Hereditary angioedema: an update on available therapeutic options

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1 DOI: /j x Review Article 663 Hereditary angioedema: an update on available therapeutic options Marcus Maurer, Markus Magerl Department of Dermatology, Venereology and Allergy, Charité University Medicine Berlin, Germany JDDG; : Submitted: Accepted: Keywords hereditary angioedema C1-INH bradykinin icatibant androgen derivatives acute therapy prophylaxis Summary There is no cure for hereditary angioedema (HAE). Therapeutic approaches consist of symptomatic therapy for acute attacks, short-term prophylaxis before surgery, and long-term prophylaxis for those with frequent and severe attacks. In Germany, C1-INH concentrate and icatibant are licensed for acute therapy. C1-INH concentrate, which is obtained from human plasma, is administered intravenously to restore the deficient C1-INH activity. This therapy, which has been available for decades, is effective and well-tolerated. Batch documentation is required by German law. The synthetic decapeptide icatibant is administered subcutaneously. It competes with bradykinin, the responsible inducer of edema formation, for binding to the bradykinin B2 receptor. Icatibant is also effective and well-tolerated, even on repeated administration. An additional human C1-inhibitor, a recombinant human C1-inhibitor and the recombinant inhibitor of kallikrein ecallantide are currently under development. There are no licensed treatment options available in Germany for long- and short-term prophylaxis. Androgen derivatives are established in long-term prophylaxis. However, they are associated with many adverse effects, some of which are severe. Many drug interactions also limit their use. They are contraindicated in pregnancy, lactation, for children and in cases of prostate cancer. Antifibrinolytics have fewer adverse effects but are also less effective than androgens. They are contraindicated in thromboembolic disease and impaired vision. If androgen therapy has too negative an effect on quality of life, it may be worth reducing the dose or discontinuing therapy entirely and treating attacks with acute therapy. Introduction Clinical signs and symptoms of hereditary angioedema (HAE) are spontaneous and recurrent attacks of swelling of deep cutaneous tissue and mucous membranes. Almost all HAE patients develop edema of the skin (Figure 1). This can be disfiguring and impede normal life and work [1]. Attacks in the gastrointestinal tract are associated with colicky pain, nausea, vomiting and diarrhea [2]. Because the clinical signs are often non-specific, HAE is often misinterpreted as appendicitis or gastrointestinal ulceration. In about onethird of patient, not indicated surgery is performed (Figure 2) [3]. Laryngeal edema is acutely life-threatening as total obstruction of the airways can develop within hours [4] and require emergency intubation or tracheotomy/ coniotomy [3]. HAE patients have a mutation of the gene for the C1 esterase inhibitor (C1-INH) on chromosome 11. To date over 200 different mutations of the C1-INH gene have been identified [5]. In about every fourth patient the mutation occurs spontaneously; family history is negative then at least with regard to siblings, parents and grandparents. The genetic defect is inherited in an The Authors Journal compilation Blackwell Verlag GmbH, Berlin JDDG /2010/0809 JDDG (Band 8)

2 664 Review Article Hereditary angioedema Figure 1: Angioedema of the tongue, right hand and right arm. autosomal dominant pattern [6, 7]. According to rough estimates the prevalence of hereditary angioedema (HAE) worldwide is about 1:10,000 to 1:50,000. It can be assumed that the number of undetected cases is high, as symptoms resemble those of other diseases and the disease is not well-known [3, 8 10]. The genetic defect leads to a deficiency of or dysfunction of C1-INH that serves as the key inhibitor of the kallikrein-kinin system. This results in increased production of bradykinin which mediates vasodilation and increased vascular permeability. As a consequence typical angioedema of HAE episodes develops [6, 11 16]. In this paper we present treatment options for HAE and based on our experience give hopefully useful tips for colleagues caring for patients with this disorder. HAE and other forms of angioedema To date three subtypes of HAE are known. The two most common can be attributed to deficiency or dysfunction of the C1 inhibitor (HAE type I or HAE type II). The