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Background: In cholinergic urticaria (CholU), itchy wheal and flare-type skin reactions are triggered by sweat-inducing activities. The CholU activity score (CholUAS) is used to assess disease activity but has not yet been validated. The aim of the study was to validate the CholUAS, develop an English version, and provide instructions for scoring., Methods: Cognitive debriefing of CholUAS was performed. Patients with CholU (n = 75) used the CholUAS on 7 consecutive days, underwent provocation testing, completed additional anchor instrument questionnaires including global evaluation tools, and established quality of life instruments. A scoring protocol for the calculation of the weekly CholUAS, the CholUAS7, was developed. The CholUAS7 was tested for validity, reliability, and influencing factors. An English version of the CholUAS was developed., Results: The final CholUAS contains 3 questions that are used for scoring as well as 1 global question. The weekly CholUAS, CholUAS7, showed excellent test-retest reliability and good correlations with anchor instruments. Statistical analysis showed no significant influence of age or duration of disease on CholUAS7 results., Conclusion: The validated CholUAS is ready for use in clinical trials and routine clinical practice., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic spontaneous urticaria (CSU) is a debilitating, inflammatory skin condition characterized by infiltrating immune cells. Available treatments are limited to improving the signs and symptoms. There is an unmet need to develop therapies that target disease-driving pathways upstream of mast cell activation to inhibit or delay the progression of CSU and associated comorbidities. Here, we aim to define disease modification due to a treatment intervention and criteria that disease-modifying treatments (DMTs) must meet in CSU. We have defined disease modification in CSU as a favorable treatment-induced change in the underlying pathophysiology and, therefore, the disease course, which is clinically beneficial and enduring. A DMT must fulfil the following criteria: (1) prevents or delays the progression of CSU, (2) induces long-term, therapy-free clinical remission, which is the sustained absence of CSU signs and symptoms without the need for treatment, and (3) affects the underlying mechanism of CSU, as demonstrated by an effect on disease-driving signals and/or a biomarker. DMTs in CSU should slow disease progression, achieve long-lasting disease remission, target disease-driving mechanisms, reduce mast cell-activating IgE autoantibodies, target cytokine profile polarization, and normalize the gut microbiome and barrier. Treating CSU at the immune system level could provide valuable alternatives to pharmacotherapy in CSU management. Specific DMTs in CSU are yet to be developed, but some show potential benefits, such as inhibitors of Bruton's Tyrosine Kinase, IL-4 and IL-13. Future therapies could prevent CSU signs and symptoms, achieve long-term clinical benefits after discontinuing treatment, and prevent associated concomitant disorders., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

In cholinergic urticaria (CholU), small, itchy wheals are induced by exercise or passive warming and reduced sweating has been reported. Despite the described reduced muscarinic receptor expression, sweat duct obstruction, or sweat allergy, the underlying pathomechanisms are not well understood. To gain further insights, we collected skin biopsies before and after pulse-controlled ergometry and sweat after sauna provocation from CholU patients as well as healthy controls. CholU patients displayed partially severely reduced local sweating, yet total sweat volume was unaltered. However, sweat electrolyte composition was altered, with increased K + concentration in CholU patients. Formalin-fixed, paraffin-embedded biopsies were stained to explore sweat leakage and tight junction protein expression. Dermcidin staining was not found outside the sweat glands. In the secretory coils of sweat glands, the distribution of claudin-3 and -10b as well as occludin was altered, but the zonula occludens-1 location was unchanged. In all, dermcidin and tight junction protein staining suggests an intact barrier with reduced sweat production capability in CholU patients. For future studies, an ex vivo skin model for quantification of sweat secretion was established, in which sweat secretion could be pharmacologically stimulated or blocked. This ex vivo model will be used to further investigate sweat gland function in CholU patients and decipher the underlying pathomechanism(s).

