insights

On this episode of Pathways to Well-Being, we welcome a pioneer in mast cell disease research, Dr. Lawrence Afrin, to provide insight on treating this complex disorder. Dr. Afrin, we’re thrilled to have you. We’re eager to learn about how you’ve been working with patients in your practice. Welcome to the show. 

Lawrence B. Afrin, MD:
Thanks. Appreciate the opportunity. 

Kalea Wattles:
I know this is a complex topic that is beloved to you in many ways. And like I mentioned, you are a pioneer in this field. We’re so fortunate to be able to speak with you. So to kick off our conversation, I thought we could explore the biologic purpose of mast cells in the body and discuss healthy mast cell function versus an unregulated, hyperactive release. I think we have the potential to villainize mast cells, but they do serve some important purposes. Can you start with maybe a little primer about mast cell degranulation and the release of mediators we’ve heard of like histamine? 

Lawrence Afrin:
Sure, mast cells are there for a reason. Their normal functioning is an important part of our immune system. We depend on them to help us resist and recover from assaults upon the body, traumas, infections, and so on and so forth. The mast cells ordinarily sit in all the different tissues in the body fairly quietly, just sensing the environment around them, largely doing nothing as long as we’re healthy. But the moment they sense an assault upon the body, they swing into action, producing and releasing various and sundry of their many, many, many different mediators, various signaling chemicals, that then waft out into the surrounding tissues. And when they come to dock or bind with other cells in the vicinity, that binding then influences the other cells to begin adjusting their functioning as is appropriate to help the body best resist and recover from whatever the specific insult that was suffered. And the whole system works very well.   

Actually, mast cells are the frontline sentinels of assaults upon the body. They respond to assault upon the body faster than any other type of immune cell. Mast cells actually swing into action in sub-second time compared to minutes to hours for other types of immune cells. And as long as they’re putting out the right mediators in the right amounts, right times, right durations, right places in the body, all is well. And we have an amazing capacity to resist and recover from assaults, but sometimes, at least some of the mast cells start misbehaving. And there can be a lot of reasons for that. But when they start putting out the wrong mediators, wrong amounts, wrong times, wrong durations, wrong places in the body, the other cells and tissues on the receiving ends of those mediators, they of course don’t know they’re getting the wrong signals. They’re just biologically programmed to react in particular ways when particular mediators come at them.  

So, the situation you get with a mast cell activation disorder, dominantly mast cell activation syndrome or MCAS, is that you have all these different tissues and organs and systems in the body that are reacting in ways they should not be reacting at the time. And that doesn’t help us resist and recover from anything. It doesn’t help us maintain or improve health. It actually just makes us sick. And the particular fashions in which any given mast cell patient is ill at any particular point is entirely dependent on which mediators are coming out of these dysfunctional mast cells in which amounts, which times, which durations, which places in the body, so extraordinarily complex system. Most doctors are taught in their, you know, decade or so of training that the mast cells produce a couple of mediators, histamine and tryptase. We have a fairly good idea of what histamine does in the human body, for example, causing itching. But we’ve been studying tryptase for more than 60 years now, and we still don’t really have a good grasp on what the principal role of tryptase is in human biology. And that just helps you understand how challenging some of this research is.  

So that’s what doctors are taught in a decades-worth of training in which they get one minute of teaching about mast cell biology and disease. They get just one minute, because we really didn’t start to understand that mast cell activation syndrome even existed up until about 16 years ago. The only other mast cell disease we knew about for the last century or so was the extremely rare disease, a cancer of the mast cell called mastocytosis, that most doctors will never see a case of in training, in a decade of training, three or four decades of practice. So if you’re never going to see a disease of the mast cell, at least any disease that you know of, then why spend much time in the training? But now that we’re starting to understand, oh, there’s this other mast cell disorder, the activation syndrome, which is incredibly prevalent, now there arises a need for doctors to understand a whole lot more about the biology of this. And it’s turning out what the biologists have long known that the doctors aren’t taught this, not yet. But what the biologists have long known is that the mast cells produce not just two mediators but actually more than a thousand, each of which has a huge range of very potent effects on different, you know, different systems, different tissues in the body. And this is the fundamental reason why this one disease, so to speak, just in a myriad different variants, why this one disease is actually capable of presenting in so many different fashions at a superficial clinical level. 

