Endotypes in chronic spontaneous urticaria

The current paradigm regarding the pathogenesis of chronic spontaneous urticaria (CSU) involves two separate mechanisms by which cutaneous mast cells and basophils are activated. Type Ia has higher IgE levels, rapidly responds to omalizumab, and possesses IgE antibody to either thyroperoxidase, IL-24, or both. Type IIb has IgG antibody to IgE receptor, activates complement, has augmented mast cell secretion via C5a, and takes longer to respond to omalizumab. Reports are mixed regarding the incidence of IgE autoantibodies in controls versus patients with CSU. Because 25% of the total population have allergic disorders associated with elevated IgE (allergic rhinitis, extrinsic asthma, atopic dermatitis), as well as a personal and often family history of atopy, any type Ia mechanism for production of urticaria has to separate out those with CSU who have atopic disease and not assume that these parameters or their IgE levels have anything to do with hive formation. The type IIb mechanism depends not only on a stimulus through an IgE receptor but also on C5a acting through the C5a receptor, together accounting for close to 40% of patients. It has been reproduced by multiple laboratories world-wide with an incidence of 25-45%. In fact, our proof-of-concept study regarding the efficacy of omalizumab to treat CSU were all based on type IIb disease with the presence of IgG antibody to the IgE receptor. We conclude that the evidence for type Ia allergy being an endotype of CSU is sparse; data are conflicting, and it's a large jump to infer a molecular mechanism or endotype. The data for a type IIb mechanism are substantial but are demonstrable in less than half the patients.