Transcript of the Panel Discussion from the 2004 TMS Annual Meeting
| Date: | October 9, 2004 |
| Location: | Springdale, Ohio |
| Moderator: | Gigi Park, Research Chair |
| Panelists: | Dr. Cem Akin – University of Michigan Dr. Leonard Bernstein – University of Cincinnati Dr. Joseph Butterfield – The Mayo Clinic (Rochester) Dr. Mariana Castells – Brigham & Women’s, Harvard Medical School |
Moderator: First I would like to introduce the panel and have them come up in the order that I present them. First I would like to invite Dr. Leonard Bernstein to come and sit on the panel. You have not met Dr. Bernstein yet. He is joining us from the University of Cincinnati where he runs the Bernstein Center of Allergy and Immunology and he currently sees 15 mastocytosis patients . . . about that. You all know Dr. Butterfield – so, Dr. Butterfield. You know Dr. Castells, Dr. Castells please. And you know Dr. Akin, so Dr. Akin please.
Before we start, I also just want to discuss a little bit about the format of how we are going to do this and how this project came to be. About 4 months ago I started soliciting questions on the list and also through the Chronicles to give the people who cannot attend these conferences the opportunity to get their questions answered by a panel who collectively have some 75 years, conservative estimate, experience in treating mast cell disease. So, I would ask that you please hold your questions until the end. I will try to get through as many as I can. We are definitely not going to get through all of them. But, I thought it was interesting to print them all and let you know what is on people’s minds. I will stop at 10 minutes to 12:00 p.m. and then we can do some question and answer follow-up from the audience. But until that time, let’s just get through these questions and give those folks who couldn’t be here an opportunity to get their questions answered. And, by the way, you all have copies of these questions in your packets which should make it easier to follow along, but I will read them as well.
The first question we have . . . and by the way these are all pretty much exactly as they were submitted. I didn’t rewrite any of them because I was afraid I would introduce some sort of bias, so this is exactly as we received them. I also didn’t write any of them.
Question 1 - The consensus proposal stemming from the Vienna conference and published in the July 2001 Leukemia Research Journal asserted that the proposed criteria would hopefully serve to distinguish mastocytosis from mast cell activation syndromes. What mast cell activation syndromes did this consensus proposal allude to?
Dr. Akin: I think the conference - what the conference did - was to propose specific criteria to recognize systemic mastocytosis as a neoplastic disorder of the mast cell and differentiate it from the hyperplastic disorders of the mast cells – mast cell hyperplasia, some of which may also be associated with mast cell activation. So, of course, there is no standard definition of mast cell activation syndrome, but there are syndromes or disease states that are associated with mast cell activation. So, one of those is, for example, idiopathic anaphylaxis. When you have anaphylaxis and you don’t have any other cause identified, then you can call it idiopathic anaphylaxis, or it’s an activation disorder of the mast cells. But, it is not a neoplastic, so the mast cells don’t have the c-kit mutation and they look like normal mast cells but they just function abnormally and we don’t know why that is. Now, another example is, for example, based on Dr. Theoharides’ work, some patients with interstitial cystitis have biopsy evidence of mast cell degranulation but it is not appropriate to say that these patients have mastocytosis based on that evidence - just based on degranulation. So, I think those are mainly normal mast cells but they are activated in a different way. So, they may be encountered in other disease states which already have their own names, like idiopathic anaphylaxis or cystitis. I am not sure if there is a distinct syndrome called mast cell activation disorder at this point. There may be, but if there is, it’s just not very well-defined. So perhaps one of the good things that might come out of this panel and the conference is that perhaps putting our brains together to see if we can review the evidence objectively and see if we can come up with diagnostic criteria if that syndrome exists.
Moderator: Anyone else on the panel have anything else to add?
Dr. Bernstein: Well, this is one of the main problems that I have, I, as an immunologist/ allergist, because patients come to me very often with anaphylactic reactions that we really can’t find a cause for. And so we classify them as idiopathic anaphylaxis – in fact, some of them don’t have elevated tryptases. We always check for that of course, but some don’t. And, they don’t have any other manifestations of mastocytosis, at least as far as we can tell. So, of course the mast cells are activated. But, the real difference here is that these patients have life-threatening episodes, and multiple life-threatening episodes. Not to say that you can’t have those with mastocytosis as well, but not as often as these patients. So, there is a difference. I’m not sure how we can tell except by observing the patients. And, I’m not sure that, if we are going to use the term mast cell activation, I think we have to say that there are a group of patients that have simply idiopathic anaphylaxis associated with it. There is something very close to this - exercise-induced anaphylaxis. We know that exercise does it, and sometimes these exercise-induced anaphylactic episodes are food-dependent and it may be non-specific – just eating any old food. And that’s really not a cause. So, if you know excitatory factors that affect these people, and I look upon them as having mast cells that are ready to be triggered, they are very highly releasable, and how that’s related, for example, to patients with proven-food allergy – multiple food allergy – you can prove it by double-blind controlled tests – their basophils seem to be easily triggered. We don’t know about their mast cells, but their basophils seem to be easily triggered from multiple stimuli. So, there are lots of unkown facts here between these different syndromes and I think that is why it is vague, and I doubt whether we can come to a consensus about that term.
Question 2 - A number of us have been diagnosed at widely-recognized research centers, e.g.. Brigham & Women’s and Vanderbilt, with Mast Cell Activation Disorder (MCAD), Mast Cell Activation Syndrome (MCAS)*, MCAS with Idiopathic Anaphylaxis (IA), Idiopathic Mast Cell Activation Disorder, or the newly-proposed Mast Cell Mediators Activation Syndrome. What is your opinion of these diagnoses?