Kalea Wattles:
I think that was a beautiful introduction. We’re understanding why this is so complex now even with that brief introduction. I want to revisit a few things you said, because I think you mentioned some trivia in there that many of us are naive to. So, number one being that mast cells may release a thousand different mediators. You’re right; we didn’t learn that in school. That is absolutely not common knowledge. The other thing you mentioned, which I thought was fascinating, was that mast cells have a sub-second response to an assault, which, I really had to pause and think about that for a moment, because that is actually profound. When we look at those assaults, well, I know that there’s a wide variety of things that might elicit a mast cell response. What are some of the things that come to your mind first? What might be some of the underlying causes of an inappropriate mast cell release?  

Lawrence Afrin:
Well, the research to date, I mean, please understand, we’ve only known about this disease for 16 years now since the publication of the first case reports. Now, it’s not that it’s a new disease, it’s just a newly recognized disease. And 16 years is not much time for research, and in truth, not much research has been done yet in this area. And I think it’s only fair to characterize all of the limited research that’s been done so far as preliminary. But all those caveats having been stated, what seems to be emerging from the preliminary research fairly consistently in the studies that have actually looked at this particular aspect of the disease is that in almost every MCAS patient, we’re actually able to find—and presently, this can only be done in the research laboratory, not in any clinical laboratories—but we’re actually able to find a bevy of different mutations in various genes inside the dysfunctional mast cells, various genes that are of importance in regulating the behaviors of the mast cells. And the research also makes clear that pretty much every different MCAS patient has a different total set of these mutations. There might be some overlap from one patient to the next, but by and large, each patient seems to have a unique set of mutations. And it’s the totality, the net result of the particular set of mutations that are present in any given patient, that drives a certain baseline level of misbehavior of those dysfunctional mast cells. And we’re not saying that all the mast cells are mutated. In fact, we know that it’s only a minority of them that are mutated.   

And we also know these mutations, by and large, are not inherited. They’re largely acquired at various stages in the patient’s life. And we’re still trying to work out how and why they get acquired. But these mutations create a certain baseline level of misbehavior of the mast cells. And then when you add into the mix the exposures that different people have to different elements of the environment, different things they take in their body, different exposures outside their body that these dysfunctional mast cells will excessively react to, you multiply all these variables together, and you get an almost infinite number of permutations of different ways this disease can behave in different people. 

Kalea Wattles:
So, it sounds like you mentioned that these are largely or appear to be acquired mutations rather than inherited mutations. So as a functional medicine practitioner, I want to believe that there’s some lifestyle factors that we may be able to modify in the future. Do you see that happening? Do you see us getting to a place where we might be able to predict what kind of, you mentioned some environmental exposures? What kind of modifiable behaviors might influence those mutations and make some recommendations in a predisposed patient? 

Lawrence Afrin:
I don’t think we’re anywhere close at this point to be… 

Kalea Wattles:
All right, it was wishful thinking. 

Lawrence Afrin:
…able to. The disease behaves so differently in every patient. There are some general themes to this. I don’t want to mislead anybody into thinking that there’s no way to see any patterns of this. There actually are patterns, and they follow pretty much along the lines of the general types of effects of the majority of the mediators that are produced by the mast cell. I mean, the symptoms of the disease are all consequent to the effects of the mediators. And given that a substantial fraction of this large set of mediators have effects that we would kind of generically categorize as inflammatory, that’s why the chronic multisystem inflammation—to be sure waxing and waning all the time, and there are, you know, acute spikes of inflammatory issues from time to time—but chronic multisystem inflammation is the universal constant clinical feature of this disease.   

A couple of other patterns we often see with this, I say chronic multisystem inflammation plus/minus allergic-type issues. That’s the second broad theme with this disease, because many of the mediators bring about symptoms that we would broadly classify as allergic. And then there’s a third broad theme to this, plus/minus abnormalities in growth and development in potentially any tissue in the body, what we medically call dystrophisms. And I say plus/minus for the allergic-type issues and the dystrophisms because actually there are plenty of mast cell activation syndrome patients who don’t have a speck of allergic-type issues or dystrophic issues in them. And then there are the mast cell patients at the opposite end of those spectrums. There are those, unfortunately, those, thank goodness, fairly few unfortunate souls who, with regard to the allergic-type issues, they are in virtually 24 by seven by 365 anaphylaxis, if you can even imagine such misery. And then other patients who are suffering an extraordinary array of dystrophic issues. Fortunately, almost always benign but occasionally malignant.   

