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Published in final edited form as: J Allergy Clin Immunol. 2024 Jun 6;154(2):255–263. doi: 10.1016/j.jaci.2024.05.025

Mast cell activation syndrome: Current understanding and research needs

Mariana Castells a,f, Matthew P Giannetti a,f, Matthew J Hamilton b,f, Peter Novak c,f, Olga Pozdnyakova d,f, Jennifer Nicoloro-SantaBarbara e,f, Susan V Jennings g, Clair Francomano h, Brian Kim i, Sarah C Glover j, Stephen J Galli k, Anne Maitland l,w, Andrew White m, J Pablo Abonia n, Valerie Slee g, Peter Valent o,p, Joseph H Butterfield q, Melody Carter r, Dean D Metcalfe r, Cem Akin s, Jonathan J Lyons t,u, Alkis Togias r, Lisa Wheatley r, Joshua D Milner v
PMCID: PMC11881543  NIHMSID: NIHMS2058149  PMID: 38851398

Abstract

Mast cell activation syndrome (MCAS) is a term applied to several clinical entities that have gained increased attention from patients and medical providers. Although several descriptive publications about MCAS exist, there are many gaps in knowledge, resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to mast cell activation in MCAS patients remain to be elucidated. Here we summarize the known literature, identify gaps in knowledge, and highlight research needs. Covered topics include contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; mechanistic research; management of typical and refractory symptoms; and MCAS-specific education for patients and health care providers.

Keywords: Mast cell activation syndrome, Mast cell, mastocytosis, hereditary alpha-tryptasemia, tryptase, mast cell activation–related disorders

Mast cell activation syndromes (MCASs) are characterized by recurrent episodes of systemic symptoms associated with the release of mast cell (MC)-derived mediators (Fig 1).1,2 The consensus diagnostic criteria of MCAS, updated in 2022, consists of the following (Table I):2–5

FIG 1.

FIG 1.

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MC mediators induce symptoms across organ systems.

TABLE I.

MCAS diagnostic consensus criteria

Criterion Description
1 Episodic, recurrent systemic symptoms, as follows, consistent with MC mediators release affecting 2 or more organs at once:

  • Skin: flushing, urticaria, angioedema.

  • GI: abdominal bloating/cramping/pain, nausea, vomiting, diarrhea.

  • Respiratory: wheezing, chest tightness.

  • Nasocular: pruritus, nasal stuffiness conjunctival injection.

  • Cardiovascular: hypotension, tachycardia, chest pain/tightness.

  • Brain: brain fog, headache.

  • Systemic: fatigue, anaphylaxis.
2 Decrease in frequency and/or severity or resolution of symptoms with antimediator therapy such as: H1 and H2 histamine receptor antagonists, antileukotriene medications (cysteinyl-leukotriene receptor blockers, 5-lipoxygenase inhibitor), prostaglandin blockers (aspirin), MC stabilizers (cromolyn sodium, ketotifen), omalizumab.
3 Evidence of elevated serum and/or urinary biomarkers of MCA at time of acute episodes on at least 2 occasions above patient baseline; serum tryptase is marker of choice, as well as 24-hour urine histamine metabolites, leukotriene E4, and PGD2 metabolites (11β-PGF2α).
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All 3 MCAS criteria must be fulfilled. Adapted from Valent et al.2

  1. Recurrent severe systemic symptoms in at least 2 organ systems consistent with MC mediator–related symptoms.

  2. Significant transient increases in serum tryptase level (20% over baseline plus 2 ng/mL) or other MC-derived mediators, such as urinary histamine/N-methyl histamine, leukotriene E4, or prostaglandin D2/2,3-dinor-11β–prostaglandin F2 alpha (PGF2α) metabolite over baseline during a period of increased symptoms.

  3. A significant response of clinical symptoms to medications that counteract MC mediator effects (eg, histamine H1 and H2 receptor blockers, leukotriene, and prostaglandin blockers), and/or suppress MC activation (MCA) (eg, sodium cromolyn, ketotifen, and anti-IgE).

