speaker-0: So hello and welcome to Let's Talk MCAS where we put all things Marcell under the microscope. So I'm absolutely delighted to welcome Dr. Lawrence Afrin to the podcast today. Dr. Afrin is a clinical hematologist and a pioneer in the field of Marcell activation syndrome. Over many years, his research and clinical work have literally transformed our understanding of Marcell diseases and they brought hope and recognition to patients across the world. He's the author of Never Bet Against Occam, which has become the seminal work for clinicians and patients alike. And I feel as though you don't really need an introduction to our community here at Marcell Action because so many of our members will be very familiar with your work. And I know that they'll be as delighted to welcome you to the podcast today as I am. So welcome and thank you so much for giving up your Saturday morning to talk to us.

speaker-1: I appreciate the opportunity, Deborah.

speaker-0: ⁓ Thank you. So as a haematologist, I'm guessing that cells kind of naturally fell into your remit, but what was it that made you particularly interested in mast cells? Did you wake up one morning and think I must devote my life to studying mast cell disease? How did that come about?

speaker-1: Well, I think it was from ⁓ my early clinical experiences. I came to make the diagnosis in my my first such patient and then ⁓ quickly began recognizing that it was the same disease, just with very different faces, ⁓ very different superficial ⁓ presentations in ⁓ startling number of other patients. And I also began recognizing very early, ⁓ right from that first patient actually, that much as you could say about any other disease, once you've made the right diagnosis and applied the treatment that's appropriate for that diagnosis, the patient actually gets better. and it was ⁓ you can imagine very gratifying, very satisfying to see so many of these long chronically, mysteriously unwell patients who were suddenly getting significantly better. and as I began to realize just how prevalent this disease is, if almost always unrecognized thus far, and how few physicians out there who are familiar with this understand it and are willing to address the complexities of this. And as so there's obviously a great need for physicians who are familiar with the disease. And when when you see ⁓ you know the life of somebody who's been chronically unwell and you see how dramatically that can be turned around, it's it's motivational. What what else can I say? ⁓ yes, I could have spent the rest of my career addressing ⁓ I'm actually not only a hematologist but also an oncologist. And ⁓ I could have spent the rest of my career addressing sort of routine, ⁓ you know, traditional cancer and blood matters. ⁓ but as I could quickly see the need for MCAS professionals ⁓ was far greater and that's something that I learned how to do fairly well, I think. So I mean it wasn't overnight, but ⁓ for roughly the last decade I've been fairly exclusively focusing on this area.

speaker-0: Yeah, and making such a big difference to such a lot of people as well. We're very grateful that you did make that decision and that you are doing that. You touched there about the prevalence and you've talked quite a lot about the fact that you believe this is far more prevalent than maybe is sometimes considered. What's led you to that conclusion? What do we know about the prevalence?

speaker-1: Well, f ⁓ of course there's the clinical experience. once you learn how the disease operates, you understand its ⁓ clinical patterns, you you quickly begin to see it everywhere. which is not surprising because in addition to the clinical experience, there's the preliminary published research addressing the epidemiology of this and ⁓ fairly consistently showing roughly 17 to 20 percent of the population ⁓ has you know one variant or another of mCAS and when you learn clinically how to recognize this and you you begin realizing that in truth you've been seeing it all day long every day left and right your whole career your whole life you just couldn't previously recognize it for what it is, because number one, nobody had ever taught you that such a disease exists. And number two, and this is a big factor too, is that the essential biology of the the the underlying ⁓ molecular genetic biology of this guarantees that in stark contrast to most other diseases which are going to clinically present with one or two Clinical patterns, this disease is virtually guaranteed to present in hundreds of even thousands of different patterns at the superficial detailed level. Yes, at the hundred thousand-foot level, there are overarching general patterns that you can learn to recognize, but the details are. almost always quite different from one patient to the next. And the fact is that when a you know, a typical doctor patient encounter, you've only got, you know, five or ten minutes, and the doctor has no choice with such limited time to focus on just one superficial issue and no time to step back or or look at the big picture of what's been going on and consider what Other illnesses might actually be underlying all the detailed issues ⁓ that are going on in the patient. So so it's this extreme heterogeneity or variability from one patient to the next that makes it difficult for doctors to recognize these pa I mean, pity the poor doctor who has to learn how to clinically recognize that. Chronically ill patient A who comes into the clinic who's looking and acting and feeling completely differently, at least at a superficial level, from chronically ill patient B who looks and acts and feels completely different from C, D, E, F and G, and yet they all just have different variants of the same root issue of mast cell activation syndrome. I'm obviously not saying that every chronically mysteriously unwell person has MCAS at the r at the root of it. That that would be idiotic. But nevertheless, we ⁓ we know from the preliminary research that it is a very prevalent disease. So it's not surprising that a significant fraction of the population of patients with chronic mysterious multisystem unwellness has one variant or another of MCAS at the root of it. You just have to learn to recognize it. And you can imagine it's even harder for that poor clinician to learn how to recognize the possibility that MCAS might be at the root of the patient's disease when he hasn't even been taught that such a disease exists. And and and I guess there's a related challenge as well that We go through, you know, roughly a decade of training and in that decade you get about one minute of teaching. I I'm not exaggerating, you get about one minute of teaching about the biology of the mast cell, and you get taught about that that there's essentially only one disease of the mast cell, and that's the incredibly rare disease of mastocytosis. ⁓ essentially ⁓ a cancer, yeah, ⁓ fortunately usually a low grade cancer, but nevertheless a a cancer of the mast cell. But it's so rare a disease that most doctors will never see a case of it in a decade of training or three or four decades of practice. So you go through your training, you come out of training, you've never seen a case of it, you've been told it's incredibly rare. It's the only disease of the mast cell you've been taught. So then somebody comes along, somebody you don't even know comes along and tries to tell you, ⁓ wait a second, there's this other mast cell disease, ⁓ MCAS, that you were never taught about. And furthermore, it's incredibly common. In fact, so common that you've actually been seeing it your entire career. You've just been missing it left and right. ⁓ you can be sympathetic ⁓ to understanding that most doctors, their reflexive reaction to being presented with that information, they say that's just not possible. You know, you're you're you're out of your mind. And they tend to deny it or or minimize, diminish it, say even if it does exist, it has to be as minimal a problem as mastocytosis is. And ⁓ one of the many things that's been particularly interesting to me over the last eighteen and a half years now. I've been spiraling down this mast cell rabbit hole is that I've been very privileged to have had the opportunity to discuss the disease with a a growing number of colleagues all over the world, not not just hematologists and colleges, but health professionals of all types. And I've been able to help them Come to understand the biology of this. I mean, in that one minute of training, we're taught there are two mediators that mast cells produce histamine and tryptase, and that's it. And you know as well as I do, that's ⁓ just the tiniest sliver of the vast set of very potent mediators these cells are producing and releasing when they're activated. so we're we're Taught very little about how these cells operate. I mean, honestly, if the only thing they did was to produce tryptase and histamine, how much trouble could they possibly cause? I mean, not much. But once I had the chance to present to my colleagues, ⁓ show them the reality of the biology of this, the vast array of mediators these cells are truly ⁓ producing, and I help them come to see the diagnosis and nail down the laboratory evidence in their first one or two, three patients. It's been very interesting to see that a large number of those professionals then circle back with me and say, ⁓ my goodness, you were right. I've been seeing this my whole career, left and right. Now that I can recognize it, well, I can diagnose it because there are tests for it. Nothing I was taught in training, but but once it's diagnosed, there are treatments. In fact, there's a wonderfully large array of treatments. ⁓ yes, it's ⁓ takes some effort to keep trying various treatments until you find the particular cocktail that works best for the individual patient. But the best thing is that most of these patients eventually piece together some mast cell-targeted cocktail that actually does get them feeling significantly better than they had ever felt previously. And for many doctors who are seeing so many patients every day, you know, minimal time to see them, and they have dizzyingly complex arrays of of problems. And the doctor runs so many tests trying to help them with their mysterious symptoms. Never finds any explanation. He tries various treatments. Most of them don't help significantly. But then he sees that when you make again the right diagnosis, you apply the treatment that makes sense and the patient gets better. You can imagine it's not only great for the for how the patient feels, but it's great for the doctors. ⁓ so I I've come to call it you know, chicken soup for the doctor's soul. ⁓ I've had a number of doctors tell me they were very close to being burnt out. and when they came across MCAS, came to understand it, yeah, it's challenging. But when patient after patient you see success, diagnostic successes, therapeutic successes, ⁓ it really buoys the ⁓ the spirits of the doctor. as well, many patients ⁓ na even before they have effective treatment. J just attaining a clear laboratory supported diagnosis that finally explains all that's long been going on in them. When so many of their prior doctors, their acquaintances, their families have long been telling them, they're you know, y you've seen so many doctors, nothing can be found, nothing is helping you, it must be in your head. And they finally ⁓ realize no, that what they've been feeling, what they've been reporting is the truth of the matter. And so finally just having an irrefutable, you know, undeniable explanation is such a powerful moment for some of these patients. Some of them ⁓ actually, you know, start shedding tears of joy when I can, you know, show them the test results and said here's the evidence.