Background: Mycosis fungoides (MF) is an indolent T-cell lymphoma that mainly affects the skin and presents with itch in more than half of the patients. Recently, the expression of Mas-related G protein-coupled receptor X2 (MRGPRX2), a receptor of mast cell (MC) responsible for the IgE-independent non-histaminergic itch, has been shown in lesional skin of patients with pruritic skin diseases, including chronic urticaria, prurigo, and mastocytosis. As of yet, limited knowledge exists regarding the MRGPRX2 expression in the skin of patients with MF., Objectives: To investigate the number of MRGPRX2-expressing (MRGPRX2+) cells in the skin of patients with MF and its correlation with clinical and laboratory characteristics of the disease., Methods: MRGPRX2 was analyzed in lesional and non-lesional skin of MF patients and healthy skin tissues by immunohistochemistry. Co-localization of MRGPRX2 with the MC marker tryptase was assessed by immunofluorescence. Public single-cell RNAseq data was reanalyzed to identify the MRGPRX2 expression on the distinct cell types., Results: In lesional skin of MF patients, MRGPRX2+ cell number was higher than in non-lesional skin and healthy control skin (mean:15.12 vs. 6.84 vs. 5.51 cells/mm 2 , p=0.04), and correlated with MC numbers (r=0.73, p=0.02). MC was the primary cell type expressing MRGPRX2 in MF patients. The ratio of MRGPRX2+ MCs to MRGPRX2+ cells in lesional and non-lesional skin correlated with the severity of disease (r=0.71, p=0.02 and r=0.67, p=0.03, respectively)., Conclusions: Our findings point to the role of MRGPRX2 and MC in the pathogenesis of MF that should be investigated in further studies., Competing Interests: SA has conducted studies for/was advisor for/was speaker for AstraZeneca, Allakos, ALK, Biocryst, CSLBehring, LeoPharma, Moxie, Novartis, Pharvaris, Sanofi, Takeda, Thermofisher. MaMe received honoraria advisory board, speaker from AbbVie, Amgen, AstraZeneca, argenx, Bayer, Beiersdorf, Celldex, Escient, Galderma, gsk, Jasper, Novartis, Pharvaris, Pfizer, Sanofi-Aventis, Tevapharm, ThirdHarmonicBio, Viforpharma, outside of submitted work. PK received honoraria advisory board, speaker from Novartis, Roche and ValenzaBio, outside of submitted work. Outside of this work, MMa is or recently was a speaker and/or advisor for and/or has received research funding from Astria, Allakos, Alnylam, Amgen, Aralez, ArgenX, AstraZeneca, BioCryst, Blueprint, Celldex, Centogene, CSL Behring, Dyax, FAES, Genentech, GIInnovation, GSK, Innate Pharma, Kalvista, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, Novartis, Pfizer, Pharming, Pharvaris, Roche, Sanofi/Regeneron, Shire/Takeda, Third Harmonic Bio, UCB, and Uriach. DT-M has received research funds and/or was advisor for Celldex, Moxie, Novartis and Sanofi. Outside of this work, CS is an employee of the GV20 Therapeutics, which develops drugs and research models for profit. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hu, Pyatilova, Altrichter, Sheng, Liu, Terhorst-Molawi, Lohse, Ginter, Puhl, Maurer, Metz and Kolkhir.)

Background: Chronic spontaneous urticaria (CSU) is believed to be Autoimmune (aiCSU) (type IIb CSU) in at least 8% of patients, associated with mast cell-activating IgG autoantibodies. Basophil tests such as the basophil activation test (BAT) and basophil histamine release assay (BHRA) are considered the best single tests for an aiCSU diagnosis. To date, the strength of associations among a positive BAT and/or BHRA (BAT/BHRA + ) and CSU features, patient demographics, and response to treatment remains poorly characterized., Objective: To evaluate the strength of current evidence on basophil tests as parameters for CSU characteristics., Methods: We performed a systematic literature search and review to assess the relationship between BAT/BHRA + and clinical and laboratory parameters of CSU. Of 1,058 records found in the search, 94 studies were reviewed by experts in urticaria and 42 were included in the analysis., Results: In CSU patients, BAT/BHRA + showed a strong level of evidence for an association with high disease activity and low levels of total IgE. A weak level of evidence was shown for the association of BAT/BHRA + and the presence of angioedema, and basopenia., Conclusions: Our results suggest that aiCSU defined by BAT/BHRA + is more active or severe and is linked to other aiCSU markers such as low total IgE/basopenia. Basophil tests should be standardized and implemented in routine clinical care to improve the diagnosis and treatment of patients with aiCSU., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The signs and symptoms of chronic urticaria (CU) are caused by the activation and degranulation of skin mast cells (MCs). Recent studies have added to our understanding of how and why skin MCs are involved and different in CU. Also, novel and relevant mechanisms of MC activation in CU have been identified and characterized. Finally, the use of MC-targeted and MC mediator-specific treatments has helped to better define the role of the skin environment, the contribution of specific MC mediators, and the relevance of MC crosstalk with other cells in the pathogenesis of CU. Here, we review these recent findings and their impact on our understanding of CU, with a focus on chronic spontaneous urticaria (CSU). Also, we highlight open questions, issues of controversy, and unmet needs, and we suggest what studies should be performed moving forward., (Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

