​

Lawrence B. Afrin, M.D.

Senior Consultant in Hematology/Oncology

Department of Mast Cell Studies

AIM Center for Personalized Medicine

Purchase, New York, USA

Entire presentation copyright © 2024 by Lawrence B. Afrin, M.D. All rights reserved.

Renegade Research

Mast Cell Activation Disease:

Current Concepts

Clinicians’ Roundtable

June 7, 2024

Learning Objectives & Disclaimers

• Learning Objectives
• Review basic concepts regarding mast cell activation disorders (MCAD, including mast cell activation syndrome (MCAS))
• Review the clinical presentation of MCAS
• General approach to diagnosis and treatment of MCAS
• Conflicts of Interest
• None
• Note that there are not yet any FDA-approved treatments for MCAS, and not even (yet) any “well-designed, non-randomized clinical trials,” let alone (yet) any “high-quality randomized controlled clinical trials” (there just hasn’t been time yet for such trials!), so by definition, all treatment options discussed in this presentation are ACCME Level Of Evidence (LOE) “C” (“consensus viewpoint or expert opinion”).

Outline

• What is mast cell activation disease (MCAD)?
• What we’ve long known:
• Allergic diseases……………………………………….....
• Mastocytosis………………………………………………..
• What’s new:
• Mast cell activation syndrome (MCAS)…….….
• Basic behavior of the disease
• Clinical presentation
• General approach to diagnosis and treatment
• Research issues

General Clinical Theme

Allergy ± Inflammation

MC Neoplasia ± Allergy

± Inflammation

Inflammation ± Allergy

± Aberrant Growth

(Dystrophism)

Two cases…

“Polycythemia vera”

“Pure red cell aplasia”

and “Burning Mouth Syndrome”?

Three

“Polycythemia vera”

• 1980s: healthy 30ish woman notices migratory rash
• Over time: fatigue, itching, vertigo, falls; evals negative
• 2005: mildly elevated hemoglobin; polycythemia vera (PV) diagnosed (incorrectly), standard therapy begun
• Steadily worsened (migratory GI symptoms, labile BP/�pulse (“POTS”), poor healing, episodic shortness of breath, frequent upper respiratory “infections” with no infectant ever found, rashes to all antibiotics), had to close her business
• 2008: self-referred for further eval

Afrin LB. Polycythemia from Mast Cell Activation Syndrome: Lessons Learned. Am J Med Sci 2011;342:44-49.

“Polycythemia vera”

• No sleep apnea, no relevant family/social/medication history
• Exam: looked tired, nothing else
• Doesn’t fit PV; what else is driving her issues including ↑hemoglobin?
• Extensive additional testing proves she doesn’t have PV – and fails to find any other known cause of ↑hemoglobin
• Possible fit with mastocytosis; is that what it is?
• No?: serum tryptase, urine N-methylhistamine normal; marrow and rash biopsies show no mastocytosis
• Yes?: sl. ↑ urinary prostaglandin D₂
• EGD/colonoscopy: normal, but biopsies taken anyway…
• …all “textbook normal” on H&E, but on IHC…

​

​

Afrin LB. Polycythemia from Mast Cell Activation Syndrome: Lessons Learned. Am J Med Sci 2011;342:44-49.

• Dx: “atypical mastocytosis”?
• Low-dose imatinib begun
• 100 mg/d x 1 week, then
• 200 mg/d
• The first week: tolerated fine, but no response
• And then, on waking the morning after the fourth dose of 200 mg………..

CD117

40x

H&E

CD25

40x

“Polycythemia vera”

• All symptoms acutely gone.

​

• Improvement sustained >12 years now.�
• All labs normalized.�
• Resumed exercise and full-time work.

Afrin LB. Polycythemia from Mast Cell Activation Syndrome: Lessons Learned. Am J Med Sci 2011;342:44-49.

“Pure Red Cell Aplasia”

• 2004: 50ish woman, worsening fatigue; severe anemia
• Dx: idiopathic pure red cell aplasia (PRCA, confirmed)
• Refractory to all standard treatments for PRCA
• Needing 3 units of blood every 2-3 wks to maintain merely half-normal hemoglobin (Hgb) level
• 2009: 6^th opinion: ROS pan-⊕, uPGD₂ ↑↑↑, Dx: “MCAS”
• Antihistamines: Good Hgb ↑ in 4 weeks, no transfusions
• Imatinib 200 mg/d added: Hgb normalized in 6 weeks
• “PRCA” relapsed 1 yr later
• Tried cromolyn (previously precluded by insurer): remission again in 4 wks

Afrin LB. Pure red cell aplasia masquerading as mast cell activation disorder. Int J Hematol 2010 Jun; 91:907-908.

“Burning Mouth Syndrome”

• 2004: 50ish woman, new constant “burning” pain throughout GI tract, pain score 10/10 in mouth
• Very extensive evaluations over a year all negative except for finding mild chronic stomach inflammation and, finally, a 100-fold elevated serum chromogranin A (CgA) (not on PPIs)
• Neuroendocrine (NE) malignancy?
• Miserable from pain, but didn’t look like she had cancer of any sort
• Extensive cancer search negative
• T0p five U.S. NE cancer experts consulted
• Unanimous opinion: ↑↑CgA must be due to NE cancer, keep looking
• MC disease?
• Blood/urine markers normal; marrow, oral mucosa biopsies normal

Afrin LB. Burning Mouth Syndrome and Mast Cell Activation Disorder. Oral Surg Oral Med Oral Path Endodontol 2011;111:465-472.

“Burning Mouth Syndrome”

• Early ’09: Revisited old gastric biopsy with CD117 staining, showing ↑↑MCs (but not in pattern suggestive of mastocytosis)
• Dx: mast cell activation syndrome (MCAS)
• Antihistamines/NSAIDs: Pain ↓ to 1/10 overnight
• MCAS found in every subsequent “idiopathic” BMS patient I’ve examined
• Different abnormal MC mediator patterns in blood/urine in different patients
• ↑MCs in GI tract biopsies when checked
• All responding to various MC-targeted therapies

Afrin LB. Burning Mouth Syndrome and Mast Cell Activation Disorder. Oral Surg Oral Med Oral Path Endodontol 2011;111(4):465-472.

Highly divergent presentations, but…

• …same root disease?
• How can “one disease” (MCAS) do this?
• Could other “weird” presentations be possible?���But hold on a second. Before talking more about this “new” mast cell disease, let’s back up to look at what we’ve long known about diseases of the mast cell…

Allergic Diseases

• Allergy, asthma, angioedema, urticaria, anaphylaxis
• 2013: 700 million suffer allergic diseases worldwide
• 10% of preschoolers worldwide now have food allergies
• Steadily increasing incidence/prevalence across all ages
• e.g., China (prevalence): 1999: 3.5%; 2009: 7.7%
• Greatest increases in children < 5 years old
• Allergic diseases are conditioned by a number of genes and influenced by environmental factors
• Incidence of allergic disease in children if…
• …neither parent suffers allergic disease: 5-15%
• …only one parent suffers allergic disease: 20-40%
• …both parents suffer allergic disease: ≥ 60%
• Relatively little mortality, but significant QoL effects

​

1. Prescott SL et al. A global survey of changing patterns of food allergy burden in children. World Allergy Organiz J 2013;6:21, pp. 1-12.

2. Pawlinska-Chmara R et al., Effect of Socio-Economic Status on Quality of Life in People Affected with Respiratory Allergy, pp. 385-392, in M. Pokorski (ed.), Neurobiology of Respiration, Advances in Experimental Medicine and Biology 788, DOI 10.1007/978-94-007-6627-3_52, Springer Science+Business Media Dordrecht 2013.

Mastocytosis: A Long History

• 1869: Urticaria pigmentosa (UP) first described
• 1877: First description of the mastzelle
• 1887: UP linked with mastzelles
• 1933: Suggestion of linkage with internal dz
• 1939: MC heparin identified
• 1949: Definitive linkage with systemic dz
• 1953: MC histamine identified
• 1984: First conception “MCAS” might exist
• 1987: MC tryptase identified
• 1988: Travis classification
• 1995: KIT activating mutation D816V identified
• 1998: Unique flow cytometric signature found
• CD117 + (CD25 and/or CD2)
• 2001: WHO classification and imatinib
• MC neoplasia is morbid only in rare, aggressive forms; MC activation is what causes symptoms

Mast Cell Leukemia

Aggressive Systemic Mastocytosis

Indolent Systemic Mastocytosis

Cutaneous

Mastocytosis

Urticarias and

Angioedema

Allergies and

Anaphylaxis

Mast Cell

Activation

Syndromes

Not Yet Otherwise Classified

Disorders featuring inappropriate mast cell

activation

Disorders also featuring inappropriate mast cell

proliferation

Systemic mastocytosis with associated

hematologic non-mast-cell-lineage disorder

Smoldering Systemic Mastocytosis

Systemic

Mastocytosis

Mastocytoma

​

​

The Spectrum of

Mast Cell Disease

We’ve Long Known

​

Prevalence of SM: ~1:100,000

Prevalence of CM: ~1:10,000

~70-90% of all SM

Prevalence of allergy:

