Antiphospholipid Syndrome and Autoimmune Dysautonomia with Dr. Jill Schofield
Dr. Michael Ruscio:
Hey, everyone. Welcome back to another episode of Dr. Ruscio Radio. Today, I
spoke with Dr. Jill Schofield and this was a pretty deep concept. And
essentially, we talk about two types of autoimmunity that may be responsible
for, if I were to kind of turn this as plainly and as simply as I can, patients
who don’t respond to any therapies. They’ve gone from doctor to doctor and
they’re just not able to see the resolution of their symptoms that they would
like. And there may be this antiphospholipid syndrome and/or autoimmune
dysautonomia that is driving this. So we talked about some of the symptoms and
history findings that may indicate that you or your patient may be a candidate.
We talk about testing, we debunk or potentially debunk that
some of the functional medicine tests here may not have gone through
appropriate validation to be able to justify. Let’s say, you performed a test.
That test informs you that you have a number of neurological antibodies. There
may not be adequate validation for some of these tests in the functional
medicine realm. So we impart a few cautions there and we talk about treatment
considerations. Some of these are things that we’re very familiar with.
Gluten-free, dairy-free, low histamine, improving one’s gut health, mass cell
activation syndrome supports.
Also, interesting that Dr. Schofield is starting to experiment
with oral immunoglobulin therapy, like our intestinal support formula and also
uses intravenous or IVIG as something that can be quite cathartic for patients
who have otherwise been unresponsive. She also provides resources where if you
feel like this is something that may be inflicting you, where you can learn
more about her and her clinic or other like clinics to help you get the support
and evaluation that you need because this, in my opinion, is definitely
something you need to work with a specialist with.
I would not say that a kind of functional medicine generalist who’s just running antibody profiles through what may not be a validated lab would really have the savvy to help. Although, they’re probably trying to do their best. It just seems that this is a very emergent, specific, specialized area and you need to be working with a specialist. She recommends either potentially a neurologist or a neuro-immunologist. But again, all those details to follow in the body of the podcast. So this is a deep one. It is a bit complicated and complex, but for those who really feel like they are floundering, I am hopeful that this will provide some insights and give you some leads to pursue. Okay. Now to the show.
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DrMR: Hi, everyone. Welcome back to another episode of Dr. Ruscio Radio. This is Dr. Ruscio. Today I’m here with Dr. Jill Schofield, and we’re going to be talking about antiphospholipid syndrome and autoimmune dysautonomia, which sounds like a mouthful. We will define the “what does this look like”, “what does this feel like”, in just a moment. But before we jump into all these details, Jill, welcome to the show!
Dr. Jill Schofield: Thank you! It’s a pleasure to be here. I appreciate your talking about this subject.
DrMR: Well, this is a subject, admittedly, I
don’t know a tremendous amount about, but I have a feeling that for complex
chronic cases, this could be an area to explore, and could be something that’s
sneaking underneath the radar of some clinicians. So, yes, I’m excited to have
you here, and I’m happy to learn more myself, and like I said a moment ago,
bring our audience along for the ride.
Before we jump in, can you tell people briefly about your background and kind of what you’re doing now in clinical practice?
DrJS: Yeah. I did my medical training at Johns Hopkins, my residency at Johns Hopkins in internal medicine, and I worked as a hospitalist for many years, where I saw a few patients with antiphospholipid syndrome and developed an interest in that.
I went on to do a special training program for two years in multidisciplinary autoimmune disease, which is not an established fellowship but more something I geared toward my interests, doing training in rheumatology, thrombosis, and neuroimmunology as well as other areas of autoimmune disease including celiac and autoimmune eye disease. Just all aspects of autoimmunity as well as training with some specialists in mast cell activation syndrome, autonomic disorders, et cetera.
I’ve really kind of focused my practice on… my primary interest is in antiphospholipid syndrome and autoimmune dysautonomia.
DrMR: And let’s define that for people because that’s a mouthful and something that people may have a fuzzy idea of what that means, but tell us, how do we define that, and more importantly, especially for the lay faction of our audience, what does this look like in terms of symptomatic presentation?
DrJS: Well, I’ll start with antiphospholipid syndrome, which is a systemic autoimmune disease, kind of a cousin of lupus. By systemic autoimmune disease, I mean that it can affect multiple organs, and is associated with a number of different auto-antibodies. The layman’s term for antiphospholipid syndrome is “sticky blood”; it’s also known as Hughes syndrome after Dr. Graham Hughes, who’s a rheumatologist in London who first described the syndrome in 1983.
It was initially described, actually, in patients with lupus because about a quarter of patients with lupus also have antiphospholipid syndrome. It was described in patients who had blood clots, or serious pregnancy complications, and those are the two clinical hallmarks of the syndrome, and the manifestations of the syndrome, that most physicians know about because those are the manifestations that are included in the criteria.
