Neha Pathak, MD, FACP, DipABLM: Previously on Health Discovered, we asked how indolent systemic mastocytosis, a condition that can affect nearly every system in the body, manages to hide in plain sight for years. Today, we're picking up where that story usually ends: at the diagnosis. Because for most people living with ISM, finally having a name for what's wrong ISM't the finish line. It's day one of learning how to manage it.

Hi, I'm Rachel Rose. I was diagnosed with indolent systemic mastocytosis in 2009. The thing that triggers my mast cell disease symptoms the most is fragrances and chemicals, and they're almost impossible to avoid. I have big curly hair, and porous hair can pick up more fragrances and chemicals, so I have to often put, like, a hat on my head to go into places like the grocery store.

Rachael Rose: Otherwise, I can have an allergic reaction to my own hair, which is a wild thing to say and sounds made up. I have to ask my friends to use fragrance-free products when we hang out, or to use unscented detergent. I can't go to people's houses if they have Glade plugins.

In indolent systemic mastocytosis, the body creates too many mast cells.

Pathak: These cells, which normally release chemicals like histamine when they encounter a threat, become abnormal and spill their contents too easily. This floods the body with reaction-triggering chemicals even when there's no real threat to respond to. Rachel's describing what that looks like from the inside, a life engineered around a trigger she can't even see.

So what can you actually do about it? I'm Dr Neha Pathak. Answers when Health Discovered returns.

Rose: The medication that I'm on has shifted over time. There are new ones on the market that didn't exist when I was first diagnosed, and those have been really helpful. Other things that are used to treat my disease are mostly designed to treat the symptoms, not the cause of the disease, and so it's like putting a Band-Aid on things, but they do help me not react as severely.

Pathak: That distinction, treating the symptoms versus treating the cause, is the single biggest shift in ISM care in the last few years. The medication that I've had the most success with so far has been the tyrosine kinase inhibitor. It wasn't the magic pill I think that, like, I really hoped it was, but it has made my life a lot easier.

Rose: I bounce back a lot faster from my allergic reactions than I had been prior to that, and that makes life a lot easier.

Most of what Rachel's been taking works downstream, antihistamines and related drugs that blunt the reaction after the mast cells have already fired. The tyrosine kinase inhibitors work upstream on the mast cells themselves.

Pathak: It's the newer approach, and it's the one that's changed the field. And it matters enormously who you're having that conversation with. Finding doctors that will treat you like a person and not just a patient and be like a team player because you know your experience better than they do.

My actual specialist lives in Boston, and I am in the Philadelphia area, so that's obviously a hike.

Rose: So I don't see her very often, which sometimes means that I'm relying more on my local doctor who doesn't know quite as much. I have yet to meet a primary care doctor who's, I think, ever met a patient who has indolent systemic mastocytosis before me.

This predicament, working with a specialist hundreds of miles away, is far more common with a condition like ISM than you might think.

Pathak: Here's Dr Tracy George, a hematopathologist at the University of Utah. We're the only academic medical center around for hundreds and hundreds of miles. So not surprisingly, patients don't wanna travel several hours to get their care here, but their physician can reach out to the center of excellence and be cared for by the original physician.

Tracy I George, MD: You know, medicine is a shared game, and we're all trying to get the best diagnosis for the patient and the best treatment, and we recognize that systemic mastocytosis is a rare disease. That's the reality of a rare disease. The physician who knows the most about your condition may be hundreds of miles away, while your local doctor may be learning it from you.

Pathak: So today, what do these treatments actually do, and how do you know if one is working? What's at risk if ISM goes unmonitored, and what symptoms should you never brush off? And who belongs on your care team when the disease sits on the border between allergy and blood?

While last episode, we talked with a hematologist, today our guest is an allergist and immunologist, Dr Jonathan Bernstein, professor of clinical medicine at the University of Cincinnati and a partner at Advanced Allergy Services and the Bernstein Clinical Research Center. And that's because ISM is both at once a mast cell disease and a blood disorder, and which specialist you land with often comes down to where you live and who's nearby.

Dr Bernstein has spent his career arguing that both are vital to overall success. Welcome to the WebMD Health Discovered podcast, Dr Bernstein. Thank you.