~1:5

Prevalence of urticaria:

~1:10

Prevalence of MCL: ~1:10,000,000

MCAD: A Brief History

• 1984-91: 1^st published hypotheses that MCAS ought to exist
• 2007: 1^st case reports of MCAS
• Some with KIT-D816V, some without
• 2007: 1^st study showing other KIT mutations in most MCAS (Bonn)
• 2008-: Non-KIT mast cell regulatory gene mutations found in SM
• 2010: 2^nd study showing KIT mutations in most MCAS (Bonn)
• KIT-D816V rare
• Few mutations in controls
• 2010: Proposal of “MCAD” (Harvard, Vienna, NIH)
• Includes 1^st proposal for MCAS diagnostic criteria
• 2011: Alternative proposal for MCAS diagnostic criteria (Bonn, MUSC)
• Revised 2016, 2017
• 2012: Revised (Vienna et al.) proposal for MCAS diagnostic criteria
• Still problematic
• “Updated” again in 2019 (now a.k.a. “consensus-1”) – no different than 2012
• 2016: Revised WHO diagnostic criteria for SM
• Mastocytosis now separate from the myeloproliferative neoplasms (MPNs)
• “Smoldering SM” added; “SM-AHNMD” shortened to “SM-AHN”
• No statement regarding MCAS
• 2020: “Consensus-2” proposal (update of alternative 2011/2016/2017 proposals) for MCAS diagnostic criteria

​

​

Key�PubMed IDs

17710669

20838788

20838788

21418662

2012: 22041891

2019: 30737190

27069254

32324159

Mast Cell Leukemia

Aggressive Systemic Mastocytosis

Indolent Systemic Mastocytosis

Cutaneous

Mastocytosis

Urticarias and

Angioedema

Allergies and

Anaphylaxis

Mast Cell

Activation

Syndromes

Not Yet Otherwise Classified

Disorders featuring inappropriate mast cell

activation

Disorders also featuring inappropriate mast cell

proliferation

Systemic mastocytosis with associated

hematologic non-mast-cell-lineage disorder

Smoldering Systemic Mastocytosis

Systemic

Mastocytosis

Mastocytoma

MCAD: Emerging Understanding

Prevalence ~17%?

Increasing prevalence

Mast Cell Leukemia

Aggressive Systemic Mastocytosis

SM-AHNMD

Indolent Systemic Mastocytosis

Cutaneous Mastocytosis

Mast Cell Activation Syndrome

0.0000001%?

17-20%?

Normal mast cell biology

• Hematopoietic origin, brief circulation
• Normally 0.05% of marrow nucleated cells
• Typically < 2% even in systemic mastocytosis
• Unique flow cytometric signature (incl. CD117+, CD25/2-)
• Maturation completed in all vascularized tissues
• Especially abundant beneath environmentally exposed mucosal/epithelial surfaces and adjacent to blood and lymphatic vessels and nerves, permitting sentinel function
• Relatively immobile once localized in peripheral tissue
• Lifespan typically several months to a few years

Kalesnikoff J, Galli SJ. New developments in mast cell biology. Nature Immunology 2008;9:1215-23.

Ribatti D. The development of human mast cells: an historical reappraisal. Exp Cell Res 2016;342(2):210-5.

Normal mast cell biology

• Functions (when appropriately stimulated):
• Synthesize active substances
• Some stored in granules of highly heterogeneous content
• Release various mediators upon various triggerings
• Phagocytose particulate material including bacteria, erythrocytes, schistosomes, metals, etc.
• KIT stem cell factor receptor and tyrosine kinase (on 4q11-12) is expressed at high levels on the mastocyte surface
• Critical for many mast cell functions including proliferation, differentiation, survival, chemotaxis, adhesion, and activation

Akin C, Metcalfe DD. The biology of Kit in disease and the application of pharmacogenetics. J Allergy Clin Immunol 2004; 114:13–19.

Gordon JR et al. Mast cells as a source of multifunctional cytokines. Immunol Today 1990;11:458.

Bradding P et al. Heterogeneity of human mast cells based on cytokine content. J Immunol 1995; 155:297.

Metcalfe DD et al. Mechanisms of mast cell signaling in anaphylaxis. J Allergy Clin Immunol 2009;124:639-648.

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​

​

Okayama Y, Kawakami T. Development, migration, and survival of mast cells. Immunologic Research 2006;34(2):97-115.

Normal mast cell biology

• Mediator release processes
• “Traditional”: degranulation
• Fulminant degranulation (e.g., anaphylaxis)
• Piecemeal (slower) degranulation
• Transgranulation
• Secretion of extracellular vesicles

Vukman KV et al. Mast cell secretome: Soluble and vesicular components. Semin Cell Dev Biol 2017;67:65-73.

Hügle T. Beyond allergy: the role of mast cells in fibrosis. Swiss Med Wkly 2014;144:w13999.

Courtesy of Prof. Peter Smith, Griffith University, Gold Coast, Australia

Normal mast cell biology

• Many triggers
• Classic: Adjacent high-affinity IgE receptors (FcεRI) with bound IgE get crosslinked by polyvalent antigen
• Physical stimuli: Pressure/trauma, heat, cold, UV, etc.
• Many other receptors for: histamine (H1/H2/H3/H4), SCF, IgG, C3a, C5a, PAF, CRF, neuropeptides (VIP, substance P, somatostatin, etc.), opioids, paralytics, benzodiazepines, cannabinoids, etc. etc. etc.
• Also many of the Toll-like receptors (affinities for various microbial proteins)

Bischoff SC et al. J Exp Med 1992;175:237.

Theoharides TC et al. Trends Pharmacol Sci 2008;29:375–382.

Conrad DH et al. J Immunol 1975;114:1688.

Woolhiser MR et al. Eur J Immunol 2001;31:3298.

Nilsson G et al. J Immunol 1996;157:1693.

Marshall JS et al. Int Arch Allergy Immunol 2003;132:87.

Church MK et al. Int Arch Allergy Appl Immunol 1991;94:310.

Stellato C et al. Anesthesiology 1991;74:1078.

Moss J et al. Anesthesiology 1983;59:330.

Miller LG et al. Pharmacology 1988;36:52–60.

Samson M-T et al. J Immunol 2003;170:4953-4962.

Kajiwara N et al. J Allergy Clin Immunol 2010;125:1137.

Theoharides TC, et al. New Engl J Med 2015;373:163-72, with permission.

​

Normal mast cell biology

• Capable of synthesizing and releasing many mediators
• Many expressible at very high levels
• Some stored in fully active form in electron-dense secretory granules, tightly packaged with serglycin proteoglycans
• A small sample:

​

​

• Heparin proteoglycan
• Chondroitin sulfate proteoglycan
• Superoxide dismutase
• Acid hydrolases
• Glucuronidase, galactosidase, hexosaminidase, peroxidase
• Arylsulphatase A
• Prostaglandin D₂, thromboxane
• Serotonin
• Antimicrobial agents
• IFN-α, IFN-β, IFN-γ, cathelicidin, LL-37
• CRH
• TSLP
• Want more? See http://www.cells-talk.com/index.php/page/copelibrary?key=mast%20cells

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• Pro-inflammatory cytokines
• IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-15, IL-16, IL-18, IL-21, IL-23, IL-25, IFN-γ, TNF-α
• Chemokines
• MCP-1, IL-8, RANTES, eotaxin, leukotrienes B₄, C₄, D₄, E₄ (SRS-A), CCL2, CCL3, CCL4, CCL5, CCL11, CCL19, CCL20, CCL21, CXCL8, CXCL10, XCL-1
• Proteases
• Tryptase, chymase, ACE, carboxypeptidase, cathepsin G, cysteinyl cathepsins, metalloproteinases
• Growth factors
• IL-3, GM-CSF, bFGF, VEGF, TGF-β, PDGF, EGF, NGF, SCF, angiopoietin
• Vascular permeability, vasodilatation
• Histamine, 5-hydroxytryptamine, tryptase, NO, VLA4
• Platelet aggregation and thrombosis:
• PAF, thromboxane

Theoharides TC et al. Differential release of mast cell mediators and the pathogenesis of inflammation. Immunological Reviews 2007;217(1):65-78.

Mast cell biology: mediator effects

• Just as molecular-scale transistors, through amplification mechanisms, can exert macro-scale control…�����

…so, too, can molecular-scale mast cell mediators, through amplification mechanisms, exert clinical-scale effects:

Weinstock LB, et al. Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment. BMJ Case Rep 2018 Jan 11;2018:bcr2017221405. DOI: 10.1136/bcr-2017-221405.

Criteria for Systemic Mastocytosis

• WHO ’16: Indol. SM, smold. SM, SM-AHN, aggressive SM, MC leukemia
• 1 major + 1 minor, or 3+ minor criteria
• Only major criterion: “Multifocal, dense infiltrates of mast cells consisting of 15 or more mast cells in aggregates detected in sections of bone marrow and/or other extracutaneous organs, confirmed by tryptase immunohistochemistry or other special stains”
• 4 minor criteria:
• More than 25% of MCs in biopsy sections or bone marrow aspirate smears showing spindle shape or atypical morphology
• Expression of CD2 and/or CD25 by marrow, blood, or extracutaneous organs MCs
• KIT codon 816 mutation in bone marrow, blood, or other extracutaneous organs
• Different KIT mutations → different phenotypes
• D816V: MC clusters, spindle forms, expression of CD25, histamine, CPA, etc.
• Extracellular domain: AKT activation
• Serum total tryptase (25% of MC protein!) persistently > 20 ng/ml

Arber DA et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391-2405.

