What is the treatment for Mast Cell Activation Syndrome (MCAS)?

Treatment of Mast Cell Activation Syndrome (MCAS)

Start with H1 antihistamines as first-line therapy, add H2 antihistamines for gastrointestinal symptoms, and ensure every patient has an epinephrine autoinjector for emergency use. 1

Stepwise Treatment Algorithm

First-Line Preventive Therapy

• Begin with nonsedating second-generation H1 antihistamines (cetirizine, loratadine, fexofenadine) at standard doses, which can be escalated to 2-4 times the standard dose for refractory symptoms 1
• Sedating H1 antihistamines (diphenhydramine, hydroxyzine) may be used but carry risks of drowsiness, impaired driving, and chronic cognitive decline, particularly in elderly patients 1
• Add H2 antihistamines (famotidine or ranitidine) as first-line therapy for gastrointestinal symptoms and to help attenuate cardiovascular symptoms 1, 2
• The combination of H1 and H2 antihistamines is particularly effective for controlling severe pruritus and wheal formation when monotherapy fails 3

Important caveat: Doses of H1 antihistamines may need to be 2-4 times higher than FDA-approved levels for adequate symptom control, but high doses can cause cardiotoxicity requiring careful monitoring 3

Second-Line Therapies

• Oral cromolyn sodium (200 mg four times daily before meals and at bedtime) is used predominantly for gastrointestinal symptoms, though its mechanism is not fully understood 4, 5

• Counsel patients that cromolyn's onset of action can be delayed and should be taken for at least 1 month before deciding efficacy; introduce at the lowest dose and gradually increase 4

• Clinical improvement with cromolyn typically occurs within 2-6 weeks of treatment initiation and persists for 2-3 weeks after withdrawal 5

• Leukotriene modifiers (montelukast, zafirlukast, or zileuton) work best in conjunction with H1 antihistamines and are most efficacious for dermatologic symptoms 4

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

• Aspirin may reduce flushing and hypotension in patients with elevated urinary 11β-PGF2α levels by inhibiting prostaglandin D2 synthesis, but must be introduced in a controlled clinical setting due to risk of triggering mast cell degranulation 4, 1

Emergency Management

• Every patient must have an epinephrine autoinjector prescribed and caregivers trained in its use 3, 1
• Administer epinephrine intramuscularly in a recumbent position immediately for hypotension, wheezing, laryngeal edema, cyanotic episodes, or recurrent anaphylactic attacks 3, 1
• Maintain supine positioning during hypotensive episodes and throughout transport to the emergency department 1
• Albuterol treats bronchospasm symptoms 1

Advanced Therapies for Refractory Cases

For patients with clonal MCAS or advanced systemic mastocytosis with symptoms refractory to antimediator therapy:

• Omalizumab (anti-IgE therapy) should be considered in cases of MCAS resistant to mediator-targeted therapies, as it prevents spontaneous episodes of anaphylaxis and reduces emergency department visits 4
• Omalizumab binds free IgE, preventing its binding to FcεRI, and reduces the severity and frequency of allergic reactions 4

Cytoreductive therapies for advanced systemic mastocytosis:

• Midostaurin is a multikinase inhibitor approved for treating advanced systemic mastocytosis with activity against wild-type and D816V Kit 4, 1
• Nausea can be controlled by taking ondansetron 30-60 minutes before midostaurin, and cytopenias can be managed by dose adjustment 4
• Cladribine can be efficacious in patients with advanced systemic mastocytosis with severe life-threatening or disabling anaphylaxis, but is associated with increased infection risk 4, 1
• Interferon-alpha is commonly used but has adverse events including flu-like symptoms, depression, hypothyroidism, and autoimmune disorders 4, 1
• Imatinib has been used but is not indicated if the D816V mutation is present, which causes resistance 4, 1

Systemic Corticosteroids

• Systemic steroids might help some patients but should be tapered as quickly as possible to limit numerous adverse effects 4

Critical Management Principles

Trigger Identification and Avoidance

• Identification and avoidance of triggers is the first step in prevention 1
• Temperature control is essential, as mast cells can be activated by hot temperatures and, to a lesser extent, cold temperatures 3
• Rational use of baths, showers, swimming pools, and air conditioning can decrease symptoms and reduce the need for antihistamines 3
• Avoid anxiety and stress, as they can trigger mast cell activation 3

Pain Management Considerations

• Opioids should be used with caution as they can trigger mast cell activation, though should not be withheld since pain itself triggers degranulation 1, 6
• Fentanyl and remifentanil are safer opioid alternatives compared to morphine or codeine 1, 6
• IV administration of opioids is generally preferred over oral administration to ensure reliable drug delivery and minimize gastrointestinal exposure 6
• Consider pre-treatment with antihistamines (H1 and H2 blockers) and mast cell stabilizers before administering opioids 6

Perioperative Management

• Benzodiazepines, H1 and H2 antihistamines, and corticosteroids are recommended perioperatively to reduce frequency and severity of mast cell activation symptoms 1
• Have emergency medications (epinephrine, corticosteroids, additional antihistamines) readily available 6

Common Pitfalls to Avoid

• Do not withhold opioids for pain control in MCAS patients, as pain itself triggers mast cell degranulation; instead, use safer alternatives like fentanyl 1, 6
• Do not introduce aspirin outside a controlled clinical setting due to risk of triggering mast cell degranulation 4, 1
• Do not discontinue cromolyn prematurely; allow at least 1 month to assess efficacy 4
• Do not overlook the need for dose escalation of H1 antihistamines to 2-4 times standard doses, but monitor for cardiotoxicity 3, 1