Recently an article was published in the Journal of Allergy and Clinical Immunology entitled "Doctor, I Think I Am Suffering from MCAS: Differential Diagnosis and Separating Facts from Fiction". In it Dr. Peter Valent, and Dr. Cem Akin contend many inconsistent and controversial statements.    

Through their reasoning they wish to downgrade thousands of patients who have symptoms of MCAS but do not meet their criterion for mediator testing, and place them into a lesser category called MCA. MCA is unfortunately, a wastepaper basket for all of the rejected patients who do not fit within Akin and Valent's MCAS criteria. MCA stands for mast cell activation and nothing more. It is not a disease classification which takes seriously the symptoms of patients but rather something that even normal people have. (Even a healthy person has mast cells that become activated now and again.)  

The mediator criterion for MCAS that Akin and Valent use is very different than the mediator criterion for MCAS which other doctors use. Many doctors look at multiple mediator readings and do not place as much diagnostic weight on tryptase. Akin and Valent rely heavily on a tryptase equation which is very difficult for many MCAS patients to meet. They appear to be excluding other mediators to the preference of tryptase in an equation that has never been validated in MCAS patients.

Mediator tests, especially tryptase, are flawed and pose many problems. Thus, it is often the case that they are not an accurate portrayal of the degree of symptoms that a patient is experiencing. The classification MCA is unjust as there are many of thousands of patients who have MCAS but do not currently fit within the mediator diagnostic criterion. It is important to understand that these tryptase-normal patients have MCAS symptoms in all levels of severity! Further exclusion by using a MCA category only complicates the matter more so and exacerbates emotional distress to this population of patients who are waiting for more support, not less.       

This article is marketed as a continuing education resource. Even though some of the information that Valent and Akin put forth is not established information/criteria many doctors are using their recommendations verbatim in their daily practices.          

We can no longer sit back and do nothing. We must advocate for change! 

Those suffering from Mast Cell Activation Disorder can undergo a large range of symptoms, and this is recognized by many doctors. However, in this article Valent and Akin want to narrow the MCAS symptom profile that is accepted for diagnosis, and create unreasonable (and unfounded) limitations on mediator testing. It appears they are trying to exclude most mediators aside from tryptase as well as narrow what symptoms are accepted as MCAS. This excludes many who suffer from this disease from getting a diagnosis. Why are they doing this?

This article (that this petition was created for) and another also by Akin and Valent, claim that there are too many people trying to seek a diagnosis called MCAS, and that these people are somehow misguided. They claim that this large group of people are not sick with MCAS but perhaps with some other mysterious disease (though they do not fully explain another disease which could completely account for the symptoms of these patients).

Thankfully, there are many doctors who do look at the complete character of MCAS, as we will show through the links in this petition and the links in our paper. When one considers the evidence and research, it becomes obvious that the fixation on mediator testing as criterion for diagnosis, especially when it is narrowed, is to the determent of MCAS patients. We need to be working towards a better understanding of the disease and stop unjustly shutting patients down from receiving a diagnosis and treatment. The thinking which is displayed in this article is harmful to MCAS patients who are being set aside as second-class patients despite their presentation of debilitating MCAS symptoms. 

 

In this article, Valent and Akin put forth a number of statements which need to be addressed. These statements are emboldened.

1- "(MCAS) is a rare condition defined by a severe systemic reaction to mast cell (MC)-derived mediators."

False! It is estimated that up to 6% of people in the states have some form of MCAS, by renowned doctors who frequently deal with nonclonal forms of MCAS. 

We are a patient population that is under-diagnosed and under-treated partly due to the type of mindset which is displayed in this article!  

 

2- "Patients with hyperadrenergic form of postural orthostatic tachycardia syndrome (POTS) and hypermobility-type Ehlers-Danlos syndrome (EDS) have also been discussed to suffer from symptoms resembling or mimicking MCA or even MCAS, but objective evidence to incriminate MC in their pathology has been lacking."

It is commonly accepted that there are connections between these conditions and that they are often found within one person. 