Note: Given that there is no consensus on terminology, for convenience sake we will use the term MCAS throughout the rest of this questionnaire/transcript.
Moderator: But we hope that you can.
I think the panel just pretty much covered the second question . The only thing I would ask is, we’ve been diagnosed with different terms – Mast Cell Activation Syndrome, Mast Cell Activation Disorder, the newly-proposed Mast Cell Mediators Activation Syndrome – would you say that those terms could be used interchangeably? Are they synonymous? Is there any difference?
Dr. Butterfield: Well, one seems to be as good as another right now. I mean, we really don’t know what we are talking about here yet so . . .
Dr. Castells: The only emphasis I would say is that although we may be looking at a wide spectrum of patients who have those, like Dr. Bernstein, said, those life-threatening episodes of anaphylaxis where they lose their blood pressure, they go into life-threatening episodes, to you know, idiopathic cystitis, or you know, interstitial cystitis; there is really a great variety, but it seems that in terms of the treatment what we have to let the public know, not only the patients but the public know, is that those patients have something wrong with their mast cells – so there is one single thing that can help them. And that thing is called epinephrine. I just want to make you aware of that because, as Dr. Bernstein said, those patients . . . I have seen patients come to my emergency room at the Brigham in Boston that are wheezing, filled with hives, and then I go downstairs and I say, "Well, how many epis has the patient received?" and they say, "Epi what?" and I say, "Epinephrine," and they say, "Well, they have already had Solumedrol and a lot of Benadryl," and I say, "That’s not the question. If you don’t use epinephrine, you know, the patients can have really bad events." So having a patient diagnosed with idiopathic anaphylaxis versus mast cell mediated syndrome or mast cell activation syndrome doesn’t matter too much as long as they both carry an epi-pen and as long as their PCPs [primary care physicians] and those around them know that they have to carry an epi-pen.
Dr. Bernstein: I have a comment following on that. I think I agree completely about the need for having epinephrine. But, we have a problem in our area, in southwest Ohio, of trying to educate the emergency room physician. They don’t even prescribe epinephrine for anything. Well, I’m exaggerating of course, some of them do, but we do need to educate them. For example, when I have a patient who has idiopathic anaphylaxis or mastocytosis and I put down on a prescription blank next time you have an episode and you have to go the emergency room, have them draw a tryptase. And I write it up, t-r-y-p-t-a-s-e, more than you would think, they do an alpha1-antitrypsin. It is amazing that we just have to educate them and I think that’s one of the purposes of this Society. I mean, even locally, I think that really you have a lot to do educating emergency room physicians.
Moderator: So, I will be calling you, Dr. Bernstein, to help me write that protocol. [laughter]. I am going to change this next question a little bit just to make it appropriate to this discussion.
Question 3 – Are there tests that you can anticipate would help to establish the diagnosis of a mast cell activation syndrome, and in your opinion is laboratory evidence necessary, or will it be necessary, in making this diagnosis as opposed to a clinical diagnosis based on symptoms, response to medications, and exclusions of differential diagnoses?
Dr. Butterfield: Well, yes. I mean, there are many disorders that can give you similar symptoms – take flushing or hypotension - many of the symptoms that we see with mast cell degranulation. So, I think it is necessary if we are going to implicate the mast cells to have evidence that at least at the time people are symptomatic that there’s increased mast cell mediator levels that we can correlate with those symptoms. Flushing has a number of causes, for example. Many of the symptoms that we see with mast cell degranulation could potentially occur in other disorders as well, so if you are going to tag the mast cells as the fall guys here then we need evidence that they are in fact degranulating at those times. So, yes.
Moderator: Dr. Castells, did you have something to add?
Dr. Castells: I would agree with that, although I would point out that we do not have the best tests available in terms of, you know, the tryptase test is a good test. I was there when Dr. Schwartz was developing it. Unfortunately, it did not come out in the real world the way we wanted it. In the tryptase tests there are two things that you test, you test that alpha tryptase and the beta tryptase. So, when you have an anaphylactic episode you have an elevation of the beta tryptase and if you send that to Dr. Schwartz that would come out elevated. But, if you send that to pharmacy or to Quest Laboratories your total tryptase may not be elevated – so what happens here is we need to keep going after those mediators but whether sensitivity of the tryptase test is high, I can’t say that it is for all the syndromes of mast cell activation.
Dr. Bernstein: And the problem may be even slightly more complicated than that because there are variants, some of which I see, in patients who have primary reactions due to metabolites in the arachidonic acid pathway, they have metabolites that give them hypertension instead of hypotension. And, Dr. Oates and Roberts down in Vanderbilt first described this. So, with such patients you have to think of an alternative approach as far as which tests to order. And, it can be, if you don’t think about that, you may miss it completely. I try to impress on my patients if I suspect mastocytosis that they really eventually have to do a bone marrow biopsy. But,you know many patients resist that. They just don’t like the idea of a bone marrow biopsy. It is really not that bad anymore, but that is my most difficult bit of advice for patients. I don’t know how else we have to find the mast cell in situ someplace. And if you don’t, you can’t rely on a laboratory test.
Dr. Butterfield: For those folks that have baseline levels of these mediators that are normal – and we rely on a panel of mediators, not just the tryptase, we check the calcitonins and the urinary histamine metabolites as well as prostaglandin metabolites, if we have a normal baseline and we are trying to incriminate mast cell products during the time of an attack, we will send them at home a mail back kit with a urine jug for them to begin to do a collection immediately after, or coincident, with their attack and some blood tubes for them to have drawn at the local emergency room to have the serum spun off and kept in the cold until it can all be put back in the mail back box , label slapped on, and sent back to us and we’ll do the assays at that time so we can catch, when symptomatic, levels of a panel of mediators and that has been helpful for a number of folks.
