Off the reservation

I am not sure how this is possible, but I have actually never interacted with Brynn Duncan. For those who don’t know, she is one of our young adult mast cell patients. She is very photogenic and seems lovely. She writes a blog about her life and her health struggles. Recently, she has been the subject of some articles on various sites (Buzzfeed, among them) and so I have read about her a lot in the last few weeks.

Today, the American Academy of Allergy, Asthma & Immunology (AAAAI) posted a link to an article in Cosmo about Brynn. (Link here: http://bit.ly/1FvAlUN) In the way that often happens when you have a relatively new, complex medical condition, people began speculating in the comments. Some had questions about her diagnosis (specifically, the criteria used, and whether she met them).

One of the better aspects of rare disease communities is that when the internet feels like doubting the disabling and life altering nature of your condition, there are plenty of people to have your back. The mast cell community showed up in the comments and made their reality known. Mast cell patients know what it is to be doubted, and to suffer for years because of that doubt. They felt that people were doubting Brynn and they reacted in the way they felt best supported her.

Also, please keep in mind that sick people who share their stories for awareness are people. They are people with boundaries and rights to privacy. It is very possible that all of the salient details are not captured in public media.

But there is another layer here that needs to be addressed. And that is this: what exactly is MCAS, and how do you know if you have it? And if you test negative, do you still have it? And that is a conversation that we need to have both inside the community, for patients, and outside the community, for providers to be able to treat mast cell patients effectively.

If you go through the peer reviewed literature, there are multiple sets of diagnostic criteria for MCAS. This is not helpful, but is pretty common for newer diagnoses. Specifically, it is not unusual for clinical entities that don’t have WHO or ICD diagnostic criteria. Clinicians group people together based upon sets of clinical findings, and sometimes lab findings, and uses those as markers for this previously undescribed entity. Doctors and scientists disagree with each other a lot, and so you develop multiple schools of thought on what constitutes X diagnosis. So you potentially multiple distinct groups of patients with the same name attached to their diagnosis. It is very confusing, and can really complicate things when you try to identify exactly what commonalities unify these people.

One of the commentors mentioned that he felt a well-known doctor in the mast cell community used very lax criteria to diagnose MCAS, and in particular, did not meet the criteria published in JACI (J Allergy Clin Immunol). For clarity when referencing my post on differing MCAS criteria, the 2010 Akin and the 2012 Akin, Valent, et al, Consensus proposal, were published in JACI. The Afrin and Molderings 2011 was published in J Hematol Oncol. Here is a comparison of published diagnostic criteria for MCAS:

Gerhard J Molderings, Stefan Brettner, Jürgen Homann, and Lawrence B Afrin. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol. 2011; 4: 10.

Cem Akin, MD, PhD, Peter Valent, MD, Dean D. Metcalfe, MD. Mast cell activation syndrome: Proposed diagnostic criteria. Volume 126, Issue 6, December 2010, Pages 1099–1104.e4 Peter Valent, Cem Akin, Michel Arock, Knut Brockow, Joseph H. Butterfield,

Melody C. Carter, Mariana Castells, Luis Escribano, Karin Hartmann, Philip Lieberman, Boguslaw Nedoszytko, Alberto Orfao, Lawrence B. Schwartz, Karl Sotlar,

Wolfgang R. Sperr, Massimo Triggiani, Rudolf Valenta, Hans-Peter Horny,

Dean D. Metcalfe. Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal. Int Arch Allergy Immunol 2012;157:215–225.

MCAD (umbrella term including both MCAS and SM) diagnosed if both major criteria, or one major criterion and one minor criterion, are present; following bone marrow biopsy, diagnosis is narrowed down to either SM or MCAS MCAS diagnosed if all criteria are met MCAS diagnosed if all criteria are met

