Transcript of the Panel Discussion from the 2005 TMS Annual Meeting
Transcript by Wanda Hermann and Valerie Slee
| Date: | October, 2005 |
| Location: | California |
| Moderator: | Valerie Slee / Marti Wolfe |
| Panelists: | Dr. Cem Akin - University of Michigan Dr. Joseph Butterfield - The Mayo Clinic (Rochester) Dr. Mariana Castells - Brigham & Women’s, Harvard Medical School Dr. Theo Theoharides - Tufts University Dr. Srdan Verstovsek - MD Anderson Cancer Center |
Question: Are there any plans to research urinary tract or GI tract manifestations in mastocytosis patients?
Dr. Theoharides: I am not sure that there are any plans in science, except my colleagues and I have been seeing a lot of patients with symptoms, especially with bladder symptoms, many of which have been classified as having what is called interstitial cystitis, which is a sterile painful bladder disorder. I know many mast cell patients have similar symptoms, some with this diagnoses of interstitial cystitis. I don’t know of any plans specifically to look for such symptoms in mastocytosis patients. But, as I have raised in the past, (actually my colleagues from Sweden and Denmark were first and second, we were third to come in line actually,) having shown that there is local mastocytosis in the bladder with many other symptoms, the question which I am going to address to my colleagues, is, ‘Since one of the major criteria for systemic mastocytosis is involvement of other than cutaneous (skin) tissue, in which case bladder would qualify, in many of these patients have at least two if not all three of the minor symptoms, why don’t we call these patients systemic mastocytosis patients?’.
Dr. Akin: I think that is a good question. I am not in the study of interstitial cystitis to check for the minor or major criteria of mastocytosis. You have the experience. I don’t know if there are plans to publish that data, but I think it would be a very useful study. For example: for someone to look for CD 25 for expression of bladder mast cells, and perhaps look for C-kit mutation and see if they meet the criteria for mastocytosis. I think as you said in your talk, the mast cells are different. The bone marrow mast cell is not necessarily the same as a bladder mast cell or a gastrointestinal mast cell. I think that the Mastocytosis Task Force will encourage those studies to be done. I am not sure that there are specific plans for those studies in the centers but I think those should be done because what we know that is true in bone marrow, may not necessarily apply to in gastrointestinal track. And that is why at this point we do not encourage the diagnosis of mastocytosis from a gastrointestinal tract biopsy, because we simply don’t know what those mast cells do or if they are similar to bone marrow mast cells.
Question: Many of us have problems with dizziness and standing for any length of time. There have been some people on the list that have reported that they have nerve damage in their inner ear that results in vertigo. Is there any relationship between this vertigo and dizziness and mast cell disease?
Dr. Theoharides: There is no evidence that I know of that links the two. Some years back with a colleague of mine, who was a neurosurgeon, actually looked for what is called acoustic neuromas. There are some benign tumors not of the inner ear but it is the nervet, that causes vertigo. Primarily because, and I may lose you here and I apologize, but there is a condition called neurofibromatosis where there is a collection of mast cells in the skin around the nerve endings. There are two types and one type has primarily such acoustic neuromas (benign tumor on the acoustic nerve), so we felt there might be some connection. We didn’t really come up with anything but it wasn’t in a comprehensive study either. The only possible stretching in the relationship we know, is that certain antihistamines are antivertigo drugs. Dramamine(dimenhydrinate) is one. Bonine, also known as Antivert (meclizine), is another. Clearly the histamine has something to do with the inner ear, not that I understand it exactly in what way. So potentially one could imagine that there is actually some dysfunction of cells that release histamine in the inner ear. You might experience problems, but I don’t know of any collection of mast cells in the inner ear either, so this all conjectural.
Question: This is a related question. What about the relationship between POTS which is Postural Orthostatic Tachycardia Syndrome and mast cell disorders. Does one cause the other or are they related in any way?
Dr. Akin: There was an abstract in last years academy meeting which came out of Cleveland clinic by Dr. Fred Shae who is an allergist on their staff, and he wanted to describe elevated tryptase levels in patients with POTS and he did look for evidence of mastocytosis in those patients and he couldn’t find any evidence in those patients, that they met the criteria for systemic mastocytosis; in other words they didn’t have increased number of mast cells, at least in the tissues that he looked at. But they did have elevated tryptase levels. It is not clear where the tryptase is coming from or whether it is involved in the pathogenisis or the symptoms of POTS, things like techycardia for example.So the first part of the question is there is so far no relationship established between POTS and mastocytosis. The only common link that connects those two entities is the elevated tryptase levels. And I do have a patient with POTS that have elevated tryptase levels and has no evidence of mastocytosis. So that confirms that finding.
Question: An article earlier this year asserts that systemic mastocytosis almost always involves the bone marrow. Additionally a former NIH hematologist noted in a June 2000 article that the incidents of marrow involvement in systemic mast cell disease is probably over estimated because many investigators required that presence of marrow disease for the diagnoses of a systemic cell disorder. What is your opinion of this statement?
Dr. Theoharides: I am walking on thin ice here, but I have been a proponent of saying that there are patients that have all the symptoms and that may never actually have had elevated mast cells in the bone marrow to the extent that many other, but not all patients, have had and have certain mutations... (clearly will be worth looking at, as our colleagues said a little while ago,) in suspected tissues other than the bone marrow. If one could at least look for such mutation but then we know that all patients have some mutations so we end up being negative there as well. I would rather there be some classifications incorporated that allows patients that do have all of the symptoms or most of the symptoms or definitive mastocytosis in other organs to be included even if it is a subheading in some way, rather than to have them hanging in the breeze and going from physician to physician. At least their care I think would be a little more focused. But I am not a hematologist and I don’t participate in these meetings so I am out of the loop here.
Dr. Castells: I just want to add something even a little bit of clarification. We do have a task force that I will talk about tomorrow in my talk. The Task Force goals right now would be to define mastocytosis. Not only as a systemic disease but also in terms of a mast cell activation syndrome in which, as all of us know, the patient will not have standard criteria of mast cell involvement but they will have all the clinical symptoms of mast cell mediators release, either by having the mast cells increased in other tissues or just having the mediators in the blood. In those patients, Dr. Akin has already found when he was with the NIH, they may have the mutation of the C-Kit patients or though they might not fulfill the center of the criteria. So I think it is a work in progress. We can say that patients who have a bone marrow biopsy that shows that they have systemic mastocytosis are a clear population. The other ones who have mast cell mediator related symptoms or whatever name we are going to choose for them, are the ones that we are working on. We are trying to define clearly what criteria will be used to define those patients.
Dr. Akin: I think the definition of systemic mastocytosis is a presence of excessive amounts of mast cells in tissue other than skin and that tissue is mostly bone marrow and we can’t go in and biopsy lungs without a good reason to look for increase number of mast cells. We can biopsy bone marrow. Probably it is the most common and accessible tissue site. That is probably why all these studies emphasize the findings in the bone marrow. We also tend to think that mast cells are produced in the bone marrow, so if there is a mast cell abnormality that is going on, it is leading to systemic mastocytosis. It would be also apparent in the bone marrow in terms of these mutational analysis and perhaps abberant surface migrates expressed by flow cytometry. But that marrow may not be correct hypothesis because there are hematopoietic cells outside of the bone marrow like in lung and other tissues and mast cells might be generated out of those tissue derived hematopoietic (blood forming) cells.
Dr. Theoharides: A database was established five years ago by the National Institute of Health for the Interstitial Cystitis Association, and it is called the Interstitial Cystitis Database. Three years ago they published an article where they sent actually 280 biopsies to upstate New York, in Buffalo, blindly to be assayed for any pathological signs of the blood of the biopsy or of the biopsy, and correlated them to clinical findings. The only pathological findings from these biopsies were increased number of tryptase positive mast cells. So this was not done by me, they were done blindly. These were biopsies that were collected, so even though one was not looking as much that we wanted to for mutations, at least there were tryptase positive mast cells and they were clearly elevated. I think there is some indication in other tissues and both a group of colleagues in Maryland and we found that there was actually very high expression of nerve growth factor locally in the bladder. even though the nerve growth factor is known to be a growth for nerves, it is also known to be growth for mast cells. So as our colleagues have said there might be other local reasons why the mast cells are induced to grow in higher numbers locally rather than systemically. We just haven’t looked at these things yet and I think this classification, if it goes through, will open up the door for other findings and other colleagues to participate in such categorizations.
Question: How can a patient in the United States get biopsies from the GI track or another internal organ properly analyzed to meet the WHO criteria?
Dr. Akin: I don’t think we have enough evidence to apply WHO criteria for any biopsies other than the bone marrow, because we just don’t know about the nature of the mast cells residing in those tissues and whether they increase in other diseased states or not. So I think that will be one of the objectives of the standardization meeting coming up in Vienna next month: to define what types of tissues should be analyzed to meet the diagnostic criteria of WHO and to encourage studies of non-bone marrow mast cells and to define criteria for those other tissues sites as well. For example, there is a study that suggests that mast cell numbers in gastrointestinal biopsies are actually lower in patients with mastocytosis than with patients of other diseases like all sorts of colitis. There are other studies that claim the opposite, that they have more mast cells in the GI tract. So which one are you going to believe? That is the dilemma that we are facing now.
Dr. Theoharides: I would like to concur with that for another reason. Even with the bladder, where we have done a lot of work and so have others, the number of mast cells are actually tenfold higher if you biopsy the muscle which is called the detruser urinae (muscle of the bladder), then if you biopsy the lining of the bladder, which is called the urothelium. In the United States, most urologist that I know do not biopsy into the muscle because they are afraid of perforation, bleeding etc… so the numbers are very different. In Europe they are more likely, at least up to now, to biopsy the muscle, therefore the numbers are higher. So it goes back to standardizing, “what are you going to biopsy?” Because if you biopsy one side you might be finding very little, than if you biopsy another. Clearly we have to do that, but I would again be a proponent of saying if someone has symptoms that are reminiscent of what we call interstitial cystitis, (which is basically pain in the bladder, pain in pelvic area for more than 3 months with negative urine cultures for urinary tract infection, frequency and urgency for more than eight times a day) These are tell tale signs of interstitial cystitis, and most good urologist would actually try a cystoscopy under anesthesia and biopsy. It is not mandatory. Under those circumstances, most of the studies have shown an increased number of mast cells, without necessarily indicating as someone having mastocytosis. But it might guide us in terms of the empirical therapy.
Dr. Butterfield: We have seen a very poor correlation between GI biopsies for mast cells and bone marrow. The gut is a big organ. There is a lot of sampling variability and if you ask, say six or ten pathologist what they would consider involvement in the gastrointestinal tract, you might get six or ten different answers, and the only answer that would satisfy many of them would be just “sheets of mast cells involving the entire tissue sample”, otherwise it depends on who analyzes the tissue.