Moderator: I am going to exercise moderator privilege and just add one question. You know, I started out with Dr. Theoharides, so I originally knew more about interstitial cystitis than I did about mast cell disease. In the beginning, the NIDDK had very restrictive criteria for diagnosing interstitial cystitis and there was a gold standard test, but over time it has evolved to the point where they do allow for a clinical diagnosis based solely on symptoms in the opinion of an experienced clinician, excluding other diseases. So, I wonder why that could not be the case with mast cell activation disorder.
Dr. Bernstein: Well, basically in most cases of interstitial nephritis, or I mean cystitis, you usually are seen by a urologist, somewhere along the line, and at least you have biopsy material. So, I think there is a local problem there as opposed to some of these mast cell activated syndromes which can be generalized, and usually are generalized, and there may be multiple organs involved. So, where do you go looking for this? In the bladder, I think you can go looking for it and yes, I think if you find evidence of it and it has all the characteristics that might be associated with mast cell activation syndrome, I might think that might be permissable, but the other ones are all over the place.
Moderator: I think my point was that they don’t require evidence. They allow for a clinical diagnosis based on symptoms even if they don’t find . . . but, I mean, that may not be appropriate for this disease. I’m just throwing it out there.
Question 4: Are there differences in treatments and precautions, including anesthesia precautions, between patients diagnosed with mast cell activation syndrome and those with mastocytosis?
Dr. Bernstein: Well, I’ll take a crack at it. I just had a patient who had an operation, so this one I am very familiar with. She of course has mastocytosis and she did very well. I mean, we loaded her up with the usual H1 and H2 antagonists and she had muscle relaxants, she needed that. We pre-tested her – incidentally, the skin test for muscle relaxants which are very important in general surgery are fairly reliable. They are not 100%, but they are fairly reliable. And she was negative, fortunately. So, although one can never rule out the possibility that you might have direct release from the mast cells with any of these agents, I just think you have to give these patients a little extra care preoperatively and in my experience – I don’t have a lot of experience with this because hopefully you try to keep our patients away from surgeons, but the few that I have done seem to be able to weather the storm pretty well.
Dr. Butterfield: It would seem a prudent thing to do if you have someone that you documented high level of mediator products at times they are symptomatic, even though you can’t document clusters of mast cells in the bone marrow, that if they have documented high levels of one or more mediators at times they are symptomatic you probably want to be prudent about it just the way you would if they had mast cell disease. It is not a great effort to do this.
Dr. Akin: And whether there is a difference between mast cell activation disorder and mastocytosis, I don’t think we have defined mast cell activation disorder so I don’t think we can answer that question when we don’t have a good definition of what mast cell activation disorder is, but in general patients with mastocytosis are at increased risk for adverse events during general anesthesia and I think the number one culprit is the muscle relaxants. In the general population who don’t have mastocytosis, about 65-70% of the anaphylactic reactions occurring during general anesthesia are due to muscle relaxants. So, I think it is – when we have a patient with mastocytosis scheduled for surgery, we always try to obtain previous surgical records and obviously make the anesthesiologist aware of the diagnosis and go over the previous records and try to stick with the medications that were used before and known to be tolerated by the patient. If there is no such history, than I think it is sometimes not possible to predict some of these events ahead of time so the best strategy is to be prepared to treat an adverse event and perhaps premedicate the patient with H1 and H2 antihistamines and give the drugs slowly, initially, if it is possible, instead of giving one big bolus dose.
Dr. Castells: I did work with Dr. Escribano in Spain where he has standard protocols for patients going into surgery with mastocytosis and empirically we have kind of adopted that for our patients with mastocytosis and patients with mast cell activation syndromes, and we have a standard dose of steroids, a standard dose of H1 blockers and H2 blockers that we give the night before and just an hour before, similar to what is done with premedication with radio contrast medium. One thing I can tell is also females in the study that was done by Drs. Akin and Metcalfe at the NIH who have children, and I suppose that there is a great deal of trauma during delivery, have been able to go through delivery whether it’s with an epidural or general anesthesia for a c-section with no problems. We have at least five women who have delivered who have mastocytosis with no problem. It seems that at least in a controlled environment we are able to control very much what happens whether it is surgery, aggressive procedures . . . I mean, colonoscopy used to be, there are several published reports in which patients had had severe events during colonoscopy because of the extent of the mast cell involvement in the gut and with those premedications it seems we have reduced the number of events.
Moderator: I think we have addressed this as well, but I just want to hear you say yes.
Question 5: Are there any plans to conduct studies on people who fit the mastocytosis profile but not the criteria?
Dr. Castells: I think this is one of the positive things that came out of bringing all of the four of us together. We are just thinking about that very actively in terms of, first of all, producing some evidence from data in terms of the patients that we already have and then putting our heads together thinking what could be, like you said, standard criteria. Is clinical criteria with some small evidence good enough to provide ground for the syndromes?
Audience: [Applause, Cheers]
Moderator: I think kind of the reason why people are asking these questions and using the terms mast cell activation syndrome, mast cell activation disorder, is that they have been given this diagnosis at various research centers. I know Vanderbilt and Brigham & Women’s use these terms and so patients are given this diagnosis and then they don’t know how to explain it – people ask them what it means and they don’t know what to say.
