Investigating Autoimmune Disorders with Jill Schofield, M.D.

[00:11] Dr. Linda Bluestein: Welcome to Bendy Bodies with the Hypermobility MD. This is your host, Dr. Linda Bluestein. Today, Jennifer Milner and I have the great pleasure of speaking with Dr. Jill Schofield, founder and director of the Center for Multisystem Disease. After completing her internal medicine residency at Johns Hopkins, Dr. Schofield underwent subspecialty training in multisystemic autoimmune disease and blood clotting disorders. In 2014, she described the association of autonomic disorders in the antiphospholipid syndrome with Dr. Graham Hughes in London, who himself had first described the antiphospholipid syndrome. Dr. Schofield was the recipient of the Dysautonomia Support Network Patient's Choice Game Changer Award in 2019 for her work in the use of immunoglobulin therapy in autoimmune dysautonomia. She also authored the chapter Autoimmunity 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 topics. Dr. Schofield, hello and welcome to Bendy Bodies. And Jennifer, hello, and it's so great to chat with you again today.

[01:28] Jennifer Milner: Good to be back as always.

[01:29] Dr. Linda Bluestein: Wonderful. So, Dr. Schofield, can you start out by giving us a general overview of autoimmune disorders?

[01:37] Jill Schofield, M.D: Sure. Autoimmune disorders are disorders 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 — our body and foreign invaders. And sometimes a mistake occurs where the immune system thinks a molecule or protein in the body is foreign. And that's when autoimmunity develops, because the immune system is then attacking something in the body.
[02:22] And that leads to tissue damage, and that manifests as symptoms depending on what tissue or tissues are damaged. So 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 — though there's not always actually damage to the thyroid.
[02:46] 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. And once there's one problem with the immune system, more problems can arise. So it can serve as a marker or red flag that the person is at risk of other autoimmune issues, and also at risk that their thyroid function might deteriorate over time.
[03:07] Thyroid autoimmune disease is an example of what we call a disease-specific autoimmune disease, where just the thyroid might be affected. But diseases like lupus, rheumatoid arthritis, and Sjögren's syndrome are systemic autoimmune diseases, where there can be problems with multiple organ systems depending on the individual case.
[03:36] So really they're a problem of dysregulation in the immune system. Only about 8% of the population will ever get an autoimmune disease. You have to inherit a genetic predisposition, and then there has to be a trigger — probably more than one trigger — for an autoimmune disease to actually manifest clinically. So it's very complex.

[04:12] Dr. Linda Bluestein: Sure. And overall, do you think the prevalence is increasing? And if so, why might that be? Or is that something that has been pretty stable over time? You mentioned 8%.

[04:25] Jill Schofield, M.D: No, the incidence is increasing for, I think, every autoimmune and immune-mediated disease, except perhaps rheumatoid arthritis, because smoking is a big trigger for rheumatoid arthritis, and the incidence of smoking has gone down, and that may be why the incidence of rheumatoid arthritis hasn't risen like most or all of the rest of the autoimmune diseases.
[04:46] And probably mast cell activation syndrome — which is not an autoimmune disease, but is an immune-mediated disease where the mast cells, which are also part of the immune system, get activated — seems to be increasing as well. In mast cell activation syndrome, the mast cells are getting activated and they're not attacking something in the body specifically; they're just releasing chemicals that are then damaging the body. I don't know that this increase has been formally published in the medical literature, but for those of us in clinical practice, it certainly seems to be exploding.
So why is this happening? There's 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 or even two generations. So it has to be a problem with our environment. Some of the things that have been suggested are all the chemicals in the environment; prior to COVID, the ability to travel from this country to that country very quickly, which leads to a shift in the microbiome — and the microbiome, we're learning, has tremendous influence on the immune system.
[06:09] Then there's the hygiene hypothesis, which is probably going to be even worse now with COVID, where we keep everything too clean. Kids aren't playing in the dirt anymore, and the immune system doesn't have anything to do.
[06:24] I'm not at all an anti-vaxxer, but the sheer number of vaccines given today compared to one or even two generations ago has dramatically increased. Every vaccine has an adjuvant, which is a nonspecific stimulator of the immune system to make us respond to the molecule of, say, a virus. If you're born with an immune system that's 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. Obviously, as we're learning with COVID, vaccines are extremely important. A hundred years ago people died of infectious diseases, and the people with an overactive immune system were in a better position. Now the tables have sort of turned.
[07:32] Those are some of the reasons that have been proposed for why we may be seeing this explosion in autoimmune diseases. And it's probably more complicated even than that. The immune system is extremely complicated, and its interaction with our environment is very complicated.

[07:50] Dr. Linda Bluestein: Sure. And what about the difference between males and females? I'm thinking of things like pregnancy and triggering events. Are there differences?

