A History of Mast Cell Activation Syndrome: Part 1

 

Criteria for mast cell activation syndrome in selected papers
Year Reference and criteria
1991 Roberts LJ, Oates JA. Biochemical diagnosis of systemic mast cell disorders. J Invest Dermatol 96:19S-25S.
Called “idiopathic mast cell activation”

Meets all following criteria:

-Evidence of increased quantities of mast cell secretory products (histamine in plasma or urine; serum tryptase; prostaglandin D2; heparin)

-Does not meet criteria for systemic mastocytosis

2002 Jordan JH, Valent P, et al. Stem Cell Factor-induced Bone Marrow Mast Cell Hyperplasia Mimicking Systemic Mastocytosis (SM): Histopathologic and Morphologic Evaluation with Special Reference to Recently Established SM-criteria,Leukemia & Lymphoma 2002; 43(3):575-582.
-Acknowledges systemic form of mast cell disease that is distinct from systemic mastocytosis.

-Describes a case in which a patient received stem cell factor and developed symptoms and signs associated with systemic mastocytosis. Focal infiltration was seen in bone marrow but lacked other markers for SM.

-Criteria used to “discriminate between reactive MC hyperplasia and true mastocytosis with certainty.”

2005 Shibao C, et al. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension 2005;45(3):385-390.
Called “mast cell activation”

Meets all following criteria:

-History of facial or upper trunk flushing

-Urine methylhistamine >230 mg/g creatinine associated with flushing episode

2007 Sonneck K, Valent P, et al. Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: Monoclonal mast cell activation syndrome. Int Arch Allergy Immunol 2007;142(2):158-64.
Meets all following criteria:

-Severe hypotension following bee or wasp stings in patients with no cutaneous lesions

-Meets ≥2 minor criteria for systemic mastocytosis

2007 Akin C, et al. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood 2007;110:2331-3.
Diagnosed in presence of one of the following minor criteria for systemic mastocytosis:

-D816V mutation

-Expression of CD25 by mast cells

Note: The paper describes the criteria as having “one or more minor criteria for systemic mastocytosis” but does not investigate presence of the other two minor criteria for systemic mastocytosis, 25% or more spindled mast cells in biopsy; or baseline serum tryptase of greater than 20 ng/ml.

2008 Butterfield JH, Weiler CR. Prevention of mast cell activation disorder associated clinical sequelae of excessive prostaglandin D2 production. Int Arch Allergy Immunol 2008;147:338-343.
Meets all following criteria:

-Elevation of serum tryptase, urinary 11b-PGF2a, or urinary n-methylhistamine

2009 Bonadonna P, et al. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased tryptase levels. J Allergy Clin 2009;123:680-686.
Diagnosis of monoclonal mast cell activation syndrome if meets all following criteria:

-Unexplained recurrent anaphylaxis

-Absence of skin lesions

-Meets one (excluding raised tryptase) or two of the minor criteria for systemic mastocytosis.

2010 Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol 2010: 126;1420-1427.
Meets all following criteria:

-Episodic symptoms with mast cell mediator release affecting ≥2 organ systems evidenced as follows: skin (urticaria, angioedema, flushing); gastrointestinal (nausea, vomiting, diarrhea, abdominal cramping); cardiovascular (hypotensive syncope or near syncope, tachycardia); respiratory (wheezing); naso-ocular (conjunctival injection, pruritis, nasal stuffiness)

-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 stabilizer (cromolyn sodium)

-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.

-Rule out primary and secondary causes of mast cell activation and well-defined clinical idiopathic entities

2011 Hamilton MJ, Hornick JL, Akin C, Castells MC, Greenberger NJ. Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J Clin Immunol 2011;128(1):147-152.
Meets all following criteria:

-Episodic symptoms with mast cell mediator release affecting ≥2 organ systems evidenced as follows: skin (urticaria, angioedema, flushing); gastrointestinal (nausea, vomiting, diarrhea, abdominal cramping); cardiovascular (hypotensive syncope or near syncope, tachycardia); respiratory (wheezing); naso-ocular (conjunctival injection, pruritis, nasal stuffiness)

-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 stabilizer (cromolyn sodium)

-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.