Question: A number of articles have suggested that patients with isolated or a cult bone marrow mastocytosis or patients where only one of two bilateral bone biopsies are positive for mastocytosis are in the early stage of mastocytosis. What does this mean?
Is it possible that these patients will not progress to classic mastocytosis but could remain in their current disease state?
Dr. Akin: That’s a good question. We don’t have any evidence at this point that those patients will progress to full blown mastocytosis. We have just recognized that clinical condition called occult bone marrow mastocytosis is basically described in a group of patients with unexplained recurrent anaphylaxis. They don’t have skin lesions of urticaria pigmentosa, but when we look at the bone marrow mast cells, they do carry those abnormal mast cells in the bone marrow. But when you look at the regular biopsies, they don’t have anything abnormal standing out. It is only when you do the flow cytometric and mutation analysis that you can demonstrate this abnormal clone. So this is why we call it occult bone marrow mastocytosis and it occurs in about a third of the patients with recurrent anaphylaxis episode. So I think it is important to rule that out. Now what we don’t know is whether these patients, if we see them five years later and repeat the bone marrow biopsy, will they have now increase number of bone marrow mast cells and have classic mastocytosis? So far, the few patients that we have been following for 3 or 4 years have stayed at that same stage with no increase of tryptase levels. Some of the bone marrow that we were able to compare did not indicate that they had progressed with the disease. So it may not necessarily represent an early stage of mastocytosis, but it may be a syndrome of it’s own.
Dr. Butterfield: When we looked at these patients looking at one side comparing to the other side, when we did bilateral biopsies, we couldn’t beforehand distinguish any of these patients apart by looking at their symptoms, as many of their laboratory tests were similar when we looked at the involvement when one biopsy was involved with mastocytosis, it appeared that most of the ones that were done on just one side had some of the lower percent involvements of bone marrow, and if we had picked the wrong side to biopsy at that time, we would have missed diagnosing the bone marrow.
Question: If a patient is diagnosed with urticaria pigmentos, wouldn’t that patient have systemic mastocytosis since the mast cells for cutaneous mastocytosis and those in the bone are all produced in the bone marrow?
Dr. Castells: I think it is a very good question. We haven’t been able to answer why this happens: (why some patients with mastocytosis would be limited to skin and others would be systemically involved). What I can say is that there were kids that have urticaria pigmentosa whom we followed for several years and when they reached puberty about 80% of them would actually be cured for urticaria pigmentosa and would not develop systemic mastocytosis. So, although we might think that the mast cells that hone to the skin are the same, they may just have different characteristic and they will not progress into systemic mastocytosis. So, in general terms we cannot say that patients who have urticaria pigmentosa has systemic mastocytosis. That is actually not true. (Whether the mast cells from the patients who would be cured came from the bone marrow, I think it is still possible.) We don’t know what happens. The kids who have urticaria pigmentosa have different mutations of the C-Kit. Some have a different mutation then adults who have systemic mastocytosis, so the mast cell that are in the skin may have grown for different reasons and that is why we are limited by the growth of the kid and the hormones at puberty. Essentially one study that was done at the NIH showed that children with urticaria pigmentosa should not be getting bone marrow biopsies. I think that is a good message that everybody else should understand.
Audience Question: What about adults?
Dr. Castells: That is a more complicated answer because my colleagues will tell you that if the patient has systemic symptoms that involve the GI tract that involve dizziness, episodes of hypertension, there are associated symptoms so that you have a high index of suspicion. Then you actually look for mediators such as tryptase and the tryptase would be elevated, with the cut-off being 20 or above, then ir there are systemic symptoms, then yes, there should be a bone marrow at that time.
Dr. Theoharides: Let me ask you, is the childhood urticaria pigmentosa likely to “disappear” in both boys and girls, or mostly for boys? Following up with the statement that you made.
Dr. Castells: I see probably more boys than girls for urticaria pigmentosa . It disappears in boys typically but I understand that some girls have disappearance of the lesions. I don’t know the proportion, and I don’t know if anyone knows the proportion.
Dr. Akin: There is a slight male preponderous in childhood urtcaria pigmentosa, at 1.5 to 1. But I think boys and girls are equally likely to have regression. We have seen patients in both boys and girls.
Question: My main question has to deal with interpreting the mast cell diagnostics to doctors not familiar with mast cell disease. It has caused many of us heart ache and misunderstanding because as mastocytosis doctors rule out systemic mastocytosis they are not necessarily ruling out mast cell activation disorders syndrome. How can we create a source of information to clarify the process to doctors who are not mastocytosis specialists in terms with what they can do next?
Dr. Castells: That is a whole symposium by itself!
Dr. Butterfield: That is common problem. It is good to have a local physician with whom you can work. Let’s perhaps talk about the mast cell activation syndrome. Frequently when we see patients for evaluation at our clinic and we sample their mediator levels in urine and blood, everything will be fine. They will be stable and feeling relatively well. So we come up empty handed. When we send patients home, we send them with a kit they can send back. They sample their blood and urine at the times of symptomatic. We use that as evidence as to whether or not they have mast cell activation syndrome or a release of mast cell mediators. If mast cells are involved in their symptoms, they got to show their card sometime. They have to get the histamine up, or the tryptase or the prostaglandins, something has to be up at sometime. If they are normal and we see them, we tend to give them mediator kits and we have set it up so that it can be all mailed back in one package with dry ice and then we have a sample when they are symptomatic and they send it back. Then we can use that to go back and write their doctors and say ‘Mrs. Jones had an attack and compared to her base line levels which were fine her prostaglandin went up tenfold and we can recommend ABCD for this. Or her N-methylhistamine and prostaglandins went up and we would make the recommendations for her treatment.
Question: So from the TMS point of view then, do all of you feel comfortable if we have a patient who contacts us and says, ‘I don’t know what to do next. My doctor doesn’t know how to treat this.’ Do you feel comfortable if we refer them to you for advice? Refer the physician, have the physician contact you?
Dr. Butterfield: Sure, we can start with that. But we would have to put in place a method to obtain samples when they are needed and run the tests that we need. Depends on where we are getting the patients in the course of things. Very early on or a long time into their course for example, we can make recommendations and get adequate follow up.
Dr. Castells: I feel very comfortable talking to the doctors. But on the other hand, what we have done in Boston is that we have the patient visit us one time. It does not necessarily have to be with me or any of us here at this table, but to see somebody who does mastocytosis and then refer the patient back to their original doctor. That works actually very well. Then the doctors feel empowered. Once you send him a letter with the description of the disease, what we have done, what findings we have found in the tissue mediators with an explanation of what needs to be done and follow up. I do have a lot of patients that I have seen only once. And I have referred them back to the original doctor.
Dr. Theoharides: What Dr. Butterfield actually said is quite important in having a kit that can be sent with dry ice etc. because many times, samples have been sent by very well intentioned physicians or by laboratories that have absolutely messed up the samples. And also, the patient should not be left with the impression that just because they send a sample, if it turns out to be negative they don’t have a problem. Because as it was amply well documented, unless you have an episode, many times the levels might be normal. You don’t want to have the patients and the physicians basically concluding that there isn’t a problem. So having it organized and having it done with a clinic or labs that have done it in the past makes a very big difference in our mind.
Question: The next section is treatment and prognosis. Does a child who had urticaria pigmentosa but has lesions that have faded and has a normal serum tryptase but still has some mastocytosis symptoms, does that child still need to avoid the medications that can cause mast cell de granulation?
Dr. Castells: I would say yes, of course. I would say the prognosis of the child is excellent. But there may be an association with other things such as atopy (hypersensitivity or allergic reaction). There are 20% of the patients who have mastocytosis who will also be allergic. Essentially we just have to look to see if the rest of the symptoms that are happening or the intolerance to the medications were just based on the presence of those increased mast cells or if there is another mechanism by which the kid might be either allergic or intolerant. I think at that stage there needs to be a visit with an allergist and reevaluation.
Question: What percentage are you seeing of patients who have the indolent form of mastocytosis that do progress to aggressive mastocytosis or mast cell leukemia?
Dr. Akin: In our experience is about 5%. Mast cell leukemia is extremely rare. We see maybe one patient per year diagnosed in the United States. In terms of indolent mastocytosis progressing to aggressive mastocytosis, it is extremely rare. Aggressive mastocytosis is usually apparent at the time of diagnoses. Otherwise, there is still a 5% chance of progressing into the aggressive form.
Question: What potential effects does an untreated mast cell disease have on major organs, such as the heart and liver? Can anything be done to reverse the damage once the mast cell disease has been diagnosed?
Dr. Castells: What I would like to say is that the untreated mast cell disease, in what we call a mast cell attack, could potential lead to variable pressure, what we call hypertension. At that time we would have what we call an anaphylaxis event in which the kidneys and the liver shut down and that is an acute event, so very progressive. It is a severe dramatic event that can happen when the blood pressure goes down. That’s acute and if the patient recovers from that, there is actually and typically not really sustained damage after that. I would say that an acute attack during mastocytosis should not lead to permanent damage. Now having said that, with the continuous and progressive release of mediators, such as the tryptase and the histamine in the blood and in other organs, we do really not know in the long term if there is any progression, if that remodels certain tissue and if there is any long standing effect. We follow very carefully, we look at liver enzymes and we see the progression: are they up? is the liver doing well? but again, it is on a patient to patient basis.
Dr. Theoharides: This basically is a question that might answer, to certain extent, the original question. With those who have bone involvement, whether it is osteoporosis or other wise, don’t you see a progression of that problem? At least from my limited experience, it seems that those patients do progress. They have more involvement of osteoporosis etc….
Dr. Castells: Yes and they can be fractures of the bones. The infiltration of the mast cells in the tissues can lead to further damage that is absolutely correct. What I want to say is that the progression of the disease is very variable amongst patients and following tryptase levels might help in some instances but it is definitely not a marker of the liver being damaged or the bone being damaged. Each organ has to be looked at separately. The clinical symptoms are the ones that dictate what we are going to be looking at. Some patients we will have to look at the liver, some patients at the bone, some patients at the skin or even the heart.
Dr. Akin: And usually the liver damage and the internal organ damage in fibrosis that you see in mastocytosis usually occurs in patients with aggressive mastocytosis. It is unusual to see a patient with indolent disease to have significant progress of liver damage.
