Symptoms, Diagnosis & Treatment Options for Mast Cell Disorders (Recording)

This webinar was recorded on September 10, 2025

Enhance your clinical skills to improve diagnosis, treatment, and patient quality of life.
Mast cell disorders can present with a wide range of symptoms and are often underrecognized or misdiagnosed, leading to delayed treatment. Early identification and targeted management can significantly improve outcomes.

Join allergist and mast cell disorder expert Dr. Lyons for a focused training designed for healthcare professionals involved in allergy, immunology, and related care. This webinar will provide evidence-based strategies for recognizing mast cell disorders, applying current diagnostic criteria, selecting appropriate treatment options, and delivering effective patient education to support long-term management.

During this webinar, participants will be able to:

1. Differentiate between common signs, symptoms, and clinical presentations of mast cell disorders across diverse patient populations.
2. Apply current diagnostic criteria and interpret available laboratory and clinical testing methods for mast cell disorders.
3. Evaluate evidence-based pharmacologic and non-pharmacologic treatment options to optimize patient outcomes.
4. Implement patient-centered education strategies to support symptom management and enhance quality of life.

Speaker:

Jonathan Lyons MD

Dr. Lyons is Professor of Medicine at UCSD where his lab uses a variety of genetic and translational approaches to identify mechanisms and pathways critical to allergic inflammation and hypersensitivity that can be targeted to conduct first in human clinical trials. His work has been pivotal in defining the field of primary atopic disorders, and his discovery and characterization of hereditary alpha-tryptasemia has changed the approach to evaluating and diagnosing mast disorders and reactions.  He has published over 80 peer-reviewed articles, authored several chapters in multiple textbooks including Middleton’s and Wintrobe’s, and presented numerous abstracts and invited lectures at national and international meetings. Dr. Lyons has been named a Lasker Scholar, and received awards from the AAAAI and Jeffery Modell Foundations, is a prior recipient of multiple NIAID Merit Awards, the Innovation in Research Award by The Mast Cell Disease Society and the Young Physician-Scientist Award from the American Society for Clinical Investigation.

This Advances webinar is in partnership with the American College of Allergy, Asthma & Immunology. ACAAI offers CMEs for physicians for this webinar. If you are a member of ACAAI, you can obtain CME through the member portal for the Advances webinars.

All attendees will receive a certificate of attendance. No additional continuing education credits are available.

CME is available through ACAAI for this webinar.

Sponsored by the American College of Allergy, Asthma and Immunology

Transcript: While this transcript is believed to be accurate, errors sometimes occur. It remains your responsibility to evaluate the accuracy and completeness of the information in this transcript. This transcript is not intended to substitute for professional medical advice.

Ruthie Marker: Good afternoon, everyone, and thank you for joining us. I’m going to wait just a minute while everyone joins the webinar and then we will get started in just a minute. All right. Hello, everyone, and thank you for joining us today. I’m Ruthie marker, the education program manager at the allergy and asthma network. I’m excited to welcome everyone to this afternoon’s webinar. We have a great session planned and I’m pleased to introduce our center, with his extensive knowledge of allergy and immunology we can look forward to an enlightening session. Before we begin today’s webinar I have a few housekeeping details to cover. We will record today’s session and upload the webinar later this week. You can access all of our work ported webinars and upcoming webinars on our website at allergy and asthma network.org. Scroll to the bottom of the page and you can look at past webinars and future events. Our webinar is scheduled to last for an hour, and this will include time for question and answers. Please feel free to submit your questions at any time throughout the webinar in the Q&A box located at the bottom of your screen. I team member will be monitoring the chat for any questions that come through, or should you need any technical assistance. This webinar is brought to you in collaboration with the American College of allergy immunology. It offers continuing medical educational credits and you can create a free ACAII account to earn credits through the medical portal. All attendees will receive a certificate of attendance. Please note that no continuing education credits will be provided. A few days after the webinar, you will receive an email with supplemental resources and information to download your certificate of attendance. With that, we will go ahead and get started with today’s presentation. Mast cell disorders encompass a range of conditions characterized by abnormal presence or activation of mast cells in the body. This can result in a wide spectrum of symptoms, some of which can be easily overlooked while others can be debilitating and life-threatening. Do the — due to the heterogeneous nature of these disorders and the variety of ways they can manifest, diagnosis can be challenging. It’s my pleasure to introduce today’s presenter who will present you with evidence-based knowledge and practical strategies for recognizing, diagnosing, and managing mast cell disorders. Dr. Lyons is a professor of medicine at San Diego to identify hypersensitivity that can be targeted in first human critical trials. Dr. Lyons’discovery and characterization of hereditary Alpha trip taste change the approach to mast cell reaction. He has published over 80 peer-reviewed articles and authored several chapters in multiple textbooks. He has also presented numerous abstracts and been invited to international meetings. He has received awards from the Jeffrey Modell foundation. I will go ahead and handed over, thank you so much for being here and we all look forward to your presentation.