Mayerhofer M et al. Unique effects of KIT D816V in BaF3 cells: induction of cluster formation, histamine synthesis, and early mast cell differentiation antigens. J Immunol 2008;180:5466-5476.

Teodosio C et al. Mast cells from different molecular and prognostic subtypes of systemic mastocytosis display distinct immunophenotypes. J Allergy Clin Immunol 2010;125:719-726.e4.

Yang Y et al. Pediatric mastocytosis-associated KIT extracellular domain mutations exhibit different functional and signaling properties… Blood 2010 Aug 19, 116(7):1114-1123.

Alvarez-Twose I et al. Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms. J Allergy Clin Immunol 2010;125:1269-1278.e2.

Schwartz LB et al. Quantitation of histamine, tryptase, and chymase in dispersed human T and TC mast cells. J Immunol 1987;138(8):2611-2615.

The Problem

Chronic Fatigue Syndrome!

Fibromyalgia!

Refractory

GERD!

POTS!

Granuloma Annulare, or Chronic� Inflammatory Demyelinating

Polyneuropathy, or…or…or…!

Just Old

Age!

What to do when it behaves like mast cell disease but isn’t just allergic disease or mastocytosis:�Consider mast cell activation syndrome

Proposed Criteria for MCAS

• Self-described “consensus” proposal (now a.k.a. “consensus-1”)
• Problem: Methods by which “consensus” was obtained
• History consistent with chronic and/or recurrent aberrant mast cell mediator release
• Problem: Few symptoms listed in proposal (e.g., flushing)
• Not SM and no better-fitting disease
• Rise in tryptase (within 4h of flare) of 20% + 2 ng/ml over asymptomatic baseline
• Problem: establishing “asymptomatic” baseline
• Problem: getting blood for tryptase level drawn within 4h of flare
• Problem: allows levels well within normal range to signify disease
• Problem: no published data whether this distinguishes nl./abnl. fluctuation in the general MCAS population despite repeated assertions otherwise
• Response to mast cell-targeted therapy
• Problem: requires therapy prior to diagnosis
• Problem: should diagnosis of this very heterogeneous disease be ruled out if merely 1 or 2 trials of empiric therapy fail?

Valent P 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 Jan;157:215-225.

Akin C et al. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol 2010; 126:1099-1104.e4.

Valent P et al. Why the 20% + 2 tryptase formula is a diagnostic gold standard for severe mast cell activation and mast cell activation syndrome. Int Arch Allergy Immunol 2019;180(1):44-51, doi: 10.1159/000501079.

Diagnosing MCAS: Criteria

• “Consensus-2” proposal:
• Major criterion:
• Constellation of clinical complaints attributable to pathologically increased MC activity (MC mediator release syndrome)
• Minor criteria:
• Multifocal or disseminated infiltrates of MCs in marrow and/or extracutaneous organ(s) (e.g., gastrointestinal or genitourinary tract; ≥20 MCs/high power field)
• Abnormal spindle-shaped morphology in >25% of MCs in marrow or other extracutaneous organ(s)
• Abnormal MC expression of CD2 and/or CD25 (i.e., co-expression of CD117/CD25 or CD117/CD2)
• MC genetic changes (e.g., activating KIT codon 419, 509, or 560 mutations) shown to increase MC activity
• Evidence (typically from body fluids such as whole blood, serum, plasma, or urine) of above-normal levels of MC mediators including: tryptase, histamine or its metabolites (e.g., N-methylhistamine), heparin, chromogranin A (note potential confounders of cardiac/renal/hepatic failure, neuroendocrine tumors, chronic atrophic gastritis, or recent proton pump inhibitor use), other relatively MC-specific mediators (e.g., eicosanoids including prostaglandin (PG) D₂, its metabolite 11-β-PGF_2α, or leukotriene E4)
• Symptomatic response to inhibitors of MC activation or MC mediator production or action
• Diagnosis made upon fulfillment of the major criterion + ≥ 1 minor criterion…
• …and, of course, no other evident diagnosis which better accounts for the full range and duration of all the symptoms and findings in the history, exam, and labs

Afrin LB et al., Diagnosis 2020 Apr 22;8(2):137-152. doi: 10.1515/dx-2020-0005, updated from Molderings GJ et al. F1000Res 2017 Oct 26;6:1889. doi: 10.12688/f1000research.12730.1, updated from Afrin LB, et al. Ann Med 2016;48(3):190-201, updated from Molderings G, et al. J Hematol Oncol 2011;4:10.

​

Same as WHO

Same as WHO

Expanded

Expanded

New

Added

Expanded

MCAS: Emerging Understanding

• Increasing estimates of prevalence
• 1-17% of the general first-world population?
• Increasing evidence of critical mast cell involvement in…

Theoharides TC. Clin Ther 2013;35:544-7.

Afrin LB. Oral Surg Oral Med Oral Path Oral Radiol Endodontol 2011;111:465-472.

Haenisch B, et al. Immunol 2012;137:197-205.

Pejler G, et al. Blood 2010;115(24):4981-4990.

Theoharides TC, et al. Biochim Biophys Acta 2012 Jan;1822(1):21-33.

Theoharides TC, et al. Trends Pharmacol Sci 2011;32(9):534-542.

Afrin LB, et al. Int J Infect Dis 2020;100:327-332.

• Irritable bowel syndrome (11%)
• Chronic fatigue syndrome (3%)
• Fibromyalgia (1-10%)
• Diabetes mellitus (2-20%)
• Acute and long Covid-19?

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• Asthma (4-20%)
• Obesity (37%)
• Depression (5%)
• Atherosclerosis (?)
• Etc. etc. etc. etc.

Brightling CE, et al. Curr Allergy Asthma Reports 2005;5:130-135.

Blanco I, et al. Clin Rheumatol 2010;29:1403-1412.

Theoharides TC, et al. J Clin Psychopharmacol 2005;25:515-520.

Theoharides TC, et al. J Clin Psychopharmacol 2004;24:577-581.

Molderings GJ, et al. PLoS One 2013;8(9):e76241

Frieling T, et al., Z Gastroenterol 2011;49:191-194.

Weinstock LB, et al. Int J Infect Dis 2021;112:217-226.

• Irritable bowel syndrome
• Chronic fatigue syndrome
• Fibromyalgia
• Diabetes mellitus

​

​

• Asthma
• Obesity
• Depression
• Atherosclerosis
• Etc. etc. etc. etc.

Est. Global Prev.

Est. Global Prev.

What Portions of These Populations Bear Clonal Mast Cell Disease?

If MCAS dominantly manifests as chronic inflammatory disease (CID), might its prevalence be even higher within populations enriched for CID

(e.g., inpatients)?

MCAS: Emerging Biology

• May be clonal in most cases…
• More than 50 mutations (mostly heterozygous, but still functionally dominant) found scattered across all domains of KIT
• Most patients have multiple KIT (and other) mutations
• No commercial assays yet for most of these mutations

Molderings GJ et al. Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder. Scand J Gastroenterol 2007; 42(9):1045-1053.

Molderings GJ et al. Comparative analysis of mutation of tyrosine kinase Kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects. Immunogenetics 2010;62:721-727.

MCAS: Emerging Biology

• KIT mutations found thus far in MCAS:
• Ligand-binding domain: W8R, C12S, del(nt a153), E53K, insertion 71 ?seq(400bp), E73R, T74R, exon 3 & 5 del and ins/del, ins nt 248a, ins Q252, K259E, H265Q, E270K, L276S
• Dimerization domain: E338K, Q346L, M351E, F355L, E359V, exon 7 ins/del, del (aa 378-390)
• Proteolytic cleavage site: L416Q, D419H, ins(nt 1282g), exon 8 del
• Membrane-spanning region: del 510-513, exon 10 ins, M541L
• Juxtamembrane (autoinhibitory) region: F584C
• Kinase insert sequence K1: S709A, del(S715), A736V, D751Y
• Kinase domain K2: F782S, N787D, H790R, D816V (rare!), S821F, A829T, A837V, L862V
• C-terminus: complex insertions

​

Molderings GJ et al. Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder. Scand J Gastroenterol 2007; 42(9):1045-1053.

Molderings GJ et al. Comparative analysis of mutation of tyrosine kinase Kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects. Immunogenetics 2010;62:721-727.

MCAS: Do the Biology Math

• MCs produce and release scores of mediators
• 1 KIT mutation ⇒ aberrant release of N mediators
• Multiple KIT mutations in most MCAS patients?
• Multiple MC genes mutated in most MCAS patients?
• Each mediator has its own unique array of direct and indirect, local and remote effects

MCAS: Presentation

• MCAS is a chronic multisystem polymorbidity of general themes of:
• Inflammation – the universal constant in MCAS
• ± allergic-type phenomena
• ± aberrancies in growth/development (i.e., dystrophisms), far more commonly benign than malignant in potentially any tissue
• can be difficult to recognize given typically slow pace of development and, often, lack of clinical significance

Afrin LB, Butterfield JH, Raithel M, Molderings GJ. Ann Med 2016;48(3):190-201.