These criteria were developed by consensus based on literature review and expert opinion, have been validated, and are considered standard.6–9 They do not preclude the possible effect of other undefined MC mediators for which there is no targeted therapy. No randomized trials have been conducted to demonstrate that a particular phenotype or MC mediator level is associated with a specific treatment response.

Patients with MCAS are divided into 5 clinical phenotypes or variants: primary form resulting from activation of clonal MC (predominantly mastocytosis), secondary MCAS involving nonclonal MCs activated by underlying conditions such as IgE-mediated allergies and other diseases, combined MCAS (activation of clonal and nonclonal MC), hereditary α-tryptasemia (HαT) associated with MCAS symptoms, and idiopathic MCAS (Table II).

TABLE II.

Classification of MCA disorders

MCAS variant Main diagnostic features Estimated anaphylaxis risk
Primary, clonal, monoclonal

  • Primary: KIT D816V mutation is detected; MCs may display CD25 and/or CD30.

  • Clonal: confirmed mastocytosis (cutaneous mastocytosis or SM).

  • Monoclonal: only 2 minor SM criteria.

 + + +
Secondary No neoplastic MCs or KIT D816V mutation. MCA is associated with IgE-mediated allergy, other hypersensitivity reactions, or immunologic disease.* + +
Combined Criteria for primary and secondary MCAS are fulfilled; HαT may be detected. + + +
HαT positive HαT is detected, and all diagnostic MCAS criteria are fulfilled. +/+++†
Idiopathic Criteria to diagnose MCAS are met, but no other variant criteria are met. +
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Adapted from Valent et al.2 The HαT genetic trait is present in 4% to 6% of White populations and is associated with duplication of TPSAB1 tryptase gene on chromosome 16. Risk score is as follows: +, increased risk; ++, high risk; +++, severe risk.

*

Non IgE-dependent mechanisms leading to MCAS include IgG mediated, complement mediated, and MRGPRX2 mediated.

†

Presentation may vary depending on number of α-tryptase genes.

Despite the current criteria and classification for MCAS, concerns about misdiagnosis—both underdiagnosis and over-diagnosis—remain.2,10 Recent studies that attempted to systematically evaluate individuals with suspected MCAS showed that only a small fraction (<5%) of patients met strict criteria for primary or idiopathic MCAS,11,12 indicating the need to address pitfalls of the current MCAS criteria and expand biomarkers.

DIAGNOSIS OF MCAS

Signs and symptoms

MCAS is defined by severe recurrent systemic symptoms related to MCA, which resemble anaphylaxis.8,9,13 In contrast, local and less severe forms of MCA do not fulfill the MCAS criteria.2 Classic MC-triggered signs and symptoms include gastrointestinal (GI) distress, nausea, abdominal pain, bloating, cramping, and diarrhea; skin signs and symptoms, including urticaria, flushing, pruritus, and angioedema; respiratory symptoms such as throat and chest tightness, shortness of breath, and wheezing; and cardiovascular manifestations, including hypotension and tachycardia. New phenotypes of non–IgE-mediated MCA have been described14 in which atypical symptoms of MCA, such as fever, chills, chest or back pain, and hypertension, may be present, which might be triggered by cytokines released from MC. These atypical symptoms may be associated with serum elevation of IL-6 and are observed in patients with acute reactions to monoclonal antibodies and chemotherapy.15 Neuropsychiatric symptoms are described in patients with MCAS including short memory span, inability to concentrate, and anxiety and depression. “Brain fog” is the term associated with these overall symptoms, and there is evidence of memory deficit and depression in patients with systemic mastocytosis (SM)16 presenting with elevated urinary prostaglandins. These symptoms occur in the context of other MC mediator–related symptoms involving other organs.