This article by doctors Seneviratne and Maitland states:

• "An abundance of MC reside in connective tissue that borders with the external world (the skin as well as gastrointestinal, respiratory, and urogenital tracts). Situated near nerve fibers, lymphatics, and blood vessels, as well as coupled with their ability to secrete potent mediators, MCs can modulate the function of local and distant structures (e.g., other immune cell populations, fibroblasts, angiogenesis), and MC dysregulation has been implicated in immediate and delayed hypersensitivity syndromes, neuropathies, and connective tissue disorders (CTDs)." 

In this video lecture on the connection between MCAS and hEDS Doctor Anne Maitland said:

• "It is very possible that there are genes that are intrinsic to the connective tissue that can impact mast cell function but now it [also] seems that there are chemicals that are solely found in mast cells that can impact the function and structure of the connective tissue." 

It is not sensical that hEDS could mimic MCAS. It is however sensical that these conditions are directly influencing each other. 

In addition, here is an article by Doctors Cheung and Vedas which states:

• "Patients with postural orthostatic tachycardia syndrome (POTS) and hypermobility often describe symptoms suggestive of mast cell activation".

They go on to conclude from the results of their study:

• "...it appears that a mast cell disorder may frequently co-segregate with POTS and a collagen disorder such as EDS."

It is also worth noting that Dysautonomia International lists MCAS as an underlying cause of Dysautonomia.

Why do Akin and Valent refuse the work of these institutions and doctors?

 

3- "Most cases present with clinical signs of anaphylaxis."

False!

At least two types of degranulation have been described for MC disease: piecemeal degranulation (PMD) and anaphylactic degranulation (AND). Many cases of MCAS do not present with anaphylactic degranulation (AND). Many nonclonal MCAS patients suffer from piecemeal degranulation (PMD). The commonly known slang term for this is leakers. Why doctors Akin and Valent leave out other forms of degranulation in MCAS is confusing.

There are no estimates on how many patients present with anaphylaxis in nonclonal MACS, but the estimates in clonal mast cell disease are 30 percent:  "It has been clearly established that the incidence of anaphylaxis is increased in mastocytosis. Several reports from Europe and the United States point to an average incidence of 30% lifetime risk of anaphylaxis in patients with mastocytosis".

This hardly describes "most cases", yet doctors Akin and Valent are now citing most cases of nonclonal MCAS have clinical signs of anaphylaxis. Why?

 

4. "some [MCAS patients] have an underlying IgE-dependent allergy. "

So.....???

I believe what they are implying here is that if a patient presents with an IgE allergy (and anaphylaxis) they should be taken more seriously in pursuing a diagnosis of MCAS, than a patient who does not. This is nonsensical:  most of us with nonclonal mast cell activation do NOT have IgE allergies. So then, why the emphasis on IgE allergies in diagnosing MCAS?

There has been a focus on IgE MC response in many MC disease studies, however, there are many other kinds of stimulus aside from IgE which can activate the mast cell. This article states "mast cells can also be activated by diverse non-IgE stimuli" and they go on to list these stimuli:

1) Stimulation via IgG 
2) Complement factors
3) Toll-like receptor ligands
4) Pathogens and their components
5) Antimicrobial peptides
6) Corticotropin-releasing hormone (CRH) 

There are many more stimuli in addition to these as well.

 

5- "...even acute allergic reactions and related symptoms may mimic MCAS. In these patients, the criteria for MCAS are not met because the reaction is not severe enough or because mostly basophils but not MC (or only few MC) are involved. Some patients may have concurrent atopic disorders (which may affect up to 20% of the population), dermographism, or urticaria but not systemic MCAS. "

In the last section I believe doctors Akin and Valent were implying that an IgE allergy (and anaphylaxis) could be an indication of MCAS. If that is true, he is now producing a contradictory statement saying that IgE allergies can mimic MCAS.

In 2012 both Valent and Akin as well other doctors published a consensus stating that IgE mediated allergic reactions are part of secondary MCAS. This consensus of doctors stated "Secondary MCAS: MCA criteria fulfilled and criteria for the diagnosis of allergy or other diseases that can produce MCA fulfilled as well". Thus, once again, we see that they do recognize how influential IgE allergies can be in MCAS.

