Linking Mast Cell Activation, Autoimmunity, and EDS with Kara Wada, MD

[00:32] Dr. Linda Bluestein: Welcome back, every bendy body, to the Bendy Bodies with the Hypermobility MD podcast with your host and founder, Dr. Linda Bluestein, the Hypermobility MD. I am so excited about this conversation today with Dr. Kara Wada. The immune system is being discussed everywhere nowadays with connective tissue disorders and how these might be interplaying with each other. We just had this preprint that came out about the kallikrein family of genes and how these might be more prominent in people with hypermobile EDS. And now we just had another paper that came out about joint hypermobility, autonomic dysfunction, gastrointestinal dysfunction, and autoimmune markers. And in this group of patients with unexplained gastrointestinal symptoms, they actually found postural symptoms in 77% of the people. They actually found autoimmune or autoinflammatory disorders in 70% of these people, and they found that 31% of the patients with those markers had CRP elevations, so signs of inflammation.
[01:36] And last but not least of the points that I want to point out from this paper, which of course I will be discussing — I'm sure with one of the authors, because this is a really important paper — later on this season, a lot of these patients, the ones that had joint hypermobility and hypermobility spectrum disorders, they were more likely to have autoimmune markers along with more severe autonomic and gastrointestinal symptom scores. So we saw 43% versus 15%. So there's so much happening in the space of the immune system and how it relates to connective tissue disorders.
So this is going to be a great conversation with Dr. Kara Wada today. Dr. Wada is a physician who is quadruple board certified in pediatric and adult allergy, immunology, and lifestyle medicine. She is also a Sjögren's patient and a life coach. She has her own podcast called Becoming Immune Confident, and I was on her podcast as a guest a while back. She shares on her podcast her recipe for success combining an anti-inflammatory lifestyle, trusting therapeutic relationships, modern medicine, and how she uses the mind to harness her body's ability to heal. This is going to be a great conversation, so be sure to stick around to the very end so you don't miss any of our special hypermobility hacks. As always, this is for educational purposes only and is not a substitute for personalized medical advice.
[02:59] So let's jump into this exciting conversation about the immune system and connective tissue disorders. I am so excited to talk with Dr. Wada today. The immune system is so important in all of the hypermobility conditions. So let's just launch right into the questions. How did you come up with the name Crunchy Allergist?

[03:22] Kara Wada, MD: So my nickname as the Crunchy Allergist really stemmed out of my final project as an allergy immunology fellow. At the end of each year and at the culmination of our fellowship training, we are expected to put together an original presentation for our entire department. Something I've always been really interested in is what type of evidence do we have to support some of those more natural or home remedy type approaches to taking care of our allergies and our immune system. And so I spent that year collating all of the research that was out there and putting that into a presentation.
[04:07] One of my colleagues who was also pretty active on social media, Dr. Dave Stukas, was like, "Well, goodness, you're kind of like the Crunchy Allergist." And so that stuck. And here we are, oh goodness, almost 10 years later and it still holds true. I like using those naturally minded but also scientifically grounded approaches to care.

[04:31] Dr. Linda Bluestein: Yeah, and I think that's so important now because of course people are getting bombarded with information, right? And it's so hard to know what's good information, what's not good information. But those holistic things can be so valuable and can be so important, and getting that from someone who is a physician, who has the medical background and the training to really advise them on that — I love that. I want to jump right into allergies specifically, because of course, when people have joint hypermobility, they're more likely to have mast cell activation syndrome, they're more likely to have dysautonomia, or more specifically, they may have POTS. But oftentimes people say, well, what's the difference though, between allergy and mast cell activation syndrome? So if you could maybe start by telling us your thoughts about that.

[05:17] Kara Wada, MD: Absolutely. So allergy is a way that our body can make memory to certain things in the environment that we have seen, primarily proteins. And those can come from pollen, like our trees or grasses or weeds, can come from molds, can come from our pets and dust mites, and also can come from foods. It's our body's ability to recognize those substances and to create an immune system memory. And that memory is encoded with an allergy-type flavor. So it's in the form of something called an IgE antibody.
[05:49] So our body sees these proteins, for whatever reason, the immune system has that coded as, "Ooh, this is a danger signal, we better remember this." And then it creates, as those T cells and B cells talk to one another, a lasting memory where those B cells and plasma cells then create this protein called an IgE antibody. Those antibodies are then expressed or kind of housed on the outside of a couple of types of allergy cells — those mast cells that you referred to, and also basophils, which are in the bloodstream, pretty close to mast cells. They're essentially the bloodstream equivalent. And it's just one way that those mast cells or those basophils can be activated or turned on to release all of those chemicals that then create the signs and symptoms of an allergic reaction.
[06:47] So just one way that those cells can be turned on. We know that with mast cell activation syndrome, there are lots of other reasons and ways that those mast cells additionally can be turned on. And it's actually not too uncommon for me to see someone with pretty significant allergy symptoms, and they may or may not know about mast cell activation, but their allergy testing may be completely normal. So then we're thinking, hmm, what are some other reasons that these immune cells may be getting turned on and triggered? And that's where that piece of mast cell activation starts coming into frame.

