A roadmap for optimal care of the patient with hereditary angioedema.

Hereditary angioedema (HAE) is defined as a rare genetic disease with recurrent episodes of localized bradykinin-mediated swelling of the deep tissues of the skin, respiratory, and gastrointestinal tracts that can be life threatening. Classification of HAE has evolved over time with our further understanding of clinical phenotypes, underlying causes, and available testing. In most cases, HAE is caused by a deficiency of C1-esterase inhibitor (C1-INH) on the Serpin Family G Member 1 (SERPING1) gene, either through decreased amounts of C1-INH protein (C1-INH–HAE, type 1) or decreased function of C1INH (C1-INH–HAE, type 2). HAE with normal C1-INH levels and function are divided into unknown cause or into non– C1-INH–HAE forms, which include known mutational defects in factor XII (called FXII-HAE in the Hereditary Angioedema International Working Group consensus), angiopoietin-1, plasminogen, and kininogen 1 genes. It is possible that, after an initial workup, a patient without a family history of HAE could be classified with an acquired form of angioedema (nonhereditary) that may later prove to be HAE due to a de-novo SERPING1 mutation. Because there are forms of nonhistaminergic (H1-antihistamine unresponsive) angioedema that appear clinically very similar to HAE, it is essential that the patient undergoes a thorough clinical history and diagnostic evaluation to ensure that he or she is properly diagnosed and classified. (Allergy Asthma Proc 41:S3–S7, 2020; doi: 10.2500/aap.2020.41.200040) DEFINITION OF HEREDITARY ANGIOEDEMA A ngioedema is defined as “a localized, self-limiting, asymmetric and disfiguring non-inflammatory edema of the deep dermis or subcutaneous or submucosal tissues that occurs as a result of vasodilation and increased vascular permeability. HAE [hereditary angioedema] comprises a group of diseases characterized by recurrent angioedema caused by excess bradykinin production, with an autosomal dominant inheritance pattern. ” Angioedema is seen in;40% of patients with chronic spontaneous urticaria (CSU) but can appear alone in up to 20% of patients. The initial approach in evaluating a patient who presents with isolated angioedema is to determine if the angioedema is responsive or unresponsive to treatments that control CSU; however, appropriate diagnostic testing, e.g., a serum C4 level, to exclude HAE as a potential cause should be obtained simultaneously. An algorithm for evaluating patients who present with wheals and/or angioedema has been adapted as part of an international guideline for the treatment of angioedema and CSU (Fig. 1). In a patient who presents with isolated angioedema and without a family history, response to treatment with H1-antihistamines is helpful both therapeutically and diagnostically. However, if a patient is not responsive to high-dose H1-antihistamines, advocated as step 2 therapy in the urticarial guidelines, it is still possible that a patient may respond to step 3 or step 4 treatments recommended for CSU with or without angioedema. In these circumstances, clinicians should broaden their differential diagnosis to include bradykinin-mediated causes of angioedema. Patients with HAE experience recurrent angioedema attacks anywhere in the body but, most notably, areas that involve the extremities, gastrointestinal tract, oropharynx, face, and genitalia. In addition, they have a reliable family history of angioedema in 75% of cases (usually in a first-degree relative) associated with C1esterase inhibitor (C1-INH) functional deficiency. However, in 25% of patients with HAE, there may be no family history because of a spontaneous de novo mutation. Bradykinin, the mediator involved in HAE, is significantly increased as the result of a deficiency and/or functional abnormality of C1-INH, which is important for regulating bradykinin formation at many sites in the contact pathway. Originalwork byDonaldson andEvans revealed,when using complement component antibodies, that patients with HAE had deficient C1-INH and that other complement components were decreased during and/or between swelling attacks. The relevance of thesefindings has subsequently been confirmed in a number of knockout mouse models and in vitro experiments that ultimately led to the development of several novel and effective therapies designed to either replace C1-INH, block bradykinin 2 From the Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Division of Immunology/Allergy Section, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio; and Bernstein Allergy Group and Bernstein Clinical Research Center, Cincinnati, Ohio JA Bernstein receives grants and honorariums from Shire/Takeda, CSL Behring, Pharming, BioCryst, Kalvista and Inovia. The remaining authors have no conflicts to declare pertaining to this article Funded by the US HAEA (US Hereditary Angioedema Association) Address correspondence to Jonathan Bernstein, M.D., Division of Immunology/ Allergy Section, Department of Internal Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML#563, Cincinnati, OH 45267 E-mail address: bernstja@ucmail.uc. edu Copyright © 2020, OceanSide Publications, Inc., U.S.A. Allergy and Asthma Proceedings S3 DO N OT C OP Y