Dr. Lyons: Thanks for having me. It’s always a pleasure to speak on topics near and dear to my heart, including mast cells, so I’m happy to speak and thank you for inviting me to give this lecture. I have some ground disclosure that have all been mitigated and they are there for you all to see. By the end of today, the hope is that we will have better skills and understanding what clonal mast cell disorders are an understanding how we approach these patients in terms of diagnosis and treatment, and we will also kind of delve into a little bit of some of the newer things on the horizon that we are excited about in the field and kind of backtrack a little bit in terms of showing how we extrapolate what we know about clonal mast cell disease and how we apply that to non-clonal disorders. This is kind of the key player in the story, this is a mast cell. This cell is born as an immature precursor in the bone marrow. If you get a pimple and have pus in their, that is one. Mast cells grow up and circulate and then the land in tissues, predominate he in the skin, whether under the direction of some of the proteins in their including stem cell factor, they become granulated and fully mature grown-up cells. And they hang out there for a long time. They can accumulate at sites of inflammation or infection and we think they help fight some of those bugs that are around as well as promote the healing process. So there’s a lot of roles that mast cells play. In the context of disease were often think about immediate hypersensitivity. Were thinking about mast cell D granula station. Those blue little dots, the big one is the nucleus, obviously. When they D granula a number of compounds, including those showing at the bottom. If histamine, prostaglandins, those are generated after the fact. It’s a slew of molecules that we collectively route for two as mast cell mediators that are released in this context and the drive a lot of the symptoms we think of. Flushing, hives, low-pressure, or passing out from low low-pressure, abdominal pain and diarrhea, nausea, and vomiting occasionally.

Some other less direct symptoms such as rainfall, bone pain, tea, some of those symptoms we think may be driven by some of these mediators in different ways than this acute problem. Most people when you think about what is an allergic reaction, you have a kid who is allergic to peanuts, they eat some peanuts, shown there in that big red dot, there isIgE sitting on the surface of mast cells, that peanut protein cross-links thousand causes activation of the mast cell and release of all these components. But there are a number of antigen and other kinds of receptors such as KIT, C3a and c 5a are drive — derived from compliment. This is a newer kid on the block in terms of an activating receptor of mast cells that’s been described in first drug reactions, we think it is probably important for some of these scavenging tight rolls where a lot of things can tickle this receptor and drive the mast cells to become active. Importantly, none of this happens in isolation. All of these can be tickled or stimulated a little bit and lower that threshold for the mast cell to become activated. Virtually all of these are being targeted in therapies are considered as targets of therapies right now either in development are actually available for clinical use and we will get to the treatment portion at the end. So how do we make a diagnosis of clonal mast cell disease? The most common versiong,r will basically what happens is that one of these mast cells gains a change in its genetics, is starts to grow a little bit unopposed. There is one clinical test available to look for this, but it can be anywhere in the genome , is to find areas that derive any gain of function in that gene that can be associated with this disorder. It’s important to know you can’t make this diagnosis without a bone marrow biopsy. There is one major criteria and there are four potential minor criteria. In order to get the diagnosis, you have to have one major and one minor criteria, or three minor criteria. There is a separate guideline that allows you to get a diagnosis of master site ptosis with just the one major criteria, but to be perfectly honest, if you see multifocal dense aggregates of mast cells in the bone marrow, the pathologist looks under that microscope at the highest power of the microscope and the sea more than 15 cells in a dense aggregate, almost always you will get a least one or two minor criteria associated with that. So it’s a little bit not so important that there’s a disorder in speech between the two. These funky shaped, spindle shaped, atypical mast cells that are the first minor criteria, and you have to have at least a quarter of them, or you have to have unusual markers that should not be there in that cell. These are markers that are usually on other concepts cells but not mast cells, so we call them a barren — aberrent.