Dr. Castells: I just will do a little pointing out, I told Dr. Bernstein that I didn’t like the name that he likes, probably because I’m just 10 years younger than he is [laughter], and it is just because the word idiopathic anaphylaxis has some notations and the initial work done on that was done by Dr. Patterson who used steroids to treat those patients. And then patients who have been labeled with idiopathic anaphylaxis have to be put on steroids as a standard of care and that’s why we don’t think it was a good idea to continue to use the word idiopathic anaphylaxis because that was synonymous with steroid usage when in fact in our standard practice we don’t use steroids anymore for those patients. So, that’s the only thing I have against the word. On the other hand, I like the word anaphylaxis because you know the people who say “I have anaphylaxis,” everybody associates that to epinephrine, and that’s the plus on that side. So again, we are a little bit divided but putting our heads together.
Dr. Bernstein: Well, I agree of course that all patients with idiopathic anaphylaxis should not be on steroids. In fact, I agree wholeheartedly with that point of view. I think it was a mistake that all these patients originally were put on steroids. Occasionally, some of them need steroids – I mean everything in medicine isn’t all white and all black – but the vast majority do not and can be controlled without steroids. I think it is a good term, yet we are just finishing up an update of the parameters of anaphylaxis for the major allergy societies and we certainly are going to keep it in there. Now we may, after this discussion, have a little explanatory paragraph about mast cell activation and the differences between how we distinguish those two. So, I have learned a little bit here right now too.
Moderator: I look forward to receiving those. Most of you have my email address.
Question 6: Could you please comment on the apparent discrepancy between serum tryptase levels, the amount of bone marrow mast cell infiltration, and symptom severity.
Moderator: I know this person. I know the person who asked this question and basically what they were asking is they have a very high tryptase level but their symptom severities don’t seem to be as severe as patients with normal or near-normal tryptase levels and that doesn’t make sense to them. So, that is the question.
Dr. Butterfield: Well, I’m not sure exactly what symptoms tryptase causes. We know histamine does certain things, prostaglandin does certain things, but to tell you what tryptase does . . . I can’t tell you any particular symptoms. Also, you are referring to the degree of bone marrow mast cell infiltration as increasing and the typtase is going higher and the symptoms are not severe – is that the point?
Moderator: They are comparing themselves to people with anaphylactic episodes and they don’t necessarily have them and so they are feeling that their symptoms are not as severe.
Dr. Butterfield: Oh, I see.
Moderator: And that does not make sense to them. And think that was their question.
Dr. Akin: Yeah, I don’t think we understand completely first of all the mediators released from the mast cells. So, just because somebody has ten times as many mast cells as another person does not mean that he is producing ten times as many of the particular mediator than the other person. So, I think that is the first point. The second is that in some patients, especially with extensive mastocytosi, with a high degree of mast cell involvement, some of those mast cells may not necessarily be as mature as normal mast cells. If I showed you the slides yesterday and Dr. Castells did today the mastocytosis mast cells have less granules in them as opposed to the normal mast cells which are fully granulated so it is possible that they may also contain different mast cell mediators and we already know that they have different surface molecule expressions. It is possible that one of the observations we make for example is that patients with anaphylactic symptoms who have fewer number of mast cells have more levels of IgE on their surface. So it is possible that there may be activated at lower thresholds, or faster, or more easily activated than a person who has more mast cells.
Dr. Castells: I think what I wanted pointed out is that what tryptase measures is how leaky the mast cells are, not how activatable they are. As Dr. Akin pointed out, the tryptase that we measure, it’s a baseline, so the patient is not having symptoms and the tryptase is elevated. It’s just the leakiness of those mast cells which are already somehow immature. It doesn’t really measure how can the mast cells release – how can they be activated. So it is a measurement of the mass of the mast cells due to that leakiness on those cells. It doesn’t predict anything. It just says probably the number of mast cells. The more you have it, the more leakiness you have and you probably have more of the bone marrow involvement. But that is all that it predicts.
Dr. Butterfield: Keep in mind also that you can elevated tryptase levels not only in mast cell disease but in other disorders in well so that perhaps there is another blood disorder smouldering in the background as well to explain the high tryptase level.
Dr. Bernstein: Just a clinical highlight about any test of this kind, we more and more are trying to base a diagnosis on evidence-based tests, common evidence-based tests, but it is predictive in a certain range of the diagnosis. But, so far there is no likelihood ratio that I know about that will help in determining severity of the syndrome. So, there are two things that have to be distinguished here – the diagnosis and the severity.
Moderator: I think we just covered question 7, so I am going to skip that question and move on to question 8.
Question 8: I'd like to know how stem stell research will impact mast cell disease research?
Dr. Akin: I tbink the first area would be in the bone marrow transplantation as they develop better strategies to identify what the stem cell markers are and isolate them more efficiently from the bone marrow or blood of the donors or the patients, then we will have better cure possibilities for patients with aggressive mast cell disorders like leukemias and such. And the second is that I think it is also equally important to know what mast cells are related – what other cells are related in terms of what they are derived from. So, they are from the same progenitor as, for example, bone osteoclasts, or cells involved in bone formation, or are they derived from the same precursors that also give rise to the blood vessels? And if so, are some of the abnormalities that we detect in mastocytosis mast cells, are they also present in other cells? So, I think it is an interesting question from that perspective as well.