speaker-0: Yeah, it's vindication for them, isn't it? It's a huge relief as well to feel that someone understands and is going to be able to do something to help them. It's wonderful. Can I ask you about the diagnostic criteria a little bit? Because you touched there on the fact that you have been an advocate for a wider diagnostic criteria. Why do you feel that's so important? Is there a danger that it could be over-diagnosed? What are your feelings about it?

speaker-1: Well, obviously there's a theoretical danger of overdiagnosis for literally any disease. But from a practical perspective, first of all, if overdiagnosis or misdiagnosis has happened, it hasn't yet been reported. I mean, admittedly, you know, not a huge amount of literature about MCAS ⁓ yet. First case reports were only about nineteen years ago. But to date, there really hasn't been a single reported case of overdiagnosis. And I think it's important to understand that the diagnostic criteria actually do require that you rule out any other diseases that could better account for the totality of what's been going on in the public. in the patient, and and that's a really important criterion. It's almost always the case in these patients that you can come up with a number of other diagnostic considerations that account for various pieces and parts of what's long been going on in the patient. But it's extremely difficult in these patients to identify any other diseases, any other known human diseases. That can actually account for the totality of the particular assortment of issues they have long been suffering, that then MCAS can explain. So when you rule out the other you know, diagnostic considerations and you see there's a a clinical course, a history, a presentation that is consistent with multi system ⁓ inappropriate activation of the mast cells. And ⁓ ideally when you also have laboratory evidence ⁓ present, then ⁓ we understand that in some countries in the world it's not possible to to run the testing and so there is an allowance in the consensus two diagnostic criteria to use ⁓ positive treatment results. from mast cell targeted treatments as as ⁓ the the final criterion. But I think we all understand that laboratory evidence is the best criterion, the most definitive criterion. So but you're right. There's ⁓ one group, the so-called consensus one group, they've long been saying ⁓ that you have to have absence of other ⁓ diagnoses a better account for what's going on. You have to have the multi-system presentation that's consistent with mast cell disease. ⁓ and they they actually insist you must also try treatments in the patient before you even have diagnosis. You must show that there is response to treatment, which with such a v variably behaving disease you can imagine that it's quite possible that the individual patient might not respond to the first one or two things that you s randomly pick to try and how many doctors would then persist after failure of one or two empiric trials to try anything else? But you know, it's ⁓ the variability of the disease guarantees there are gonna be plenty of patients who won't respond significantly to the first one or two things you try, but then will respond very well to things you try later. ⁓ But the consensus one group requires demonstration of response to treatment in order to make a diagnosis. And finally, they require two particular ⁓ features. ⁓ you you must have there's a little bit of ⁓ soft language in there to allow for exceptions, but for the most part they insist on seeing recurrent anaphylaxis and seeing a rise in the tryptase level by a certain margin during a flare of symptoms ⁓ compared to a ⁓ a baseline asymptomatic tryptase level but i have long had problems with those criteria because number one ⁓ anaphylaxis is a feature that's seen in only a small minority of nCAS patients ⁓ And so not having anaphylaxis certainly doesn't rule out the disease. It just says you don't have an anaphylaxis inducing variant of the disease. And with regard to the tryptase, ⁓ first of all, these patients are always symptomatic in one fashion or another, to one extent or another. There really is no such thing as an asymptomatic. Mast cell patients, so there is no such thing as a baseline asymptomatic tryptase level. And the the marginal increase in tryptase has to be found within four hours of onset of a flare of symptoms. And you can understand all the practical challenges in getting such testing done. And ⁓ furthermore, ⁓ we've come to learn through the research, the published research over the years that tryptase is an excellent marker of how many mast cells you have in you. ⁓ so if you have a cancer of the mast cell, you would expect to find a substantially elevated level of tryptase. But if the disease of the mast cell you have is one of inappropriate activation, rather than inappropriate proliferation, then the tryptase level is going to be elevated little to none. And that's actually what is seen in the great majority of cases of MCAS. about 85% of MCAS patients, ⁓ as judged by the Consensus II criteria, have a normal tryptase. ⁓ they always will. And most of the remaining 15%, we've learned in the last decade that even that is not due to you know, inappropriate activation of the mast cell. Rather that modest persistent elevation in tryptase is coming about because those patients have sort of accidentally inherited from one parent or another an extra copy of the gene for making tryptase. So those patients are genetically hardwired so that every mast cell they ever produce will over express tryptase by a small margin. ⁓ That's the condition called hereditary alpha tryptasemia. So tryptase great marker for the extremely rare disease of mastocytosis, but it began to be realized many years ago that tryptase is a fairly poor marker of activation. Yeah, there are occasional sort for example ⁓ anaphylaxis, a good number of ⁓ cases of anaphylaxis, perhaps even ⁓ a majority of cases of anaphylaxis where the tryptase level will spike up. But there are also many patients who have anaphylaxis and do not see the tryptase level budge one bit, and it just underscores that it's not the greatest marker for activation of the mast cell. So anyway, that's what the Consensus One group focuses on, recurrent anaphylaxis and this marginal tryptase elevation. And you can imagine that given that these cells produce hundreds and hundreds of different mediators, of course there are going to be variants of the and many variants of the disease where tryptase is just not a factor. And if you don't establish the diagnosis, you know, based on such narrow criteria. If you deny the diagnosis because they don't have anaphylaxis, they don't have this marginal tryptase elevation during a flare, then they're going to continue to be mysteriously unwell challenges to their doctors for years, for decades to come, they may well go cradle to grave. Chronically unwell, never having a diagnosis established, never finding effective treatment. It's a life that's lost. And that's the biggest tragedy of all, in in my opinion. So the consensus two criteria, no, you can't measure all of these hundreds of mediators. ⁓ the truth is, but there are roughly about ten ⁓ mediators ⁓ that are measurable in the clinical laboratory and which are fairly specific to the mast cell. So that's what we measure. I mean, if you're only measuring ten out of many hundreds of mediators, obviously the the symptoms that they're having are probably coming about from aberrant release of mediators other than the few that you're measuring. I mean what we're measuring is a terribly poor surrogate for the totality of the signaling chaos that's going on in the disease. But Nevertheless, this is the best we can measure, and they are mediators that are fairly specific to the mast cell. So when we find them to be elevated, it's a marker of ⁓ fair fairly confident marker of activation of the mast cell. And then again, presuming you meet those other diagnostic criteria we talked about, then you you have a diagnosis, ⁓ a sensible clinical diagnosis, and you can begin sensibly trying the fortunately. great many different treatments already found helpful in various mast cell patients. And usually some cocktail of treatments or another does significantly help them. So to go back to your original question, and I'm sorry I'm so verbose. It's just my style, but yes, technically overdiagnosis is a risk. But it's never been demonstrated. And instead I think you can understand from my diatribe that under diagnosis is the far greater hazard. And unfortunately I see this happening almost every day in my clinic where patients who, you know, thanks to the help of friends and the internet and other information sources, they come to suspect they have MCAS and then they consult various doctors who either don't know about it or Maybe they ⁓ come to see a physician who's familiar with the consensus one perspective, but then they say, Look, you've not had anaphylaxis, and then a tryptase level is checked and it's normal and the doctor in his authoritative white coat ⁓ tells the patient, No, you don't have a mast cell disease. Well, doctor, what do I have that's made me sick for the last forty years? And well, I'm sorry, I I don't know, you know, I can't help you. I've got other patients I have to see, please go away. And this just is so kind of tragic in in my opinion. So you know, I I prefer not to ⁓ I try very hard not to make guesses about this, not to make a clinical di I understand there are plenty of places in the world where you can't access the testing. And in that situation you do the best you can, you know? And if the best you can means that you just Empirically try some mass-targeted treatments in a patient you're suspecting has MCAS, then and if that's how you come to make the diagnosis, then okay. You know, better for the patient to be diagnosed and treated than not diagnosed and not treated. But here where I am, I'm fortunate to have ready access to the testing. And so I try very hard to ⁓ get a clear laboratory-supported diagnosis. ⁓ and not just one piece of laboratory evidence. I far prefer to find ⁓ multiple pieces of laboratory evidence, because you know as well as I do that even here in twenty twenty six medical testing is not Star Trek and any test could be abnormal, you know, once by chance or error. So I try very hard to find multiple pieces of laboratory evidence ⁓ supporting the diagnosis according to the Consensus two criteria in order to establish the diagnosis and then proceed with treatment. Every once in a while I do find a patient who actually does meet the diagnosis ⁓ by the consensus one criteria. I would say it's probably one percent or fewer of my ⁓ total population of MCAS patients, which gives you a sense of the underdiagnosis problem. But when I find such patients, you know. Fine, we have a diagnosis according to peer reviewed published diagnostic criteria. And so let's get busy treating the patient. I I just want the patients to get better, and we are now able to recognize there's this disease. It's present in an awful lot of patients who couldn't otherwise get clear answers for their troubles and ⁓ helpful treatment. So As long as you take care to get the evidence, it's just hard for me to see the harm. as long as you're you know, you try to be worth it.