[08:03] Jill Schofield, M.D: There's a much greater incidence of autoimmune disease in females. That's not fully understood — it's not as simple as hormones. Certainly we think hormones play a role, because the period of time from menstruation through menopause — say age 15 to 50 — is when we see the most autoimmune disease.
[08:26] And some of the autoimmune diseases have a very high ratio. Sjögren's, I think, is 9 to 1; lupus, it's 8 to 1, somewhere in that ballpark. It's dramatically higher in women. People are studying that — differences in B cells in women versus men, et cetera. It's not as simple as hormones, but that's felt to play a role. Just another of the many areas we have a lot to learn about.
[08:59] It doesn't seem like there's such a difference in female-to-male ratio in MCAS, though. That's just my anecdotal experience. It doesn't seem as strongly female predominant in MCAS as autoimmune disease.

[09:20] Dr. Linda Bluestein: That's interesting, because we know that for EDS — Ehlers-Danlos syndromes — and for mast cell activation syndrome, which we'll refer to as MCAS a lot through this conversation, and for dysautonomia, those are more prevalent in females than males. So that was the next thing I was going to ask you about: could you describe the relationship between autoimmune disorders, dysautonomia, EDS, and MCAS?

[09:48] Jill Schofield, M.D: Yeah, absolutely. All of those things seem to be much more prevalent symptomatically in women than males, except for MCAS. But there seems to be this tremendous link between all of those conditions that those of us in the trenches are noticing.
[10:09] I know that some of the MCAS group with a much more narrow definition of MCAS has tried to refute that link. But if you see patients, you know there's a very strong link. I think of it as three gears — taking EDS out of it for a moment. There's the autonomic nervous system, which is the master regulator, and we're learning that it regulates the immune system along with everything else. And then there are the two arms of the immune system: the primitive arm, or first responders, where the mast cells reside; and then there's the sophisticated arm, or the acquired arm of the immune system, where autoimmunity resides.
[10:46] I think of all these things as interacting like three gears, and when one gets off, I start to see the others get off too. We know it has been demonstrated in the medical literature that there is a link between autonomic nervous system disorders and Ehlers-Danlos Syndrome — that link has been established. There's also early, preliminary, small-study evidence suggesting a link between EDS and autoimmunity, as I wrote in that chapter in Disjointed, and I think that will be shown to be true.
[11:30] The link between EDS and MCAS 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 mast cell activation clinically, whether it's proven objectively or not.
[11:59] And there are hypotheses about why we may not have an identifiable mutation in collagen or collagen regulatory genes in hypermobile EDS patients — that at least a subset of those patients, it may be because the original mutations are in mast cells, and some of the mast cell mediators are damaging to tissue. For example, if you go to the store and buy meat tenderizer, it has one ingredient: tryptase.
[12:34] On the other hand, I have also seen MCAS in patients with Marfan syndrome. So it's not going to be that simple — it's very complicated. It's going to be incredibly interesting over the next 10 years to see what shakes out, especially as people do really good research in MCAS, which hasn't occurred a lot yet because it's so new.

[12:57] Dr. Linda Bluestein: Sure. Could you go into a little bit of detail about what autonomic disorders are, and why people who are bendy should know about them? I know you work a lot with people who have dysautonomia, especially autoimmune forms.

[13:23] Jill Schofield, M.D: Well, it has been shown — I believe the number is around 80% in the formal published studies — that 80% or so of people with EDS will have symptoms and/or abnormal autonomic testing. So it's an extremely strong link, and that's why people with EDS should know about it.
[13:56] Dysautonomia is the umbrella term we use for any dysfunction of the autonomic nervous system, as the name says. It encompasses a number of different disorders. POTS, or postural orthostatic tachycardia syndrome, has quickly become the most famous. On a spectrum with POTS, there's orthostatic intolerance, neurocardiogenic syncope, and inappropriate sinus tachycardia.
[14:27] These all have very specific criteria for how we diagnose them, but in general they're treated similarly, and they have similar multi-system symptoms. The most specific symptom I would say is feeling lightheaded when you stand up. But we also see severe fatigue, palpitations or tachycardia — which means a fast heart rate — exercise intolerance or any exertional intolerance, including intolerance of cognitive exertion, like thinking about complicated things. And of course syncope, or near-passing-out or passing out.
[15:18] That's kind of the range of symptoms we see most often in people with dysautonomia, although many of those symptoms overlap with MCAS, for example, which makes it complicated. That's why I say the most specific symptom is feeling lightheaded when you stand on a regular basis. Not everybody with autonomic disorders passes out.
[15:49] 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. When we stand, there's an immediate displacement downward of blood due to gravity, and if we didn't make some sort of compensation, we would all pass out. The autonomic nervous system is what makes that compensation.
[16:22] Looking at blood pressure and heart rate provides a window into 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, say, a tumor you can see on an X-ray. That's why I think we're so far behind in learning about autonomic disorders.

[16:50] Dr. Linda Bluestein: And how do you differentiate autoimmune from non-autoimmune dysautonomia?