cause of the very rare third subtype (HAE type III) that predominantly affects women is still not fully clarified [3, 17]. For targeted therapy it is important to differentiate hereditary angioedema from other bradykinin-mediated angioedema [11 14] and in particular from histaminemediated angioedema in urticaria and anaphylaxis [18 20] (Table 1). There is no curative therapy for HAE. Therefore emphasis is on treatment and prophylaxis of attacks. First, potential triggers of HAE attacks must be identified. These include foci of infection, medications containing estrogen (contraceptives, hormone replacement), drugs such as ACE inhibitors/ AT1 receptor blockers and physiologic or psychological stress [6]. It is the responsibility of the treating physician to judge the relevance of such factors in each case. If a relation to the occurrence and severity of the attacks is suspected, the patients can try to avoid these triggers. In some cases this can represent an unreasonable effect on quality of life, so that the preventive strategy must be tailored to the individual patient and his situation. There are three different treatment approaches in the medical care of HAE patients [6]: Acute therapy of attacks Short-term prophylaxis before surgical or dental procedures Long-term prophylaxis in cases with frequent and severe attacks Acute therapy Acute therapy is particularly indicated in severe or life-threatening attacks in order to rapidly reduce swelling. This is especially the case for painful abdominal swelling as well as attacks in the headand-neck and laryngeal regions but also for cutaneous edema that affect the patient s quality of life [6]. As expected from its pathomechanism, HAE-induced swelling does not respond to antihistamines, corticosteroids or epinephrine [9, 12, 22]. These drugs are only effective in histamine-mediated angioedema (Table 1). They are nonetheless administered routinely in emergency situations such as attacks in the headand-neck region. If treatment does not lead to a response, angioedema of a nonallergic genesis must be suspected and therapy be changed promptly. It is of great importance for the treating physician to adequately inform and follow HAE patients. Patient information brochures and edema diaries can be sensible aids. Emergency alert cars with therapy recommendations can help emergency physicians recognize HAE, which is usually otherwise unknown. Every HAE patient should therefore receive an emergency alert card and always carry it with him. C1-INH concentrate Since the end of the 1970s, a purified, pasteurized and lyophilized C1-INH concentrate (Berinert P) derived from blood plasma has been available in Europe for the acute therapy of HAE attacks (Table 2). The C1-INH concentrate replaces missing C1-INH activity [6, 8]. The efficacy and tolerability of C1-INH in the treatment of skin edema, abdominal attacks and laryngeal edemas has been demonstrated in a multitude of clinical applications and retrospective studies [6, 8, 23 25]. The IMPACT program (International Multicenter Prospective Angioedema C1-INH Trials) constituted a prospective clinical trial. In IMPACT patients (intention-to-treat population) with moderate to severe abdominal and facial attacks were treated with 10 or 20 units C1-INH concentrate per kg body weight or placebo [26]. With the lower dosage there was no significant advantage of C1-INH concentrate versus placebo. With the higher dosage attack symptoms improved significantly more rapidly than with placebo, with a median of 0.5 versus 1.5 hours (Figure 3). After about five hours signs and symptoms JDDG (Band 8) The Authors Journal compilation Blackwell Verlag GmbH, Berlin JDDG /2010/0809

3 Hereditary angioedema Review Article 665 Figure 2: Local edema of the mucous membrane of the small bowel wall (red circles) with free fluid (ascites) around the bowel loops (CT image left) and scars of a 16-year-old HAE patient due to non-indicated surgery (right). Table 1: Differential diagnosis of angioedema induced by histamine and bradykinin and angioedema of different origin. Mast cell mediator-mediated angioedemas ( with wheals ) Anaphylaxis Urticaria Spontaneous urticaria Acute spontaneous urticaria Chronic spontaneous urticaria Autoreactive Infection Intolerance Other causes Induced urticaria Physical urticaria Exercise-induced urticaria Contact urticaria Bradykinin-mediated angioedemas ( without wheals ) Hereditary angioedemas Type I C1 inhibitor deficient Type II C1 inhibitor defective Type III