  my headaches I've had every day for 10 years have gone away.  

00:49:44 

Jill Schofield 

My thinking, I can think again, I couldn't think at all. And so he proposed yeah. Years ago, trial of heparin,  which is a blood thinner in patients who had severe migraine. Hadn't had a blood clot that had the antibodies and  showed in this very short publication. It was leery like a half a page, probably wouldn't have gotten published  today, that Most or all of them, their headaches improved. So, but that is a phenomenon that hasn't taken off in  the broader medical community, but it's been an interest of mine. It's another feature of that might make you  suspect APS as if someone has migraine and they respond to the antithrombotic therapy. That is a, I hope  publication will increase awareness about this very important phenomenon because there are people who've had  debilitating migraines every day and you put them on Plavix and they go away completely.  

00:50:39 

Jill Schofield 

And, memory loss. I have actually this incredible case of this older guy who was diagnosed with Alzheimer's  and Oh, another feature of antiphospholipid is low platelets just can be just mild, low platelets, and also go  lowest white count. This guy was diagnosed with Alzheimer's and his doctor had APS and she noticed his  platelet count was low. She tested him and he had a really high antibodies and so on. And I, he required antiplatelet and anticoagulation. He was like a new person. He got off his air ACEP for is Alzheimer's that he  didn't have and his functional ability improved dramatically. This is like a really important piece of it that I  target. That is again, another emerging area, but it's a simple trial. The people who respond it's dramatic. So  that's one piece. I wonder, I personally wonder, I think I, I wish somebody would study this.  

00:51:42 

Jill Schofield 

W we think that people, by the way, who respond, that we think it's working because they're sludging of the  blood, it's sticky. It's like running old oil through your car doesn't work quite right. The brain is really dependent  upon proper oxygenation and blood flow. I think that, I wonder if, the small fiber nerves are so tiny, they're  perfused by blood vessels that are smaller in diameter. I've been told than the actual diameter of a red cell. That  would be a prime location where sledging can occur. Right. I just, I think, I've seen teenagers where if we treat them who, and they have headache, and so we treat them with aspirin or Plavix, it makes their headaches go  away. And I treat them. The other drug that I often use is Plaquinel, which I'll come back to, which is an  immune modulator and get them on Plaquinel and vitamin D and Plavix or aspirin.  

00:52:39 

Jill Schofield 

They can go from being very severely and we treat their pots with salt and fluids or whatever. They can go from  being severely disabled to basically feeling normal most of the time. And they stay that way. Whereas if we  catch them later, they, that's not the outcome. There's this, there's the sticky blood side. And then there's the auto  immune side. I really liked the drug Plaquinel, hydroxy chloroquine. It's not as well studied in antiphospholipid  syndrome. Some people don't use it, but I love it. I I've seen it really stabilize my patients anecdotally. It hasn't  been again well studied. It has been studied in a number of studies in patients with antiphospholipid antibodies  and pregnancy dramatically improves outcomes, but it's been best studied in lupus where it improves, makes  people live longer, dramatically improves flares. There's significant overlap between lupus and antiphospholipid  syndrome. 

00:53:42 

Jill Schofield 

Quarter of patients with lupus have antiphospholipid antibodies or antiphospholipid syndrome. It also, it  interferes with the way that, and I phospholipid antibodies kind of carry out their evil humor. It has, it reduces  the risk of blood clots and lupus has been studied in lupus. I wonder if those are the people that have  antiphospholipid antibodies, but so I use that drug and I recommend that drug, all of my patients who have  persistent and I phospholipid antibodies and a clinical picture that fits with it. 80% of patients notice improved  symptoms, most commonly fatigue, joint pain, and or neuropathic pain like sharp shooting pains or tingling, or  those kinds of symptoms. I recommend it even if there is no symptom MADEC improvement, cause it's, I feel  like it's doing important things in the background and it doesn't suppress the immune system. Overall it's an  extremely safe drug, despite, the kind of bad rap that people were trying to give it and, to try to get people I  think not to use it for COVID.  