[16:59] Jill Schofield, M.D: Diagnosing autoimmune disease is very complicated. Everything has to have criteria — very specifically defined boxes — and in autoimmune disease it's very complicated, similar to MCAS. We have similar difficulties coming to agreements on how to define these categories.
[17:23] But in general, the biggest thing would be autoantibodies. Though it's more than that — you can't just have POTS and have autoantibodies. You have to take into account the symptoms, what else might be going on, whether there's MCAS — it's very complicated.
[17:48] There are autoantibodies that have been associated in the medical literature with dysautonomia, usually small fiber or autonomic neuropathy. The red flags for me are: a family history of autoimmune disease, because if there's a genetic predisposition, you may fall into that 8% of people. Although because there's a general increase in autoimmune disease, not everybody does have a family history. So family history of autoimmune disease is really important to me.
[18:45] A subacute or acute and progressive onset also always makes me think of an autoimmune cause. And certain clinical features make you think about autoimmune disease, like Raynaud's. And if there's a trigger — though there is not always a trigger. Pregnancy can be a trigger. Surgery, car accident, concussion, vaccine, infection — those are all kinds of triggers. So if someone was fine and then one of these triggers occurred and then they were getting very sick quite quickly and in a progressive fashion, that's the person I'm really worried may have an autoimmune cause.
There are a number of autoantibodies that I test for, and then we see what shakes out. We start trying to treat the person's POTS, and if there seems to be MCAS, we try to treat the MCAS. I always repeat the antibodies three months later. If they're still positive and the person is just not improving, and in fact getting worse, that's when I really pursue that diagnosis as being the driving force.
[20:17] This is a very emerging area, so nobody does things the same way, including what antibodies you test for. For example, I really like this panel called the Novel Sjögren's Panel. There's only very minimal publication about it in the medical literature — in fact there was a poster presented at the International Autoimmunity meeting some years ago, and perhaps something that didn't quite make it into the formal medical literature. But I've been ordering that test, which has been commercially available since 2012, ever since I saw this very first inkling of a link, because we know that Sjögren's is a very important cause of autonomic neuropathy.
[21:02] We also know that the tests that are included in the criteria for Sjögren's — the SSA, and it used to be SSA and SSB, now it's only SSA — are terribly insensitive. Almost worthless, especially in the population of young people who get severely disabling dysautonomia.
[21:33] I like that Novel Sjögren's panel. It really seems to correlate with some of the clinical manifestations we see in Sjögren's — things like an abnormal Schirmer's test, which actually tests tear production in the office; dry eyes; dry mouth; Raynaud's, which very often goes with Sjögren's; and often significant hair loss, although that's not at all specific to Sjögren's, since we see it in MCAS too. There tends to be a phenotype, and the people who have that phenotype, I often do see a positive Novel Sjögren's panel. But it hasn't been officially studied. It's not in the criteria. These are not slam-dunk easy diagnoses to make, and it's very frustrating, I'm sure, for patients.
[22:29] We all wish it were much simpler — like, you get an X-ray, you've got a tumor; you get a biopsy, you've got cancer. It's not like that.

[22:37] Dr. Linda Bluestein: Right, which is why I say all the time, these conditions are just a horrible match for the way healthcare is right now, because it's absolutely not set up for this.

[22:47] Jill Schofield, M.D: Yeah. I think what needs to happen in the healthcare system is they have to recognize there are complex patients, and that the providers seeing those patients need more time. Period. And right now, it doesn't exist like that.
[23:04] You can spend an hour, you can put a really long note, you can 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 the four hours of time it takes.
[23:28] And so that's my call to action — if any insurance people are listening, we need to have a definition of complex patients with multisystem disease that doesn't fall into the current boxes of medicine. Because right now, most of us who do this work have been forced to go into a cash-only practice. And that's not because we're greedy. It's because we couldn't do the work by taking insurance.
[24:15] People aren't going to do it if they're not making anywhere near what they would make doing some other kind of work in the field — you need some level of compensation that makes taking on the stress and responsibility of that work sustainable. I was probably making a quarter of what my colleagues would make while working much, much harder. That's just not sustainable. Providers are going to cash-only because it's the only way we can do this work and have enough time to spend with patients to really get to the bottom of these complicated cases. You cannot do it in an hour. Period. You can't provide the education. You can't try to sort out which pieces are involved.
[24:49] We hope with time that's the only solution — that insurers have to recognize there are complex patients. I think they will with time. I think they'll recognize that mast cell, POTS, and EDS are complex conditions. But we need more work and more research. There's no funding in this kind of research. Those of us doing it spend hours and hours of our time trying to write papers without any compensation or support. It's very, very difficult.

[25:20] Jennifer Milner: And we also need, as much as we need insurance companies to recognize it, we need more doctors who can work multi-systemically as well. There are only so many patients you can see, right?

[25:35] Jill Schofield, M.D: Exactly. There's no training program for multi-system disease, so I kind of made up my own. It has no name, so I can't call it a fellowship, but I spent two years working with various people I wanted to learn from in multi-system autoimmune disease.
[25:50] I hope a fellowship like that will eventually be developed, but there aren't a lot of people doing the work. And the people doing the work are overburdened because there are too many patients and not enough providers. Most of them are not in academia because academia hasn't supported it — they don't have a box for it. They don't have a department of multisystem disease, so you don't fit into their world.
[26:22] But it'll happen one day. It's going to take time. The right person will come along and make it happen.