So before we jump into our conversation for today, I'd love to start by asking about your own personal health discovery, whether it's in your work with patients or your research, what questions or issues arose that inspire the work that you're doing?

Jonathan A. Bernstein, MD: My patients are my inspiration. When they come in, you don't know what they're coming in for. They have complex, unexplained problems that they've seen multiple doctors and have had multiple treatment plans, unsuccessful. So this is what inspires me to help them, because thinking outside the box, digging deeper, venturing outside my scope of practice, this is what keeps me engaged and motivated, is to really impact our care of patients.

Pathak: So today we're picking up where the puzzle has already come together. Someone has a diagnosis of ISM. And you heard Rachel at the top of the show. She was diagnosed in 2009, and years later she's still describing normal things like going to the grocery store or a friend's house as hurdles she has to get over.

So now that a patient like that is sitting in your office, what's the most important thing you want them to understand about this condition?

Well, I think important to confirm the diagnosis and to make sure they meet the criteria, and then to stage them based on the type of disease they have. Is it indolent? Is it aggressive? Is there associated hematologic malignancies? Is it more advanced disease? Fortunately, some of the more advanced forms of this disease is very rare, and most patients have indolent systemic mastocytosis.

I think that many of these patients have lived with this for a long time, didn't understand why they're flushing all the time, why they're having heart racing, why they're having dizziness, why they're having bone pain and severe fatigue, and they just think it's something they have to live with.

So I think it's important to reassure patients, to let them know that there is a body of evidence and guidelines and other information that's been compiled to really understand the disease. And now we're to the point where we are starting to develop therapies that target this condition and that can improve patients' well-being and quality of life.

Pathak: As you were sort of listing off the variety of symptoms that someone may have been living with and is sort of anticipating living with into the future, I'd love for you to help us understand the range of treatment options. So are the treatment options going to be helping with a particular symptom, or do we have treatment options that treats the condition so that all symptoms that are downstream—

Bernstein: Mm-hmm.

Pathak: —will also be improved?

Bernstein: Until recently, we've been using just antihistamines and, you know, things that block histamine receptors. There are some drugs that are mast cell stabilizers. They're not approved in the United States. We have to sometimes get them compounded. But, you know, people come in, and they're on all kinds of things, and a lot of times people are on steroids because of the symptoms their doctors give them, and that's something we don't wanna manage these people with.

Bernstein: It's not really recommended. So symptomatically, we've been treating patients with the medicines that we have readily available based on their organ system involvement and what they need. But there are some parts of the treatment just that aren't responsive to these therapies. I mean, some of these patients have skin lesions, cutaneous involvement, cutaneous mastocytosis, very annoying, very disfiguring, but also itchy and problematic.

But some of them have symptoms of flushing and heart racing and dizziness, and, you know, they may have headaches, they have bone pain, they have a lot of fatigue, gastrointestinal symptoms, bloating, diarrhea. I should say that these symptoms can overlap and actually mimic other's conditions, so it's important to make sure we have the right diagnosis.

It's an interesting process, and because there weren't any specific treatments available, doctors did their best treating them symptomatically, but these patients suffered quite a bit. Now, we have more effective treatments which target c-kit receptors, but it's not completely selective. But it is a very good treatment for indolent systemic mastocytosis and very well-tolerated, and it's made a big difference in the lives of these patients who before had nothing.

There is other treatments in the pipeline that are coming down. These are more selective c-kit inhibitors. There's BTK inhibitors that are being worked on. These are all in Phase III clinical development, and there is some data that's been reported recently showing efficacy, but they're still not approved by the FDA in the United States.

That's really helpful in terms of giving us the breadth of symptoms that someone might feel and sort of where treatment is going.

Pathak: But I'd like to take a little bit of a step back, 'cause I imagine that patient that is walking into the exam room that's just gotten this diagnosis, and as you said, really we've dug deep to rule out some of these other conditions that may have overlap. They're learning not only about their condition, but a lot of new terms are being thrown at them.

So you mentioned treatments like antihistamines, which I think a lot of people are familiar with, but then you also mentioned mast cell stabilizers. So help us understand what these treatments are doing.

Well, they're—they work different ways, but they're preventing activation of mast cells. So there's medicines like ketotifen, which is an antihistamine, but it's shown in patients who are taking ketotifen, the mast cells don't release as much tryptase or other bioactive mediators.