2011 Molderings GJ, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol 2011;4:10.
Mast cell activation disease is used here as an umbrella term that includes both MCAS and SM. Mast cell activation disease is diagnosed if both major criteria, or one major criterion and one minor criterion, are present. Following the diagnosis with mast cell activation disease, a bone marrow biopsy is used to narrow the diagnosis down to either SM or MCAS.

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)

– Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity (mast cell mediator release symptom)

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)
2012 Alvarez-Twose I, et al. Validation of the REMA score for predicting mast cell clonality and systemic mastocytosis in patients with systemic mast cell activation symptoms. Int Arch Allergy Immunol 2012;157:275-280.
Mast cell activation syndrome predicted if REMA score <2:

+1 if male

-2 if female

+1 Absence of urticaria, pruritis, and angioedema

-2 Urticaria, pruritis, and/or angioedema

+3 Presyncope and/or syncope

-1 Baseline serum tryptase <15 ng/mL

+2 Baseline serum tryptase >25 ng/mL

2012 Valent P, Akin C, Brockow K, Butterfield JH, Carter MC, Castells MC, Escribano L, Schwartz LB, Horny HP, Metcalfe DD, et al. 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.
Meets all following criteria:

-Typical clinical symptoms

-Increase in serum total tryptase by at least 20% above baseline plus 2 ng/mL during or within four hours after a symptomatic period

-Response of clinical symptoms to histamine receptor blockers or MC-targeting agents e.g. cromolyn

Primary MCAS:

-Mast cells express CD25 and/or have the CKIT D816V mutation

-Patient has systemic mastocytosis or monoclonal mast cell activation syndrome

Secondary MCAS:

-Patient also has allergies or another condition that activates mast cells

Idiopathic MCAS:

-No explanation found for MCAS symptoms

Note: This paper states that it is possible to have both primary and secondary MCAS at once. “In some patients, the evaluation will show that both a primary MCAS and additional secondary MCAS (e.g. mastocytosis plus IgE-dependent allergy) are present.”

2013 Afrin LB. Presentation, diagnosis, and management of mast cell activation syndrome. In: David B. Murray (ed), Mast Cells. Nova Science Publishers, Inc. 155-229.
  Mast cell activation disease is used here as an umbrella term that includes both MCAS and SM. Mast cell activation disease is diagnosed if both major criteria, or one major criterion and one minor criterion, are present. Following the diagnosis with mast cell activation disease, a bone marrow biopsy is used to narrow the diagnosis down to either SM or MCAS.

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)

– Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity (mast cell mediator release symptom)

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)
2013 Picard M, Castells M, et al. Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clin Ther 2013;35:548-562.
Meets all following criteria:

-Typical signs and symptoms of mast cell mediator release (affecting at least two organ systems): skin: flushing, pruritis, urticaria, angioedema; cardiovascular: hypotension; respiratory: wheezing, throat swelling; GI: diarrhea; naso-ocular: pruritis.

-Objective evidence of mediator release: elevated serum tryptase: 20% + 2 ng/mL above baseline; elevated 24-hour urinary histamine metabolites (methylhistamine); elevated 24-hour urinary prostaglandins (prostaglandin D2; 11b platelet derived growth factor 2a)

-Response to therapy that blocks mast cell mediator activity: H1 receptor with or without H2 blockers, ketotifen, cromolyn sodium, aspiring, and leukotriene receptor antagonists.

2013 Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Curr Allergy Asthma Rep 2013;13(1):10-18.
Meets all following criteria:

-Presence of symptoms from at least two different organ systems: skin (flushing, urticaria, pruritus, dermatographism); gastrointestinal (abdominal pain and diarrhea); pulmonary (wheezing and shortness of breath); upper respiratory (nasal congestion or pruritus, throat swelling); cardiac (tachycardia, syncope or near-syncope); neurologic (concentration difficulties, headache).

-Patient response to medications that block mast cell mediators

-Increase in serum total tryptase by at least 20% above baseline plus 2 ng/mL during or within four hours of characteristic symptoms

Note: This paper also states that a 24-hour urine collection for the measurement of n-methylhistamine and prostaglandin D2, or its metabolite 11b-prostaglandin F2a should be obtained after the onset of symptoms.