[26:35] Dr. Linda Bluestein: Yes, I hope so too. I've had patients who have been turned down from academic centers, with the academic centers saying, "We have nothing to offer you." And I think it's because they know they're not going to get compensated like they would for doing a surgery or procedure — and they know these patients don't need procedures and surgeries. They need time.

[27:30] Jill Schofield, M.D: That's actually good that those centers told patients they had nothing to offer, because for the most part they're right. Rather than having the person go to that appointment, get nothing, and be referred to another doctor who also does nothing — that's exhausting, stressful, and leads to medical PTSD. So in a way, I don't think that's necessarily a bad thing. The academic centers, in my experience, have not embraced these conditions either for patients or for physicians trying to do the work.

[27:30] Dr. Linda Bluestein: I agree. And I think that's actually a good message for us to get out through this podcast — that doesn't mean there isn't somebody out there who can help you. I think patients get very discouraged when they receive one of those letters. Without naming where they came from, patients have brought me those letters, and it can be very discouraging. "Wow, if that academic center can't help me, is there really somebody out there who can?"

[27:58] Jill Schofield, M.D: Yeah, everybody has ended up for the most part outside of academia, even though it would be best if we could be in academia. Because we need to do research in these fields and we need support. To do good research, you have to have support — clinical research coordinators, people who can help you submit the protocol. It's a very complicated and painful subject.
[28:25] As somebody who's tried to do the research with no support, it's just exhausting. But we still forge ahead and try to do it on the side, write papers that share our experience treating these patients, in the hope they'll have some impact — that somebody in a better position to do better research can use it as a framework. Kind of preliminary information.

[29:02] Dr. Linda Bluestein: You mentioned small fiber neuropathy briefly. Could you explain a little bit about what that is, why people who are bendy should know about it, and how you work it up?

[29:14] Jill Schofield, M.D: Sure. There are two kinds of nerves. There are large fiber nerves, which are involved with moving your limbs, telling you where in space your limbs are, and touch. And then there are the small fiber nerves, which, as their name says, are very small, and they are not picked up on the test used to evaluate large fiber neuropathy, which is the EMG and nerve conduction testing. Because the small fiber nerves are so small, their electrical activity is so weak, they're not picked up on that test.
[29:43] Until the last few years, there was really only a skin biopsy where you could look at the small fiber nerves and actually say they're abnormal. The small fiber nerves have two functions. Their autonomic ones control all of these autonomic functions we're talking about, and then they also control pain, temperature sensation, and itch.
[30:06] So there are autonomic small fiber nerves and sensory small fiber nerves, and those can be diagnosed by skin biopsy. These nerves go to every gland, organ, and blood vessel in the body, and the easiest place to look at them is the skin. There is also a test called the QSART or Q-Sweat, which looks at sweating function. In my experience, it's a terribly insensitive test. If you have a negative QSART or Q-Sweat, in my opinion that does not even remotely begin to rule out small fiber neuropathy or autonomic neuropathy.
[30:50] The reason EDS patients should know about this is that it has actually been published in the literature that almost everybody who has EDS has small fiber neuropathy. However, there are many causes of small fiber neuropathy — diabetes is number one, and then there's HIV, hepatitis C, certain vitamin deficiencies, Lyme disease, autoimmune disease. So the presence of small fiber neuropathy doesn't tell us the cause in any way.
[31:16] The way that I diagnose autoimmune small fiber neuropathy is: first, a consistent clinical picture with the right kind of symptoms; then persistent positivity of one or more autoantibodies that have been associated with it; and a skin biopsy that shows you have it. I personally only do a skin biopsy if I'm trying to get a trial of IVIG, because then the insurance company can wrap their head around, "okay, there are these autoantibodies, these nerves are damaged, we think they're linked." Otherwise I don't usually do a skin biopsy — I just clinically suspect it based on the nature of their physical exam.

[32:09] Dr. Linda Bluestein: And that's a perfect lead into my next question, which is what criteria do you use for determining if someone is a candidate for IVIG?

[32:18] Jill Schofield, M.D: The things I just mentioned, plus they're severely disabled — they can't work, and/or they can't go to school. IVIG is extremely expensive and burdensome. By that I mean it requires a lot of time getting IV or subcutaneous infusions. Any parenteral, non-oral therapy has higher risks, although I consider the risk relatively low for IVIG — it's quite safe, but there are risks. So those are the criteria I use.

[32:59] Dr. Linda Bluestein: Okay. And can you tell us a little bit about antiphospholipid syndrome? I know this is another area of expertise of yours.