Bernstein: So they're stabilizing, and they make eye drops, they make nasal sprays, as well as medicines you can take orally to help with gastrointestinal symptoms. And they don't work in everybody, but they do seem to work better in patients who have systemic mastocytosis.

So then I'd love to dig into another piece that you mentioned, which is the c-kit inhibitor.

Pathak: So that's really more targeting a specific part of that cascade that's causing the mast cells to be abnormal. Can you talk a little bit about that piece of treatment?

So they're targeting this, this mutated c-kit receptor, and in doing so, you can prevent mast cell activation, you can deplete mast cells, and improve clinical symptoms.

Bernstein: And of course, there's ways of looking at what types of symptoms. There's different patient-reported outcome measures. There's objective scales for looking at improvement in response to treatment. That's how we do clinical trials. So, and this is what medicines like avapritinib have demonstrated, and some of these newer agents appear to be demonstrating as well.

Pathak: So you've given us sort of an array of options. How do you decide, what's your sort of algorithm when you have that patient in front of you to decide which of these paths you're gonna go down?

Well, first of all, it depends on what they've tried previously and what their experiences have been, and if they don't have any prior treatment, we're gonna start with antihistamines and see how they respond.

Bernstein: So the most important thing when you're dealing with patients is to provide options, options that are realistic. It's about treating the patient, and they have to buy into it. They have to understand what's going on. Education is extremely important. I love what you said because I do think that when patients are empowered, they become the experts.

Pathak: And so if a patient came in and they said, "Listen, I took the medication, and now my symptoms are only happening 50% of the time," is that success, or is there some other marker that you're looking for?

Well, anything going in the positive direction is good, but when you give a mouse a cookie, they want a glass of milk, and when they want a gl—when they get a glass of milk, they wanna see what's in the refrigerator.

Bernstein: So patients wanna feel better and better. So, you know, so 50% may be a good start, but they might wanna feel like 75%. Maybe they still have some gastrointestinal issues. Maybe they still have some fatigue. They still have some bone pain. So it's not 100%, but it's certainly better. They're more functional.

They're able to go to work. They're able to participate in social activities and leisure activities, so they can focus more. There's still a lot, you know, sometimes they have a lot of brain fog. It's that terminology, cognitive decline, that we have to a—address. So I think it is variable. We try to use, as I mentioned earlier, objective scores as well, patient-reported outcome measures to get a better sense.

Sometimes people are happy with that, and they don't wanna take more medicine. Other people wanna feel a bit better, and depending on the options, they'll consider it.

When we come back, the symptoms Dr Bernstein tells every ISM patient never to ignore, what he's monitoring for behind the scenes, and why bone health turns out to be one of the quiet risks of the disease.

Pathak: More when Health Discovered returns.

We're back with Dr Jonathan Bernstein, allergist and immunologist at the University of Cincinnati. Before the break, we were talking about what better realistically looks like on treatment for indolent systemic mastocytosis. That the goal is a functional life, not necessarily a symptom-free one. But when you accept that some symptoms are going to stick around, you need to know which ones shouldn't be tolerated.

So I asked him what symptoms should an ISM patient never ignore?

If they have evidence of lymph nodes appearing, if they have abdominal pain, if they have severe symptoms, respiratory issues, we'd certainly wanna make sure that we're dealing with indolent systemic mastocytosis and that they're not having a transition to more advanced disease, aggressive disease, or even hematologic malignancies that can occur.

Bernstein: So this requires constant monitoring with blood counts and other screening tests to make sure they're improved. And fortunately, as I said earlier, 80 to 85% of patients stay in that indolent phase, but it can transition and, and can advance or patients can present with that. So I think they shouldn't ignore symptoms.

I think it's always important to tell the, a doctor. I think sometimes patients feel like they're being hypochondriacs if they keep talking about symptoms, but that's really up to the doctor to reassure the patient that they should feel free and comfortable reporting things to them 'cause it may be significant.

Pathak: Now, we've talked about the patient where we've thought through their treatment. We've t—we've talked about a little bit of what their journey might look like on treatment as we get to better symptom control, red flags that they should be aware of. I'm also really curious about lifestyle changes or changes in daily habits that can also play a role in reducing some of the mast cell activation.

Do we have any evidence for different lifestyle or habit changes that might be helpful?