[07:31] Dr. Linda Bluestein: So could a person have allergy and not mast cell activation syndrome, or mast cell activation syndrome and not allergy, or both?

[07:41] Kara Wada, MD: Absolutely. I go back to middle school English class when we had to use those Venn diagrams, right? What's the same, what's different. And so there is varying amounts of overlap between those conditions.

[07:56] Dr. Linda Bluestein: Okay, okay. And another term I think that gets so confusing for people — and I'm an anesthesiologist, and we talked on your show, which was so much fun — as an anesthesiologist, my understanding of anaphylaxis was completely different from my understanding of anaphylaxis now. And of course, that word gets thrown around, and I would love to hear you describe what is anaphylaxis.

[08:20] Kara Wada, MD: Yeah, so anaphylaxis is caused by a significant number of those mast cells getting triggered at one time. And what will happen as a result of that — in how we clinically diagnose it — is the patient is having symptoms that are affecting more than one system in their body. So, if someone just has hives or swelling, that's affecting one system, their skin. If though they have hives and swelling plus changes where their blood pressure drops, or profuse vomiting, or they have trouble with wheezing, any combination of these — that is when that label of anaphylaxis comes into play.
[09:02] The other little caveat, the asterisk on the diagnostic criteria, is if someone has cardiovascular collapse — they've passed out, their heart has stopped — you don't need more than one organ system for that to count, especially in the context of knowing that there was an allergic trigger for that very unfortunate event.

[09:23] Dr. Linda Bluestein: Mm-hmm, okay, okay, great. So it takes two systems. It does not have to have the airway edema, that feature that I always thought you had to have in order to meet the definition of anaphylaxis. Interesting, okay.

[09:38] Kara Wada, MD: Yeah, and I think one other misperception that comes into play is that the skin has to be involved, but 20% of cases of anaphylaxis — food allergy, in the operating room, bee sting — may be completely without any skin findings or swelling at all. And this is actually the situation that we need to be, especially as physicians, more attuned to, because these are the situations that more often have a delay in diagnosis, delay in treatment. And with a delay in treatment, there is increased risk of really severe downstream consequences of maybe not being treated quickly or adequately enough.

[10:20] Dr. Linda Bluestein: Getting back to mast cell activation syndrome for a second — there's primary mast cell activation syndrome, secondary mast cell activation syndrome. And when it's secondary, meaning secondary to something else, it could be secondary to an immune deficiency, right? That's not an uncommon situation. I feel like there's so much confusion though between immune deficiency and autoimmunity. So, can we first talk about immunodeficiency and why for this population that's so important for people to be aware of?

[10:50] Kara Wada, MD: Yeah, primary immune deficiency and secondary immune deficiency are much more common than I think we realize. And we know and recognize that there is a really long gap between when, looking back, patients start having symptoms and when they're diagnosed. The most recent statistic for common variable immune deficiency, which is one of the more common types, is about 7 years between onset of symptoms and diagnosis.

[11:19] Dr. Linda Bluestein: Wow.

[11:19] Kara Wada, MD: So in an immune deficiency, the immune system has a harder time — either one, recognizing that there is an infection going on; two, creating memory to say, "Oh goodness, we've seen this infection before, we know what to do." So it might be a little bit like starting from scratch every time you get the common cold, as opposed to having some memory to that or even memory from your vaccines and being able to recognize and respond more appropriately.
[11:53] The other thing that will happen if you have a low immune system or an immune deficiency is that you have an infection and the immune system isn't necessarily able to respond as robustly or as strongly as it should. And so that infection may become more severe, it may damage more tissue. When we think about bacterial infection, our mind sometimes goes to an abscess or pneumonia where there's maybe pus involved. Sounds gross, but this is what happens. And there's that tissue damage related to that.
[12:34] The immune system not only is trying to fight off those bacteria and make memory to those bacteria, it's also responsible for the cleanup process and the repair process afterwards too. The reason I mention that is because it's not uncommon for me to see in clinic patients who have immune deficiencies and also have autoimmunity, which is an overreaction of the immune system where the immune system is recognizing some of our own parts and pieces — or as my kids say, their bits and bobs — as a danger signal, creating inflammation and chronic inflammation in particular areas.
[13:16] What is thought to happen is if the immune system is not able to clean up after an infection or another inflammatory insult, that opens the door for the immune system to misrecognize our own parts and pieces as a danger signal, inappropriately so. And so for many of these immune deficiencies, you also will see an increased risk of autoimmunity and sometimes allergies too that go along with them.
[13:48] So if anyone out there is having situations where they get recurrent sinus infections, or they're an adult getting ear infections more than once in a great long while, or they're an adult who has had more than one true pneumonia — these are things that as an immunologist, my mind is clued in to. We need to start thinking about checking some labs and evaluating the immune system's ability to recognize and create memory to these infections, typically through some blood work.