[33:07] Jill Schofield, M.D: Yes, one of my goals in life is to increase awareness about this link, because I think it will be shown, with time, to be a very important association with small fiber neuropathy.
[33:23] And the reason it's important is, well, it's autoimmune and we have treatments for it. But it's also very important because these patients are at risk for blood clots — which can be very severe. Blood clots of the arteries would most commonly be a stroke, but it can mean a heart attack, and rarely it can mean a clot to the artery perfusing your leg and you lose your leg. So these are very serious issues.
[33:57] In the veins, blood clots most commonly present as a blood clot in the leg or arm, or in the lungs as a pulmonary embolus. Those can be fatal or extremely disabling events.
[34:10] That's why I think this link is so important. And it's just very confusing and complicated because — again, we come back to the problem with criteria. The criteria for antiphospholipid syndrome were intended to be used for research purposes, to capture a uniform population of patients with this very heterogeneous syndrome who have blood clots, because blood clots are a big deal. But there are no diagnostic criteria, so the research criteria get used for diagnosis, and they focus on blood clots.
[34:47] So if there's a doctor who doesn't really know much about this, they quickly Google it and they see these criteria and they say, "Oh yeah, there's no link with POTS and antiphospholipids, so those antibodies you have don't mean anything." They don't pay any attention to it until or unless you've had a blood clot — which to me is a failure, because if you've had a blood clot, especially if it was a massive stroke or a fatal pulmonary embolus, that's a big deal.
[36:22] That's why I'm very passionate about this. Another thing in the criteria that I find problematic is that it has been shown the higher the antibody levels and the more antibodies you have, the more likely you are to have a blood clot. But I have people with very minimally elevated antibodies who have had a blood clot. And the criteria actually call for a high-titer antibody — significantly higher than what the people who designed the assay said a positive is. A lot of my worst patients have minimally elevated antibodies, but they are positive and they have clinical features.
We call it antiphospholipid syndrome only if you've had a blood clot; otherwise there is an ICD-10 code for "antiphospholipid antibody positive." But there's this very specific phenotype of people who have antiphospholipid syndrome or antiphospholipid antibody positive.
[37:35] The clues that might suggest you're at risk: frequent migraine, often refractory, often with aura — a visual kind of change that comes on before the migraine. Raynaud's. Memory loss — more than just brain fog, and that can be hard to tease out because everybody with POTS has brain fog. But it's often a bigger complaint in people with antiphospholipid. Many people in their 20s or 30s are worried they have dementia or Alzheimer's. There are blank spells in their thinking where they can't remember the name of their best friend from 30 years ago — just more prominent memory loss.
[38:30] And then there's a skin finding called livedo reticularis, which is a lacy pattern of the skin. You can Google it, and you'll get the worst possible pictures, but it's usually not as bad as the pictures you'll see on the internet. It's most often present on the inner part of the arm and around the knees or thighs, and it often comes out when people get out of the shower — going from hot to cold — or when they're in the cold. For some people it's there all the time; for others it's more fleeting. That's a really important clinical clue that this diagnosis should be considered.
Obviously, if someone has had a blood clot and they have POTS, you better start thinking about antiphospholipid. And then there are pregnancy complications: recurrent miscarriage, especially late miscarriage after 10 weeks; stillbirth; preeclampsia; eclampsia; and seizures. And some more subtle ones like thickening of the heart valves — I always look very carefully at the echos of all my patients with POTS. 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 abnormal.
[40:12] And white matter change on brain MRI — a lot of neurologists say, "Oh, that's nothing, it's just due to your migraines." But 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.
[40:33] So that's the clinical phenotype. It's almost always women, but I have a few men, and they often don't fit that phenotype quite as well — they're more likely to have memory loss and less likely to have migraine. But there aren't enough patients to really characterize it well. It's very female predominant, like lupus and Sjögren's, though there are men who get it.

[41:04] Dr. Linda Bluestein: Interesting. And I saw in one of your papers that there was even a relationship between antiphospholipid antibody syndrome and CRPS — complex regional pain syndrome — and EDS, which is fascinating.

[41:20] Jill Schofield, M.D: Yeah, thanks for asking about that. CRPS, or complex regional pain syndrome, is another way in which this autonomic neuropathy can look clinically. Some people have POTS, some people have severe gastroparesis or other GI dysmotility, some people have complex regional pain syndrome — and some people have all of them. It can look differently in different patients.
[41:57] All of the patients I have had with complex regional pain syndrome — which is a very severe pain syndrome that develops most commonly after a fracture or some other injury to an extremity — have had either MCAS and/or antiphospholipid syndrome. And you can almost always tell which one they're going to have, because the APS people have the migraines, the Raynaud's, the white matter change. And the mast cell people have hives, abdominal pain, diarrhea. You can tell. But they can have both too. I've never had a patient with CRPS who didn't have one or the other.
[42:45] But this is a super emerging concept as well. People are just beginning to think about what might be the cause of CRPS. We're happy if somebody has actually gotten a diagnosis, because that is very difficult for people to get.
[43:01] And CRPS is the most painful condition there is, period. There's the Montreal Pain Scale, which goes up to 55 instead of 0 to 10 — they were trying to characterize people who are at a 10 and spread them out to see who was worse. And the very most painful condition on it is CRPS, even more painful than childbirth without anesthesia or amputation without anesthesia. So it's extremely painful, and these patients get just written off and told they're crazy. It's very tragic.