speaker-0: that tragedy of that wasted life aren't you by by diagnosing and getting them on the right treatment.

speaker-1: That's what I like to think.

speaker-0: You're too optimistic. ⁓ Can I ask you about biopsy? Because it's very rarely done here in the UK, it's not widely available, but reading your book I see that you do quite a lot of biopsies. Do you find that helpful?

speaker-1: Yeah, actually I don't pursue biopsies very often at all because it's just not necessary. First of all, biopsies by and large are invasive procedures, whereas assessment of the mast cell mediator levels in the blood and the urine, this is what we consider to be non-invasive testing. And the fact is that if the specimens are handled properly from beginning to end. We almost always find the evidence we're looking for to clinch the diagnosis again per the consensus two criteria within a reasonable number of rounds, roughly ⁓ within three rounds of of ⁓ properly handled ⁓ non-invasive testing. Actually the majority of patients we find it in the first round, ⁓ properly handled testing, but you know, there are minorities that we need a second round, just occasionally we have to go to a third round. It is a rare patient where we just can't find it through the non invasive testing and we have to go ⁓ pursuing a a new or a an additional set of biopsies, usually in the GI tract, but the fact is the great majority of these patients have long had unwellness that long ago led them to undergoing diagnostic evaluations that included biopsies of one tissue or another that was involved with the mast cell disease. And even though you can't go back to old blood and urine specimens to retest them for evidence, fortunately, the pathologists hang on for for many good reasons. They hang on to the old biopsies typically for 10 to 20 years, sometimes even longer. And once you apply the appropriate special processing, ⁓ into these tissues, the special processing that is necessary to be able to recognize the mast cells for what they are, then you you you see it. And and so many of these patients they've already had biopsies taken. But with the routine processing, it just couldn't be recognized what was going on in them. And so part of the initial diagnostic evaluation I take my patients through is that we go to some effort to track down where the old biopsies are accumulating dust in a pathologist's filing cabinet, ⁓ an archive somewhere, and we then apply the ⁓ appropriate special processing. And most of the time the pathologist then provides me a report ⁓ showing me that. ⁓ yeah, there's clearly an abnormal number of mast cells here. No, it's not an excessive number of mast cells. It's anywhere close to what you see in the cancerous situation of massytosis. And these mast cells in MCAST don't have certain other characteristic abnormalities of the mast cells that you see in mastocytosis. But nevertheless, there's clearly an abnormal number of these cells. There are some arguments out there in the literature about what constitutes ⁓ the correct upper limit of normal, but most most physicians working in this area, at least who adhere to the consensus two criteria, have a are fairly comfortable with 20 mass cells per high power field in the GI and ⁓ genitourinary tract tissues being a a reasonable threshold and upper limit of normal. And it's very common. For these patients to be found to have ⁓ with the appropriate special processing, increased numbers of mast cells in these old biopsies. I mean, this is such an important finding, th this discovery of this special processing, the special staining that f finally identifies the mast cells for what they actually are, that they're not these other sort of more common cells, lymphocytes, plasma cells, macrophages, histocytes, and so forth, that no, these are not those cells, these are unique cells that are now called mast cells. The discovery that ⁓ there are mast cells, ⁓ and that it requires special processing ⁓ to identify them was such a significant finding that this is part of what ⁓ Paul Ehrlich actually won the Nobel Prize in Medicine for back in nineteen ⁓ eight. I mean, maybe today we don't consider it to be such a big deal, but you know, back then it was such a big deal, it actually contributed to his winning ⁓ I mean he there were other things he did in his ⁓ illustrious career too that led to him winning that prize, but This was a significant part of it. ⁓ I mean how many doctors can lay claim to having discovered an entirely new type of cell that, you know, has has never been seen before?

