Background: Cold urticaria (ColdU) is a common type of chronic inducible urticaria. Patients with typical ColdU develop wheals in response to standard cold stimulation tests (CSTs), an ice cube (ICT) or TempTest ®. As of now, the evaluation of CST response is visual and subjective. Validated, robust, and objective test readouts lacking today are needed. Methods: We subjected 63 patients (39 with typical ColdU and 24 with atypical ColdU) and 15 healthy controls (HCs) to TempTest ® CSTs and critical temperature threshold assessments. Blood microcirculation photoplethysmography (PPG) measurements were performed 5 min before and 10 min after the ICT on the volar forearm. Results: PPG amplitudes reflected normal baseline skin blood perfusion in patients with typical or atypical ColdU. Ice cube CSTs induced a marked increase in blood perfusion and PPG amplitudes in typical but not atypical ColdU, with distinct pre-post CST changes in PPG amplitudes in the former. The ratio of post-provocation and baseline PPG amplitudes ( R PPG) in typical ColdU patients exceeded that in atypical ColdU patients and HCs more than 3-fold. Almost all typical ColdU patients (98%), but only 13% of atypical ColdU patients and 7% of HCs had R PPG >3. PPG results matched those of CSTs in 94% of all tested individuals. Conclusion: Photoplethysmographic assessments of CST responses appear accurate and provide objective readouts. PPG may be of use in diagnosing ColdU, distinguishing typical and atypical ColdU, and more precise threshold testing.

Background: Information/communication technologies such as mobile phone applications (apps) would enable chronic urticaria (CU) patients to self-evaluate their disease activity and control. Yet, recently Antó et al (2021) reported a global paucity of such apps for patients with CU. In this analysis, we assessed patient interest in using apps to monitor CU disease activity and control using questions from the CURICT study, Methods: The methodology for CURICT has been reported. Briefly, a 23-item questionnaire was completed by 1,841 CU patients from 17 UCAREs across 17 countries. Here, we analyzed patient responses to the CURICT questions on the use of apps for urticaria-related purposes. Results: As previously published, the majority of respondents had chronic spontaneous urticaria (CSU; 63%; 18% chronic inducible urticaria [CIndu]; 19% with both), were female (70%) and in urban areas (75%). Over half of patients were very/extremely interested in an app to monitor disease activity (51%) and control (53%), while only ~1/10 were not. Patients with both urticaria types vs those with CSU only (OR, 1.36 [1.03-1.79]) and females vs males (OR[95%CI], 1.47 [1.17-1.85]) were more likely to be very to extremely interested in an app to assess disease control. Conclusions: Overall, patients with CU were highly interested in using an app to assess their disease activity and control. Development of well-designed apps, specific to disease types (CSU, CIndU, CSU+CIndU, etc), validated by experts across platforms would help improve the management and possibly outcomes of CU treatment while providing important patient information to be used in future research.

Autoimmunity is the break of tolerance to self-antigens that leads to organ-specific or systemic diseases characterized by the presence of pathogenic autoreactive antibodies (AAb) produced by plasmablast and/or plasma cells. AAb are prevalent in the general population and not systematically associated with clinical symptoms. In contrast, in some individuals, these AAb are pathogenic and drive the development of signs and symptoms of antibody-mediated autoimmune diseases (AbAID). AAb production, isotype profiles, and glycosylations are promoted by pro-inflammatory triggers linked to genetic, environmental, and hormonal parameters. Recent evidence supports a role for pathogenic AAb of the IgE isotype in a number of AbAID. Autoreactive IgE can drive the activation of mast cells, basophils and other types of FcεRI-bearing cells and may play a role in promoting autoantibody production and other pro-inflammatory pathways. In this review, we discuss the current knowledge on the pathogenicity of autoreactive IgE in AbAID and their status as therapeutic targets. We also highlight unresolved issues including the need for assays that reproducibly quantify IgE AAbs, to validate their diagnostic and prognostic value, and to further study their pathophysiological contributions to AbAID.

