Recombinant human C1 esterase inhibitor for hereditary angioedema attacks: A European registry.

BACKGROUND: Hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (C1-INH-HAE) is characterized by recurrent swelling attacks. A European treatment registry was established to review the adverse event profile and efficacy of recombinant human C1 esterase inhibitor (rhC1-INH) for HAE attacks. METHODS: Individuals with C1-INH-HAE were enrolled following a decision to treat with rhC1-INH and provision of written informed consent. Medical history and baseline HAE information were collected at screening. Healthcare providers entered data on HAE attacks, response to treatment, and adverse events using a web-based questionnaire. RESULTS: From July 1, 2011, through December 1, 2019, 71 patients with C1-INH-HAE (30 male/41 female; mean age, 47.3 years; age range, 19-78 years) in 9 countries reported 2356 attacks and were treated with rhC1-INH. Before registry entry, patients, including 20 (28.2%) who were on maintenance therapy/prophylaxis at registry enrollment, experienced a mean of 25 HAE attacks per year (median, 16 [range, 0-185]). Most treated HAE attacks were abdominal (46.1%), followed by peripheral (38.3%), oro-facial-pharyngeal (14.8%), urogenital (3.2%), and laryngeal (2.6%). The mean rhC1-INH dose was 3307 U (43.3 U/kg). Patients reported symptom improvement within 4 h for 97.8% of attacks (2305/2356) with rhC1-INH; most attacks (99.8%; 2351/2356) required only 1 dose. Five attacks were treated with a second dose (total rhC1-INH dose administered for attack, 4200 U). No hypersensitivity, thrombotic/thromboembolic events, or drug-related serious adverse events were reported. CONCLUSION: The rhC1-INH treatment registry provided real-world data on the treatment of 2356 HAE attacks that were consistent with clinical trial data of rhC1-INH in patients with C1-INH-HAE.

How Angioedema Quality of Life Questionnaire Can Help Physicians in Treating C1-Inhibitor Deficiency Patients?

The Angioedema Quality of Life Questionnaire (AE-QoL) is an angioedema (AE)-specific validated questionnaire, which surveys the quality of life of diagnosed patients. The questionnaire has been used in multiple clinical trials. Our aim was to investigate how the questionnaire can assist physicians in the everyday practice of following up and managing C1-inhibitor deficiency patients. In a prospective trial conducted in our center between 2016 and 2018, 125 hereditary angioedema and 10 diagnosed with acquired angioedema completed an AE-QoL during their annual follow-up visit. Laboratory indices (i.e., complement levels) were obtained for each patient. Statistical analysis comparing clinical data with QoL parameters was performed. Results of the analysis show that AE-QoL total score and number of AE attacks per year correlated well (r = 0.47; p < 0.0001). Women reached higher AE-QoL total score values than men, over a 3-year period (p = 0.0014). The highest AE-QoL total scores were reached by the 41-60-year age group; we obtained a similar result, when analyzing the four domains. No correlation was found between the AE-QoL total score and complement parameters. Patients with a negative correlation between AE-QoL total score and number of AE attacks had a positive correlation with psychologic attributes like fatigue/mood and fears/shame domains. Patients that acquired HAE showed a significant correlation between the annual number of AE attacks and the AE-QoL total scores (r = 0.46; p < 0.0001). The study establishes the use of AE-QoL as a clinical tool for follow-up which can help in the complex assessment of both hereditary and acquired HAE patients, and help to develop better therapeutic strategies.

Pathways of Neutrophil Granulocyte Activation in Hereditary Angioedema with C1 Inhibitor Deficiency.

