Remibrutinib inhibits hives effector cells stimulated by serum from chronic urticaria patients independently of FcεR1 expression level and omalizumab clinical response.

BACKGROUND: Despite advances in the treatment of chronic urticaria, in a significant percentage of the patients symptoms are not fully controlled with conventional approaches. New strategies under development include blocking intracellular mediators of mast cell and basophil activation. OBJECTIVE: We aim to investigate the effects of the Bruton's tyrosine kinase (BTK) inhibitor remibrutinib on human blood basophils and CD34+ -derived mast cells activation induced by serum obtained from chronic urticaria patients. METHODS: Twenty-two patients with chronic spontaneous urticaria (mean age 52 years, 27% women) and 22 patients with chronic inducible urticaria (46 years, 27% women) were included in the study together with a sex-matched control group. Patients were classified as responders or non-responders to anti-IgE therapy on the basis of their clinical data, FcεR1a expression on blood basophils and total IgE levels. Changes on CD63 expression-as an activation marker-, were used to evaluate in vitro the response of basophils and mast cells to serum exposure and the inhibitory effects of remibrutinib. RESULTS: Remibrutinib inhibits degranulation induced by IgE cross-linking in mast cells and basophils and also the activation triggered by factors present in the sera of spontaneous and inducible chronic urticaria patients. Patient's serum induces a greater degranulation of effector cells than controls. Activation of mast cells and basophils by patient sera and remibrutinib effects were not related to omalizumab responsiveness. CONCLUSION: Remibrutinib inhibits activation of human basophils and mast cells induced in vitro by exposure to the serum of chronic urticaria patients independently of their response to omalizumab.

IgE and high-affinity IgE receptor in chronic inducible urticaria, pathogenic, and management relevance.

BACKGROUND: IgE and high-affinity IgE receptor (FcεRI) expression on basophils have been scarcely explored in patients with chronic inducible urticaria (CIndU). OBJECTIVES: To investigate baseline serum IgE and FcεRI expression on blood basophils in a large cohort of CIndU patients and its relationship to treatment response. METHODS: Baseline total serum IgE and basophil FcεRI expression measured by flow cytometry in 165 patients with CIndU was studied. The relationship of both parameters with the response to antihistamine and anti-IgE (omalizumab) treatment was considered in a subsample of CIndU patients. FcεRI expression in basophils was assessed by mean fluorescence intensity (MFI) and basophil FcεRI standardized density (receptors/cell). RESULTS: The median FcεRI expression standardized per density in blood basophils was found significantly higher in patients with CIndU compared to HCs. A positive correlation was found between IgE serum levels and basophil FcεRI expression. Basal FcεRI expression was not related to antihistamine treatment response. However, it was related to omalizumab, and patients responding to omalizumab showed higher basal basophil expression of FcεRI levels. Non-responders to the antihistamine showed significantly higher IgE serum levels. CONCLUSIONS: FcεRI receptor overexpression in patients with CIndU shows almost the same pattern than chronic spontaneous urticaria. It seems to be independent of CIndU subtypes. Although additional studies would be welcome, our work highlights the relevance of FcεRI receptor regulation in CIndU supporting autoimmune basophil and mast cell activation and may be a biomarker for response to anti-IgE therapy.

The mRNA-1273 Vaccine Induces Cross-Variant Antibody Responses to SARS-CoV-2 With Distinct Profiles in Individuals With or Without Pre-Existing Immunity.

mRNA-based vaccines effectively induce protective neutralizing antibodies against SARS-CoV-2, the etiological agent of COVID-19. Yet, the kinetics and compositional patterns of vaccine-induced antibody responses to the original strain and emerging variants of concern remain largely unknown. Here we characterized serum antibody classes and subclasses targeting the spike receptor-binding domain of SARS-CoV-2 wild type and α, ß, γ and δ variants in a longitudinal cohort of SARS-CoV-2 naïve and COVID-19 recovered individuals receiving the mRNA-1273 vaccine. We found that mRNA-1273 vaccine recipients developed a SARS-CoV-2-specific antibody response with a subclass profile comparable to that induced by natural infection. Importantly, these antibody responses targeted both wild type SARS-CoV-2 as well as its α, ß, γ and δ variants. Following primary vaccination, individuals with pre-existing immunity showed higher induction of all antibodies but IgG3 compared to SARS-CoV-2-naïve subjects. Unlike naïve individuals, COVID-19 recovered subjects did not mount a recall antibody response upon the second vaccine dose. In these individuals, secondary immunization resulted in a slight reduction of IgG1 against the receptor-binding domain of ß and γ variants. Despite the lack of recall humoral response, vaccinees with pre-existing immunity still showed higher titers of IgG1 and IgA to all variants analyzed compared to fully vaccinated naïve individuals. Our findings indicate that mRNA-1273 vaccine triggered cross-variant antibody responses with distinct profiles in vaccinees with or without pre-existing immunity and suggest that individuals with prior history of SARS-CoV-2 infection may not benefit from the second mRNA vaccine dose with the current standard regimen.

Relevance of the Basophil High-Affinity IgE Receptor in Chronic Urticaria: Clinical Experience from a Tertiary Care Institution.

BACKGROUND: The high-affinity IgE receptor (FcεRI) expression on effector cells has been poorly characterized in patients with chronic urticaria (CU) to date. OBJECTIVES: To investigate the FcεRI expression on blood basophils in a large cohort of patients with CU and its potential relationship with relevant features of the disease. METHODS: Basophil FcεRI expression was measured by flow cytometry in 287 patients with CU (192 with chronic spontaneous urticaria and 95 with chronic inducible urticaria) at their initial evaluation in our department. A control group of healthy nonatopic individuals was included to provide reference data, and the effect of antihistamine and anti-IgE therapy on the basophil FcεRI expression was also evaluated in a cohort of patients with CU. RESULTS: The median FcεRI expression was found significantly higher in patients with CU compared with healthy controls (P < .0001). A positive correlation was found between serum IgE levels and basophil FcεRI expression (R = 0.422; P < .001). Significantly higher FcεRI levels on basophils were detected in patients with CU who presented with concomitant atopic features (P = .003), negative autologous serum skin test (P = .002), negative autologous plasma skin test (P = .009), or undetected levels of antithyroid antibodies (P = 0.01). Baseline FcεRI expression was not related to the activity and duration of the disease, and was not significantly modified during antihistamine therapy; however, it correlated with the clinical response to omalizumab (P = .003). CONCLUSIONS: Although further multicenter studies are needed to corroborate these findings, the assessment of basophil FcεRI levels might be relevant in daily clinical practice supporting an autoimmune pathogenesis and predicting response to anti-IgE treatment.