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Hereditary Angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2), by providing guidance on common and important clinical issues, such as: 1) How should HAE be diagnosed? 2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? 3) What are the goals of treatment? 4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast feeding women? 5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients., Competing Interests: Dr. Maurer reports personal fees from Alnylam, grants and personal fees from BioCryst, grants from Centogene, grants and personal fees from CSL Behring, grants from Dyax, grants and personal fees from Kalvista, grants from Pharming, personal fees from Pharvaris, grants and personal fees from Shire/Takeda, outside the submitted work. Dr. Magerl reports personal fees and non-financial support from Shire/Takeda, personal fees and non-financial support from CSL Behring, personal fees from Pharming, personal fees and non-financial support from Biocryst, during the conduct of the study; personal fees and non-financial support from Shire/Takeda, personal fees and non-financial support from CSL Behring, personal fees from Pharming, personal fees and non-financial support from Biocryst, personal fees from Kalvista, personal fees from Octapharma, personal fees from Novartis, outside the submitted work. Dr Betschel has received fees for advisory boards, presentations and research from CSL and Takeda. Advisor fees from Biocryst and Kalvista, Octapharma, Pharming, outside of the submitted work. Dr. Aberer has nothing to disclose. Dr. Ansotegui has nothing to disclose. Dr. Aygören-Pürsün reports personal fees from Biocryst, personal fees from Biomarin, personal fees from Centogene, grants and personal fees from CSL Behring, personal fees from Kalvista, personal fees from Pharming, personal fees from Pharvaris, grants and personal fees from Shire/Takeda, outside the submitted work. Dr. Banerji reports grants from Takeda, Biocryst, other from Takeda, Biocryst, Pharming, CSL, Kalvista, Pharvaris, outside the submitted work. Dr. Bara reports personal fees from commercial sponsor, outside the submitted work. Dr. Boccon-gibod reports grants, personal fees and non-financial support from Takeda, grants, personal fees and non-financial support from Biocryst Pharmaceutical, non-financial support from Pharming, outside the submitted work. Dr. Bork reports grants and personal fees from CSL Behring, personal fees from Shire/Takeda, personal fees from Pharvaris, outside the submitted work. Dr. Bouillet reports grants and personal fees from Takeda, Biocryst, Novartis, and GSK. H. B. Boysen has nothing to disclose. Dr. Brodski has nothing relevant to disclose. Dr. Busse reports grants and personal fees from CSL Behring, BioCryst, Takeda; personal fees from Medscape, CVS Health, Novartis, Regeneron Dr. Bygum reports grants and personal fees from CSL Behring, grants from BioCryst, personal fees from Takeda/Shire outside the submitted work. Dr. Caballero reports grants, personal fees and other from CSL-BEHRING, grants, personal fees and other from TAKEDA, personal fees and other from PHARMING NV, personal fees from OCTAPHARMA, personal fees and other from BIOCRYST, personal fees and other from NOVARTIS, outside the submitted work. Dr. Cancian reports and has received grant research support and/or speaker/consultancy fees from BioCryst, CSL Behring, Kalvista, Pharming, Shire (a Takeda company) and SOBI; has received funding to attend conferences/educational events from CSL Behring, Menarini, MSD, Novartis, Pharming and Shire; is/has been a clinical trial/registry investigator for BioCryst, CSL Behring, Kalvista, Novartis, Pharming, Shire and UCB. Dr. Castaldo has nothing to disclose. Dr. Cohn reports personal fees from CSL Behring, personal fees from Shire/Takeda, personal fees from Ionis Pharmaceuticals, Inc, personal fees from KalVista, personal fees from BioCryst, personal fees from Pharming, personal fees from Pharvaris, personal fees from Sanofi/Genzyme Europe, outside the submitted work. Dr. Csuka has nothing to disclose. Dr. Farkas reports grants and personal fees from CSL Behring, grants and personal fees from Shire/Takeda, grants and personal fees from Pharming Group NV, personal fees from Biocryst Pharmaceuticals, personal fees from Kalvista, personal fees from ONO Pharmaceuticals, outside the submitted work. Dr. Gompels reports fee for CSL and conference attendance support, member of the immunology clinical reference group, clinical trial work for Novartis, BioCryst. Dr. Gower