Hereditary angioedema (HAE) with C1-inhibitor deficiency belongs to bradykinin-mediated angioedemas. It is characterized by recurrent subcutaneous and/or submucosal swelling episodes (HAE attacks) and erythema marginatum skin rash as a pre-attack (prodromal) phase. HAE attacks were shown to be accompanied by peripheral blood neutrophilia. We aimed to find molecular mechanisms that may explain the distinct role of neutrophil granulocytes in HAE. Plasma levels of blood cells and factors related to neutrophil activation (cytokines, chemokines, chemotactic factors, enzymes, and neutrophil extracellular trap) were measured in plasma samples obtained from patients during symptom-free periods (n = 77), during prodromal phase (n = 8) and attacks (n = 14), during a spontaneously resolved attack (n = 1), and in healthy controls (n = 79). Higher counts of white blood cells, lymphocytes, and neutrophil granulocytes were found in symptom-free patients compared with controls; these cell counts were elevated further during HAE attacks. The level of chemokine (C-C motif) ligand 5, monocyte chemoattractant protein-1, and myeloperoxidase were also higher in the symptom-free patients than in the controls. Levels of monocyte chemoattractant protein-1, leukotriene B4, neutrophil elastase, and myeloperoxidase were elevated during attacks. During erythema marginatum, white blood cells and monocyte count and levels of interleukin 8 were elevated compared with symptom-free period. Similar changes were detected during the attack follow-up. We conclude that the activation of NGs in symptom-free periods and a further increase observed during attacks suggests that NGs may be involved in the pathomechanism of HAE with C1-INH deficiency.

The Importance of Complement Testing in Acquired Angioedema Related to Angiotensin-Converting Enzyme Inhibitors.

BACKGROUND: Angiotensin-converting enzyme inhibitors may cause angioedema. Currently, no laboratory method is available for identifying acquired angioedema related to angiotensin-converting enzyme inhibitors. However, establishing the diagnosis is possible from the medical history and the preexisting angiotensin-converting enzyme inhibitor therapy, as well as by excluding other angioedema types. OBJECTIVE: To evaluate the results of complement testing in patients experiencing angioedema while taking angiotensin-converting enzyme inhibitors. METHODS: Between 2005 and 2019, a total of 149 patients taking angiotensin-converting enzyme inhibitors were referred to our Angioedema Center for the diagnostic evaluation of recurrent angioedema episodes. Complement measurement was performed on these patients. RESULTS: The mean age of the 149 patients treated with angiotensin-converting enzyme inhibitors at the onset of the index angioedema episode was 55.8 years. The mean interval between the introduction of angiotensin-converting enzyme inhibitor therapy and the occurrence of the initial symptoms of angioedema was 43 months. The most commonly used angiotensin-converting enzyme inhibitor was perindopril (32.9% of the patients). The initial angioedema episode involved the face in 50.3%, the lips in 40.9%, and the tongue in 33.5% of the patients. Angiotensin-converting enzyme inhibitors were discontinued in all 149 patients, and at the same time, a complement test was performed. The complement tests confirmed hereditary angioedema with C1-inhibitor deficiency in 2 patients and an additional 12 family members. Acquired angioedema with C1-inhibitor deficiency was found in 3 patients. CONCLUSIONS: Excluding hereditary angioedema and acquired angioedema with C1-inhibitor deficiency is indispensable for establishing the diagnosis of acquired angioedema related to angiotensin-converting enzyme inhibitors.

Patterns of C1-Inhibitor/Plasma Serine Protease Complexes in Healthy Humans and in Hereditary Angioedema Patients.

C1-inhibitor (C1-INH) is an important regulator of the complement, coagulation, fibrinolytic and contact systems. The quantity of protease/C1-INH complexes in the blood is proportional to the level of the in vivo activation of these four cascade-like plasma enzyme systems. Parallel determination of C1-INH-containing activation complexes could be important to understand the regulatory role of C1-INH in diseases such as hereditary angioedema (HAE) due to C1-INH deficiency (C1-INH-HAE). We developed in-house ELISAs to measure the concentration of complexes of C1-INH formed with active proteases: C1r, C1s, MASP-1, MASP-2, plasma kallikrein, factor XIIa, factor XIa, and thrombin, as well as to determine total and functionally active C1-INH. We measured the concentration of the complexes in EDTA plasma from 6 healthy controls, from 5 with type I and 5 with type II C1-INH-HAE patients during symptom-free periods and from five patients during HAE attacks. We also assessed the concentration of these complexes in blood samples taken from one C1-INH-HAE patient during the kinetic follow-up of a HAE attack. The overall pattern of complexed C1-INH was similar in controls and C1-INH-HAE patients. C1-INH formed the highest concentration complexes with C1r and C1s. We observed higher plasma kallikrein/C1-INH complex concentration in both type I and type II C1-INH-HAE, and higher concentration of MASP-1/C1-INH, and MASP-2/C1-INH complexes in type II C1-INH-HAE patients compared to healthy controls and type I patients. Interestingly, none of the C1-INH complex concentrations changed significantly during HAE attacks. During the kinetic follow-up of an HAE attack, the concentration of plasma kallikrein/C1-INH complex was elevated at the onset of the attack. In parallel, C1r, FXIIa and FXIa complexes of C1-INH also tended to be elevated, and the changes in the concentrations of the complexes followed rather rapid kinetics. Our results suggest that the complement classical pathway plays a critical role in the metabolism of C1-INH, however, in C1-INH-HAE, contact system activation is the most significant in this respect. Due to the fast changes in the concentration of complexes, high resolution kinetic follow-up studies are needed to clarify the precise molecular background of C1-INH-HAE pathogenesis.