Yeah, some people have advocated certain diets, and there's not a lot of strong evidence for histamine-free diets. But, you know, if patients don't tolerate a food or foods, as long as it's not restrictive and they're able to have proper nourishment, I don't typically harp on that.

Bernstein: But there are times patients come in and they say certain foods seem to, you know, aggravate them, and we try to make some sense out of it and figure out— is this an intolerance? What is going on, and how can we allow them to have a broader selection of foods in their diet? Now, I think that they should really have the same recommendations that we recommend for any patient, good eating habits and exercise and, and, and such.

Pathak: And I imagine stress management is also something patients want to talk to you about. With any chronic condition, we know it can take an emotional toll, but particularly a condition like this where symptoms can feel very uncomfortable. How do you talk to patients around the emotional toll?

Well, certainly there's anxiety that can occur and sometimes depression just because they feel like there's no hope, and so you reassure them, and you educate them.

Bernstein: When you tell patients that, "You're gonna do okay, you're gonna get better, we're gonna help you," that to me is, and to them is, it's like throwing them a life jacket, and they're very reassured and very happy. It makes a big difference when they know they have somebody in their corner that's going to work for them to help them feel better.

But we do address those issues. As I say to my patients, I'm an internist before I'm a specialist, and, uh, I will manage those issues if they need something for sleep or something for anxiety, and we'll address that. This is true of any chronic disease, as you've mentioned, but more so with something that's rare, like indolent systemic mastocytosis and, you know, am I gonna die from this?

And the issue is, no, they're not gonna die from this. We don't want them to live where they're feeling like they're going to die. So we're going to improve their condition, and they should be able to live long, normal lives as a result.

I find also that with my patients that have chronic conditions, particularly chronic conditions that are rare, there is the benefit of frequent check-ins.

Pathak: So whether that's a phone call or being able to communicate via a portal, what is the standard process with regard to checking in with the healthcare team with ISM?

Bernstein: Well, initially, we'll see the patients, uh, obviously for the first visit, and we'll see them more frequently the second visit, and as they start to stabilize, we'll spread the frequency out.

They have access to the portal. They have access to cell phones. But, you know, initially they might be bouncing up and down, but as they start to stabilize and feel better, they become more calm, more comfortable with the disease, with the diagnosis, and so normally I'll see my patients with indolent systemic mastocytosis a couple times a year.

But they have access to me in between, so it's not like they're, you know, have to wait six months. If something comes up, we can see them either through telehealth or in person or just answer their questions through the portal. So, yeah, I think having that continuity of care and that accessibility is very important to patients in general.

Pathak: And what does standard monitoring look like? So aside from seeing your healthcare team, what labs are you checking? What other tests are you doing in—to ensure that someone is not sort of decompensating without you knowing about it?

Bernstein: Well, I like to get a baseline DEXA scan. You know, I like to make sure, as I said, they don't have organomegaly.

I can do that by physical exam, but oftentimes, you know, spleens are hard to feel. I just want to make sure that's okay. We'll get the routine blood work up front, you know, CBC with diff, CMP, you know, make sure they—

If there's other things that we suspect, you know, we want to make sure their liver's fine, their kidneys are fine.

I think a DEXA scan, depending on what type of symptoms they're having, should be done periodically every year or every other year, depending on what the type of disease they have, more frequently. If they have more severe disease, determine if they need to be on some type of bisphosphonate or some other type of treatment.

But if they're on different drugs that might affect liver or kidney function, we want to check that, make sure we're monitoring that over time as well.

Pathak: Yeah, so it's a combination of the testing you're doing is not one to monitor the condition, and then the other piece is to monitor side effects from the treatment.

Bernstein: Mm-hmm.

Pathak: So you're checking bone health through the DEXA because of the condition or because of treatment?

Bernstein: The condition. Patients with mast cells, one of the things released is heparin. Heparin has—causes osteoporosis. It causes bone loss.

Pathak: Oh.

Bernstein: So, so they oftentimes have an accelerated osteoporosis or osteopenia osteoporosis, so we want to monitor that as well.

It's a potential complication.

Pathak: Oh, okay. Really interesting. I, I did not know that. So I wanted to then ask you about when things might shift in a patient's health. So aside from their management of their ISM, if they have another condition, if they need to go in for a procedure or they're going in for a colonoscopy, are there certain things that they should be aware of and ensure that their health professional knows so that it doesn't trigger a mast cell reaction?