MCAS: Presentation

• Typical presentation
• Age of onset: typically < 20 but unrecognized for decades
• Escalations of baseline MC misbehavior may shortly follow (by a few days to a few months) major physical or psychological/emotional stressors
• Usually MULTISYSTEM; can affect every system
• Symptoms virtually always at least “inflammatory” in nature
• Perplexingly inconstant course:
• Abnormalities often externally inapparent (“she looks fine!”)
• Chronic or waxing/waning or episodic (“flares”, “spells”)
• Different symptoms at different times
• Often no apparent triggers
• Mediators:
• Tryptase (total & mature) usually normal (reflects MC load >> activation)
• Heparin, CGA, PGD₂ and histamine (& metabolites), LTE4 often elevated
• Many MDs, many dx’s (often non-specific, idiopathic, “somatic”)
• Patients commonly cease reporting symptoms – ROS important!

1. Afrin LB, Butterfield JH, Raithel M, Molderings GJ. Ann Med 2016;48(3):190-201.

2. Zenker N, Afrin LB. Blood 2015;126:5174.

3. Schwartz LB. J Immunol 2003;170(11):5667-73 and Immunol Allergy Clin N Am 2006;26:451-63.

4. Hamilton MJ et al. J Allergy Clin Immunol 2011;128;147-52.

4. Vysniauskaite M et al. PLoS One 2015 Apr 24;10(4):e0124912.

5. Ferrer M et al. Clin Exp Allergy 2010 Dec;40(12):1760-6.

6. Sala-Cunill A et al. Int Arch Allergy Immunol 2013;160(2):192-9.

Age

Baseline Aberrant Constitutive and Reactive Mast Cell Mediator Production/Release

Stressor

Stressor

Stressor

Stressor

MCAS: Presentation

• Constitutional
• Fever, chills, fatigue, sweats, weight ↑ or ↓ or ↑↓, pruritus
• Odd and prolific sensitivities (drugs, foods, environs, implanted materials)
• Eyes
• Irritation, episodic inability to focus vision, blepharospasm
• Ears
• Irritation, hearing deficit and/or tinnitus
• Nose
• Irritation, sores, epistaxis, coryza
• Oral/esophageal
• Irritation, sores, dysphagia, globus

Afrin LB, Butterfield JH, Martin R, Molderings GJ. Ann Med 2016;48(3):190-201.

MCAS: Presentation

• Nodes
• Borderline pathologic, waxing/waning, migratory adenopathy
• Left upper quadrant (splenic?) discomfort common
• Path: usually reactive lymphocytosis, occ. sinus histiocytosis
• Pulmonary
• Waxing/waning migratory edema/inflammation (e.g., cough)
• Dyspnea (normal PFTs; “I just can’t catch a deep breath”)
• Cardiovascular
• Unprovoked presyncope/syncope, labile BP/pulse, palpitations
• Chest pain: coronaries usually clean, but occ. aggressive CAD
• Arterial, venous malformations; episodic migratory edema
• Takotsubo (acute balloon CHF), Kounis (allergic angina) synd.

​

Afrin LB, Butterfield JH, Martin R, Molderings GJ. Ann Med 2016;48(3):190-201.

MCAS: Presentation

• GI
• Inflammation (any/all luminal segments, solid organs)
• Refractory GERD, IBS, mild ↑LFTs common
• Diarrhea 🡘 constipation
• Queasiness, nausea, vomiting (sometimes “cyclical”)
• Malabsorption common (gen., or selected micronutrients)
• Hepatic involvement common, usually inflamm./fibrosis
• GU
• Inflammation (any/all luminal segments, solid organs)
• e.g., “interstitial cystitis”
• ↓ libido, infertility

​

Afrin LB, Butterfield JH, Martin R, Molderings GJ. Ann Med 2016;48(3):190-201.

MCAS: Presentation

• Musculoskeletal and Joints
• Myositis, osteopenia and/or osteosclerosis
• Diffusely migratory soft tissue pain; “fibromyalgia,” “CRPS”
• NSAIDs/narcotics often unhelpful (may trigger flares!)
• Skin/Integument
• Lesions (many types), rashes (many types, often migratory), pruritus, flushing, angioedema, dermatographism
• Hair/nail/dental dystrophy
• CNS/PNS
• Headache, vertigo, syncope, tic/tremor, weakness, dysautonomia
• Migratory paresthesias, insomnia very common
• Wide range of psychiatric disorders also found in MCAD

Afrin LB, Butterfield JH, Martin R, Molderings GJ. Ann Med 2016;48(3):190-201.

MCAS: Presentation

• Heme
• Counts often normal, or…
• ↑ or ↓ H/H (subtle ↑ RDW, MCV, and/or MCH common)
• ↑ or ↓ WBC (subtle/intermit. ↑ monos, eos, &/or basos common)
• ↑ or ↓ plts
• ↑ or ↓ clotting
• Marrow
• Usually normal (histology, IHC, cytogenetics, flow, PCR)
• Most common abnormality: mild dysplasia (“unclass. MDS/MPN”)
• Immunity
• Hypersensitivities, ↑ risk for malig., autoimm., infection
• Poor healing

Afrin LB, Butterfield JH, Martin R, Molderings GJ. Ann Med 2016;48(3):190-201.

MCAS: Presentation

• Endocrinologic/metabolic
• Delayed puberty/menarche, dysmenorrhea
• Osteopenia/osteoporosis, osteosclerosis
• Hypo/hyperthyroidism, hyperferritinemia (inflammatory)
• ↑ or ↓ electrolytes, ↑ lipids (often hypertriglyceridemia)
• Growth/Development
• Poor healing
• Cysts, fibrosis, endometriosis, vascular anomalies, cancer
• Connective tissue weakness (e.g., hypermobile Ehlers Danlos Syndrome)?
• Autism spectrum disorders?
• Inflammatory lipodystrophies (e.g., Dercum’s disease)?

​

​

Afrin LB, Butterfield JH, Raithel M, Molderings GJ. Ann Med 2016;48(3):190-201.

Afrin LB. Am J Med Genet C Semin Med Genet 2021 Dec;187(4):466-472.

Herbst, K.L., 2019. Endotext [Internet], https://www.ncbi.nlm.nih.gov/sites/books/NBK552156/.

MCAS and POTS: A Few Notes

• In some portion of the POTS population, is that disease rooted in certain patterns of chronic aberrant mast cell mediator expression? 25+ years of tantalizing hints, e.g….

• 25+ years of tantalizing hints of MCAS underlying at least some POTS:

• Roberts 2nd LJ. Recurrent syncope due to systemic mastocytosis. Hypertension 1984;6(2 Pt 1):285–94.
• Shibao C et al. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension 2005 Mar;45(3):385-90.
• Garland EM et al. Postural Tachycardia Syndrome: Beyond Orthostatic Intolerance. Curr Neurol Neurosci Rep 2015 Sep;15(9):60.
• Afrin LB et al. Characterization of Mast Cell Activation Syndrome. Am J Med Sci 2017 Mar;353(3):207-215.
• Stewart JM et al. Pediatric Disorders of Orthostatic Intolerance. Pediatrics 2018 Jan;141(1):e20171673.
• Weinstock LB et al. Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment. BMJ Case Rep 2018 Jan 11;2018:bcr2017221405.
• Blitshteyn S, Chopra P. Chronic Fatigue Syndrome: From Chronic Fatigue to More Specific Syndromes. Eur Neurol 2018;80(1-2):73-77.
• Bonamichi-Santos R et al. Association of Postural Tachycardia Syndrome and Ehlers-Danlos Syndrome with Mast Cell Activation Disorders. Immunol Allergy Clin North Am 2018 Aug;38(3):497-504.
• Kacar M et al. Selective Response to Omalizumab in a Patient With Concomitant ncMCAS and POTS: What Does it Teach us About the Underlying Disease? J Investig Allergol Clin Immunol 2018 Aug;28(4):261-263.
• Arnold AC, Ng J, Raj SR. Postural tachycardia syndrome – Diagnosis, physiology, and prognosis. Auton Neurosci 2018 Dec;215:3-11.
• Goodman BP. Evaluation of postural tachycardia syndrome (POTS). Auton Neurosci 2018 Dec;215:12-19.
• Doherty TA, White AA. Postural orthostatic tachycardia syndrome and the potential role of mast cell activation. Auton Neurosci 2018 Dec;215:83-88.
• Chen G et al. Postural Tachycardia Syndrome in Children and Adolescents: Pathophysiology and Clinical Management. Front Pediatr 2020 Aug 20;8:474.
• Vadas P et al. Cosegregation of postural orthostatic tachycardia syndrome, hypermobile Ehlers-Danlos syndrome, and mast cell activation syndrome. Ann Allergy Asthma Immunol 2020 Dec;125(6):719-720.
• Tu Y et al. Mechanisms and management of gastrointestinal symptoms in postural orthostatic tachycardia syndrome. Neurogastroenterol Motil 2020 Dec;32(12):e14031.
• Schofield JR. Persistent Antiphospholipid Antibodies, Mast Cell Activation Syndrome, Postural Orthostatic Tachycardia Syndrome and Post-COVID Syndrome: 1 Year On. Eur J Case Rep Intern Med 2021 Mar 22;8(3):002378

MCAS and POTS:�A Few Notes

• A few small studies to date have suggested an association between MCAS and POTS. For example:
• Afrin LB et al. Characterization of Mast Cell Activation Syndrome. Am J Med Sci 2017;353(3):207-215 (online suppl. Table 1).
• Increasing clinical observation, too, suggests an association between MCAS and POTS.
• BUT…
• Association ≠ Causation!!!!!!!!!!
• Much more research is required to PROVE (or disprove) that certain variant(s) of MCAS cause some forms of POTS.