So, you got these vast spectrums of the allergic issues and the dystrophic issues, but it’s the inflammation that is the universal constant to this disease. Now, to be clear, there are lots of other mediators too that have effects that really don’t fit well into any of those three categories. So the disease certainly can drive a lot of other symptoms as well. But if you’re looking for a broad description of the disease, then chronic multisystem inflammation plus/minus allergic issues plus/minus dystrophisms, that’s the hundred-thousand-foot view of what this disease looks like clinically. It’s just that when you dive into the details, the specific inflammatory issues that are going on in any patient, the specific types of allergic issues, the specific dystrophic issues, it is a unique assortment of specific issues in every mast cell patient.  

Kalea Wattles:
Incredibly unique, and really presents some challenges for the primary care doctor who might not see this in practice with frequency. 

Lawrence Afrin:
Although, I will challenge you on that.  

Kalea Wattles:
Oh, they do see it with frequency. They just don’t recognize it, right?  

Lawrence Afrin:
There you go.  

Kalea Wattles:
Yep. 

Lawrence Afrin:
I mean the preliminary—the preliminary epidemiologic research in this area is suggesting that it may be as prevalent as about 17% to 20% of the population. And if you think about the implications of that, it means that every doctor, and I do mean every doctor, has been seeing this left and right all day long, every day, their whole career. They just couldn’t previously recognize it for what it is, because number one, they haven’t been taught that such a disease exists.  

And the other big factor, the other big confounding factor impeding diagnosis is that the biology is so complex that it’s guaranteed to present in a thousand, in ten thousand different ways at the superficial clinical level. And how do you learn the patterns to that? I mean, that’s what diagnosis is, whether you’re a doctor or a car mechanic. You know, you go to school. You learn the different diseases, the way they operate, and most diseases have one or two ways that they operate, whether it’s a disease of the human body, a disease of the car. So then when the patient comes in, you take a history, you do a physical. You may run a test or two. You match up all those data points against your learned database of the different disease patterns, and that’s how you make a diagnosis. And that all works fine for most diseases. But now there comes this disease, and I say that facetiously, because it’s not a new disease, but now we have to start learning how to recognize this disease whose fundamental biology is such that it’s pretty much guaranteed to present in a thousand different ways. I mean, this is a real challenge, not only for individual doctors but, if you think about it, for the educational system, the medical educational system too. How do you didactically teach this in the classroom? How do you even teach it in the clinical training experiences? Especially when the teachers themselves in the education system don’t yet have any familiarity with this. I mean, we’ll get there, you know, eventually, but nobody should fool themselves that it’s going to happen anytime quickly. 

Kalea Wattles:
You know, what almost seems like the pattern is that it defies our pattern recognition, everything we thought we knew? 

Lawrence Afrin:
Well, it can be difficult learning about it on your own. But once you start to understand, like I said, this broad pattern I described a moment ago, and then a patient comes in, and you look at what’s typically a long problem list that the patient has accumulated over the past, you know, 10, 30, 60 years. And so many of the items on the problem list are -itis, -itis, -itis, -itis, -itis, you know, inflammation, inflammation, inflammation in one system, one tissue, one organ after another. And then you look at the allergy list, and you see the patient has quite the array of allergies and sensitivities, many of which really don’t make any sense at all. You know, those drugs are almost always extremely well tolerated. And then you start looking further at the problem list, and you realize there are dystrophisms here that, usually benign and minor, but nobody’s ever explained them before. That’s when you start realizing, “Oh okay, maybe this is the one of those patients.”   

Listen, I’m not about to say that MCAS is the explanation for every patient with chronic mysterious multisystem illness. That’d be dumb. What I’m trying to say is, we now understand that there exists this disease that is capable of behaving in this fashion. So now, when a doctor sees a patient who superficially has these features I’ve been describing, it now becomes reasonable to at least consider the possibility that maybe what’s at the root—or maybe the patient really isn’t so uniquely unlucky as to have coincidentally acquired so many different problems, all of them developing independently of one another. And maybe what’s been going on is just one thing that really is biologically capable of driving most or all of the issues the patient has been suffering.   

