Mast Cell Activation Syndrome Update—A Dermatological Perspective
Abstract
:1. Introduction
2. Mast Cell Basic Physiology
3. Mast Cells as Immune Tissue Effectors
4. Role of Mast Cells in Pathology
5. Mast Cells in the Skin
6. MCAS
6.1. MCAS Clinical Manifestations
6.2. MCAS Diagnostic Criteria
- Clinical: typical MC activation symptoms, which are episodic, recurrent, severe (often taking the form of anaphylaxis) and systemic (involving two organ systems at least);
- Laboratory: markers of MC activation—event-related serum tryptase level elevated above 120% of the individual’s serum baseline + 2 ng/mL;
- Therapeutic: clinical response to drugs that counteract MC mediators or prevent their release.
6.3. MCAS Classification
6.4. Histamine Intolerance
6.5. Hereditary Alpha Tryptasemia (HαT)
6.6. Cutaneous Manifestations
- Maculopapular cutaneous mastocytosis (urticaria pigmentosa)—hyperpigmented macules, papules or nodules usually on the trunk associating Darier’s sign (formation of a wheal in response to stroking/rubbing the skin), although the absence of it does not rule out the diagnosis [163];
- Diffuse cutaneous mastocytosis—a rare variant of cutaneous mastocytosis with onset usually at birth or in early infancy [164], manifesting in children with generalized erythema and thickened skin, variable pigmentation and in some cases with papules and intense dermographism [165]; in adults it presents with extensive bullae, that sometimes can be hemorrhagic, and which progress to erosions, desquamation and finally hyper-pigmentation and also intense dermographism [165]
6.7. Treatment
7. Pharmacological Treatment
- An epinephrine autoinjector should be carried by all patients who had an anaphylaxis episode in their personal history—especially patients with known allergies to insect venoms—or who have a known risk of developing one. Epinephrine should be administered intramuscularly as soon as the first signs are noticed, or after insect bites and stings, in a dose of 0.01 mg/kg to a maximum of 0.5 mg in adults and 0.3 mg in children [167].
- Antihistamines are the first line of treatment for patients with non-life-threatening symptoms. They act by binding to, and blocking histamine receptors in the target tissues, thus reducing the impact of MC degranulation. Decades of clinical practice have established that the use of antihistamines alleviates symptoms such as itching, pain, urticaria, and acid reflux [169]. If symptom control cannot be achieved with the highest recommended doses of H2 antihistamines, a combination of non-sedating H1 and H2 antihistamines can be attempted, especially if the patient associates gastric symptoms [170]. Most patients have benefited from long-term antihistamine use, with good tolerance and minimum side effects [170].
- Leukotriene inhibitors are used in asthma and respiratory symptoms with probable underlying bronchoconstriction with allergic triggers that do not fulfil the criteria for asthma. They are also used in the treatment of allergic rhinitis, psoriasis and atopic dermatitis. Drugs with two mechanisms of action are currently approved: leukotriene receptor blockers (montelukast and zafirlukast) and 5-lipoxygenase inhibitors that block synthesis of leukotrienes from arachidonic acid (zileuton). Leukotriene inhibitors can be prescribed in combination with antihistamines [171,172,173].
- MC stabilizers increase the threshold for MC degranulation signaling. Cromolyn sodium and nedocromil are currently approved. Although very promising on paper, these drugs are not more effective than antihistamines and leukotriene inhibitors, with possibly more significant side effects. Consequently, they are not routinely prescribed. Moreover, ketotifen (a second-generation H1 receptor antagonist with higher brain permeability compared with the newer second-generation antagonists desloratadine and levocetirizine) has MC stabilizer activity. Desloratadine and cetirizine have also been reported as MC stabilizers, although doses significantly higher than the ones currently used for therapy were required [174,175,176,177,178].
- Steroids should only be used short term for acute exacerbations of symptoms not controlled by standard therapy. Potential uses include edema, urticaria, wheezing, diarrhea and severe pain [179].
- Biologics: omalizumab, an IgE receptor blocker, effectively controls MC-mediated symptoms, improves the patients’ quality of life, and should be recommended as low-dose long-term therapy to persons at risk of anaphylaxis [180,181]. Emerging kinase inhibitors (imatinib, mitostaurine, avapritinib) inhibit MC proliferation and IgE-dependent MC activation. These drugs may represent future effective therapies for patients with advanced systemic mastocytosis [168].
- DAO oral supplements should be considered in the case of HIT [182].
