What are all the medications used to treat Mast Cell Activation Syndrome (MCAS)?

Medications for Mast Cell Activation Syndrome (MCAS)

The cornerstone of MCAS pharmacotherapy consists of H1 and H2 antihistamines as first-line agents, with oral cromolyn sodium added for gastrointestinal symptoms, and additional targeted therapies layered based on specific symptom patterns and severity. 1

First-Line Preventive Medications

Antihistamines

• H1 antihistamines are the primary preventive therapy, with nonsedating second-generation agents preferred (e.g., cetirizine, loratadine, fexofenadine) at standard doses, which can be increased to 2-4 times the standard dose for refractory symptoms 1
• H2 antihistamines (e.g., famotidine, ranitidine) should be used as first-line therapy for gastrointestinal symptoms and may help H1 antihistamines attenuate cardiovascular symptoms 1
• Sedating H1 antihistamines (e.g., diphenhydramine, hydroxyzine) may be used but carry risks of drowsiness, impaired driving ability, and chronic cognitive decline, particularly in elderly patients 1

Mast Cell Stabilizers

• Oral cromolyn sodium (200 mg four times daily) reduces abdominal bloating, diarrhea, and cramps, with potential benefits extending to neuropsychiatric manifestations 1, 2
• Clinical improvement typically occurs within 2-6 weeks of treatment initiation and persists for 2-3 weeks after withdrawal 2
• Divided dosing with weekly upward titration to the target dose improves tolerance and adherence 1

Second-Line and Adjunctive Therapies

Dual-Action Agents

• Doxepin is a potent H1 and H2 antihistamine with tricyclic antidepressant activity that may reduce central nervous system manifestations, though it carries similar cognitive risks as sedating antihistamines and may increase suicidal tendencies in children and young adults with depression 1

Prostaglandin Pathway Modulation

• Aspirin (up to 650 mg twice daily as tolerated) may reduce flushing and hypotension in patients with elevated urinary 11β-PGF2α levels, but is contraindicated in those with allergic or adverse reactions to NSAIDs 1

Leukotriene Pathway Inhibitors

• Cysteinyl leukotriene inhibitors (e.g., montelukast) or 5-lipoxygenase inhibitors (zileuton) may reduce bronchospasm or gastrointestinal symptoms, particularly if urinary LTE4 levels are elevated 1

Additional Antihistamine Options

• Cyproheptadine, a sedating H1 antihistamine with anticholinergic and antiserotonergic activities, may help gastrointestinal symptoms 1
• Ketotifen, a sedating H1 receptor antagonist approved for allergic eye disease but available as compounded tablets, though evidence of superiority over other antihistamines like diphenhydramine is lacking 1

Corticosteroids

• Steroid taper/burst (initial oral dosage of 0.5 mg/kg/day, followed by slow taper over 1-3 months) may be useful for refractory signs or symptoms 1
• Prophylactic dosing of 50 mg prednisone at 13 hours, 7 hours, and 1 hour before radiologic or invasive procedures may prevent MC activation when it has been problematic previously 1
• Long-term use is limited by significant side effects 1

Biologic Therapy

• Omalizumab has demonstrated prevention of anaphylactic episodes in some patients with MCAS or systemic mastocytosis, and may enable patients to tolerate needed insect venom immunotherapy 1

Acute Management Medications

Emergency Interventions

• Epinephrine autoinjector (two devices should be carried) is essential for patients with history of systemic anaphylaxis or airway angioedema, administered intramuscularly for hypotensive episodes, laryngeal angioedema, or bronchospasm 1
• Albuterol (via nebulizer or metered-dose inhaler) treats bronchospasm symptoms 1
• Supine positioning is critical for hypotensive episodes and should be maintained during transport to emergency department 1

Advanced/Cytoreductive Therapies (for Advanced Systemic Mastocytosis)

For patients with aggressive systemic mastocytosis, smoldering systemic mastocytosis with severe refractory symptoms, or mast cell leukemia:

• Midostaurin (tyrosine kinase inhibitor) 1
• Cladribine 1
• Imatinib (only if KIT D816V mutation negative or unknown, or if eosinophilia with FIP1L1-PDGFRA fusion gene present) 1
• Interferon-alpha preparations (interferon alfa-2b, peginterferon alfa-2a, or peginterferon alfa-2b) ± prednisone 1

Critical Management Principles

Trigger Avoidance

• Identification and avoidance of triggers (insect venoms, temperature extremes, mechanical irritation, alcohol, specific medications including aspirin, radiocontrast agents, certain anesthetic agents) is the first step in prevention 1

Perioperative Considerations

• Benzodiazepines, H1 and H2 antihistamines, and corticosteroids are recommended perioperatively to reduce frequency and severity of mast cell activation symptoms 1
• Opioids (morphine, codeine) should be used with caution as they can trigger mast cell activation, though should not be withheld since pain itself triggers degranulation; fentanyl and remifentanil are safer alternatives 1, 3
• Intravenous administration of opioids is preferred over oral to ensure reliable delivery and minimize gastrointestinal exposure 3

Important Caveats

• Compounding drugs to eliminate additives is not recommended, as controlled studies in chronic urticaria patients ruled out additive allergies in all tested patients 1
• Cognitive decline has been reported with H1 blockers having anticholinergic effects, especially concerning in elderly populations 1
• Antihistamines work better as prophylaxis than acute treatment because once histamine-mediated symptoms appear, it is too late to block histamine already bound to receptors 1