reports Industry funded research/investigator: BioCryst, Kalvista, Pharming, Pharvaris, Takeda/Shire/Dyax Consultant: BioCryst, CSL Behring, Fresenius Kabi, Pharming, Takeda/Shire/Dyax Speakers Bureau, Faculty, Peer Reviewer: BioCryst, Pharming, Takeda/Shire/Dyax Advisory Committee/Board: BioCryst, CSL Behring, Fresenius Kabi, Pharming, Takeda/Shire/Dyax. Dr Grumach reports grants from Shire/Takeda and personal fees from CSL Behring, Takeda, and Catalyst for educative programs and consulting. Dr. Guidos-Fogelbach has nothing to disclose. Dr Hide reports personal fees from BioCryst, CSL Behring, Takeda and Torii. Dr. Kang has nothing to disclose. Dr. Kaplan has nothing to disclose. Dr Katelaris reports grants from CSL Behring, personal fees from CSL Behring, personal fees from Takeda, during the conduct of the study. Dr. Kiani-Alikhan reports personal fees from BioCryst, personal fees from CSL Behring, personal fees from Takeda, outside the submitted work. Dr. Lei has nothing to disclose. Dr. Lockey has nothing to disclose. Dr. Longhurst has consulted for, acted as speaker for or collaborated in research with the following: Adverum, BioCryst, CSL Behring, GSK, Intellia, Ionis, Kalivista, Pharming, Pharvaris, and Takeda. Dr. Lumry has consulted for, acted as speaker for or collaborated in research with the following: Adverum, Astra Zeneca, BioCryst, Biomarin, CSL Behring, Fresenius Kabi, GSK, Intellia, Ionis, Kalivista, Pharming, Pharvaris, Sanofi Regeneron, Takeda and Teva. Dr. MacGinnitie reports personal fees from Biocryst, during the conduct of the study. Dr. Malbran has nothing to disclose. Inmaculada Martinez Saguer has received research grant support and/or speaker/consultancy fees from BioCryst, CSL Behring, KalVista, Pharming, and Takeda. Dr. Matta has nothing to disclose. Dr. Nast has no conflict of interest in relation to this manuscript. Dr. Nguyen has nothing to disclose. Dr. Nieto-Martinez has nothing to disclose. Dr. Pawankar declares no conflicts of interest in relation to this manuscript. Dr. Peter has nothing to disclose. Dr. Porebski is or recently was a speaker and/or advisor for CSL Behring, Takeda, Pharming, and has served as an investigator for clinical trials sponsored by BioCryst Pharmaceuticals. Dr. Prior reports receipt of research grant support and/or speaker/consultancy fees from CSL Behring, Pharming, and Shire (currently Takeda). Dr. Reshef Received research grants, speakers and consulting honoraria from CSL Behring, Stallergens, Teva, Pharming, BioCryst, Pharvaris, Takeda (Shire) - not related to the article. Dr. Marc Riedl has received research grants from BioCryst, CSL Behring, Ionis, Kalvista, Pharvaris, and Takeda outside the submitted work; consultancy fees from Astria, BioCryst, Biomarin, CSL Behring, Cycle Pharma, Fresenius-Kabi, Ipsen, Kalvista, Ono Pharma, Pfizer, Pharming, Pharvaris, RegenexBio, and Takeda outside the submitted work. Dr. Bruce Ritchie has received Research grants from CSL-Behring, and has participated in clinical trials with Biocrist, CSL-Behring, Ionis, Kalvista, Pharvaris, and Takeda. The University of Alberta has received donations in lieu of consultancy fees to Dr. Ritchie from CSL Behring, Takeda. Dr. Sheikh reports other from Takeda, grants from CSL Behring, outside the submitted work. Dr. Smith reports other from BioCryst, during the conduct of the study; personal fees from Takeda/Shire, personal fees from CSL Behring, outside the submitted work. Dr. Späth reports other from CSL Ltd, outside the submitted work; and Expert in an ongoing litigation. Dr. Stobiecki reports other from Takeda, Biocryst, Pharming, Kalvista, fees from CSL Behring, Takeda, Biocryst, outside the submitted work. Dr. Toubi has no conflict of interest in relation to this manuscript. Dr. Varga has no conflict of interest in relation to this manuscript. Dr. Weller reports personal fees from Biocryst, CSL Behring, MOXIE and Pharvaris as well as grants and personal fees from Shire/Takeda, all outside the submitted work. Dr. Zanichelli has no conflict of interest in relation to this manuscript. Dr. Zhi has nothing to disclose. Dr. Zuraw has been a paid consultant for Biomarin, CSL Behring, Cycle Pharma, Fresenius-Kabi, and Takeda. He serves on adjudication boards for Novartis and Genentech. Dr. Craig does research for CSL Behring, Ionis, Takeda, Kalvista, Pharvaris, BioMarin, and Biocryst. He speaks for CSL Behring, Takeda and Grifols. He has a grant to support education from Takeda. He consults with Spark, CSL Behring, Takeda, BioMarin, Pharming and Biocryst., (© 2022 The Author(s).)