Dr. Butterfield: Many of these problems can be treated to some degree now any ways. For example: the bone problems and osteoporosis as well as many of the symptoms having to do with liver infiltration and large spleen, such as hepatosplenomegaly and ascites. Many of these problems can be treated as well. It is worth considering that the treatment can be offered for these. We don’t have to let them go, but of course if you have already had a pathologic fracture or a collapsed vertebrate, that can’t be reversed. So some things are more easily addressed than others.
Dr. Verstovsek: It seems to me that the one aspect of this question is, when is a good time to start therapy of any kind? Because many times we say just watch and wait. There is no real answer to that question. It depends on the case. It depends on the involved organ, on the period of progression, if you see any of osteoporosis you follow it yearly with the testing and then it depends on also the risk and the benefit of the ratio of the medication that you would want to use, being that chemotherapy or the biological agent or something that may come along as the field develops.
Question: Part of the next question will be answered tomorrow when we have Dr. Chin about an epinephrine drip. One of the questions that came up for many people is: When is it necessary to use an epi (epinephrine) pen? Epi is short acting how many times is it safe to use another one?
Dr. Castells: There are ACLS guidelines actually that can be used for the epinephrine and those would depend on the blood pressure. You can use an Epi pen times 3 at five minute interval and that’s what the ACLS guidelines would say. If the patient continues to have hypotension and the blood pressure doesn’t go up, you just infuse an epinephrine drip directly into the vein. Essentially if the symptoms continue, epinephrine can be used at least 3 times at 5 to 10 minute intervals each time, depending if using the junior or the adult Epi pen. Everybody should be very acquainted with the Epi pen. Everybody should train their family members. Everybody should have one in hand right now. There are a lot of things that pertain to the Epi pen that should be addressed.
Dr. Theoharides: I have always conceded the Epi pen as a way to buy time. If someone has a real anaphylaxis shock or a real crisis and Epi pen will not necessarily solve the problem. Many families have known from the past how badly off they might be when they have a crisis My impression would to be to use the Epi pen and then go for help rather than wait at home and hope that everything will go away. I would always like to err on the side of being cautious than rather to be repeating it twice.
Dr. Butterfield: I would like to add to that. There are some patients that are not helped with the Epi pen. They can take multiple injections of the Epi pen and they do not improve. They know this. And that is a sign that other forms of treatment are probably needed.
Question: The literature refers to the problems of tachyphylaxis with antihistamines and cromolyn that initially provide potent therapeutic effects. How high a dose of cromolyn would you prescribe to a patient who benefits from it in a dose dependent fashion, but who’s symptoms remain severe at a dose 800 mg. per day or even 1600 mg. per day.
Definition of Tachyphylaxis - you start off taking a drug and you get a good effect from it. Then you are having to take more and more of the drug to achieve the same effect, because you begin to get a diminished response to your routine dose.
Dr. Theoharides: First let me say something that has been absolutely puzzling. As a graduate student, we wrote a paper in Science actually 25 years ago showing that cromolyn works very well with rat mast cells. It works very poorly with human mast cells in culture. Meaning that it does not block human mast cells very well, regardless of what it does in the whole body. So I have always been puzzled. Also I have been puzzled because in the laboratory mast cells tachyphylax, meaning they are not inhibited any more, even in the rat, if you give the drug for more than 30 seconds. If you give the drug one minute prior before trigger, mast cells are not inhibited anymore. That does not happen in the human. I am not sure how cromolyn works to be honest. Over the years we have seen more publications that it doesn’t block the mast cells, it might be blocking other organs, such as the bronchi or the skin rather than the actual mast cells. So having said that, I have no idea how tachyphylaxis really develops and how high one can go. Probably we should be guided by the side effects, because you have the GI effects and many people cannot tolerate the powder, etc. I don’t have any other answer. In contrast to some other colleagues I have not found cromolyn that helpful in many patients. Others, it does help.
Dr. Castells: I would add something to this even more powerful. When I was a student, there was a receptor that had been found in mast cells with the cromolyn protein that binds very clearly to what was called 70 kilodalton band and that was 1979. It is now 2005, and the receptor has not been found yet.
Dr. Theoharides: I have an answer to that. We actually published on 70 kilodalton protein and I have heard about 15 trials to get funding. have never got funding and without funding, you cannot isolate any receptors. So it wasn’t for a lack of trying. Believe me.
Dr. Castells: No, no I want to say that it is puzzling that a drug that has brought much to the field of asthma and mastocytosis, we still don’t know how it works. So we have absolutely no idea how this cell gets into the mast cell, how it binds to it and what it exactly does. For me cromolyn has been extremely helpful. Dr. Frank Austin, with whom I work, published a paper on the neuropsychiatric symptoms of patients on cromolyn and yet the absorption of cromolyn in the gut is less than 1%. So again another one of the mysteries is that if the cromlyn is extremely poorly absorbed yet the clinical symptoms were dramatically improved from 800- 1600 mg. of cromolyn a day. And the patients had improvements that were dramatic. I can tell you from the paper that were published at that time and from my own experience.
Dr. Theoharides: I led to something the group up here in the front doesn’t know. But we have been recently isolating mast cells with facts analysis, and interesting enough, even cromolyn not only doesn’t get absorbed very well from the gut, and even less is absorbed in the brain, if you add the cromolyn directly into the brain mast cells it inhibited very well, unlike other cells. So that gives credence to that paper that was published. Even though I don’t think the author had any idea why it was so. The structure of cromolyn is very similar to the structures of some naturally occurring flavinoids. such as quercitin and myricetin. These flavinoids are extremely lipophilic, they get into the brain, they get absorbed very well and they have a much longer lasting inhibition. They do not show anaphylaxis at all. Unfortunately, because they are natural, no company is interested in them which is why we have been struggling for years to get them off the ground. But we had a paper that was published just last month for the British Journal for Oncology, where we showed with human culture mast cells we can block almost 100% most of the cytokines that are of interest. So if we can actually get something like this in a clinical trial, I would be absolutely delighted because I think we can do better than cromolyn.
Dr. Akin: The other point is that cromolyn as far as I know is not specific for mast cells either. It also blocks eosinophil mediators and neutrophil mediator release.
Question: Since I have systemic mastocytosis and elevated eosinophils in the GI tract even if my mutated mast cells were gone I would still have the same symptoms. My doctor explains that the mast cells activate the eosinophils and the eosinophils activate the mast cells. I believe that having both conditions are quite common, but is anything being done to target the eosinophils as well?
Dr. Theoharides: There is actually a drug that is available in Europe, Canada, Mexico and Japan, but not in the United States, although we do have a form of it in eye drops in the United States for allergic conjunctivitis called Ketotifen. That is actually very useful for eosinophilic gastroenteritis, extremely useful. We have many patients in Boston that actually bring it in either from Europe or from Mexico. So that is a possible angle that one can take.
Dr. Akin: And also Gastrocrom inhibits eosinophil degranulation as well. I am not aware of any new drug development efforts targeting eosinophils.
Dr. Verstovsek : The other aspect of the question is about the causes of this condition. It is more likely that this is one disease rather than two diseases at the same time. It might be that they present it in a different aspect in different patients. (There may be) different types of the cells that are involved in different patients, but it is more likely that there is one cause for it, (rather than) you have multiple causes for multiple conditions. So, if one treats the mast cells, for example, with the agent that would eliminate the mast cells, that would be different from the medications that were mentioned so far. One may expect resolution of the eosinophil as well, because one feeds the other. They are connected in the body. That would be the ultimate goal of the new therapies that would come along in our research effort-- that we target the causes of the disease and that would eliminate the cells that cause the problems. And in this case most likely that would be both (types of cells).
Dr. Butterfield: I would like to mention that eosinophils are normal constituents in the lining of the gastrointestinal tract. They are normally found there in moderate numbers. We do treat eosinophilic gastrointestinal disorders: as eosinophilic esophagitis and gastroenteritis are the latest of a number of these. In many of these we really haven’t looked for mast cells. They are probably there but they really have not been looked for.
Question: It seems that my body requires more medication than a normal person does. It requires more antihistamines as well as more pain medications. How do we explain this? The person asking the question says “more medication than the normal person”.
Dr. Akin: I think we touched on it yesterday when we discussed tachyphylaxis. Where you would need more of the same medicine because the receptor of the surface of the cell becomes less sensitive to the same amount of medicine with prolonged use: so that (is known to happen) with pain medicines, for example, and it is also been reported for antihistamines.
Dr. Theoharides: In addition, there are individuals that are more or less, let’s call it “susceptible” to pain. For instance, there are some individuals that can metabolize or break down drugs faster than others, that require more medication. We should also mention that there are a number of medications that may be taken at the same time for other reasons or other diseases that can interfere with the action, or the benefit of, some pain killers or other drugs. So it is very difficult to answer the question without knowing the history of the patient, other problems they have, as well as (all) the other medications they are taking.
Dr. Butterfield: It could be a problem of absorption as well.
Question: Please discuss the best medications for those of us who battle nausea, and at times vomiting, with episodes.
Moderator: We did discuss some of this yesterday.
Dr. Theoharides: There are a number of medications that I am sure all of you know that can be taken for nausea and vomiting. Some of these drugs are Compazine, Tigan, Zofran, and Phenergan. Many of them work differently. And many patients are more tolerant and get more benefit from some of those. We have given a drug that might be absolutely without any adverse effect to some patients, and other patients might not be able to tolerate it. So the best thing I can do is say, don’t give up with one medication. Try a second and a third. Sometimes you might need a combination of such medications to get the best benefits, and it also depends whether the nausea and vomiting is entirely derived from a masto problem or there might be other reasons. And there may be many other reasons why one might have nausea and vomiting, and the address to those might be different as well.
Question: I have IC symptoms, especially at night. Sometimes I get up 20 or 30 times during a night and can only urinate a little at a time. What do you recommend for treatment?
Dr. Theoharides: Some of the symptoms are reminiscent of what we have mentioned off and on, which is call interstitial cystitis, which itself is a rather vague diagnosis. It would require many hours to go into both the definition, and the diagnosis of that, as well as treatment. So it is almost impossible to really give a straight answer. If it is interstitial cystitis, and the typical definition for most urologist would be that you would have symptoms with a lot of urgency, frequency, but with a lot of pelvic pain, not necessary just bladder pain, for over six months, without any urinary tract infection (that is very important). Then one can address it with some of the drugs that we give for other reasons,( for example), some of the old tricyclic antidepressants because they have a number of benefits, or with some(other) so called “bladder lining drugs. One is a drug(Elmiron). The other is actually a dietary supplement (quercitin). But again it is very difficult to generalize to that question ,because, like I said ,even interstitial cystitis can be a shadowy diagnosis at times. But I will be happy to talk to who ever asked that question later, because we have a lot experience with interstitial cystitis.