speaker-0: It's a shame that it's not used more routinely,

speaker-1: ⁓ so so yes, I I don't have to run biopsies most of the time, but usually that material is available and so I just bundle it in. ⁓ the the reevaluation of the old biopsies, I just bundle it in to the diagnostic testing I run in most of my ⁓ new patients.

speaker-0: And as you say, that information is just sitting there waiting to be found and we have the test. So why not use it? That's very interesting. Yeah.

speaker-1: I think my personal record was in doing this. I actually on one patient found an old biopsy from twenty-five years earlier that was still on file. And the patient, of course, had ⁓ this is a patient in I think his mid-thirties or so, and he had had a lifetime of mysterious unwellness, including GI unwellness, and around age 10 or so he actually was so sick he was subjected to his first endoscopies and the original reading was normal. And but but the specimens sat there for twenty five years and once we finally got them reprocessed, boom. Not normal. There it was. Been sitting there all waiting to be discovered.

speaker-0: So interesting isn't it? It's like a treasure waiting to be discovered. A lot of our community members are really fascinated and there's a lot of talk about the big question if you like is what causes someone to develop MCAS? Is it a primary condition? Is it genetic? Is it a mutation, a methylation, or is it something environmental? Is it like an infection that they've caught like COVID or gut microbiome? What's going on do you think for people?

speaker-1: That that's a great question and obviously a critically important question because if you don't understand what's causing it, then it's very easy to go trying treatments that have little chance of helping. there are some fairly rare MCAS patients in whom it truly is an autoimmune disease where Certain auto antibodies targeted against the mast cell can attack the mast cells and drive activation of the mast cells. Those those patients are fairly rare. And there are some ⁓ actually there are many patients who have other diseases where mast cell activation is a consequence of those other diseases like various infections or cancers where There's just a natural heightened activation of the mast cells in response to the infection or the cancer that that's further aggravating their symptoms. But the great majority of people who have MCAS, at least from my experience, ⁓ and what we've been seeing so far in the literature, it appears to be that it's various mutations in various genes. inside the dysfunctional mast cells, various genes that are of importance in regulating the behaviors of the mast cells, that it's these mutations which we've learned from the research, a highly different set of mutations. It's usually not just one gene, it's usually multiple mast cell regulatory genes that are mutated, but a highly unique ⁓ set of genes and mutations in the individual patient. And this is probably why the disease behaves at a superficial clinical level so differently from one patient to the next. But fundamentally, it's mutations in the various mast cell regulatory genes that seem to drive ⁓ the misbehavior of the mast cells, both at a sort of chronic baseline level as well as abnormal reactivity to. Assaults upon the body, you know, infections and traumas and other stressors. but ⁓ to be clear, we're not saying that these mutations are inherited. We know from the research so far, the preliminary research, they're almost never inherited. And in fact, they're usually acquired ⁓ mutations at various stages in a mast cell patient's life, typically starting pretty early. But as the patient's life goes on, then from time to time, Usually shortly following major physical or psychological stressors, there's potential for them to acquire additional mutations in the stem cell, the mutated stem cell that of course is the progenitor for the actual mutated mast cells themselves, because the mast cells are derived from a stem cell. But there's ⁓ from time to time there are additional mutations that hit these mutated stem cells. And this then leads the further mutated mast cells to to misbehave even more egregiously. And this is how the disease acquires its natural lifetime course of periodically just stepping up its baseline level of misbehavior. So th they're not by by and large not. inherited mutations that are acquired and we're still trying to learn why and how they get acquired. We're beginning to get some very early thoughts on that. I can talk about that in a minute if you want, but and we're even and we're not even saying that these are mutations that are in every mast cell in a mast cell patient's body. They're not. I mean the fact is the mutated stem cells are derived from mutated stem cells. And no, it's not all the stem cells that are mute. It's only a a tiny ⁓ fraction of the stem cells that are mutated. and it's a real testament to the Potency of the mediators that are getting inappropriately released from these mutated dysfunctional mast cells, that such a small amount of these mediators are being released inappropriately from such a small number of these mutated dysfunctional mast cells, and yet the symptoms can be so profound. You get a real healthy respect for the potency of these mediators when you think about the basic. Mathematical aspects of this. So this is what the ⁓ the preliminary published research is showing is usually going on. And the one mutation that you find in the large majority of cases of mastocytosis, that that incredibly rare cancerous disease of the mast cell, you almost never find that mutation in MCAS. ⁓ when you do, you you call that MCAS monoclonal MCAS, ⁓ different name for it, even though as far as we know it behaves the same as every other form of MCAS. But the fact is, it's this huge potpourri of acquired mutations, ⁓ very different from one patient to the next. It seems to be what's driving the disease. Unfortunately, the only mutation. That we can actually routinely test for at present in most clinical laboratories around the world is that one mutation that shows up fairly reliably in mastocytosis. But it's almost never seen in MCAS. And therefore, even though in the research laboratory we can virtually always find all these. Acquired mutations in some fraction of the patient's mast cells at the clinical laboratory, that testing's not available. So we're kind of forced at present to technically declare most MCAS patients to have mast cell activation of unknown cause. So in other words, idiopathic. Mast cell activation syndrome. So that's the diagnosis that has to be assigned to most MCAS patients at present. But it's just because that the testing that's been in a very few research laboratories around the world for the last 20 years to that can identify these mutations, that testing has not yet migrated to any of the clinical genetics laboratories. One of the highest priorities ⁓ that I think ⁓ on the research agenda for this field is that as soon as this ⁓ testing begins to migrate to any of the clinical laboratories, then we need to immediately begin routinely running this genetic testing on these patients to start amassing a data bank. Of which mutations are present in the mast cells in which patients, so that we can not only start correlating which mutations seem to drive which symptoms, but also, and probably even more importantly, start correlating which mutations seem to respond best to which particular treatment. So we can start getting away from the whole. trial and error ⁓ business, which comprises 99% of our treatment efforts in these patients, and we can instead start much more smartly and reliably predicting which treatments are likely going to best help which particular patients based on which particular mutations are at the heart, the root of the misbehavior of their mast cells. But At present, unfortunately, I'm from what I'm seeing in the laboratory market, I'm still maybe I'm pessimistic about this, but I'm still expecting it's gonna be at least another ten or twenty years before this testing even begins to migrate ⁓ to any of the clinical laboratories. I've told ⁓ most of my patients in whom we've established a clear diagnosis that I said the the The first clinical laboratory anywhere in the world that begins to offer this testing. Yeah, I want to send you and all of my other thousands of mast cell patients to that laboratory on day one. ⁓ it'll be a very long line at the lab that day, but I want to start learning which mutations are in which patients for these reasons I just outlined to you. And I think it will be a absolute breakthrough in this field. ⁓ diagnostic ⁓ right now, you know, finding the elevated levels of the mediators, this is very technically challenging testing. I'll be the first to acknowledge this. and the genetic testing, once ⁓ the the genetics laboratories begin adopting the techniques that have been discovered in the research laboratories, and it's really not all that challenging a set of techniques. It's just that the laboratories, they don't know anything more about MCAS than anybody else. They they don't know it exists. So they think the only mast cell disease is mastocytosis, a very rare disease, why would they go to any effort to develop new testing techniques for a mast cell disease that they assume is so rare? But once the technology actually ⁓ starts Getting adopted in the genetics laboratories, that's going to be a far easier way to get the laboratory evidence that proves the presence of MCAS in the patient. ⁓ And then we will be able to start identifying all these different variants of MCAS ⁓ and just get a whole lot smarter about understanding why the disease is operating the way it is in that patient and. what we can specifically do for that patient that is gonna be most likely to help that patient. It's gonna be utterly transformative, but we've gotta get the the commercial laboratory industry to understand the existence of this disease, just like we have to get the medical profession to understand the existence of this disease, and the f the the pharmaceutical industry to understand the existence of this disease. And you know, with all those changes, ⁓ obviously that's going to be transformative ⁓ for what maybe 20% of the population. ⁓ all in due time. All in due time, as they say, it it never happens as quickly as you as we all might prefer. You know, that old proverb, the journey of a thousand miles begins with the first step, and the last 20 years or so, we've just been taking some very

speaker-0: Be good.