In chronic spontaneous urticaria (CSU), wheals, angioedema, or both appear spontaneously for > 6 weeks. Current recommended treatment options for urticaria target mast cell mediators such as histamine, or activators, such as autoantibodies. The goal of CSU treatment is to treat the disease until it is gone as effectively and safely as possible. As no cure is available for CSU as of now, the treatment is aimed at continuously suppressing disease activity, with complete control of the disease and a normalization of quality of life. To achieve this, pharmacological treatment should be continued until no longer needed. Treatment of CSU should follow the basic principles of treating as much as needed and as little as possible taking into consideration that the activity of the disease may vary. Since CSU is a disease with spontaneous remission, it is hard to tell, in patients with complete control and no signs or symptoms, when medication is no longer needed. The current international guideline for urticaria suggests that the treatment can be stepped down once a patient is free of signs and symptoms. Other reasons for stepping down the treatment of CSU patients include safety concerns or issues, pregnancy or wanting to become pregnant, and economic factors. As of now, it is unclear over which period, with what intervals and with which dosages CSU treatment should be stepped down. Guidance on this is needed for all recommended therapies: (i) standard-dosed second-generation H1-antihistamine (sgAH), (ii) higher than standard-dosed sgAH, (iii) standard-dosed omalizumab, (iv) higher than standard-dosed omalizumab, and (v) cyclosporine. However, there is a lack of controlled trials on the step down and discontinuation of these treatments. Here, we aim to provide a summary of what is known and what needs to be investigated in further studies, based on our own experience and real-world evidence., (© 2023. The Author(s).)

Background: Chronic inducible urticaria (CIndU) is characterized by mast cell (MC)-mediated wheals in response to triggers: cold in cold urticaria (ColdU) and friction in symptomatic dermographism (SD). KIT receptor activation by stem cell factor (SCF) is essential for MC function. Barzolvolimab (CDX-0159) is a humanized antibody that inhibits KIT activation by SCF and was well tolerated in healthy volunteers with dose-dependent plasma tryptase suppression indicative of systemic mast cell ablation., Methods: This is an open-label, trial in patients with antihistamine refractory ColdU or SD, receiving one IV dose of barzolvolimab (3 mg/kg), with a 12-week follow-up. Primary endpoint was safety/tolerability; pharmacodynamic (PD)/clinical endpoints included serum tryptase, plasma SCF, skin MC histology, provocation tests, urticaria control test (UCT), and dermatology life quality index (DLQI)., Results: Analysis populations were safety (n = 21) and pharmacodynamics/clinical activity (n = 20). Barzolvolimab was well tolerated; most adverse events were mild and resolved. Treatment resulted in significant depletion of skin MCs, decreased tryptase (

Introduction: In mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, itch is a frequent clinical symptom. Whether mast cells (MCs), eosinophils (Eos) or their mediators play a role in MF-associated itch or disease severity is controversially discussed. Here, we explored the role of MC and Eo numbers in the skin as well as blood levels of their mediators in disease severity and itch., Methods: In 10 patients with MF and 10 matched control subjects we assessed disease severity, itch, and quality of life impairment using dedicated tools such as the mSWAT, ItchyQoL and DLQI. We analyzed skin biopsies and measured serum levels of tryptase, a mast cell mediator, as well as of the eosinophil products eosinophil cationic protein (ECP) and major basic protein (MBP)., Results: The presence of chronic itch, in four of 10 patients, was associated with significantly higher disease severity (mSwat), larger body surface area affected, and stronger QoL impairment (Itchy-Qol, DLQI). Serum levels of tryptase, but not ECP and MBP, were linked with patient-reported disease severity, body surface area affected, and the presence of itch. Three of the four patients with chronic itch, but none of the six patients without, had tryptase levels above >6µg/l. Numbers of MCs in the papillary dermis were higher in MF skin lesions then in non-lesional skin of MF patients and skin of healthy controls., Discussion: The