Evidence of MC mediator release

The event-related increase in serum tryptase levels over baseline is the most specific marker of MCA.6–8 Systemic MCA may be documented by an increase in the serum tryptase level by 20% above the individual’s baseline level + 2 ng/mL.8,13 This increase can be captured within 4 to 6 hours of a MCA event, including anaphylaxis, with the peak within 30 to 60 minutes after acute onset of symptoms and baseline levels at least 24 hours after complete resolution of the signs and symptoms. A level of baseline serum tryptase (BST) >8 ng/mL suggests a genetic variant of the tryptase gene TPSAB1 observed in patients with HαT and/or a clonal MC disorder.17,18 A ratio of acute tryptase/BST exceeding 1.6 provides an optimized diagnostic rule with high sensitivity and specificity in SM and HαT, but in order to cover all disorders (all ranges of basal tryptase), the 20% of baseline + 2 ng/mL formula should be applied.19 Patients with HαT and/or SM have greater diurnal variations in baseline tryptase without MCA symptoms as a result of their higher baseline levels.19,20

Tryptase measurement is currently underutilized by medical specialists, emergency departments, and urgent care clinics; limitations are linked to a delay in laboratory performance and reporting more than 48 to 72 hours after the event. This must be addressed to secure the diagnosis of all MCAS variants and to provide a needed instrument to distinguish anaphylaxis from conditions that mimic this potentially life-threatening condition. The absence of an increase in serum tryptase does not preclude MC involvement, MCAS, or anaphylaxis, and the search for other reliable and more sensitive and/or specific MC-specific mediators is needed. Disease reacting to triggers that bind to the novel MRGPRX2 MC receptor may not manifest with systemic elevations of tryptase or other mediators at the time of acute symptoms.

Other MC-derived mediators, which may reflect MCA, include an event-related increase in blood histamine, urine N-methyl histamine, leukotriene E4, prostaglandin D2 (PGD2), and a PGD2 metabolite, 11β-PGF2α(Fig 2). These mediators may be more sensitive for specific phenotypes of MCAS and for mild forms of MCA not fulfilling MCAS criteria. Recently a range has been proposed for increases above baseline and includes urinary N-methylhistamine >400 μg/g Cr and 11β-PGF2α>3500 ng/d.21

FIG 2.

FIG 2.

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Differential MCA and mediator release.

Advantages of urine testing include real-time collectionand all diagnostic MCAS criteria are fulfilled and at-home performance, without relying on acute care facilities.21 Nonvalidated serologic markers utilized to detect MCA22 include chromogranin A,23 serotonin, and heparin. Further studies are needed to validate their specificity and significance in MCAS, and they are not recommended for diagnosis of MCAS.22

An unresolved issue is the management of patients with clinical signs and symptoms suggestive of an MCA-related disorder (MCAD, including response to medications that block MC mediators) with negative MC mediator testing during periods of symptoms. A recent study in patients with HαT + MCAS presenting with chronic symptoms indicated that urinary N-methyl histamine and PGD2 metabolites were not elevated at times when they were not actively presenting symptoms of MCA compared to patients with mastocytosis, who present with elevated baseline levels.24 A recent study of 69 patients with postural orthostatic tachycardia syndrome (POTS)-like symptoms found that 29 (65%) of 44 patients who also reported MCA symptoms had elevations of MC biomarkers (52% histamine in plasma or urine, 36% prostaglandins in plasma or urine, and 9% tryptase), while none of those without symptoms of MCA had elevation of mediators.25 Current laboratory testing for MCA is limited, and empiric MCAS treatment with safe and well-tolerated medications can be considered in patients without evidence of mediators.

Response to MC-directed therapies

Reduction of symptoms of MCA by medications that block the action of MC-derived mediators, such as antihistamines, cyclooxygenase inhibitors, leukotriene receptor blockers, and 5-lipoxygenase inhibitors, are suggestive clinical evidence for MCAS. Further evidence for MCAS includes a response to medications that hinder MCA, such as ketotifen and sodium cromolyn; that block IgE, such as omalizumab; and that decrease the numbers of MCs, such as glucocorticoids.4,26 Tyrosine kinase inhibitors such as imatinib, which bind to cell surface–mutated and wild-type KIT, can decrease MC numbers and symptoms of MCA.27 Tyrosine kinase inhibitors addressing mutated KIT on codon D816V such as midostaurin and avapritinib have been shown to reduce bone marrow MCs, skin MCs, serum tryptase, and symptoms of MCA.28