I’ve had the great privilege in the last 15 years of assisting a growing number of doctors come to recognize this disease in their first one or two or three patients. And an interesting pattern has emerged in that many of those doctors then take their valuable time to contact me again, you know, a year or two later specifically to tell me, “I can see it now. I’ve been seeing these patients left and right my whole career. I just couldn’t previously recognize them for what they are. But now that I can recognize them, thank goodness there’s testing that’s available to prove that this is what’s going on.” And once a diagnosis is established, it’s like any other diagnosis. You apply the right treatment for the right diagnosis, and the patient actually gets better. I mean, not a hundred percent, but nevertheless significantly better. And you know, what a concept, give the right treatment for the right diagnosis, the patient gets better. 

Kalea Wattles:
Yeah, personalized medicine. That’s what we really believe in here in the functional medicine world. You mentioned that there’s some testing available, and I feel like this is a great source of confusion and intimidation for many clinicians. Will you give us a little bit of insight about what you might be looking for just, you know, at a standard lab workup? And then, what are some other biomarker clues that might signal dysregulated mast cell activity? 

Lawrence Afrin:
Yeah, you know, the standard or…routine testing, you know, routine blood counts, routine chemistries, routine, you know, thyroid function tests and so on, routine nutritional tests, quite often are utterly unrevealing in these patients or at worst demonstrate very modest abnormalities that the clinician knows in his or her clinical heart really can’t even begin to explain the severity of any of the patient’s symptoms. And one instead has to look fairly specifically for the mediators. And you can’t even go looking for just any mediators the mast cell puts out. The fact is the great majority of the mediators produced by the mast cell actually can’t even be measured in the clinical laboratory at present. They can be measured in the research laboratory. That’s how we know they exist. But only a minority can be measured in the clinical laboratory. And of the minority we can measure in the clinical laboratory, the great majority of those are not particularly specific to the mast cells.   

So, for example, yes, I can go measuring in the clinical laboratory a level of interleukin-6, and it’s a potent inflammatory mediator. And if I find an elevated level of IL-6 in the blood or the urine, then yes, there’s a significant inflammatory state in that patient. And yes, the mast cell does produce a lot of IL-6, but so too do a lot of other cells. So if I find an elevated level of IL-6 in somebody, it doesn’t even begin to tell me that the mast cells are the root of the trouble. So instead, you know, you can’t look at the non-specific mediators. It turns out that out of the thousand plus, there are only roughly 10 that we can measure in the clinical laboratory and which are relatively specific to the mast cells, so that’s what we measure. But I’ll be the first to acknowledge this is technically challenging testing.  

There are a lot of biological and logistical reasons why we might go to all the effort and expense to run one round of blood and urine testing on a patient with suspected MCAS. And it’s easily possible we might get back a set of all negative results no matter how symptomatic the patient is on the day that we’re collecting the specimens. But I’ve learned the hard way with this disease. There’s nothing about a set of negative results on one round of this challenging testing that even begins to invalidate, or refute, or negate, even a single element of their histories, which usually have long been at least shouting, if not screaming mast cell activation to any clinician who has actually learned what that shout sounds like and looks like. And again, that’s the problem. It’s an educational problem. Come back in 50 years, every doc coming out of training will know about this like today they know about diabetes and hypertension, but it’s going to take a long time to get there.  

So we run these mediator tests. Sometimes, we find the evidence we’re looking for in the first round of testing. My own style of practice, and I know different doctors have different styles, my own style, I tend to go up to about three rounds of non-invasive testing before we then think about doing something invasive like GI tract biopsies. But honestly, most of these patients have had enough GI troubles somewhere along the way that they already had seen one or more gastroenterologists. They had already had upper and/or lower endoscopies done. They had biopsies obtained. And you know, you can’t go back to old blood and urine specimens to retest them. They have no shelf life. They got thrown out almost immediately. But fortunately, the pathologists hang on to the old biopsies for about 10 to 20 years. And you can go back to the old biopsies and get them retested with the special processing that’s required to see the mast cells there. Because you have to understand what the routine processing that the pathologist applies to these tissues. You actually cannot see the mast cells in the tissues. Well sorry, correction: with the routine processing, the pathologist sees the cells that are the mast cells, but he cannot recognize that they are mast cells because with the routine processing—what clinicians are taught as hematoxylin and eosin staining, H&E staining—with the routine processing, the mast cells very reliably masquerade as other types of cells that are commonly seen in those tissues. And it’s not until the special and frankly somewhat expensive processing is done, CD117 staining tends to be the best, it’s not until that special processing is done on the tissues that the pathologist suddenly realizes, “Oops, it looks like a lot of those cells that I had thought were lymphocytes and plasma cells and macrophages and histiocytes and spindle cells. Nope, what they actually are are mast cells.” But he’s just got no reason to go doing that special and again, somewhat expensive processing unless he’s been told by the gastroenterologist or, you know, whoever is obtaining the biopsies. Unless that clinician has told the pathologist that there is a clinical suspicion of mast cell disease, then the pathologist has no reason to go doing this special processing.  

