What is the treatment for Mast Cell Activation Syndrome (MCAS) associated hives in patients with a Mas-related G-protein coupled receptor X2 (MRGPRX2) variant?

From the Guidelines

Treatment for MRGPRX2 variant-associated MCAS (Mast Cell Activation Syndrome) hives should start with H1 antihistamines like cetirizine (10mg daily) or fexofenadine (180mg daily), which can be increased up to four times the standard dose if needed, as recommended by the AAAAI Mast Cell Disorders Committee Work Group report 1.

Key Treatment Components

• Add H2 blockers such as famotidine (20mg twice daily) to enhance effectiveness, as suggested by the AAAAI Mast Cell Disorders Committee Work Group report 1.
• Mast cell stabilizers like ketotifen (1-2mg twice daily) or cromolyn sodium (200mg four times daily) help prevent mast cell degranulation, as noted in the NCCN Clinical Practice Guidelines in Oncology 1.
• For severe flares, short courses of oral corticosteroids like prednisone (20-40mg daily for 3-7 days) may be necessary, as indicated by the AAAAI Mast Cell Disorders Committee Work Group report 1.
• Leukotriene inhibitors such as montelukast (10mg daily) can provide additional relief, as suggested by the NCCN Clinical Practice Guidelines in Oncology 1.

Additional Considerations

• Identify and avoid triggers specific to MRGPRX2 variant MCAS, which often include certain medications, preservatives, and dyes rather than typical IgE allergens, as explained by the AAAAI Mast Cell Disorders Committee Work Group report 1.
• The MRGPRX2 receptor variant makes mast cells more reactive to non-allergic stimuli through a direct activation pathway rather than the traditional IgE-mediated pathway, explaining why conventional allergy testing may be negative, as noted in the AAAAI Mast Cell Disorders Committee Work Group report 1.
• Regular skin care with fragrance-free products and cool compresses during flares can provide symptomatic relief, as suggested by general dermatological principles.
• For persistent cases, consider consulting with specialists in mast cell disorders for advanced therapies like omalizumab or other biologics, as recommended by the NCCN Clinical Practice Guidelines in Oncology 1.

From the FDA Drug Label

Clinical Pharmacology In vitro and in vivo animal studies have shown that cromolyn sodium inhibits sensitized mast cell degranulation which occurs after exposure to specific antigens. Cromolyn sodium acts by inhibiting the release of mediators from mast cells. The FDA drug label does not answer the question.

From the Research

MRGPRX2 Variant and MCAS Hives Treatment

• The MRGPRX2 receptor has been identified as a key mediator of itch and mast cell-mediated hypersensitivity reactions, including pseudoallergies and inflammatory diseases 2, 3.
• Studies have shown that MRGPRX2 is constitutively expressed by human skin mast cells and modulates cell degranulation, producing pseudoallergies manifesting as itch, inflammation, and pain 3.
• In the context of Mast Cell Activation Syndrome (MCAS), MRGPRX2 has been implicated in the pathogenesis of various skin disorders, including chronic spontaneous urticaria, rosacea, atopic dermatitis, and mastocytosis 4, 5.
• Research has focused on developing potent and selective antagonists to pharmacologically characterize the biological role of MRGPRX2, with the goal of investigating its relevance in skin disorders 5.
• Elevated MRGPRX2 levels have been related to disease severity in patients with chronic spontaneous urticaria, suggesting that serum MRGPRX2 could be a useful biomarker for indicating severe CSU 6.

Potential Treatment Options

• The development of MRGPRX2-specific antibodies and inhibitors could be used for the modulation of allergic and inflammatory diseases mediated via this receptor 4.
• Small-molecule HDP mimetics that display both direct antimicrobial activity and activate MCs via MRGPRX2 have been developed, which may provide a novel approach for the treatment of antibiotic-resistant cutaneous infections 4.
• Pharmacological blockade of the mast cell MRGPRX2 receptor using potent and selective antagonists, such as Compound B, has shown promise in blocking Substance P-mediated degranulation and itch in established behavioral scratching models 5.

Diagnostic Considerations

• The diagnosis of pseudoallergic reactions mediated by MRGPRX2 is generally viewed as a process of exclusion, once other non-immune and immune processes are ruled out 3.
• The use of MRGPRX2 transfected cells to assess MRGPRX2 activation via two pathways, the G-protein-independent β-arrestin pathway and the G-protein-dependent Ca2+ pathway, may aid in distinguishing MRGPRX2-mediated reactions from other mechanisms 3.