A lack of response to histamine blockade may reflect a nonhistaminergic MCAS endotype or an alternative diagnosis.10 Other conditions such as cardiovascular, GI, endocrine, neoplastic, infectious, and various neuropsychiatric conditions should be considered. Fig 3 shows the MCA diagnostic algorithm. Controlled studies are needed to assess MC-derived mediators and response to medications in patients with irritable bowel syndrome, Ehlers-Danlos syndrome (EDS), dysautonomia, POTS, and chronic fatigue in which MCA may contribute as secondary cause of symptoms.29

FIG 3.

FIG 3.

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Diagnostic algorithm for evaluation of MCA symptoms.

MCAS variants are currently managed on the bases of signs and symptoms attributable to MCA, underlying disease, and presence of comorbidities.30 Patients with SM may present with symptoms of MCA and have a concomitant IgE-dependent allergy and/or HαT.30 Some patients present MCA in one organ such as in allergic rhinitis, urticaria, asthma, and eosinophilic GI disorders;3,5 or they present with mild multiorgan symptoms and may not fulfill strict MCAS criteria.2 Constitutional and functional symptoms have been attributed to MCAS when associated with other MCA symptoms.10 The role of MCs in immune surveillance, tissue repair, and interconnectivity with neurons and connective tissue cells has been established in vitro and in rodent models.31,32 Human studies have provided evidence of the role of MCs and MCA in rhinitis, asthma, urticaria, food allergy, and anaphylaxis, but there is limited evidence of the role of MCs in neurologic and psychiatric symptoms associated to MCAS. The observed tissue colocalization and interactions between MC and other cell types has suggested a link between MC mediators and multifactorial syndromes, such as POTS, variants of EDS, multiple chemical sensitivity/toxicity-induced loss of tolerance disorders, and chronic fatigue syndromes.33–35 However, evidence for a meaningful effect of MC mediator–targeted medications in these disorders has yet to be confirmed.

DISEASE ASSOCIATIONS AND MECHANISTIC RESEARCH

Mechanistic research into the etiology of MCAD and MCAS hinges on the definition of the disease itself. Objective and comprehensive observations regarding symptom presentation, phenotyping, and endotyping should control for referral and ascertainment biases. In understanding MCA in the context of other diseases, one pattern that emerges is the presence of multiple comorbidities, which may shed light on etiologies. While some patients present with a central symptom such as flushing or diarrhea that can be attributed to MCA and the actions of mediators such as histamine or prostaglandins, many present with comorbidities such as joint pain, fatigue, and other chronic GI complaints for which the role of MC mediators is poorly understood. Single-cell studies evaluating RNA and proteins targets in nonclonal MCA patients are lacking and should provide evidence of cellular and molecular targets with potential therapeutic applications.

Genetic variants and HαT

The strongest known risk factor for allergic diseases is family history. Several familial disorders leading to recurrent MCA have been uncovered, such as 2 autosomal-dominant physical urticarias in the form of congenital vibratory and cold urticaria caused by ADGRE2 and PLCG2 pathogenic variants.36

HαT is a recently described genetic trait reported among 5% to 7% of Whites.17,37 In HαT, increased TPSAB1 copy number encoding α-tryptase results in increased BST levels as a result of promoter-driven overexpression of the replicated gene.37 Given the apparent high frequency of asymptomatic individuals with HαT,38 screening of sufficiently large phenotypic populations and large phenotype-wide association studies are necessary to determine which symptoms and diagnoses are associated with HαT.