So I’ve had cases where we were able to go back to biopsies that were sitting in the pathologist’s archive for 20 years. And you haul out those dust-covered specimens, and you take a fresh slice. And you do the special processing, and there it is, there’s the evidence. It was sitting there for 20 years. It’s just that nobody knew to look for it in the past. So I’ll be the first to acknowledge it’s challenging testing, but honestly, why would we expect it to be simple? I mean, if there were anything about this disease that were easy or simple, we would’ve figured it out a long time ago. The only problems left to be solved are the complicated ones, and it does not get any more complicated than mast cell disease. 

Kalea Wattles:
I’m understanding that more and more as this conversation goes on. I have a really great gastroenterologist who I refer to here in the Seattle area, and I’ve actually had their office send me back reports with, I think they report it back as mast cells per high power field is how I normally see it on the report. And I haven’t even had to ask for it. They have just done it. But I hear from other…  

Lawrence Afrin:
You have remarkably… 

Kalea Wattles:
It’s very hard to get them to do it. I mean, is this still controversial or is this becoming more mainstream? 

Lawrence Afrin:
You have remarkably enlightened pathologists or gastroenterologists. I don’t know who’s sparking that testing in your case, whether it’s the GI doctor asking for it or the pathologist just having the insight to do it on their own. But you are very lucky in your area. There is some controversy about this area still persisting. There are some doctors who feel that, I mean, they’ve published that, in their opinion, there is no number of mast cells you could count in a tissue which they would consider to be abnormal, a position which I just respectfully have to disagree with.  

But then, there’s another group of doctors large and growing who, to be fair, the data on this are far less than perfect. There is ample room, ample need for much more rigorous and definitive study in this area. But you piece together all the flawed studies that have been done in this area over the last, oh, roughly 20 years or so. And a threshold of somewhere around 20 mast cells per high power field is probably a reasonable threshold for distinguishing between normal being below 20 and abnormal being above 20. But, you know, it’s not called a mast cell activation syndrome for nothing. And you have to, I mean, all the issues in the disease are coming about not because there’s any increased number of mast cells, but all the symptoms are coming about because of the inappropriate activation of the mast cells, the inappropriate production and release of all these different mediators. And the truth of the matter is that under the microscope, at least in the routine clinical pathology laboratory, there is nothing you can do under the microscope that will give you a clear indication of what the activation state actually is of any mast cell you’ve identified under the scope. So, you know, when we take an increased number of mast cells as a piece of laboratory evidence contributing toward or supporting a diagnosis of MCAS, let’s be clear that we are inferring from that increased number of mast cells that if there is something already going awry with mast cell biology in that patient to lead to an increased number of mast cells, then probably there’s also increased activation of those mast cells. But you can’t actually see the activation under the microscope. It’s the elevated levels in the blood or the urine of these few mediators that are relatively specific to the mast cell; that’s really the definitive evidence of activation.  

So even once I’ve found increased numbers of mast cells in a biopsy or two from one of these patients, it’s my own style to still at least try, make a diligent effort in the blood and urine testing to find at least one or two elevated mediator levels to complement the suggestive biopsy findings. And in fact, the way the diagnostic criteria, at least, there are two different sets of diagnostic criteria out there in the literature at present: the so-called consensus two diagnostic criteria, by which I tend to abide. You don’t even need biopsy evidence to make the diagnosis; just finding elevated mediator levels alone is sufficient. Together with, of course, a history that’s consistent with the disease and absence of any other disease that could better explain what’s going on with the patient. You know, that’s how we make the diagnosis. 