00:54:49 

Jill Schofield 

That would be if I find often teenagers who have these antibodies, they have pots, they have clinical features of  antiphospholipid syndrome. It says vitamin D Plaquenil. If they have headaches responsive to aspirin or Plavix,  that cocktail seems to be magical. Wow. So not everybody. And that can happen in adults too. If they're  diagnosed earlier, it's just people, some people, the whole thing gets kicked off very by some trigger. There is  just that's, they need IVG, but those are the pieces that are different and people who don't have the antidote. The  other thing is just the awareness and recognition that if you have those antibodies, no matter how low they are,  in my opinion, you are at risk for blood clot. You have symptoms of a blood clot. You better go get checked out  sooner rather than later. Also if you have a surgery, we recommend it's kind of, evidence-based  recommendation.  

00:56:01 

Jill Schofield 

That's not widely recognized in the medical community that you have antiphospholipid antibodies, even if you  haven't had a blood clot and you have a surgery, which is any surgery increases the clotting risk for a period of  time proportionate to the nature of the surgery. We recommend using, anticoagulation for some period of time  after a surgery, it might be a few days. It might be a few weeks, depending, like I said, orthopedic surgeries are  

very high risk and the same is true with pregnancy because that also is a very prothrombotic or high clotting  risk, state in the postpartum period. Somebody with antiphospholipid antibodies should be treated with  anticoagulation after they deliver for the fourth trimester. I think, the presence of the antibodies, even if you  don't have the syndrome, are, they're an important risk factor for clots that can, should, can, and should affect  how we take care of that person.  

00:57:00 

Jill Schofield 

Also along the same lines, if it's a woman and they have those antibodies and they're going to get pregnant, they  need to be followed by high risk. The pregnancy needs to be monitored much more carefully. They should take  aspirin. I believe they should take Plaquinel significantly reduces, pregnancy complications. And, I've had  patients who have had severely terrible pregnancy outcomes. They didn't know they had antiphospholipid antibodies, and then we find out they have it. We treat them with the things I'm talking about, plaque when  they're all vitamin D aspirin and they do great and they get monitored closely. The fetus is monitored regularly,  et cetera. And usually they do very well. If we know about it, people do much better than if we don't know about  it until they have a bad event.  

00:57:58 

Linda Bluestein 

And to the healthcare system. We’re talking about earlier to me, this as anesthesiologist, that's one of the  definite things that you always consider is what type of surgery is it? And then there's different protocols for  different, to prevent the blood clots. If you can further delineate who is at higher risk, as opposed to just right  now, we treat most everybody the same. So if we knew in advance, no, these people have this antibody they're at  higher risk. I think that's really good information that, yeah. And, and what dose of aspirin are you usually  using? 

00:58:36 

Jill Schofield 

Yeah, usually most people respond to 81, but I have a few people who don't respond to 81 and respond to three  25, but Plavix, one of the things that showed in the paper that I recently submitted is that Plavix is much more  effective than aspirin. I don't know why that is. I like, I personally think Plavix is safer than aspirin. I worked as  a hospitalist for many years, so I use Plavix every day, but a lot of physicians are not familiar with it. For some  reason, they think it's a scary drug, but basically Plavix and aspirin, both inhibit platelets or make platelets less  sticky or the life of the platelet irreversibly for the life of a platelet, which is 10 days. They both do that exact  same end point by a slightly different mechanism, but aspirin at the same time, as you were taking to the GI  track.  

00:59:29 

Jill Schofield 

That combination can increase risk of GI bleeding and trouble there. Whereas Plavix doesn't do that. So that's  why I consider it safer. It doesn't have any GI side effects or it doesn't cause GI inflammation. So I love Plavix.  It's very well tolerated. The dose is 75 milligrams a day, but it does require a prescription. For whatever reason,  it just works significantly better than aspirin. The P value was like less than 0.001 or something like that. It was  just much more effective. But, there is the problem of some doctors think it's a scary drug and it requires a  prescription.  