[43:32] Dr. Linda Bluestein: Yes, it definitely is. And among the many painful conditions that our EDS population is at higher risk for — also things like adhesive arachnoiditis, which is another super painful condition — it's especially important to recognize these things since there are so many comorbid conditions that we can at least try to do something about.

[44:14] Jill Schofield, M.D: Right. There is treatment for CRPS. People who get into physical therapy right away, and then if there is MCAS or an autoimmune cause — my patients who've had antiphospholipid syndrome respond to IVIG. But the biggest thing is to get the pain under control with things like gabapentin, getting into therapy, and trying to avoid opiates if possible.
The clinical clues for CRPS are that you had a recent fracture and your pain is just way out of proportion to what they're expecting — it's getting worse, not better. And then there are autonomic findings, because it is a disorder of the autonomic nerves or small fiber nerves. There's temperature change on the affected limb, color change, swelling of the affected limb — because the autonomic nerves go to the tiny blood vessels, and when they're dysregulated, there can be edema. And there can be change in the growth of hair and nails, which is also something the autonomic nervous system regulates.
[45:28] There can probably be itch too, though small fiber neuropathy patients in general can show up with itch. With CRPS, the pain predominates — they might have itch, but it would just be drowned out by the pain.

[45:39] Dr. Linda Bluestein: Yeah, I've definitely seen the itch, not so much with the CRPS specifically. And you studied 22 patients in your 2017 paper, "Autonomic Neuropathy in Its Many Guises as the Initial Manifestation of Antiphospholipid Syndrome." I found this really fascinating — 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 you also talked about the high percentage of autoimmune disease, most commonly thyroiditis. Do you have any thoughts about that paper in particular?

[45:43] Jill Schofield, M.D: Not really in the sense that there weren't enough patients for any statistically significant findings — it was really just an observation. And it's also very confusing in EDS. When you say sensory, I should clarify: all of my patients in that paper had the skin biopsy analyzed both for the autonomic nerves — quantitated as what's called the sweat gland nerve fiber density — and for the sensory nerves — quantitated by the epidermal nerve fiber density. The people without EDS were more likely to have just the autonomic, rather than both the autonomic and the sensory.
[47:13] But I don't know what that means. And as I said, there weren't enough patients. As I mentioned before, we don't know why almost every EDS patient, if you do a skin biopsy, has small fiber neuropathy. If you ask me for my hypothesis: there's a super strong link with mast cell activation, and the mast cells line up along these autonomic small fiber nerves and interact intimately with them both anatomically and functionally. I think if the mast cells are overactive and dumping toxic mediators on those nerves, they're not going to look normal or act normal on the skin biopsy. In other words, the patient is going to have symptoms — you know, they eat something with red dye and they get burning pain all over their body, and you know there's a link with mast cells and small fiber neuropathy if you're in the trenches seeing these patients. But it hasn't been published yet. I hope somebody is publishing it right now as I speak, because I know mast cell activation is a cause of small fiber neuropathy. Since everybody with EDS seems to have mast cell activation, I think that's the reason.
[48:21] But then there are the people who get autoimmunity on top of it, and I do the skin biopsy to try to prove my case that it's autoimmune, as I mentioned, to get a trial of IVIG. But I could pretty much already know that the person's going to have small fiber neuropathy even before the biopsy, because its presence doesn't tell us the cause.
[48:46] So it's very complicated, and it gets back again to you can't just look at the biopsy and the antibodies. You have to look at the whole person's whole clinical picture — the fact that they are not responding to treatment for POTS, like salt and fluids and exercise and the pharmacologic medications we have. They're not responding to the mast cell therapy. They're just getting worse and worse. They have the autoantibodies. And they have a clinical picture — say they have antiphospholipid antibodies, livedo reticularis, Raynaud's, white matter change, and valvular thickening. Then you're like, okay, they should get a trial of IVIG because I think this is autoimmune.
[49:29] It's very complicated. You really have to spend a lot of time going through all of these pieces. And it also takes time as you follow somebody. If I see somebody early on and I'm worried about an autoimmune cause — they have a family history of autoimmunity, I run these antibodies and they come back positive — I don't just pull out IVIG the next day. I only save it for the people who aren't responding to the other things, because a lot of people do respond to those even if they have autoantibodies.

[49:56] Dr. Linda Bluestein: And what other things do you treat antiphospholipid syndrome with?