MC-mediator tryptase, in MF, is linked to disease activity and impact, most prominently to itch. Our findings call for larger studies that explore the role of MCs, tryptase and other MC mediators as drivers of itch and their role in MF pathogenesis., Competing Interests: DT-M has received research funds and was advisor for Celldex, Novartis, Sanofi and Moxie. MMe is or recently was a speaker and/or advisor for AbbVie, Amgen, ArgenX, AstraZeneca, Bayer, Celldex, Celgene, Escient, Galderma, Grünenthal, GSK, Menlo, Novartis, Pfizer, Pharvaris, Roche, Sanofi-Aventis, Third Harmonic Bio. MMa is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Aralez, Genentech, GSK, Menarini, Merckle Recordati, Moxie, Novartis, Sanofi, MSD, and Uriach. SA has conducted studies for received research funds/was advisor for Allakos, ALK, AstraZeneca, CSL Behring, LeoPharma, Moxie, Novartis, Sanofi, Takeda, Thermofisher. Published results are part of the study ROBERTIS, funded by AstraZeneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Terhorst-Molawi, Lohse, Ginter, Puhl, Metz, Hu, Maurer and Altrichter.)

Background: Cold urticaria (ColdU) is a form of inducible urticaria where cold induces wheals and/or angioedema. The burden of disease is high and linked to trigger thresholds, exposure, and avoidance. There are presently no validated patient-reported outcome measures (PROMs) to assess and monitor disease activity. Our objective was to develop a disease-specific activity score for ColdU that is easy to administer and evaluate., Methods: A Cold Urticaria Activity Score (ColdUAS) questionnaire was developed, directed by PROM developing guidelines. After the generation of a conceptional framework, the item generation phase included the literature research on ColdU signs and symptoms and on comparable tools for similar diseases and 47 ColdU patient interviews. Subsequently, an impact analysis for content validity was performed. The final selection of items underwent expert review for face validity and cognitive debriefing., Results: The ColdUAS, a self-administered questionnaire for the prospective assessment of disease activity in patients with ColdU, consists of 4 items: 1. the frequency and severity of the signs (wheals and/or angioedema), 2. the frequency and severity of the symptoms (e.g., itch and burn), 3. the exposure to specific triggers, and 4. the avoidance of these triggers. The recall period for each item is the last 24 h., Conclusions: The ColdUAS is the first disease-specific PROM to assess ColdU disease activity. It may help to better assess patients' disease status in routine clinical practice as well as in clinical trials. Anchor-based approaches are currently used to validate the ColdUAS., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Cholinergic urticaria (CholU), a frequent form of chronic inducible urticaria, is characterized by itchy wheals and angioedema in response to sweating. As of now, the rate and pathophysiological relevance of impaired sweating in patients with CholU are ill-defined., Aim: To assess in CholU patients the rate and extent of impaired sweating and its links to clinical and pathophysiological features of CholU., Patients and Methods: We assessed sweating in patients with CholU ( n = 13) subjected to pulse-controlled ergometry (PCE) provocation testing. Pre- and post-PCE biopsies of lesional (L) and non-lesional (NL) skin were analyzed for the expression of acetylcholine receptor M3 (CHRM3) and acetylcholine esterase (ACh-E) by quantitative histomorphometry and compared to those of healthy control subjects (HCs). CholU patients were assessed for disease duration and severity as well as other clinical features., Results: Of the 13 patients with CholU, 10 showed reduced sweating in response to PCE provocation, and 3 had severely reduced sweating. Reduced sweating was linked to long disease duration and high disease severity. CholU patients with impaired sweating responses showed reduced sweat gland epithelial expression of CHRM3 and ACh-E., Conclusion: Reduced sweating is common in CholU patients, especially in those with long-standing and severe disease, and it can be severe. Reduced expression of CHRM3 and ACh-E may be the cause or consequence of CholU in patients with impaired sweating, and this should be explored by further studies., Competing Interests: DT-M has received research funds/was an advisor for Celldex, Novartis, Sanofi, and Moxie. MM is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Amgen, Aralez, ArgenX, AstraZeneca, Celldex, Centogene, CSL Behring, FAES, Genentech, GIInnovation, Innate Pharma, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, Novartis, Roche, Sanofi/Regeneron, Third HarmonicBio, UCB, and Uriach. SA has been a speaker and/or advisor for and/or has conducted studies for AstraZeneca, Allakos, GSK, Leo Pharma, Lilly, Moxie, Novartis, Thermo Fisher, and Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Scheffel, Vera, Liu, Günzel, Terhorst-Molawi, Maurer and Altrichter.)