Question: Do allergy shots help some in the group by eliminating some of the triggers? And are they worth the risk for someone with mast cell disease?
Dr. Akin: That is an interesting question. The allergy shots can help if the person has specific antibodies against certain allergens which can be found out through an allergy evaluation. There are two ways of finding that out. One is a skin testing and the other one is a blood test that is called RAST. Patients with urticaria pigmentosa may have hyper-excited mast cells on their skin, so I think a skin testing can be less reliable in those patients. RAST testing is the one that I prefer. If the patient has symptoms of rhinitis (runny nose), stuffy nose, allergy symptoms, and perhaps asthma, and there is evidence that this is mediated through the allergic antibodies then I think that person can benefit from allergy shots. But it needs to be done very carefully, because allergy shots can also trigger mast cell activation and anaphylactic reactions even in patients without mastocytosis so I think it always needs to be done by someone who is licensed in administering allergy shots, and the patient needs to be observed in an allergist office for at least a half an hour after the shots. Also a group of patients can have severe anaphylactic reactions after bee stings. That is another important issue. There are no guidelines whether these patients, there is not right or wrong, whether these patients should be put on immunotherapy or allergy shots. Again my personal approach is to consider allergy shots, if there is evidence that there are IG antibodies produced against these bee venoms or wasp venoms.
Question: What treatment if any is recommended for neuropathy: painful burning, numbness and tingling?
Dr. Theoharides: Again these symptoms may derive from masto or from other reasons. It may be important for us first to make as good a diagnosis of the origin as possible. But regardless, most typical drugs used are again the older tricyclic antidepressants, such as amitryptiline, or doxipen which is known by the name of Sinnequan, usually at lower dosages than were used to treat depression, so 50 – 75 mg at night primarily. They tend to be very sedating. And some of them tend to actually make you gain weight. So you’ve got to consider all of that. The most recent drugs, which used to belong, or do belong in the category, and I don’t mean to say this and scare you, are antiseizure and antiepileptic drugs. They are classified that way, (but can be used for other conditions).One of the most common ones is gabapentin which is also called Neurontin. There you can start very low and your physician might increase it. You can start at 200mg three times a day and go all the way up to 800 mg three times a day. It doesn’t really have that many side effects, sometimes a little gastrointestinal irritation. But many patients do get a lot of benefits. There are (other) newer drugs in the same category as Neurontin. These are some drugs that we can use.
Question: I have systemic mastocytosis and I am 58. I have been injecting interferon alpha 2B for over 5 years now with excellent results. Are there any long term effects of staying on interferon alpha 2B if I live to be 70 or more? Are there any plans to administer trials of calcineurin inhibitors to see whether such medication is effective systemically, with pathological mast cell and basophil activation?
Dr. Butterfield: I will take a stab at the first part. We have used interferon alpha for five or more years in a number of patients with no particular problems. No particular side effects. It appears to be very safe. The people who develop side effects initially, such as trouble with myalgic pains and flu like symptoms tended to tachyphylax -- meaning you get used to those side effects and then tolerated the medication quite well. More recently, we have been using a lot higher doses of interferon alpha for the patients we have been treating. And I can’t comment about too many patients that have received the higher doses but we’ve gone five years with doses of 10 million units three times a week and that seem to be tolerated quite well.
Dr. Verstovsek: I would like to add the experience in other similar diseases, such as chronic myeloleukemia, essential thrombocytopenia, and polycythemia vera , where interferon has been used over the last 20 years with some success. There are no long term side effects in terms of inducing any cancer or making the disease progress, and things like that. It is just what needs to be routinely monitored for any biological side effects in terms of effecting the thyroid function, or effects of the bone and things like that. Once you are on a stable dose for 5 years, and it is working for you, the usual routine otherwise is to continue like that because it is beneficial for you.
Question: What new medications are being researched or developed for mastocytosis aside from chemotherapy or targeted therapy drugs?
Dr. Theoharides: We heard a lot the first day about different types of therapies, and again today. Last night we were discussing among colleagues here that certain natural compounds called flavonoids, and there is a paper out there using isolated cultured human mast cells, that seem to have a lot of benefit blocking mast cell activation. We are trying to figure out ways to increase the absorption of such natural substances so that we can get higher levels in the blood. But that is done sort of almost anecdotally, there is no company as such that is interested in pursuing that right now. So therefore I cannot answer the question by saying what is in the pipeline. But I am very hopeful that we may be able to convince some people to take a crack at it.
Dr. Castells: There is some interest in producing compounds that would block tryptase, and so there have been some models for developing antitryptase medications that have been researched. Not necessarily for mastocytosis, per se, but in the field of asthma. So we will be having some more data, and some more information about antitryptase medications in the future.
Dr. Butterfield: And one medication we are trying is Tamoxifen. It’s not a chemo drug. It’s not a mediator blocker, but it does seem to increase the rate that mast cell apotose, or die in the test tube. It is something in between the chemo drugs and is just the mediator blocker
Dr. Akin: And the other issue that as you heard in one of yesterday’s lectures, is this: Histamine has four different types of receptors. Right now we have medicines to block two of those. Medicines like Benadryl, Zyrtec, and Allegra block the first receptor(H1), and Ranitidine, Pepcid block the second type of receptor(H2). And there are some drug development efforts, not for mastocytosis but for allergic disease patients in general, to target those remaining H3 and H4 receptors.
Question: The NIH’s protocol consent for the study on hematologic parameters in mastocytosis and unexplained anaphylaxis and flushing informed participants that standard medical treatment for anaphylaxis or flushing includes H1 antihistamines for itching and H2 antihistamines may also be suggested if you produce excess stomach acid. What if the doctors we see, or our insurance companies, do not recognize those treatments as standard? How do we help insure more widespread recognition so that many patients who suffer from recurrent episodes of anaphylaxis and flushing also warrant treatment for their more chronic mediator symptoms?
Dr. Akin: It is a constant battle with insurance companies. I don’t think anybody would argue that the standard H1 and H2 antihistamine coverage would be appropriate for a patient with recurrent anaphylaxis. It is more difficult to treat flushing. We did have some patients with recurrent flushing who really did not respond to any of the medications but I think considering that these medications have been around for a long time, relatively benign medications with relative little side effects, those are commonly used. I think, I don’t know what to do with the insurance companies, but a letter from the prescribing physician might help sometimes.
Question: Is there any evidence that systemic mastocytosis or mast cell activation syndromes are related with autoimmune disorders or are they autoimmune disorders?
Dr. Theoharides: The proper definition of autoimmune disorders is when the body basically does harm to itself. So I would say (my personal opinion) is yes. But that is not how we define autoimmune disorders in the text books, so from that point a view, probably not. In autoimmune disorders there is a panel of markers that we look for (by blood test), and that panel of markers doesn’t seem to be elevated in mastocytosis. If you would to try to argue with insurance companies whether mastocytosis is an autoimmune disease, the answer is no. If you were to ask me if this is an autoimmune disease in the proper sense, I would say yes.
Dr. Verstovsek: I would like to add a comment on systemic mastocytosis. We have talked about the classification and this classification is in World Health Organization classification of hematological malignancies. Systemic mastocytosis is a disease where the mast cells are abnormal by the different features (they exhibit), and it is considered to be hematological malignancy. And it is very well regarded as such. And the insurance companies should not have a problem with that. We have had several patients asking me for certification of that and it is easy to substantiate.
Question: Are there any studies that are looking at the hormone factors in females? It seems that there are many in the group that were first diagnosed with severe endometriosis, adenomyosis, fibroids, polycystic ovaries and/or polycystic breast disease. Please discuss what options there are to treat problems resulting from hormonal factors.
Dr. Theoharides: Dr. Butterfield mentioned a moment ago the use of Tamoxifen. Tamoxifen is, probably as most of you know, a blocker for the hormone estrogen. So I would imagine he has a reason for using it, which we will hear about. We published a few years back a couple of articles showing that human mast cells, both cultured, including the mast cells that Dr. Butterfield had given us, as well as bladder biopsies from patients with interstitial cystitis, (both) express receptors for estrogen. This is the same type of receptors that say, breast cancer cells do. In a number of studies, if we gave mast cells in culture a lot of estrogen, I mean a lot, much more than the body normally makes, their activation became heightened. I stress a lot because I am not sure whether that will reflect what may happen in humans. We also published a couple of papers just over the last year, and some other colleagues also did right after that, showing that in slides of endometriosis taken from biopsies of the peritoneal cavity, wherever there was endometriosis, there was a collection of mast cells, and those mast cells also had receptors for estrogen. We have also heard, over the course of the last day or so, a number of patients who, for what ever reason, might have had a hysterectomy, and many of their symptoms have disappeared. I think there are a lot of tell-tale signs that there is some involvement. I tend to think again that there is. There hasn’t been any request for funding from the government, to the best of my knowledge, to study the effect of sex hormones in mast cell activation. And a puzzle that also exists is that the endometrium has a lot of mast cells, and the content of histamines during the cycle in women changes along with their cycle. We don’t quite understand what that means. But we routinely say, and we still do, that if anybody is on birth control pills, and on antihistamines, the birth controls might not work and they run the risk of getting pregnant. So we have, inherently, the fear that there is something going on, but we don’t quite understand it.
Dr. Castells: I strongly agree with Dr. Theo comments, and I would add that there is an initiative at the NIH in terms of research on woman hormones and their impact, (although I have not seen a research proposal), on the direct effect of mast cells .There is a big interest because the uterus is filled with mast cells, and the type of mast cells that are there (in the uterus) are the same type that are in the skin. And there is data that we have, that patients that have, like I mentioned before, acute attacks of mast cell activation, do have bleeding after that. So there is a full activation of the mast cells in the uterus. So, in terms of what can be done either to prevent or to treat those episodes, on the other hand, the research is now growing in terms of finding that association.
Dr.Butterfield: We’ve had a similar experience with uterine bleeding following severe attacks of mast cell activation or degranulation. Whether it is from prostaglandin release or some other factor we are not certain. The other reason that we were interested in trying Tamoxifen in mast cell disease is we have detected estrogen receptors and progesterone receptors on mast cells. And others have used Tamoxifen in the test tube to affect the growth of mast cells, and it does hasten their death. And it’s the side effect profile of Tamoxiphen that has been well as described—there’s a lot of experience with it. It doesn’t seem to affect other blood cells. So it doesn’t have many of the draw backs of say interferon, cladribine, or some of the other chemo drugs.
Question: Why have so many of us experienced an adverse reaction to IV Benadryl - preservative free even - especially when we can tolerate oral Benadryl. This is something that has totally baffled my local physicians but they have clearly witnessed two separate but identical reactions to even to slowly pulsed preservative free IV Benadryl?