2013 Valent P. Mast cell activation syndromes: definition and classification. Allergy 2013; 68:417-424.
Meets all following criteria:

-Clinical signs of severe recurrent (or chronic) systemic mast cell activation

-Biochemical evidence of mediator release, preferably 20% + 2 ng/mL elevation of tryptase

-Positive response to mast cell stabilizers and medication to counter mediator symptoms

Further characterization of MCAS:

Primary MCAS:

-Presence of CKIT D816V mutation; paper states that that “usually these mast cells express CD25”

-Meets all three criteria listed above

Secondary MCAS:

-Presence of underlying allergic or atopic disorder that demonstrates mediator release without clonal mast cells

-Meets all three criteria listed above

Idiopathic MCAS:

-MCAS criteria are fulfilled, but no underlying reactive disease, no allergen-specific IgE, and no clonal mast cells are detectable

-Meets all three criteria listed above

Note:

In this paper, mastocytosis with any type of mast cell activation is denoted SMSY where mast cell activation syndrome criteria are not satisfied

2014 Akin C. Mast cell activation disorders. J Allergy Clin Immunol Pract 2014:2;252-257.
Monoclonal mast cell activation syndrome when following criterion is met:

-Presence of “one or both” markers of clonality (CD25 and/or presence of CKIT D816V mutation)

-Fails to meet other criteria for systemic mastocytosis

Primary mast cell activation syndrome when following criteria are met:

-Meets criteria for idiopathic mast cell activation syndrome

-Mast cell activation in any form of mastocytosis

-Mast cell activation recorded as SMSY (Sy is for symptoms)

For secondary mast cell activation syndrome, meets following criteria:

-Meets criteria for idiopathic mast cell activation syndrome

-Symptoms caused by another condition triggering mast cell activation

For idiopathic mast cell activation syndrome, meets following criteria:

-Presence of symptoms that involve more than one organ system: naso-ocular and respiratory: naso-ocular, wheezing, conjunctival erythema, itching and watering; skin and soft tissues: urticaria, angioedema, itching; gastrointestinal: vomiting, abdominal cramping, diarrhea; cardiovascular: flushing, tachycardia, hypotension

-Favorable response to mast cell mediator targeting agents

-Elevation of a validated marker of mast cell activation during a symptomatic period

Note: This paper does not include spindling of mast cells as a marker of clonality. Spindled mast cells are included in diagnostic criteria of systemic mastocytosis but not used here for diagnosis for MMAS. Baseline tryptase over 20 ng/mL is also not here.

2014 Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3(1):1-17.
Mast cell activation disease is used here as an umbrella term that includes both MCAS and SM. Mast cell activation disease is diagnosed if both major criteria, or one major criterion and one minor criterion, are present. Following the diagnosis with mast cell activation disease, a bone marrow biopsy is used to narrow the diagnosis down to either SM or MCAS.

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)

– Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity (mast cell mediator release symptom)

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)

2014 Ravi A, Butterfield J, Weiler CR> Mast cell activation syndrome: improved identification by combined determinations of serum tryptase and 24-hour urine 11b-prostaglandin F2a.
Meets all following criteria:

-Presence of typical symptoms of mast cell activation

-Increased level of serum tryptase or 11b-prostaglandin F2a

2015 Pardanini A. Systemic mastocytosis in adults: 2015 update on diagnosis, risk-stratification, and management. Am J Hematol 2015;90:251-262.
Diagnosis of “prediagnostic ISM” or “Monoclonal mast cell activation syndrome” if meets all following criteria:

– Meets one or two minor criteria for systemic mastocytosis

2015 Theoharides TC, et al. Mast cells, mastocytosis, and related disorders. N Engl J Med 2015;373:163-172.
Meets all following criteria:

-Presence of typical symptoms of mast cell activation

-Increase of serum tryptase by 20% + 2 ng/mL within four hours after acute onset of symptoms

2017 Afrin LB, et al. Characterization of mast cell activation syndrome. Am J Med Sci 2017; 353(3):207-215.
Mast cell activation disease is used here as an umbrella term that includes both MCAS and SM. Mast cell activation disease is diagnosed if both major criteria, or one major criterion and one minor criterion, are present. Following the diagnosis with mast cell activation disease, a bone marrow biopsy is used to narrow the diagnosis down to either SM or MCAS.