Background: Cold urticaria (ColdU), that is, the occurrence of wheals or angioedema in response to cold exposure, is classified into typical and atypical forms. The diagnosis of typical ColdU relies on whealing in response to local cold stimulation testing (CST). It can also manifest with cold-induced anaphylaxis (ColdA). We aimed to determine risk factors for ColdA in typical ColdU., Methods: An international, cross-sectional study COLD-CE was carried out at 32 urticaria centers of reference and excellence (UCAREs). Detailed history was taken and CST with an ice cube and/or TempTest ® performed. ColdA was defined as an acute cold-induced involvement of the skin and/or visible mucosal tissue and at least one of: cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms., Results: Of 551 ColdU patients, 75% (n = 412) had a positive CST and ColdA occurred in 37% (n = 151) of the latter. Cold-induced generalized wheals, angioedema, acral swelling, oropharyngeal/laryngeal symptoms, and itch of earlobes were identified as signs/symptoms of severe disease. ColdA was most commonly provoked by complete cold water immersion and ColdA caused by cold air was more common in countries with a warmer climate. Ten percent (n = 40) of typical ColdU patients had a concomitant chronic spontaneous urticaria (CSU). They had a lower frequency of ColdA than those without CSU (4% vs. 39%, p = .003). We identified the following risk factors for cardiovascular manifestations: previous systemic reaction to a Hymenoptera sting, angioedema, oropharyngeal/laryngeal symptoms, and itchy earlobes., Conclusion: ColdA is common in typical ColdU. High-risk patients require education about their condition and how to use an adrenaline autoinjector., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Cholinergic urticaria (CholU) is a common type of chronic inducible urticaria. Little is known about the burden of the disease and its unmet medical needs., Aim: To characterize the unmet medical needs of patients with CholU., Methods: Patients with CholU ( n = 111) took part in a German online survey that assessed their symptoms, diagnostic delay, impact on daily life, quality of life (QoL), and their experience with physician care., Results: Virtually all patients reported typical signs and symptoms of CholU, i.e., whealing (93.7%) and itching (91.9%), in response to typical trigger situations, such as physical activity, passive warming, or stress. Despite this, patients reported a marked diagnostic delay of 30.2 months (range from 0 to 279 months). Only 38% of the patients received a blood examination, and only 16% underwent provocation testing for diagnosing CholU, as recommended by the international guidelines. Physician contacts were common, but patient satisfaction with their disease management was low. In total, 90.1% of the patients stated to have an uncontrolled disease, resulting in a strong impact on their everyday activities, sleep, and QoL., Conclusion: Patients with CholU exhibit many important unmet needs, and improvement in the diagnostic workup and patient care is needed, as are better treatment options., Competing Interests: KW is a speaker and advisor and has received research funding from Biocryst, CSL Behring, Dr. Pfleger, FAES, Moxie, Novartis, Shire/Takeda, and Uriach. MM is a speaker and advisor and has received research funding from Allakos, Amgen, Aralez, ArgenX, AstraZeneca, Celldex, Centogene, CSL Behring, FAES, Genentech, GIInnovation, GSK, Innate Pharma, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, Novartis, Roche, Sanofi/Regeneron, Third HarmonicBio, UCB, and Uriach. SA has been a speaker and advisor and has conducted studies for Astra Zeneca, Allakos, GSK, LeoPharma, Lilly, Moxie, Novartis, Thermo Fisher, and Sanofi. DT-M has been an advisor and has received research funding from Moxie, Novartis, Celldex, and Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Altrichter, Mellerowicz, Terhorst-Molawi, Grekowitz, Weller and Maurer.)

