INTRODUCTION
Patients suffering from the bradykinin-induced genetic disease hereditary angioedema (HAE) show recurrent swelling of subcutaneous and submucosal structures. The attacks can affect almost every part of the body and may lead to a life-threatening situation in case of laryngeal edema. In contrast to allergic angioedema, symptoms are non-pruritic. Triggering factors as well as the frequency of attacks and impairment of the patients’ quality of life vary greatly between individuals.1 The prevalence of diagnosed cases of HAE type I and II (caused by a mutation leading to decreased (=type I) or dysfunctional (=type II) C1-Inhibitor (C1 INH)) is approximately 1.5 per 100 000.2 A third and even rarer type of HAE is known as HAE with normal C1 INH (nC1 INH-HAE). In some of these patients, mutations in the coagulation factor FXII gene, angiopoietin gene, or plasminogen gene are found, but in the majority of cases, the genetic alteration is unknown.3
In HAE type I and II, the mutations are located in the SERPING1 gene on chromosome 11, which encodes for C1 INH. According to a recent publication of Ponard et al, 748 different SERPING1 variants have been found until today in HAE patients.4 It is assumed that no genotype-phenotype relationship exists in HAE.5 C1 INH is involved in numerous physiological processes, including the complement system, the coagulation, and kinin systems.6 Physiologically, the protease inhibitor C1 INH has an inhibitory effect on the synthesis of the tissue hormone BK by blocking kallikrein.7 Kallikrein, on the other hand, cleaves BK from the high-molecular-weight kininogen (HMWK).8,9 BK, in turn, increases vascular permeability and vasodilatation, thus leading to local edema formation.10
For the acute treatment of HAE type I and II attacks, several therapeutic options are available: plasma-derived C1 INH concentrate replaces the missing or dysfunctional complement system regulator and is administered intravenously (Berinert®, Cinryze®). One recombinant human intravenous C1 INH agent is available (Ruconest®) and also licensed for HAE type I and II acute treatment. Icatibant, a specific antagonist of BK 2 receptor (Firazyr®) is the only subcutaneous licensed acute treatment option in the EU in HAE therapy. In the US, ecallantide, an inhibitor of plasma kallikrein (Kalbitor®, sc) is another approved therapy for acute angioedema in HAE patients.11 Most patients diagnosed with HAE are educated in self-application of their medication, which enables direct and successful treatment of edema in most cases.
In HAE type I and II, the mutations are located in the SERPING1 gene on chromosome 11, which encodes for C1 INH. According to a recent publication of Ponard et al, 748 different SERPING1 variants have been found until today in HAE patients.4 It is assumed that no genotype-phenotype relationship exists in HAE.5 C1 INH is involved in numerous physiological processes, including the complement system, the coagulation, and kinin systems.6 Physiologically, the protease inhibitor C1 INH has an inhibitory effect on the synthesis of the tissue hormone BK by blocking kallikrein.7 Kallikrein, on the other hand, cleaves BK from the high-molecular-weight kininogen (HMWK).8,9 BK, in turn, increases vascular permeability and vasodilatation, thus leading to local edema formation.10
For the acute treatment of HAE type I and II attacks, several therapeutic options are available: plasma-derived C1 INH concentrate replaces the missing or dysfunctional complement system regulator and is administered intravenously (Berinert®, Cinryze®). One recombinant human intravenous C1 INH agent is available (Ruconest®) and also licensed for HAE type I and II acute treatment. Icatibant, a specific antagonist of BK 2 receptor (Firazyr®) is the only subcutaneous licensed acute treatment option in the EU in HAE therapy. In the US, ecallantide, an inhibitor of plasma kallikrein (Kalbitor®, sc) is another approved therapy for acute angioedema in HAE patients.11 Most patients diagnosed with HAE are educated in self-application of their medication, which enables direct and successful treatment of edema in most cases.