Kalea Wattles:
I’m going to go out on a limb and ask this question to you of, you know, if we collect a really thorough history on a patient and we see that they have migraines and IBD, and they have dermatographia, can we just make the assumption this patient has problems in activation of their mast cells and just treat it? Do we need to do all the testing? 

Lawrence Afrin:
Yeah, that’s an excellent question. And again, different doctors have different styles. I get that. I’ll tell you that’s not my style, and there are a number of reasons for it. But perhaps the most important reason that I strongly prefer to go to quite a bit of effort to obtain the laboratory evidence that will finally nail down the diagnosis per the peer-reviewed published diagnostic criteria, the reason I do this is that these patients, it’s not me they’re having to convince that they’ve got a mast cell activation syndrome. I’ve come, you know, to see thousands of these patients, and as you’d expect of anybody who sees thousands of cases of any disease, I think I’ve gotten to a point where I can smell this disease at a thousand paces. So it’s not me they have to convince they’ve likely got this. But the problem is that with the education about this disease at its present virtually nil state, and the fact that most of these patients are not going to have any doctor relatively close by who has any significant expertise in this disease, and so fundamentally, they’re going to have to be working with their local doctors, not only now, but for the rest of their lives, to manage the issues that come about, the multisystem issues that come about from this disease. So therefore, they’re going to have to be convincing their local doctors for the rest of their lives that they’ve got this disease that most of their local doctors have never even heard of. And even if they have heard of it, they probably don’t have much familiarity with it yet. And my experience has shown that, yeah, these patients can come see me or some other expert in this area. They can get a letter in their chart that says, yeah, they likely have the disease, but there’s nothing that’s going to attest to the patient’s local doctors that the patient really does have a mast cell activation syndrome. There’s nothing that’s going to attest louder than the laboratory evidence. It’s the laboratory evidence that’s going to speak the loudest by far on the patient’s behalf in convincing the local doctors the patient really has this disease.   

And you see, it’s when the local doctors, the other doctors the patient is seeing, when they don’t believe the patient has this or even if they kind of at some superficial level, they accept that the patient has this, but they don’t understand. They don’t take to heart that it’s the root issue. That’s when it starts becoming all too easy for those doctors to start making treatment decisions that are not going to be in the patient’s best interest because of the mast cell disease and the way it behaves. So I’ve learned you’ve got to really convince the local doctors that the patient has this disease that the doctors have never heard of before. And you can imagine that the bar is high for convincing a doctor who’s been through a long and hard education at the hands of, you know, some of the best teachers in the business. And in all that time, all that effort, they were never taught that such a disease exists. The bar is high, and it’s the laboratory evidence that helps best with convincing the other doctors that the patient really has this disease. And it is something that the other doctors, they may not want to have to learn about a new disease, but nevertheless, if they’re going to serve the patient the best, they do need to learn about this disease and how it operates. 

Kalea Wattles:
This makes good sense to me. Data speaks. And like you said, patients have likely been carrying around this narrative that they’re unlucky or that they, that there’s a psychosomatic component, which maybe there are in some folks. But I think that that’s really beautifully stated, that we’re building a case here for better or for worse. We knew that this conversation could go on for days even, and we have one hour. And I know we’re approaching the end of our time together, and I want to look ahead. I know everyone is really interested in, well, what do we do now, when we have our diagnosis now, what do we do? So are there some therapeutic modalities that you’re willing to highlight for us, some of your favorites? I’m sure that, you know, there’s a vast variety of treatment plans that you could choose from, but we’ve seen some research that talk about some antihistamine therapies, things like vitamin C and quercetin, some of our favorites in the functional medicine world. Have you seen any benefit to these therapeutics, or do you have some favorites that you would share with us?  

Lawrence Afrin:
It’s highly different with each patient, as you might expect, because the disease is fundamentally biologically behaving in quite different ways in different patients. We tend to start with, at least from a pharmacologic perspective, we tend to start with the antihistamines, both the H1 blockers and the H2 blockers, because in most mast cell patients, some combination of H1 and H2 blocker really does bring significant improvement in at least some of their symptoms. And these drugs are cheap, and they’re long-term safe. So since you have to start your trials of these many, many, many different drugs that have been shown helpful in various mast cell patients, since you have to start your trials somewhere, it kind of makes all the sense in the world to start with the antihistamines. Yes, there are occasional patients where you can find reasons to start somewhere else. But if you’re looking for generalities, we tend to start, at least pharmacologically speaking, with the antihistamines.  