Background: The diagnosis of typical cold urticaria (ColdU) relies on whealing in response to local cold stimulation testing (CST). It can also manifest with cold-induced anaphylaxis (ColdA). Till date, it is largely unclear how often patients with ColdU receive adrenaline treatment and are provided with an adrenaline autoinjector (AAI). Methods: An international, cross-sectional study, COLD-CE (i.e., comprehensive evaluation of ColdU and other cold-induced reactions), was carried out at 32 UCAREs. Detailed histories were taken and CST with an ice cube and/or TempTest ® performed. ColdA was defined as an acute cold-induced (i.e., by cold water, air, or surfaces) involvement of the skin and/or visible mucosal tissue and at least one of the symptoms (cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms). Results: Of the 551 ColdU patients, 75% ( n = 412) had a positive CST. Of them, concomitant chronic spontaneous urticaria was diagnosed in 10%. Of 372 patients with stand-alone ColdU, 69% were women and 91% adults. Their median age was 36 (IQR 26 - 48) years. Patients were also categorized into residents of countries with a tropical ( n = 33), temperate ( n  = 264), or cold ( n  = 75) climate (Table 1: R13C1, R17C1, R21C1). AAI was more often prescribed to residents of temperate than tropical countries (30% vs. 12%, p  = .038; Table 1: R31C1), although the frequency of ColdA did not significantly differ between these countries (44% vs. 42%, p  = 1.000; R29C2). Residents of tropical countries had a higher frequency of ColdA induced by cold air than residents of temperate (36% vs. 12%, p  = .001; R29C4) or cold (36% vs. 12%, p  = .007; R25C4) countries. Cardiovascular manifestations induced by cold air were diagnosed in 33% ( n  = 11) of residents of tropical countries, but only 18% ( n  = 2) and 36% ( n = 4) of them had received adrenaline and AAI, respectively (R13 - 15C7). Furthermore, hypotension and/or loss of consciousness induced by cold air occurred in 18% ( n = 6) of patients, but only 17% ( n = 1) received adrenaline (R13 - 14C10). ColdA was induced by complete cold water immersion in 9% ( n = 3) of patients, and none of them received adrenaline treatment nor AAI (R13 - 15C3). Conclusion: Our findings suggest that ColdA is undertreated and call for changes in ColdU management., (© 2022 Bizjak, Košnik, Dinevski, Thomsen, Fomina, Borzova, Kulthanan, Meshkova, Aarestrup, Ahsan, Al-Ahmad, Altrichter, Bauer, Brockstädt, Costa, Demir, Criado, Ensina, Gelincik, Giménez-Arnau, Gonçalo, Gotua, Holm, Inomata, Kasperska-Zajac, Khoshkhui, Klyucharova, Kocatürk, Lu, Makris, Maltseva, Pasali, Paulino, Pesqué, Peter, Ramón, Ritchie, Valle, Rudenko, Sikora,Wagner, Xepapadaki, Xue, Zhao, Terhorst-Molawi, Maurer [Author(s)], licensee HBKU Press.)