≠

How Might MCAS Drive POTS (and other Dysautonomias)?

• First of all, anatomy: again, where are the mast cells in the human body?
• All vascularized tissues, but sparsely distributed in most tissues – and dominantly sited not only at the environmental interfaces but also in the walls of all vessels and sheaths of all nerves!
• Secondly, biology: do mast cells produce mediators which can drive tachycardia and vasodilation?
• Absolutely! Almost too many to count!
• Mast cells express more than 1,000 mediators (and more than 250 receptors).
• The potential for direct and indirect, and even circular, signaling, and signaling involving (abnormal) mast cells and other (normal) cell populations is vast.
• Note there is no requirement that the mast cells themselves inappropriately express the key aberrantly expressed mediator (or its promoter or inhibitor). It may be sufficient simply for dysfunctional mast cells to over- or under-express a key promoter or inhibitor of the key proximate mediator.

Ibelgaufts H. COPE: Cytokine Online Pathfinder Encyclopedia. http://www.cells-talk.com/index.php/page/copelibrary?key=mast%20cells

How Might MCAS Drive POTS (and other Dysautonomias)?

• Let’s keep in mind, too, the wide range of other dysautonomias besides POTS which MCAS might drive in some patients; for example:
• Temperature regulation
• Blood pressure regulation
• Flushing
• Sweat regulation
• Respiratory regulation
• Sleep regulation
• Glucose/electrolyte/hormone regulation
• “Energy”/mood/anxiety regulation
• Etc. etc. etc.

Ibelgaufts H. COPE: Cytokine Online Pathfinder Encyclopedia. http://www.cells-talk.com/index.php/page/copelibrary?key=mast%20cells

Which MC Mediators Might Drive POTS (and Other Dysautonomias?

Ibelgaufts H. COPE: Cytokine Online Pathfinder Encyclopedia. http://www.cells-talk.com/index.php/page/copelibrary?key=mast%20cells

• Histamine?
• Interleukins?
• Prostaglandins?
• Leukotrienes?
• Adrenomedullin?
• Atrial natriuretic factor (ANF)?
• Angiotensin?
• Apelin?
• Brain natriuretic peptide?

​

​

• Calcitonin gene-related peptide (CGRP)?
• Cathepsin L?
• Chymase?
• Relaxin?
• Urocortin-2?
• VEGF-165?
• Any mediator leading to increased nitric oxide?
• Etc. etc. etc.

How Might MCAS Drive POTS?

• Another possibility: autoimmunity against relevant cardiovascular targets
• Again, MCAS frequently drives aberrations in the immune system…
• …including spurious/random production of antibodies the immune system has no legitimate business producing
• Most such antibodies don’t have a clinically relevant target (even though some of them may mimic clinically relevant antibodies, register positive on tests for such, and lead to erroneous diagnosis and treatment of autoimmune or infectious diseases)…
• …but there’s obviously a possibility that certain spuriously/randomly generated antibodies might target cardiovascular (and/or neural?) antigens which could lead to tachycardia and/or hypotension

How Might MCAS Drive POTS?

• Are there arguments against autoimmune POTS (and other autoimmune dysautonomias)?
• If certain autoantibodies drive POTS, why do the kinetics of a POTS flare not come anywhere close to the kinetics with which autoantibody titers can fluctuate?
• Or could it be an even more complex, multifactorial matter of (relatively) stable levels of cardiovascularly-targeted autoantibodies creating a state of potential for POTS flares, and then flaring levels of certain mast cell mediators actuate that potential?
• Seems complicated.* Occam’s Razor favors simplicity, i.e, just flarings of MCAS, with no need for autoantibodies to get involved.

​

*Indeed, some antibodies previously suspected to be involved in POTS, engendering a great amount of expensive testing over many years, have more recently been shown to likely not be involved: Hall et al., Circulation 2022, DOI: 10.1161/CIRCULATIONAHA.122.059971.

If the mast-cell-based somatic mutations of MCAD/MCAS are central to POTS (and other dysautonomias), what are the chances whole genome/exome sequencing will find them?

• Minimal.
• Most current WGS/WES technologies/approaches will find and call mutations present in ~20% or more of the sequenced cell population.
• Mast cells comprise ~0.02% of peripheral blood leukocytes.
• This is why mast cells are never reported in a leukocyte differential except in the very rare case of mast cell leukemia.

How will we find mast-cell-based somatic mutations central to POTS and other dysautonomias?

• Sequence the mast cells – just the mast cells.
• Extract the mast cells from the sample (blood is probably the easiest/safest tissue to access which will provide the greatest number of mast cells), either by…
• Immunomagnetic beads (cheap, laborious)�or
• CD117-based flow cytometric sorting (expensive machine, quick)
• Sequence (Sanger, NGS, etc.) the extracted mast cells.
• Dysfunctional mast cells (all progeny of an identically mutated stem cell or multipotent progenitor cell, of course) certainly don’t comprise all the mast cells in an MCAS patient, but prior research has shown repeatedly this sequencing approach reliably detects a menagerie of (mostly somatic) mutations in the mast cells in MCAS patients.

1. Molderings et al., Scand J Gastroenterol 2007. 2. Molderings et al., Immunogenetics 2010. 3. Altmüller et al., Immunogenetics 2017.

How will we find mast-cell-based somatic mutations central to POTS and other dysautonomias?

• Barrier: No clinical sequencing lab anywhere on the planet – yet – which offers mast-cell-focused sequencing.
• Many labs will do sequencing focused on tumor cells or other cells, but none yet are willing to focus on mast cells.
• Therefore, mast-cell-focused sequencing presently can be done only in research labs.

How will we find mast-cell-based somatic mutations central to POTS and other dysautonomias?

• If not already found by research labs, the mast cell mutational profiles common in POTS likely will quickly become apparent once mast-cell-focused sequencing becomes clinically available.
• Physicians attending to MCAD/MCAS patients likely will routinely order clinically available mast-cell-focused sequencing, primarily to learn of correlations between mutational profiles and effective therapies (to short-circuit the present “trial and error” approach to finding those therapies effective in the individual patient), but correlations between mutational profiles and clinical symptoms/phenotypes will “fall out” from such data, too.
• Identification of POTS driver mutations should permit identification/design of both mechanisms underlying symptoms and rational therapies.

MCAS: Diagnosis

• Best diagnostic aids:
• Most physicians’ best friend: a complete history and exam
• Faith in Occam’s Razor: which scenario is more likely?�
• Multiple diagnoses/problems all independent of each other��

MCAS: Diagnosis

• Best diagnostic aids:
• Most physicians’ best friend: a complete history and exam
• Faith in Occam’s Razor: which scenario is more likely?�
• Multiple diagnoses/problems all independent of each other��vs.�
• One diagnosis that’s biologically capable of causing most or all of the findings (i.e., the simplest solution, even if it’s not the most immediately obvious solution)

MCAS Differential Diagnosis

• Need to carefully consider the many diseases which drive chronic multisystem inflammatory ± allergic ± dystrophic issues, e.g. (note some of these may, in at least some cases, actually be consequential to MCAS):

• Autoimmune diseases
• Adrenal insufficiency
• Adult Still’s disease
• Cellular and humoral immunodeficiency syndromes
• Eosinophilic disorders (e.g., eosinophilic esophagitis)
• Gulf War Illness/Syndrome

• Inborn metabolic errors
• Infections (esp. tick-borne/pet-borne diseases)
• Malignancies (esp. hematologic)
• Mitochondrial diseases
• Porphyrias
• Etc. etc. etc.

MCAS Differential Diagnosis

• Also, in patients with literally life-long multisystem inflammation (i.e., extending back to infancy or early childhood), be sure to test for the autoinflammatory syndromes (AISs)
• Scores of different diseases born of mutations in >150 genes coding proteins regulating various aspects of inflammation
• An AIS mutation transforms an inflammation-regulating protein that’s normally an “on/off switch” into a “switch that’s stuck permanently on”
• Formerly called the periodic fever syndromes – until it became clear fever was not a reliable feature of many of these syndromes
• Testing previously difficult and expensive, now easy (even internationally) and inexpensive (e.g., Invitae (155 genes), Fulgent (47 genes), Mayo (18 genes), ARUP (10 genes), etc.)
• Many AISs (though not all) are treatable
• Will require testing (not yet clinically available) for somatic mast cell mutations to distinguish whether AIS patients’ sole problem is their germline mutation vs. germline + somatic (mast cell) mutations, but either way, decreasing AIS-driven inflammation may (should?) decrease mast cell activation

MCAS�Diagnostic�Work-Up:�2024

Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014 Mar;3(1):1-17.