The criteria for antiphospholipid syndrome, known as Sydney Criteria, were never really intended to be used for diagnosis; they were intended to capture a uniform population of patients for research purposes in this very complex, multi-system autoimmune disease which, like lupus, can present in many different ways. And while the focus of those criteria are on the clotting events, because those are probably the most important, there are a number of other manifestations that have been associated with antiphospholipid antibodies that can be just as disabling.
Dr. Hughes likes to refer sometimes to the syndrome as a neurological condition in which blood clots might occur because any number of neurological complications can occur in the context of antiphospholipid antibodies. He and I and a couple of other colleagues described in 2013 the link between antiphospholipid antibodies and autonomic neuropathy, or POTS. This has turned out to be, I believe, will be shown to be a very important link with patients with severely disabling POTS or other autonomic manifestations, which can also be severe GI dysmotility, although they often go together, POTS and severe GI dysmotility, in patients who have an autoimmune cause, because it’s due to an autonomic neuropathy or damage to the autonomic nerves by the autoimmune attack, so to speak.
So, the autonomic manifestations are not included in the formal criteria, and that’s part of the problem with the criteria. They’re just capturing sort of the tip of the iceberg, and so, it creates problems in that patients aren’t actually meeting the criteria for the syndrome, but the antibodies are probably playing an important role in their illness, and these patients have a high rate of response to IVIG, which is an immune treatment.
What is dysautonomia?
- Dysautonomia is an umbrella term used to describe several different medical conditions that cause a malfunction of the Autonomic Nervous System.
What is Antiphospholipid syndrome?
- Antiphospholipid syndrome occurs when your immune system mistakenly creates antibodies that make your blood much more likely to clot.
Symptoms to Look Out For
DrMR: I want to get over to the treatment in more detail, of course, momentarily, but for people who are maybe floundering, they’ve seen a few doctors, maybe they’ve seen a GI specialist, maybe they’ve seen a thyroid specialist, and they feel like they’re not really getting anywhere, or maybe they’re getting small improvements with… Maybe they were diagnosed hypothyroid and now they’re on medication, and they had IBS, and the IBS has improved somewhat but not that much, and they still have this litany of symptoms.
Can you help describe, and I know this may be a hard question, but is there a typical constellation of symptoms or patient type, just for the people listening to or reading this, they can start to flag if, “Okay, this is something I may want to pay attention to and seek out some care for”?
DrJS: Yes, that’s a great question, thank you
for asking it. There is a phenotype of patients with dysautonomia that kind of
make me think they may have antiphospholipid antibodies associated.
- They often have refractory migraine, accompanied with visual aura where they see squiggly lines or flashing lights that precede the onset of their migraine.
- They often have prominent memory loss or blank spells in their thinking.
- They often have Raynaud’s, which is, change in color of the skin in response to the cold of the fingertips and/or toes, usually white but it can also be red or purple. It’s just usually the fingertips, not the whole hand or foot.
- They often have a characteristic skin finding known as livedo reticularis, which is a very important manifestation of antiphospholipid syndrome. It’s a lacy appearance to the skin, most often present on the arms and/or the legs, often around the knees, and it’s often more prominent with a temperature change or in the cold.
- If there is a history of recurrent miscarriage or especially late miscarriage after 10 weeks, preeclampsia, stillbirth, history of any kind of blood clot in the arteries or the veins, and also low platelet count (thrombocytopenia); often patients with antiphospholipid syndrome will run a low white count in the three or four range.
- They often have a family history or a personal history of another autoimmune disease such as Hypothyroidism, which is frequently autoimmune and often is comorbid with antiphospholipid antibodies.
So, that would be the clinical kind of picture that would raise my interest as to that possibility. Also, patients with an autoimmune form of dysautonomia, most often they have an acute or subacute onset of their illness that tends to be progressive and quite severe. Not always, it’s not always severe, but the patients that we’re going to end up treating with IVIG, they become very severely affected to where they usually can’t work or attend school.
DrMR: And so, I’m assuming, kind of like I alluded to a moment ago, these patients are probably floundering for a while before they find themselves a clinician such as yourself. Is that an accurate assumption?
DrJS: Usually, yes.
DrMR: You’re definitely helping us kind of throw out some flags for people to hone in on; is there anything else kind of while we’re on this that, if a patient has had X, Y, or Z… You just listed a number of things, but anything else you want to chime in there to prompt them to maybe look into working with a specialist like yourself?
DrJS: Well, one important issue also about the “criteria”, for APS that I mentioned, in general, the higher the antibody level, the greater the risk for clotting. And so, the people who made the criteria, they set an arbitrary cutoff level of moderate to high titer when they were trying to capture this uniform population of patients for research purposes, focusing on the clotting patients. That was different than the cutoff that the scientists who made the assay set as positive. And so, oftentimes the patients, in my experience, with antiphospholipid antibodies associated with autonomic neuropathy, they often have lower than this arbitrary cutoff set in the criteria.
And so, if these patients see rheumatology or hematology who have these research criteria listed, they’ll often discount these lower positive results when in fact, in my experience, they’re very clinically important. They’re often IgM antibodies as opposed to IgG, for reasons that aren’t entirely clear why these IgM antibodies seem to be associated with these neurological manifestations. I have my own ideas, which is sort of beyond the scope of this talk, but they often get discounted as probably not important, when I think they are important.