Dr. Castells: I have to say that mast cells are very resilient cells and there is in the literature people who have had bone marrow transplants for other hematological malignancies and they continue to have those darn mast cells there and they continue to be there. So, you can’t kill the mast cells that easily. So, at this point, they don’t do a lot of damage when they are there to a certain extent but we don’t really know how to kill them. They are very, very, resistant. Even radiotherapy doesn’t work for mast and bone marrow ablation may or may not work for them. So, I think we are at a very, very early step and very early age in which this would be helpful for this kind of disease. It is very preliminary at this point.
Question 9: How often should a mast cell disease patient be seen by doctor(s), and in what specialty areas?
Dr. Butterfield: I think we might have touched on that before.
Moderator: We did, but we have a new audience.
Dr. Butterfield: Well, how often may depend on how severe the disease is when they are initially seen. Someone with severe disease, aggressive mast cell disease, may be more frequently. Someone with quiescent disease, that’s very stable, less frequently. At least initially, we’ve been checking – well, I think that gets on the next question. Specialty areas, it probably doesn’t matter a whole lot as long as the doctor is comfortable seeing mast cell disease or can work with someone that is comfortable seeing the disease and can work as a team. Let me just get back to the how often. If patients are stable, we see them about once a year. If they are not stable, we see them as often as needed - perhaps even every couple of months, every month or two. We are in contact with their doctors, however, very often, very frequently, and personally I have had collaborations with hematologists, general internists, family practitioners, dermatologists, and endocrinologists because the entry point for a lot of these folks to have their mast cell disease diagnoses is quite variable and they can start off with many other consultants.
Question 10: What tests should mast cell disease patients have regularly and how often?
Dr. Akin: I think after the initial evaluation I usually recommend to my patients that they have a tryptase level checked at least yearly and a complete blood count with differential and perhaps liver function tests at the minimum and on top of that if they have abnormal test results noted during the initial evaluation then they need to follow up on those as well. And we also talked about bone densitometry yesterday, for example, I always recommend the bone densitometry test to be obtained and if it is abnormal again periodic follow up every 6-12 months. If it is normal, perhaps every 4-5 years.
Dr. Castells: I strongly agree with that and I would add that the blood cell count is very important because of that potential for a myleodysplastic/myeloproliferative association with the mastocytosis. So not only the tryptase or the mediators that validate the disease but a white cell count would be very important.
Question 11: At what point should treatment be started for a mast cell disease patients and how is it determined what treatments are appropriate?
Dr Butterfield: Are you referring to cytoreductive treatments to reduce mast cell numbers or just mediator blocking medications?
Moderator: I didn’t ask this question, so you are asking me to interpret . . . .
Dr. Butterfield: Is the asker here?
Moderator: No. These are all people who actually couldn’t be here and that was the whole point of formulating this list of questions, so these came from the email list and from solicitation in the Chronicles.
Dr. Butterfield: Well, at least initially you can use the symptoms, clinical findings and laboratory reports to target the area that’s probably the most problematic for the person presenting. It it’s perhaps GI complaints, you can target your treatment towards medications for the gastrointestinal tract. If it’s a bone problem you would want to maybe target your treatment a little differently. In use these types of mediator blocking medications of course differ to some degree. If it were for the bone, perhaps alpha interferon might be used earlier than in other patients. If it was gastrointestinal symptoms with ascites, portal hypertension, and malabsorption then steroids might be used earlier. So, it depends to a degree on what the leading complaint is. Perhaps someone will come in with multiple organs involved and then you have to sort of put together a medication program to target those areas that are most problematic for that patient. Then, as far as the cytoreductive treatment goes, that might occur earlier on with someone with aggressive mast cell disease or someone with deteriorating clinical status that may have presented with an earlier stage and is deteriorating rapidly and not responding to mediator blockades.
Question 12: When should steroids be added as a treatment for mast cell disease(s)?
Dr. Akin: I think there are three instances where steroids are helpful, at leas,t and the first one is intractable diarrhea, the second is liver problems with collection of fluid in the belly, it is called ascites, and the third one is recurrent anaphylaxis occurring maybe more than six times per year or so, not just one or two episodes, but frequently enough to consider the addition of a medication like a steroid which has a lot of side effects so you need to balance the side effects of steroids which are many including gastrointestinal problems, ulcers, immunosuppression, reduction in bone density which the patient already has susceptibility for – but I think in those three incidences probably the benefits outweigh the risks.
Question 13. I’d like to hear about the musculoskeletal aspects of mast cell disease that are acknowledged but not much discussed in the literature. Also laryngitis/pharyngitis is another area of relative literature silence, please comment.
Dr. Bernstein: Well, we’ve already discussed the bone symptoms. As far as laryngitis/pharnygitis is concerned, patients who happen mostly to be atopic have true inhalant allergies and will frequently have post-nasal drip and if it’s untreated will create unpleasant symptoms in the nasal pharynx, even in the larynx, until it is handled properly, and in fact if it is refractory to treatment may be a reason to go in to the possibility of avoiding things that can be avoided, at least that should be done, so at that point maybe an ear nose and throat or an allergy consult might be appropriate.
Dr. Butterfield: There are a couple patients described with mast cell pharyngitis, and I don’t think it was just in patients with masto, but there was a localized infiltration of mast cells in the tissues of the soft palate and the problem was localized swelling, so that can occur as an isolated symptom as well.
Question 14. Do people who have mastocytosis but not the c-kit mutation have visibly different looking mutated mast cells? I’m asking this because I suspect the accepted criteria for diagnosing mastocytosis is biased toward finding the c-kit mutation. Is this true?
Note to the audience: More than one mutation has been identified. However, generally speaking it is safe to assume that the questions refer to the most common codon 816 c-kit mutation.