speaker-1: tiny initial steps, but already, in spite of the challenges of the testing, in spite of the challenges of figuring out the optimal treatment in the individual patient, nevertheless, we're already seeing so many patients who are getting so much better. Patients who previously would have gone cradle to grave, seriously unwell, dismissed as psychosomatic, and now we can diagnose them, we can treat them give them a a more comfortable and more productive ⁓ remainder of their lives. So we're we're making progress.

speaker-0: But the whole genetic thing would be a complete game changer wouldn't it? And as you say, you could then tailor treatments and work out which treatment might work better for one person than the other rather than this guessing that we have to do now. I'm fascinated by the causes of these acquired genetic mutations. What are those in brief? you summarize it? I'm sure it's incredibly complex.

speaker-1: It it it actually is incredibly complex and and we're just at the very beginning of gaining an understanding of what's probably going on here. But I mean we we've long known that there's a strong familial propensity for MCAS. ⁓ once you found the disease in one member of a family, the odds are about seventy-five percent that you will find it. In at least one first degree blood relative. If you go looking for it, the odds only go up from 75% if you expand the search beyond the first degree. And yet, when you actually run in the research laboratory, you run the genetic testing in the mast cells, ⁓ in the different affected members of an affected family, you find there are different mutations. And yet, if there's a familial propensity, then something must be getting inherited. But we know it's generally not the mutations in the mast cell regulatory genes. And we're just beginning to gain a sense in roughly the last ten, fifteen years that it's not genetic mutations that are getting inherited. And rather ⁓ there's a whole nother set of sort of ancillary genetic type information, ⁓ not the genome that's in us, the the the DNA sequence ⁓ in us, but the Epigenes, the epigenome. It's a set of molecules that modify the DNA. and the pattern of the epigenome in the individual patient is as unique as the genome is, and the epigenome is inheritable just like the genome is inherited. And you can understand that with regard to the genes, the genome that we understandably have evolved over millions and millions of years. We have evolved very good mechanisms at the molecular level in our body to ⁓ you know, th there are trillions of DNA replication events going on in our bodies every day as millions and billions of cells divide and It is inescapable that even though DNA replication ordinarily is a pretty robust process, in the reproduced strands of DNA, you get new strands that almost always are identical to the initial strand. But nevertheless, if you have trillions of DNA replication events going on every day, then obviously there are going to be occasional errors. In fact, all of us Are developing mutations in various cells in our body, millions of mutations every day. And the only reason we don't all devolve, ⁓ probably while we're still in the womb, into balls of cancer as a result of all these mutations ⁓ that are constantly developing is that we have developed mechanisms for monitoring the integrity of our DNA. And these mechanisms, when they're operating normally, they detect the emergence of a mutation very quickly and then either repair it, or if it's a type of mutation that is not reparable, then that cell is very quickly routed down a cell suicide pathway. The cell just dies and that potentially dangerous mutation can't persist. That's the normal mechanism, but Turning out that ⁓ a lot of that activity for monitoring the integrity of the DNA and repairing the mutations is actually handled by products of the epigenome. And you can get mutations in the epigenome just like you can get mutations in the genome. And when you develop mutations in the epigenome that happen to affect the integrity of the DNA monitoring and repair mechanisms, then you're no longer going to be catching the mutations and repairing them as robustly as you were doing in the normal situation. And mast cell disease is not the only example of what we're beginning to see as an epigenetically ⁓ rooted disease. ⁓ It's beginning to look like it's various mutations, ⁓ epigenetic mutations that are allowing mutations in the genes, ⁓ you know, at the DNA level to persist. And when that happens, and it happens to be a mutation in a gene that ⁓ is in a stem cell, and it happens to be a gene that is of relevance to the regulation of the mast cells that can be derived from the stem cells, then you've got misbehavior of the the progeny mast cells. and welcome to MCAS. That's what we're just beginning to think is going on. And I have grossly oversimplified it, but

speaker-0: Yeah, I'm sure it's fine.

speaker-1: We'll come back in I don't know a few centuries and maybe we'll have made some significant progress in really understanding all this and figuring out how to fix it. ⁓ but we got a we got a long way to go.

speaker-0: It's a long way to go. It's incredibly complex, isn't it? But that's really fascinating. Thank you so much for explaining that. Can I ask about... A lot of our community members are kind of trapped in a bit of a cycle where they're massively inflamed and they're struggling to onboard anything. They're reacting to everything that they try. They may have, you know, nutritional deficiencies, anemias and things like that, but they just can't get any foods or supplements in. How do you start with that kind of complex picture? Where do you break that cycle of inflammation?

