What is the best approach to manage a patient with Mast Cell Activation Syndrome (MCAS) and proctocolitis?

Management of MCAS with Proctocolitis

Begin with H1 and H2 antihistamines as first-line therapy, add oral cromolyn sodium for gastrointestinal symptoms including proctocolitis, and follow standard DGBI management principles for any remaining lower GI symptoms. 1, 2

Initial Pharmacologic Approach for MCAS

The foundation of MCAS management targets mast cell mediators through a stepwise approach:

First-Line Therapy

• Start with non-sedating H1 antihistamines (fexofenadine or cetirizine) at 2-4 times FDA-approved doses to control systemic symptoms including tachycardia, flushing, and abdominal discomfort 1, 2, 3
• Add H2 receptor antihistamines immediately for gastrointestinal symptoms, as they work synergistically with H1 blockers and specifically target gastric hypersecretion 1, 2, 3
• These medications work prophylactically rather than acutely, so consistent daily dosing is essential 1

Second-Line: Mast Cell Stabilization

• Add oral cromolyn sodium 200 mg four times daily for persistent gastrointestinal symptoms including diarrhea, abdominal pain, nausea, and cramping 4
• Cromolyn is FDA-approved specifically for mastocytosis and has demonstrated clinical improvement in 2-6 weeks in controlled trials 4
• Progressive introduction reduces side effects such as headache and abdominal pain 2
• Benefits persist for 2-3 weeks after withdrawal, confirming therapeutic effect 4

Managing the Proctocolitis Component

The 2025 AGA guidelines provide specific direction for lower GI symptoms in patients with MCAS:

Diagnostic Evaluation

• Follow standard DGBI diagnostic strategies using positive symptom-based diagnosis with limited noninvasive testing 1
• Perform anorectal manometry, balloon expulsion test, or defecography if symptoms include incomplete evacuation, as pelvic floor dysfunction (particularly rectal hyposensitivity) is highly prevalent in this population 1
• Consider celiac disease testing earlier in the evaluation given the variety of GI symptoms 1

Symptom-Targeted Treatment

For proctocolitis-specific symptoms after mast cell stabilization:

• For diarrhea: Use loperamide, bile acid sequestrants (cholestyramine, colestipol, colesevelam), eluxadoline, or 5-HT3 antagonists (alosetron) 1
• For constipation: Trial osmotic/stimulant laxatives, lubiprostone, guanylate cyclase-C agonists (linaclotide, plecanatide), prucalopride, or tenapanor 1
• For abdominal pain: Consider antispasmodics (hyoscyamine, dicyclomine, peppermint oil) or neuromodulators (tricyclic antidepressants, SSRIs, SNRIs, pregabalin, gabapentin) depending on pain characteristics 1

Critical Caveat

Avoid opiates entirely for abdominal pain management in this population 1

Additional Mediator-Blocking Agents

If symptoms persist despite H1/H2 blockade and cromolyn:

• Cyproheptadine (sedating H1 blocker with antiserotonergic properties) specifically helps diarrhea and nausea 1, 2
• Leukotriene inhibitors (montelukast or zileuton) may reduce GI symptoms, particularly if urinary LTE4 levels are elevated 1, 3
• Proton pump inhibitors when H2 antihistamines fail to control upper GI symptoms 2

Refractory Cases

For MCAS resistant to standard mediator-targeted therapies:

• Consider omalizumab for prevention of anaphylactic episodes 1, 2
• Short-term corticosteroid burst (0.5 mg/kg/day prednisone with slow taper over 1-3 months) for refractory symptoms, but avoid long-term use due to side effects 1, 3

Emergency Preparedness

All patients with MCAS and proctocolitis require:

• Epinephrine autoinjector prescription with training on use for any history of systemic anaphylaxis or airway angioedema 1, 3
• Supine positioning training for hypotensive episodes 1, 3
• Albuterol inhaler for bronchospasm 1, 3

Common Pitfalls to Avoid

• Do not use first-generation H1 antihistamines (diphenhydramine, hydroxyzine) long-term in elderly patients due to cognitive decline risk and cardiovascular concerns 1, 3
• Introduce all medications cautiously in controlled settings, as paradoxical mast cell activation can occur 2, 3
• Do not rely on dietary restriction alone without pharmacologic management—this is insufficient and not guideline-recommended 5, 3
• Avoid eliminating drug additives through compounding, as evidence from chronic urticaria studies shows no benefit 3

Treatment Monitoring

• Assess clinical response within 2-6 weeks of initiating cromolyn sodium 4
• Guide therapy by symptoms and elevated mast cell mediator levels rather than arbitrary timelines 3
• Consider multidisciplinary care given the multisystemic nature of MCAS and overlapping conditions 1, 6, 7