Background: In chronic spontaneous urticaria (CSU), the guidelines recommend very limited diagnostic procedures during the routine workup, although additional investigations might be indicated in some patients with CSU. For physicians treating patients with CSU, it is often difficult to decide which diagnostic tests are useful., Objective: To provide recommendations on what diagnostic tests should be performed on which patients with CSU., Methods: We performed an extensive literature search on the respective topics and identified relevant questions that should prompt diagnostic procedures based on the published evidence and expert consensus among all authors., Results: We provide questions, diagnostic testing, where appropriate, and recommendation that should be included when assessing the history of a patient with CSU, to explore and rule out differential diagnoses, to assess patients for underlying causes and modifying conditions, to explore patients for comorbid diseases and consequences of having CSU, and to assess patients for CSU components that can help to predict their disease course and response to treatment., Conclusions: Here, we provide physicians treating patients with CSU with information about which clues should lead to which tests and why., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: Cryoproteins, such as cryoglobulins, cryofibrinogens and cold agglutinins, precipitate at low temperatures or agglutinate erythrocytes and dissolve again when warmed. Their pathogenetic and diagnostic importance in cold urticaria (ColdU) is unclear. In this study, we aimed to characterize the prevalence of cryoproteins in patients with ColdU., Methods: We conducted 3 analyses: i) a systematic review and meta-analysis of published data using an adapted version of the Joanna Briggs Institute's critical appraisal tool for case series, ii) a retrospective analysis of 293 ColdU patients treated at our Urticaria Center of Reference and Excellence (UCARE) from 2014 to 2019, and iii) a prospective observational study, from July 2019 to July 2020, with 49 ColdU patients as defined by the EAACI/GA2LEN/EDF/UNEV consensus recommendations., Results: Our systematic review identified 14 relevant studies with a total of 1151 ColdU patients. The meta-analyses showed that 3.0% (19/628), 1.1% (4/357) and 0.7% (2/283) of patients had elevated levels of cryoglobulins, cryofibrinogens and cold agglutinins, respectively. Our retrospective analyses showed that cryoproteins were assessed in 4.1% (12/293) of ColdU patients. None of 9 ColdU patients had cryoglobulins, and one of 5 had cold agglutinins. In our prospective study, none of our patients had detectable cryoglobulins (0/48) or cryofibrinogens (0/48), but 4.3% (2/46) of patients had cold agglutinins (without any known underlying autoimmune or hematological disorder)., Conclusion: Our investigation suggests that only very few ColdU patients exhibit cryoproteins and that the pathogenesis of ColdU is driven by other mechanisms, which remain to be identified and characterized in detail., Competing Interests: KK is or recently was a speaker and/or advisor for and/or has received research funding from Berlin Chemie, CSL Behring, Moxie, Novartis, Roche and Shire/Takeda. SA is or recently was a speaker and/or advisor for and/or has received research funding from AstraZeneca, Allakos, Sanofi, Moxie and Novartis. MM is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Amgen, Aralez, ArgenX, AstraZeneca, Celldex, Centogene, CSL Behring, FAES, Genentech, GIInnovation, Gilead, Innate Pharma, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, Novartis, Roche, Sanofi/Regeneron, Third HarmonicBio, UCB, and Uriach. MB is or recently was a speaker and/or advisor for Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ginter, Ahsan, Bizjak, Krause, Maurer, Altrichter and Terhorst-Molawi.)

Mast cell-activating signals in cold urticaria are not yet well defined and are likely to be heterogeneous. Cold agglutinins and cryoglobulins have been described as factors possibly associated with cold urticaria, but their relevance has not been explained. We performed a single-center prospective cohort study of 35 cold urticaria patients. Cold agglutinin and cryoglobulin test results, demographics, detailed history data, cold stimulation test results, complete blood count values, C-reactive protein, total immunoglobulin E levels, and basal serum tryptase levels were analyzed. Forty six percent ( n = 16) of 35 tested patients had a positive cold agglutinin test and 27% ( n = 9) of 33 tested patients had a positive cryoglobulin test. Cold agglutinin positive patients, when compared to cold agglutinin negative ones, were mainly female ( P = 0.030). No gender-association was found for cryoglobulins. A positive cold agglutinin test, but not a positive cryoglobulin test, was associated with a higher rate of reactions triggered by cold ambient air ( P = 0.009) or immersion in cold water ( P = 0.041), and aggravated by increased summer humidity ( P = 0.007). Additionally, patients with a positive cold agglutinin test had a higher frequency of angioedema triggered by ingestion of cold foods or drinks ( P = 0.043), and lower disease control based on Urticaria Control Test ( P = 0.023). Cold agglutinin levels correlated with erythrocyte counts (r = -0.372, P = 0.028) and monocyte counts (r = -0.425, P = 0.011). Cryoglobulin concentrations correlated with basal serum tryptase levels (r = 0.733, P = 0.025) and cold urticaria duration (r = 0.683, P = 0.042). Results of our study suggest that cold agglutinins and cryoglobulins, in a subpopulation of cold urticaria patients, are linked to the course and possibly the pathogenesis of their disease., Competing Interests: MB has been a speaker and an advisor for Novartis. MM is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Aralez, ArgenX, AstraZeneca, Celldex, Centogene, CSL Behring, FAES, Genentech, GIInnovation, Innate Pharma, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, MSD, Novartis, Roche, Sanofi/Regeneron, Third HarmonicBio, UCB, and Uriach. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bizjak, Košnik, Terhorst-Molawi, Dinevski and Maurer.)