Low and high IgE is linked to improvement and worsening of chronic urticaria during pregnancy, respectively Kocatürk E, Thomsen SF, Al-Ahmad M, Gimenez-Arnau A, Conlon N, Savk E, Criado RF, Danilycheva I, Fomina D, Khoshkhui M, Gelincik A, Degirmentepe EN, Demir S, Ensina LF, Kasperska-Zajac A, Rudenko M, Bauer A, Medina I, Maurer M.1 Urticaria Center of Reference and Excellence (UCARE), Dept. of Dermatology, Koç University School of Medicine, Istanbul, Turkey [email protected] Urticaria Center of Reference and Excellence (UCARE), Center of Reference and Excellence (UCARE), Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark [email protected] Urticaria Center of Reference and Excellence (UCARE), Microbiology Department, Faculty of Medicine, Kuwait University, Safat, Kuwait [email protected] Urticaria Center of Reference and Excellence (UCARE), Department of Dermatology, Hospital del Mar, IMIM, Universitat Autònoma, Barcelona, Spain [email protected] Urticaria Center of Reference and Excellence (UCARE), Dermatology, and Immunology, St James’s Hospital, Dublin, Ireland [email protected] Aydın Adnan Menderes University, Aydın, Turkey [email protected] Urticaria Center of Reference and Excellence (UCARE), Faculdade de Medicina do ABC (FMABC), Santo André, Brazil [email protected] Urticaria Center of Reference and Excellence (UCARE), NRC Institute of Immunology FMBA of Russia, Moscow, Russia [email protected] Urticaria Center of Reference and Excellence (UCARE), First Moscow State Medical University, Moscow Center of Allergy and Immunology , Clinical Hospital 52 , Ministry of Moscow Healthcare, Moscow, Russia [email protected] Urticaria Center of Reference and Excellence (UCARE), Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran [email protected] Urticaria Center of Reference and Excellence (UCARE), Istanbul Faculty of Medicine Istanbul University, Istanbul, Turkey [email protected] Urticaria Center of Reference and Excellence (UCARE), Okmeydani Training and Research Hospital, Istanbul, Turkey [email protected] Urticaria Center of Reference and Excellence (UCARE), Istanbul Faculty of Medicine Istanbul University, Istanbul, Turkey [email protected] Urticaria Center of Reference and Excellence (UCARE), Federal University of São Paulo, Sao Paulo, Brazil [email protected] Urticaria Center of Reference and Excellence (UCARE), European Center for Diagnosis and Treatment of Urticaria (GA2LEN UCARE Network) Medical University of Silesia in Katowice, Poland [email protected] Urticaria Center of Reference and Excellence (UCARE), The London Allergy & Immunology Centre, London, United Kingdom [email protected] Urticaria Center of Reference and Excellence (UCARE), Department of Dermatology, University Allergy Center, University Hospital Carl Gustav Carus, Technical University Dresden, Germany. [email protected] Urticaria Center of Reference and Excellence (UCARE), the Centro Médico Vitae, Buenos Aires, Argentina [email protected] Urticaria Center of Reference and Excellence (UCARE), Dermatological Allergology, Allergie-Centrum-Charité, Dept. of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Germany [email protected] Editor,PREG-CU, the recent study on pregnancy and chronic urticaria (CU) by the Urticaria Centers of Reference and Excellence (UCAREs), showed that CU improves in half (51.1%) of patients during pregnancy, whereas 28.9% and 20% of patients, respectively, experienced worsening and no change. Low disease activity, no angioedema, and no treatment before pregnancy were risk factors for worsening during pregnancy (1).We hypothesized