Bernstein: Yeah, we obviously we hope that they're stable. If they're having anaphylaxis, which is a severe form of reactions, we might pretreat them for some of these reactions. We wanna make the physicians aware of that. They have to have epinephrine available, things of that nature. But hopefully when they're starting to undergo procedures, they're gonna be relatively stable and they're not having these reactions.

That's the goal. I would say if they have the procedure, if that's the first time, I would probably ask for some biopsies just to look and see what the number of mast cells are in their GI tract. That's useful.

But we do want the doctor who's doing the procedure recognize that they have this condition and that there's emergency treatment available if they should start having worsening of their systemic mastocytosis symptoms, the worst scenario being anaphylaxis and respiratory issues and swelling and such.

But fortunately, it doesn't happen very often, but I think it's something, as a general rule, we have to communicate with the other doctors who are involved in their healthcare.

Pathak: That's really helpful. And as you were talking, I was thinking through who all should be part of an ISM patient's care team. Who is the main point of contact generally?

Should they be looking for a specialist? Should they be working with an allergy immunologist? Help us understand who's part of the care team.

Bernstein: Well, I definitely think a specialist should be involved, one that has knowledge about this condition. Again, hematologist oncologists have always played an important role because they see these patients oftentimes first line.

They do the bone marrow biopsy. Some of them manage the cases, some of them don't wanna manage them, and they send them off to the allergist immunologist for further care because it's mast cell-driven, which is a, a disease process that we take care of.

So it really depends on what part of the country you're in and, you know, the centers and everything else.

So, but it's basically a condition that we share. There's overlap, but it depends on the area. It depends on the availability of good, uh, well-trained physicians in this area.

It's always nice to have patients in a facility where there's also clinical trial opportunities 'cause that advances disease. We encourage patients with this condition to participate because if they want advanced treatments, we have to have newer therapies, and that takes patient participation.

Pathak: Help us understand how someone can recognize whether or not a clinical trial is an option for them.

Bernstein: Right. Patients have different preferences and values, and it's shared decision-making, but if... the important thing is to give them options. But if they're not responsive, then we have to advance their therapy.

But it's not for everybody. It's a time commitment. It does require following certain rules and regulations, and that they don't always get drug initially. They might get a placebo. So there's that element, but a lot of the patients then at the end up on active therapy.

It's important we—to partner with patients with clinical trials because we can't do it without patients, and we can't advance the treatment options.

But we always wanna make sure first do no harm to the patient and help them be part of the decision process.

Pathak: Yeah. I'd like to circle back now to the patient that we started talking about, the person who's newly diagnosed. What is the counseling that you give in that initial session or the first few sessions to help them understand what their quality of life is going to look like over many years?

Pathak: What can they expect? What should they anticipate, and what are the best strategies to maintain a good quality of life? Well, after we characterize them and manage that effectively, they should have a normal life. They should have no effect on leisure activities, work, school, whatever they're doing, and that's what they can expect.

Bernstein: Now, is it 100% for everybody? No, but we should be able to get them feeling like a seven or an eight on a scale from one to 10. And again, sometimes patients feel so better from some symptoms, they-- Like some symptoms like flushing. I had a patient the other day tells me, "My flushing is better, my palpitations are better," and that's what causes anxiety when your heart starts fluttering.

"But I still have bone pain, I still have fatigue." But you know, she had three kids sitting out there, and she's starting to work now. She's gonna be a teacher. She just finished her teaching degree, and she's got kids that she's taking care of, and she's got an active life. But she still has some bone pain, she still has some fatigue, she still has some other milder symptoms that are important and that we need to hopefully address.

But I think the expectations, the reassurance that we give patients that there is treatment options, and that they can have a normal life, and they have a normal life expectancy, and this is not what's going to do them in. And we're going to make sure that they can feel as good as they can be based on what we have available.

Pathak: Really, really powerful, I think, counseling that you're starting someone off on their journey with ISM. And as our time together comes to a close, I'd love to end our episode by having you speak directly to our audience. For someone who's listening, who's recognizing themselves in what we've talked about in our conversation today, what's one thing or one piece of advice you'd offer them that they can do that's actionable this week to better manage their concerns around the diagnosis or their symptoms?