- Dizzy when standing
- GI impaired motility
- Migraine with visual aura
- Prominent memory loss
- Raynaud’s (very cold fingers/toe tips)
- Livedo reticularis (skin has lacy appearance)
- Miscarriage, still birth, preeclampsia
- Blood clots, low platelet count
DrMR: I’m assuming but I’m not sure on this. Can the antiphospholipid antibodies be run through the big box labs like Quest or LabCorp?
DrJS: There are three that are included in the so-called “criteria” antibodies.
- The anticardiolipin, IgG and IgM
- Beta-2 glycoprotein IgG and IgM
- The lupus anticoagulant test, which is a functional clotting test, not an antibody test
Then there are a number of “non-criteria” tests that also are available for testing by LabCorp and Quest.
- Antiphosphatidylserine prothrombin
- Antiphosphatidyl ethanolamine
There are others. There was a concept introduced in I guess it was 2003, I think, in the beginning, I could have that date wrong, of seronegative antiphospholipid syndrome, meaning the antibodies are negative but the person has the syndrome.
A number of those patients have been found to have these “non-criteria” antibodies that have been linked with the syndrome but not yet accepted as part of the research criteria, and I have found those antibodies important also because often, if you run the whole panel of the criteria and the non-criteria ones, often patients have more than one, and that then gives more validity, I think, to the lower numbers.
Proper Interpretation of Test Results
So, if a physician is wondering if it’s important because it’s relatively low-positive and they happen to have three different antibodies, it tends to give it more credibility to people, or make it seem like, “Yeah, these antibodies probably really are important.” But occasionally, people have just one antibody, and it can still be important. You have to take these tests and put them together with the clinical picture.
Also, on the flip side of that is, let’s say somebody has a really high level, and it was ordered for not a good reason. I mean, we shouldn’t really be ordering these tests unless somebody has clinical features of the syndrome, but there could be a patient who has a very high titer antibody and they don’t have any clinical manifestations at all. So, you’ll have to look at the antibody test with the clinical picture and clinical phenotype of the patient. Are they sick or are they not? Et cetera. So, in my experience, low antibodies can be very important.
DrMR: And again, when you say low, you’re
meaning it is flagged positive.
DrMR: But it’s just a low level… Okay.
DrMR: Just making sure.
DrJS: Yeah, some of the labs will call it borderline positive, low positive, and then medium, and high. That’s in particular for the anticardiolipin and the beta-2 glycoprotein. Some of the non-criteria antibodies, they don’t really give ranges like that, it’s either positive or it’s negative, but if it’s barely above the positive, people will still have a tendency, some physicians will still have a tendency to discount it because it’s not sky-high. I think that, again, comes from the fact that when these research criteria were made, it was arbitrarily set that they should be medium to high titer to be important, and in my experience just simply isn’t true.
It does correlate in general, when you take large numbers of patients that, in general, the higher the level, the higher the risk of blood clotting. That’s not necessarily true for these neurological manifestations, and the people with low titers can still have blood clots, and indeed, patients with seronegative can still have blood clots.
So, they are flagged as positive, and that’s an important point because sometimes, patients think just because they have a number for that test, it’s positive; that’s not true. Everybody has a number. So, if it’s two or three when the cutoff is greater than 10, then two or three is negative.
Working with an Experienced Clinician
DrMR: Now, obviously, this suggests that working with a good clinician is going to be crucial, and this is one of the things that irks me in the area where I have a body of knowledge, which is a mild elevation of antibodies is sometimes taken completely out of context of the patient, and a strong diagnostic proclamation is made even though clinical features, signs, and symptoms don’t support that, and then the patient is subjected to unnecessary fear and treatment.
I think this happens more kind of in alternative and functional realms. So, I could see here, if someone wasn’t doing this with an experienced clinician, they could get a very inaccurate read, either overzealous or too conservative, if the contextual weighing of lab findings and presentation wasn’t analyzed in order to provide the best diagnosis.
I think you were just saying that, but I just want to echo that for people, and double-check that I’m kind of interpreting that correctly.
DrJS: Yes. I agree.
DrMR: Now, there’s also these emergent functional medicine labs that are testing arrays of antibodies, and I saw a patient the other day, and it was some lab I had never heard of, something like Neuro Minder, or Neuro Eval and they run just this litany of neurological antibodies.
DrJS: Neural Zoomer?
DrJS: Yeah, I don’t know the significance of
those antibodies, either.
DrMR: Okay. Yeah.
DrJS: I don’t really put any weight in them because I haven’t seen any… I could have missed the publications, but I haven’t seen those published in association with the diseases I treat, like POTS. So, that’s not something that I personally would treat with immune-modulatory therapy. I could be wrong; as I said, it’s just not something that I’m aware of that’s been published.