Major Criteria

Multifocal of disseminated dense infiltrates of mast cells in bone marrow biopsies and/or in sections of other extracutaneous organ(s) (GI tract biopsies; CD117-, tryptase- and CD25- stained)
Episodic symptoms consistent with mast cell mediator release affecting ≥2 organ systems evidenced as follows:
  1. Skin: urticaria, angioedema, flushing
  2. Gastrointestinal: nausea, vomiting, diarrhea, abdominal cramping
  3. Cardiovascular: hypotensive syncope or near syncope, tachycardia
  4. Respiratory: wheezing
  5. Naso-ocular: conjunctival injection, pruritus, nasal stuffiness
Typical clinical symptoms
Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity (mast cell mediator release symptom) A decrease in the frequency or severity or resolution of symptoms with antimediator therapy: H1– and H2-histamine receptor inverse agonists, antileukotriene medications (cysteinyl leukotriene receptor blockers or 5-lipoxygenase inhibitor), or mast cell stabilizers (cromolyn sodium) Increase in serum total tryptase by at least 20% above baseline plus 2 ng/ml during or within 4 h after a symptomatic period
Evidence of an increase in a validated urinary or serum marker of mast cell activation: documentation of an increase of the marker to greater than the patient’s baseline value during a symptomatic period on ≥2 occasions or, if baseline tryptase levels are persistently >15 ng, documentation of an increase of the tryptase level above baseline value on 1 occasion. Total serum tryptase level is recommended as the marker of choice; less specific (also from basophils) are 24-hour urine histamine metabolites or PGD2 or its metabolite 11-β-prostaglandin F2. Response of clinical symptoms to histamine receptor blockers or MC-targeting agents e.g. cromolyn
Rule out primary and secondary causes of mast cell activation and well-defined clinical idiopathic entities

Minor Criteria

Mast cells in bone marrow or other extracutaneous organ(s) show an abnormal morphology (>25%) in bone marrow smears or in histologies
Mast cells in bone marrow express CD2 and/or CD25
Detection of genetic changes in mast cells from blood, bone marrow or extracutaneous organs for which an impact on the state of activity of affected mast cells in terms of an increased activity has been proved
Evidence of a pathologically increased release of mast cell mediators by determination of the content of:

  1. Tryptase in blood
  2. N-methylhistamine in urine
  3. Heparin in blood
  4. Chromogranin A in blood
  5. Other mast cell specific mediators (leukotrienes, PGD2)

 

Additionally, there are differences of opinion on whether or not having a primary mast cell disease (mastocytosis, etc) disqualifies you from having MCAS. Most agree that MCAS can be secondary to another condition, including a number of autoimmune conditions. However, whether allergic type symptoms accompanying systemic mastocytosis, for example, qualifies as MCAS is still not agreed upon. Some feel that these symptoms are inherently part of the SM diagnosis, and that MCAS is a diagnosis of exclusion. Others feel SM refers to a proliferative condition, whereas MCAS refers to the inappropriate allergic response. It is a mess for patients, caregivers, researchers, doctors familiar with the condition and doctors who aren’t.

Compounding this issue is the fact that the test most doctors are likely to be familiar with (tryptase) often yields results in normal range. Sometimes, patients experiencing flagrant anaphylaxis under the banner of MCAS will not even demonstrate the 2ng/ml + 2% above baseline that some experts consider indicative of degranulation. Tryptase, like all other mediator tests used to diagnose MCAS, is time sensitive. But sometimes one normal tryptase is enough for doctors to dismiss MCAS as a possible diagnosis (for the record, about 15% of SM patients also have normal tryptase levels).

But then how do you know it’s MCAS and not something else? Therein lies the crux. I think for patients who are experiencing unmistakable anaphylaxis resolved by epinephrine, it is a smaller jump of logic to land on MCAS. But what about so many mast cell patients with non-specific symptoms and negative test results? Do they all have MCAS?

The answer is that we don’t know, and furthermore, that it depends heavily on how you define it. Many doctors use response to typical mast cell medications (antihistamines, stabilizers) as proof of MCAS. But mast cells are involved in so many types of inflammation that treating mast cell degranulation is likely to help with a number of other conditions as well. If the patient is improving, I think most doctors are inclined to continue treatment while still looking for other possible causes. But what if the patient doesn’t improve? What if they get worse?

Diagnoses of exclusion can be dangerous in that many times it is eventually proven wrong. Treating for the wrong disease can be disastrous – both in the potential adverse effects and in the potential to mask the true diagnosis indefinitely. I understand the reluctance to operate under an unusual diagnosis with no empirical proof that it is the right one.