You have to specify we need to stay for these aberrant markers. If you don’t get a biopsy that’s not in the skin, it has to be not just isolated to skin, then you can get the diagnosis. Importantly there are other two other criteria for diagnosis, also having eight trip taste above 20, and we will dig into how the 20 level is a little bit in flux right now based on WHO guidelines where they say to adjust it, which is something we described almost 10 years ago. So what does it look like? It’s not subtle if you find it, but it can be spotty. This is an example of mast so site ptosis in a patient. You next this is a bone marrow biopsy, this is the basic staining they do for any first half. What you get is this cellular dense space were normally you would see these fat spots, the circles are fat in the marrow. You should not have lots and lots of cells like this, so that is abnormal. Can see little disruption of the architecture so as not looking homogeneous across the area. When you stay for tryptase, you will see there is a dense aggregate, you can see way more than 15 cells in this area and you can see some of them are spindle shaped. That long skinny looking cell over there on the far right, those would be considered — I’ll just get my laser going here. Those would be considered spindle shaped. So in addition to the bone marrow biopsy, one of those minor criteria is identifying these gain of function mutations. So what tools do we have to do that? There are three commercially available tests, two which are completely useless in evaluating patients for master site ptosis. This is identified to identify patients who are suspicious of having cancer. Recent useless in master site ptosis — mastoc ytosis, one and 20 and the kit would have to be mutated. The issue, if you recall, mast cells are deposited in tissues. That single clone grows out and — goes out and grows. So the frequency is much lower than 5%, in a circulating cell type. So using the NGS panel, we really can’t detect this disorder. I will skip down to the ASO-PCR, that used to be the gold standard. You can see it’s an improvement on NGS, but we’re still only at 0.1%, that is one in 1000 samples, and that is insufficient.

The advancement recently in technology and the last 5-10 years is the development of something called droplet or digital droplet PCR. It’s a much more sensitive technique and is the one that should be ordered currently. It’s available pre-much in every major clinical laboratory. We are doing a factor of 10 better roughly than the allele specific and that’s best we can do right now, with the lower limit of detection pointed out at about 0.3%. It does pretty well, it’s not perfect. This is data from an abstract that was presented last year at the American Society of hematology meeting. There are better techniques in the wings. Duplex testing or RCA, you can see again were doing about tenfold better again. It’s likely that some of these may become clinically available in the next year or so. Importantly, the duplex sequencing, while it looks not just for the one variant that is common, only about 5% with mastocytosis have a different change, at least based on the literature, maybe little higher than that but that is current Lee the current dogma. That said, and kids it is a different disorder so we have difficulty identifying what the variant actually is. So this two-part sequencing would not only be more sensitive by factor of 10, but also give us broader specificity, like we would be able to find more variancts. So I mentioned this tryptase of 20, while that still the recommended guideline, the WHO now says we are supposed to adjust it. A common genetic trait is present just shy of 6% of the general population in the United States. It is caused by extra copies of this TPSAB1 gene, shown here in red. Everybody walking around, it can encode for alpha or beta tryptase, as the name would indicate. Where as TPSAB2 only codes for beta, you can have alpha or beta at that locus. When you have extra copies of alpha, they are sort of a replication of the adjacent alpha so you get to her three or five or 10 at a time. We’ve seen individuals with up to 10 as shown down here on the bottom left. This leads to higher blood levels of tryptase because of overexpression of the replicated copy. With each extra copy, rather than going up by factor of four which is the general average in the general population, you go to 14. Knowing this and knowing this is the major driver, we want to figure out what is the normal tryptase. You can see in data we generated a few years ago, these are all individuals that had blood levels of tryptase measure. On the Y axis is tryptase and on the X axis is the number form. It’s a linear association between the number of copies and the tryptase level. Over here you can see if you have no tryptase or no replications, your log transfer values are close to one. As you go up you can see the increase from gene dosage impact of one extra copy, 3, 5, seven, and 10 extra copies. From these data we can determine what an actual upper limit of normal is based on this major genetic driver. Lots of other things have been reported to affect tryptase levels, but essentially this is really the only thing that’s cleaning — clinically meaningful. Except for advanced renal failure, this is really the one thing that impacts renal failures. So based on these, we were able to identify, quite fortuitously, the upper limit for people without replications is actually 11.4. And I said fortuitously because most clinical laboratories report the upper limit of normal as 11.4.