Moderator: I would love to know why this happens.
Dr. Theo: We have discussed this among ourselves yesterday………….. I have no clue.
Audience: Laughter
Dr. Theoharides: We came up with all kinds of possibilities. I still have no clue. There is a minority of individuals that might be intolerant. I don’t want to say allergic, to a number of drugs, including antihistamines. The only thing I can suggest is when you push as we say intravenous Benadryl you give so much, that maybe this intolerance basically surfaces while if you take it by mouth, you can tolerate it. I really don’t have no idea.
Dr. Butterfield: What are you needing intravenous Benadryl for? Is it something that intramuscular didn’t work for?
Dr. Theoharides: Something given before contrast media…..?
Dr. Butterfield: Contrast media? Because we usually give it by IM, and it seems to go fine. You could try IM for example. I don’t know if that will be tolerated, though, or not.
Dr. Theoharides: Dr. Butterfield made a good point. Benadryl is not given by IV unless someone has a catastrophic problem and you go to the emergency room, in which case they will give you steroids, epinephrine and other things. But sometimes Benadryl might be given IV just before contrast media studies like a CAT scan study etcetera, if someone has been either allergic or intolerant, to avoid a possible problems. (Since) they already give you already an intravenous catheter to administer the contrast media, it is easy to give the Benadryl through that. I am not familiar with giving intravenous Benadryl at a regular setting.
Moderator: This next question was actually taken out and then someone asked me to put it back in for Dr. Theo to answer.
Question: I read that mast cells are actually protective against parasites. If so, is this a protective mechanism gone awry--similar to sickle cell anemia, which is protective against malaria?
Dr. Theoharides: The second part I will take it for granted and I will not make a comparison because even that is actually a little bit controversial. I don’t have much doubt that any cell type especially with the immune system is there for a reason not to cause damage. God and nature would not have put the cell there to create a disease. And our ancestors clearly were exposed to many more parasites than obviously any of us have. Since there is evidence that the mast cells are (either) protective, or just participating in the immunity against parasites, I would agree that that is probably one of the reasons why the mast cells are there. Now if I were to make a different analogy, some of you may have heard, that we have an asthma epidemic in the United States, in spite of better antibiotics, better air conditioners, better vacuum cleaners, better bronchodilators, etc. There was a wonderful little article that I was reading in the New England Journal of Medicine a few years ago, the title was “Eat Dirt”, meaning get out there and expose the kids to whatever we were exposed to when I was growing up and playing with dirt and eating raw fruit off the trees, with dust and what have you, so that the body could get bits and pieces and be exposed to X,Y and Z. And when they (the mast cells) see it later in life, they don’t freak out that they have never seen it (the dirt, dust, etc). So maybe that’s part of it: that the mast cells that are involved in asthma heavily just haven’t seen many of these triggers for many years, and now they respond over and beyond. That is not what happens in mastocytosis. I don’t think that is what it is. But I clearly think that they still have, as what we have heard earlier today, some protective function. To give you an example, there was a wonderful set of papers published about two years ago, where they inoculated, they injected well known bacteria that caused urinary tract infections called E.Coli into the tummies, or the peritoneal cavities, of mice. The mice either had mast cells or they didn’t have mast cells. The mice that did not have mast cells died. The animals that had mast cells managed to respond, and eventually deal with the infection. So I think we still need mast cells for many reasons. The question is, how can we harness the good part of the mast cells from the bad part? And that is actually a lot of our research. How can we make the mast cell to release selectively what we want and block what we don’t want?
Question: What causes me to turn red and sometimes blue with the reaction?
Dr. Castells: Red would be that there is more blood flow in that area, so it would just be mediated by prostaglandins and leukotrienes, and so the redness is a sign that the blood flow is activated. The blue would be that there is less oxygen, so wherever the initial part may be, there are a lot of blood vessels that are are open and working. If the blood pressure starts to go down a little, then less oxygen would be present. Yes, indeed there are a lot of changes that come in the color of someone going into an anaphylactic event.
Dr. Theo: As many patients know, the blue intends to be more of the extremities, whereas the redness in general tends to be more in the face and torso. Many patients that have gone through an episode clearly are scared of another episode for a good reason. Whenever we are scared, we panic, again for a good reason. But when we panic, we hyperventilate, which means that we blow off a lot of carbon dioxide. Our brain knows how and when to breath, not because of how little oxygen we have, but how much carbon dioxide we have. If you breathe out a lot of the carbon dioxide, the brain knows that is not the way that we breathe. So,we start actually clamping down on the extremities, getting paresthesias, and getting pins and needles-- which might be construed sometimes, mistakenly, as a stroke or some other brain problem when there isn’t any there.
Question: Why do so many of us scar so badly after surgery? Develop scar tissue and keloids? Is this related to mast cell mediators affecting the fibrin tissue?
Dr. Theoharides: For me it is impossible to answer that question: everybody gets keloids after surgery, so what is more than less? There is no question that over the years, that mast cells have been associated with fibrosis. That is has been shown in the linings, that has been shown in the uterus, that has been shown in the skin and most recently in endometriosis. Now whether that fibrosis contributes a little more to the keloids or not, I have no idea.
Question: Is there a link between mast cell disease and other conditions such as multiple sclerosis, fibromyalgia, chronic fatigue syndrome, thyroid disease or and interstitial cystitis? I might add multiple chemical sensitivity.
Dr. Theoharides: I will take the first crack, for I am sure my colleagues will (also) answer. First of all there is no doubt that many of these conditions, especially chronic fatigue and fibromyalgia, might be more likely to be present in patients with mastocytosis, including interstitial cystitis. Even if were to look at interstitial cystitis patients, there are about 40% chance of those patients having all of the other conditions, except for multiple sclerosis, than the overall population. So there seems to be some association; whether that association is linked to mast cells or not, is difficult to say. Even though in certain diseases, such as interstitial cystitis, it is definitively shown that this is mast cells are higher in number and more activated. We’ve published a lot of research papers, and there is a bit more clinical evidence now that the mast cells may control the opening to the brain, or what we call the blood brain barrier. And therefore, the T-cells that are involved in multiple sclerosis might find it a little bit easier to get in. Does that mean that mast cells cause multiple sclerosis? No. Could they possibly contribute? Possibly yes. With chronic fatigue syndrome, no one really knows what it is, nor with fibromyalgia. It is considered to be a neuroimmune, if not an autoimmune, disorder. We recently sent in an application just two weeks ago suggesting that there may be a connection with mast cells in the brain with chronic fatigue syndrome. If that fares well, next year I will tell you about it.
Dr. Castells: Now we will just dwell a little bit more on the chronic fatigue syndrome. Patients who actually have allergies, just allergies and not mastocytosis, tend to get very fatigued and tired during the allergy season, especially the spring season and the fall season. That is due to not only of the release of the histamines and the other mediators, but T and F Alpha tumor necrosis factor. They have a lot of that and a lot of the other thing we call cytokines. Indeed, when mast cells release, they release some of the mediators that can induce fatigue so it is very, very hard not having standard criteria for chronic fatigue syndrome to differentiate what could be fatigue syndrome or chronic fatigue syndrome, and the effects of ongoing chronic mast cell release.
Moderator Marti Wolfe: I would like to take a crack at that myself because I have been working on it for about six months now. The data for the connection between interstitial cystitis, fibromyalgia, multiple chemical sensitivity, and chronic fatigue syndrome from the epidemical logical data are quite robust. That is a very strong connection. It is more difficult to establish (a connection) for the mast cell disorders because that patient population is much smaller, so epidemiology is more difficult to establish. However, there is an investigation going on now about a common mechanism at a basic level biochemical mechanism that may, if it pans out, tie all of those things together.
Question: What exactly happens that results in many of us developing osteoporosis? As some have asked on the list, do we expect that mast mediators may also cause osteoporosis in people who have mast activation but not in those with mastocytosis?
Dr. Theoharides: The mast cells do release mediators that activate osteoclasts they basically chew up the bone and release calcium. We don’t know all of them, but we do know some of them. Patients who have mastocytosis can potentially have more such mediators, and we know that many patients who have mastocytosis have bone involvement. But I can’t quite say which type of mastocytosis is more likely to lead to this epidemiologically, which my colleagues could probably answer better.
Dr. Butterfield: In addition to increase bone remodeling in systemic mast cell disease, the other part of the problem is malabsorption of things like calcium and vitamins that you need to rebuild the bones normally.
Dr. Castells: I was going to add that in terms of the molecular level interleukin-6, (Dr. Theoharides has a very nice paper about this), is one of the factors we think that is linked to the bone loss of density, and then proteoglycans, which are also a part of the mast cell granules, also can impact on bone density, and they can actually destroy bone. So there are several factors that are in mast cells that can actually make bone loss density very clearly established by molecular levels.
Question: How many people in the United States are estimated to have the various kinds of mast cell disorders, mast cell activation syndrome, systemic mastocytosis and the pediatric kinds of these conditions? Specifically please break these down into subsets.
Moderator: So I think they want to know how many people have mastocytosis, how many people have mast cell activation disorder or syndrome, and how many children have some form of pediatric mast cell disease?
Dr. Butterfield: I think I have seen some data for the general population, please correct me if I misstate this, but I think it was two patients per 300,000 of the population. It is more in a dermatology practice. As far as the mast cell activation syndrome goes, we tend to see maybe 10, 15 or 20 patients with these indeterminate types of symptoms. It could be construed as being due to mast cell degranulation or mast cell activation for every one true mast cell disease patient we see. A lot of people come in thinking they have mastocytosis and they don’t. We cannot document it either by bone marrow biopsy or by mediator profile. So, there are a lot of these patients. For the patients with mastocytosis I think the numbers were put on the screen today, I think it was 80% or more are just the indolent form with just five or less % being the more aggressive forms, those associated with nonmast cell hematologic disorders, and aggressive mast cell disease. The least common would be the mast cell leukemia, and then, last of all, the mast cell sarcoma would be the least frequent 1% or less.
Question: I, like many people of the group, have developed thyroid disease, after a systemic mastocytosis diagnosis; why does this happen?
Dr. Castells: The thyroid disease, particularly Hashimoto’s disease, is more common in females and females run from around the 30’s and the 40’s. We don’t have good numbers comparing the instances of that thyroiditis or inflammation of the thyroid in the general population, compared to the patients who have mastocytosis. So it might be that number is the same to the general population and so we don’t have yet to find final the connection.