that patients with chronic spontaneous urticaria (CSU) that worsens during pregnancy are more likely to have type I autoimmune CSU, also called autoallergic CSU. We also hypothesized that patients who improve during pregnancy are more likely to have type IIb autoimmune CSU (2). This hypothesis is supported by the immunological changes observed during pregnancy, i.e., decreased Th1 and Th17 immunity and a switch to a Th2-type cytokine profile (3).To test this hypothesis, we retrieved total IgE levels of CSU patients who gave consent to be included in the PREG-CU study (1). Elevated IgE levels have been reported to be linked to autoallergic CSU, whereas low IgE is a marker of type IIb autoimmune CSU (4).Total IgE blood levels were available for 115 of the 218 CSU patients not treated with omalizumab enrolled in PREG-CU. The median IgE level was 106 (range: 3-1664 IU/mL), more than half of patients (51.3%) had elevated IgE (≥100 IU/mL), and 17.4% had low IgE (<40 IU/mL). Most patients with mild disease (51%) or moderate disease (61%), but only one in four patients with severe disease (26%) had elevated IgE levels (≥100 IU/mL). IgE levels were lower in patients with severe disease (68 IU/mL) vs mild (112 IU/mL; p=0.009) or moderate disease (128 IU/mL; p=0.018), and low IgE levels (<40 IU/mL) were more frequent in patients with severe than mild disease (36.8 vs 11.6%; p=0.034).CSU patients who got worse during pregnancy had higher IgE levels (154 vs. 82.2 IU/mL; p=0.033) and numerically higher rates of elevated IgE (57.5 vs. 46%) compared to patients who got better during pregnancy. In contrast, patients who improved during pregnancy more often had low IgE levels than patients who deteriorated (22 vs. 12.5%), but this was not statistically significant. One in three of our patients (34.9%) had elevated anti-TPO, another marker of type IIb autoimmune CSU, but this was not linked to improvement during pregnancy.Worsening of CSU during pregnancy in patients with high IgE levels may be explained, in part, by the role that IgE and Th2 immunity play in the pathogenesis of their CSU. High IgE, in CSU, has been linked, in some studies, to autoallergy, characterized by the presence of IgE autoantibodies (5). Pregnancy skews immunity towards Th2 responses and patients with Th2-driven diseases, including allergies, often experience worsening of their disease during pregnancy (3). Improvement of CSU during pregnancy in patients with low IgE may point to a role of Th1 and Th17 cytokines in the pathogenesis of their disease. Low IgE is a type IIb autoimmune CSU marker, which is linked to Th1 and Th17 autoimmunity (6). Pregnancy decreases Th1/Th17 immunity, and patients with TH1/TH17-driven autoimmune diseases often experience improvement during pregnancy (3). Our finding that elevated IgG-anti-TPO, another marker of type IIb autoimmune CSU, is not linked to CSU improvement during pregnancy remains unexplained. Many CSU patients with IgG-anti-TPO also have IgE-anti-TPO and vice versa, which could point to both autoallergic and autoimmune drivers of their CSU. Better biomarkers are needed to identify which patients have autoallergic CSU, autoimmune CSU, both or none of these.Our findings support the notion that CSU is a heterogeneous disease, with at least two endotypes, i.e., autoallergic and autoimmune. Further studies are needed to better characterize the course of disease during and after pregnancy, in patients with autoallergic CSU and with autoimmune CSU. IgE levels may help to predict which CSU patients get worse and which improve when they get pregnant.