[14:24] Dr. Linda Bluestein: When would you work someone up for autoimmunity?

[14:28] Kara Wada, MD: So typically with autoimmunity, we are going to think about that in situations where someone has ongoing or chronic inflammation. And oftentimes we are able to center in on this a little bit better when it is affecting a particular organ system — a little easier sometimes than when it's the whole body. So, you know, you think about someone who maybe has inflammatory bowel disease, something like Crohn's or ulcerative colitis. That is something you can kind of zone in on because they're primarily going to be complaining of signs and symptoms related to that: chronic diarrhea, blood in the stool, stomach pain and having to go to the bathroom that's waking them up from sleep, weight loss and fever — some really significant signs and symptoms of inflammation.
[15:27] Other times, joint stiffness, especially in the morning, is one thing that really clues us in to think, could this be an inflammatory arthritis or a connective tissue issue? I think part of it really is listening to the patient, hearing their story, and looking and listening for those signs and symptoms of inflammation — redness, swelling, stiffness, pain, fever. And I also listen for that difficulty with, "I get a cold and it just takes me forever to get over it." That's another situation where I'm thinking, is there some chronic inflammation that is really making it challenging for this person to recover?

[16:16] Dr. Linda Bluestein: Just recently, this big preprint came out of MUSC and they talked about the kallikrein genes, and now there's all the talk about the complement system. Those of us that went to medical school, some of these things are a little more distant in our minds, and we're trying to sort out, wait, what's the complement system? How does this play a role with the immune system? What should we know about that?

[16:40] Kara Wada, MD: Interestingly, I have not had a chance to pick it up and read the paper quite yet, but I have certainly followed some of the same people and seen this exciting headline. And I find it really interesting because one of the conditions I care about and care for in the clinic with some regularity — it's a rare condition, but I work at a university and see some of these rare conditions a little more often as a result of that — hereditary angioedema, which is a condition where folks will have a deficiency in a particular enzyme or protein that makes them at greater risk of having swelling episodes. So, swelling of their lips, their voice box, their gut. And this is related to overlapping cascades: complement, cholecystokinin, and bradykinin.
[17:36] One of the medications that we have available to treat is directly related to cholecystokinin and decreasing that activity. And so it just has me wondering, okay, one, would there be any role for this medication or the research from that medication to provide some additional insight into what we're learning about hypermobile Ehlers-Danlos? And where we're going to use that moving forward in hopefully gaining some better understanding of the pathophysiology of where this connective tissue meets inflammation, and shining some more light on that.
[18:25] Because the reality is that within especially academic allergy immunology practices, many folks are still very much within the Consensus 1 box. And I think sometimes reluctant to accept this association that you and I see all the time between hypermobility and the immune system misbehaving, as I love to refer to it. And I think it's another piece in the puzzle that is going to shed light, give us a better idea and vision of what's going on, and hopefully convince some of those holdout colleagues with that evidence that what we're seeing is the reality.

[19:13] Dr. Linda Bluestein: Yeah, and I'm so glad you brought up Consensus 1, because I was a co-author — played a minor role — in Consensus 2. And it's like so many people do not have a positive tryptase. And it's so frustrating, of course, for them as patients to be not just denied a diagnosis, but to be denied care or suggestions or anything. Which is why I was so excited after you interviewed me for your podcast — I was like, I can't wait to talk to you here and get your take on these things. Because I think that's the thing that surprised me the most in working with this population is how much low-hanging fruit there actually is, and how much we actually can help people, which is of course really exciting. How do you handle the whole tryptase situation?

[20:00] Kara Wada, MD: So typically I will check it in part because if it is elevated, that just takes me down a different pathway of other things I want to consider. And also if it's not elevated, okay, let's keep moving on. Let's check your urine studies. If those aren't elevated, still let's continue to work on what our goals together as physician and patient are, whether that's to decrease itching, to improve digestion, to feel more comfortable and confident navigating the outside world, staying in work.
[20:45] When a tryptase is elevated, some things I want to be thinking about: one, could this be mastocytosis? Mastocytosis is, in 95% of cases, caused by a mutation in the KIT gene, which results in mast cells behaving differently. You'll see typically an increase in number and a change in how they look under the microscope in the bone marrow, the gut, or other tissues. And the reason it's important to recognize and identify these patients is that, especially if they have pretty significant symptom burden, there are specific targeted treatments that are available and some that are in trial that can be quite helpful. So we don't want to miss that.
[21:39] There also is, I think, an increased recognition for hereditary alpha tryptasemia. It wasn't something that I think there was even one little mention of during my fellowship training. Now in the last 5 to 8 years, there's really been an increased awareness and understanding that this little quirk — some folks having additional copies of the gene that creates tryptase — affects up to 6% of the population. And there's a simple mouth swab test to screen for that condition, which may provide some insight like, "Oh, that's why I'm so much like my mom. We have the same genes, literally." And not everyone is symptomatic with this condition, but for those that are, this provides some additional insight as to why they may have more of these symptoms that may or may not look like mast cell activation.
So I think those are the ways that I find tryptase helpful. And I also don't let a negative tryptase — I don't throw out the baby with the bathwater.