speaker-1: I mean, I'm sure different physicians who are familiar with MCAS have different approaches to doing this. Nobody has written the book yet that defines the the one right way, the one best way to to do this. And it may well be there is no one best way. Nobody would be surprised about that given how variably the disease behaves. But I've learned over time. You can always find exceptions, of course, but in general, I consider step one toward gaining significant improvement in these patients to actually be no particular treatment at all, and rather to identify the patient's triggers as precisely as you can, and then do your best to avoid them, because it's actually kind of hard for any drugs to gain good sustained control. Over dysfunctional mast cells as long as the patient is continuing to ingest or otherwise expose himself/herself to a trigger. Yes, over time, as they come to gain better control over the disease, they may well manage to regain some measure of tolerance to things which previously have become intolerable. In fact, I saw a patient, I saw two patients just yesterday. Who had ⁓ just with some early treatments had regained remarkably improved tolerance to many things they had long found intolerable. But that's over time. So to begin with, identify the triggers as best you can, do your best to avoid them. And in many patients, they keep diaries on this to better highlight the patterns of them. In some patients, it's various substances or various activities or various ⁓ stressors or various physical forces that can be ⁓ triggers. Those are very common ⁓ triggers. But given that you brought up the point of patients who are reacting to everything they're trying, I w I think it's important to understand for any patient and any doctor attending to mast cell patients, they need to understand that Reactions to medication products that are being newly tried in a mast cell patient, that's actually a pretty common circumstance. But when that happens, it's almost never the drug triggering the dysfunctional mast cells. It's almost always one or more of what we very generically call the excipients. The fillers, the binders, the dyes, the ⁓ preservatives. I mean, these are the ingredients that are almost always labeled as inactive ingredients. And I've learned to hate that term because yes, they're inactive for most people, but for a mast cell patient, any excipient that is, of course, not a natural constituent of the human body, like water or salt, has potential. To be regarded by a dysfunctional mast cell as a threat that is going to drive immediate ⁓ further activation of the mast cells, sometimes in subtle fashions, sometimes in very egregious fashions. ⁓ And so when a patient is trying a new product and within the first few doses, they start having an adverse reaction. You don't go giving up on the drug. Just because they had an adverse reaction to the first formulation of that drug, instead you look at the ingredient list, you do the best you can, and I'll be the first to acknowledge the challenges in this, but you do the best you can to identify which excipient is likely the troublemaking trigger. And then you work to find an alternative formulation. Whether commercially available or compounded. And I know in the UK you don't have many compounding pharmacies. That's another challenge for dealing with this disease in the UK. But ⁓ nevertheless, you try the alternative formulation, and if you have a better experience with that product, you just proved it's not the drug that's the problem, it's the excipient. And at that point, it's the excipient that goes on the patient's allergy list, not the drug. And frankly, at that point, you then have to look at the full ingredient list for everything else the patient is taking to make sure they don't contain even a trace amount of that triggering excipient. Cause let me tell you something, mast cell patients, as they know even better than I, they can easily go from looking and feeling the picture of health to looking and feeling like death warmed over within minutes, sometimes even within seconds of exposure to even a trace amount of whatever it is that's a trigger in them. So step one. I recognize all the challenges in doing this, but there's no getting around it. Step one now and for the rest of the patient's life is to identify the triggers as precisely as you can. Do your best to avoid them. I'm well aware of the challenges in doing and I have I tell my patients, I have no expectation that every time you have a flare that you're going to be able to identify what the trigger was. In fact, I expect That for most of your flares, you probably won't be able to pin down what the trigger was. But if you don't even try, then the outcome's going to be a foregone conclusion because you will continue exposing yourself unknowingly to a trigger. And you will continue having flares of the disease no matter what drugs you're taking. In mast cell disease, triggers always trump drugs. Drugs never trump triggers. I mean, Not not fully. You you may be able to make some progress controlling some symptoms to some degree using some mast cell targeted treatment, even while you are still exposing yourself to a trigger. But I promise you, you'll never find the maximum amount of benefit that that drug could bring you for controlling the disease if you keep exposing yourself to a trigger. Mast cell patients and their doctors alike ignore. Or discount the significance of step one at their peril. And this happens not only with medication products, but ⁓ I have no end of patients coming to me and say, ⁓ I I I've been found to be deficient in vitamin D, but I can't take vi I react to vitamin D. And I point out to them that the vitamins are called vitamins because they are vital for human life. If you actually started reacting to vitamin D, you would have died a long time ago. So by definition, you're not reacting to the vitamin D, and instead, there's some excipient. Now, if you're lucky, the troubling excipient will be one of the known listed other ingredients in the product, but it's always possible. And this is why I prefer the term excipients. It's a little more generic than just the listed inactive ingredients. But it's always possible there are unknown, unlisted, sort of by definition contaminating ingredients, and there's the possibility that the patient might be reacting to that. But I promise you, you're not reacting to vitamin D. Okay. and if you, together with your pharmacist and the physician, you're all sufficiently diligent in trying enough. ⁓ alternative approaches to getting vitamin D into you, then yeah, you're gonna find success with that, you know?

speaker-0: It's that diligent patient trial and error.

speaker-1: So that's step one. Step two is finding their optimal H1 blocker, ⁓ histamine H1 receptor blocker, and optimal histamine H2 receptor blocker. I've learned that for reasons we are nowhere close to understanding, most mast cell patients have considerably different experiences with different H1 blockers and different H2 blockers, even though obviously all the H1 blockers are engaging with the same receptor. And the same with the H2 blockers, but nevertheless, each drug is a different molecule, and the different molecules engage with these receptors in slightly different fashions. And for many patients, it makes a big difference. And so I asked my patients to systematically try the different available H1 blockers, find their best one. And similarly, I'm really oversimplifying here in the interest of time, but and then find their optimal H2 blocker. And then they've got their optimal antihistamine regimen. And we usually have them start with that because the fact is most of these patients do find significant improvements in at least some of their symptoms with some combination of H1 and H two blocker. And these drugs are cheap and they are long-term safe. So since you have to start your trials of these fortunately great many drugs that have been found helpful in various mast cell patients, somewhere, it kind of makes all the sense in the world to start with the antihistamines. Yes, there are occasional patients who have particular reasons why they would rather start with something else. Everybody's different. But for most patients, starting with the antihistamines as the first pharmacological maneuvers toward controlling the disease, it's an eminently A sensible place to start. So that's step two. And then as I tell my patients, steps, and I'm not trying to make light of the situation. I understand the gravity of this, but nevertheless, steps three through N are to try. Try, try, try, try, try, try, try, try the many, many, many, many other drugs which have been found helpful in various mast cell patients. ⁓ yes. At present, lacking any better understanding of the size, the biology of this, not being able to reliably predict which drugs are going to best help the individual patient, I'll be the first to acknowledge 99 plus percent of this is trial and error, where where the the decision making as to the sequence of trying these different drugs in the individual patient is guided largely by the experience acquired. From having seen many other patients. Not any published studies. There there aren't. But when you don't have any studies at all, it's not like the anecdotal experience is completely worthless. I mean, I I I do understand that this is at least in part of my ego talking, but I'd like to think I've gained at least some clinical gut intuition. Across having ⁓ seen, you know, thousands of mast cell patients over the last 18 years, I'd like to think I've gained at least some intuition as to which drugs tend to be helpful for which types of symptoms and which types of mast cell patients. So for my individual patient, when I see particular symptoms, particular features, I just tend to think, well, let's try these particular drugs sooner rather than later. ⁓ but you can imagine that with the symptom profile being so different in different patients, it's usually a considerably different sequence of treatment trials we go through.

speaker-0: Can I ask, what about neurological symptoms? Because a lot of our community find, you know, a lot of horrible neurological symptoms which are not well understood. Do you find a particular treatment better for those patients or is it there's no rhyme nor reason?