Mast cells are (in)famous for their role in allergic diseases, but the physiological and pathophysiological roles of this ingenious cell are still not fully understood. Mast cells are important for homeostasis and surveillance of the human system, recognizing both endogenous and exogenous agents, which induce release of a variety of mediators acting on both immune and non-immune cells, including nerve cells, fibroblasts, endothelial cells, smooth muscle cells and epithelial cells. During recent years, clinical and experimental studies on human mast cells as well as experiments using animal models have resulted in many discoveries that help decipher the function of mast cells in health and disease. In this review we focus particularly on new insights into mast cell biology, with a focus on mast cell development, recruitment, heterogeneity and reactivity. We also highlight the development in our understanding of mast cell driven-diseases and discuss the development of novel strategies to treat such conditions.

A document by Xiaoting Song. Click on the document to view its contents.

A document by Miao Yu. Click on the document to view its contents.

Background: The efficacy and safety of omalizumab in adult patients with refractory chronic urticaria (CU) is well established, but there is little information on the treatment of children. Here, we assessed the efficacy, time to onset of effects, improvement of quality of life, and safety of omalizumab in children and adolescents with CU. Methods: Patients aged < 18 years with antihistamine-resistant CU were treated with 150 or 300 mg of omalizumab every four weeks. We used the recently validated Chinese version of urticaria control test (UCT) to assess disease control status, children’s dermatology life quality index (CDLQI) to evaluate quality of life impairment, and monitored adverse events to assess the safety. Results: We treated 12 CU patients (7 female, mean age 10.2 ± 4.4 years, range 3–16) with omalizumab. Two thirds (67%) of the patients achieved well-controlled CU (defined as a UCT score ≥ 12) after the first administration. The UCT score significantly increased from 2.5 (0.0-5.8) at baseline to 12.0 (1.3-13.8) after four weeks (Z=-3.063, P=0.002) and 15.0 (13.5-16.0) after 16 weeks (Z=-3.065, P=0.002). The CDLQI score decreased from 17.5 (14.5-20.5) at baseline to 9.0 (3.0-13.8) after four weeks (Z=-2.984, P=0.003) and 2.0 (0.0-6.8) after 16 weeks (Z=-3.063, P=0.002). No adverse events were observed. Conclusion: Omalizumab is effective, fast acting and safe for children and adolescents with antihistamine-resistant chronic urticaria.

This systematic review evaluates the efficacy, safety and economic impact of dupilumabcompared to standard of care for uncontrolled moderate-to-severe atopic dermatitis (AD). Pubmed, EMBASE and Cochrane Library were searched for RCTs and health economic evaluations. Critical and important AD-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. Seven RCTs including 1845 subjects > 12 years treated with dupilumab16 to 52 weeks were evaluated. For adultsthere is high certainty that dupilumabdecreasesSCORAD (MD -30,72; 95%CI -34,65% to -26,79%) and EASI-75 (RR 3.09; 95%CI 2.45 to 3.89), pruritus (RR 2.96; 95%CI 2.37 to 3.70), rescue medication (RR 3.46; 95%CI 2.79 to 4.30), sleep disturbance (MD -7.29; 95%CI -8.23 to -6.35), anxiety/depression (MD -3.08; 95% CI -4.41 to -1.75) and improves quality of life (MD -4.80; 95% CI -5.55 to -4.06). The efficacy for adolescents is similar. Dupilumab-related adverse events (AEs) slightly increase (low certainty). The evidence for dupilumab-related serious AE is uncertain. The incremental cost-effectiveness ratio ranged from 28,500 £ (low certainty) to 124,541 US$ (moderate certainty).More data on long term safety are needed both for children and adults, together with more efficacy data in the paediatric population.

This systematic review evaluates the efficacyand safety of omalizumab for chronic spontaneous urticaria (CSU). Pubmed, EMBASE and Cochrane Library were searched for RCTs. Critical and important CSU-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. Ten RCTs including 1620 subjects aged 12 to 75 years old treated with omalizumab for 16 to 40 weeks were evaluated. Omalizumab 150 mg: does not result in clinically meaningful improvement(high certainty) of the urticaria activity score (UAS)7 (mean difference (MD) -5; 95%CI -7.75 to -2.25) and the itch severity score(ISS)7 (MD -2.15; 95% CI -3.2 to -1.1); does not increase (moderate certainty) quality of life (QoL) (Dermatology Life Quality Index (DLQI); MD -2.01; 95%CI -3.22 to -0.81); decreases (moderate certainty) rescue medication use (MD -1.68; 95%CI -2.95 to -0.4). Omalizumab 300 mg:results in clinically meaningful improvements(moderate certainty)of the UAS7 (MD -11.05; 95%CI -12.87 to -9.24), theISS7 (MD -4.45; 95%CI -5.39 to -3.51), and QoL (high certainty)(DLQI; MD -4.03; 95% CI -5.56 to -2.5); decreases (moderate certainty) rescue medication use (MD -2.04; 95%CI -3.19 to -0.88) and drug-related serious AEs (RR 0.77; 95%CI 0.20 to 2.91).