[50:00] Jill Schofield, M.D: Oh, good question. I think of antiphospholipid syndrome as having two components. There's the sticky blood piece — which is the layman's term for antiphospholipid syndrome — and then there's the autoimmune piece.
[50:20] One of my areas of interest, and I just submitted a paper about this with 78 patients with antiphospholipid antibodies and severe migraine, is antithrombotic therapy. That would include either medications that target the platelets, like aspirin or Plavix, or in some people, anticoagulation.
[50:44] This is a phenomenon that was first described by Dr. Hughes in the early days. He noted that when he treated patients with antiphospholipid syndrome who had a blood clot with blood thinners, so many patients would say, "My headaches, which I've had every day for 10 years, have gone away, and I can think again." He proposed many years ago a trial of heparin — a blood thinner — in patients who had severe migraine, hadn't had a blood clot, but had the antibodies. And he showed in a very short publication — literally about half a page, one that probably wouldn't have gotten published today — that most or all of them had their headaches improve.
[51:18] That phenomenon hasn't taken off in the broader medical community, but it's been an interest of mine. Another feature that might make you suspect APS is if someone has migraine that responds to antithrombotic therapy. I hope this 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.
And memory loss too. I actually have this incredible case of an older man who was diagnosed with Alzheimer's. Another feature of antiphospholipid syndrome, by the way, is low platelets — can be just mild low platelets — and also a mildly low white count. This man was diagnosed with Alzheimer's, and his doctor noticed his platelet count was low and tested him. He had really high antibodies, and he required antiplatelet and anticoagulation therapy. He was like a new person. He got off his Aricept for the Alzheimer's he didn't actually have, and his functional ability improved dramatically.
[52:45] So that's one piece — the antithrombotic side. And I personally wonder, and I wish somebody would study this: we think it's working because there's sludging of the blood. It's sticky — like running old oil through your car. Your car doesn't work quite right, and the brain is really dependent on proper oxygenation and blood flow.
[53:15] I wonder if these small fiber nerves, which are so tiny and perfused by blood vessels that are smaller in diameter than the actual diameter of a red cell — I've been told — are a prime location where sludging can occur. I've seen teenagers where we treat them with aspirin or Plavix and their headaches go away, and we treat them with Plaquenil — which I'll come back to — get them on Plaquenil and vitamin D and Plavix or aspirin, and treat their POTS with salt and fluids or whatever. They can go from being severely disabled to feeling normal most of the time, and they stay that way. Whereas if we catch them later, that's not the outcome. So there's a real difference between catching it early versus late.
[54:12] Then there's the autoimmune side. I really like the drug Plaquenil — hydroxychloroquine. It's been studied in a number of studies in pregnancy: for patients with antiphospholipid antibodies and pregnancy, it dramatically improves outcomes. But it's been best studied in lupus, where it makes people live longer and dramatically improves flares. And there's significant overlap between lupus and antiphospholipid syndrome — a quarter of patients with lupus have antiphospholipid antibodies or antiphospholipid syndrome.
Plaquenil also interferes with the way the antiphospholipid antibodies carry out their effects and reduces the risk of blood clots. I use that drug and recommend it in all of my patients who have persistent antiphospholipid antibodies and a clinical picture that fits.
About 80% of patients notice improved symptoms, most commonly fatigue, joint pain, and/or neuropathic pain — like sharp shooting pains or tingling. I recommend it even if there is no symptomatic improvement, because I feel 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 bad rap people were trying to give it in attempts to dissuade people from using it for COVID.
[56:03] So often it's teenagers who have these antibodies, have POTS, and have clinical features of antiphospholipid syndrome. The combination of vitamin D, Plaquenil, and if they have headaches responsive to aspirin or Plavix, that cocktail seems to be magical. Not everybody needs IVIG — and that can happen in adults too if they're diagnosed early. It's just that some people have the whole thing kicked off very aggressively by some trigger, and then they need IVIG.
[56:44] But those are the pieces that are different from people who don't have the antibodies. And 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. If you have symptoms of a blood clot, you better go get checked out sooner rather than later.
[57:05] And also, if you have surgery — it's kind of an evidence-based recommendation that's not widely recognized in the medical community — if you have antiphospholipid antibodies, even if you haven't had a blood clot, any surgery increases the clotting risk for a period of time proportionate to the nature of the surgery. So we recommend anticoagulation for some period of time after surgery — it might be a few days, it might be a few weeks, depending. Orthopedic surgeries are very high risk.
[57:42] The same is true with pregnancy, because that is also a very prothrombotic state, especially in the postpartum period. So somebody with antiphospholipid antibodies should be treated with anticoagulation after delivery for the fourth trimester.
[57:56] The presence of the antibodies, even if you don't have the syndrome, is an important risk factor for clots that can and should affect how we take care of that person. Also, if it's a woman and she has those antibodies and she's going to get pregnant, she needs to be followed by high-risk OB. Her pregnancy needs to be monitored much more carefully. She should take aspirin. I believe she should take Plaquenil, which significantly reduces pregnancy complications.
[58:37] I've had patients who had severely terrible pregnancy outcomes. They didn't know they had antiphospholipid antibodies. Then we find out they have it, and we treat them with Plaquenil, vitamin D, and aspirin, and they do great. The fetus is monitored regularly, and usually they do very well. So if we know about it, people do much better than if we don't know about it until they have a bad event.