speaker-1: No, I think the antihistamines ⁓ many times can be helpful. Obviously, ⁓ many of the H1 blockers, because of their chemistry, they're not even able to penetrate into the central nervous system. Those are the so-called non-sedating atrium blockers. So with patients with a lot of central neuronal issues, it's always possible that the ⁓ the the atrium blockers that can penetrate into the central nervous system, not at the higher dosing levels that Will bring sedation, but at lower levels can be more helpful than the non-sedating atrium blockers. For some patients, chronic use of low doses, ⁓ not non-addicting doses of the benzodiazepines can be helpful for some patients. ⁓ we're finding an increasing number of patients in whom the GLP1 receptor agonists ⁓ can be helpful. But many patients and their doctors struggle to understand why they're having all these central neuronal issues. But again, once you come to understand the not only the biology, all these hundreds of mediators that the mast cells are producing, but you also come to understand the anatomy of this disease that is not taught in train in that one minute in training, once you understand it, it makes all the sense in the world. Cause if you ask yourself, Well where are the mast cells in the body? Well, in truth they're everywhere, but in most tissues in the body very sparsely distributed. I could do a random biopsy of most tissues in the body. I'd be hard pressed to find even a single mast cell under the microscope. Where the mast cells are dominantly found is at the environmental interfaces, so the skin, the respiratory tract, the GI tract, the genitourinary tract, the They're at the environmental interfaces and directly abutting all vessels and all neurons, peripheral and central. So it's common for mast cell patients to have a lot of central neuronal problems. And I I really don't care whether you superficially categorize any such central neuronal problems as neurologic problems or cognitive problems or psychiatric problems or dyautonomic problems like, you know, temperature and blood pressure and pulse control and sleep control and hunger control, appetite control, ⁓ all these automatic systems. I don't care how you superficially categorize any of those issues. They're all central neuronal issues that are coming about because one group of central neurons or another is not behaving normally. and is producing those symptoms, but it's not happening because there's anything fundamentally wrong with the neurons. The neurons are normal, but they are just constantly reacting as they are genetically hardwired to do. They are constantly reacting to the constant assault of these incredibly potent inflammatory mediators that are constantly emerging to one degree or another From the literally adjacent, fundamentally dysfunctional mast cells. You got not only billions of neurons up here, you got millions of mast cells. And so at that point, it just becomes a matter of which particular mediators are hitting on which particular neurons that determines which particular central neuronal symptoms the individual patient is going to be suffering at any point in time. ⁓ and it's parti I mean the the the mediators being released by mast cells elsewhere in the body, there actually are multiple mechanisms by which they can th those mediators also can come to impact the neurons up here. But you can understand that it's dominantly the mediators coming from the mast cells up here that are impacting the neurons up here. And once you can gain better control of those mast cells, then you see a remarkable improvement in These neurologic and cognitive and psychiatric and dysautonomic ⁓ symptoms.

speaker-0: Yeah, that makes perfect sense. Thank you so much for explaining that. I think that will be helpful for a lot of people because they think, am I going mad? These symptoms, you know, my brain, but it makes sense as you say when you understand the mouse cells.

speaker-1: I understand they're feeling the way they're feeling. I mean, the anxiety disorders like ⁓ you know, anxiety and panic and obsessive compulsiveness, ⁓ the anxiety and the mood disorders, ⁓ dominantly depression, but sometimes other mood disorders, are some of the most common psychiatric issues we see in this disease, but it's not because it's a primary psychiatric disease. It is a secondary psychiatric disease. It's coming about because of the Primary mast cell disease. So again, I told you before that every doctor has been seeing this left and right. And when I say every doctor, I mean every doctor. And that absolutely includes psychiatrists, you know. And I do know a very few psychiatrists who have begun to understand all this, and they are tickled. At seeing the improvements they're seeing in their psychiatrically ill patients who previously had proved refractory to so many different psychiatric treatments, but then you get the mast cell disease identified and controlled. And it's sort of amazing how much better these patients get. ⁓ but that's just a few psychiatrists. And I could say the same thing about every other ⁓ domain in medicine at present. Come back in 50 years. ⁓ I mean, we were talking just before we started the recording that I'm aware now that in just ⁓ just last year, the very first medical school anywhere on the planet, ⁓ the the very first formal lessons in medical school about MCAS began ⁓ here in the US ⁓ in 2025. But that's just one school. And that's just the medical students. And ⁓ so it's gonna be a l I mean, come back in fifty years. Every doctor coming out of training will know about this disease. Like today they come out of training knowing about, you know, diabetes and hypertension, but it's gonna be a long time getting there. So I understand the frustrations patients have with their doctors, but go easy on your doctors. They've been doing the best they can, operating within the box that was constructed for them through their long and expensive training. And unfortunately, some of that training, ⁓ sort of role modeling, watching what their superiors, what their their professors or teachers do when they see a situation of a mysteriously ill patient and they they don't know of any disease that can account for what's going on with the patient. Unfortunately a lot of the teaching is to pronounce if the patient is psychosomatic ⁓ or equivalent rather than the far more productive approach to just say, I don't know. And I'm sorry, but I just don't know. And you're gonna have to keep working with other doctors who hopefully are gonna be smarter than I am to help you figure it out. ⁓ I mean to be cle to be fair, there is a real disease of psychosomatism, ⁓ but it's rare. Okay. And MCAS is common. ⁓ so to assume these patients are psychosomatic is horribly ⁓ counterproductive for them. You know, the the psychological damage and the delays in diagnosis, the losses in productivity, yada yada yada, it's it's immense.

speaker-0: It is definitely, absolutely. Finally, I mean you talked about it there a little bit but you know what's happening that gives you hope for the future in terms of drug development or research or organizations

speaker-1: Yeah, I I think that frankly the most helpful thing is the education. I mean, there are a couple of organizations that have developed ⁓ professional societies that have developed to support sort of a consensus one based perspective on MCAS. And more recently, the International Society for Mast Cell Activation Syndromes, ⁓ is MCAS or is MCAS. is another ⁓ nonprofit professional society that opened its doors, so to speak, to support sort of a consensus two ⁓ based ⁓ approach to this. ⁓ and and it's good to see all that development going on. So professionals who are coming to recognize the existence of this and they're looking for peer support and reviewing cases, you know, how do I address this situation? That's you know, trying to pick the brains of the more experienced people. It's good to have these professional networks available. But I'm even more encouraged to see that again, just last year we finally got the first formal education at the freshman medical student level that hit the first medical school anywhere in the world. The disease has been taught to a slight extent at the subspecialty level in the the allergy immunology fellowship training programs for the last few years, but ⁓ it's been largely a consensus one-oriented approach to it. So there may be some limitations on how the graduates ⁓ from those programs are able to help the patients who come to them for for evaluation. But When it finally starts getting taught at the freshman medical student level, and as these young trainees are then working through the next 10 years of their training, and they're going to start seeing lots of patients in whom the rest of the team they're working with can't figure out what's going on, but these young trainees are Then realize, aha, I was taught something that really can explain all this. And those young trainees can then help, you know, older trainees and and and the professors come to understand this. I think there's going to be sort of a an exponential increase in the awareness and the recognition of this. ⁓ once you actually start getting the formal education in at the earliest stages, it's gonna take time, never happens as quickly as we all might prefer. But then, as more of the profession comes to be aware of it, not just the medical profession, but you can understand that at the same time, the pharmaceutical industry, the laboratory industry, all these ancillary fields. will also start to recognize the existence of it. It'll just start getting more and more attention as befits a disease that probably is present in about 20% of the population. And then we're just going to see exponential ⁓ explosion in the ⁓ the education, the teaching, the research, ⁓ the science, the understanding of what's going on here, the development of better diagnostic techniques, better therapeutic techniques. I'll be six feet under long before ⁓ any of that comes to pass, but it's very clear that that's likely going to transpire.

speaker-0: Yeah, that's sort of, yeah. Once the education piece spreads, that's the start, isn't it? And everybody can then start to share that information. And in the meantime, the patients, you know, there are medications, like you say, like the GLP-1 drugs and other medications that are coming online and being repurposed. So, you know, there is still hope because that's going to take a long time. But there are ways that patients can manage their symptoms. in the interim and see improvements.