Chronic spontaneous urticaria is characterized by a perivascular non-necrotizing cellular infiltrate around small venules of the skin. It consists primarily of CD4(+) lymphocytes, a prominence of the T helper (Th)2 subtype but also Th1 cells, with Th17 cell-derived cytokines elevated in plasma. There are also neutrophils, eosinophils, basophils, and monocytes. Chemokines derived from mast cells and activated endothelial cells drive the process. Although the role of the cellular infiltrate has not previously been addressed, each constituent can contribute to the overall pathogenesis. It is of interest that CSU responds to corticosteroid, yet, short-term steroids do not affect autoimmunity or degranulation of mast cells, and act on margination of cells along the endothelium and chemotaxis to enter the surrounding dermis. In this review, we address each cell's contribution to the overall inflammatory response, as it is currently understood, with a view toward development of therapeutic options that impede the function of critical cells and/or their secretory products., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Guidelines for the treatment of chronic spontaneous urticaria (CSU) recommend the use of the IgE-targeted biologic omalizumab in patients with antihistamine-refractory disease. The rationale for this is supported by the key role of IgE and its high-affinity receptor, FcεRI, in the degranulation of skin mast cells that drives the development of the signs and symptoms of CSU, itchy wheals, and angioedema. Here, we review the current understanding of the pathogenesis of CSU and its autoimmune endotypes. We describe the mechanisms of action of omalizumab, the only biologic currently approved for CSU, its efficacy and ways to improve it, biomarkers for treatment response, and strategies for its discontinuation. We provide information on the effects of the off-label use, in CSU, of biologics licensed for the treatment of other diseases, including dupilumab, benralizumab, mepolizumab, reslizumab, and secukinumab. Finally, we discuss targets for novel biologics and where we stand with their clinical development. These include IgE/ligelizumab, IgE/GI-310, thymic stromal lymphopoietin/tezepelumab, C5a receptor/avdoralimab, sialic acid-binding Ig-like lectin 8/lirentelimab, CD200R/LY3454738, and KIT/CDX-0159. Our aim is to provide updated information and guidance on the use of biologics in the treatment of patients with CSU, now and in the near future., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Hereditary angioedema (HAE) is caused by deficiency or dysfunction in the C1 inhibitor (C1-INH) protein. C1-INH replacement therapy is used to treat patients with HAE to restore the missing or dysfunctional protein. In vitro studies showed that C1-INH inhibits prekallikrein activation and bradykinin formation in a dose-dependent manner when added to the plasma of patients with HAE. HAE is highly variable in clinical presentation, and early studies suggested that there was not a clear relationship between functional C1-INH levels and disease activity. Later, a threshold of approximately 40% functional C1-INH was identified, above which patients' risk of an attack was diminished. Long-term prophylaxis with plasma-derived C1-INH effectively reduces attack frequency and severity. Pharmacokinetic modeling shows that functional C1-INH levels are associated with the relative risk of having an attack. Subcutaneous administration of C1-INH results in consistently high levels of functional C1-INH activity, whereas intravenous administration results in periods of low trough functional C1-INH activity before the next scheduled dose, increasing the risk of an angioedema attack. These studies suggest that measurement of functional C1-INH activity may be useful as a biomarker of the risk of an attack in patients with HAE who are receiving long-term prophylaxis with plasma-derived C1-INH., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Chronic urticaria is defined as the presence of urticaria for a period exceeding 6 weeks, assuming symptoms for most days of the week. It is divided into chronic inducible urticarias and chronic spontaneous urticaria, previously termed chronic idiopathic urticaria. The latter designation emphasizes that patients can experience urticaria independent of any exogenous stimulus even if one can define circumstances that may worsen symptoms. A search for such an external "cause" is fruitless because the underlying abnormality is "intrinsic," whether it is autoimmune, or some unknown process. Approximately 40% of patients with chronic spontaneous urticaria report accompanying episodes of angioedema, whereas 10% have angioedema as their primary manifestation. In most cases, it is a self-limiting disorder, persisting for 2 to 5 years in most cases, although 20% of patients suffer for more than 5 years. The treatment that has evolved is largely empiric, based on double-blind, placebo-controlled studies whenever possible, but is not yet targeted to any particular pathogenic mechanism. In this article, we review the current status regarding pathogenesis, discuss the diagnostic workup, and update the approach to treatment including consideration of published guidelines, our own experience, and guideline updates that are being prepared., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Chronic urticaria (CU) has a major effect on patients' quality of life. While there have been progressive advances regarding its pathogenesis and treatment, much remains to be done. Registries of other chronic non-communicable diseases have shown many benefits, such as additional basic knowledge and management approaches to diabetes mellitus. Standards of care as well as diagnostic approaches can be elaborated and compared from different sites, using validated instruments. Registries in allergic diseases are also becoming well recognized, and the first registry on CU, accessible from SLaai's webpage, includes parameters for identification, evaluation and management. In our vision, informatics strategies have the potential to improve care for chronic illnesses such as CU. The registry represents a valid instrument from which to obtain a sufficient sample size for epidemiological studies and/or clinical research planning, including feasibility and potential enrollment. It can also provide invaluable data for adapting guidelines to local populations, as well as diagnostic approaches and cost-effective interventions in the context of organizational efforts to improve patient care.