HαT was first described in families with symptoms suggestive of MC mediator release in association with increased TPSAB1 copy numbers.17 In the initial literature, two thirds of the subjects reported symptoms of MCA, including urticaria, flushing, asthma, anaphylaxis, and episodic GI distress. HαT was associated with connective tissue abnormalities, chronic musculoskeletal pain, and/or POTS-like symptoms, and over half reported neuropsychiatric diagnoses. Some of these associated symptoms have not been replicated in further and more extensive studies. Multisystem complaints are common in symptomatic individuals with HαT, including skin and GI symptoms. In the GI mucosa of subjects with HαT, increased MC with elevated FcεR1, HLA-DR, and CD203c expression, increased effector memory T cells, and class-switched memory B cells, as well as increased epithelial pyroptosis (inflammatory cell death) have been observed compared to individuals with quiescent Crohn disease.39 Chronic intestinal inflammation may contribute to GI symptoms in HαT, potentially independent of MCA.39 In a retrospective study of patients with HαT, GI manifestations were the only symptoms associated with MCA that failed to respond to omalizumab.40 Heterotetramers of α/β-tryptases occur in HαT patients and can selectively activate PAR2 on endothelial cells, leading to increased permeability and enhanced vibration-associated MCA.41

HαT is enriched in patients with SM,42,43 in Hymenoptera-allergic patients with severe anaphylaxis,44,45 and in patients with idiopathic anaphylaxis.42,43,45,46 Emerging evidence among food-allergic patients suggests that an effect on anaphylaxis severity may be a generalizable phenomenon related to the relative number of α-tryptase to β-tryptase copies.47

In genome- and phenotype-wide association studies, the chromosomal locus linked to HαT has been shown to be associated with risk for mastocytosis,48 chronic urticaria, and MC mediator levels in serum.49,50 Studies of patients with high BST levels due to HαT and SM have also expanded diagnostic considerations for MCA and MC disorders.8,9,38,50,51

Autoimmunity

Autoimmune etiologies have been proposed for MCAS on the bases of epidemiologic observations regarding onset, triggers, and demographics. MCAS has been reported in conjunction with congenital connective tissue disorders (such as hypermobility EDS) and dysautonomia (as in patients with POTS or autonomic failure),17,52,53 for which an association with autoimmunity has been suggested. Patients with hypermobility EDS have an increased risk of developing inflammatory diseases, including celiac disease54 and eosinophilic esophagitis,53 compared to the general population and also have an increased prevalence of autoantibodies, including antinuclear and antiphospholipid antibodies. A high rate of comorbid immune disorders is also evident, such as Hashimoto thyroiditis and rheumatoid arthritis, and common variable immunodeficiency has been reported in patients with dysautonomia.54–56 Symptomatic individuals with HαT have been reported to have increased levels of GI-associated autoantibodies of unclear significance.39 Further studies are needed on the role of autoantibodies in MCA and the potential for immunotherapeutic interventions.54,57

Neurologic associations

Neurologic symptoms, in addition to skin, GI, and cardiovascular manifestations, are common in patients with MC disorders.13,56,58 Orthostatic intolerance, palpitations, dyspnea, chronic fatigue, pain, and brain fog are commonly reported. Small-fiber neuropathy associated with autonomic dysfunction may underlie some of the symptoms.58 Autonomic dysfunction can mimic symptoms ascribed to MCA, such as flushing, abnormal GI motility and pain, palpitations, and orthostatic intolerance, making it difficult to differentiate between GI complaints due to the local effect of MC mediators or due to enteric neuropathy. The true incidence of neurologic complications in MC disorders has not been defined. In HαT, neurologic complications were found in 22% of patients and postural tachycardia syndrome (POTS) in 12%—which may be in part be due to referral and ascertainment biases.18 In a recent study of 493 patients with POTS (of which 86% were female), only 7.2% of individuals had a BST level of ≥8 ng/mL, and only 3.6% had a BST level of >11.4 ng/mL.55 Because most patients did not undergo genetic testing, the rate of HαT could not be confirmed, but on the basis of tryptase level, it was likely <7.2%—no higher than in the general population.59 POTS has been confirmed in patients with MCA symptoms such as flushing and elevated urinary methylhistamine.34 In a referral population with neurologic symptoms, quantitative autonomic testing of MCAS patients with elevated MC metabolites and symptomatic HαT patients showed mild-to-moderate dysautonomia associated with small-fiber neuropathy.58