Dr. Akin recently wrote an UpToDate article, stating that:

• "Secondary mast cell activation disorders include classic allergic disorders and other conditions in which mast cells are apparently normal in quantity and function but are responding to an identifiable external stimulus. Activating stimuli include allergens, autoantibodies, physical factors, infections, drugs, or products of complement activation. Potentially, any acute igE allergic reaction can start a mediator cascade that could last weeks to months in an individual and harness a systemic MCAS."

What is confusing is that Akin is claiming that in some instances IgE responses can be so powerful that they actually activate the presence of this disease in a person, while other times they can be so mild that a person can have an IgE reaction that "mimics" MCAS. How does Akin determine which type of response a patient is having? . Furthermore, a tryptase mediator test can not show the difference between an acute IgE response and other kinds of MCAS reactions. So, how does Akin know when an acute IgE response is NOT MCAS?

The problem with this line of thinking is twofold. One, we know that Akin is measuring the degree of a patients suffering largely by the degree of which their mediator tests are elevated. If a patient comes into his office with recurrent symptoms indicative of MCAS but tests with normal mediator levels, what I believe he is saying here, is that he will just chalk that up to the reaction being not severe enough to denote a diagnosis of MCAS. Unfortunately this approach completely ignores the fact that there is not one single test of which 50% MCAS patients test positive for, and as we will further discuss, that the tryptase test in particular is not the correct lens of which to see the degree of an MCAS patient's suffering.

This new theory of an IgE response mimicking MCAS appears to be Akin's way of justifying that he is not diagnosing those who do have MCAS symptoms but do not test with elevated mediators. Thus, he would then want to put such patients into the lesser category of MCA, which isn't really a diagnosis at all as it isn't a disease. It is however, one way to deal with these complicated patients. 

Until we have tests which can either detect this disease or not (meaning the tests are 100% accurate or very close to it in detecting the disease), no patient should be being turned away from diagnosis or treatment when their symptoms most fit MCAS more than any other disease. The criteria for diagnosis need to be adjusted to support this. 

The second problem with this line of thinking is that there is evidence which shows he is incorrect. He states an IgE response mimicking MCAS happens when it is "not severe enough or because mostly basophils but not MC (or only few MC) are involved". Many patients with idiopathic MCAS have normal numbers of mast cells, thus there is no way to quantify how many mast cells are involved. The important feature of mast cell activation is the release of powerful mediators which can cause severe systemic reactions, even in patients with low mast cell burden.

As far as a patient reacting through a basophil reaction:  how do we know that the Mast Cell did not first produce a mediator which communicated to the basophil that it needed to react? If the pathology begins with the MC is it still considered MCAS? The complicated pathology of MCs and how they affect other cells has not been fully discovered. MCs communicate with many types of cells and are so key in allergic responses that it seems very preemptive to make statements suggesting that if it is basophil it is not MCAS. Again, how does he KNOW that basophils are not being stimulated by MC mediators? Or that the IgE response of the basophil has not created an MCAS comorbidity? 

 

6- "Patients with multiple chemical and environmental intolerances or multiple food intolerances should not be diagnosed as MCAS"

False! The MC is a complicated structure that is involved in a great deal of processes in the human body. This is due to the number of receptors it has and the amount of mediators within the cell. When the receptors become activated, they release specific mediators held within the cell. The mediators released correspond to the receptors that have been activated. 

Much attention is placed on the IgE receptor because of its link to allergies and anaphylaxis, however other receptors are also important in understanding the complete character of the disease. 

One of these receptors is IgG. As this article delineates “Mast cells can be activated by IgG immune complexes binding pro-inflammatory FcγRI, FcγRIIA, or FcγRIII, which are variably expressed on mouse and human mast cells. These receptors induce a signaling cascade resembling IgE–FcεRI activation that elicits cytokine secretion, arachidonic acid metabolism, and degranulation."