a) with factor XII defect b) without factor XII defect Acquired angioedemas Acquired C1 inhibitor deficiency (autoantibodies to C1-INH, consumption) *RAAS inhibitor-induced angioedemas (e. g. by ACE inhibitors) Other angioedemas (not mediated by mast cell mediators or bradykinin) *ACE = angiotensin converting enzyme, RAAS = renin-angiotensin-aldosterone system had disappeared completely, in the placebo group after 7.8 hours. Adverse effects occurred significantly less frequently in patients treated with C1-INH than with placebo. No seroconversion for HIV, hepatitis viruses or parvovirus B19 was observed. A subsequent open study (IMPACT-2) examined the time until improvement of symptoms using the licensed dosage of 20 units C1-INH per kg. An interim analysis of 37 patients with 353 HAE attacks confirmed the results of IMPACT-1 with regard to the time until the first improvement of symptoms. The time until complete disappearance of symptoms was between 2.5 hours for laryngeal attacks and 30 hours for peripheral attacks as well as facial swelling [27]. C1-IHN is generally well-tolerated. Temperature elevation, injection site reactions and allergic-anaphylactic reactions were observed in rare cases [28]. Individual cases have been reported where long-term therapy with C1-INH concentrate led to an increased frequency of HAE attacks. What causes this is unclear [29]. In administration of heterologous proteins over a long period of time antibodies can be produced. Despite safety measures on production using human blood plasma the transmission of pathogens cannot completely be excluded. As for all blood products patient- and product-oriented batch documentation is required for C1-INH concentrate by the German transfusion law. Immunization against hepatitis A and B is recommended for patients. Interactions have not been observed to date [28]. C1-INH has been established in the acute therapy of HAE for decades. In severe attacks it can be used in pregnancy and during delivery [6]. It must be noted that it is licensed on the basis of study data in a dosage of 20 units C1-INH concentrate per kg body weight (20 U/kg) and that children receive the same dose as adults [28]. In The Authors Journal compilation Blackwell Verlag GmbH, Berlin JDDG /2010/0809 JDDG (Band 8)

4 666 Review Article Hereditary angioedema Table 2: Information for the administration of C1-INH concentrate and icatibant. C1-INH concentrate Icatibant Product name Berinert P 1 Firazyr 2 Mechanism of action Substitution of deficient C1-INH activity [28] n Selective competitive antagonist of the bradykinin B2 receptor [32] Licensed 3 Since 1979 [28] + Since 2008 [32] - For adults and children [28] + For adults [32] - Administration Side effects Security measures Expiration / storage Medication costs* Intravenous injection or infusion / powder must be dissolved [28] 20 units C1-INH concentrate per kg [28] -> For an attack one bottle with 500 units per 25 kg is needed Temperature elevation, reactions at the injection site [28] Possible allergic reactions [28] - Blood product, therefore batch documentation [28] Expiration date of powder 30 months [28] + Powder stable at room temperature, the dissolved product must be used immediately [28] Manufacturer price per bottle (500 units): Over 50 kg 3 bottles = Over 75 kg 4 bottles = Over 100 kg 5 bottles = Subcutaneous injection / ready-to-use syringe [32] 30 mg icatibant in 3 ml solution [32] -> For an attack one ready-to-use syringe independent of weight is needed - Local reactions at the injection site [32] - Nausea, abdominal pain, weakness, dizziness, headaches, obstructed nose, exanthem, elevated creatinine phosphokinase, abnormal hepatic function parameters [32] - Not a blood product + Expiration date of ready-to-use syringe 24 months [32] - Stable at room temperature [32] + n Manufacturer price per ready-to-use syringe (independent of weight) Medication not used up must be disposed of [28] - Solution is used up completely + 1 CSL Behring, 2 Jerini AG/Shire Human Genetic Therapies, 3 for Germany + Advantage over other product; - Disadvantage in comparison to other product; n neutral, kg kilogram body weight *The actual pharmacy prices may differ from the manufacturer price, further (small) deviations may occur depending on country n n Figure 3: Median time to onset of symptomatic improvement with C1-INH concentrate at a dose of 10 and 20 units per kg body weight compared with placebo [26]. practice too low dosages are often administered. The cost