8. Discussion
9. Conclusions
10. Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Organ/System | Diagnostic Symptoms | Non-Diagnostic Symptoms |
---|---|---|
Cutaneous | Flushing, pruritus, hives, angioedema | Dermographism, urticaria, rashes, edema/migratory edema, alopecia, poor healing, onychodystrophy |
Respiratory | Shortness of breath, laryngeal edema, wheezing, hypoxia, nasal congestion, sneezing | Dyspnea, asthma, cough |
Gastrointestinal | Vomiting, abdominal cramps, diarrhea | Constipation, alternating diarrhea/constipation, gastroesophageal reflux, dyspepsia, dysphagia, heartburn, nausea, elevated transaminases, hepatomegaly, multiple chemical/food sensitivity |
Cardiovascular | Hypotension, syncope, collapse, incontinence | Chest pain, palpitations/dysrhythmias, systolic hypertension (mild/moderate), tachycardia |
General | Fatigue, weight loss or gain, obesity, fever, chills, sweats, frequent or odd infections, heat and/or cold intolerance | |
Allergologic | Multiple/odd drug reactions | |
Neuro-psychiatric | Headaches, migraines, cognitive disfunction/brain fog, insomnia, anxiety, depression, dysautonomia symptoms (POTS), tremor, paresthesia | |
Musculoskeletal | Myalgia, arthralgia, joint hypermobility, fibromyalgia-type pain | |
Urogenital | Dysuria, frequency, urgency, prostatitis, polycystic ovarian syndrome, endometriosis | |
Ophthalmologic | Eye irritation, conjunctivitis, visual anomalies | |
Ears, nose, throat | Tinnitus, hearing loss, rhinitis, sinusitis, sore throat, oral irritation/sores | |
Hematological | Easy bleeding/bruising | |
Lymphatic system | Adenopathy/adenitis | |
Stomatological | Dental deterioration |
Flushing | fever, emotion, exercise, temperature changes, foods (spicy, fish—scombroid poisoning) or beverages (alcohol ingestion), medications (e.g., calcium channel blockers, nicotinic acid, disulfiram combined with alcohol) rosacea, climacteric flushing, carcinoid syndrome, pheochromocytoma, mastocytosis, anaphylaxis, thyroid—medullary carcinoma, VIPoma, renal cell carcinoma, neuro-psychiatric (anxiety disorders, Parkinson’s, multiple sclerosis, migraine, trigeminal nerve damage, Frey syndrome, Horner syndrome, Streeten syndrome, autonomic epilepsy, orthostatic hypotension), sarcoid, dumping syndrome, arsenic intoxication, basophilic granulocytic leukemia, malignant histiocytoma, idiopathic flushing |
Pruritus | xerosis, scabies, noncutaneous causes (e.g., cholestatic/non-cholestatic hepatobiliary diseases, hyperthyroidism, uremic pruritus, myeloproliferative disorders such as Hodgkin/non-Hodgkin lymphoma, lymphocytic leukemia, polycythemia vera ± aquagenic pruritus, essential thrombocytosis, diabetes), psychogenic (depression, anxiety, obsessive-compulsive disorder, somatic symptom disorders, psychosis, substance use), subclinical mastocytosis, drug induced—either directly or via cholestasis (e.g., morphine-based analgesics, angiotensin-converting enzyme inhibitors, selective serotonin re-uptake inhibitors, nonsteroidal anti-inflammatory drugs can induce chronic pruritus without associated cutaneous lesions); for localized pruritus: spinal nerve compressions, notalgia paresthetica, small fiber neuropathy, parasitoses (e.g., enterobiasis) |
Urticarial lesions | acute/chronic urticaria, urticarial vasculitis, urticarial dermatitis, urticaria multiforme, drug and viral exanthems, autoinflammatory syndromes (cryopyrin-associated periodic syndromes, Schnitzler syndrome, adult-onset Still disease, Gleich syndrome, neutrophilic urticarial dermatosis), hypereosinophilic syndromes, autoimmune progesterone dermatitis, polymorphic light eruption |
Angioedema | bradykinin-mediated angioedema, hereditary angioedema, granulomatous cheilitis at an initial stage, eosinophilic cellulitis (Wells syndrome), allergic contact dermatitis (e.g., to hair dye), photoallergy |
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Mihele, D.M.; Nistor, P.A.; Bruma, G.; Mitran, C.I.; Mitran, M.I.; Condrat, C.E.; Tovaru, M.; Tampa, M.; Georgescu, S.R. Mast Cell Activation Syndrome Update—A Dermatological Perspective. J. Pers. Med. 2023, 13, 1116. https://doi.org/10.3390/jpm13071116
Mihele DM, Nistor PA, Bruma G, Mitran CI, Mitran MI, Condrat CE, Tovaru M, Tampa M, Georgescu SR. Mast Cell Activation Syndrome Update—A Dermatological Perspective. Journal of Personalized Medicine. 2023; 13(7):1116. https://doi.org/10.3390/jpm13071116
Chicago/Turabian StyleMihele, Dana Mihaela, Paul Andrei Nistor, Gabriela Bruma, Cristina Iulia Mitran, Madalina Irina Mitran, Carmen Elena Condrat, Mihaela Tovaru, Mircea Tampa, and Simona Roxana Georgescu. 2023. "Mast Cell Activation Syndrome Update—A Dermatological Perspective" Journal of Personalized Medicine 13, no. 7: 1116. https://doi.org/10.3390/jpm13071116
APA StyleMihele, D. M., Nistor, P. A., Bruma, G., Mitran, C. I., Mitran, M. I., Condrat, C. E., Tovaru, M., Tampa, M., & Georgescu, S. R. (2023). Mast Cell Activation Syndrome Update—A Dermatological Perspective. Journal of Personalized Medicine, 13(7), 1116. https://doi.org/10.3390/jpm13071116