I can get into the back of the napkin, dumb luck math but it has to do with the prevalence of the general population and how these clinical laboratories pseudo-normalized data. Importantly, if you have one extra copy of tryptase, your upper limit is closer to 40. If you have two is close to 60, four, it’s 100-120, although the sample size is quite small went to get that far out so there’s probably more variability in this data than we realize. But it’s important because this would alter that 20 level as to what should be the upper limit of normal and what you would use to identify patients who likely have mastocytosis or a clonal mast cell problem. There have been two propose ways to try to adjust for this. Neither is accepted yet, but both have been published and ours has data behind it. The other is just sort of expert opinion, and both work pretty well, actually, with one important caveat. If you look at the middle level, the top one is the average level tryptase tryptase of, the median level for each group of individuals with extra copies, or those without. The middle line, that upper limit 99.5% probability or predictive interval, those are the levels that we came up with based on our data. The bottom line was sort of a simplified method or try to figure out how to adjust for this. It assumes that were using that 20 cut off is what is abnormal. Basically what you do is take the tryptase level from the patient and divide by one plus the number of extra copies. So if they have a tryptase of 10 and they don’t have a hat, the upper limit would be 10 or the normalized level would be 10, I should say. But if they had a tryptase of 50 and they had one extra copy, you divided and say the tryptase is 25. By being 25, it would be above the level of 20. If you invert that situation, you see you would have to get a tryptase of 40 if you have one replication, 60 if you had two, and so on, in order to get above that 20. Interestingly, those levels match up quite nicely with our predicted level. Awfully close and to get out here where the levels are sparse and it’s hard to know what the level is important caveat is it doesn’t adjust for those who don’t have — in the in there maybe some sort of consensus recommendation where the recommendation is if you don’t have hat, 11.4 your cut off. If you do, you can use either these methods but the numerical one is probably a little easier. Although at the end I will show you a link, we have developed an online tool so you just put in your patients genotype and it will spit out whether they are below or above this line. So why do we care? Why is this important and how does it impact patient care? This was a gentleman we saw a few years ago who began anaphylaxis to peaches in his 40’s.

