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肥大細胞活化症候群（Mast Cell Activation Syndrome, MCAS）近年來備受患者與醫界關注，許多人因反覆出現「突然末梢腫脹、發紅、低血壓、頭暈」等症狀而懷疑自己是否罹患此症。2024年6月發表於《Journal of Allergy and Clinical Immunology》（JACI）的權威論文《Mast cell activation syndrome: Current understanding and research needs》，由國際頂尖過敏免疫專家Mariana Castells等人共同撰寫，系統整理了MCAS的當前理解，並明確指出診斷、機制與治療的知識缺口。本文將根據這篇最新共識，為您詳細拆解MCAS的全貌，幫助您釐清迷思、掌握正確就醫方向。
注意：本文僅供參考，非醫療診斷或治療建議。任何症狀請盡速就醫，由過敏免疫科或風濕免疫科醫師評估。
一、什麼是肥大細胞活化症候群（MCAS）？為何突然爆紅？
一、什麼是肥大細胞活化症候群（MCAS）？為何突然爆紅？
肥大細胞（mast cell）是人體免疫系統的重要守衛，正常情況下會釋放組織胺（histamine）、前列腺素、細胞因子等介質，幫助對抗感染或過敏原。但在MCAS患者身上，肥大細胞「過度活化」，即使沒有明顯過敏原，也會反覆釋放大量介質，造成全身多系統症狀。
這篇2024 JACI論文指出，MCAS並非單一疾病，而是「一系列臨床實體」的總稱。它可能獨立存在，也可能伴隨其他疾病（如過敏、自體免疫、感染後遺症）。與傳統過敏不同，MCAS的發作常呈陣發性、嚴重且多器官同時受影響，嚴重時類似過敏性休克（anaphylaxis），卻又沒有明確IgE介導的過敏原。
常見症狀（至少2個器官系統同時出現）：
皮膚/末梢：潮紅、蕁麻疹、血管性水腫（手腳突然腫脹、發紅）
心血管：低血壓、心跳加速、頭暈（尤其是姿勢改變或「倒置」時）
腸胃：腹痛、腹瀉、噁心、嘔吐
呼吸：喘鳴、鼻塞
神經/精神：腦霧、記憶力下降、焦慮、憂鬱
其他：疲勞、關節痛、發燒感
這些症狀與您先前描述的「末梢突然腫脹、發紅、倒置頭暈、血壓低」高度吻合，常讓患者誤以為是單純過敏或低血壓。
二、2022更新版MCAS診斷標準（共識核心）
二、2022更新版MCAS診斷標準（共識核心）
論文詳細列出2022年國際共識診斷標準，必須同時符合以下3項才能診斷MCAS（Table I）：
反覆嚴重全身症狀：至少2個器官系統出現符合肥大細胞介質釋放的症狀（如上述）。
生物標記物明顯升高：發作時血清tryptase（類胰蛋白酶）比基準值高20% + 2 ng/mL；或尿液其他介質（如N-甲基組織胺、11β-PGF2α）升高。
治療反應良好：使用抗組織胺（H1/H2阻斷劑）、肥大細胞穩定劑（cromolyn、ketotifen）或抗IgE藥物（如omalizumab）後，症狀明顯改善。
重要提醒：單靠症狀無法診斷，必須有客觀的介質升高證據。論文強調，目前只有不到5%的「疑似MCAS」患者能完全符合嚴格標準，許多人可能屬於「MCAS-like」症狀群。
診斷流程圖（論文Fig 3簡化版）：
出現多系統症狀 → 測基準tryptase → 發作時重測 → 排除其他疾病（如肥大細胞增多症） → 試用MCAS藥物觀察反應。
三、MCAS的五大分類（Table II）
三、MCAS的五大分類（Table II）
論文將MCAS分為五大變異型，每種成因與風險不同：
類型
特徵
常見情形
風險
原發性（Primary/Clonal）
肥大細胞有KIT D816V基因突變
合併肥大細胞增多症（SM）
較高
繼發性（Secondary）
由其他疾病觸發（如IgE過敏、感染）
過敏、慢性感染、腸道問題
中等
合併型（Combined）
同時有原發+繼發因素
複雜病例
高
HαT陽性
遺傳性α-色胺酶血症（TPSAB1基因多複本）
家族史、4-6%白人盛行
中等
特發性（Idiopathic）
找不到明確原因
最常見女性患者
視症狀
遺傳性α-色胺酶血症（HαT） 是近年重要發現，基準tryptase >8 ng/mL常提示此型，易合併多系統症狀與過敏風險。
四、MCAS的機制研究還有那些缺口？
四、MCAS的機制研究還有那些缺口？
論文坦承，目前對MCAS的根本機制仍不完全清楚：
肥大細胞為何「活化閾值降低」？
單細胞層級的研究不足（尤其是非克隆性MCAS）。
與自體免疫、姿勢性心搏過速症（POTS）、Ehlers-Danlos症候群（EDS）、小纖維神經病變的關聯仍在探討。
神經精神症狀（如腦霧）可能與腦部低灌注或肥大細胞-神經交互有關，但證據有限。
NETosis（中性粒細胞胞外陷阱）與肥大細胞的交互作用，也被提及為可能的發炎放大機制。
未來研究需求包括：大型臨床試驗、基因-環境交互分析、新型生物標記物開發。