01:00:14 

Linda Bluestein 

Right. And, and I'm recalling also when I interviewed one of our mastermind colleagues and also one of our  coauthors in the book disjointed, Paul D Atwal. I interviewed him and were talking about Plavix. And, and the  genetic, I don't know exactly what it is, but there's some genetic marker that, a certain percentage of the  population, which was not an insignificant percentage of the population would not be sensitive to it. The  interesting thing is, I wonder if some of those people that don't respond to it's not because it's not really the right  approach, but it's genetics, some genetic.  

01:00:52 

Jill Schofield 

To do with the metabolite. And there is a test. I often I test sometimes I test for it. I mean, the cardio, it hasn't  been found in the cardiovascular literature that I'm aware of to be worth doing. They don't do it as a matter of  routine, but, I usually that is a reason. And then there's also aspirin resistance. Like that's something now that  shows up on 23 and me, you have aspirin resistance. Okay. That's why if one, if a person fails one, I usually  

switch them to the other and vice versa because people respond. That was another thing we showed in this paper  is everybody's different in the way they respond, which cocktail, which drug or drugs works for one person it's  different from person to person. It's very individualized and symptom driven rather than a one size fits all  approach. It's a simple, two week trial, it's usually dramatic either.  

01:01:47 

Jill Schofield 

Yup. Just takes it away or it doesn't do anything. It's like any drug trial, we stop it if there's no benefit. I think it's  telling us in the patients who have headaches every day for 10 years, who take Plavix and their headaches go  away, that it's, kind of their own internal gauge that their blood stickiness is now. Right. Because we don't have  a test for that. We don't have a test for overall blood stickiness. The rate of bleeding we found in this study was  extremely well. I think it's because of that phenomenon, like it's normalizing, it's a readout that it's normal that  their level of blood stickiness, so to speak is where it should be. If, and there was no bleeding in any of the PA  78 patients during the trial, the two week trial two to four week trial, it depends upon the duration of the trial.  

01:02:48 

Jill Schofield 

Of course depends upon the frequency of the symptoms. If somebody has migraine every day, two week trial,  you should be very clear either this works or it doesn't work.  

01:02:59 

Linda Bluestein 

Sure, absolutely. So, so, we are going to be talking to Dr. Schofield, again, in part two of this conversation,  which, we're going to be super excited for you to hear in the meantime, Dr. Scofield, was there anything else that you want to share for this? This part is more kind of the provider part and, the more academic part, if you  will, do you have a call to action for providers or, any other, specialists taking care of this population? And then  could you also let people know where they can find you?  

01:03:35 

Jill Schofield 

I have my own practice called the center for multi-system disease in Denver, Colorado, and you can Google it  and you can find out how to reach me there. Yeah, I mean, my, that we just talked about my most passionate  topic, which is the link between antiphospholipid syndrome and pots, and also the link with refractory migraine.  The call to action of providers is to have a think about it and be to start to recognize this clinical phenotype,  which is more than just pregnancy complication and thrombosis it's does do, are you seeing a patient? Do they  have livido reticularis is take a look at their skin. Do they have Raynauds? Do they have white matter change?  that stress fractures or current stress fractures we see in patients because they're not getting enough blood flow  to the bone, and if they want to get stress fractures, mild, low platelet count, mild, low white count in three to  four range, thickening of valves in the body of the echo report.  

01:04:38 

Jill Schofield 

If you see this kind of, not everybody has all of those things, but many of the patients have three or four Oh, and  memory loss. If they're complaining my memory, I'm worried have Alzheimer's. Those are, those are, that's the  clinical phenotype, when think about it because I considered a failure. If somebody meets the criteria for  antiphospholipid syndrome, because most of the people have clues that they could have been diagnosed before  they had at that serious outcome.  

01:05:11 

Linda Bluestein 

Well, well, that's great information and thank you so much for chatting with us. And we're gonna be looking  forward to part two that's. Thank you. If you've enjoyed this program, please like share, subscribe and leave a  review. This podcast is for informational purposes only, and is not a substitute for medical advice. Please see  

your own medical team prior to making any changes to your healthcare. Bendy body's original music is by  Andrew Savino and sound editing is by Rhett Gilt. Thank you so much for tuning in, and we will see you next  time on bendy bodies with the hypermobility MD.