Summary and Conclusions: New Perspectives in Hereditary Angioedema: Molecular Mechanisms and Therapeutic Choices: A CME Symposium Presented at the World Allergy Congress, Buenos Aires, Argentina (December 2009)

1 H ereditary angioedema (HAE) is a relatively rare disease, with an estimated prevalence of approximately 1 per 50,000 in the general population. Despite its rarity, HAE has become an area of intense interest within the medical community. This interest likely reflects several different aspects of HAE, including: the high potential for significant morbidity and mortality associated with attacks of angioedema in HAE patients, the frequent failure to make an accurate and timely diagnosis, the progress in unraveling the underlying pathophysiology of HAE, and the tremendous advances in treatment options. To limit the morbidity and mortality that has long afflicted patients with HAE, it has become increasingly important that the clinician understand both the underlying mechanisms of swelling in HAE and the newer treatment strategies that have been developed for HAE. This supplement contains 3 reviews that summarize the current state-of-the-art regarding the pathophysiology and treatment of HAE. The pathophysiology of HAE is reviewed by Zuraw in this supplement. The discovery that HAE patients were deficient in C1 inhibitor (C1INH) quickly led to the subsequent discovery that the protein could either be nonsecreted (Type I HAE) or dysfunctional (Type II HAE). These observations led to the cloning of the gene for C1INH (SERPING1), and the discovery that HAE ultimately results from a mutation of that gene. Type II HAE has been found to result almost exclusively from mutations on the C1INH reactive mobile loop, while Type I HAE results from mutations scattered throughout the gene. C1INH inactivates a large number of plasma serine proteases, including the complement proteases and contact system proteases. In the absence of sufficient C1INH, these proteolytic cascades become dysregulated. An elegant series of experiments demonstrated that bradykinin, generated through activation of the plasma contact system, is the primary mediator of swelling in HAE. Once generated, brady-kinin binds to bradykinin B2 receptors on vascular endothe-lial cells and increases vascular permeability primarily by disrupting the tight junctions that normally prevent water movement through the endothelial layer. Bradykinin catabo-lism is mediated by several peptidases, and there is evidence that variation in the level of these peptidases by drugs or genetic polymorphisms may influence bradykinin actions. C1INH replacement therapy is reviewed by Frank in this supplement. Although several antifibrinolytics and ana-bolic androgen drugs can decrease HAE attack frequency and severity when administered prophylactically, their efficacy was not perfect and was further limited by side effects. While C1INH concentrates have been …