[22:56] Dr. Linda Bluestein: Yeah, for sure. And I tell people, if we check the tryptase and it's normal, to me that doesn't mean anything other than it's helpful for ruling out mastocytosis.
[23:07] We're going to take a quick break and then we are going to come back and talk about mast cell activation syndrome treatment. So we'll be right back.
[23:46] And we're back, and I'm so excited to talk about mast cell activation syndrome treatments. But I first want to go back to inflammation because I know that so many people, when you were talking about inflammation before, they're like, "Wait, that's me. I feel like that's totally me, even though my CRP is normal, my C-reactive protein is normal, my ESR or sedimentation rate might be normal." And we don't have great tests for that — we can do like the 17 different cytokine panel, the Mayo Clinic cytokine panel, but we don't have great tests quite yet. Can you explain a little bit more about the role that inflammation plays in these conditions, because I think that's really important.

[24:32] Kara Wada, MD: Absolutely. Inflammation has become one of these keywords that we're all honing in on and has become a bit of a boogeyman, especially knowing that chronic inflammation is really at the root of all of the diseases that really affect us in modern living. But at its core, inflammation is our body's natural and necessary response to infection and to injury. It is our body's ability to recognize and repair, to get everything back to that really happy place of homeostasis. Think of it as that Goldilocks of everything being perfect — always in a little bit of flux, but in that nice spot.
[25:24] When inflammation though sticks around like an unwelcome houseguest and becomes chronic — in allergies, in autoimmunity, in cancer — that is when it becomes problematic. And that is the bad inflammation that we talk about when we are thinking about autoimmune or autoinflammatory conditions. The distinction between those being: are there signs of immune system memory, or is it parts of our immune system that don't necessarily capture memory but are likely epigenetic changes that have resulted in parts of our immune system remaining on or more active than normal?

[26:10] Dr. Linda Bluestein: Okay, and I'm so glad you brought up the word epigenetics. If you would elaborate about epigenetics, you're probably going to do a better explanation than I am.

[26:20] Kara Wada, MD: So I think of epigenetic changes as essentially the on and off switches determining if our genes — the things we've inherited — are expressed or not expressed. And maybe a better analogy than a light switch sometimes is a dimmer switch, because it's not always on or off, but it may be subtle adjustments as to how much of a protein is expressed or not expressed too.

[26:50] Dr. Linda Bluestein: That leads into my next question. What about the role of hormones? How do hormones play into all of this?

[26:57] Kara Wada, MD: Oh goodness, how do we count the ways? We know there's this rule of thumb with pregnancy, for instance, that we learn to tell our patients, and it seems to hold true in allergic conditions and in autoimmune conditions — broad brushstrokes — but about a third of patients will get better with those hormone changes associated with pregnancy. A third of patients, their underlying inflammatory condition will stay the same. And a third of patients, it will get worse, whether it's chronic hives or asthma or lupus. So we've known for a long time with data from pregnancy, but also looking at data surrounding puberty — maybe a little less data around menopause, because who wants to study menopause? I say that facetiously, of course.
[27:56] But especially estrogen and testosterone, progesterone — these all have significant impact on our tissues. We know tissue laxity, pregnancy, carrying a pregnancy — I'll defer more to you on those aspects — but also on our immune system functioning as well. And there is variability between patients even with the same condition, that some of these shifts can affect us differently.

[28:32] Dr. Linda Bluestein: Okay. And we talked about dysautonomia or dysfunction of the autonomic nervous system kind of at the very beginning. And of course, a lot of people that have Ehlers-Danlos syndromes or hypermobility spectrum disorders or mast cell activation syndrome very commonly will have some dysfunction of their autonomic nervous system. And sometimes they do meet the criteria for POTS, or postural orthostatic tachycardia syndrome. Is the autonomic nervous system connected to the immune system? I know that's a huge topic — that could be a huge conversation just right there.