Question: Many of us with mast cell disease suffer from very painful recurrent oral esophageal/gastrointestinal yeast that requires 14 – 21 days of treatment with oral diflucan. This seems to always puzzle our physicians, yet there are several of us that experience this. How can we interest mast cell researchers in pursuing the association between mast cell disease and the occurrence chronic candidiasis?
Dr. Akin: If you have chronic candidiasis there are certain other conditions that need to be checked, for example, diabetes or any immune deficiencies type of disorders. Or if you are on chronic steroids, either inhaled steroids for asthma or oral steroids like prednisone that would all predispose to you of having candida infections. Mast cells disease in its indolent form, which is the most common form, is not associated with immune suppression. It is not an immune deficiency disease. Neither is it an autoimmune disease. It is a neoplastic proliferation of mast cells. I think again if you have chronic candidiasis, then the other conditions need to be ruled out.
Question: At last year’s conference Dr. Akin mentioned hemangiomas being associated with mast cell diseases. Can you expand on this? Can this be related to extramedulary hematopoiesis?
Dr. Akin: I am not sure in what context I mentioned this but I thought we had a couple of patients with hemangiomas. I don’t know if they are incidental findings but there is no description of hemangiomas being more common in mast cell disease. So I think if I was misunderstood last year, I apologize for that.
Question: I would like to know what causes the spleen to swell or to become enlarged. My daughter will soon be 14 and the doctor told us last week that he could feel the tip of her spleen.
Dr. Theoharides: I am sure all of us could answer that in different kinds of ways. But the spleen can enlarge for all kinds of reasons. I think very appropriate examination and history might actually reveal reasons other than mastocytosis. It is really very hard to answer that question without knowing more details. I mean, clearly, some patients with mastocytosis have enlarged spleens. But that could be from all kinds of other reasons which are much more common than mastocytosis.
Dr. Castells: The enlargement of the spleen that we have seen in the patients with chronic indolent mastocytosis is due a lot to the fact their bone marrow does not produce efficiently enough of the blood cells that are needed, and then that supply of blood cells are done by the spleen. What is call hematopoiesis is done in the spleen. And that makes the spleen enlarge. That we have seen with frequency in patients with long standing mastocytosis of the indolent type.
Question: Is there any way I can lessen the effects of mast cell pharyngitis(sore throat)?.
Dr. Butterfield: We reported one case of mast cell pharyngitis in which the patient had swelling as the primary problem, swelling of the soft pallet and respiratory compromise. We tried various antihistamines. We tried cromolyn gargles. We tried a variety of things. And the only thing that worked for the swelling problem was a uvulopoietopharyngeoplasty, where they removed the uvula tissue. The tissue was just crammed with mast cells. The patient did not have any evidence of systemic disease. We compared the tissue the number of mast cells in this patients tissue with about a half of dozen of samples from patients that had had a uvula uvulopoietopharyngeoplasty for sleep apnea, and there was substantially increase number of mast cells in this patient’s soft pallet. The only thing that worked for the swelling was surgery. I don’t know what other symptoms they are referring to here. But for swelling, nothing else seemed to work well.
Question: Every time I have had an attack, I have terrible shaking, as if terribly chilled, although I may or may not feel chilled at the time. I totally cannot control it no matter how hard I try to stop shaking. What is the cause of this?
Moderator: And actually that question several people asked. We have combined it.
Dr. Theoharides: I don’t know the answer but I am confused by the question. Chills are one thing, shaking is another. Are we asking chills, meaning someone feeling cold or trembling because they feel cold? Or shaking because….
Moderator: They look like they are having chills but they are not, they actually are not feeling cold, they are just shaking. Is there anybody here that asked that question that could clarify it?
Audience member: I have that.
Audience member: I have that too.
Audience member: I have that.
Laughter in the group.
Moderator: Do you actually feel cold?
Audience member: What it is, is that if someone is actually looking at you, they would think that you are cold, but you are not really cold.
Audience member: Have you taken your blood pressure when this happens?
Audience member: Yes, and it drops.
Dr. Castells: We don’t really know what it is due to but that question is very important. If the blood pressure is going down, then there is poor perfusion to the muscles, in the legs, in the extremities, in some parts of the body so the body is actually trying to help that the blood vessels can continue to provide circulation to those muscles and that might induce some twitching of the muscles so the blood pressure and the release of histamines and the other mediators to the blood stream can actually induce those rigors.. Truly we don’t have any animal data to support which of the mediators or which one it would be. I have encountered the phenomenon in a lot of my patients with mast cell activation syndrome, where they start to shake but shortly after they recover from the profound attack of hypotension. And this is the only explanation, why the blood pressure is recovering. The muscles are trying to get the blood flow continued.
Dr. Butterfield: I just want to use this as an opportunity to suggest having a mediator kit for these times. Doing a sample, that is only way we find out. You have to do the basic stuff here. Basic information.
Audience member: When we do the sample do you take the precautions of stopping our antihistamines?
Dr. Butterfield: Yes, but I mean taking an antihistamine won’t prevent histamine from being released.
Dr. Theoharides: Dr. Butterfield said that taking antihistamine does not prevent histamine from being released: that is not entirely true. Some of the newer antihistamines and two of them were just released in Europe, can actually block histamine release to a fairly decent extent.
Dr. Butterfield: This is after the fact though, that is already going on.
Dr. Theoharides: True…..With a 24 hour urine, I would rather you don’t put anything on board. With 24 hour urine, it might actually continue to block. In any event, if you have an attack, it is better to get the kit and get the sample in regardless. And take care of yourself, with that said you do take the medication. But strictly research wise, some antihistamines could actually affect release. The reason I asked about the shaking is because we had three kids that were referred to us for some reason all from Europe. They had diagnoses of seizures or epilepsy for a number of years. They were treated totally unsuccessfully with antiseizure medication. We had diagnosed that they actually had systemic mastocytosis. That changed all of that and they haven’t had any problems since. Their presentation was shaking, which was considered to be seizures. That is why I was saying, that kind of shaking is different than the rigors, the trembling. But to a patient the difference might not be as apparent. I just wanted to make sure that I mentioned that.
Audience member: I’ve got that terrible shaking as a result from the medication when I woke up from having anesthesia.
Dr. Theoharides: That can be a quite common presentation after anesthesia. It happens to people that don’t have mastocytosis. Although it might be worse in patients with mastocytosis, (but) I don’t have any experience with people with this; that is why we put warm blankets, etc., when patients come out from anesthesia.
Question: Please discuss why so many of us suffer from severe headaches that sometimes last for days. Some have headaches that are one sided why others seem to have pain all over. What medications are best to break up a headache?
Dr. Theoharides: As I said the other day, we have been studying the possibilities of the mast cells may go with migraines for many years. If you just give histamines to an individual who doesn’t have mastocytosis you are going to get a headache. Most people are going to get a headache. Migraines and other so called vascular headaches, the throbbing pain of the headache, is associated with vasodilation. Histamines will do that and something called vascilidatory peptide, will do it and two or three other substances. That doesn’t mean to say that the mast cells are the only cells involved in the migraine type of headache, but clearly they could participate. Hydroxyzine has been one of the better most innocuous drugs that one can use and many patients are actually are on it, primarily because it is one of the drugs that does get into the brain. And you do want something to get into the brain if you are likely to deal with migraines. For children, we are using a quite safe drug called cyproheptadine or Periactin, which actually affects both histamine and serotonin, because especially for migraines, serotonin it is another molecule that is very heavily involved in most of the drugs for abortive treatment, meaning after you get a headache it blocks actually serotonin. And in some cases, the old drugs called beta-blockers such as propanolol or inderal might be given prophylactically. There are also patients that get such presentations with their ovulation or premenstrually. That happens with just migraines areas in general and with patients that may have mastocytosis. And in those cases, if those are severe, we actually put them on Tamoxifen or another drug called Lupron, which is actually used in endometriosis, and which actually puts you through menopause. But that is if you have very frequent problem.
Question: Please discuss why some have severe chest pain with reactions. My EKG is normal except for sinus tachycardia. What medications should be considered to treat this pain? Nitroglycerin seems to do nothing for it. Besides epinephrine and intravenous H1 and H2 blockers are there any other medications that could help?
Dr. Castells: I am not going to discuss the medications, maybe someone else can. I am just going to say that this case illustrates a case presentation that happened in the New England Journal of Medicine a few years ago in which a patient came to one of the hospitals in Boston with chest pain and he had a very expensive work up for coronary disease after he was seen by 10 or 14 of the best cardiologists, there somebody noted that in his skin, he had those kind of brown dots. And then some body did a tryptase level and indeed the patient had systemic mastocytosis and he had never had any complaints except that time he had presented with excruciating chest pain. The mast cells are actually in the pericardium, the envelope of the heart has a ton of mast cells. And there are a lot of mast cells around the coronaries. So there is indeed a population of mast cells that are in the heart. We have never studied those mast cells in patients with mastocytosis whether they are increased or not we don’t really know and I don’t know of another study maybe somebody knows about it. But chest pain essentially can happen. As either a presenting symptom of systemic mastocytosis or associated to the episodes of acute release of mediators.
Dr. Theoharides: I led to that. A group of investigators headed by Dr. Marone in Italy has published over the last five years, numerous articles, after isolating mast cells from human heart tissue, from people that had died etc. And they showed that not only were they numerous as we have heard but they do not respond to the same molecules as other cells. For instance: morphine, will stimulate skin mast cells, they showed that it does not affect heart mast cells. So point number one they were different. Point number two is there is a syndrome that was published first almost 15 years ago in the New England Journal of Medicine, called Allergy and Induced Myocardial Infarction; in fact the person who published that sometimes has been associated with a syndrome called the Kunik syndrome: where people had actually chest pains and some of them had myocardial infarction. And no one really associated(allergy) other than there was tons of histamine elevated during that attack. In one instant it was actually anaphylaxis. In a couple of other instances it was not anaphylaxis. And in fact he, meaning the original author, recently asked me to help him write a review on this. The mast cells in the coronary and in the pericardium can be activated by some other molecules that are not the typical triggers of mast cells that will be too complicated to get into. So I wouldn’t be surprised but I don’t think this is necessarily a common presentation.
Dr. Akin: Another cause of chest pain would be acid reflux. So this also needs to be considered.
Moderator: Do mastocytosis patients carry less oxygen in their blood during the course of exercise? If so, does this explain in part the fatigue? Are there other hypothesis for the mechanism behind fatigue, particularly vexing symptoms for so many?
