CIndU Pathophysiology: Mast Cells, BTK Signaling, and Targeted Inhibition

"CIndU Pathophysiology: Mast Cells, BTK Signaling, and Targeted Inhibition" features Dr. Finklea breaking down the immunology that connects CIndU to a new therapeutic target.

Dr. Finklea explains that the pathophysiology of CIndU is not fully elucidated, but it appears to be primarily mast cell driven. Basophils, eosinophils, TH2 cells, B cells, and even peripheral nerves may also play a role. Mast cells are activated through two immune pathways. Type 1 is autoallergic, in which IgE cross-links with autoallergens such as IL-24, thyroid peroxidase, or double-stranded DNA and engages the high-affinity Fc epsilon receptor. That triggers signal transduction through Bruton tyrosine kinase and causes degranulation of histamine and pro-inflammatory cytokines, producing wheals, itch, and angioedema. Type 2B is autoimmune and IgG mediated, attacking the receptor or receptor-bound IgE without needing an autoallergen. Both pathways converge on BTK. She believes CIndU leans toward the type 1, IgE-mediated route. Her evidence includes responses to anti-IgE therapy, higher IgE levels, normal basophils, less CRP elevation, and fewer comorbid autoimmune conditions such as thyroid disease.

Subtypes add nuance. Cholinergic urticaria may involve adrenergic and cholinergic pathways, delayed pressure urticaria shows neutrophils in tissue, and symptomatic dermatographism involves the MRGPRX2 receptor and possibly the gut microbiome. Dr. Dasilva notes that varied pathways, cytokine profiles, and involved cells within each subtype explain why dermatologists rely on so much trial and error. He adds that no single therapy will work for everything, which makes convergence on BTK mechanistically interesting and explains the interest in studying remibrutinib in CIndU. Dr. Finklea describes remibrutinib as a highly selective BTK inhibitor acting downstream of the Fc epsilon receptor, so blocking this signal should prevent degranulation regardless of pathway. She finds it compelling that the REMIND study tested three clinically distinct forms: symptomatic dermatographism, cold urticaria, and cholinergic urticaria.

The next episode in this series, "CIndU Phase 3 REMIND Study Design and Provocation Testing Endpoints," features Dr. Dasilva and Dr. Finklea reviewing the REMIND trial design and how its provocation tests work.