[29:05] Kara Wada, MD: I'm going to throw one more condition in the mix that's near and dear to my heart, which is Sjögren's disease, which is one of the number one autoimmune causes of POTS and dysautonomia. When we think about where this malfunction is going on, I always, at least from my point of view, like to think back to what's going on with the mast cells, because they are physically located, one, in our connective tissues, but also two, right nearby — if not touching — those small fiber nerves that are responsible for much of our autonomic nervous system function.
[29:50] This was the hot topic — not specifically dysautonomia, but this interface between mast cells and the nervous system, and frankly, the immune system and the nervous system — at our American College of Allergy, Asthma, and Immunology meeting this past spring. And I think it's a hot topic for ongoing discussion in research surrounding these two systems that, frankly, for a long time, much of medicine has siloed. I know at least at our institution, the neurologists are over in their institute, we're over with the ear, nose, and throat docs doing our thing, the rheumatologists are over in a different area. And so bringing together some of these disciplines is really necessary to better understand how mast cells are playing a role, how the macrophages — in particular microglial cells, which are the central nervous system's equivalent of macrophages — how those may be playing a role.
[30:54] We know that those cells in particular can be — to name one of my favorite books — both angels and assassins, both calming inflammation and promoting inflammation within the central nervous system and elsewhere too. And I know talking with the folks from Dysautonomia International, in particular Lauren Stiles — who I swear should have an honorary medical degree — some additional research has been honing in on the ganglia. So these little transformer boxes outside of our brain, these areas that are really hard to assess clinically. We don't have good studies to look at them on imaging or to necessarily test them. But that's an area of focus that I think has come into the discussion of where some of this inflammation may be occurring as well.

[31:58] Dr. Linda Bluestein: Yeah, and that's such an important point because you and I both know that so often the frustration that patients experience is that they go in for an evaluation and nothing shows up, right? All their labs are normal, their imaging is normal, but they know that they don't feel good. And then oftentimes what ends up happening is the doctor gets the sense from the person, "Oh, you want to be sick." I literally had a doctor say that to me. I had a rheumatologist say that to me — "Oh, you want to have a rheumatologic condition?" Like, no, I don't want to have a rheumatologic condition, but I don't feel good. I know something's wrong. I've got so many problems and nothing shows up. That's challenging.

[32:30] Kara Wada, MD: I always go back to that meme/comic with the high five of "Your labs are normal" and then the poor patient is drowning. It is such an accurate reflection of that situation that I swear I hear from probably 95% of patients who are coming in with this constellation of symptoms.

[33:00] Dr. Linda Bluestein: Definitely. Okay, so in terms of — you were mentioning autoimmunity and epigenetics, or we were talking about epigenetics. So are autoimmune conditions increasing? We know that obviously we have a lot of things in our environment that we were not exposed to before. What's happening in that space?

[33:22] Kara Wada, MD: Yeah, so one of the really big paradigm shifts that has occurred over my career, which I continue to nerd out about, is this change from when I went through medical school. The idea was, oh, we are seeing more allergies, we're seeing more autoimmune disease because we're cleaner. We have antibiotics, we have hand sanitizer, moms are vacuuming more. That's the problem. And the reality is that a little bit of that's probably playing a role, but there is this overarching hypothesis that's really come to the forefront called the epithelial barrier hypothesis — which, goodness, it's a mouthful. But what it's really explaining is that our bodies have ways of interacting with our outside world, and that's through our skin, our gut, and our airway. And at these interfaces, we have these barriers, these epithelial barriers — that's the name of the types of cells or tissue.
[34:22] And those barriers are supposed to be somewhat permeable. We want to absorb oxygen, we want to absorb nutrients, we want to be able to process vitamin D through our skin. But there also should be an element of selectivity. There should be some bouncers there that are doing a good job of keeping the bad stuff out. And unfortunately, there are a lot of things that come into play in our everyday modern existence that essentially put more chinks in our armor and leave us with those barriers being a little more leaky or permeable than they ought to be.
[35:03] And what happens when that barrier is more permeable is you also see a change in the microbes that live in us and on us. You see typically a loss in the amount of diversity, a change in the types of microbes and/or their behavior. So on the skin, for instance, you might normally see Staph epidermidis. In the case of eczema, more often you may see Staph aureus, and that Staph aureus may also be producing toxin, which happens to make the skin more leaky. What will happen then is some of these microbes themselves or their products, and other things we're exposed to in the environment, find their way not on the outside but on the inside and in contact with our immune system. So our immune system then gets turned on and we can see the propagation of inflammation — various kinds and flavors of inflammation — that then has downstream effects.
[36:07] So one of the main examples we see in allergy, for instance, is eczema. In little babies who have significant eczema, we see a markedly increased risk of development of food allergy. The thought being that the immune system is seeing food through the skin, through that leaky barrier, before it's able to get tolerance and build tolerance through the gut. And so that change in how the immune system is exposed and trained is different, and you see a difference in how it might respond in a given susceptible person.
[36:48] We'll also see crosstalk between exposure to air pollution, developing eczema, putting us at increased risk for various autoimmune diseases — changes in the gut microbiome increasing our risk of psoriatic arthritis, MS. So there's crosstalk: a leaky barrier in one spot may create a problem elsewhere in the body.