of the medication depends on the body weight of the patient. A solution once prepared must either be used immediately or be discarded. Additional information on the practical use of the concentrate is found in Table 2. Icatibant Since July 2008 the synthetic bradykinin B2 receptor antagonist icatibant (Firazyr ) expands the options for acute therapy of HAE attacks (Table 2). Ten years previously it had been shown that bradykinin is the key mediator of edema in hereditary, acquired and ACE inhibitor-induced angioedema [12]. A pilot study confirmed that selective antagonism of the bradykinin B2 receptor with icatibant reduces both the bradykinin concentration as well as edema signs and symptoms in the HAE patients studied [30]. For the European licensing agencies, in a randomized, double blind, controlled JDDG (Band 8) The Authors Journal compilation Blackwell Verlag GmbH, Berlin JDDG /2010/0809

5 Hereditary angioedema Review Article 667 Figure 4: Median time to a minimum 30 % improvement in symptoms in patients receiving icatibant / placebo (results of FAST-1) or icatibant / tranexamic acid (results of FAST-2 [31]). multicenter study (FAST-2: For Angioedema Subcutaneous Treatment) 74 patients with moderate to severe cutaneous and abdominal attacks were treated with icatibant 30 mg subcutaneously (n = 36) or tranexamic acid mg tablets over 2 days (n = 38) [31]. The primary endpoint an at least 30 % improvement of symptoms was achieved significantly more rapidly with icatibant (2.0 hours versus 12.0 hours with tranexamic acid; Figure 4). In a further study where icatibant was compared to placebo (FAST-1) this endpoint was also achieved in markedly shorter time (2.5 versus 4.6 hours), but lacking statistical significance. The secondary endpoints of both studies proved the superiority of icatibant. In comparison to tranexamic acid the median time to the first improvement of symptoms was 48 minutes versus 7.9 hours, until remission of the attacks by at least 90 % 10 hours versus 51 hours. All differences were highly significant. Laryngeal attacks were treated unblinded in the controlled study phase. The first improvement of symptoms came after a median of 36 minutes in FAST-1 and 60 minutes in FAST-2. In the subsequent open phase of the studies the efficacy of icatibant was similar to that in the controlled phase. Even in recurrent attacks, including laryngeal attacks, in 90 % of cases a single icatibant injection was sufficient. The agent can thus be employed again and again. Icatibant has a favorable safety profile; serious side effects were not observed in clinical studies. Consistent are slight reactions at the injection site that disappear without further measures. Antibody production was not observed. According to the prescribing information caution is warranted for the use of icatibant in patients with acute ischemic myocardial disease, instable angina pectoris as well as in patients in the weeks following a stroke. As icatibant is not metabolized via oxidative pathways, is not an inhibitor of important cytochrome P450 isoenzymes and does not induce CYP 1A2 and 3A4, corresponding pharmacokinetic drug interactions are not expected [32]. Even though has been available only since 2008, the efficacy and tolerability seen under study conditions is also confirmed in clinical practice [33]. Icatibant is available ad 30 mg in 3 ml solution as a ready-to-use syringe for immediate subcutaneous injection in an HAE attack. In almost all cases a single injection is sufficient. There is no experience with children to date [32]. The cost of the medication corresponds to the price of the ready-to-use syringe. This and further information on practical use are found in Table 2. Medications for the future? At present two other substances are under development for the acute therapy of hereditary angioedema. A recombinant human C1 inhibitor (Rhucin ) that is obtained from rabbit milk is intended to compensate the lack of the body s own C1-INH and be employed in the therapy of edema attacks. Phase II and III studies have been completed and confirm its efficacy [34]. The study population was so small that neither immunogenicity with repeated administration nor anaphylactic or allergic reactions could be evaluated, so that it has not yet been licensed in the European Union [35]. The recombinant protein is being tested in further studies. The recombinant kallikrein inhibitor DX-88 (ecallantide) reduces the release of bradykinin, the final product of the kallikrein-kinin