Cold urticaria (ColdU) is a common form of chronic inducible urticaria characterized by the development of wheals, angioedema or both in response to cold exposure. Recent research and guideline updates have advanced our understanding and management of ColdU. Today, its pathophysiology is thought to involve the cold-induced formation of autoallergens and IgE to these autoallergens, which provoke a release of proinflammatory mediators from skin mast cells. The classification of ColdU includes typical and atypical subtypes. We know that cold-induced wheals usually develop on rewarming and resolve within an hour and that anaphylaxis can occur. The diagnosis relies on the patient's history and cold stimulation testing. Additional diagnostic work-up, including a search for underlying infections, should only be done if indicated by the patient's history. The management of ColdU includes cold avoidance, the regular use of nonsedating antihistamines and the off-label use of omalizumab. However, many questions regarding ColdU remain unanswered. Here, we review what is known about ColdU, and we present important unanswered questions on the epidemiology, underlying pathomechanisms, clinical heterogeneity and treatment outcomes. Our aim is to guide future efforts that will close these knowledge gaps and advance the management of ColdU., (© 2020 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Objective: Immunoglobulin E (IgE) and its receptor, FcɛRI, importantly contribute to the pathophysiology of chronic spontaneous urticaria (CSU). Recent findings point to a possible role of total IgE as a marker of CSU disease activity, endotypes, and responses to treatment. The evidence in support of total IgE included in the diagnostic workup of patients with CSU has not yet been reviewed., Methods: Publications were searched via PubMed. The search terms used were "chronic urticaria" and "total IgE." Studies were screened by titles and abstracts, and 141 were used in the review., Results: CSU patients frequently had elevated total IgE serum levels (up to 50%), but normal or very low total IgE levels also occurred. High total IgE may represent high disease activity, longer disease duration, high chance of responding to omalizumab treatment, quick relapse after stopping omalizumab, and lower chance of responding to cyclosporine. Low IgE, in contrast, may suggest Type IIb autoimmune CSU, poor response to treatment with omalizumab and a better chance to benefits from cyclosporine treatment. Furthermore, IgE in different CSU cohorts may have different physicochemical properties that could explain differences in treatment responses to IgE-directed therapies., Conclusion: The results of our review suggest that total IgE is a valuable marker for CSU, and we recommend its assessment in the routine diagnostic workup of CSU patients., Competing Interests: Sabine Altrichter is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, AstraZeneca, Moxie, Sanofi and ThermoFisher., (Copyright © 2021 The Korean Academy of Asthma, Allergy and Clinical Immunology · The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Background: Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear., Case Presentation: We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2 + T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4 + CD8 + population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4 + CD8 + T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology., Conclusions: This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.

Background: Vibratory angioedema (VA) is a subtype of chronic inducible urticaria that manifests with erythematous wheals or angioedema after skin exposure to vibration. Because the condition is rare, the available information is limited., Objective: To systematically review the clinical manifestations and treatment options of VA., Methods: Relevant literature published until August 2020 was searched using the terms "vibratory urticaria," "vibratory angioedema," "vibratory-induced angioedema," and "vibratory-induced urticaria." Preferred Reporting Items for Systematic Reviews and Meta-analysis recommendations were applied to this systematic review., Results: On the basis of review of 22 studies (16 case reports, 4 case series, and 2 cohort studies) that had a combined total of 83 patients, we propose that VA be classified as hereditary VA (33.7%) and acquired VA (66.3%). Vibration-induced itching was frequent in both subgroups. Patients with hereditary VA more commonly had wheals and systemic symptoms, whereas patients with acquired VA more frequently had angioedema, burning, pain, or tingling. Although many VA treatments are used, there is little information on their efficacy. Most patients do not achieve complete control., Conclusions: The novel VA classification proposed could help clinicians with the diagnostic workup of patients with VA. Because of the paucity of reported cases, firm recommendations for the treatment of VA are currently not possible. For patients with acquired VA, we suggest second-generation H 1 -antihistamines as the first-line treatment. Controlled therapeutic trials are needed and should be performed., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)