[37:11] Dr. Linda Bluestein: It is amazing how connected things are, yet, like you said earlier, how we were taught that there are these separate systems and that we're not really taught how they talk to each other. So super fascinating. And getting back to mast cell activation syndrome, because I know a lot of people are going to want to know this — we all probably treat mast cell activation syndrome a little bit differently, but there are for sure some common threads and some things people can do on their own. We're going to talk about what people should do if they don't have someone like you on their team, because I'm sure everyone listening to this now is like, "Oh my gosh, how do I get an appointment with Dr. Wada?" And we'll of course talk about where they can find you. What kind of treatments do you find most effective in mast cell activation syndrome?

[37:58] Kara Wada, MD: So it depends on when someone has found me. Sometimes early in the game we're able to work on some of this low-hanging fruit that you mentioned — working with what I call the front door and the back door of those mast cells, the H1 and H2 blockers. And sometimes that takes a significant amount of trial and error, trying the different types that are out there. Some people do best with fexofenadine, others get really, really sleepy with cetirizine. So then maybe we try loratadine or desloratadine. Maybe we'll try the children's version because they just need a little bit. There's a lot of trial and error and nuance.
Additionally, certain patients — and I'm always pleasantly surprised — famotidine, which is a common H2 blocker, for some folks just seems to be extra helpful. And in others, not so much. So usually we'll work through H1 and H2. We'll talk about maybe trying a leukotriene-based blocker, typically montelukast, talking through some of the pros and cons. It does have a black box warning due to concerns about a rare side effect of mood changes, but I think it's really important to have that shared decision-making with the patient.
[39:23] After that, we're usually also talking a little bit about lifestyle and nutrition. What are some antioxidants that we can easily add in that may be helpful? Quercetin, vitamin C, luteolin — some of these things that have a pretty good safety profile. One of the big struggles that sometimes comes up, and absolutely understandably so, is that patients with mast cell activation often may have trouble with excipients, which are the extra things within a medication — the extra ingredients, the fillers, binders, those sorts of things. So trying to parse out if we think that's an issue is a challenge. And then in someone who is highly reactive, deciding at what point we feel comfortable trying some medications that are injection-based.
[40:23] So, if I have a patient who has more run-of-the-mill chronic hives and swelling or chronic urticaria, Xolair — omalizumab — is a game changer. It is an antibody-based medication that essentially lowers the ability for those IgE antibodies to bind to the outside of mast cells and overall decreases the amount of IgE in the body. It's helpful for those who have hives, even hives that are unrelated to allergy, which we're still trying to totally understand — we don't totally understand why that fully works, but it does work really well. But if I have a patient who is very reactive to medications in general, often the idea of using a medication that's injected once a month and is going to be in their system for 4 weeks — that's a big ask. And that's usually a lot of discussion from my standpoint too, like, is the juice worth the squeeze? Is the risk-benefit there? And are there ways that we might try a test dose to see if someone tolerates it okay as well?
[41:44] I also have added low-dose naltrexone to my toolbox. I probably have a couple dozen patients on it, but I've really been happy — patients have been happy — with how they've responded to that. And then also thinking about some other medications that are available and approved outside the US, a little more challenging to get here — things like ketotifen, which can be compounded. And then gastrocrom and cromolyn sodium has also been a game changer. I certainly have some patients where it doesn't seem to be a great fit, but goodness, we've had some issues with patients getting it. There have been some shortages, and that's really frustrating because for those that it works, it's like, we want to keep that available to them.

[42:38] Dr. Linda Bluestein: And it's such an old drug. I was prescribed cromolyn when I was a teenager. And so that was a long time ago. So it's so frustrating when we have these generic drugs that have been around forever that we can't get. Really, really crazy.

[42:53] Kara Wada, MD: And where the price point is so high too.

[42:55] Dr. Linda Bluestein: Right, yes, even though it's generic. That is an excellent point. So there are going to be people listening to this that are like, wow, this is a great wealth of information, but they're still frustrated because they don't have their own health advocate and they're dealing with a complex condition that's so misunderstood. Are there some key steps that they can take?