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)

– Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity (mast cell mediator release symptom)

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)

2017 Akin C. Mast cell activation syndromes. J Clin Immunol 2017;140:349-55.
Meets all following criteria:

-Episodic multisystem symptoms consistent with mast cell activation

-Appropriate response to medications targeting mast cell activation

-Documented increase in validated markers of mast cell activation systemically (i.e., either in serum or urine) during a symptomatic period compared with the patient’s baseline values (serum tryptase, urinary histamine metabolites, urinary prostaglandin D2 or metabolites, urinary leukotriene E4)

2019 Valent P, Akin C, Butterfield JH, Horny HP, Schwartz LB, Metcalfe DD. Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome. J Allergy Clin Immunol Pract 2019;x:x-x.
Meets all following criteria:

-Typical clinical signs of severe, recurrent (episodic) systemic mast cell activation are present (often in form of anaphylaxis) (definition of systemic: involving at least 2 organ systems)

-Involvement of mast cells is documented by biochemical studies; preferred marker: increase in serum tryptase level from the individual’s baseline to plus 20% + 2 ng/mL (other mast cell derived markers of mast cell activation (histamine and histamine metabolites, PGD2 metabolites, and heparin) have also been proposed, but are less specific compared with tryptase)

-Response of symptoms to therapy with mast cell stabilizing agents, drugs directed against mast cell mediator production, or drugs blocking mediator release or effects of mast cell derived mediators

About the upcoming series on “A History of Mast Cell Activation Syndrome”

Hey, MastAttackers,

About two weeks ago, there were some frantic posts about a recently published paper around criteria for MCAS and how this paper would change things/affect people. At that time, I told people I was working on a response and would get it out as soon as I could. I started working on it pretty much immediately.

What didn’t occur to me at the time was that it would be really difficult to explain the context and meaning around various sets of criteria without literally going through all the literature exhaustively and showing how different groups of researchers and clinicians define MCAS and how that has changed over time. As far as I can tell, this information had never been compiled in an accessible format. So I just did it myself, from 1991-2019.

This information forms the basis of a multipart series I’m posting on MastAttack entitled “A History of Mast Cell Activation Syndrome: Living Criteria and the Lives They Define.” In this series, I will discuss in very explicit terms how these various sets of criteria were devised and why – specifically, who did clinicians and researchers envision as the population who had MCAS – and what did MCAS mean to them at the time they defined it in that way. Additionally, I will include information on how clinicians intended to treat these conditions at the time they were defined – arguably the aspect of MCAS management that most affects safety and quality of life for patients.

I wrote this introductory “this is what’s coming your way” post instead of launching right into the meat of this series to set the tone for the discussions that I am sure (and hope) will ensue around these posts in the week to come. I hope that everyone will approach this with a sense of openness and fairness. I will try to do the same and will trust the community to let me know if I don’t meet that expectation.

I also want to be clear about the fact that there will be frank discussion of various treatments for MCAS patients, including the use of IV diphenhydramine, tyrosine kinase inhibitors, and other chemotherapy agents. Be respectful of the fact that many MCAS patients have severe and dangerous symptoms that require aggressive management. I know that information about this topic has been restricted in the past, including by me, for professional reasons. I am happy to be able to discuss this topic more openly now and look forward to making this information more accessible both for patients and for providers.

It is my sincere hope that as a community we can move away from the idea of “these criteria are the right criteria” and “these criteria are the wrong criteria” despite the fact that we all – including me – have a set of “pet criteria” that we think of as being most accurate. It’s not just unhelpful, it’s damaging both to patients and to the community, which is often perceived as disorganized and divided. By having a clear understanding of what these various criteria are, and what purpose they serve in various research and clinical groups, I believe it will be much easier to have meaningful conversations around the different forms of mast cell disease and how best to serve the people who live with these conditions.

Ask any questions you would like as the information in this series is shared (the MastAttack Facebook group is the best place to reliably get responses from me). References will be at the bottom as usual for my technical posts. I trust the community to fact check me and please let me know if I have made a mistake in anything shared so that I can correct it as quickly as possible.

While I have your attention, I would like to update you on a few other things as well. I think most people know that my health took a pretty serious downward turn about a year ago. Shortly after that, my father died. For obvious reasons, I was unable to continue working on a lot of ongoing MastAttack projects and could not keep up with consult requests or email questions. I appreciate your patience and understanding as I’m getting things sorted out again. I am happy to tell you that I will be wrapping up the 107 series in the next couple of months. I will share more specific information about other projects as things develop.

Thanks for your help and support. I have really missed being involved in the community and look forward to reconnecting.

Lisa