cascade. In three phase II studies intravenous ecallantide demonstrated a more rapid improvement of symptoms in comparison to placebo in the therapy of acute HAE attacks. Two phase III studies with subcutaneous administration of ecallantide confirmed its efficacy in moderate to severe HAE attacks (review in [36]). In the USA, ecallantide is already licensed under the name Kalbitor for acute therapy of HAE patients. An application for licensing has not yet been made in the nations of the European Union. Short-term prophylaxis Short-term prophylaxis may be indicated before surgical or traumatic dental procedures in HAE patients for whom these events are known triggers of attacks. There are no licensed substances available in Germany; all use is on an off-label basis. For small procedures it is sufficient to have C1-INH concentrate or icatibant available for immediate use. Many authors recommend oral prophylaxis with androgen derivatives. Danazol should be administered 5 days before and 2 days after the procedure at a dose of mg/kg daily ( mg daily; not in the first two trimesters of pregnancy), stanozolol 48 hours before and after the procedure 2 6 mg daily [6, 8]. Successful use of icatibant as short-term prophylaxis was recently reported in connection with a small surgical procedure on the thyroid gland [37]. Before larger surgical procedures especially in the vicinity of the airways and swallowing apparatus C1-INH concentrate can (in case of intubation must) be infused 1 1 ½ hours before the procedure at a dose of 500 units for each begun 50 kg body weight [6, 8]. For possible follow-up treatment, further doses should be available. As a further alternative antifibrinolytics are available. By inhibiting fibrinolysis they reduce consumption of C1-INH. Tranexamic acid can be administered 48 hours before and after procedure at a dosage of 1 g q.i.d. in adults and 0.5 g q.i.d. in children [6]. This alternative is rarely employed in German-speaking nations. The Authors Journal compilation Blackwell Verlag GmbH, Berlin JDDG /2010/0809 JDDG (Band 8)

6 668 Review Article Hereditary angioedema Table 3: Anabolic adverse effects and risks of androgen therapy: organ damage/ toxicities, tumor development and cardiovascular diseases. Increased risk for Organ damage/ toxicities Tumor development Cardiovascular diseases Organs and side effects Long-term prophylaxis When HAE patients have frequently recurring and severe attacks, a long-term prophylactic strategy may be indicated to reduce frequency and severity of edema attacks. The threshold for continuous drug prophylaxis is highly variable individually depending on impact on quality of life and risk. This should be agreed upon following intensive consultation. For prophylactic therapy very often androgen derivatives and antifibrinolytics are still being employed. In Germany these agents are not licensed for prophylaxis of HAE attacks; their use is on an off-label basis. Liver Cholestatic icterus [51] Elevated liver enzymes [44] Pancreas Pancreatitis [52, 53] Liver Hepatocellular adenomas and carcinomas [44, 51, 54] Benign biliary hamartomas [44] Peliosis hepatis [51] Prostate Prostate cancer [55] Benign prostate hypertrophy [55] Decreased HDL cholesterol and elevated LDL cholesterol [56, 57] Activation of blood coagulation [58] Hypergobulia [43] Elevated arterial blood pressure [44] Androgen derivatives Since decades androgen derivatives have been used for the prophylaxis of HAE attacks. They can be administered orally and are considered despite not being licensed as first-line therapy for longterm prophylaxis as they more effectively reduce frequency and severity of HAE attacks then antifibrinolytics [6, 8]. Due to the long delay in the onset of action, they are not suitable for therapy of acute attacks [6, 38]. In 1960 within the framework of an empirical study for the first time the prophylactic effect of an androgen (methyltestosterone) in a family with suspected HAE was reported. In 1976 the first study with the androgen derivative danazol showing a strong reduction in HAE attacks and an increase in the serum concentration of C1-INH was published. Later further androgen derivatives such as stanozolol and oxandrolone were employed in prophylactic therapy of HAE patients [39]. The exact mechanism of action is still unclear. In principle, only 17 -alkylated androgens are effective in the prophylaxis of HAE attacks. Only these androgen derivatives elevate the concentration of C1-INH [40], which is why increased