[58:42] Dr. Linda Bluestein: And from the healthcare system perspective — as an anesthesiologist, one of the things you always consider is what type of surgery it is, and there are different protocols to prevent blood clots. But if you can further delineate who is at higher risk, as opposed to just treating most everybody the same, that's really, really good information. And what dose of aspirin are you usually using?

[59:47] Jill Schofield, M.D: Usually most people respond to 81 milligrams, but I have a few who don't respond to 81 and do respond to 325. Plavix — one of the things I showed in the paper I recently submitted is that Plavix is much more effective than aspirin, and I'm not entirely sure why.
[1:00:05] I personally think Plavix is safer than aspirin. I worked as a hospitalist for many years, so I used Plavix every day, but a lot of physicians aren't familiar with it — they think it's a scary drug. Basically, both Plavix and aspirin inhibit platelets, making them less sticky, irreversibly for the life of a platelet, which is 10 days. They both do that same endpoint by slightly different mechanisms. But aspirin is also irritating to the GI tract, and that combination can increase the risk of GI bleeding, whereas Plavix doesn't do that. So that's why I consider it safer — it doesn't cause GI inflammation.
[1:00:59] I love Plavix. It's very well tolerated. The dose is 75 milligrams a day. It does require a prescription, and for whatever reason, it just works significantly better than aspirin — the p-value was like less than 0.00001 or something like that. It was just much more effective. But some doctors think it's a scary drug and it requires a prescription.

[1:01:26] Dr. Linda Bluestein: Right. And I'm recalling when I interviewed our Mastermind colleague and co-author in the book Disjointed, Puldeep Atwal. We were talking about Plavix, and the genetic — I don't know exactly what it is, but there's some genetic marker where a not-insignificant percentage of the population would not be sensitive to it. So I wonder if some of those people who don't respond to it, it's not because it's not the right approach, but it's genetics.

[1:02:04] Jill Schofield, M.D: Yeah, that has to do with the metabolizer status. There is a test for it, and sometimes I test for it. It hasn't been found in the cardiovascular literature to be worth doing as a matter of routine, but that is a reason some people don't respond. And then there's also aspirin resistance — that's actually something that now shows up on 23andMe.
[1:02:29] So that's why if a person fails one, I usually switch them to the other, because people respond differently. That was another thing we showed in this paper — everybody's different in the way they respond. Which drug or drugs works for one person is different from person to person. It's very individualized and symptom-driven rather than one-size-fits-all.
[1:02:47] And it's a simple two-week trial. It's usually dramatic — either it takes it away, or it doesn't do anything. Like any drug trial, we stop it if there's no benefit.
[1:03:04] And I think it's telling us something in the patients who have had headaches every day for 10 years, take Plavix, and their headaches go away — it's their own internal gauge that their blood stickiness is now right, because we don't have a lab test for overall blood stickiness. The rate of bleeding in the study was extremely low, and I think it's because of that phenomenon. It's normalizing something — their level of blood stickiness, so to speak, is where it should be. And there was no bleeding in any of the 78 patients during the two- to four-week trial.
[1:03:53] The duration of the trial depends on the frequency of the symptoms. If somebody has migraine every day, a two-week trial should make it very clear: either this works or it doesn't.

[1:04:12] Dr. Linda Bluestein: Sure, absolutely. So we are going to be talking to Dr. Schofield again in Part 2 of this conversation, which we're super excited for you to hear. In the meantime, Dr. Schofield, was there anything else you want to share for this part? This is more the provider and academic part. Do you have a call to action for providers or other specialists taking care of this population? And could you let people know where they can find you?

[1:04:47] Jill Schofield, M.D: I have my own practice called Center for Multisystem Disease in Denver, Colorado. You can Google it and find out how to reach me there.
And my call to action to providers is to think about it, and to start recognizing this clinical phenotype — which is more than just pregnancy complication and thrombosis. Are you seeing a patient who has livedo reticularis? Take a look at their skin. Do they have Raynaud's? Did they have white matter change on MRI? We also see recurrent stress fractures in patients because they're not getting enough blood flow to the bone. Mild low platelet count. Mild low white count in the 3 to 4 range. Thickening of valves noted in the body of the echo report.
[1:05:53] Not everybody has all of those things, but many patients have three or four. And if they're complaining, "My memory — I'm worried I have Alzheimer's," that's the clinical phenotype. Think about it. Because I consider it a failure if somebody meets the criteria for antiphospholipid syndrome, meaning they've had a serious clotting event, because most of these people had clues that they could have been diagnosed before that serious outcome.

[1:06:24] Dr. Linda Bluestein: Well, that's great information, and thank you so much for chatting with us today. We're looking forward to Part 2.

[1:06:34] Jill Schofield, M.D: Yes, thank you.

[1:06:35] Dr. Linda Bluestein: 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 Bodies original music is by Andrew Savino, and sound editing is by Rhett Gill. Thank you so much for tuning in, and we will see you next time on Bendy Bodies with the Hypermobility MD.