What is the appropriate treatment regimen for mast cell activation syndrome?

Treatment of Mast Cell Activation Syndrome

Begin with high-dose non-sedating H1 antihistamines at 2–4 times the standard FDA-approved dose combined with an H2 antihistamine, and prescribe two epinephrine auto-injectors immediately for all patients. 1

Foundational First-Line Therapy

Start every patient on dual antihistamine blockade:

• Non-sedating H1 antihistamines (cetirizine, fexofenadine, or loratadine) at 2–4 times standard dosing to control flushing, pruritus, urticaria, tachycardia, and abdominal symptoms 1, 2
• H2 antihistamines (famotidine) added simultaneously for enhanced gastrointestinal symptom control and overall mediator blockade 1, 2
• Avoid chronic first-generation sedating antihistamines (diphenhydramine, hydroxyzine) in elderly patients due to anticholinergic-related cognitive decline 1

Mast Cell Stabilizer for Persistent GI Symptoms

Add oral cromolyn sodium 200 mg four times daily when gastrointestinal manifestations (diarrhea, abdominal pain, cramping, bloating) persist despite antihistamines 1:

• Titrate using divided doses with weekly upward adjustments to improve tolerance 1
• Reassess symptom control at 4–6 weeks 1
• Particularly effective for reducing bloating, diarrhea, cramps, and may improve neuropsychiatric symptoms 1

Second-Line Leukotriene-Targeted Therapy

Add montelukast 10 mg daily when antihistamine response is suboptimal or urinary leukotriene E₄ is elevated 1, 2:

• Reduces bronchospasm, gastrointestinal symptoms, and synergizes with H1 antihistamines for skin manifestations 1
• Alternative leukotriene antagonists include zafirlukast or zileuton 1

Aspirin Therapy for Specific Mediator Profiles

Consider aspirin 325–650 mg twice daily for patients with flushing and hypotension when urinary 11β-prostaglandin F₂α is elevated 1, 2:

• Contraindicated in individuals with NSAID hypersensitivity 1, 2
• Use cautiously as aspirin can paradoxically trigger mast cell activation in some patients 1

Additional Pharmacologic Options

For specific symptom patterns:

• Cyproheptadine (sedating H1 antihistamine with antiserotonergic activity) may alleviate gastrointestinal and musculoskeletal symptoms 1
• Doxepin (potent H1/H2 antihistamine with tricyclic properties) can lessen central nervous system manifestations but causes drowsiness, cognitive decline in older adults, and increased suicidal risk in younger patients 1, 2
• Omalizumab (anti-IgE monoclonal antibody) has prevented anaphylactic episodes in reported cases, though evidence is limited 1

Corticosteroid Strategy for Refractory Disease

Reserve systemic corticosteroids for refractory MCAS only 1, 2:

• Start prednisone ≈0.5 mg/kg/day (≈50 mg) and taper slowly over 1–3 months 1
• For procedures with prior mast-cell activation, give 50 mg prednisone at 13 h, 7 h, and 1 h before the intervention 1
• Long-term use is discouraged due to significant adverse effects 1

Critical Emergency Preparedness

Prescribe two epinephrine auto-injectors (0.3 mg for adults) for every MCAS patient to carry at all times 1, 2:

• 20–50% of patients with systemic mastocytosis experience systemic anaphylaxis 1
• Instruct patients to assume supine position promptly during hypotensive episodes 1, 2
• Administer intramuscular epinephrine immediately for hypotension, laryngeal angioedema, or severe bronchospasm 1, 2
• Transport to emergency department by ambulance while remaining supine 1, 2

Peri-operative and Procedural Management

Premedicate with H1 and H2 antihistamines plus corticosteroids before surgery, invasive procedures, or contrast imaging 1, 2:

• Ensure multidisciplinary coordination among surgical, anesthesia, and allergy teams 1
• Maintain normothermia and minimize unnecessary trauma 1
• Preferred agents: propofol (induction), sevoflurane/isoflurane (inhalation), fentanyl or remifentanil (analgesia), lidocaine or bupivacaine (local), rocuronium or vecuronium (muscle relaxation) 1, 2
• Avoid: atracurium, mivacurium, succinylcholine, morphine, codeine 1, 2

Pain Management Principles

Do not withhold analgesics despite concerns about triggering 1, 2:

• Untreated pain itself is a potent trigger for mast cell degranulation 1, 2
• Use fentanyl or remifentanil as safer opioid alternatives when opioid analgesia is required 1, 2
• Avoid morphine and codeine 1, 2

Acute Episode Management

During acute episodes:

• Obtain serum tryptase within 30–120 minutes of symptom onset and compare with baseline 1
• Immediately discontinue any suspected triggering medication or exposure 1
• Provide fluid resuscitation for hypotension and intravenous epinephrine for severe reactions 1
• Give adjunctive corticosteroids and H1/H2 antihistamines 1
• Conduct comprehensive allergic work-up (specific IgE testing, skin prick/intradermal testing) to identify IgE-mediated hypersensitivities 1

Trigger Identification and Avoidance

Identify and avoid common triggers 1, 2:

• Insect venoms, extreme temperatures, mechanical irritation, alcohol, aspirin, radiocontrast agents, certain anesthetic agents 1
• For patients with systemic mastocytosis and history of systemic anaphylaxis to insect stings, provide lifelong venom immunotherapy 1
• Using omalizumab during immunotherapy may lower anaphylaxis risk 1

Tailoring Therapy to Mediator Profiles

Adjust treatment based on urinary mediator levels:

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

Critical Pitfalls to Avoid

Do not:

• Eliminate additives in drugs used for anaphylaxis by compounding them—this practice is unsupported by controlled challenge data 1
• Rely on plasma or urine histamine levels as biomarkers; instead, use histamine metabolites for monitoring 1
• Use heparin or chromogranin A as markers of mast-cell activation, as they have not been validated 1

Advanced Cytoreductive Therapies

For aggressive systemic mastocytosis, smoldering systemic mastocytosis with severe refractory symptoms, or mast cell leukemia 2:

• Consider midostaurin, cladribine, imatinib, or interferon-alpha preparations 2

Special Population Considerations

Pregnancy:

• Manage with 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 1

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 is a second-line option for bisphosphonate-non-responders or those with renal insufficiency 1