Dr. Castells: I think that we have gone through fatigue and the mediators Tumor Necrosis Factor Alpha (TNF-A )is pretty well known. Some other like interleukin 1 is also released from mast cells. So fatigue can be a chronic vexing symptom. And as much as the mast cells continue to release, it might be very difficult to block. The patients with mastocytosis carry the same amount of oxygen which is carried by the red blood cells not the mast cells, and so that there is definitely not something that would prevent them from exercising. They should be able to. Other things that should prevent them from exercising are like we said, the fatigue or the deconditioning. There are a lot of patients who have been deconditioning by their multiple attacks that have been induced sometimes by exercise so they are quite deconditioned. But essentially oxygen is the same as in normal people.
Dr. Theoharides: Even though that is absolutely correct, there are cases, not necessarily in mastocytosis patients, of exercise induced hives, exercise induced asthma, and exercise induced anaphylaxis with no clue of what really goes on there. We tend to think and there is some evidence that some stress hormones or the ones I was talking about activate the mast cells under the stress of the exercise. But that is as far as I know.
Moderator: Another hypothesis that has some good data to support it is fatigue caused by oxidated damage to the electron transport chain of mitochondria and that connection in preliminary trials some people have been significantly helped by taking antioxidants. And that has relieved their fatigue.
Question: What can be done when lymph nodes swell? What course of action should be taken?
Dr. Theoharides: You have to see a very good physician to begin with. Lymph nodes can be increased because you have an infection, can increase because you have an allergy, and can increase because you have mononucleosis: going to worst (case scenario) you have lymphoma, so forth and so on. Sometimes they can react to a viral infection. And those will go away. You can get pharyngitis you can get lymph nodes around your neck swell and then a week later they are gone. So it depends on how long they last, how big they are, how old you are, they could be tell tale signs of all different kinds of problems. Clearly they have to be evaluated, especially if they are persistent. And especially if they are associated with other tell tales. For example: someone having night sweats, fevers of unexplained origin and lymph node enlargement--then you start to wonder about all kinds of things.
Question: Dr. Theoharides can you explain briefly your studies on flavinoids.
Dr. Theoharides: Our studies of flavinoids actually started from a long time ago, not because we thought about it. As I was telling my colleagues last night, a wonderful physician scientist, Dr. Elliott Middleton, who unfortunately died some years back, had spent most of his adult life studying flavinoids. He died actually quite bitter, because he never got any funding to actually take him any where. As I had said last night, I was very moved when his family after he had died, called me up and asked me if I could actually write a review postthumously with his name. Which I did two years ago, it was published in pharmacological reviews. These are wonderful compounds. There are about three thousand flavinoids in nature. They are found only in plants and mostly in seeds, or at least the seeds are richer. So we consume them basically through our foods. And unfortunately we don’t consume as much because the way our food is done over the years. To give you a quick example, the change of color in the leaves in the north east, about this time of year in Boston, actually are due to flavinoids to a large extent. As the temperature drops, the plants actually try to prevent themselves from freezing. Various flavinoids are being developed. Each flavinoid is a different color and that is how we get most of the colors. Not all of them are good. We studied about 100 of them. We parachuted down to about 6. Unfortunately only one is available in pure form to be sold over the counter. And it is called Quercetin. The reason I stressed that is because there are many preparations that are there that you might find, that are called citrus flavinoids, bio flavinoids, and soy flavinoids: they contain so many flavinoids, I could not begin thinking whether they might be doing good or injustice to the reason you are taking them. Now how do they act? They seem to be actually affecting various systems. I was saying last night to my colleagues, that they, at least Quercetin, and about four such molecules which we tested, and there is a recent paper on the table there, they inhibit for instance, tyrokinase, and we heard a number of times during the last day and today tyrokinase are involved with the c- kit etc… They are not specific, but they inhibit that. They inhibit mast cell activations from different other ways. Now why haven’t people used more flavinoids? First because they are not pure. I actually visited Florida about three months ago at The Department of Citrus because they throw away the pulp because most of us don’t like pulp in our orange juice or grapefruit juice. The pulp is extremely rich in flavinoids and we were trying to convince them to possibly work with them to try and isolate some of the flavinoids from the pulp. So that they may get some benefits and some money and then we may have a better source. They haven’t quite agreed to that yet, even though we are very excited about it. There are at least two sources of very pure Quercetin available. One is a company here in California call the Allergy Research Group. They have 300 mg pills of Quercetin. I don’t know how pure they are, because they don’t state the purity and they don’t state the source, although if you get to calling them, they might tell you. Two old patients of mine, who became friends, created a small independent company in Florida and there is actually a preparation that has Quercetin along with chondroitin sulfate, because we published two years ago, chondroitin sulfate can block mast activation We felt that because the blockade is at two different places, you might get synergism, which is more inhibitions with both drugs than just either one alone. That’s called Algonot and it is algonot.com. But we are actively trying to better what is available because Quercetin is very lipophilic, meaning they like lipids. So we are trying to make what we call liposomes: mixed the Quercetin or any other flavinoids we might come up with, with some oil to allow the intestines to actually absorb it better. This preparation in Algonot is actually mixed with olive seed oil, a way in which to make this very crude liposome. No large companies so far have been interested so for there is very little stuff that one can do without a large company interested in that. I think that if we could get enough Quercetin or some of the other flavinoids that seem to have similar action into the body, I see no reason why we wouldn’t have benefit. We started talking to some of the colleagues last night about the possibility of maybe of even doing a small study even in mastocytosis patients there is absolutely no adverse effects. If we can get enough in there, we might end up actually seeing some benefits which might be the beginning of maybe convincing other companies to think other wise.
Question: The last question is sort of a complex one. It’s asking of the reliability of the standard markers for mast cell disorders, in particular a comparison between the results of the things that are currently the standard markers and then clinical symptoms. This person is concerned that there are people who display symptoms clinically who do not have display any of the standard by marker tests and his concern is about resolving some of those conflicting results.
Dr. Theoharides: Dr. Butterfield yesterday indicated quite appropriately that many times you just don’t catch any elevation of the markers, which is number one. Number two any time that we look at results of let’s say tryptase or histamine or what ever remember we might have a number let’s say over 20 being positive but that just indicates the mean with what we call a standard deviation. Meaning that you look at 100 patients; some have a hundred some have five and you get the meaning that over 20 is positive. But that alone indicates that some patients are below the 20. And you just decide that that is a more reasonable number to go by. So you have to actually look at a lot of things and that is why we have the criteria rather than going only tryptase level. As Dr. Castells has indicated we have measure interleuktin 6 and even though interleuktin 6 is elevated in a lot of inflammatory infections disorders it seem to be very evaluated in most of the patients we saw, especially if they have bone disease. I think as we investigated the mast cell they might be others. We are in the process of trying to collect serum to measures in other molecule, vascular endothelial growth factor that I told you yesterday that seem to be induced to be released from mast cells under stress. If we have enough serum from enough patients to call it, eventually some years from now it might be one of the additional factors one could measure. But it has been very difficult to collect serum from patients that have a very good diagnosis. Regardless what the diagnosis is. In other words, a lot of patients will agree to send in the serum. And then you find out either they never had a decent diagnosis. They have never had a biopsy of any kind. So once you get the serum and get the results, you don’t know how to analyze the results because they are all over the place. That is why what has been going on in the Brigham and other places might be very important in terms of getting the number of patients, knowing exactly the quality of the diagnosis and then getting the blood. So you don’t waste your time and then you are waste the time of the patient as well because you will be confusing them rather than helping them.
Dr. Butterfield: Right there is a variety of symptoms obviously people can have of mastocytosis. And as you recall from the slides that were shown, mast cells are just power houses. They are factors for the production of multiple cytokines, multiple interleukins and right now we are talking about assaying a hand full of these routinely in a clinical lab, in a clinical setting rather than a research lab. You can do cytokine profiles in the serum of patients of mast cell disease. And you can assay for 60 or 100 different cytokines and chemokines that they produce and it could be quite a job to sort through all these and as our knowledge increases the number of products of these mast cells and the effects of these products and other cells it just cascades, so it could be a numerous number of potential things that could be looked at so I think we have just scratched the surface of what we are doing now.
Moderator: We have a little bit of time left so if you would like to ask a question to the panel please raise your hand, state whether or not if you want it directed toward any one specific physician or whether or not you want to address it to the whole board.
Question from the audience: This is for Dr.Butterfield. You mentioned the work with tamoxifen conceptionally , because it probably hasn’t happened yet. Arimedex, aromacin, etc. would they be conceptionally do the same thing?
Dr. Butterfield: I think they work a little differently. One is an estrogen receptor blocker; the others are aromitase enzyme inhibitor, where they prevent the production of estrogen. I don’t know of any in vitro data of the arimidex or one of those. I don’t know of any in vitro data on any of those. I really don’t know. (Inaudible) If they are blocking estrogen production or effect.
Question: This has to do with the lymph nodes. When my daughter was two (before she was diagnosed with mastocytosis) she had lymphadenopathy real bad. And they actually thought she had lymphoma. So we went through all of those tests and everything. By the time she was six her lymph nodes had gone down finally and went away and were replaced with brown flat macules. Have you ever heard of that?
Dr. Theoharides: I have never heard of it, but I am sure if I understood, ‘replaced by macules’ right over the lymph nodes?
Audience member: All of the areas where the lymph nodes are – example behind the knee.
Dr. Theoharides; This is a first for me.
Audience member: It was really weird because I didn’t know what the flat spots were. I thought they were bruises for awhile and then of course later when she was diagnosed, I knew what it was. At they would turn red.
Dr. Theoharides: Did they ever biopsy the lymph nodes?
Audience member: No. Her GP was begging them to do it and they wouldn’t do it. This was done at the Children’s hospital in San Diego. I left there.
Dr. Castells: What I can say is the kid that I presented with the skull mastocytoma, he indeed had a lot of lymph nodes around that. I didn’t present his full clinical history. He has the mastocytoma and a lot of the cervical lymph nodes were also inflamed. We did biopsy the lymph nodes along with the mastocytoma. They were full of mast cells. Once the mastocytoma was gone the lymph nodes were gone at the same time. We didn’t have to take them out. He never had brown spots or urticaria pigmentosa.
Audience member: Now some of the lymph nodes are coming back. I was just curious about that.
Dr. Theoharides: I had a question I was asking one of the patients earlier so I might as well ask it now, in case the society can do something about it. I am very interested in knowing if the incidence of breast cancer in female patients with mastocytosis is actually higher than the overall population. Maybe we can do this by putting a question on the website to see if we can get any answers. It seems like I have already spoken to enough people here that have had breast cancer which is a little more unusual considering the population. And since there has been some interest, and we have also been working on mast cells in breast cancer, for all kind of reasons. I just want to have an answer, there doesn’t seem to be an answer and there is no publication out there.