The IgG receptor is linked to inflammatory responses throughout the body including arthritis and multiple sclerosis. How do Akin and Valent know that the mediators that are released, are not contributing to multi-system inflammation such as the presence of food sensitivity, that is often seen within the MCAS patient? 

Furthermore, as MC aggregates can be located in the gut where IgG antigens are moving about, they can inevitably lock onto mast cell IgG receptors, activating them. Doctor Krystel-Whittemore describes this process:

• "When the gastrointestinal tract is exposed to an antigen, its response is to increase fluid secretion, increase smooth muscle contraction, and increase peristalsis. Proteins derived from different plants and animals can act as antigens and activate the immune system in vulnerable subjects. The antigen (peptide) permeates through the epithelial layer of the mucosa of the gut and binds to IgE on mucosal mast cells."

In that quote doctor Krystel-Whittemore was describing IgE response but this also applies to IgG as well. When one is tested for food sensitivities an IgG test is conducted. IgG is indicative of food sensitivity where as IgE is indicative of food allergy. However, an IgG activation pathologically produces a response to antigens that can mirror that of an allergic response!

There is evidence that supports this as the IgG receptor is linked to anaphylaxis (in addition to inflammation). IgG receptors on the MC, specifically FcγRIIA can set off the polymorphism c.7421871A>G... and this can induce anaphylaxis! This article states, FcγRIIA can set off the polymorphism c.7421871A>G. leading to "hyperactive. Risk factor for IVIg anaphylaxis." There it is. The research that supports that one can have anaphylaxis induced from IgG response! There needs to be more research on the relationship between food sensitivity and anaphylaxis, however, because of this research we cannot say conclusively that it does not happen. 

I think the question is, if a patient presents with symptoms indicative of MCAS and food sensitivities which clearly escalate each other, WHY WOULDN’T mast cells be involved in the presence and increase of those food sensitivities? 

On a personal note, I have been living off of the same 5-10 foods for several years now (and for very good reason). The response to foods to which I am intolerant  produces various kinds of sickness and anaphylaxis. I have a diagnosis of idiopathic anaphylaxis because many kinds of foods induce anaphylaxis even though I have few IgE allergies. I am not alone. We need to take seriously that thousands upon thousands of MCAS patients regularly report to their doctors that food sensitivities (not just allergies) directly correlate to primary MCAS symptoms.

Food intolerance IS an example of MCAS hypersensitivity. There is NO DOUBT about this for those of us that live it as a daily reality. We eat and then anaphylaxis and other symptoms of MCAS result. I'm not sure why Valent and Akin lack this perspective. They appear to be focused on tryptase and heightened anaphylaxis which might narrow their perspective.

Let us be clear: for many patients, Mast Cell Activation results in escalation of food, chemical and environmental intolerances. This is a key and major characteristic of the disease in terms of both diagnosis and treatment which should not be overlooked!  

Dr. Anne Maitland has this to say on the topic of chemical sensitivity in the MCAS patient:

• "We have embodied, inherited responses to injuries. To recognize and respond to injury. What has happened with industrialization is that we have so dramatically changed our environment. All of us have a tendency to focus on what we have a lot of control on, meaning what we eat but here is the thing... you maybe eat three or four times a day. You might drink a little bit more than that. You breathe eighteen times per minute. And your skin is constantly exposed to the environment. So your body has to has to figure out what should stay and what should be kept out. At the forefront of this is the mast cell... If there is a perceived danger you are going to increase the presence [of mast cells]"

Overall, we know little about the pathology and nature of chemical sensitivity at this time, but what we do know is that like food intolerance, there is a large number of MCAS patients who have chemical sensitivity. For those who experience this, the degree of reaction can be debilitating and according to many thousands of people, it can induce anaphylaxis. We do not know whether chemical sensitivity produces MCAS or if MCAS results in the development of chemical sensitivity, or both. That being said, it is standard practice to recommend that patients remove exposure to synthetic chemicals (i.e. perfumes, laundry soaps, harsh cleaning agents) as a part of their MCAS treatment, acknowledging that these things can be triggers. Thus, at the very least the symptomatic characteristic of chemical sensitivity SHOULD be considered, along with other symptoms when issuing a diagnosis. 