DrJS: So, I don’t know what those mean,
DrMR: Okay. Well, I’m glad to hear you say that, because looking at that test, I am, at that point, outside of my area of specialty, and I, on the one hand, want to be open-minded, but on the other hand, I’ve just become so circumspect because it seems these antibody labs are popping up left, right, and center, and making these strong claims.
I think where the wheels really fall off the argument, is A) Validation, as you said. Do these markers even show any correlation to a disease condition? But then, B) do they help you treat the patient any differently? It sounds like it’s probably a No on both of those, given that, again, your assumption is correct, which is there hasn’t been anything published. Of course, if there has been, then the narrative changes. But again, just for the people who are maybe having some brain fog and other neurological symptoms, they run something like the Neural Zoomer, I’m a bit cautious with what that really tells them other than maybe scaring them into having this litany of antibodies, and don’t even know what the normative range should be. So, if you’re positive, that may mean literally nothing.
DrJS: Yeah, and now, the antibodies that I use
to make a diagnosis of autoimmune dysautonomia include the Mayo dysautonomia panel,
or the Mayo paraneoplastic panel, and the GAD 65, which is not part of the Mayo
dysautonomia panel, but it is part of the paraneoplastic panel.
Those antibodies sometimes occur on their own, such as the voltage-gated potassium channel, antibodies voltage-gated calcium channel, antibody… And sometimes they occur in association with the antiphospholipid or other systemic autoimmune antibodies that have been linked with autonomic dysfunction, so that panel carries weight for me, and then any of the Sjogren’s antibodies. And Sjogren’s is very much well-recognized to occur in association for many, many years with autonomic neuropathy.
The problem is that the antibodies… It’s very similar to antiphospholipid syndrome in which the research criteria that were recently updated by ACR and EULAR, the Rheumatology Societies of America and Europe, include only the SSA and the SSB antibody.
Actually, I think it now just includes the SSA antibody, the most updated criteria. That antibody misses the vast majority of patients with autonomic neuropathy. That’s kind of well-recognized. Unfortunately, no new antibodies have been added to the criteria, so basically we’re missing most of the patients with autonomic neuropathy due to Sjogren’s syndrome, which can be extremely disabling. I’ve been using the novel Sjogren’s panel by IMCO in New York, which has been commercially available since 2012, since about 2015, so I have a lot of experience with it, and in my experience, it correlates with clinical manifestations of Sjogren’s such as dry eyes by the Schirmer’s test, which is part of the diagnostic criteria, and Raynaud’s, and clinical just subjective dry eyes and dry mouth, and low white count, and just other things that go with Sjogren’s syndrome, and also correlates with response to IVIG, and those antibodies often occur together with the antiphospholipid antibodies. And then celiac disease has been recognized in association with autonomic neuropathy, as well, and that sometimes is comorbid with antiphospholipid thyroid and Sjogren’s; sometimes people can have all four of those together.
Lupus is always talked about in association, but in my experience, very rare, very rare to be linked with autonomic neuropathy. I have one or two patients, but way more with antiphospholipid and Sjogren’s. But really, any systemic autoimmune disease I’ve seen in association with autonomic neuropathy. But celiac, antiphospholipid, and Sjogren’s, and those anti-neuronal antibodies are by the far the most common.
Now emerging is this link between dysautonomia and the adrenergic and muscarinic receptor antibodies. This is a really complicated area because Dr. Kem’s lab out of the University of Oklahoma has shown a link with these antibodies and POTS, but he has done this very complex functional assay that’s probably never going to be commercially available because it’s so labor-intensive. And there is another way to test for these antibodies, done in Germany – CellTrend antibodies, and those are done by ELISA, which is a more simple way to test things, but the accuracy is not yet clear.
So, that’s being worked out, whether the ELISA test accurately predicts these pathogenic antibodies or antibodies that are causing disease or not. But that’s a very interesting area, a hot topic right now, that is under ongoing research by a couple of different groups. We eagerly await those results. Currently, my practice and everybody’s a little bit different because this is an emerging area so there are no evidence-based guidelines for us to go off of, but in my practice is, I order those antibodies only in my patients who I feel almost certainly have an autoimmune form of dysautonomia for the reasons I mentioned; they have a strong family history of autoimmune disease, they have a comorbid autoimmune disease themselves like autoimmune thyroid disease; they have this subacute, acute, and severely progressive and disabling form of dysautonomia, and they have tested negative on two occasions for all those other ones I just mentioned.
Then I will send them for those CellTrend antibodies, and if they’re positive, I have been able to use those to get a trial of IVIG, and those patients have all responded to a trial of IVIG. So, that’s kind of my personal practice and, as I said, the reason I don’t order them up-front is that I’m not certain yet whether those antibodies performed by the ELISA, the more simple test, are pathogenic or not.