Dr. Akin: Well, I don’t think the criteria are biased towards finding the c-kit mutation. We have diagnosed patients without c-kit mutation who fit the criteria otherwise with mastocytosis and some of them are treated with Gleevec because they don’t have the c-kit mutation so if we didn’t think that they had mastocytosis we wouldn’t have treated them with Gleevec. But, do they have visibly different looking mutated looking mast cells? The first issue before addressing that question is how do we know that patient doesn’t have the c-kit mutation? I mean, is our test as sensitive as we would like it to be? And the answer is it depends on which sample you look for. So, a lot of patients have c-kit mutation analyzed in their blood, in the peripheral blood, for example, and that is not a very good sample to have the c-kit mutation analyzed because you need to look at the tissue in which these abnormal mast cells reside and that is usually the bone marrow or the skin. And, you need to find the way to enrich these mast cells. So, in our experience we look at bone marrow samples and we find a way to enrich these mast cells based on different surface marker expression profiles, for example. We find the mutation in about 90% of the patients and another 10% we don’t.
Moderator: Do you have any theories on the 10% in which you don’t find the c-kit mutation?
Dr. Akin: No, I don’t. Well, and I’m talking about the 816 c-kit mutation. A few of them have other mutations. But, no, I don’t know about the others. Of course, the pediatric patients, they have mastocytosis but most of them do not have the c-kit mutation and we do not know what the pathology is in those patients, I mean what kind of mutation they have or if they have any kind of mutation.
Dr. Castells: I think there was a study describing a non-activation mutation in the pediatric patients at the 839 codon also, so there has been a variety of mutations and so far the screening test is the 816 mutation. I mean, Dr. Butterfield described this cell line that had another one in the 506 mutation. You know, I think there are a lot of mutations. The only test we have right now available, at least we use more commonly, is the 816 mutation, so I don’t think we can say more about the other ones.
Dr. Akin: We actually described a variant of mastocytosis last year, it was published in Blood, it is called well differentiated systemic mastocytosis. In those patients they don’t have the classic 816 mutation, some of them have mutation at other sites, some of them don’t have any c-kit mutations, so the answer to the first part of the question is yes they might look different.
Question 15: Some doctors have said that there are supposed to be some wonder drugs coming out for mast cell disease in the near future. Is there any updated information on them? When will clinical trials be started for these drugs? And who will be the appropriate candidates for these trials?
Dr. Akin: Well, I don’t want to do all the talking, but I think this is an area that I was involved in so, there are some new drugs that will be coming out for clinical trials. They mainly fall into the category of tyrosine kinase inhibitors which is what Gleevec is, but first Gleevec does not inhibit c-kit mutation, so there is a lot of effort on the part of drug companies to develop new drugs that can inhibit that mutated c-kit and they are hoping to use those drugs not only in mastocytosis but also in other malignancies in which c-kit is mutated, like acute myeloid leukemias, and also chronic myeloid leukemia where patients who are on Gleevec acquire resistance to the drug after being on the drug for several months, so I think the applications of that research is more than mastocytosis. It is a good development for us that they are interested in this area. So there are different companies coming out with these drugs, and I can think of at least two or three new drugs that might be coming out and I think in the next 6 months to a year you will see the opening of multi-center clinical trials for some of these drugs and the multi-center studies will be done, as far as I know, in addition to the University of Michigan where I am at, NIH will probably get involved, and Mayo Clinic will be involved, and I’m not sure if Brigham & Women’s have plans.
Dr. Castells: I wanted to add also something about the new drugs. There is one specific drug that is now available, that’s called Xolair, it’s anti-IgE. That is used for patients with allergies with asthma and at Brigham we are one of the multi-centers for the study of that Xolair drug on patients with anaphylaxis for peanut. So, for patients with mast cell activation syndrome there is a lot of interest if the working diagnosis is that the IgE would be driving those mast cells. So, you may hear in the news that Xolair is the new wonder drug for allergies also. Whether we think that this will be applicable to the mast cell activation syndrome, idiopathic anaphylaxis, I think is still being debated right now, but you may hear a lot about that.
Moderator: I believe that there is a board, too, somewhere where we posted the clinical trials that we are aware of – some at MD Anderson, where they are doing a clinical study with Ontak, I know that one. Did that happen? [“no” from the audience] That didn’t happen? I will get that for you. I brought a copy with me. If it’s not here, I’ll get it for you. I promise.
Question 16..What drugs/treatments are in the pipeline – not just c-kit therapy, but any other promising mast cell stabilizers or medications to combat particular mediators or there effects?
Moderator: Xolair would be one of them, perhaps . . .
Dr. Castells: Like I mentioned, in mastocytosis we don’t have any evidence that IgE is one of the driving forces here and in fact I think that the data points out that mast cells in mastocytosis have less IgE receptors so I’m not convinced that Xolair might be in that direction, but for mast cell activation syndromes the IgE might be one of the driving forces and that definitely. We are one of the centers at the Brigham in Boston that will be working on that, but initially we will be working on patients who have a defined allergy, the peanut allergy essentially. In terms of other new antihistamines, I think that there are a lot of antihistamines down the pipe that are coming, but in terms of mast cell stabilizers, I am not aware of anything.
Dr. Bernstein: Well, if there is pulmonary involvement, we usually use nedocromyl. Nedocromyl is a very good mast cell stabilizer for pulmonary involvement, but it’s not much good for anything else. But as far as antihistamines go, I think we really shot our wad with antihistamines. We are involved with all the new antihistamines, and I don’t know of any particular one that is being investigated, unless you do . . .