synthesis of C1-INH in the liver is discussed as mechanism of action [6]. In contrast, studies exist which show that androgen derivatives can control HAE attacks without affecting C1-INH [41]. The most experience for HAE prophylaxis exists for danazol [40, 42 44]. Consensus recommendations consider the dosage necessary for prophylaxis to be 200 mg once or twice daily with the individual required dose also possibly higher [6]. The many known side effects of androgens are problematic. These already occur at therapeutic dosages and increase in frequency and severity with the dose [44]. With respect to the dosage of danazol two different recommendations exist [8]: The Milan protocol suggests starting with a high dose of mg danazol daily for one month and in a stepby-step fashion determining a minimal dose of 50 mg daily on five days per week by titration. In the event of breakthrough attacks the dose is increased until finally the optimal therapeutic dosage is found. The Budapest protocol recommends starting with a lower dose of 200 mg danazol daily for one month. With lack of response the dose is gradually increased to up to 400 mg daily for two to four weeks. When symptom control is achieved, the dose can be decreased in a step-by-step manner but only to minimally 50 mg daily. In practice a maintenance dose of less than 200 mg danazol daily is strived for. Danazol and other 17 -alkylated androgens have a series of side effects that particularly in long-term therapy can significantly impair quality of life. These include virilization, menstrual irregularities up to amenorrhea, infertility, loss of libido, acne as well as psychological abnormalities such as depression and aggressivity. The risk of side effects increases with the dose [44]. Androgenic effects make long-term therapy especially in women, children and adolescents problematic. During pregnancy androgens are absolutely contraindicated; androgen prophylaxis should be avoided in children and adolescents [6]. Anabolic androgen effects in a usually decade-long prophylactic HAE therapy also result in unwanted effects. The most common problem is weight gain which only can be counteracted by great discipline in nutrition and sufficient physical activity. Further, muscle cramps and headaches occur [44]. Other anabolic side effects that not only impair quality of life, but can also have fatal consequences are liver and pancreatic damage, tumors, especially of the liver, as well as cardiovascular damage (Table 3). Close monitoring of therapy is essential when using androgens. In addition to clinical examination and interviewing the patients semiannual laboratory controls of blood count, liver enzymes, serum lipids, creatinine kinase and urinalysis. Ultrasonography of the liver should be performed at least annually [6, 8, 44]. Interactions with other drugs must be considered, especially in longterm use. For example, danazol can potentiate the effects of anticoagulants [45], elevate the concentration of carbamazepine [46] or lead to insulin resistance [47] and thus impair the effectiveness of antidiabetic drugs. JDDG (Band 8) The Authors Journal compilation Blackwell Verlag GmbH, Berlin JDDG /2010/0809

7 Hereditary angioedema Review Article 669 Figure 5: Mechanisms of action of therapeutic drugs for the treatment of HAE. The kallikrein-kinin system is initiated by the coagulation factor XII a (FXIIa) that cleaves prekallikrein. This gives rise to the active enzyme kallikrein, which in turn releases bradykinin (BK) from bound high molecular weight kininogen (HMWK). Bradykinin binds to the bradykinin B2 receptor of endothelial cells. C1-INH and rhc1-inh (recombinant human C1-INH) inhibit both factor XIIa and kallikrein, ecallantide specifically inhibits kallikrein and icatibant blocks the binding of bradykinin to the bradykinin B2 receptor. Anabolic androgens presumably increase hepatic synthesis of C1- INH, antifibrinolytics inhibit activation of plasminogen, leading, in turn, to a reduced consumption of C1- INH. It is a challenge for the treating physician to balance the impairment of quality of life by HAE attacks with the side effects and risks of long-term androgen therapy and possible drug interactions. In addition to the problem of off-label use a further hurdle for the use of androgens exists in Germany: They are considered doping agents. In Germany they are subject to the limitations of paragraph 6a of the Drug Law (Arzneimittelgesetz). Danazol, stanozolol and oxandrolone are not available