五、MCAS的治療與管理策略
五、MCAS的治療與管理策略
目前尚無「治癒」方法，目標是控制症狀、減少發作：
第一線：H1/H2抗組織胺 + 肥大細胞穩定劑（如cromolyn）。
第二線：抗IgE（omalizumab）、白三烯阻斷劑、黃酮類化合物。
頑固型：酪胺酸激酶抑制劑（TKI）等新型藥物（需更多研究）。
生活調整：低組織胺飲食、避免已知觸發物（壓力、溫度變化、某些藥物）、壓力管理。
共病處理：合併POTS、腸道問題、憂鬱症時需多科合作。
論文特別強調患者教育與心理支持的重要性：許多MCAS患者面臨誤診、孤獨、憂鬱，需加入患者團體（如The Mast Cell Disease Society）。
六、為什麼需要更多研究？對患者的啟示
六、為什麼需要更多研究？對患者的啟示
這篇JACI論文總結：MCAS影響生活各層面，但證據基礎仍薄弱。缺乏大型隨機對照試驗、標準化治療指南，以及對醫師與患者的系統教育，導致許多人延誤診斷或接受不適當治療。
對您（或類似症狀者）的實用建議：
記錄症狀日誌（時間、誘發因素、血壓、tryptase值）。
就醫時主動詢問「是否符合MCAS診斷標準？」並要求測基準與發作時tryptase。
若有家族史或慢性共病，優先考慮HαT檢測。
找到專科醫師（台灣可至大型醫學中心過敏免疫科）。
2024 JACI這篇共識論文為MCAS提供了清晰的當前藍圖，也清楚點出未來努力方向。MCAS不再是「神祕疾病」，但仍需更多科學證據才能讓每位患者獲得精準診斷與有效治療。如果您正因類似症狀困擾，請盡快就醫，帶上這篇論文摘要與醫師討論，或許能加速找出答案。
參考來源：Castells M, et al. Mast cell activation syndrome: Current understanding and research needs. J Allergy Clin Immunol. 2024. （全文可至JACI官網查閱）
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J Allergy Clin Immunol. Author manuscript; available in PMC: 2025 Aug 1.
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
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PMCID: PMC11881543 NIHMSID: NIHMS2058149 PMID: 38851398
The publisher's version of this article is available at J Allergy Clin Immunol
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).
The consensus diagnostic criteria of MCAS, updated in 2022, consists of the following (Table I):
FIG 1.
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: H
1
and H
2
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 E
4
, and PGD2 metabolites (11β-PGF2α).
All 3 MCAS criteria must be fulfilled. Adapted from Valent et al.
Recurrent severe systemic symptoms in at least 2 organ systems consistent with MC mediator–related symptoms.
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 E
4
, or prostaglandin D
2
/2,3-dinor-11β–prostaglandin F
2
alpha (PGF2α) metabolite over baseline during a period of increased symptoms.
A significant response of clinical symptoms to medications that counteract MC mediator effects (eg, histamine H
1
and H
2
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.
