Severe chronic spontaneous urticaria responding and not responding to omalizumab: analysis of the prognostic value of known and novel in vitro variables

<b>Background.</b> Chronic spontaneous urticaria (CSU) response to anti-IgE treatment can be rapid, late or absent. Recently, potential mechanisms of activation of mast cells alternative to FceRI, including mas-related G protein-coupled receptor X2 (MRGPRX2), activation of coagulation cascade, and activation of eosinophils have been described. We measured several potential in-vitro markers, including well-known MRGPRX2 activators, in sera of patients CSU both responding and not responding to omalizumab. <b>Methods.</b> D-dimer, substance P (SP), eosinophil cationic protein (ECP), soluble MRGPRX2, IgE anti-FceRI, IgE anti-FceRII, IgG anti-FceRI and IgG anti-FceRII were measured in 32 patients with severe CSU at baseline and one week after the start of omalizumab therapy, and in 20 healthy controls. <b>Results.</b> At baseline CSU patients showed significantly higher levels of D-dimer, IgE anti-FceRI, IgG anti-FceRI, and ECP (p < 0.001 in all cases), and significantly lower levels of soluble MRGPRX2 (p = 0.009) than controls. The two groups showed similar levels of IgG and IgE to FceRII and SP. One week after the first omalizumab administration there was a significant drop of IgE anti-FceRI (p < 0.001) and D-dimer (p = 0.028), in early responders. SP increased in all CSU patients (p < 0.001) irrespective of the final response to omalizumab. IgE anti-FceRI response at one week was associated with the final response to omalizumab (OR:0.12 [95%CI 0.01-1.06]). <b>Conclusions.</b> Severe CSU is associated with high plasma levels of several biomarkers including D-dimer, IgE anti-FceRI, IgG anti-FceRI and ECP and low levels of soluble MRGPRX2. IgE anti-FceRI response at one week may predict the final response to omalizumab.