[43:18] Kara Wada, MD: First and foremost, I think learning how to best communicate your story can be really helpful in feeling more confident in advocating for yourself. The reality is that our medical system, at least here in the US, is frankly a dumpster fire in many ways. It's really broken — not obviously for patients. I too suffer from an autoimmune disease. I have some dysautonomia as well. And I think it's that experience on the patient side of things that has only made me more acutely aware of, one, the privilege I have, absolutely. And two, how can we maybe come together, and how can I help patients understand — step into the doctor's shoes just for 30 seconds — so that they can understand how to better communicate to someone who, as a physician, maybe hasn't been in your shoes.
[44:23] So I think taking some time before a visit to come to this place of: what is my goal for this visit? What do I need to communicate to the doctor or other healthcare professional? And then trying to come up with a little bit of a game plan related to that.
[44:45] I think one other little tip I'd put in there is when you call to schedule your appointment, you can ask whoever the scheduling person is, "How long is this appointment scheduled for?" And that at least might give you a better idea. You could even ask, "Does this person double book, where maybe that 15-minute appointment is actually 7 and a half minutes?" So you kind of have a better idea. And if you are someone who has a really complex history, maybe share that with the scheduler. Say, "Hey, I have a pretty complex history. Is there any way to have an appointment slot that might allow for a little extra time? Or if I send my records ahead, would the doctor maybe take a look at them ahead of time?" Every office is going to be a little bit different in how they handle those situations, but those are questions that you absolutely have the right and ability to ask. And I think sometimes that answer back is also helpful to take note of — it's a two-way street. Certainly there are limitations sometimes within our networks and so on and so forth. But really having that trusting therapeutic relationship is so critical, especially for those of us that have chronic multisystem inflammatory disorders.
[46:04] So, preparing for your visit, knowing your story, owning your story. And then I think the third and final thing is you have to unfortunately get comfortable with being uncomfortable, because as I mentioned, the system we all know is not made for us. And it's going to require us to sometimes have to advocate more than we would like, and be a little bit of a pest at times — to check in on things, follow up on things. It may require us to have to call and get records and do things that we really shouldn't have to do necessarily, but we do. And it requires us sometimes to revisit areas that have been traumatic. For so many that have experienced trauma within the medical system — which we know for hypermobile EDS is pretty much everyone.

[47:16] Dr. Linda Bluestein: Right, right. It's extremely common, unfortunately. And I think those are such great tips and hopefully everyone will take those to heart because it is important to advocate for yourself, but also physicians are in such a difficult place nowadays. The system isn't set up for either of us. It's not set up for the physicians that are caring for complex patients, and it's not set up for complex patients. So we're really struggling.

[47:39] Kara Wada, MD: And one of the areas that I think is on my to-do list to focus in on too is medical education. As medical students and residents — well, maybe a little bit more in residency — we're always asked to answer the question with one answer. Whether it's through a case-based learning environment where we're all talking together about a particular case, or it's one of our board examinations where there's one right answer. And the reality is, for those of us, the increasing number of us with chronic multisystem conditions, there's more than one right answer. And that's just not part of the teaching paradigm that, at least, was how I was taught through medical school.
[48:36] So it's really created — I've kind of had to learn as I go — to accept that as a physician I don't have, especially in my field, very many quick fixes. I occasionally get those runny noses I can fix pretty quickly. Asthma I can get under control. Those are great quick wins. But more often than not, especially in mast cell disorders, I am putting on my waders and going into that muddy science. It's challenging because I need to build trust with that patient across from me who has great reason not to trust me as part of the system. And also dealing with pressures — thankfully not too bad where I am — but pressures from administration to see more patients, less time, and so on and so forth.

[49:37] Dr. Linda Bluestein: Exactly. So in terms of lifestyle solutions — because we know that those do exist, right? But speaking of the time you have for a visit, some of those are kind of time-consuming. This is a great way to share some of the more cost-effective lifestyle solutions that you've discovered. What are some of those that have really made a difference in managing your own autoimmune condition?

[50:00] Kara Wada, MD: Yeah, so I think a few that for me have been game changers. One is I need my sleep. I am someone who needs a good 8 hours, sometimes a little more. Occasionally if I'm in a good place I can do a little less. But it's really been a non-negotiable. It's really rare that I'm going to purposely stay up past 9 o'clock. Just won't do it.
Number two is really honing in on managing my mind. I have always been a type A go-getter. Got the to-do list a mile long, wanting to make sure I do things to the best of my ability. And if I don't, having a lot of that negative self-talk coming in after. So I think learning various tools to help pull me out of that constant fight-or-flight have been really helpful. Meditation — I try to get at least 5 or 10 minutes in each morning before I pick up my phone to check other things. I have a pretty regular journaling routine and I've been playing around with some different vagal nerve stimulation exercises. I'm always trying out new things. Dabbled in some of the dynamic neural retraining. I think there's some really cool tools out there that frankly have very little risk aside from the time that we invest in them, and have good evidence to say — you may not have the evidence specifically for mast cell yet, but in other conditions that may affect our health we know that they're helpful.
[51:53] And then coming in third and fourth, hand in hand: nutrition and movement. As a teen, I was always pretty active on sports teams, although I wasn't super athletic. I liked to run. And as I had increased back stiffness and pain, and having kids and just life, I kind of fell out of those habits. And so really recommitting — I turned 40 this spring, and so my goal at the beginning of the year was to get strong, but to do that in a way that was fun and that I could stick with for the long term, knowing that those muscles were going to help provide some cushion for my joints and help support my connective tissues.
[52:46] And nutrition — really focusing in on a plant-forward diet. I'm fortunate that I don't have any issues with histamine intolerance. I know that's something that those with mast cell might recognize as a trigger, along with other foods that might trigger things. But really, at the end of the day, aiming for the least restrictive but also nutrient-dense: plant foods, all the variety of colors, getting some plant proteins in there during the week too, and those healthy fats. Really a far cry from that low-fat sugar replacement Pop-Tart toaster strudel breakfast that I was raised on.