He had eaten peaches before and never had a problem. There are parts of the world where peach allergy is more common, but he was in North America, the United States, and is not a super common allergy here. His exam was benign, he didn’t have any skin lesions, so we measured a tryptase that was 14 and he didn’t have HaT. This is an aspirate from his bone marrow. You can see KIT positive sales, this is a cool instrument where you can stain the cells with anybody, if you hit it with a laser it emits light. And then you make all the cells march in file. You hit it with a bunch of lasers and detectors see those antibodies around there as these kind of little dots. Each one of these dots is a cell from the patient’s bone marrow aspirate. The two upper quadrants are all mast cells, but you can see two of those aberrant markers that are positive in about half the cells. This patient would meet the criteria at the time. It was also positive, he does not have all three and the bone marrow otherwise did not show any aggregates or abnormalities. However, if you adjust that tryptase level because he had above 11.4 and he didn’t have HaT. There are important applications in getting him targeted therapy should he need it. There’s also important implications in terms of identifying patients who have high tryptase in the absence of HaT. It is not just clonal mast cell disease, I want to show you how rare it is to have a tryptase above eight in the absence of mastocytosis. This was almost 700 patients. You can see less than 2% of them had a tryptase above eight that we could explain by either HaT, systemic mastocytosis, or both. Only five out of the 671 had a tryptase above 11.4 that could explain. In all five of these individuals we found variants in the genes that are predisposing genes for myeloid malignancy or myeloid dysplasia. So it suggests having a high tryptase in the absence of having HaT is indicative of most commonly mastocytosis but effectively others. A second group showed similar and found that having high tryptase in the absence of HaT had a specificity of almost 98% of identifying mastocytosis in a fair number of patients. We generally think of using tryptase as a screening tool because of this. However the sensitivity is fairly important. It doesn’t rule out the diagnosis of clonal mast cell disease. This is a study of patients largely from — from Slovenia patients were screened not just using peripheral blood — I hope what you can appreciate here is that tryptase levels in these — these are all bee sting anaphylaxis patients. The average level hovers around 4-5, which is the same as the general population. There are outliers you will pick up but normal patients have tryptase below 11.4. While it is important to measure the tryptase level and it is helpful, we need to really be sure were screening for particulate drugs or insects things, particularly adults. So moving from diagnosis of clonal disease to diagnosis of reactions, tryptase is useful there too. The reason I’’m talking so much about tryptase is it is a unique protein and it’s made in abundance by mast cells and almost exclusively by mast cells and healthy individuals. Based on some old experiments that we really couldn’’t do any more, where they tookde allergic patients and then stung them to see if it went up. Histamine goes up very quickly and then comes right back down. So it’s not super useful unless you are right there when an allergic reaction happens, like it is going away within minutes. However, tryptase stays up, the top two or up to four hours and the last one goes up to 12 hours.

You can see within the first four hours or so time period, getting pretty good elevation over baseline. Once you get up to about six hours, you’re losing that difference. If you measure it right away, those tryptase that are low initially at least in ANB, if you measure too soon, within 15-20 minutes of the reaction, you might actually miss the rise. The goal is around an hour, certainly two still fine, four is probably OK, but if you wait until six, it’s a little too late. Based on observation it was proposed that an increase of tryptase of roughly 20% over your baseline plus two nanograms, let’s say your baseline is five, it would need to go up by at least three, 20% plus two. If you go from five to eight, that’s consistent with the clinical diagnosis of anaphylaxis. Importantly, in all the algorithms and all the position statements on the diagnosis of anaphylaxis, tryptase is not included because it’s a clinical diagnosis. While it’s useful and helpful, it doesn’t actually make the diagnosis of anaphylaxis that clinical presentation does. But tryptase isn’t the only mediator that arises. The others are metabolites of important mediators. I mention histamine going up right away. One of the major metabolites of histamine is shown in that chart it in the third one over in green. That one can be measured historically in 24 hour urines, but some people are doing a spot urine collection as opposed to a 24 hour collection but the gold standard remains 24 hour collection. In addition to histamine, there are breakdown products of liquid mediators. This is a terminal degradation product of prostaglandin d2, and then LTE4 which is the leukotriene in that pathway that has a longer half-life than the others. These are all patients who had physician diagnosed anaphylaxis. You can see that on average they go up, in some folks I don’t rise super substantially, and if you look on the far right, the tryptase level increase shown in the dashed line is far above what we establish as the upper level of difference, now it’s plain where that number comes from in a second pivot one of the complications or difficulty in using these markers is that we don’t know how variable they are and what else they are associated with. So often they’re measured in patients being evaluated for clonal mast cell disease, but we don’t really have clear identification of what a level should be or is. Importantly, this group showed the most common clinical association with having elevated urinary mediators was allergic rhinitis. Importantly, the folks at had it the highest, they showed it went down substantially with immunotherapy. So it likely local activation by Allergan of mast cells in the nose, that once patients became desensitized through Allergan immunotherapy or allergy shots to environmental allergens, they stopped making those prostaglandins and normalized. I just thought that was fascinating and interesting. Importantly, we don’t know what variability of most of these are but we do know that they are area bowl. For instance if you Tase — if you take mast cells and grow them in culture come there’s a diurnal variation in secretion of histamine. There’s also variation by age and size of histamine.