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DrMR: Yes. So, a lot there to dig into. I guess I want to zoom this out a little bit. Because I’m trying to think about the clinicians here, but also the laypeople who are trying to be their own health advocate, and help provide them a road forward. One of my fears and I think you spoke to this, but I just want to make sure that for our lay audience, they didn’t miss it; it sounds to me like the labs you’re using are fairly kind of in-the-box, conventional labs. I mean, yes, it seems there’s much to be learned here, and pioneered, and criteria that are changing, but my fear is that providers who are well-intentioned but probably a little undereducated, are running something like the Neural Zoomer or a Cyrex panel for different antibodies, telling people that they have all types of autoimmunity, which I think is heavily questionable, and then using that to push them into a really strict gluten-free diet, and maybe handfuls of supplements.
My fear there is, it’s not a validated test or tests that are being used, and then the treatment may have some validity, but I’m thinking that what may happen in some of these cases is there’s… gluten-free diet is the only treatment, so everyone’s being given that as a recommendation, kind of the hammer/nail parallel. Do you see that? Can you speak to that? I’m not sure how much you’re seeking kind of in the integrative realm, but that’s one major fear I have for patients, and I’m hoping to help dispel any of that, if you may.
DrJS: I guess I tend to see the patients who
failed the functional medicine route, and I’m sure that that route helps a
number of patients, but I think if there’s a true autoimmune driver, then I’m
seeing those patients who failed that route. I do see people getting those
Cyrex and Neural Zoomer, and again, I don’t use those antibodies; I use, like
you said, strictly traditional tests orderable by LabCorp. 100%, that’s all I
I think that a trial of a gluten-free diet is useful in patients with these disorders. My experience has been that it’s my patients who have mast cell activation syndrome, probably half of them seem to improve sometimes dramatically with gluten-free and/or dairy-free, and/or histamine, attention to the high histamine food, anti-inflammatory, non-processed diet more than my autoimmune patients. But I consider it a trial because it doesn’t help everybody.
I have been surprised over the years how many of my mass cell activation syndrome patients can just really improve dramatically by that route. But for me, it’s a trial. I recommend a month or so trial of whatever diet, and if it doesn’t help you, then it’s kind of a win-win. I look at it as a win-win in that if it helps you, great, and if it doesn’t, you can go back to eating it.
DrMR: And there’s actually a great point that you made there that I just want to echo because another one of my concerns is that the gluten-free diet is being recommended, and then despite no symptomatic improvement, they’re being told that they have to follow that forever because of the antibodies found on the lab test. And that’s where I think we go from taking something that can help people, gluten-free, dairy-free, and now we’re kind of beating someone over the head with it, and we’re forcing them to adhere to it even in the absence of any symptomatic benefits.
So, it’s great that you say you use that, you see benefit, but it also seems pretty prudent to say if you’ve given this an honest trial for roughly 30 days, and you’re not seeing anything, you don’t have to make your life necessarily harder in complying with the diet if it doesn’t seem to be moving the needle forward at all.
DrJS: That’s my approach.
- Anticardiolipin IgG and IgM
- Beta-2 glycoprotein IgG and IgM
- Lupus anticoagulant test
- All available through Quest and Labcorp
- Low positives can be diagnostic but must be paired with symptoms/presentation
Tests that may not be validated
For diagnosis of autoimmune dysautonomia
- Mayo dysautonomia panel
- Mayo paraneoplastic panel
- GAD 65 (which is not part of the Mayo dysautonomia panel, but is part of the paraneoplastic panel)
What About the Health of the Gut?
DrMR: Yeah, well, I mean, that seems pretty reasonable. Do you notice the health of one’s gastrointestinal tract seems to be important? And maybe a corollary between IBS symptoms, or therapies that improve IBS leading to, I’m assuming, MCAS patients improve. I’m not so much clear on the autoimmune dysautonomia, but wondering what kind of gut connection you’re seeing there.
DrJS: Well, I think we have a lot to learn about all of this, but my feeling is probably, everybody with these disorders has “leaky gut.” That’s probably where it all started. Hippocrates was probably right, I feel. What’s the right way to treat it and deal with it? Everybody seems to have their own approach. I mean, I am not a big believer in the importance of SIBO, for example, because I feel like all of my patients have autonomic dysfunction unless we found a successful treatment for that to improve the GI motility significantly, that if we treat SIBO, small intestinal bacterial overgrowth which arises commonly due to this dysmotility of the gut, that it’s just going to come back in days, weeks, or at best, months.
Yeah, so, I don’t even know where to begin with that topic. People ask about that every day, and every provider seems to have a different theory about it. I have other colleagues who I respect greatly who are much more aggressive at treating SIBO. I just haven’t seen success with it.
DrMR: And when you say motility treatments, are
you talking about treating the underlying autoimmunity to the nervous system,
which is affecting the motility, or more so a traditional type of prokinetic
agent? Or maybe both?
DrJS: Well, I feel like those prokinetic drugs, if you have an important underlying cause such that you have severe disease, don’t treat it well enough to prevent recurrence of SIBO if you treat it, whereas if I have somebody who has autoimmune dysautonomia and who’s a great responder to IVIG.