 

7- " When the reaction is not severe and the serum tryptase does not increase over the individual's baseline during the event, the patient may still suffer from MCA and an IgE-dependent reaction, but the likelihood of MCAS is very low. "

And:

" A key diagnostic marker is the event-related increase in MC tryptase over the individual's baseline, measured in the symptom-free interval. When the tryptase elevation exceeds a certain threshold (20% from baseline plus 2 ng/mL) the diagnosis of MCAS is very likely. Less severe and localized forms of MCA do not fulfill MCAS consensus criteria"

False... and it is very important to understand why. 

Consider the fact that studies of MCAS have progressed using only the patient population that is positive on mediator testing. They use patients who test with elevated levels as starting criteria to be in the study, which is great for understanding that subset of MC patients but not MC patients as a whole. In addition, it is problematic using a ‘baseline’ in MCAS criteria because each person is at a different point in their illness. 

MCAS is complicated, but we won't get anywhere in our understanding until we look at the complete character of the disease. Many people with MCAS do not test with an increase in serum tryptase or other mediators regardless of severity. There are several reasons why an MCAS patient may not test with an elevated tryptase level:

• >>1 MCAS patients may not have a rise in tryptase.
  • This is a statement from the Mayo Clinic: "The levels of the protrypases reflect the total number of mast cells within the body, but are not an indication of mast cell activation." Thus, if you have normal numbers of mast cells, you may not have increased total tryptase upon testing. 
  • Did you know that 20-30% of those with SM are not producing elevated tryptase? With that in mind, how can those with MCAS, which is supposed to be less severe than SM, be expected to produce elevated tryptase?
  • Tryptase rise is not always an indicator of the severity of anaphylaxis. Here is a study showing that, and another which states “The diagnosis of anaphylaxis is based on clinical history since no reliable biological marker is currently available to confirm the diagnosis.” (Please note, we go into this in more detail in our paper. This is only a short summary of our research on this topic.) Therefore, it is reasonable to conclude that if it is not an indicator of the severity of anaphylaxis to the point where it is determined that tryptase markers are NOT reliable criteria for diagnosing anaphylaxis then why is tryptase determined reliable criteria for diagnosing MCAS? After all, anaphylaxis is the symptom that it is supposed to be measuring. Clearly tryptase is not the whole story.
• >> 2 MCAS patients may be producing low tryptase levels BUT still produce MCAS symptoms.
  • There is a lack of research and consensus as to what the pathological cut-off is in determining what constitutes "elevated" of individual mediators, including tryptase. 
• >> 3 MCAS patients may be producing high mediator levels but due to the fallible nature of the tests, these levels may not be detected.
  • The tryptase blood samples that are taken are temperature sensitive and must be kept cool--many times the samples do not keep. MCAS experts will sometimes request that the lab follows special instructions but this appears to not be common practice. False negatives are common. As doctors/insurances are often unwilling to repeat tests, this creates a type of gamble for patients, who hope that they are not going to be among those who experience false negatives or come back in normal range. Medical care should not be a gamble.
• >> 4 MCAS patients may be producing high tryptase levels but due to the difficulty of capturing a sample at the right time, may not be easily detectable through testing.
  • Patients are asked to have their blood drawn during the height of a reaction. It can be difficult for patients to gauge when the height of their reaction will be and to travel during this time.
• >> 5 MCAS patients may be producing high tryptase levels but due to the location of the release, these levels may not be detected.
  • There is evidence that tryptase released by mast cells at mucosal sites may not diffuse into the circulation as efficiently as that released near blood vessels, and mast cells at mucosal surfaces contain less tryptase. Thus, these tests may not pick up mediators that are not released in the blood stream.
• >> 6 MCAS patients may be producing high mediator levels but are producing mediators that do not correlate to the current tests.
  • There are over 200 markers which are released during MC activation (few of which can be tested in clinical studies). Dr. Lawrence Afrin has this to say on mediator testing “Although there are ways the research laboratory can test for any of the 200+ mediators the mast cell is presently known to produce, at present we can test in the clinic for only a small handful of these mediators, and even those tests are difficult to perform accurately.” 