Dr. Castells: No, the only thing I could say is about the Ketotifen, which is a wonderful antihistamine, at least we have used it for over 20 years at the Brigham, and without any permission from the FDA, and we ask our patients to pick it up from Canada or from Mexico or from Europe. I mean, it is all over the world, except here. I mean, in the form that we want it. Because there is Ketotifen in eye drops, so we have it in that form, and we can use it. So, when patients ask why the FDA won’t approve it – is it a poison? No, it isn’t a poison. My allergic patients with conjunctivitis use it all the time. But, it is not in the form where we can take it orally here, and I think there is a big effort, I am supposed to send some paperwork through the FDA, I am the designated one, and I haven’t started the effort, anyway, to pass it through the FDA, but the Ketotifen is supposed to have mast cell stabilizing options not only the typical antihistamines and it is being used for asthma also. There are nice studies showing . . . it is one of my favorites antihistamines, so I am biased, with that I like it. I think 1 to 2 to 4 milligrams a day is very powerful for patients and there are very little if any side effects.
Dr. Bernstein: Well, the reason that Ketotifen is not available, I know about this, is that when the first studies that were done, clinical studies, they were double-blind, randomly controlled studies that didn’t show efficacy in large studies. And, it’s just like any other drug. There may be people who respond, and maybe mastocytosis is different and probably is, but originally we studied it for allergic rhinitis and it was simply not effective. Now, if the company wants to invest in other studies they would have to show . . . in order to get a drug approved by the FDA you have to show two studies that have efficacy. In fact, the evidence that I saw, and I was on the pulmonary drug advisory committee at that time at the FDA really the drug did not show efficacy. I mean, people were pushing it, obviously, because it does have, anecdotally, does have effect, and in fact I remember I used to try to get some of my patients on it but it got to be such a chore and also I wondered what the reliability of it was from Mexico, to be honest about it, so I stopped doing that.
Dr. Akin: Other potential drugs, in terms of antihistamines, there are more than H1 and H2 receptors that the histamine binds to. There are actually 4 histamine receptors. There are H3 and H4 receptors that were described within the last, I think, 5 years. H3 receptors are found primarily in the brain and are very involved in neuro-psychiatric manifestations of histamine. So, I think there are some drug developments efforts to block those H3 receptors. And, H4 receptors, we don’t know what they are but only what functions they do. They are mainly on immune cells, immune system cells and lymphocytes, and I am sure there are some development efforts on those areas as well. And the other area is cytokine secreted by mast cells, for examples tumor necrosis factor alpha, we already have drugs blocking tumor necrosis factor alpha approved for use in colitis and I believe rheumatoid arthritis. But, we don’t know how effective they are in mast cell disease patients so I think that is also an open question. And there is an antimonoclonal antibody against IL-6 which is also known to be elevated in mastocytosis but we don’t know how effective it will be in mastocytosis.
Dr. Bernstein: The possibility of some of these monoclonal antibodies against cytokines is still very much with us. I think we are going to see a lot of new drugs in that area. One drug that we are investigating in our center right now is an anti-TNF alpha different than the ones that are commercially available for the treatment of asthma and if that does work for asthma, it might be logical to try it for mastocytosis.
Question 17: What are your recommendations on pain medications/dosage?
Dr. Butterfield: What type of pain? Like bone pain?
Moderator: Again, I didn’t write this question, so . . .[audience responds – bone pain]
Dr. Butterfield: Well, bisphosphonates have been tried with some benefit for bone pain, I think they are the leading medication for bone pain right now.
Dr. Castells: I think that all the other codeine or morphine derivatives, I don’t think we should discuss them because it is a double-edged sword. I provide data supporting that they activate mast cells and then on the other hand they provide some relief for pain, but I think it is on a case by case basis that this needs to be discussed. I don’t think there is any general data to support what would be universally good for all the patients.
Dr. Butterfield: The other medication for bone pain I think that’s been tried is mythromycin. Intravenous mythromycin has been recorded in one or two cases. We tried it in one patient and it seemed to help, at least temporarily.
Question 18. I have met families where there have been multiple blood relatives with diagnoses or symptoms of mast cell disease, but the literature indicates that mastocytosis does not run in families. Is there a potential familial component of mast cell disease and/or mast cell activation disorders? And, does the panel feel that, like cancer, there can be a genetic predisposition but that a trigger must occur for the disease to develop?
Dr. Akin: Well, I think it does run in families in 2-5% of the patients. It is a rare occurrence, but there are a handful of cases reported in the literature and it is also our experience as I alluded to yesterday, from the NIH experience, we have three families out of, I don’t know, 200 or 250 patients that we’ve seen, so it does run in families in certain individuals, but that is not to say that it is familial in everybody. And we have seen, I mean, there are patients who have had their tubes tied so that they wouldn’t have children for the fear of transmitting the disease to the next generation and I think that is totally inappropriate. That is not to say, though, that of course there is some genetic component that is inherited from the parents that makes the mast cells more easy to be activated. So, for example, why are we seeing anaphylaxis in some patients and not in others? Could there be a genetic component that spreads down from the parents that makes these patients more susceptible to have anaphylaxis than others? I mean, we see osteoporosis more severely in some patients than others. So, there could be certain genetic components that might be inherited, but not the disease itself for most patients.
Dr. Castells: I also don’t think there has been any clustering of the bad mastocytosis, so that the mast leukemia or the mast cell sarcomas, I haven’t seen any reports of that being considered familial, so if there is a familial component, which I believe there might be, it would be for the good mastocytosis, the ones that are the indolent or the cutaneous mastocytosis. So again, as Dr. Akin said, there is no reason to tie tubes or to think anything has to be done to eliminate certain genes at this point.
