Background: Autoimmune chronic spontaneous urticaria (aiCSU) is an important subtype of chronic spontaneous urticaria (CSU) in which functional IgG autoantibodies to IgE or its high-affinity receptor (FcεRI) induces mast cell degranulation and subsequent symptom development. However, it has not been tightly characterized. This study aimed to better define the clinical and immunological features and to explore potential biomarkers of aiCSU.Methods: This was a multinational, multicenter study of 182 CSU patients. The clinical features studied included: urticaria activity and impact (UAS7 and quality of life); autologous serum skin test (ASST); IgG anti-FcεRI and IgG anti-IgE; IgG-anti-thyroperoxidase (IgG anti-TPO); total serum IgE; and basophil reactivity (BASO) using the basophil activation test (BAT) and basophil histamine release assay (BHRA). Results:Of the 182 patients, 107 (59%) were ASST+, 46 (25%) were BASO+, and 105 (58%) were IgG anti-FcεRI+/IgE+. Fifteen patients (8%) fulfilled all three criteria of aiCSU. aiCSU patients appeared more severe (UAS7 21 vs 9 P < 0.016) but showed no other clinical or demographic differences from non-aiCSU patients. aiCSU patients also had markedly lower total IgE levels (P < 0.0001) and higher IgG anti-TPO levels (P < 0.001). Of biomarkers, positive BAT and BHRA tests were 69% and 88% predictive of aiCSU, respectively.Conclusions: aiCSU is a relatively small but immunologically distinct subtype of CSU that cannot be identified by routine clinical parameters. Inclusion of BHRA or BAT in the diagnostic workup of CSU patients may aid identification of aiCSU patients, who may have a different prognosis and benefit from specific management. K E Y W O R D Sautoimmune CSU, autologous serum skin test, basophil activation assays, chronic spontaneous urticaria, IgG autoantibodies

IgE treatment with omalizumab was shown to be effective in chronic 7 spontaneous urticaria (CSU) in randomized controlled trials (1) and real life studies 8 (2) (3). Omalizumab, the first licensed therapy for H 1-antihistamine refractory CSU, 9 prevents IgE binding to its high-affinity receptor (FcεRI) (4). As a result, free serum 10 IgE levels decline and the expression of FcεRI receptors on basophils and mast cells 11 is down-regulated (4). Moreover, omalizumab appears to dissociate pre-bound IgE 12 from mast cells and basophils (4). 13 The exact mechanisms of action of omalizumab in CSU are not fully understood, and 14 the therapeutic response remains difficult to predict. The characterization of 15 responders vs. non-responders to omalizumab therapy could help to understand its 16 mode of action and to establish predictors of response in clinical practice. 17 Here, we compared complete responders (CR) to non-responders (NR) and partial 18 responders (PR) to identify predictors for response. In total, we analyzed 85 patients 19 from 4 GA²LEN urticaria centers of reference and excellence (UCAREs) (5), 43 CR, 20 23 PR, and 19 NR to omalizumab treatment (Table 1). Complete, partial and non-21 response was defined as the reduction of signs and symptoms by ≥90%, by ≥30% 22 but <90%, and by <30% (physicians global assessment), respectively, after 2 four-23 weekly injections of omalizumab 300 mg. All centers provided data on NRs 24 comparing patient characteristics, laboratory values, and treatment response. In 25 addition, all centers were asked to provide data on at least one PR and CR per 26 entered NR. Because different methods of total IgE assessment with different 27 reference values were used, the total IgE-values were transferred to percentage 28 scores of the respective upper reference value. Total IgE levels of 0%-10%, >10%-29 50%, and >50%-100% were regarded as low normal, mid normal, and high normal, 30 whereas total IgE levels of >100%-250%, >250%-1000%, and >1000% were 31 regarded as slightly elevated, moderately elevated, and highly elevated. Statistical 32 analyses were done with SPSS (IBM SPSS Statistics, Version 22).

Background: IgG autoantibodies against the high-affinity IgE receptor, FcɛRIα, contribute the pathogenesis of autoimmune chronic spontaneous urticaria (CSU). However, it is not known whether such patients also exhibit IgM or IgA autoantibodies against FcɛRIα. To address this question we developed an ELISA to assess serum levels of IgG, IgM, and IgA autoantibodies against FcɛRIα and investigated whether their presence is linked to clinical features of CSU including the response to autologous serum skin testing (ASST). Methods: Serum samples of 35 CSU patients (25 ASST-positive) and 52 healthy control individuals were analyzed using a newly developed competitive ELISA for IgG, IgM, and IgA autoantibodies to FcɛRIα. Results: One in four CSU patients (8/35, 24%) had elevated serum levels of IgGanti-FcɛRIα compared with (3/52, 6%) healthy controls. More than half of patients had IgM (21/35, 60%) and IgA (20/35, 57%) vs (3/52, 5%) each in healthy controls. Elevated IgM, but not IgG or IgA, autoantibodies were significantly more frequent in ASST-positive CSU patients (18/25, 72%) compared with ASSTnegative patients

There are two subtypes of CholU patients with different gender ratios, disease duration and comorbidities. These findings suggest that two distinct underlying pathogenetic pathways are relevant in these two subgroups of patients with CholU.

The MAS is a disease-specific, valid and reliable patient-reported outcome measure for adult patients with cutaneous and indolent systemic mastocytosis. It may serve as a valuable tool to measure and monitor mastocytosis activity, both, in clinical trials and in routine care.