Usually, in my experience, they don’t need to treat their SIBO because it’s going to go away, because their motility improves. So, those are the main patients where I have the most success in really dramatically improving their functional ability and their disease process. Maybe that would be the person where, if they continued to struggle with GI symptoms after getting their life back, so to speak, by being able to return to work and significantly improving their functional ability, that I would consider giving them, say, Rifaximin, which is a broad-spectrum antibiotic that is used to treat SIBO.
Because I feel like antibiotics, you’re destroying all of your good bacteria at the same time, so I’m kind of hesitant to treat it when I haven’t found it, personally, in my practice at least, to result in any meaningful improvement.
DrMR: Well, I think there’s definitely a case
to be made there with someone who has some type of severe motility impairment,
and I question how helpful the motility agents are. On the one hand, I’m open,
on the other hand, they don’t seem in some cases to deliver the benefit that
they’re purported to deliver, and I wonder if, for a subset of patients who
experience that, there could be another deeper underlying cause present.
DrMR: The IVIG therapy, can you tell us a little bit about that? And I just want to draw one distinction for our audience. We’ve talked about oral immunoglobulin therapy; ImmunoLin, formerly prescription EnteraGam. That seems to be helpful in IBS. There’s been a handful of studies documenting that benefit. But that is different from what you’re describing, which is IVIG. So, I just want to preempt any confusion on behalf of our audience. But tell us more about IVIG, because I’m assuming a number of our audience maybe have heard that one or two times, but they don’t even really know what it is. So, give us the primer there.
DrJS: Yeah, and just one more comment that you spoke to which is, in my experience, if there is a major autoimmune driver, those what I call Band-Aid treatments like the motility agents or the drugs to treat POTS like midodrine or things like that, a Florinef, they tend to be less effective until you treat the underlying autoimmunity. Whereas other people who have less severe forms, they may respond quite well to those drugs, and they may have pretty good efficacy.
I have also developed a little bit of interest in that serum bovine immunoglobulin. I think there is good data for that in a lot of studies. I’m not sure quite what the role of it yet is in my mind, but I’ve started to use some of that, as well.
DrMR: Because that’s something that I’d be curious about. I know you just said you’re kind of early, but obviously, in terms of ease of accessibility, that’s an attractive option for patients. Do you feel that it would be warranted for someone who, let’s say they are having a hard time finding a doctor who practices as such, but they might be able to find their way to the immunoglobulin, the oral bovine immunoglobulin. Would you say it’s worthwhile to perform an experiment on this? Are you seeing some benefit from it?
DrJS: Well, I see little risk in it. As I said, it’s just the very early days for me in using and recommending that, so I can’t really comment, but I’m using it in patients. For example, patients who have persistently positive celiac antibodies despite all these treatments, I’m recommending it to those patients to see if we can convert their celiac antibodies, who are on a gluten-free diet but they’re still positive. Things like that, or people who’ve been diagnosed with microscopic colitis, just kind of this vague, immune-mediated condition that we treat with steroids, Budesonide oral steroids, and I hate to give steroids, so I feel like it’s worth trying in that context. So, I’m just using it personally in a really narrow way right now.
DrMR: I’m sorry, you said you felt there was little risk, or there is a risk?
DrJS: I feel like there’s little risk.
DrMR: Got you. I just wanted to make sure.
DrJS: There’s not any risk that I know of.
DrMR: Sure, agreed, agreed.
DrJS: Other than the cost! I mean, you know…
DrMR: Sure, yeah.
DrJS: The cost pales in comparison to the cost of IVIG, which is an extremely expensive therapy, very hard to get covered by insurance because of the cost. It’s well over $100,000 a year. Immunoglobulin are basically the antibody molecules in our blood. It’s derived from blood donors; thousands of blood donors go into each batch, and the blood is donated. And the cells, the red cells, and the white cells and the platelets are removed, and the liquid part of the blood is where the antibodies reside, and that’s then purified and then given to the patient.
It was used initially over 30 years ago as a treatment for immune deficiency; in other words, patients who made too few antibodies. So, it was very logical that we would give those patients somebody else’s antibodies, and that has been used very effectively in that context for immune deficiency for, again, over 30 years, and it’s FDA-approved for that indication.
It was noted in the early days that a boy who had immune deficiency also had autoimmune thrombocytopenia, or autoimmune low platelet count because immune deficiency and autoimmune diseases often go hand in hand. And they noticed that when this boy got IVIG for his immune deficiency that his platelet count always came up. And they had some other kids with those two problems, and they looked into their case and found a similar thing. And then IVIG got studied for autoimmune diseases, and it’s been shown to be effective in pretty much any autoimmune condition you can find in the literature.
The way it works in autoimmune disease is not clear. There are over 10 different mechanisms proposed which are extremely complicated, and it may work by different mechanisms in different autoimmune diseases, but one simple way that’s probably incorrect but a simple way to think about it is, every system in the body has a negative feedback loop, and if you flood the immune system with a whole bunch of auto-antibodies, it may tell the immune system, “Well, we got too much here, slow down, slow down,” and slow down kind of autoimmune reactions.
