Beyond Antihistamines: Mapping CIndU Therapies to the Mast Cell

In "Beyond Antihistamines: Mapping CIndU Therapies to the Mast Cell," our experts turn to what comes after antihistamines fail.

Dr. Cotter asks Dr. Trotter what options exist for patients who are not controlled on up-dosed antihistamines. She shares breaking news that remibrutinib had been approved for symptomatic dermographism. Before that approval, clinicians turned to agents approved for CSU, namely omalizumab, dupilumab, and remibrutinib, using them off label. Mechanistically, these agents target pathways relevant to CIndU. Anecdotally, patients treated for CSU who also have CIndU often improve in both conditions.

Historically, Dr. Trotter used immunomodulators with limited success. Guidelines mention cyclosporine. Clinicians have also tried methotrexate, H2 blockers, leukotriene inhibitors, and tricyclic agents such as doxepin. Options were limited, but she sees an approved therapy and an active pipeline as reasons for optimism.

Dr. Finklea then maps therapies to the mast cell, from extracellular to intracellular. Dupilumab blocks the IL-4 receptor alpha, dampening type 2 inflammation that primes mast cells. It also reduces B-cell class isotype switching to IgE and may quiet sensory nerves. Omalizumab binds IgE directly, preventing it from engaging its receptor on the mast cell and blocking downstream degranulation.

Among investigational agents, barzolvolimab is a monoclonal antibody that blocks stem cell factor binding to the KIT receptor. Because that interaction keeps mast cells alive, blocking it induces apoptosis and depletes mast cells. Moving intracellularly, remibrutinib inhibits Bruton tyrosine kinase, a key step in signal transduction that drives histamine and cytokine release.

Two further oral agents are under investigation. Ritlecitinib, already approved for alopecia areata, inhibits JAK3 and the TEC kinase family and modulates cytokine release. Povorcitinib, a JAK1 inhibitor, acts furthest downstream and also modulates a broad range of cytokines.

Our next episode, "Off-Label Biologics in CIndU: Real-World Lessons and Mixed Evidence," turns to real-world experience with the biologics used off label for years.