This topic is too big to fully go into here but if you are interested in the scientific research that shows that tryptase is ineffectual in use as a way to measure the severity of MCAS please read our paper. We go over many key points with supporting research, including how:

• MCAS patients have MCAS WITHOUT anaphylaxis. 

• MCAS patients CAN test within normal tryptase range AND STILL HAVE anaphylaxis.

Valent and Akin push the effectiveness of tryptase testing again and again, ignoring clinical research which supports the inefficiency of tryptase testing (as we have shown here and show in our paper). MCAS patients are only trying to get to the answers, diagnosis, treatments and care that they need. Why do these doctors push the validity of tryptase in diagnosing MCAS when it is obvious that this mediator cannot be reliably tested for within most MCAS patients? 

This statement was also included in the "Doctor, I think I am suffering from MCAS" article:

• "As mentioned before, an increasing number of patients are referred because they believe or had been informed that they are suffering from MCAS. Many of these patients do not fulfill the criteria of MCAS and do not optimally respond to MCAS therapies. This, in turn, leads to more frustration in both patients and caregivers as well as to the inappropriate use of health care resource."

I personally feel that we are worth all of the medical attention and diagnostic efforts that are available! It is not fair to say that we do not fulfill Akin and Valent's criteria because these criteria are flawed! (Mediator testing should not constitute impassable criterion considering all of the problems it poses.) We are NOT in any way, shape, or form an "inappropriate use of health care resource" as it pertains to any kind of MC doctor and before I believe that this grouping of patients is not responding to MCAS therapies I will need to see hard evidence of that. Again, if MCAS best describes the symptom profile, the patient should be treated and diagnosed accordingly. 

 

IN CONCLUSION

What I really wish I could communicate to these doctors is something I cannot effectively do through words. It is the feeling one has when being rejected by doctors time and time again while simultaneously undergoing extreme sickness. I'm referring to being on the brink of death from MCAS symptoms yet not being able to get anyone to care. This past year I went from doctor doorstep, to doctor doorstep seeking help, barely able to walk, talk or eat I might add. I was either turned away or doctors showed a complete lack of interest. There were a few who wanted to help but did not have the expertise. I did not have access to MC specialists beyond allergists because my tryptase was in normal range and the allergists I had knew little about the disease. I did not have access to doctors who would repeat testing and my insurance would not cover it. It is an unrealistic expectation and non-reality for many of us to ask our doctors to repeat these tests.  

If Valent, Akin understood that one CAN have extreme hypersensitivity resulting in anaphylaxis with NEGATIVE tryptase I believe this would help to change how MCAS is addressed as a whole. I wish they also understood that there is a large range of symptoms which comprise the complete character of this disease. The more these aspects of the disease are understood, the more doctors across the country will be better apt to help MCAS patients.

These mediator tests are simply not up to par and are creating widespread exclusion of a patient population that at times desperately needs medical attention because of MCAS symptoms. Within MCAS, the behavior of the MC is to activate, to release mediators and those mediators have a large range of effects on the body. We must consider the entire systemic effects of this disease and the many ways in which it manifests.

Right now it feels as though many times we have doctors representing us who are not compassionate to our suffering or supportive in our attempts to seek care and treatments. Certainly this is how I feel about the way in which Akin and Valent continue to try to cast us aside. Should a patient population as vulnerable as this, that suffers from anaphylaxis and other debilitating reactions really be put through such continued and unfounded conflict? No. We shouldn't have to endure this. We deserve medical care, emphasis on both "medical" AND "care". It is time for change. 

By signing this petition you are asking the Journal of Allergy and Clinical Immunology as well as doctors Valent and Akin to remove this damaging article that holds inconsistent/controversial statements and is insulting to MCAS patients.

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Disclaimer: I am not a lawyer or medical professional. This petition should not be considered a substitute for medical or legal advice. I am a patient advocate.