MCAS: Prognosis

• No epidemiologic studies of prognosis yet
• Present gestalt impression:
• After the first three years, survival curves parallel the general population (similar to indolent systemic mastocytosis (ISM))
• So, like allergic diseases and ISM, reduced survival is a relatively small problem in MCAS, and instead most suffer reduced quality of life (anywhere from mild to severe, variable over time) until the disease is accurately diagnosed and effectively controlled
• Many therapies (targeting many receptors and pathways) found helpful in various MCAD/MCAS patients
• Most cytotoxic chemotherapy quite unlikely to help MCAS
• Most MCAS pts eventually identify a significantly helpful regimen…
• …and given they’ll likely live a normal lifespan, the improved quality of life they can achieve – once correctly diagnosed – is important!

Roberts LJ, Anthony LB, Oates JA. “Disorders of Vasodilator Hormones: Carcinoid Syndrome and Mastocytosis” in Wilson JD, Foster DW, Kronenberg HM, et al., eds., Williams Textbook of Endocrinology, 9th ed., 1998, W. B. Saunders Company, Philadelphia, pp. 1718-1732.

Lim K-H, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood 2009;113:5727-5736.

MCAS: Treatment

• 2024: Largely as for indolent mastocytosis
• Identify and avoid triggers
• Inhibit mediator production
• Inhibit mediator release
• Block actions of released mediators
• Cytotoxic and cellular therapy only for aggressive SM, MCL
• Secondary issues and comorbidities

Again, all treatment options for MCAS discussed in this presentation are ACCME Level Of Evidence “C” as detailed in the Disclaimer slide near the beginning of this presentation.

MCAS: Treatment

• 2024: Largely as for indolent mastocytosis
• “Step 1” (now and for the rest of the patient’s life, or at least until cure becomes possible): IDENTIFY THE PATIENT’S TRIGGERS AS PRECISELY AS POSSIBLE, AND THEN DO ONE’S BEST TO AVOID THEM.
• It is HARD for any drug to gain good, sustained control over dysfunctional mast cells as long as the patient is simultaneously and persistently ingesting, or otherwise exposing himself/herself to, a trigger.
• Later, as the disease comes under better control, some intolerances may lessen/remit; OK to (cautiously) re-try exposures to known triggers as better control is attained

Again, all treatment options for MCAS discussed in this presentation are ACCME Level Of Evidence “C” as detailed in the Disclaimer slide near the beginning of this presentation.

MCAS: Treatment

• 2024: Largely as for indolent mastocytosis
• Identify and avoid/treat triggers:
• Antigens
• Environmental (natural and/or artificial, solid/liquid/aerosolized)
• Inhaled/ingested (foods, medications)
• Implanted
• Physical activities
• Stressors (physical and/or psychological/emotional)
• Physical forces (heat, pressure, humidity, acidity, specific radiation wavelengths)
• Complicating chronic active infections
• Or, if avoidance not possible, consider desensitization therapy if feasible
• Medication excipients often are prominent triggers
• Don’t give up on the drug if it quickly appears intolerable (the drug may work wonderfully well once divorced from the triggering excipient mixed with it in the formulation initially randomly selected), and instead try at least one or two alternative (commercial or compounded) formulations with different excipient packages not containing the suspected trigger.
• Low-histamine diets, diamine oxidase supplementation
• Explantations of triggering materials may be needed

Again, all treatment options for MCAS discussed in this presentation are ACCME Level Of Evidence “C” as detailed in the Disclaimer slide near the beginning of this presentation.

MCAS: Treatment

• 2024: Largely as for indolent mastocytosis
• Identify and avoid triggers
• Inhibition of mediator production
• Steroids (long-term issues), NSAIDs (possibly more likely to be helpful in patients with elevated prostaglandin moieties)
• Caution re: NSAIDs: some patients react to them; avoid them, or start “low and slow,” if concerning history present
• Vitamin C
• Possibly also hydroxyurea (or even IMiDs?), TKIs
• Inhibition of mediator release (stabilization)
• Blockade of released mediators
• Rarely (if ever): Cytotoxic therapy
• Hypothetical: Cellular therapy
• Secondary issues and comorbidities

Again, all treatment options for MCAS discussed in this presentation are ACCME Level Of Evidence “C” as detailed in the Disclaimer slide near the beginning of this presentation.

MCAS: Treatment

• 2024: Largely as for indolent mastocytosis
• Identify and avoid triggers
• Inhibition of mediator production
• Inhibition of mediator release (stabilization)
• Cromolyn (oral and/or inhaled – non-absorbed)
• Can trigger flares 1^st few days; tachyphylaxis can abrogate efficacy
• Pentosan (especially for interstitial cystitis)
• Tyrosine kinase inhibitors
• Interferon (& pegylated form?)
• Omalizumab (anti-IgE)
• Azathioprine, other immunosupp.
• JAK1 and mTOR inhibitors?
• Benzodiazepines and imidazopyridines; cannabinoids; low-dose naltrexone
• e.g., lorazepam, clonazepam, flunitrazepam, zolpidem; cannabidiol
• Estrogen receptor modulators? CGRP blockers? TSLP inhibitors? Dupilumab (anti-IL4/IL13)?
• Blockade of released mediators
• Rarely (if ever): Cytotoxic therapy
• Hypothetical: Cellular therapy
• Secondary issues and comorbidities

Imatinib (approved for CML, ASM, et al.)

Dasatinib (approved for CML, ALL)

Nilotinib (approved for CML)

Sunitinib (approved for renal cell Ca, GIST, pNET)

Midostaurin (approved in AML, ASM/MCL)?

Avapritinib (approved in GIST, ASM, ISM)? Masitinib?

Molderings GJ et al. Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedebergs Arch Pharmacol 2016 Jul;389(7):671-94.

Again, all treatment options for MCAS discussed in this presentation are ACCME Level Of Evidence “C” as detailed in the Disclaimer slide near the beginning of this presentation.

MCAS: Treatment

• 2024: Largely as for indolent mastocytosis
• Identify and avoid triggers
• Inhibition of mediator production
• Inhibition of mediator release (stabilization)
• Blockade of released mediators
• Antihistamines (even cont. IV diphenhydramine in severely afflicted pts)
• Often impressive benefits even absent rhinosinusitis and dyspepsia
• Can also stabilize mast cells via their autoexcitatory H₁/H₂ receptors
• Leukotriene antagonists
• Calcium/vit. D, bisphosphonates, denosumab for osteoporosis/osteopenia
• TNF antagonists (etanercept, adalimumab, infliximab)?
• IL-1 antagonists (e.g., anakinra), IL-1β antagonists (e.g., canakinumab)?
• In development: inhibitors of tryptase, chymase, H₃ receptors, etc. etc.
• Rarely (if ever): Cytotoxic therapy
• Hypothetical: Cellular therapy
• Secondary issues and comorbidities

Again, all treatment options for MCAS discussed in this presentation are ACCME Level Of Evidence “C” as detailed in the Disclaimer slide near the beginning of this presentation.

MCAS: Treatment

• 2024: Largely as for indolent mastocytosis
• Identify and avoid triggers
• Inhibition of mediator production
• Inhibition of mediator release (stabilization)
• Blockade of released mediators
• Rarely (if ever): Cytotoxic therapy
• Hydroxyurea (may work well for bone pain, as in sickle cell disease), alkylators, taxanes, etc.
• Fludarabine, cladribine, cytarabine, etc.
• Alemtuzumab, daclizumab
• Hypothetical: Cellular therapy
• Secondary issues and comorbidities

Again, all treatment options for MCAS discussed in this presentation are ACCME Level Of Evidence “C” as detailed in the Disclaimer slide near the beginning of this presentation.

MCAS: Treatment

• 2024: Largely as for indolent mastocytosis
• Identify and avoid triggers
• Inhibition of mediator production
• Inhibition of mediator release (stabilization)
• Blockade of released mediators
• Rarely (if ever): Cytotoxic therapy
• Hypothetical: Cellular therapy
• Allogeneic stem cell transplantation
• Likely to be extremely challenging
• Secondary issues and comorbidities

Again, all treatment options for MCAS discussed in this presentation are ACCME Level Of Evidence “C” as detailed in the Disclaimer slide near the beginning of this presentation.

MCAS: Treatment

• 2024: Largely as for indolent mastocytosis
• Inhibition of mediator production
• Inhibition of mediator release (stabilization)
• Blockade of released mediators
• Rarely (if ever): Cytotoxic therapy
• Hypothetical: Cellular therapy
• Treatment of secondary issues and comorbidities
• Frequent mistake by patients and providers: Assuming a symptom (new or old, chronic or acute) is directly due to MCAS
• MCAS does not render one immune to developing other disease
• Regardless of the likelihood that a symptom may ultimately stem from MCAS, rule out other reasonable diagnostic considerations before assuming MCAS is the (direct) cause!
• Illnesses secondary to mast cell disease require full treatment until the mast cell disease is controlled, and even then…
• “…the horse is sometimes already out of the barn”: malignancy and autoimmunity rarely, if ever, spontaneously remit simply with control of the underlying mast cell disease

Again, all treatment options for MCAS discussed in this presentation are ACCME Level Of Evidence “C” as detailed in the Disclaimer slide near the beginning of this presentation.