But actually, I don’t even regard the antihistamines as step one in managing this disease. Step one that I teach all of my patients is to identify their triggers as precisely as they can and then to do their best to avoid them for the simple reason that it’s actually kind of hard for any drug to gain good, sustained control over dysfunctional mast cells as long as the patient is simultaneously and persistently ingesting or otherwise exposing herself or himself to a trigger. I mean, over time, these patients may well regain some measure of tolerance to things that previously had become intolerable. But that’s over time, you know, so to begin with, identify your triggers as precisely as you can. Do your best to avoid them. In some people, it’s certain substances. In some people, certain activities. In some people, certain physical forces. In some people, various physical or even psychological stressors. So the triggers can really be all over the map, and it often takes just an awful lot of diligence in, you know, every time you have a flare of any of your symptoms, then yeah, no, you can’t think when you’re in the middle of a flare, you’re sick. But after you’ve recovered, you have to have the diligence. Many, many patients, what they find helpful is just maintaining a little diary. You don’t have to be elaborate about it. But every time you have a flare of symptoms, then after you’ve recovered, you put a short entry in the diary as to where you had been at the time, what you were doing at the time, what you had most recently ingested, what the weather was like in the area at the time, any noticeable odors or other major sensory stimuli that had been in the area at the time, any major stressors, physical or psychological, they had been suffering at the time. So they may not be able to pin down at the moment what the trigger of that flare of symptoms, but hopefully, over time, the patterns will start to become more apparent.  

So step one: identify triggers the best they can. Do their best to avoid them. And let me also mention in that context another important thing for mast cell patients to understand that’ll last, a good lesson that’ll last them, well, for the rest of their lives. It’s quite common, actually, for mast cell patients to suffer adverse reactions to medication products, particularly fairly soon out of the starting gate, you know, within the first few doses of trying any new product. But when such adverse reactions happen, it’s actually almost never the drug in the product that is triggering their dysfunctional mast cells to further activate and further spew out all these potent mediators that are actually causing all the symptoms. Instead, it’s almost always one or more of what we call the excipients, the fillers, the binders, the dyes, the preservatives, and so forth. Almost always one or more of the excipients is actually triggering the reaction by the mast cells.  

So anytime a mast cell patient’s having an adverse reaction to a product being newly tried, and this even includes refills if you notice that the pharmacist has inadvertently switched you from one formulation of a given drug to a different formulation of a different drug, but when you’re taking a new product and pretty soon you start having an adverse reaction, you don’t give up on the drug. You give up on the product, and then you work with a pharmacist to look at the full ingredient list on the troublesome product. You do your best, do the best you can to try to figure out which excipient was likely the trigger. And I’ll be the first to acknowledge that’s going to be challenging for a lot of reasons, and sometimes there’s a lot of guesswork involved. You do the best you can. But once you finally think you’ve got some idea of what the trigger is, then you work with a pharmacist to find some other formulation of the same drug, same dose that just does not have the suspected offending excipient in the mix. And you try that product, 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 excipients. And at that point, it’s the excipient you put on your allergy list, not the drug. And frankly, at that point, you then have got another job to do because you then got to look at the full ingredient list for everything else you’re taking and make sure they don’t contain even a trace amount of that triggering excipient. Because let me tell you something, mast cell patients 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 for them.   

So step one, identify their triggers best they can. Do their best to avoid them. Step two, identify their optimal antihistamine regimen, and there’s a number of these H1 blockers available, a number of H2s available. I understand why anybody might initially think, “Oh, they’re all just different H1s. They probably all work about the same.” And the same with the H2s. But I’m telling you, it’s been my pretty consistent experience in tending to many thousands of these patients over the last 15 years, when the individual patient actually does the diligence to systematically try the different H1s and the different H2s, they almost always come back from that set of experiments and they tell me, “Oh yeah, no question about it. It’s this particular H1 and this particular H2 that clearly serves me better than the other H1s and the other H2s.” My problem is, I’ve been doing this for 15 years now, I haven’t even begun to figure out how to reliably predict which H1 and which H2 is going to best serve the individual patient. And if they’re likely going to live another few decades, you know, why would you want to make do for another few decades with what might be a suboptimal antihistamine regimen? So it takes, you know, a few months to work through the trials of these different drugs. But if in the end, I mean, many of these patients, they come back, and they tell me their best H1 or H2 is serving them starkly better than even their second best.  

