How should mast cell activation syndrome be treated?

Treatment of Mast Cell Activation Syndrome

Start all patients with MCAS on high-dose non-sedating H1 antihistamines (cetirizine, fexofenadine, or loratadine) at 2–4 times the standard FDA-approved dose combined with an H2 antihistamine (famotidine or ranitidine), and prescribe two epinephrine auto-injectors to carry at all times. 1, 2

Foundational Pharmacologic Therapy

First-Line Antihistamine Regimen

• Initiate non-sedating H1 antihistamines at 2–4 times standard dosing to control histamine-mediated symptoms including flushing, pruritus, urticaria, tachycardia, and abdominal discomfort 1, 2

  • Cetirizine 20–40 mg daily, fexofenadine 360–720 mg daily, or loratadine at equivalent high doses 2, 3

• Add H2 antihistamines (famotidine 20–40 mg twice daily or ranitidine) for enhanced control of gastrointestinal symptoms and overall mediator blockade 1, 2, 3

• Avoid chronic use of first-generation sedating H1 antihistamines (diphenhydramine, hydroxyzine) in elderly patients due to anticholinergic-related cognitive decline 1, 2

Mast Cell Stabilizer Therapy

• Add oral cromolyn sodium 200 mg four times daily for patients with persistent gastrointestinal manifestations (diarrhea, abdominal pain, cramping, bloating) or inadequate response to antihistamines 1, 2, 4

  • FDA-approved for mastocytosis with documented improvement in diarrhea, flushing, headaches, vomiting, urticaria, abdominal pain, nausea, and itching 4

• Titrate cromolyn using divided doses with weekly upward adjustments to the target dose to improve tolerance and adherence 1, 2

  • Reassess symptom control at 4–6 weeks, as cromolyn requires this duration to demonstrate efficacy 3

Second-Line and Adjunctive Therapies

Leukotriene-Targeted Therapy

• Add montelukast 10 mg daily (or zafirlukast or zileuton 600 mg four times daily) when urinary leukotriene E₄ is elevated or antihistamine response is suboptimal 1, 2, 3
  • Reduces bronchospasm, gastrointestinal symptoms, and synergizes with H1 antihistamines for skin manifestations 2

Aspirin Therapy

• 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 as aspirin can paradoxically trigger mast cell activation in some patients 2

Additional Pharmacologic Options

• Cyproheptadine 4 mg three times daily (sedating H1 antihistamine with antiserotonergic activity) may alleviate gastrointestinal, musculoskeletal symptoms, and provide migraine prevention 1, 2, 3

• 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, and may increase suicidal tendencies in children and young adults with depression 1, 2

Biologic Therapy

• Consider omalizumab 150–300 mg subcutaneously every 2–4 weeks for refractory cases despite maximal antimediator therapy 2, 3
  • Has prevented anaphylactic episodes in reported MCAS cases, though evidence is limited to case reports 2
  • FDA-approved for IgE-mediated food allergy with demonstrated efficacy in reducing allergic reactions 5

Corticosteroid Strategy

• Reserve systemic corticosteroids for refractory disease: start approximately 0.5 mg/kg/day prednisone (≈50 mg) and taper slowly over 1–3 months 1, 2

• 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 2

• Long-term corticosteroid use is discouraged due to significant adverse-effect profile 2

Emergency Preparedness and Acute Management

Anaphylaxis Preparedness

• Prescribe two epinephrine auto-injectors (0.3 mg for adults) for every MCAS patient to carry at all times due to heightened anaphylaxis risk 1, 2, 3

  • Among patients with systemic mastocytosis, 20–50% experience systemic anaphylaxis 1

• Instruct patients to assume a supine position promptly during hypotensive episodes 1, 2, 3

Acute Episode Management

• Administer intramuscular epinephrine immediately for hypotensive episodes, laryngeal angioedema, or severe bronchospasm 1, 2, 3

  • If epinephrine is used, the patient should be taken to the emergency department by ambulance while remaining supine 1

• Obtain serum tryptase within 30–120 minutes of symptom onset and compare with the patient's baseline level 2

• Discontinue any suspected triggering medication or exposure immediately 2

• Provide fluid resuscitation for hypotension and administer intravenous epinephrine for severe reactions 2

• Give adjunctive corticosteroids and H1/H2 antihistamines (diphenhydramine 50 mg and famotidine 20 mg) at symptom onset 2, 3

Peri-operative and Procedural Management

Premedication Protocol

• Premedicate with H1 and H2 antihistamines plus corticosteroids before surgery, invasive procedures, or contrast imaging to prevent anaphylaxis 2

• Ensure multidisciplinary coordination among surgical, anesthesia, and allergy teams; review prior anesthetic records and avoid known triggers 2

Preferred and Avoided Anesthetic Agents

• Preferred agents: propofol (induction), sevoflurane/isoflurane (inhalation), fentanyl or remifentanil (analgesia), lidocaine or bupivacaine (local), rocuronium or vecuronium (muscle relaxation) 2, 3

• Agents to avoid: atracurium, mivacurium, succinylcholine, morphine, codeine 2, 3

• Maintain normothermia and minimize unnecessary trauma in the operating room 2

Pain Management

• Never withhold analgesics despite concerns about triggering mast cell activation, as untreated pain itself is a potent trigger for mast cell degranulation 2, 3

• Use fentanyl or remifentanil as safer opioid alternatives to morphine or codeine when opioid analgesia is required 2, 3

Trigger Identification and Avoidance

• Identify and avoid triggers including insect venoms, temperature extremes, mechanical irritation, alcohol, aspirin, radiocontrast agents, and certain anesthetic agents 1

• For patients with systemic mastocytosis sensitive to insect venom, particularly with a history of systemic anaphylaxis to a prior insect sting, undergo lifelong venom immunotherapy 1

  • Using omalizumab during immunotherapy appears to reduce the risk of anaphylaxis to venom immunotherapy 1

Tailoring Therapy to Mediator Profiles

• If urinary LTE₄ is elevated, prioritize leukotriene antagonists (montelukast, zafirlukast, zileuton) 2

• If urinary prostaglandin metabolites are elevated, consider low-dose aspirin as an adjunct 2

• Conduct a comprehensive allergic work-up (specific IgE testing, skin prick/intradermal testing) to identify IgE-mediated hypersensitivities 2

Special Populations and Considerations

Pregnancy

• Manage MCAS in pregnancy with a multidisciplinary team (high-risk obstetrics, anesthesia, allergy) 2
  • Current data indicate no impact on fertility and insufficient evidence of increased maternal or fetal adverse outcomes compared with the general population 2

Bone Health

• Provide calcium and vitamin D supplementation for patients with osteopenia/osteoporosis 2

• Use bisphosphonates (alongside antihistamines) to alleviate bone pain and improve vertebral bone-mineral density 2

• For refractory bone pain or worsening BMD on bisphosphonates, consider PEG-interferon-α 2

• Denosumab (anti-RANKL antibody) is a second-line option for bisphosphonate-non-responders or those with renal insufficiency 2

Critical Pitfalls to Avoid

• Do not eliminate additives in drugs used to treat or prevent anaphylaxis by compounding them, as this is not recommended and has been disproven in controlled challenges 1

• Do not use plasma or urine histamine levels as biomarkers; histamine metabolites are recommended instead 1

• Do not use heparin or chromogranin A as markers of mast cell activation, as they have not been validated 1

• Refer to specialized centers with mastocytosis expertise for optimal management, particularly when dealing with complex or refractory presentations 2, 3