Moderator: Do you want them to specify when they respond to the website whether or not they have confirmed mastocytosis or if they have mast cell activation syndrome?
Dr. Theoharides: We should break it down into both categories. Or else it would be impossible to tell. And also it is very important in order to use such statistics, to have as many responders as possible because in the past when we have tried to publish results with questioners from the internet, they ask you how many hits you get per month. So if you get maybe a thousand hits per month in this particular question there were only 20 answers, even though those 20 questions might be all positive( will answer the question as we all had this problem) it doesn’t mean anything. Then you divide it over the 1000 hits you normally have. I mean if you put it up, I would really encourage, if the board decides, for the people you to answer. Because it is a useful piece of statistic that may lead us one way or another.
Please note: We have contacted Dr. Theoharides to remind him to design this questionnaire for the website.
Question: For Dr. Castells I mentioned my 34 year old son to you earlier who they say is having panic attacks. Earlier in the questioner there was a question about children in Europe who they thought were having seizures. Ends up they had mastocytosis. As I told you, I believe my father had mastocytosis as well as I. Does it make any difference that my son had allergies at seven and benign focal epilepsy at nine? Is that the kind of diagnosis that is pretty definitive or would this be like the European children that he was told he had epilepsy, but instead he might of had mastocytosis.
Dr. Theoharides: I don’t think that those are enough to make a diagnosis. I think it is suggestive of maybe the same association with the European children that I had mentioned. But I am not sure I would do anymore than that. However, I would like to mention that I forgot. Two papers were published, one within last year in the Journal of General Psychiatry by a professor at Columbia University of New York. She was doing what we call ‘family linkage studies’ meaning trying to see in family members over a number of generations if certain diseases track together and if they do, what that might mean. So she published that she tracked actually interstitial cystitis and panic disorder. Not panic attacks but panic disorder which is a little more defined. Not only did she track the two together, she actually identified that both had linkage chromosome 13, even though they haven’t identified exactly where. So to the extent it is the first time that another disease is associated with mast cells. In fact in their papers they talked about mast cells and were referring our work without me even knowing about it. I went and met her. It might be a reason to consider panic syndrome in mastocytosis if panic syndrome also occurs more often which I don’t know. Maybe the society or some of us could make contact with her and she might not have thought of mastocytosis patients in term in familiar studies. I am pretty sure she had and there might be a reason to bring her aboard.
Question: I flush an awful lot is there one thing I can do or any medications that I can take more of that can help my flushing.
Dr. Castells: Most of the flushing is induced by the prostaglandin D2 so aspirin has been very helpful. We use aspirin up to 1200 mg and sometimes higher. It has to be enteric coated aspirin so it won’t hurt your stomach, and some patients who have intolerance to the non-steroidal antiinflammatories we have desensitized those patients to the aspirin before we start on them on high doses. But it is extremely effective.
Dr. Theoharides: In certain patients that flush, it is not prostaglandin D2 or at least not enough because some patients don’t respond. And we know that that’s the case because many patients flush when they have a syndrome called carcinoid syndrome which is not a cancer, derived from cells that look like mast cells called enterochromaphin cells from the gut. And there is serotonin involved, and in certain other conditions patients that take a vitamin called niacin sometimes to lower cholesterol, and they also flush. In there it is not prostaglandin D2. We have actually done work in animal models, which we have finished the work and we are about to publish, where we are actually correcting certain things. You cannot induce flushing in animals. You can increase the temperature. You can measure the temperature in the ear after injecting molecules that are likely to cause the equivalent of flushing in humans. You can get prostaglandin D2 to be elevated, where you will then get a lot of serotonin release from platelets. So for patients that don’t respond to what we commonly use, such as high dose of aspirin in the like, sometimes indomethacin is even better. Indomethacin is like an aspirin. Indomethacin is available in suppositories. It can bypass the stomach, to the extent that all of these things can do a job, especially a dose in daily high levels. Then we start thinking of drugs that might also block serotonin. I mentioned a drug once earlier that it may actually help with headaches. Periactin/Cyproheptadine, which is an antihistamine and antiserotonergic, and is very safe. You can actually add that and if it helps, so be it. We also show that Quercetin, even in animals, block the temperature rise in the animals very well. So if nothing works you can also try that. It has no side effects. And it might be helpful.
Dr. Butterfield: There are a lot of reasons for flushing. If these suggestions are not helpful you might look into a problem of sweating. If you have a sweating disorder, where you are sweating more say, on your face and less on other parts of your body, it may be a problem with your autonomic nervous system, causing a patchy uneven sweating on your skin. That may be interpreted if you are mostly sweating here, your neck, chest and face as a flushing problem rather it is a sweating problem. And you interpret as a flushing problem because you look red. But if you are not sweating normally on your torso say your back or legs, you are sweating more here, it will seem like you are flushing but you are doing most of your sweating there so it will be a sweating problem rather than a flushing problem. There is a sweating test, called a sweat test that is done to see if your body is sweating normally.
Question: Especially for those of us who don’t really have a true systemic mastocytosis. This is probably for Dr. Theoharides. Could there be a connection between leaky gut syndrome, flushing or some of the reactions that we have? If there is, what could be done for that condition?
Dr. Theoharides: I don’t really have an answer. I was discussing earlier with another patient that what I just alluded to the previous question. Not everything has to be mastocytosis. We have had patients with concurrent conditions, such as you could have both carcinoid and mastocytosis. But it is so easy to test for that because the 24 hour urine that you do for mastocytosis, not that that necessarily is the primary criterium, you could check for that or you could check for another called pheochromocytoma, which can also cause flushing. But it also can cause high blood pressure, which is the opposite of what happens in mastocytosis. Also we heard many times over the last couple of days that there are a number of mediators that release from mast cells that can cause vasodilatation therefore possibly flushing. There are not necessarily just histamine or prostoglandins. They are vascular endothelial growth factors that could be triggers, and aspirin and antihistamine may not block those. And I really think that patients with or without mastocytosis actually respond to different things at different times. It is very difficult to generalize. Now with a leaky gut syndrome, I am not sure if I would necessarily tie that to flushing although I would tie it other possible problems. So I really don’t know. Being primarily from an oncologist, my take always is, let’s try what is available, maybe sequentially and exhaust the possibilities before we start going into what I called earlier exotic kind of problems. Sometimes trying a second and a third thing, might help. You very well know as we know that many physicians and companies would not allow you trying one thing after another, especially when those things are not well defined for that particular problem. So where do you go? In conditions like these sometimes we have to try, even though the insurance might not cover it in the beginning, just to find out if it works. Because as you very well know if it works, that is what really what counts. And not who will cover it. You can go back and fight the company.
Dr. Castells: And we shouldn’t forget in terms of females, about flushing due to female hormones, perimenopausal. In general terms, perimenopause can be five years before the menopause and five years after menopause. So you can go 10 years with some flushing that is induced by female hormones. Just as a general message. We have to think of that too.
Dr. Theoharides: I will throw suggestions but when ever we are ready to eat or drink our brain automatically activates a nerve that sends branches to the linings of the lung and to the gut. It is called the vagus nerve and then releases acetylcholine. Acetylcholine is a neuro transmitter --very important in the brain and the rest of our body in how our muscles work. But there are two papers, and then subsequently some additional papers, indicating that acetylcholine might not trigger the mast cells all by itself. There was a phenomenal paper in a very good journal of Nature many years ago that people have not been able to at lease duplicate, but since there has been reports that acetylcholine, in addition to other triggers, can activate the mast cells. And the mast cells in the gut are known to release a lot of histamine and then release gastric acid secretion etc. Now could it be that nerve branches, such as the ones from the vagus, might release molecules that are vasodilatory that actually cause you to flush when you are about to eat? I am stretching it. But it might be. At least we know the nerves that are activated during the process that we are about to eat might activate the mast cells, except the vagus doesn’t send branches to the skin. So I have got a think of another connection to the skin that can actually explain the flushing.
Dr. Castells: I think we could talk a couple of hours of the food connection and the mast cells I would just say that Dr. Austen taught me how to diagnose mastocytosis. He said to me, ‘when you have a patient that comes to the office and said that they flush, ask them ‘when you drink wine do you flush?’ And if the patients say ‘yes’, mastocytosis. So what I am saying is that this is actually one of the cardinal symptoms. And what wine does to mast cells in the stomach have not been studied. And we don’t know much. We think that tyramine may be an inducer so, besides the factors that Dr. Theohardis has mentioned, there is also the directive fact of cold things, mast cells with cold will become more activated. And the direct effect of the food in the mast cells that are very very close to the surface of the stomach. The mast cells are in the lining of the mucus of the stomach. So the food could actually directly get in contact with that. So just remember about the wine.
Dr. Theoharides: I would just like to mention, I am advertising for all of us here, in the January issue of TransImmunology which is a fairly decent journal, there will be a paper that two colleagues of mine from Germany and I coauthor, that is called ‘The Brain Skin Connection’, with very nice color graphics. So you might actually like it. We had a good time writing it.
Question: Is mastocytosis, the flushing with wine and alcohol, the only thing that can make that happen?
Dr. Castells: No, you can also flush with alcohol and not have mastocytosis.
Moderator: A lot of people report on the email list and we see this quite a bit that they have low serum ferritin levels and a lack of stainable iron when they bone marrow biopsies done. Sometimes even in the presence of having normal hemoglobin and hematocrit.. And we see people write in a lot and say, ‘all my blood work was normal and I am not anemic but my serum ferritin is 4.’ Do you have any explanation for this?
Dr. Castells: You know low ferritin is a problem with females mostly. Not with males. We have encountered that losses during the menstrual period have been accounted for the low ferritin. It is corrected by replacing the iron. I have not seen any data on males having low ferritin.
Audience member: I have seen it in males
Dr. Castells: Excuse me? You have seen it males too? I haven’t seen it. Very common in females though.
Audience member: Why does this happen?
Dr. Castells: In connection with mastocytosis we don’t really know. We don’t know if it is associated to mastocytosis. It is a common problem in the population. If you sample all the women in this room, 20% or 30% will have low ferritin. It is a bad comparison because we might have a lot of instances of mastocytosis. But if you sample 100 women not having mastocytosis 20% of them will have low ferritin. And that is almost all physiological type of problem. I don’t know of any study that has linked that or the frequency be higher in females with mastocytosis. I don’t know that.
Audience member: So low ferritin is common in females that have mastocytosis?
Dr. Castells: And the general population.
Audience member: but with boys?
Dr. Castells: I haven’t seen that. And the ferritin hasn’t been reported to be low in series of men. I have not seen that.
Moderator: It looks like there are no questions left. I would like to thank this wonderful panel for giving us their time.
Thank you all.