on the German market. If these agents are imported and employed, the physician must justify their use and inform the patient about the doping problem [48]. Antifibrinolytics Antifibrinolytics have been used in the prophylaxis of HAE attacks since the 1970s. Their use is also on an off-label basis. Tranexamic acid or -aminocaproic acid are administered orally; they inhibit plasminogen activation and thus fibrinolysis which results in reduced consumption of C1-INH. The initial dose for tranexamic acid is g two to three times daily with a stepwise reduction depending on clinical findings to 0.5 g once or twice daily [6]. The effectiveness of antifibrinolytics is lower than that of androgen derivatives. Both agents are contraindicated in thromboembolic diseases and visual disturbances. Side effects include nausea, dizziness, diarrhea, fatigue and muscle cramps. A possible tendency for thrombosis must be considered during therapy with antifibrinolytics [6, 8, 49]. Tranexamic acid or -aminocaproic acid are rarely used in German-speaking nations for prophylaxis of HAE. C1-INH concentrate Some authors recommend using C1- INH concentrate prophylactically for patients frequently affected when androgens or antifibrinolytics are insufficiently effective, have too strong side effects or are contraindicated [6]. Up to twice weekly units C1-INH should be administered by infusion (over 100 kg body weight 1500 units) [6, 8]. A variation of continuous prophylaxis is the individual replacement therapy. Here patients experienced in self-infusion are instructed to initiate C1-INH concentrate therapy at the first signs of an acute attack. The first experiences with this long-term therapy with C1-INH con- The Authors Journal compilation Blackwell Verlag GmbH, Berlin JDDG /2010/0809 JDDG (Band 8)

8 670 Review Article Hereditary angioedema centrate exist in Germany [50]. In the USA a C1-INH concentrate derived from human plasma is licensed under the trade name Cinryze expressly and exclusively for prophylaxis of HAE attacks. Conclusions and outlook Even though hereditary angioedema cannot be cured, acute attacks can be treated symptomatically with success. For this purpose C1-INH concentrate derived from blood plasma (Berinert P) and synthetically produced icatibant (Firazyr ), tow effective and well-tolerated treatment options that act at different sites of the pathophysiologic cascade, are available. While C1-INH concentrate acts in an early stage of the kallikrein-kinin system, icatibant displaces bradykinin from its receptor on the vessel endothelium (Figure 5). Further agents such as recombinant human C1 inhibitor (Rhucin ) and recombinant kallikrein inhibitor ecallantide will after licensing expand options for acute therapy of HAE attacks. For short- and long-term prophylaxis no licensed medications are available today. Androgen derivatives, that probably increase production of C1-INH in the liver (Figure 5), are established in longterm prophylaxis; their use is limited by a high risk of side effects, drug interactions and contraindications. Antifibrinolytics possess only low effectiveness in prophylactic therapy and are therefore not an alternative. First experiences are being acquired with C1-INH for a long-term therapy strategy. When prophylaxis with androgens is not effective or their side effects impair the patient too greatly, it may be reasonable to reduce the dose or even completely discontinue them. Attacks that then occur are treated according to acute therapy for which effective medications are available. The treating physician must balance the impairment of quality of life of the patient due to androgen prophylaxis against the (re-)occurrence of acute HAE attacks in order to select the individual best therapy possible. Conflict of interest Marcus Maurer has received grant/ research support and/or personal benefits for lectures or expert committees from Almirall, Essex Pharma, Jerini/Shire, Novartis, Schering-Plough, UCB, and Uriach. Markus Magerl has been a speaker for Almirall, Essex Pharma, and Jerini/Shire. <<< Correspondence to Prof. Dr. Marcus Maurer Charité University Medicine Berlin Department of Dermatology, Venereology and Allergy Allergy Center Charité Charitéplatz 1 D Berlin, Germany Tel.: Fax: marcus.maurer@charite.de References 1 Bracho FA. Hereditary angioedema. Curr Opin Hematol 2005; 12: Bork K, Staubach P, Eckardt AJ, Hardt J. Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency. 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