It is FDA-approved for a condition called CIDP, chronic inflammatory demyelinating polyneuropathy, which is a chronic form of Guillain-Barré syndrome, and it’s an immune-mediated peripheral nerve disorder of the large nerves that are involved with motor function. That has been one of the FDA-approved indications for IVIG that’s analogous to autoimmune autonomic neuropathy, which affects the small-fiber nerves instead of the large-fiber nerves like CIDP. And some people meet the criteria for both, so there’s some overlap.
That’s how IVIG came to be used for small-fiber neuropathy, and we hope that it will be FDA-approved in the coming years. There are ongoing randomized controlled trials for it right now based on large case series showing efficacy. It can be given either IV, intravenously.
It is long infusion because patients with dysautonomia don’t tend to tolerate it as well as other patient populations, for reasons which are not entirely clear but may be because of mast cell activation. So, it’s a long infusion. The best-case scenario, it’s given all day once a month. I usually start my patients off once a week so that they’re getting a lower dose more often, and as we increase the time on treatment, they can usually tolerate more all at once, and many people get to where they can get the whole infusion once a month after time.
It can also be given now subcutaneously, meaning under the skin, once a week. And usually, most of my patients with both cases infuse at home with a nurse. With the IVIG, the nurse stays for the entire infusion; with subcutaneous, the patient self-administers after two or three training sessions. It can be difficult to get insurance, as I said, to cover this.
DrMR: I was just going to ask that. Is that one
of the main hurdles, cost and coverage?
DrJS: Yes. And also, it’s a very burdensome therapy. So even if I have patients who have autoantibodies that have been associated with dysautonomia, I don’t ever start out with IVIG first, because some people do well by targeting their POTS and targeting their mast cell activation and things like that, and as I said, usually it will declare itself by a failure to respond meaningfully to those treatments, that the autoimmunity needs to be treated.
30 day diet trial is warranted, consider:
- Gluten free
- Dairy free
- Low histamine
- Consider support for the gut
- Some SIBO patients may need motility support
- Blood donor derived immunoglobulins
- Effective for any autoimmune disease
MCAS and Treatment
DrMR: Now, with mast cell activation, one of the things that I’ve noticed, and this isn’t completely accurate but it’s kind of a loose analogy to help people visualize the concept, there’s a spectrum. On the one hand, we have histamine and tolerance, on the other hand, mast cell activation syndrome. And I’ve certainly noticed, as we help a patient’s digestive health improve, either their histamine intolerance or their presumed MCAS symptoms improve… I say “presumed” because I’m not going through the rigors of the diagnostic protocol I think Afrin has laid out, or at least he may be aware of.
We do use a questionnaire that I believe was also developed by Afrin that’s kind of a subjective symptom questionnaire to try to firm that up. But in any case, we see an improvement of this kind of presumed constellation of symptoms associated with either histamine or MCAS as we improve one’s gut health. I guess the question I’m leading to here is, I’ve been using some of the natural mast cell stabilizing agents because many of our patients don’t want to go on medications, and even though we recommend some of the over-the-counter antihistamines as maybe a bridge, a lot of them would rather try natural agents first. And I’m still trying to make up my mind with how some of these therapies work. From my initial perspective, I think they may be helpful, but I’m wondering if you could speak to MCAS treatments that you have found helpful.
And I’m glad that you mentioned, sounds like you have this tiering where you don’t go right to IVIG. You look to the mast cell agents first, and then, I guess, finally consider IVIG. But curious your thoughts there in general, and also on cromolyn, Gastrocrom; what are you finding to be some of the more helpful MCAS therapies?
DrJS: I practice very similarly to Dr. Afrin in that I usually… Well, one difference, I’m not sure that Dr. Afrin would agree about the role of diet. For me, I have, as I said, been struck by how important that can be in treating mast cell. Then I usually go first to the antihistamine trials, H1 blockers and/or H2 blockers, and then there’s a long list of other drugs, many of which are over-the-counter. But there isn’t a right way to go, and it’s very much kind of a crapshoot like… one patient, this drug works; one patient, that drug works; one patient, this one works.
So, there’s no right answer to the order, in my opinion, what to try first. It just seems that overall, for all comers, the antihistamines as a class seem to be the most effective for most patients, but I have some patients for which neither H1 nor H2 blockers work at all.
So, it really depends on the patient, for me. I feel like if a patient wants to try over-the-counter things, or, sorry… well, antihistamines are over-the-counter, but maybe they’re not considered so natural because they used to be prescription as, say, Vitamin C or quercetin or things like that. I mean, I feel like any of those might be helpful in any given patient, and it’s very hard to predict which one’s going to work for which patient.
DrMR: Are you seeing… and this may be prone to individual variance, but I’m wondering if there’s a trend; will someone respond to some of the antihistamine agents or mast cell stabilizers, does that give you reassurance that, “Okay, we’re on the right track,” and now, for the people who are at least in part responding to the MCAS agents, that tells us that they’re more likely to respond to the IVIG? Or do they have no correlation to each other?