So when you see those sorts of differences, you say, “Hey, take the time. Figure out your best H1 and H2.” And then, I mean, that’s step two optimal antihistamines. And then, steps three through n are to try. Try, try, try, try, try, try, try, and then try some more these many, many, many, many other drugs which have been found helpful in various patients. I mean, some people are so lucky they find very helpful treatment very quickly and cheaply. Others are literally working on this for a few years. But you also have to keep in mind that with almost every drug that makes sense to try for this disease, we figure out in only about a month whether any given drug is going to bring the patient significant benefit or not. And if you get a month or two into trying some drug for this disease and the best the patient can say about it is, “Yeah, I’m maybe a little bit better,” that’s not nearly good enough to warrant keeping the drug in the regimen for the rest of the patient’s life. You got to ditch it. You dump it. You got to be ruthless about it, and you move on and try something else. I learned quite some time ago that it’s a pretty good bet that when the treating doctor and the patient together, the two of them stumble across the particular drugs, that is the particular molecules that just happen to be the right molecular keys for fitting into the particular molecular lock that is the individual mast cell patient’s particular variant of this highly variable disease, they’ll come back in just a month, and the doc will walk in the exam room, and his head’s spin 360 it’ll be so obvious how much better they are.   

You’ve got to be realistic. Very complex disease, there’s no way any one drug is going to fix all their problems. You know, one drug helps some problems over time. You find other keepers that significantly help other problems. And in that fashion, you piece together what in the end is usually a pretty small cocktail of mast cell–targeted drugs that gets the patient to the goal of feeling significantly better than the pre-treatment baseline the majority of the time. That’s the best you can do. We’re not curing this. We’re not going to get them perfect. But most of them have been sick enough long enough in enough different ways that when you tell them the goal is getting them significantly better than the pre-treatment baseline, the majority of the time, they’re delighted with that as the goal. And many of them are able to get back to a good life even though they may not have perfect control over it. 

Kalea Wattles:
It really takes an incredible investigation and engagement from the patient. This therapeutic partnership you’ve described where both the practitioner and the patient have to be diligent in the investigation I think is one of my most important takeaways from what we’ve spoken about today. And it sounds like, I was going to ask you, you know, in your 15 years of experience treating MCAS patients, is recovery possible? But I think you’ve just answered my question, that we can get to an improved state of an improved quality of life. 

Lawrence Afrin:
Now, we are…in spite of how ridiculously immature the state of the science in this area is, I wouldn’t even characterize it as infantile or neonatal. I think we’re at an embryonic state in our understanding of this. But in spite of that, we’re blessed to already have a boatload of treatments that have already been found helpful in various mast cell patients. And I’ve been quite tickled, as you might imagine, to have experienced that the large majority, the great majority of patients who have this disease, if both the patient and the treating doctor, both of them can be sufficiently patient and persistent in working through the trials of these different treatments, patient and persistent and methodical, trying to make one change at a time, you don’t have to spend long with trying each intervention, but you do have to try to do one change at a time as best you can. Because the moment either the patient or the doc starts making two or more changes around the same time and then the patient gets either better or worse, neither the doc nor the patient has any idea which change is making the patient better. Yeah, there are emergencies now and then when the patient and the doc have no choice but to make multiple changes around the same time. You know, that’s life, and you deal with it. But as much as possible, one change at a time, and it just doesn’t take long. So you don’t persist with something for, you know, four months, six months, a year if you’re just not seeing a significant improvement. That is not the right molecular key for fitting into the lock that is the individual mast cell patient’s particular variant of this highly variable disease. So you figure out the keys. And in my experience, most of these patients actually do sooner or later piece together some cocktail. Usually a pretty unique cocktail to the individual patient, but they usually eventually piece together some cocktail that really does get them to the goal that I just mentioned. 

Kalea Wattles:
Well, I think it’s appropriate to close on that note of empowerment. So, Dr. Afrin, thank you so much for being with us. I feel so fortunate we’ve been able to tap into your wealth of knowledge on this topic today. You’ve given us so much to think about, and I hope I can check back with you in 15 years and see how we have evolved in that time. Thank you so much for being on the show. 

Lawrence Afrin:
You’re welcome. Thank you.  

Kalea Wattles:
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