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.
Criteria for primary and secondary MCAS are fulfilled; HαT may be detected.
HαT is detected, and all diagnostic MCAS criteria are fulfilled.
Criteria to diagnose MCAS are met, but no other variant criteria are met.
Adapted from Valent et al.
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.
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,
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.
In contrast, local and less severe forms of MCA do not fulfill the MCAS criteria.
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 described
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.
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)
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.
Systemic MCA may be documented by an increase in the serum tryptase level by 20% above the individual’s baseline level + 2 ng/mL.
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.
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.
Patients with HαT and/or SM have greater diurnal variations in baseline tryptase without MCA symptoms as a result of their higher baseline levels.
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 E
4
, prostaglandin D
2
(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.
FIG 2.
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.
Nonvalidated serologic markers utilized to detect MCA
include chromogranin A,
serotonin, and heparin. Further studies are needed to validate their specificity and significance in MCAS, and they are not recommended for diagnosis of MCAS.
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.
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.
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.
Tyrosine kinase inhibitors such as imatinib, which bind to cell surface–mutated and wild-type KIT, can decrease MC numbers and symptoms of MCA.
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.
A lack of response to histamine blockade may reflect a nonhistaminergic MCAS endotype or an alternative diagnosis.
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.
FIG 3.
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.
Patients with SM may present with symptoms of MCA and have a concomitant IgE-dependent allergy and/or HαT.
Some patients present MCA in one organ such as in allergic rhinitis, urticaria, asthma, and eosinophilic GI disorders;
or they present with mild multiorgan symptoms and may not fulfill strict MCAS criteria.
Constitutional and functional symptoms have been attributed to MCAS when associated with other MCA symptoms.
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.
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.
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.
HαT is a recently described genetic trait reported among 5% to 7% of Whites.
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.
Given the apparent high frequency of asymptomatic individuals with HαT,
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.
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.
Chronic intestinal inflammation may contribute to GI symptoms in HαT, potentially independent of MCA.
In a retrospective study of patients with HαT, GI manifestations were the only symptoms associated with MCA that failed to respond to omalizumab.
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.
HαT is enriched in patients with SM,
in Hymenoptera-allergic patients with severe anaphylaxis,
and in patients with idiopathic anaphylaxis.
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.
In genome- and phenotype-wide association studies, the chromosomal locus linked to HαT has been shown to be associated with risk for mastocytosis,
chronic urticaria, and MC mediator levels in serum.
Studies of patients with high BST levels due to HαT and SM have also expanded diagnostic considerations for MCA and MC disorders.
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),
for which an association with autoimmunity has been suggested. Patients with hypermobility EDS have an increased risk of developing inflammatory diseases, including celiac disease
and eosinophilic esophagitis,
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.
Symptomatic individuals with HαT have been reported to have increased levels of GI-associated autoantibodies of unclear significance.
Further studies are needed on the role of autoantibodies in MCA and the potential for immunotherapeutic interventions.
Neurologic associations
Neurologic symptoms, in addition to skin, GI, and cardiovascular manifestations, are common in patients with MC disorders.
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.
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.
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.
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.
POTS has been confirmed in patients with MCA symptoms such as flushing and elevated urinary methylhistamine.
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.
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.
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.
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.
Cerebral hypoperfusion also has been implicated, as patients with MC disorders reportedly have reduced orthostatic cerebral blood flow,
which may impair brain function because reduced cerebral blood flow can be associated with cerebral hypoxia.
In rats, cerebral hypoperfusion may impair neuronal functioning and lead to neuroinflammation,
which can result in central sensitization
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 H
1
/H
2
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.
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.
Although anecdotal efficacy of low-dose naltrexone with and without intravenous immunoglobulin has been described, these treatments are uncontrolled and controversial.
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.
MCA and MCAD also impose a substantial burden on patients and their families, supporting the need for patient and caregiver education.
A recent study of individuals with MCAD found that many participants reported feeling depressed, lonely, and poorly understood.
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.
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.
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.
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 D
2
PGF2α
Prostaglandin F
2
alpha
POTS
Postural orthostatic tachycardia syndrome
SM
Systemic mastocytosis
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