Bernstein: Well, I would make sure you're communicating with your physician who's managing this. If they don't have the, uh, expertise or the wherewithal to help manage this condition, you need to find a specialist in your area, whether it be an allergist-immunologist or a hematologist-oncologist, someone knowledgeable about systemic mastocytosis who can provide you with a background understanding of the condition, do a complete assessment, and to make sure you're on the right therapies, and who listens to you, who actually allows you to talk during the visit.

It's not just talking at you. So we need these back-and-forth conversations to really understand what's going on with you, and we wanna hear from you so we can help you. This is the most important thing. You have to be active and seek care. There is, there's a lot of great things happening in this disease space.

You have to be, you know, assertive to really make sure you get the proper care. Those are great tips for becoming engaged, if you're not already, with your healthcare team to best manage your condition. So I wanna thank you so much for your time, Dr Bernstein. It's my pleasure. Find a specialist who knows the disease.

Pathak: That's Dr Bernstein's advice, and he's right. But if you remember Rachel's story, the nearest doctor who knows anything about ISM might be in another state. So we called someone who spent the last decade building the fix. Dr Tracy George is a hematopathologist at the University of Utah and Huntsman Cancer Institute.

She's one of the doctors who reads the biopsy to make the diagnosis, usually without ever meeting the patient. She's also a founding member of the American Initiative in Mast Cell Diseases, the group behind a network of centers of excellence built for ISM. So for a patient who has a first-time diagnosis of systemic mastocytosis, I think they need to go to a center of excellence or reference center.

George: Those are listed on the AIM website, www.aimcd.net. And there's these centers of excellence all over the Americas right now. I think we're up to 35. And so hopefully there's one near the patient. But I think it's important, especially for a first-time diagnosis. But here's the part you might not expect. Going to one of these centers doesn't mean moving your care there.

Good physicians don't mind getting help. For example, we're located in the Intermountain West. We're the only academic medical center around for hundreds and hundreds of miles. So not surprisingly, patients don't wanna travel several hours to get their care here. But their physician can reach out to the center of excellence.

Perhaps they wanna get, I don't know, the pathology slides reviewed, or just wanna talk to someone, and they can do that, and the patient then can be cared for by the original physician, but they're just getting expert advice from the center of excellence. So that's one way to do it. Or the patient comes to the center of excellence, they get a second opinion, which confirms the diagnosis.

They get some recommendations. Those recommendations go to the treating physician at the original site, and, uh, everything's copacetic. That's how, you know, physicians gain expertise because then they are speaking with the physicians at the center of excellence, and they're upping their game, learning how to care for these patients.

Pathak: A special thank you to our guests. To find out more about Rachel Rose, follow her podcast, Mastcast. And for more information about Dr Jonathan Bernstein, Dr Tracy George, and indolent systemic mastocytosis, including a link to the Centers of Excellence directory and to the Mast Cell Disease Society, make sure to check out our show notes.

Before we wrap, here's what I'm taking away. Treatments for ISM work on two levels. There are therapies that manage symptoms, so that's antihistamines and mast cell stabilizers, and then there are therapies aimed at the driver of the disease itself, the targeted treatments. Define what working means with your doctor up front.

While you may never get back to being symptom-free, back to work and back in your life is possible with a plan for all remaining symptoms. This condition needs monitoring, not just medicating. For example, bone loss. Mast cells release heparin. Heparin drives bone loss, so a baseline DEXA scan is part of standard of care.

And a small number of people do shift toward more advanced disease over time, which is why new lymph nodes, new abdominal pain, or worsening breathing are never something to sit on. Building your care team with purpose. ISM is shared territory between allergy immunology and hematology oncology, so loop in your primary care doctor and make sure anyone doing a procedure on you knows you have this condition.

And if no one near you has seen this disease before, your own doctor can call a center of excellence. You don't have to move your care there. And lastly, advocate for yourself above all else. Rachel put it best. This is their job, but it's your life. Thank you for listening. Please take a moment to follow, rate, and review this podcast on your favorite listening platform.

If you'd like to send me an email about topics you're interested in or questions for future guests, please send me a note at [email protected]. This is Dr Neha Pathak for the WebMD Health Discovered Podcast.