You have to adjust what is a normal level based on those factors, and we don’t really know how variable it is in humans who are asymptomatic. We do know how variable tryptase s are, at least in this real-world study that we published a few years ago. These are patients with either allergic disease, a variety of allergic diseases, or those who had serial measurements. Each individual cover — colored line is a different person, and is showing by age, so you can see each individual over time but also in the cohort is a function of age. There is no real trend by age or time, these levels kind of go all over the place. The same is true on patients with mastocytosis. They even go up all over the place even more. Including this guy who into over 1000 and back down again, despite having no key symptoms. This worried us a little bit in terms of the usefulness of using 20% plus two, because going from a couple hundred to a couple thousand is way more than 20% plus two and really suggested that maybe this sort of standard math would not apply as well or work as well for patients with high tryptase levels. So we sought to try to identify the simplest way to determine what a meaningful change in tryptase levels is. Suffice it to say what we try to do was maximize both the sensitivity and specificity of using a ratio. We found it just a simple ratio of an acute level to a baseline level was the easiest way to do this we identified these three different cutoffs where this ratio of 1.685 maximized both sensitivity and specificity. So simply, give us the biggest bang for our buck to use tryptase to identify those having hypersensitive reactions. There is a nice tool I will show you online that you can use but I just kind of want to show you have the data perform. That optimize level in green is at 1.685 where sensitivity and specificity are maximize. These are all just baseline levels, these first four groupings, and you can see that there are still some people whose variability is falling outside of those ranges. We also identified two others with a high probability and low probability because often times as clinicians when we are seeing patients, we have a pretest probability.

We have someone perhaps who has had a passive exposure to an atypical agent that’s not usually in Allergan versus someone who ingested a common allergen and never had it before or just got an injection of a medicine or a bee sting that they identified. So the pretest probability is quite different. That’s why we identified both high sensitivity and spent it to be as shown there. Importantly, the high-sensitivity threshold of 1.37 captured everybody on the far right that was diagnosed by physician is having anaphylaxis. We thought this would be a little bit of an improvement and we wanted to see how much it was. Using our cutoffs we found a false discovery rate and compared that to what it would’ve been had we been using 20% plus two. You can see that finding still about 4% who were being misclassified when they were just having baseline variability. Using our new optimized approach, whereas using the 20% plus two almost one in four basically were having being falsely classified when they were just having baseline variability. Others have seen the same thing, a smaller study may have exaggerated the effect size but they saw almost half their patients would’ve been misclassified. So while the 20% plus two works great if you have someone who has a normal tryptase level, 20% plus two and one point 685 are exactly the same for level of about 4.6, which is roughly the median level in the general population who doesn’t have HaT. It kinda falls apart when you have a patient with high tryptase. If you have a patient with HaT or clonal mast cell disease, this has been well-established across groups and is being recommended by consensus statements now as well. This is called the tryptase calculator, it is misspelled on purpose. As of today’s taping, presentation, etc., it has been taken down from the NIH website, so that is good. You put in your baseline tryptase level of your patient and you have these three choices, it defaults to the possible suspicion, that’s the optimize, but if you think it’s likely, that’s the high-sensitivity ratio and if it is less likely that is high specificity. You don’t have to stick to a formulaic decision. You go in and say it’s possible, history is a little fuzzy, you ask it to analyze your data, and then you get this result. You had this blue line which is the threshold. First of all, below the yellow line, nobody cares, it is grayed out. The blue line is sort of, if you are below that blue line, that’s just baseline every ability, but if you’re above, that’s consistent with the clinical diagnosis of anaphylaxis. If you had 22 and you went up to 30, which would mean 20% plus two, and you do the same calculation, you see now the patient just has baseline variability despite that the — that’s what this improved specificity that the other approach provides. Where these two lines cross where they’re identical, that’s about 4.5. So what about these other mediators and how are we using them?

