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

Treatment of Resistant Mast Cell Activation Syndrome (MCAS)

For resistant MCAS, a stepwise approach using combination therapy is required, starting with high-dose H1 and H2 antihistamines, adding oral cromolyn sodium, then incorporating leukotriene modifiers, aspirin (if tolerated), and considering omalizumab for refractory cases. 1

First-Line Therapies

Antihistamine Combinations

• H1 Receptor Antihistamines:

  • Use non-sedating H1 antihistamines (cetirizine, fexofenadine) at 2-4 times standard doses 1
  • Target symptoms: flushing, pruritus, urticaria, tachycardia, abdominal discomfort
  • Caution: First-generation antihistamines (diphenhydramine, hydroxyzine) may cause sedation and cognitive decline, especially in elderly patients 1

• H2 Receptor Antihistamines:

  • Options: famotidine, cimetidine
  • Target symptoms: gastrointestinal symptoms and cardiovascular manifestations
  • Often used in combination with H1 blockers for synergistic effect 1

Mast Cell Stabilizers

• Oral Cromolyn Sodium:
  • FDA-approved for mastocytosis 2
  • Dosing: Start low and gradually increase to 200 mg four times daily (before meals and at bedtime) 1
  • Target symptoms: diarrhea, abdominal pain, bloating, cramps, and possibly neuropsychiatric manifestations 2
  • Clinical improvement typically occurs within 2-6 weeks of treatment initiation 2

Second-Line Therapies

Leukotriene Pathway Modifiers

• Leukotriene Receptor Antagonists:

  • Options: montelukast, zafirlukast
  • Most effective for bronchospasm and gastrointestinal symptoms
  • Consider especially if urinary LTE4 levels are elevated 1
  • Works best in conjunction with H1 antihistamines 1

• 5-Lipoxygenase Inhibitor:

  • Option: zileuton
  • Alternative approach to blocking leukotriene pathway 1

Prostaglandin Inhibition

• Aspirin:
  • May reduce refractory flushing and hypotensive episodes associated with PGD2 secretion 1
  • Start at low dose and may increase up to 650 mg twice daily as tolerated
  • CAUTION: Must be introduced in a controlled clinical setting due to risk of triggering mast cell degranulation 1
  • Contraindicated in patients with history of allergic reactions to NSAIDs 1

Third-Line Therapies for Resistant Cases

Corticosteroids

• For refractory symptoms:
  • Initial oral dosage: 0.5 mg/kg/day
  • Followed by slow taper over 1-3 months
  • Not recommended for long-term use due to side effects 1
  • Consider for pre-procedure prophylaxis: 50 mg prednisone at 13 hours, 7 hours, and 1 hour before procedures 1

Biological Therapy

• Omalizumab:
  • Consider for prevention of anaphylactic episodes in resistant MCAS 1
  • Has shown efficacy in case reports for preventing spontaneous episodes of anaphylaxis 1
  • Expensive but may be cost-effective by preventing emergency department visits 1

Novel Approaches for Highly Resistant Cases

• JAK Inhibitors:
  • Tofacitinib has shown promise in case reports 3
  • Targets downstream inflammatory effects regardless of upstream mutations
  • Consider in severely affected, therapy-refractory patients 4

Acute Management

• Epinephrine autoinjector:

  • Essential for patients with history of systemic anaphylaxis or airway angioedema 1
  • Instruct patients on proper use and when to administer

• Positioning:

  • Train patients with recurrent hypotensive episodes to assume supine position immediately 1

• Bronchodilator:

  • Albuterol via nebulizer or metered-dose inhaler for bronchospasm 1

Practical Considerations and Pitfalls

Trigger Avoidance

• Identify and avoid known triggers (temperature extremes, mechanical irritation, alcohol, certain medications) 1
• Careful review of prior reactions to medications is critical 1

Medication Considerations

• Start medications at low doses and titrate up gradually
• Allow sufficient trial periods (e.g., at least 1 month for cromolyn) before determining efficacy 1
• Be aware of potential cognitive effects of antihistamines with anticholinergic properties, especially in elderly patients 1

Monitoring Response

• Assess response to each medication before adding another
• Consider measuring mediator levels (tryptase, urinary histamine metabolites, prostaglandins) to guide therapy 5

Multidisciplinary Approach

• For severe cases, especially those with systemic manifestations, involve specialists in allergy/immunology and relevant affected organ systems 1

Remember that treatment of resistant MCAS requires patience and methodical addition of therapies. The goal is to find the combination that provides the best symptom control with minimal side effects.