A retrospective review of medical records from 195 individuals found that the percentage of patients with clinical MCAS within the group of POTS and EDS was 31%, compared to 2% within the non-POTS and non-EDS group.60

The cause of pain in MCAS and the mechanisms by which peripheral nerve fibers might be injured are not completely understood and are attributed to the strategic location of MCs in the epineurium, perineurium, and endoneurium of peripheral nerves, which could release mediators causing neurodegeneration and activation of nociceptors.61,62

Brain fog and fatigue are important and disabling complaints involving the central nervous system that may be the result of a direct effect of MCs and/or MC mediators on the brain. Cleavage and activation of PAR2, which is a major target for tryptase, has been shown to contribute to sickness-like behavior in mouse models.63,64 Cerebral hypoperfusion also has been implicated, as patients with MC disorders reportedly have reduced orthostatic cerebral blood flow,58 which may impair brain function because reduced cerebral blood flow can be associated with cerebral hypoxia.65 In rats, cerebral hypoperfusion may impair neuronal functioning and lead to neuroinflammation,65 which can result in central sensitization66 and subsequent development of pain syndromes, headaches, and diffuse body aches.

Symptom management

Interventional studies in patients with MCAD are lacking, highlighting the need for double-blind, placebo-controlled trials of symptomatic patients with H1/H2 antihistamines, MC stabilizers, leukotriene receptor antagonists, and other drugs. Additional therapies are supported by data derived from patients with clonal MC disorders, which may warrant further evaluation in MCAD contexts. Omalizumab has been reported to reduce the frequency and severity of anaphylaxis in case reports and noncontrolled small case series of patients with SM, and in retrospective analyses of symptomatic individuals with HαT referred for MCAD, a similar effect has been reported.18,67 Such trials would provide diagnostic validation and could be used to correlate measured mediator levels at baseline, during symptoms, and after therapy, as well as to define therapeutic options in this symptom complex.

In addition to therapies derived from treatment of clonal MC disorders, novel approaches warrant further study. Flavonoid-containing compounds such as luteolin inhibit MCA in vitro, but in vivo studies are lacking to address efficacy in controlling MCA.68 Although anecdotal efficacy of low-dose naltrexone with and without intravenous immunoglobulin has been described, these treatments are uncontrolled and controversial.69 Small molecules including tyrosine kinase inhibitors targeting KIT, Btk, and JAK inhibitors as well as biologics targeting MC inhibitory receptors such as Siglec molecules require further exploration.

Care coordination, disease burden, and psychosocial needs

One of the most challenging aspects of managing MCA involves delivery of care. The heterogenous clinical presentations, complicated diagnostic criteria, limited provider knowledge and experience, and few diagnostic tools and therapeutic targets require patients to be evaluated by many subspecialists. Thus, there is a pressing need for well-coordinated networks of providers who can assist in the management of these patients.70–72

MCA and MCAD also impose a substantial burden on patients and their families, supporting the need for patient and caregiver education.71 A recent study of individuals with MCAD found that many participants reported feeling depressed, lonely, and poorly understood.73 In fact, almost three quarters of the sample reported clinically meaningful levels of depressive symptoms, and most have substantially more symptoms than can be ascribed to MCAS.74

Some of the stressors reported by MCAD patients are modifiable. For example, participants reported high levels of loneliness, which was strongly associated with depression. There is evidence from other chronic illnesses that cognitive behavioral therapy focused on challenging maladaptive social cognitions effectively reduces loneliness.75 Patient groups, even virtually, might be a valuable resource for individuals with MCAD because they offer a safe space to discuss challenges and offer opportunities to exchange support and information as well as learn self-management skills. Online forums facilitated by peers have been shown to improve individuals’ psychological adjustment to chronic illness and reduce loneliness.76,77 No psychological interventions have been validated in this population, making this an area that requires significant attention and research. Of note, psychiatric conditions such as somatoform disorder and avoidant restrictive food intake disorder may mimic MCAD.