I’ve talked ad nausea him about tryptase, so we can ignore that. Talked about all the others require in most cases a 24 hour urine, some sinners may be doing spot urine although I haven’t figured out how we would order that at this point. But what about these other guys? There’s no consensus on the level that you need to meet to reach anaphylaxis for any of these others. Some people have proposed a doubling, even for the PGF 2 alpha. Depending on the mediator you’re measuring. Conversely, were trying to diagnose clonal mast cell disorders, there is good specificity of levels in patients that are already diagnosed. Those levels are little bit more , a little better established. That’s diagnosis of anaphylaxis in clonal mast cell essays — disease. Basically all of the same stuff is just translated. This is sort of an algorithm looking at this, moving from diagnosis to management. Importantly, and one thing that gets often overlooked is patients with clonal mast cell disease often have bone problems. They develop osteopenia, osteoporosis and have a lot of bone pain often as well. We talk about things to potentially measure over time, including tryptase levels, importantly, measuring bone density over time is critical, especially if they have early onset bone density issues. Some patients with clonal mast cell disease — there are four diagnosis, is predominately age one, although age two can be added. Patients with bone density issues, getting calcium and vitamin D is imperative. Some patients and in selected individuals, aspirin can be used because it can block the generation of some of the mediators we discussed. Certainly for skin, G.I. and systemic anaphylaxis, it’s in the next category. Use of advanced drugs, we usually seek out support from our colleagues to do those things. That’s really kind of the next step. We talk about managing these patients, we need to engage our teammates, and this is really a multidisciplinary approach that needs to be taken with these patients when they present with complex features. Finally, as will move beyond alert dermatologic, gastrointestinal consultations, wind we think about sending for — evaluation? I will get into some of those symptoms. That’s the same decision point where we consider — only one is approved. Cyclosporine is an add-on therapy, and whether that might be of benefit in some of these patients is not really well-known. — not incorporated into the guidelines for treatment of those patients. They fit somewhere into this algorithm. Based on a cohort of expert opinion. So when do we consider referral or potentially side a reductive therapy? It’s really patients who are having uncontrolled symptoms or disease, and particularly B findings. If you have two or greater of theseB findings. Lots of mast cells are greater than 30% in the bone marrow. Or of low frequency of greater than or equal to 10%. Or they have abnormalities in their bone marrow that looked like Milo proliferative syndrome but don’t meet the criteria of that. These are all the areas that could be affected in the advanced disease. These are patients who can get quite sick and we need help from oncology doctors. As I mentioned, the only FDA approved drug for systemic mastocytosis, it doesn’t block as much and is quite selective.

People are also working on a number of other drugs. Imatinib is approved for advanced disease and should be reserved or merely for specialized centers or hematology-oncology doctors. PTK inhibitors and other selective KIT inhibitors are all in development right now for treatment of systemic mastocytosis, and other drugs are being developed for other diseases that may be applied but these are specifically understudy for systemic mastocytosis. These are QR codes to those two tools on the NIH website. Either one you can find if you just google them as well, but overly bees will be helpful to you as well in practice, or if you just kind of want to learn it by your self, you can play with these a little bit. The key takeaways really, BST levels are variable and likely these other mediators are as well and were trying to work to understand how to adapt our understanding of use of them in order to better use them for diagnostic purposes. Right now the variability is impacting our ability to correctly interpret them. It’s important that when we are interpreting a tryptase level that were thinking about HaT and making sure we understand what of the tryptase level is affected by that, and having a level above 11.4 is suggestive of mastocytosis or another issue. The 20% plus two rule works great with patients with normal tryptase levels, but the ratio is important to consider when we talking about patients with high levels. Hopefully in then your future, we have better assets than we did, but hopefully we will have better assets to detect these variants soon. Currently we still have to use biopsy of non-skin tissue in order to make the diagnosis of mastocytosis, so we have eight ways to go there in terms of noninvasive diagnostic testing. Finally, we do have lots of — it’s exciting that we have a drug approved for us and hopefully will have others in the not-too-distant future to help our patients better. But that, I’m happy to take some questions. This is kind of a fun slide that was commissioned years ago saying, I think they are in cahoots. I’m happy to take any questions that people might have.

Ruthie: Thank you so much for that presentation. I know I learned a lot, and I hope that our audience did as well. I have a couple of questions, one, I feel like you touched on, so I will ask it and maybe you can elaborate. Our tryptase levels always elevated in mast cell activation syndrome?

Dr. Lyons: No. In general, actually, any of these disorders, HaT is the only one where the baseline level is consistently elevated. Were looking for an acute increase during asymptomatic episode, and that’s what helps us get that diagnosis.