However, there is also a long precedent in medicine in treating “like” diseases with treatments defined for its look alike condition. For example, treating someone who “looks” like they have lupus, as regards symptoms or borderline laboratory findings, with lupus medications is not unusual. And I think that this needs to be considered. Because at the end of the day, MCAS patients are sick. These are people who often have severe, life threatening anaphylactic episodes and daily symptoms that affect their ability to function in the world. Making an educated guess and proceeding cautiously is a well established practice in medicine.

All biomarkers were once unknown. Medicine, and science, are living entities that evolve over time. Eventually causes for diseases are identified and tests developed, and then better tests. This is just another example of not being able to detect well something we haven’t known for very long we needed to look for.

In spite of these difficulties, I think it’s important for clinicians not to lose sight of this fact: MCAS is real. And it’s quite possible that it’s not as rare as we think. One researcher has estimated that MCAS associated mutations may occur in over 5% of the population (Molderings 2014). If this bears fruit, then these people in your office needing help are only the first wave of a growing population that is allergic to the world. We are off the reservation right now, but these people still need help.

 

References:

G.J. Molderings. The genetic basis of mast cell activation disease – looking through a glass darkly. Critical Reviews in Oncology/Hematology 2014.

G.J. Molderings, B. Haenisch, M. Bogdanow, R. Fimmers, M.M. Nöthen. Familial occurrence of systemic mast cell activation disease. PLoS One, 8 (2013), p. e76241

Gerhard J Molderings, Stefan Brettner, Jürgen Homann, and Lawrence B Afrin. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol. 2011; 4: 10.

Cem Akin, MD, PhD, Peter Valent, MD, Dean D. Metcalfe, MD. Mast cell activation syndrome: Proposed diagnostic criteria. Volume 126, Issue 6, December 2010, Pages 1099–1104.e4

Peter Valent, Cem Akin, Michel Arock, Knut Brockow, Joseph H. Butterfield, Melody C. Carter, Mariana Castells, Luis Escribano, Karin Hartmann, Philip Lieberman, Boguslaw Nedoszytko, Alberto Orfao, Lawrence B. Schwartz, Karl Sotlar, Wolfgang R. Sperr, Massimo Triggiani, Rudolf Valenta, Hans-Peter Horny, Dean D. Metcalfe. Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal. Int Arch Allergy Immunol 2012;157:215–225.

Juan-Carlos Cardet, Maria C. Castells, and Matthew J. Hamilton. Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome. Curr Allergy Asthma Rep. Feb 2013; 13(1): 10–18.

Britta Haenisch, Markus M. Nothen and Gerhard J. Molderings. Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunology 2012, 137, 197–205.

Matthieu Picard, Pedro Giavina-Bianchi, Veronica Mezzano, Mariana Castells. Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes. Clinical Therapeutics, Volume 35, Issue 5, May 2013, Pages 548–562.

 

`

3 Responses

  1. Mark March 18, 2015 / 11:12 pm

    This was an interesting read. As a layperson, I couldn’t understand everything here, but the key point I took away here is there’s still a lot of disagreement among the experts on what constitutes masto, MCAS, MCAD, etc. It’s also good to see that people with these diseases have each other’s backs against ignorant trolls (and even ignorant doctors!) who think they’re not real or that we’re hypochondriacs. Even people with medical and scientific backgrounds can be written off as crazy. Thank you again, Lisa, for posting this, and for all that you do for us. Keep up the good fight!

  2. Kelly March 19, 2015 / 1:16 am

    I wondered about your thoughts as the day unfolded. Thank you for your input and clarity.
    Be well.

  3. Mark Beckwith March 19, 2015 / 1:00 pm

    Brilliant post, Lisa. We spent the week with Drs. Metcalf and Carter, and I’d say we got a good dose of “we can’t figure it out.” At least when physicians of this caliber say that, you know where you stand and you don’t think to yourself quietly “I wonder if they know what they are doing.” Then, to me, though I don’t mean to speak for my wife the patient (but my [current] career is in rare disease), it’s more like going on an adventure with some really great people (as long as you have an EpiPen or two on hand, just in case.)

Comments are closed.