speaker-1: That's right. Most patients, at least in my experience, they they do sooner or later, piece together some cocktails, usually a stepwise approach. They find one keeper that significantly helps some of their symptoms. ⁓ they try other treatments that turn out to be failures, but over time they acquire more keepers. They come to piece together. What in the end is usually a pretty small cocktail, but a highly unique cocktail of mast cell targeted treatments that really does get them to the goal. I mean, maybe eventually with fancy genetic or epigenetic engineering, we'll be able to cure it, but no, we're not curing it anytime soon. You can't even control such insane complexity. There's no way you're going to get any of these patients feeling perfect if they even had any way of knowing what that feels like. ⁓ you can't even control such complexity well or satisfactorily for a hundred percent of the time. There's such complex biology, there's always gonna be some ups and downs of this. These patients learn better and better over time how to control the flares of this. So the goal is to get them to the point where they're feeling significantly better than the pretreatment baseline the majority of the time. In other words, when they're feeling well enough, whatever that means to them for enough of the time, whatever that means to them, that at that point, it's just not worth it to them to keep trying yet more mast cell targeted treatments in the hope of achieving an even better degree of baseline control over the disease, then at that point, congratulations, you're at the goal. And you likely will sit pretty tight with that degree of I mean, there'll always be some ups and downs, but you'll be upping and downing about a baseline. Going be pretty stable for long periods of time to come. There's always the risk of these escalations soon after a major stressor. and if an escalation happens and the disease worsens, then at that point, if you want to resume trying more mast cell-targeted treatments to regain better control over the heightened symptoms that had emerged at that point, nothing wrong with doing that, and many patients are successful. You may not be able to yet fix the underlying mutations that developed, but the symptoms that are coming about from the inappropriate mediator release, yeah, there there's ⁓ you know many ⁓ pharmacologic and sometimes even non-pharmacologic opportunities for controlling ⁓ that. So Most of these patients, they do sooner or later piece together some cocktail of mast cell targeted treatment that really does get them to the goal. So given that that's possible in most of these patients, why wouldn't you try? I mean, I understand all the challenges, but still, given what's at stake, you know, the patient's health, the quality of their life, why wouldn't you try?

speaker-0: Yeah, if it's your life, you've got to invest in that haven't you and keep trying and trying to find the exact thing that works for you and that's where the hope lies doesn't it? And sometimes it isn't the pharmaceutical kind of answer is it? Sometimes people find improvements through all sorts of things as well, other interventions.

speaker-1: By and large, most patients come to need at least some mast cell targeted pharmacological support to really attain the maximal level of control they can gain over the disease. But you're right, there are some non pharmacological approaches which sometimes can bring very significant improvements in some mast cell patients. So just a challenge of figuring out Which treatments are gonna best serve the individual patient. But you've got the time. The patient and the doctor, they've got the time. Yes, we all would prefer if we could find the optimal treatment immediately, but that's just not the reality of this at present, given the complexity and and and the lack of scientific understanding ⁓ so far of of this. This is much more trial and error, but still. We have so many options that have been found helpful and some cocktail really does prove significantly helpful for most patients.

speaker-0: Yeah and that's where the hope lies doesn't it? They've just got to keep being patient and doing the trial and error.

speaker-1: Th the these are the core, the cardinal principles I teach all my patients and their local treating doctors for managing such an insanely biologically complex disease across the course of a lifetime. Principles of patience, persistence, and a methodical approach, one change at a time, as best as is possible for the simple reason. At the moment either the patient or the doctor starts making two or more changes in the regimen around the same time and the patient then gets either better or worse, neither the patient nor the doctor is gonna have any idea which change is making them better or worse. It's a holy mess, ⁓ to sort out. Yes, everybody in life from time to time faces urgencies, emergencies where The patient and the doctor have no choice but to make multiple changes around the same time. But as much as is possible, one change at a time with these patients and almost every drug that makes biological sense to try for this disease, we figure out in just a month. And so it doesn't take long to figure this out for each thing you try, but you do have to have the patience, the persistence, a methodical approach, one change at a time to work your way through this. But There are a lot of things that make eminent biological sense to try given what we already know about the biology of these cells. There are a great many treatments that make sense to try. So why wouldn't you try?

speaker-0: Yeah, absolutely. This has been so fascinating. Thank you so much Dr. Afrin for your time. If people want to find out more about this, what do you recommend? Where can they find your work? How can they read more about your studies and your research?

speaker-1: Most of my papers in the literature are open access. You know, you can just go to pubmed.gov and ⁓ you know, there are a few books in the field that have been published by various folks. Yes, mine is one of them, but there are others out there too. I think there are fact I know there are a number of ⁓ patient support groups, ⁓ such as ⁓ yours and ⁓ Let me just, I mean you you you plug my book, I'll plug your book. ⁓ the the book that you came out recently, ⁓ that Mass L Action recently published, providing guidance for patients and and their doctors. I I think it's an excellent resource. Kudos to you and ⁓ the rest of ⁓ your colleagues there for putting that together. I think that that's an excellent place to start. And You you read. Yeah, some articles are closed access, but thanks to the internet, an awful lot of information out there is open access. Yeah, well, when you're looking for specific advice on how to treat your individual situation, I understand the temptation to go asking in patient support groups for advice, but when you're getting advice from folks who are not, you know, trained medical professionals. Sometimes that can be some dubious ⁓ advice. so if you have the option, probably better to be consulting with a medical professional who has familiarity with this disease, but I'll be the first to acknowledge it is pretty hard still at present and likely will continue to be that way, to find medical professionals who have any ⁓ significant familiarity with this disease. But Those ⁓ you know, such professionals obviously are the the best resources to consult for decisions about the individual patients' health. But if you're just looking for general information, there are books out there, there are papers out there, you know, go to go to PubMed.gov and just search for mast cell activation syndrome and see what pops up. Yeah.

speaker-0: It's good for patients to understand their own condition, it, and to understand managing triggers and things like that.

speaker-1: ⁓ you know, a lot of yes, a lot of articles in the medical literature contain so much medical gobbledygook that nobody other than a medical professional could understand them. But nevertheless, there's still an awful lot of information in these articles in the peer reviewed professional literature. So a lot of information there that patients can easily understand and that might help ⁓ them, you know, come to understand how the disease is behaving in them and And just set their mind more at ease that they understand why they've been having the troubles they've been having and maybe give them some ideas about how to pursue the matter diagnostically or therapeutically. I mean, it all goes back to that old saying, knowledge is power. And you know, one one I I learned a long time ago, the very worst thing you can have with any disease is pain. But the second worst thing you get with any disease is loss of control. You just don't know what's going on. You can't predict what the future is is gonna be. So gaining the knowledge, gaining an understanding of what's going on and seeing that you do have options for diagnosis and for treatment, this can be enormously relieving ⁓ for many, many patients.

speaker-0: Yeah, absolutely. I completely agree. Yeah, that sense of powerlessness.

speaker-1: It's why education is such a big component of modern human society. I mean, we we long ago recognized the value of education. Whether whether you're getting it from somebody else or you're self educating, ⁓ you know education is is useful.

speaker-0: Absolutely That is well, I am so grateful to you for your time. Thank you so, so much. I've learned so much listening to you. And I really, I'm sure that our community members who will listen to this will get so much out of it. So thank you once again so much for joining us today.

speaker-1: Pleasure and thanks again for the opportunity and thanks so much for all the rest of the work your organization is ⁓ is doing.

speaker-0: Thank you. Thank you so much for listening and being part of our community at Marcel Action. If you enjoyed today's episode, please subscribe or follow for more great conversations. And why not share with someone else who might find it helpful.