Ruthie: Think is so much. We have time for a couple more. What strategies do you use to counsel patients when mast cell disorders — with mast cell disorders on trigger avoidance, medication use, and emergency preparedness, and how do you tailor this guidance for different patient populations?

Dr. Lyons: Generally speaking, obviously every patient is different. I talk about, there are common triggers that we know of, and I generally review those with every patient with either clonal mast cell disease or current mast cell activation which include certain medications like insides or –NSAIDS that are direct — alcohol, exercise, physical or emotional stress, temperature exchange — changes and exertion are all common causes for general mast cell activations. Beyond that, there aren’t specific triggers that are universal. Many patients will report triggers and I think keeping — I encouraged him to keep a diary oftentimes. I also emphasize the fact that oftentimes these are unprovoked, idiopathic type recurrent events, so having prophylactic treatment and then a plan for acute treatment of the reactions, depending on what the nature of the reactions are, which could include — and emphasizing the fact that these may not be extrinsic, because the fears that sometimes patients start limiting foods or other things quite substantially, and then end up — I had one patient who became vitamin B12 deficient because of such a limited diet. So you have to really be careful in counseling them to not necessarily assume everlasting that happened right before they had an event was a trigger necessarily. The other thing that is super useful is biofeedback, particularly in mastocytosis patients where you can help mitigate the severity of an episode using mine-body biofeedback techniques. There are great data, but anecdotally and clinically, something we did regularly for patients at NIH and many patients have had success with. When I said there are great data, it hasn’t been studied prospectively, but the outcomes think speak for the use of that technique.

Ruthie: Thank you. We have a position that is stating that she has very many patients with hypermobility and symptoms consistent with mast cell activation in respiratory G.I. tracts and skin, but no elevated tryptase levels. She is managing with antihistamines and sometimes it’s as far as utilizing mono Lucas, but should she be tryptase tryptase analyzing levels each year to look for increase over time?

Dr. Lyons: No, there’s no reason to really trend the tryptase over time. Let’s say you had measure couple in their consistently one level. We don’t generally recommend trending them in that context unless they have a known clonal problem and they have new symptoms, where some patients we trend once a year or once every other year if they have known clonal disease. But there is no recommendation to trend that.

Ruthie: We will take one more question before rewrapped up for today. Can you speak more specific to H1 and H2 treatment the Yui — you have seen work, or ones to be wary of?

Dr. Lyons: H1, generally we recommend second-generation and non-sedating. For H2’s, I don’t know that there’s any that are more efficacious or more specifically recommended than the other, and honestly,H2 generally doesn’t help — there’s literature that when the patients were infused with histamine 40 years ago, you could see that they would get widened pulse pressure and both H1 and H2 would fix it. Anecdotally or clinically, most patients don’t seem to improve substantially be lined — beyond H1 on H2. Up to four times the daily dose is the kind of the standard for H1. Is forcing to be leery of, there are potential concern potential concerns for the sedating group of histamine use, there some long-term outcome data in terms of risk for dementia and things like that. In high dose and especially in smaller kids, we had one patient who developed mild psychosis from off target effects of sedating antihistamines. So it’s good to be leery of lots of old school, although some patients will take diphenhydramine or something like that at night to help sleep , Chai don’t really fret about, but we do discuss those — which I don’t really fret about, but we do discuss those potential risks.

Ruthie: Thank you so much again for this incredible presentation and for answering some questions here at the end. No our attendees appreciate that. In a few days we will email you with a link to the recording as well as a webinar evaluation and supplemental resources. Before we conclude today, I want to mention our upcoming webinar October 8, it’s going to cover drug allergies, diagnosis and treatment, presented by Dr. Castel’s. She will is for the pathophysiology of drug-induced allergy reactions, diagnostic tools such as skin testing, and current therapies including — including desensitization protocols and Biologics. The please stay tuned for that. As always, thank you to ever — from everyone at allergy and asthma network where we advocate for better outcomes, access, and education for treatment. Thank you again, Dr. Lyons, for being with us today. Thank you so much, and have a great day.

Dr. Lyons: Thanks a lot.