DrJS: I feel like if they’re responding well to the mast cell treatment, I hope that maybe they won’t need IVIG. Because as I mentioned, the people where the autoimmunity’s a driver, they often aren’t responding well to any of the other treatments.
DrMR: Ah, okay. Okay, that makes sense. What
about stem cells? I’ve seen a couple patients who… they were very challenging
cases, only probably two, actually, over the last seven years. So, this is not
a frequent occurrence, but who went and did stem cell injections. I believe
they were IV stem cells, the method of administration, and they reported quite dramatic
benefits. Do you think that stem cells have any role to play here?
DrJS: Only in a research study. I would try all these other more proven options first. I’m not sure if the patients you saw were having ablation of their bone marrow, like they were having a stem cell transplant to reset their immune system, or if you’re referring to a different use of stem cells, but there are one or more places studying the use of stem cell transplant or bone marrow transplant for patients with refractory autoimmune disease. And those would be very, very, very last resort because it’s not without serious risk.
DrMR: Okay, that’s fair. Just wanted to ask in case there was something there that I wasn’t aware of. As we move to a close, is there any kind of parting thoughts that you’d want to leave people with? But I’m sorry, let me take one step back.
- Low histamine diet
- Antihistamine trial H1 blockers and/or H2 blockers
DrMR: For someone who’s saying, “This
sounds like me,” is there a type of doctor they should look for? Is there
the luxury of maybe having some kind of checklist one can fill out on the
internet to help give them a score? You know, where do people go who know very
little, but they’re looking to get help?
DrJS: Well, there aren’t a lot of us doing
this work yet, unfortunately, for the treatment of autoimmune dysautonomia, or
autoimmune small-fiber neuropathy. But it’s increasingly recognized, and I hope
it’s only going to be even more increasingly recognized. I feel like today,
it’s only the patients who are highly educated who are really pushing the
envelope. If they go to a physician who isn’t kind of embracing what they’ve
learned, you need to keep going until you find somebody who does, and it’s…
unfortunately, the squeaky wheel gets the oil.
DrJS: That’s unfortunately where we are with this today, but there are more and more physicians… Probably the number one specialty embracing it is neurology because they’re aware of small-fiber neuropathy, and that if they’re kind of following the field, they would be the most likely group of physicians who you might find somebody to help you with. Neuroimmunology, even just neurology, and the way we make the diagnosis of small-fiber neuropathy is either with the skin biopsy or with the QSART test, which is… the latter QSART or QSWEAT test is only available in a few locations. In my experience, it isn’t very sensitive. Maybe 50% of the time, it’s abnormal, and even any slight abnormality seems to be, in my experience, important.
But skin biopsy, I think is, at least in my experience, seems to be more sensitive, and a number of places are now doing it. And then, that coupled with pertinent auto-antibodies can help the people make the diagnosis.
What type of doctor to seek out
- Neurologist or neuroimmunologist because they’re aware about small-fiber neuropathy
Where to Learn More
DrMR: And where would you like to point people if
they wanted to learn more? I know you have a website. Please mention that, and anywhere
DrJS: I have a website, Center for Multisystem
Disease; I have listed a number of my own publications on there. Dysautonomia
International is an excellent resource. They have many of their videos on
Vimeo.com, talking about all aspects of dysautonomia, which is kind of an
I think that’s really the best. Now, antiphospholipid syndrome… There is less information available. Dr. Graham Hughes who first described the syndrome has a number of excellent videos online just by Googling them on YouTube. And there is a really good patient forum for antiphospholipid syndrome called… I think it’s still under Health Unleashed through the United Kingdom. And you would put antiphospholipid syndrome or Hughes syndrome. And then, Dr. Hughes has GHICworld.org is another site.
DrMR: Awesome! Well, thank you for all those resources. It gives people plenty of places to hopefully track down the help or the information that they need. And is there anything that you want to leave people with?
DrJS: No, just if you feel you have these
conditions, be persistent. Unfortunately, you have to be persistent, and I’ve
found that most of the patients who make their way to my practice have some
component of medical PTSD from dealing with the medical community’s lack of
knowledge so far about these conditions. And it’s not the fault of the
physicians. It’s just sort of, these are kind of emerging conditions and
there’s not really any training probably yet in medical school or maybe even
But I’ve been really amazed over the last five years, the dramatic increase in awareness to where most physicians five years ago never even heard of POTS, whereas now, I feel like most have. So, it’s really encouraging, the increasing awareness that I credit pretty much completely to the internet, and podcasts like this, and nonprofit organizations like Dysautonomia International and the Ehlers-Danlos Society and others.
DrMR: Great. Well, Jill, thank you. I agree
with you that there’s probably not enough information about this type of
therapy for patients, and certainly, I acknowledge there’s a subgroup of
patients that I think all providers really struggle with. And so, just super
grateful for the conversation today so that we can provide people with a lead
to hopefully find their way to someone who can really get to the core of what’s
driving their ailments. So, just really appreciate the time today.
What do you think? I would like to hear your thoughts or experience with this.