MCAS: Treatment

• Note there are “complementary” treatments, too, in these various therapeutic categories. For example:
• Inhibition of mediator production and/or release
• Vitamin C (note kidney stone patients may want to avoid this)
• Vitamin D
• Alpha lipoic acid
• N-acetylcysteine
• Palmitoylethanolamide (PEA)
• Cannabidiol (CBD)

1. Hagel AF et al. Naunyn Schmiedebergs Arch Pharmacol 2013 Sep;386(9):789-93.

2. Molderings GJ et al. Naunyn Schmiedebergs Arch Pharmacol 2016 Jul;389(7):671-94.

Again, all treatment options for MCAS discussed in this presentation are ACCME Level Of Evidence “C” as detailed in the Disclaimer slide near the beginning of this presentation.

MCAS: Treatment

• Many “natural herbs and supplements,” too, have anti-inflammatory activity and have potential to help control MCAS via COX-1/-2, MAPK, NFkB, and other pathways, e.g.:�

1. Maroon JC et al. Surg Neurol Int 2010;1:80.

2. Attiq A et al. Front Pharmacol 2018 Sep 7; 9:976. doi: 10.3389/fphar.2018.00976.

• Flavonoids (e.g., quercetin, luteolin, ruten)
• Stilbenoids (e.g., resvera-trol)
• Alkaloids (e.g., berberine)
• Lion’s mane
• Elderberry
• Omega-3 essential fatty acids
• White willow bark

​

• Turmeric/curcumin
• Green tea
• Pycnogenol
• Boswellia
• Cat’s claw
• Capsaicin
• Ginseng

​

Again, all treatment options for MCAS discussed in this presentation are ACCME Level Of Evidence “C” as detailed in the Disclaimer slide near the beginning of this presentation.

MCAS: Treatment

• Non-pharmacologic therapies occasionally can be helpful, too
• For example, certain behavioral re-training programs
• Typically require longer periods (3-6 months) to see improvement than required by most pharmacological interventions
• Mechanisms unclear, but seem likely related to the known close interactions – even physical abutment! – of neurons and mast cells throughout the body, with constant mediator “cross-talk” between such dyads

1. Blennerhassett MG et al. Cell Tissue Res 1991 Jul;265(1):121-8.

2. Theoharides TC et al. Trends Pharmacol Sci 2004 Nov;25(11):563-8.

3. Theoharides TC. Life Sci 1990;46(9):607-17.

4. Barbara G et al. Gastroenterology 2007 Jan;132(1):26-37.

5. Newson B et al. Neuroscience 1983 Oct;10(2):565-7,569-70.

6. Van Nassauw L et al. Autonom Neurosci 2007 Apr 30;133(1):91-103.

Shown with permission from ref. 6 below.

Again, all treatment options for MCAS discussed in this presentation are ACCME Level Of Evidence “C” as detailed in the Disclaimer slide near the beginning of this presentation.

MCAS: Key Nursing Care Issues

• Patient-Professional Trust Issues
• An MCAS patient’s distrust of health care professionals (MDs, RNs, etc.) is born out of years of:
• Professionals not listening to patient’s complaints
• Professionals denying/dismissing/mocking patient’s complaints
• Misdiagnoses of psychosomatism & Munchausen’s (& by proxy) despite careful case review showing such just isn’t possible
• Note neuropsychiatric issues (most common psych issues: anxiety, depression) are COMMON in MCAS but almost always are SECONDARY to the MCAS
• Repeated failure to think of, and establish, convincing/unifying diagnoses
• Repeated failure to find significant/explanatory abnormalities in tests
• Repeated failure of empirically tried treatments to provide significant benefit
• Repeated failure to identify sensible directions for further investigation

​

MCAS: Key Nursing Care Issues

• MCAS patients often have remarkable sensitivities/ reactivities to:
• Substances
• Foods
• Odors/fragrances
• MCAS patients CAN smell, and react to, food odors in the nurses’ lounge at the opposite end of the ward
• Chemicals (detergents, soaps, petroleum-based products…), whether natural or artificial, whether liquid or solid or aerosolized
• Environmental exposures: pollens, molds, animal danders, etc.
• Medication products (ESPECIALLY EXCIPIENT INGREDIENTS!)
• When an MCAS patient tells you he/she can only tolerate certain formulations of a drug, he/she is not kidding!
• Intolerable formulation = risk for anaphylaxis or other serious rxns
• These are the patients with the “impossible” reactivities, i.e., reactivities to medications “everybody” tolerates, reactivities to “inert” implanted materials, apparent reactivities to saline

MCAS: Key Nursing Care Issues

• MCAS patients often have remarkable sensitivities/ reactivities to:
• Activities
• MCAS is highly associated with chronic fatigue syndrome (CFS)
• Poor stamina, unusual post-exertional fatigue
• MCAS is highly associated with postural orthostatic tachycardia syndrome (POTS)
• Poor tolerance of orthostatic changes
• Significant lability of BP and/or pulse is COMMON
• MCAS is highly associated with hypermobile Ehlers Danlos Syndrome (hEDS)
• Diffuse pain; sometimes trivially easy joint dislocations
• MCAS patients often easily bruise/bleed from trivial triggers
• Aberrant heparin release by dysfunctional mast cells in a particular site + very short half-life of heparin at body temperature = significant LOCAL bleeding with no detectable significant SYSTEMIC coagulopathy

MCAS: Key Nursing Care Issues

• MCAS patients often have remarkable sensitivities/ reactivities to:
• Physical forces
• Changes in TEMPERATURE (note, too, their frequent dysautonomias include frequent poor temp./sweat regulation)
• Changes in PRESSURE (sometimes as subtle as changes in air pressure, such as with an approaching storm)
• Loud noises (misophonia)
• Low wavelengths (bass tones, vibrations)
• High wavelengths (high audio tones, ultraviolet (e.g., from not only sun but also fluorescent lights!), radio (WiFi!), gamma (radiotherapy))
• Electric shocks (static electricity exposures)
• Curiously, ECT usually is well tolerated, possibly due to mast-cell-stabilizing pre-medications

Characterization of MCAS

Afrin LB, Self S, Menk J, Lazarchick J. Am J Med Sci 2017;353(3):207-215.

Characterization of MCAS

Afrin LB, Self S, Menk J, Lazarchick J. Am J Med Sci 2017;353(3):207-215.

Characterization of MCAS

Afrin LB, Self S, Menk J, Lazarchick J. Am J Med Sci 2017;353(3):207-215.

Characterization of MCAS

Afrin LB, Self S, Menk J, Lazarchick J. Am J Med Sci 2017;353(3):207-215.

Characterization of MCAS

Afrin LB, Self S, Menk J, Lazarchick J. Am J Med Sci 2017;353(3):207-215.

Characterization of MCAS

Afrin LB, Self S, Menk J, Lazarchick J. Am J Med Sci 2017;353(3):207-215.

• Adrenal fatigue/insufficiency/deficiency
• Adult Still's disease
• Alagille Syndrome type 2
• Allergic rhinitis
• Alopecia areata
• Alopecia universalis
• Anemia of chronic inflammation
• Ankylosing spondylitis
• Anti-phospholipid antibody syndrome
• Anxiety/panic disorders
• Aplastic anemia
• Asthma
• Atypical angina
• Atypical nephrolithiasis
• Autism spectrum disorders
• Autoimmune polyendocrine syndrome type II
• Behcet's disease
• Bell’s palsy
• Benign ethnic leukopenia
• Benign neoplasia (any type; e.g., lipomas, cysts, etc.)
• Bipolar affective disorder (type 1 or 2)
• Bleomycin-induced pulmonary fibrosis
• Blood pressure lability
• Blurry vision (episodic)
• Budd-Chiari syndrome
• Bullous pemphigoid
• Burning mouth syndrome
• Cannabis hyperemesis syndrome
• Cataplexy
• Celiac disease
• Chilblains
• Cholecystitis
• Cholelithiasis
• Chronic constipation (idiopathic)
• Chronic cough (idiopathic)
• Chronic diarrhea (idiopathic)
• Chronic dyspepsia (idiopathic)
• Chronic fatigue syndrome
• Chronic inflammatory demyelinating polyneuropathy
• Chronic low back/pelvic pain (idiopathic)
• Chronic nausea (idiopathic)
• Chronic rhabdomyolysis
• Collagenous colitis
• Colon cancer
• Congestive heart failure
• Contact dermatitis
• Coronary and peripheral artery disease
• Cranio-cervical instability (CCI)
• Cronkhite Canada syndrome
• Cyclic vomiting syndrome
• Delayed-type hypersensitivity drug reaction
• Depression
• Diabetes insipidus and mellitus (types 1 and 2)
• Difficult/complicated sickle cell anemia