CONCLUSIONS

MCASs comprise an array of syndromes and diseases presenting with different phenotypes with the central pathophysiologic mechanism of local and/or systemic MCA, which may affect many aspects of an individual’s life. The lack of evidence-based diagnostic guidelines, a paucity of correlative diagnostic parameters, inconsistent symptomatology, limited physician knowledge, and lack of coordinated physician networks collectively present challenges for both patients and providers. Furthermore, misattribution of symptoms un-related to abnormal MC activity, as MCAS can lead to inappropriate treatments, misplaced hope, and failure to better understand alternative diagnoses. Currently, signs and symptoms of MCAS are consistent with patients of all ages, including the pediatric age group, although few data are available in children. Female sex is overrepresented in idiopathic MCAS, underscoring the need for research regarding the underlying mechanisms and genetic/hormonal alterations in MCA.

Large, coordinated, multicenter diagnostic and therapeutic trials are needed to increase insight into phenotypes and relevant therapeutic tools. Research aimed at identifying new mediators and molecular targets that can define the endotypes of MCAD, as well as disorders that present with similar symptoms, will lead to better interventional approaches. Disseminating information to providers about the challenges facing patients, as well as objective information to patients, may help patient–provider relationships. Interventions aimed at alleviating emotional distress in patients with MCAD and MCAS should be sought. The partnership and collaboration between the American Initiative in Mast Cell Diseases and the European Competence Network on Mastocytosis have been key in establishing definitions, criteria, and classifications of MCAS and MCAD and have been instrumental in affecting basic and clinical research in the field. The Mast Cell Disease Society as well as European, Australian, and worldwide patient associations have provided patients and family members with a voice to engage care providers and researchers about the pressing needs to advance the field, find a cure, and reduce patient suffering.

DISCLOSURE STATEMENT

M.C.C. and D.D.M. were supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not represent the official views of the NIH.

Disclosure of potential conflict of interest: M. Castells has received research funding and consulting fees from Blueprint Medicines and consulting fees from Cogent Biosciences. M. P. Giannetti has received research funding and consulting fees from Blueprint Medicines and consulting fees from Cogent Biosciences. M. J. Hamilton has received consulting fees from Blueprint Medicines. P. Novak has received funding from Mona Taliaferro/Bay Shore Recycling, the National Heart, Lung, and Blood Institute (NHLNI; 1OT2HL156812-01), and FBRI (2022A018462); is current or previous shareholder of Moderna, Edidas Medicine, Novavax, and Pfizer; and has received royalties from Oxford University Press. J. Nicoloro-SantaBarbara has received consulting fees from Cogent Biosciences and Blueprint Medicines. S. C. Glover received consulting fees from Blueprint Medicine, Janssen, BMS, AbbVie, and Takeda. S. J. Galli has received research funding from and is scientific advisor to Evommune; and is on the scientific advisory board of Jasper Therapeutics. A. White is on the speakers bureau at Blueprint Medicines; and received consulting fees from Cogent Biosciences and Blueprint Medicines. P. Valent received funding from BMS/Celgene and AOP Orphan; and consultancy fees from Novartis, BMS/Celgene, Blueprint, Pfizer, Cogent, and Stemline. J. H. Butterfield has received a fee for the licensing of HMC-1 cell lines. D. D. Metcalfe has received consulting fees from Visterra. J. D. Milner has received consulting fees from Blueprint Medicines. The rest of the authors declare that they have no relevant conflicts of interest.

We thank Andrew Espeland, Grace Godwin, Julia Middlesworth, and Julia Douvas for their contributions and assistance.

Abbreviations used

BST

Baseline serum tryptase

EDS

Ehlers-Danlos syndrome

GI

Gastrointestinal

HαT

Hereditary α-tryptasemia

MC

Mast cell

MCA

MC activation

MCAD

MCA-related disorder

MCAS

MCA syndrome

PGD2

Prostaglandin D2

PGF2α

Prostaglandin F2 alpha

POTS

Postural orthostatic tachycardia syndrome

SM

Systemic mastocytosis

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