Dr. Bernstein: In my experience familial occurrence is sporadic and rare. I have one family in which I think it exists, but again it is not the usual.
Moderator: I guess I would ask the same question for people who you would deem as having idiopathic anaphylaxis or mast cell activation disorder, is there a potential familial component there? I think you generally answered it for mastocytosis.
Dr. Bernstein: Well, I can definitely answer it for idiopathic anaphylaxis. We see a lot of those and there hasn’t been any familial kind of tendancy for that to occur in families.
Moderator: I’m going to address this question to Dr. Castells:
Question 19: What, if any efforts are there or could there be to coordinate and share research/info not only with other masto researchers but researchers of mast cells and their role and prospective treatments in other diseases like allergies, asthma, migraines, interstitial cystitis (IC), GI pathology? What would minimize the prospects that some discovery about mast cells by asthma researchers unimportant to their asthma research but perhaps tremendously important for those with systemic mast cell disease or migraines or IC or fibrotic diseases would be picked up and pursued by other researchers?
Dr. Castells: I think that I will answer that briefly if I understand it correctly. I came to this field of mastocytosis because was interested actually in mast cells and my initial research was basic laboratory research on mast cells – how mast cells were activated, how they were made, what were the expressions of the proteases in the mast cells – then I became an allergist and an allergist means that I was caring for patients with asthma, with rhinitis, with food allergies, GI symptoms, and then, because of that, I said, “wow, then there are patients who do have more mast cells.” So I came to this field and became enamored with the disease. So what I am saying is that I collaborate at the Brigham & Women’s Hospital in Boston with Harvard Medical School researchers that do research in asthma and that’s how the Xolair proposal came about, where some of monoclonal antibodies, I mean they asked me, “do you think that Xolair that could be something that has a role in mastocytosis?” So there are very intertwined possibilities in all the areas. Mast cell disease and mast cell research is not a big area so far. It may good for some reasons, it may be bad because there is not a lot of funding. I was at a New Mexico meeting a few months ago, which we call it the big mast cell meeting, there were maybe 200 or 250 basic researchers of mastocytosis. If you go to one of those cardiology meetings you find 5,000 researchers. So, essentially, we know each other. The mast cell people who do basic research – we know each other, or at least we know each by name or we read each other’s papers. I don’t think that anything that could be relevant to mast cells would escape this field of mastocytosis, at least from this table here we are all very, very familiar with at least basic research in mast cells. So I think that would be frontier in mast development and mast cell diseases would come up to the mastocytosis field.
Dr. Bernstein: I agree with that completely. I think Frank Austen, who is your boss actually, I guess started out with mast cells, because he was interested in allergic aspects of it and he has always had that interest throughout the years and I’m sure that’s how you . . .[laughing]
Dr. Castells: [laughing] He drove me here! He said, "You have to care of my patients with mastocytosis!" And I said, okay! [loud applause from audience].
Dr. Butterfield: You know, with papers appearing on the web and the ability to search and do research at your computer it is very easy to stay up to date on most things the way the web is now.
Moderator: I’m going to make this the last formal question that we read from the list in the interest of time.
Question 20. Is there a link between Mast Cell Disease and Gulf War Illness?
Dr. Bernstein: Well actually, as a matter of fact, our laboratory has some experience with that and we came about this through a serendipitous manner. Actually, we have been doing a lot of work on seminal plasma hypersensitivities, anaphylaxis that occurs after sexual intercourse, and we’ve isolated some of the actual proteins that cause this. And, we’ve kept up this research – different varieties of this – but one of things that the War Department, or the Defense Department, I guess it is the War Department these days (laughs), but one of the things that the Defense Department wanted to establish was whether or not certain veterans coming back from the Gulf War complained of unusual burning sensation, urethral burning sensation, and their wives complained of unusual burning sensation after intercourse. And this was a considerable number of veterans. There was a cluster of them. So we were awarded some money to study this and we in fact found that there was a higher percentage of these veteran’s wives who developed a specific IgE antibodies against these fractions and in fact it turned out that the incidence of these reactions in the Gulf War population was considerably higher than what we had found in people who have this problem spontaneously. And we do see a lot of patients because we are a center for this and we get a lot of patients filtered in to us from all over the country. So there is that relationship, but that’s really an allergic kind of a thing. It isn’t mastocytosis. It’s just all of these people have developed this and their mast cells are triggered as a result of an Ige type of mechanism.
Moderator: I apologize that we could not get through more questions.
Dr. Castells: I wanted to add something. I was just thinking about it, when you asked me a question about how mastocytosis related to the other mast cell diseases. I would say that major steps towards understanding how mast cells function have come actually from this small group. I would say that all the interest that has been on Dr. Metcalfe, Dr. Akin, and others in trying to understand why you guys are sick has produced gigantic advances in understanding mast cell biology. So, I think we all have to be very focused on the importance of this disease because, you know, when we described that the c-kit was mutated that was a gigantic step in understanding how mast cells actually reproduce, how they live, how they proliferate. So this disease is actually at the cornerstone of how we understand the mast cells and how we understand more about their biology, and all of the allergic diseases related to mast cells, and that not only holds true for asthma, for allergic rhinitis, but also rheumatoid arthritis is supposed to be a disease that is also mast cell mediated, multiple sclerosis, and I could name maybe ten more of those diseases. So I just wanted you to be aware that this is really the most important disease for mast cell development and mast cell biology. [applause].