• Diverticulitis
• Dysphoric milk ejection reflex (D-MER)
• Eclampsia
• Eczema
• Endometriosis
• Eosinophilic esophagitis (EoE)
• Eosinophilic colitis/gastroenteritis
• Epiploic appendagitis
• Erectile dysfunction
• Erythema multiforme
• Erythromelalgia
• Essential tremor
• Exploding head syndrome
• Fibromuscular dysplasia (FMD)
• Fibromyalgia
• Fibrous histiocytoma
• Focal segmental glomerulonephritis
• GastroEsophageal Reflux Disease (GERD)
• Gilbert’s syndrome
• Gleich syndrome
• Gout (some forms)
• Granuloma annulare
• Gray platelet syndrome
• “Growing pains”
• Gulf War Illness/Syndrome
• Hajdu-Cheney Syndrome
• Hashimoto's thyroiditis
• Hemorrhagic hidradenitis
• Heparin-induced thrombocytopenia
• Hidradenitis suppurativa
• Histiocytosis X and Erdheim-Chester syndrome
• Hodgkin’s lymphoma
• Hyperemesis gravidarum
• Hypermobile Ehlers Danlos Syndrome (hEDS)
• Hypersensitivity vasculitis
• Hypertension (essential)
• Idiopathic adenopathy
• Idiopathic anaphylaxis
• Idiopathic angioedema
• Idiopathic bradycardia
• Idiopathic conjunctivitis
• Idiopathic delayed puberty
• Idiopathic edema
• Idiopathic elevated erythrocyte sedimentation rate or C-reactive protein
• Idiopathic fibrosis/sclerosis (e.g., mediastinal, retroperitoneal)
• Idiopathic hemochromatosis
• Idiopathic hemorrhagic or embolic stroke or TIA
• Idiopathic hepatitis/transaminitis
• Idiopathic hypercoagulability
• Idiopathic hypereosinophilic syndrome
• Idiopathic hypoglycemia
• Idiopathic hypokalemia
• Idiopathic hypomagnesemia

Prepared by Larry Afrin, M.D., AIM Center for Personalized Medicine., copyright © 2008-2021, all rights reserved, contact drafrin@aimcenterpm.com for usage inquiries.

• Idiopathic hypotension
• Idiopathic hypothyroidism
• Idiopathic immunodeficiency
• Idiopathic nonspecific autoimmunity
• Idiopathic pancreatitis
• Idiopathic paresthesias (periph. neuropathy) (EDN-related?)
• Idiopathic pruritus
• Idiopathic pulmonary fibrosis
• Idiopathic rash
• Idiopathic splenomegaly
• Idiopathic/inappropriate sinus tachycardia
• Idiopathic vasculitis
• Idiopathic weight gain
• Idiopathic weight loss
• Implant-related illness (IRI)
• Infertility
• Inflammatory bowel disease (Crohn and ulcerative colitis)
• Interstitial cystitis
• Irritable/inflammatory bowel syndrome
• Juvenile rheumatoid arthritis
• (Progressive) Kaposi’s sarcoma
• Kidney failure
• Keratosis pilaris
• Kleine-Levin Syndrome
• Lactose/fructose/sucrose intolerance
• Leukocytosis (idiopathic)
• Leukopenia (idiopathic and “benign ethnic”)
• Loin pain hematuria syndrome
• Low libido
• Lupus
• Lymphocytic colitis
• Macrophage activation syndrome/HLH (HPS)
• Malignant neoplasia (any type)
• Median arcuate ligament syndrome
• Mesenteric adenitis
• Micronutrient malabsorption/intolerance
• Microscopic colitis
• Migraine and other idiopathic headaches
• Miscarriage (early or otherwise)
• Misophonia
• Mitochondrial neurogastrointestinal encephalopathy (MNGIE)
• Mixed connective tissue disease
• Monoclonal gammopathy of undetermined significance
• Multiple chemical sensitivity (MCS)/toxicant-induced loss of tolerance (TILT)
• Multiple Evanescent White Dot Syndrome (MEWDS)
• Multiple sclerosis
• Myelofibrosis
• Myasthenia gravis
• Myelodysplastic syndrome (esp. w/ nl. cytogenetics)

• Narcolepsy
• Nephrolithiasis
• Night chills (idiopathic)
• Night sweats (idiopathic)
• Neuromyelitis optica
• Nocturnal leg cramps (idiopathic)
• Non-alcoholic steatotic hepatitis (NASH)
• Non-celiac gluten sensitivity
• Nonspecific arthritis
• Nonspecific myalgias
• Nonspecific vasculitis
• Nutcracker syndrome
• Obesity
• Obsessive-compulsive disorder
• Osteopenia/osteoporosis
• Osteosclerosis
• Panic disorder
• Paroxysmal dystonia or torticollis in infancy
• Paroxysmal exertion-induced dyskinesia
• Paroxysmal hypnogenic dyskinesia
• Paroxysmal kinesigenic dyskinesia
• Paroxysmal non-kinesigenic dyskinesia
• Pelvic congestion syndrome
• Pelvic floor instability
• Pemphigus vulgaris
• Periodic hypokalemia
• Periodic paralysis
• Persistent genital arousal disorder (PGAD)
• Polycystic kidney disease
• Polycystic ovarian syndrome (PCOS)
• Polycythemia (without JAK2 mutation)
• Polymyalgia rheumatica
• Post-coital dysphoria (PCD)
• Post-orgasmic illness syndrome (POIS)
• Post-partum depression/psychosis
• Post-traumatic stress disorder
• Postural orthostatic tachycardia syndrome (POTS)
• Pre-eclampsia
• Premature contractions
• Premenstrual dysphoric disorder
• Premenstrual syndrome
• Prostate cancer
• Pseudoxanthoma elasticum
• Psoriasis
• Red Ear Syndrome
• Refractory dizziness
• Relapsing polychondritis
• Restless genital syndrome
• Restless leg syndrome
• Rheumatoid arthritis

• Sarcoidosis
• Schizophrenia
• Schnitzler syndrome
• Scleroderma
• Senile purpura
• Serpentine fibula-polycystic kidney syndrome
• Severe postprandial fatigue
• Sickle nephropathy
• Sickle pulmonary hypertension
• Sjogren’s disease
• Small fiber neuropathy
• Small intestinal bacterial overgrowth (SIBO)
• Spontaneous human combustion
• Substance abuse
• SUNCT (Short-lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing)
• Tachy-brady syndrome
• TEMPI syndrome
• Temporomandibular joint (TMJ) syndrome
• Thrombocytopenia (idiopathic)
• Thrombocytosis (idiopathic and essential)
• Thyroid dysfunction (hyperthyroidism or hypothyroidism, detectably autoimmune or not)
• Tics (idiopathic)
• Tinnitus (idiopathic)
• Tn polyagglutination syndrome
• Unchelatable sickle transfusional hemosiderosis
• Unspecified connective tissue disease
• Unspecified porphyria
• Unspecified sideroblastic anemia
• Urticaria (all forms)
• Uveitis
• Vascular anomalies (aneurysms, hemangiomas, etc.)
• Vestibular neuritis
• Waldenstrom’s macroglobulinemia
• Wolff-Parkinson-White syndrome

�Total: 240

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Prepared by Larry Afrin, M.D., AIM Center for Personalized Medicine., copyright © 2008-2021, all rights reserved, contact drafrin@aimcenterpm.com for usage inquiries.

MCAD: Other Research Ideas

• Characterization of Mast Cell Regulatory Gene Mutations in MCAS
• MCAD in Chronic Fatigue Syndrome
• MCAD in Fibromyalgia
• MCAD in Irritable Bowel Syndrome
• MCAD in Refractory GERD
• MCAD in Asthma
• MCAD in Obesity
• MCAD in Hypermobile Ehlers-Danlos Syndrome
• MCAD in Postural Orthostatic Tachycardia Syndrome
• MCAD in Atherosclerotic Vascular Disease
• MCAD in Multiple Chemical Sensitivity (MCS)/Toxicant-Induced Loss of Tolerance (TILT)
• MCAD in Gulf War Illness
• MCAD as a Significant Modifier in Sickle Cell Disease
• Etc. etc. etc. etc.

MCAD: What’s next?

• RESEARCH
• Improved diagnostic techniques
• Early genomic sequencing of isolated mast cells to distinguish primary from secondary disease and identify mutational patterns correlating with various clinical presentations?
• Etiology
• Environmental? Genetic? Epigenetic? Viral?
• Therapy
• Predictive biomarkers
• Targeted therapies
• EDUCATION (providers, payers, patients, grantors)

Summary

• Tryptase dominantly reflects total body MC load, not activation state
• MCAD symptoms usually from MC activation, not MC load
• Most MCAD patients…
• …have normal survival, making disease control even more important (QoL!)
• …can eventually find significantly helpful therapy once diagnosed
• Challenges:
• Heterogeneity of MCAS (mutational origin?)
• Many helpful therapies already found, but few�biomarkers yet identified which reliably predict�helpful therapy; persistence at trial & error needed
• Education of patients, providers, payers, regulators,�grantors, pharma, etc. etc. etc.

​

Questions?

Questions later?

drafrin@aimcenterpm.com