[53:42] Dr. Linda Bluestein: Yeah, I remember when all that sugar-free stuff came out and it was like, oh, even as a teenager, I was like, is this really a good idea? Okay, so we always like to finish every episode with a hypermobility hack. And you've already given us so many great hacks and tips. This could be a hack related to the immune system, or something that you've learned from your own conditions, or something that your patients have found valuable. Do you have a hack that you can share with us?

[54:12] Kara Wada, MD: I don't know so much if it's a hack, but I think a really important lesson that I'm continually needing to relearn — and I think has been important for many of my patients too — is learning to listen to our bodies and tune in to what our bodies are telling us. So much of medical training is learning to ignore your hunger, ignore your need to go to the bathroom, ignore your body's cries to sit down or to sleep. And so I would just say: spend that time reconnecting with who you are and what your body is telling you, because if you listen, oftentimes it will clue you in to what you need.

[55:00] Dr. Linda Bluestein: Love that. I never thought about it that way before, but you're right. Now it's like, oh, I get to go to the bathroom whenever I want. But yeah, for all those years, not being able to go to the bathroom or eat — so those are such great points. This was such a great conversation. It was so great to chat with you, Dr. Wada. And before you go, could you tell us if you have any special projects that you're working on or any special research that you're doing, and also where we can find you?

[55:30] Kara Wada, MD: So I have a couple things coming up. This is the third year I'll be hosting the Virtual Sjögren's Summit. So I was diagnosed with Sjögren's disease about 5 years ago and realized that goodness, what I learned to answer those multiple choice questions right was not the reality. I learned the reality from my fellow Sjögren's community. So it's a 2-day free event where we all come together to learn, to be empowered, and to advocate and grow together. So if folks want to check that out, it's SjogrensSummit.com.
[56:01] And then otherwise, the best place to connect is probably either on Instagram or through my website. I'm @ImmuneConfidentMD — formerly the Crunchy Allergist, but kind of also evolving and building that confidence together, both in allergic and autoimmune awareness and education. And over on my website, I think one resource that would be really helpful for this group — I took the new patient paperwork that I put together for my new mast cell patients and turned it into a little workbook to help those coming to see me in clinic, but also those who may be going to see their own healthcare providers, put their story and all their information in one place. So that they can print it out and share their story.
[56:55] And I think the real keys in that at the end are: what are your goals? And is there anything I need to know to better take care of you? Those aren't questions that we always remember to ask our patients. We should. And so my hope is that if your doctor is quickly looking through and taking that information in, the most important information will also catch their eyes and their hearts as well. So that's over at DrKaraWada.com. We'll make sure that's in the free resources section.

[57:37] Dr. Linda Bluestein: I just wanted to make sure that we know exactly where to find that because that sounds like an incredible resource. Well, thank you so much again, Dr. Wada. It was so great to chat with you. I know I learned a lot, and I'm sure everyone else will as well. So thank you.

[57:52] Kara Wada, MD: Thank you so much, Linda. This has been fantastic, and I can't wait until we get to talk again.

[58:00] Dr. Linda Bluestein: Wow, that conversation with Dr. Wada was so great, and I hope you enjoyed it as much as I did. I'm sure that there were so many insights and just such valuable information that she shared. And I just want to thank you so much for listening to this week's episode of the Bendy Bodies with the Hypermobility MD podcast. Please help us spread the word about joint hypermobility and related conditions by sharing this podcast and leaving us a review. This really helps to raise awareness about these complex conditions.
[58:28] You can find me, Dr. Linda Bluestein, on so many different social media platforms: Facebook, Instagram, X, and LinkedIn @HypermobilityMD. If you'd like to meet with me one-on-one, check out the available options on the services page of my website at hypermobilitymd.com. You can find Human Content, my producing team, @HumanContentPods on TikTok and Instagram. You can also find full video episodes on YouTube at Bendy Bodies Podcast. To learn more about the Bendy Bodies Program disclaimer and ethics policy, submission verification and licensing terms, and HIPAA release terms, or to reach out with any questions, please visit bendybodiespodcast.com. Bendy Bodies Podcast is a Human Content production. Thank you so much for being a part of the community, and we'll catch you next time on the Bendy Bodies Podcast.