How to treat resistant Mast Cell Activation Syndrome (MCAS)?

Treatment of Resistant Mast Cell Activation Syndrome (MCAS)

For resistant MCAS, a stepped approach using combinations of H1/H2 antihistamines, cromolyn sodium, leukotriene inhibitors, and omalizumab is recommended, with consideration of tyrosine kinase inhibitors in severe refractory cases. 1

First-Line Therapies

Antihistamine Combinations

• H1 receptor antagonists:

  • Non-sedating options (preferred): Fexofenadine, cetirizine at 2-4 times FDA-approved doses
  • Can help with dermatologic manifestations (flushing, pruritus), tachycardia, and abdominal discomfort 1
  • Caution with first-generation antihistamines (diphenhydramine, hydroxyzine) due to sedation and potential cognitive decline, especially in elderly 1

• H2 receptor antagonists:

  • Options: Famotidine, ranitidine, cimetidine
  • Target gastrointestinal and vascular symptoms 1
  • Use in combination with H1 blockers for enhanced effect 1

Mast Cell Stabilization

• Cromolyn sodium:
  • FDA-approved for mastocytosis 2
  • Particularly effective for gastrointestinal symptoms (diarrhea, abdominal pain) 2
  • Dosing: Start low and gradually increase to 200 mg 4 times daily (before meals and at bedtime) 1
  • Clinical improvement typically occurs within 2-6 weeks of treatment initiation 2
  • Benefits persist for 2-3 weeks after treatment withdrawal 2

Second-Line Therapies

Leukotriene Pathway Modifiers

• Leukotriene receptor antagonists: Montelukast, zafirlukast
• 5-lipoxygenase inhibitor: Zileuton
• Most effective for respiratory and gastrointestinal symptoms, especially if urinary LTE4 levels are elevated 1
• Work best in conjunction with H1 antihistamines 1

Aspirin

• Consider for refractory flushing and hypotensive episodes associated with PGD2 secretion 1
• May require dosing up to 650 mg twice daily 1
• Important caution: Must be introduced in a controlled clinical setting due to risk of triggering mast cell degranulation 1

Corticosteroids

• For refractory symptoms: Initial oral dosage of 0.5 mg/kg/day, followed by slow taper over 1-3 months 1
• Consider 50 mg prednisone at 13 hours, 7 hours, and 1 hour before procedures when mast cell activation has been problematic 1
• Not recommended for long-term use due to side effects 1

Advanced Therapies for Resistant Cases

Biologics

• Omalizumab:
  • Consider for MCAS resistant to mediator-targeted therapies 1
  • Particularly effective for preventing anaphylactic episodes 1
  • Reduces severity and frequency of allergic reactions 1
  • Though expensive, may reduce emergency department visits and lost work time 1

Signal Transduction Inhibitors (for severe refractory cases)

• Midostaurin:

  • Multikinase inhibitor with activity against wild-type and D816V Kit 1
  • Approved for advanced systemic mastocytosis 1
  • Side effects include nausea (manageable with ondansetron) and cytopenias 1

• Other tyrosine kinase inhibitors:

  • Masitinib: Active against wild-type Kit and Lyn tyrosine kinases; common side effect is asthenia 1
  • Imatinib: Not effective if D816V mutation is present 1
  • Avapritinib: More selective D816V Kit inhibitor showing rapid and durable responses in advanced systemic mastocytosis 1

Acute Management for Breakthrough Symptoms

• Epinephrine autoinjector: Essential for patients with history of systemic anaphylaxis or airway angioedema 1
• Supine positioning: For recurrent hypotensive episodes 1
• Bronchodilators: Albuterol via nebulizer or metered-dose inhaler for bronchospasm 1

Avoidance Strategies

• Identify and avoid known triggers 1
• Avoid temperature extremes (hypothermia or hyperthermia) 1
• Avoid unnecessary trauma that could trigger mast cell activation 1

Special Considerations

Perioperative Management

• Multidisciplinary approach involving surgical, anesthesia, and perioperative medical teams 1
• Pre-anesthetic treatment with anxiolytics (benzodiazepines), antihistamines (H1 and H2 blockers), and possibly corticosteroids 1
• Safer anesthetic agents include propofol, sevoflurane, isoflurane, fentanyl, remifentanil 1
• Avoid muscle relaxants atracurium and mivacurium; rocuronium and vecuronium may be safer 1

Pregnancy Management

• Multidisciplinary team including high-risk obstetrics, anesthesia, and allergy 1
• Focus on trigger avoidance, prophylactic antihistamines, as-needed corticosteroids, and epinephrine for anaphylaxis 1
• For severe refractory cases during pregnancy, interferon-alfa can be considered 1
• Avoid cladribine and tyrosine kinase inhibitors during pregnancy 1

Monitoring Response

• Regular assessment of symptom improvement
• Consider serum tryptase levels during acute episodes (within 30-120 minutes of symptom onset) 1
• Compare to baseline tryptase level after recovery 1