What is the recommended treatment approach for mast cell activation syndrome?

Treatment of Mast Cell Activation Syndrome

First-Line Pharmacologic Therapy

Initiate non-sedating H1 antihistamines (cetirizine, fexofenadine, or loratadine) at 2–4 times the standard FDA-approved dose as the cornerstone of MCAS treatment. 1 This higher dosing is essential to adequately control histamine-mediated symptoms including flushing, pruritus, urticaria, tachycardia, and abdominal discomfort. 1

• Add an H2 antihistamine (famotidine or ranitidine) to the H1 blocker for enhanced control of gastrointestinal symptoms and overall mediator blockade. 1
• Avoid chronic use of first-generation sedating H1 antihistamines (diphenhydramine, hydroxyzine) in elderly patients due to anticholinergic-related cognitive decline. 1
• Evaluate therapeutic response over a 2–6 week period before escalating therapy; lack of improvement indicates the need for additional interventions. 2

Second-Line: Mast Cell Stabilizer

Prescribe oral cromolyn sodium 200 mg four times daily for patients with persistent gastrointestinal manifestations or inadequate response to antihistamines. 1 The FDA label confirms that cromolyn improves diarrhea, flushing, headaches, vomiting, urticaria, abdominal pain, nausea, and itching in mastocytosis patients. 3

• Clinical improvement occurs within 2–6 weeks of treatment initiation and persists for 2–3 weeks after withdrawal. 3
• Titrate using divided doses with weekly upward adjustments to the target dose to improve tolerance and adherence. 1
• Cromolyn reduces bloating, diarrhea, cramps, and may improve neuropsychiatric symptoms. 1

Leukotriene-Targeted Therapy

Add montelukast 10 mg daily when urinary leukotriene E₄ is elevated or antihistamine response is suboptimal. 1 This reduces bronchospasm, gastrointestinal symptoms, and synergizes with H1 antihistamines for skin manifestations. 1

• Zafirlukast serves as an alternative leukotriene receptor antagonist. 1
• Consider zileuton as an alternative 5-lipoxygenase inhibitor in similar contexts. 1
• Leukotriene antagonists work synergistically with H1 antihistamines and are particularly efficacious for dermatologic symptoms. 2

Aspirin Therapy (When Indicated)

Use aspirin 325–650 mg twice daily for patients with flushing and hypotension when urinary 11β-prostaglandin F₂α is elevated. 1 Introduction must occur in a controlled clinical setting because aspirin can provoke mast cell degranulation. 2

• This therapy is contraindicated in individuals with NSAID hypersensitivity. 1

Additional Pharmacologic Options

• Cyproheptadine (sedating H1 antihistamine with antiserotonergic activity) may alleviate gastrointestinal and musculoskeletal symptoms. 1
• Doxepin (potent H1/H2 antihistamine with tricyclic antidepressant properties) can lessen central nervous system manifestations but may cause drowsiness and cognitive decline, especially in older adults. 1
• Omalizumab (anti-IgE monoclonal antibody) has prevented anaphylactic episodes in reported MCAS cases, though evidence is limited to case reports. 1

Corticosteroid Strategy

Reserve systemic corticosteroids for refractory disease: start approximately 0.5 mg/kg/day prednisone (approximately 50 mg) and taper slowly over 1–3 months. 1

• For procedures with prior mast cell activation, give 50 mg prednisone at 13 hours, 7 hours, and 1 hour before the intervention to blunt peri-procedural activation. 1
• Long-term corticosteroid use is discouraged due to significant adverse-effect profile. 1
• Use corticosteroids for prolonged episodes after initial stabilization with epinephrine. 1

Emergency Preparedness (Critical Safety Measures)

Prescribe two epinephrine auto-injectors for every MCAS patient to be carried at all times due to heightened anaphylaxis risk. 1

• Instruct patients to assume a supine position promptly during hypotensive episodes. 1
• Administer intramuscular epinephrine immediately for severe reactions with hypotension or laryngeal angioedema. 1

Acute Episode Management

Obtain serum tryptase within 30–120 minutes of symptom onset and compare with the patient's baseline level. 1

• Immediately discontinue any suspected triggering medication or exposure. 1
• Provide fluid resuscitation for hypotension and administer intravenous epinephrine for severe reactions. 1
• Give adjunctive corticosteroids and H1/H2 antihistamines. 1
• Conduct a comprehensive allergic work-up (specific IgE testing, skin prick/intradermal testing) to identify IgE-mediated hypersensitivities. 1

Peri-operative Management

Premedicate with H1 and H2 antihistamines plus corticosteroids before surgery, invasive procedures, or contrast imaging to prevent anaphylaxis. 1

• Ensure multidisciplinary coordination among surgical, anesthesia, and allergy teams; review prior anesthetic records and avoid known triggers. 1
• Maintain normothermia and minimize unnecessary trauma in the operating room. 1
• Preferred agents: propofol (induction), sevoflurane/isoflurane (inhalation), fentanyl or remifentanil (analgesia), lidocaine or bupivacaine (local), rocuronium or vecuronium (muscle relaxation). 1
• Agents to avoid: atracurium, mivacurium, succinylcholine, morphine, codeine. 1

Pain Management (Critical Caveat)

Do not withhold analgesics; untreated pain itself can trigger mast cell degranulation. 1

• Use fentanyl or remifentanil as safer opioid alternatives to morphine or codeine when opioid analgesia is required. 1

Tailoring Therapy to Mediator Profiles

• If urinary LTE₄ is elevated, prioritize leukotriene antagonists (montelukast, zafirlukast, zileuton). 1
• If urinary prostaglandin metabolites are elevated, consider low-dose aspirin as an adjunct. 1

Special Populations: Pregnancy

• Manage MCAS in pregnancy with a multidisciplinary team (high-risk obstetrics, anesthesia, allergy). 1
• Current data indicate no impact on fertility and insufficient evidence of increased maternal or fetal adverse outcomes compared with the general population. 1

Special Populations: Bone Health

• Provide calcium and vitamin D supplementation for patients with osteopenia/osteoporosis. 1
• Use bisphosphonates (alongside antihistamines) to alleviate bone pain and improve vertebral bone mineral density. 1
• For refractory bone pain or worsening BMD on bisphosphonates, consider PEG-interferon-α. 1
• Denosumab (anti-RANKL antibody) is a second-line option for bisphosphonate non-responders or those with renal insufficiency. 1

Treatment Algorithm Summary

1. Start: H1 antihistamine at 2–4× standard dose + H2 antihistamine 1
2. If inadequate response at 2–6 weeks: Add cromolyn sodium 200 mg QID 1, 2
3. If elevated urinary LTE₄ or persistent symptoms: Add montelukast 10 mg daily 1
4. If elevated urinary prostaglandin metabolites: Consider aspirin (in controlled setting) 1, 2
5. If refractory: Systemic corticosteroids (0.5 mg/kg/day prednisone, taper over 1–3 months) 1
6. Always: Prescribe two epinephrine auto-injectors 1