Background: Data from the 3 omalizumab pivotal trials in patients with chronic idiopathic urticaria/chronic spontaneous urticaria (CIU/CSU) represent the largest database of patients reported to date with refractory disease (omalizumab, n = 733; placebo, n = 242)., Objective: The objective of this study was to compare results from ASTERIA I and II, which included only approved doses of H1-antihistamine as background therapy based on regulatory authority requirements, to those from GLACIAL, which permitted higher doses of H1-antihistamines as well as other types of background therapy, in a post hoc analysis., Methods: Efficacy data from the placebo, omalizumab 150-mg, and omalizumab 300-mg treatment arms of ASTERIA I and II were pooled and analyzed (n = 162 and n = 160, respectively). The 300-mg treatment arm analyses were compared with the analysis of data from GLACIAL (n = 252) using analysis of covariance models. The key efficacy endpoint was change from baseline to week 12 in mean weekly itch severity score (ISS); other endpoints were also evaluated. Safety data were pooled from all 3 studies., Results: Mean ISS was significantly reduced from baseline at week 12 in the pooled ASTERIA I and II omalizumab 150- and 300-mg treatment arms and in the GLACIAL omalizumab 300-mg arm. The weekly ISS reduction magnitude at week 12 was similar between the omalizumab 300-mg groups in the ASTERIA I and II pooled and GLACIAL studies. Similar treatment effect sizes were observed across multiple endpoints. Omalizumab was well tolerated and the adverse-event profile was similar regardless of background therapy for CIU/CSU. The overall safety profile was generally consistent with omalizumab therapy in allergic asthma., Conclusion: Omalizumab 300 mg was safe and effective in reducing CIU/CSU symptoms regardless of background therapy., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

: Urticaria and angioedema are common clinical conditions representing a major concern for physicians and patients alike. The World Allergy Organization (WAO), recognizing the importance of these diseases, has contributed to previous guidelines for the diagnosis and management of urticaria. The Scientific and Clinical Issues Council of WAO proposed the development of this global Position Paper to further enhance the clinical management of these disorders through the participation of renowned experts from all WAO regions of the world. Sections on definition and classification, prevalence, etiology and pathogenesis, diagnosis, treatment, and prognosis are based on the best scientific evidence presently available. Additional sections devoted to urticaria and angioedema in children and pregnant women, quality of life and patient-reported outcomes, and physical urticarias have been incorporated into this document. It is expected that this article will supplement recent international guidelines with the contribution of an expert panel designated by the WAO, increasing awareness of the importance of urticaria and angioedema in medical practice and will become a useful source of information for optimum patient management worldwide.

Angioedema can be caused by either mast cell degranulation or activation of the kallikrein-kinin cascade. In the former case, angioedema can be caused by allergic reactions caused by immunoglobulin E (IgE)-mediated hypersensitivity to foods or drugs that can also result in acute urticaria or a more generalized anaphylactic reaction. Nonsteroidal anti-inflammatory drugs (cyclooxygenase 1 inhibitors, in particular) may cause angioedema with or without urticaria, and leukotrienes may have a particular role as a mediator of the swelling. Reactions to contrast agents resemble allergy with basophil and mast cell degranulation in the absence of specific IgE antibody and can be generalized, that is, anaphylactoid. Angioedema accompanies chronic urticaria in 40% of patients, and approximately half have an autoimmune mechanism in which there is IgG antibody directed to the subunit of the IgE receptor (40%) or to IgE itself (5%-10%). Bradykinin is the mediator of angioedema in hereditary angioedema types I and II (C1 inhibitor [INH] deficiency) and the newly described type III disorder some of which are caused bya mutation involving factor XII. Acquired C1 INH deficiency presents in a similar fashion to the hereditary disorder and is due either toC1 INH depletion by circulating immune complexes or to an IgG antibody directed to C1 INH. Although each of these causes excessive bradykinin formation because of activation of the plasma bradykinin-forming pathway, the angioedema due to angiotensin-converting enzyme inhibitors is caused by excessive bradykinin levels due to inhibition of bradykinin degradation. Idiopathic angioedema (ie, pathogenesis unknown) may be histaminergic, that is, caused by mast cell degranulation with histamine release, or nonhistaminergic. The mediator pathways in the latter case are yet to be defined. A minority may be associated with the same autoantibodies associated with chronic urticaria. Angioedema that is likely to be life threatening (laryngeal edema or tongue/pharyngeal edema that obstructs the airway) is seen in anaphylactic/anaphylactoid reactions and the disorders mediated by bradykinin.