Clinical Characteristics and Safety of Plasma-Derived C1-Inhibitor Therapy in Children and Adolescents with Hereditary Angioedema-A Long-Term Survey.

BACKGROUND: Plasma-derived C1-inhibitor (pdC1-INH) is a first-line therapy for hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) in pediatric patients. OBJECTIVE: We intended to study the clinical characteristics and safety of treatment with pdC1-INH in this population. METHODS: In the prospective, long-term survey, real-world data on pdC1-INH (Berinert, CSL Behring) use in pediatric patients, diagnosed and followed up at our Angioedema Reference Center, were analyzed for the period from 1986 to 2018. RESULTS: A total of 70 pediatric patients (31 boys and 39 girls) experienced a total of 3009 HAE attacks. The most common location of HAE attacks was subcutaneous. HAE attacks of any location were more frequent in girls versus boys, except for genital edema. Among the 70 patients, 37 received pdC1-INH for 456 HAE attacks, or as prophylaxis (69 vials). On average, 14.2 vials were administered per patient. The distribution of pdC1-INH use in the different age groups was as follows: no use (0-1 years), 0.11 vials/year (1-3 years), 0.7 vials/year (3-6 years), 1.26 vials/year (6-12 years), and 1.28 vials/year (12-18 years). No systemic allergic reactions, viral transmission, development of anti-C1-INH antibodies, or thromboembolic events occurred in relation to treatment with this drug. CONCLUSION: We confirmed that the clinical manifestations and the use of pdC1-INH are different in the various age groups of pediatric patients with C1-INH-HAE. Our long-term survey shows that the use of pdC1-INH is safe in this patient population.

Changes of coagulation parameters during erythema marginatum in patients with hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) is characterized by recurrent episodes of subcutaneous/submucosal edema, which may be preceded by erythema marginatum (EM) as a prodromal symptom. Our aim was to analyze the changes occurring in the parameters of the coagulation system during the development of EM and HAE attacks. MATERIALS AND METHODS: Eight C1-INH-HAE patients (1 male, 7 females, median age: 41.7 years) were studied. Blood samples were obtained from all patients (during symptom-free periods, EM, and HAE attacks), as well as from 20 sex- and age-matched healthy controls. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, D-dimer, Factor V, Factor VII, Factor X, Factor XI, and Factor XII levels were measured. RESULTS: D-dimer levels were significantly lower, whereas aPTT was significantly prolonged in healthy controls vs. the values measured during the symptom-free period (p = 0.0497; p = 0.0043), in the presence of EM (p = 0.002; p = 0.0002), or during HAE attacks (p < 0.0001; p = 0.0002). We observed the following differences between samples taken during HAE attacks vs. in symptom-free periods: D-dimer levels were significantly elevated (p = 0.0391), while aPTT was significantly shorter during HAE attacks (p = 0.0159). D-dimer levels were significantly higher during EM than in symptom-free periods (p = 0.0078). Comparing the samples drawn during EM or during HAE attacks, there were no significant differences in the study parameters. CONCLUSIONS: D-dimer levels were elevated during EM and this suggests that EM may be part of the HAE attack. Nevertheless, further research into the complement and kinin-kallikrein systems is needed in more patients for a better understanding of the pathomechanism of EM.

Evaluation of the efficacy and safety of home treatment with the recombinant human C1-inhibitor in hereditary angioedema resulting from C1-inhibitor deficiency.

OBJECTIVE: Conestat alpha, a C1-inhibitor produced by recombinant technology (rhC1-INH) is an acute treatment for edematous attacks occurring in hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE). Our study evaluated the efficacy and safety of rhC1-INH administered during HAE attacks, and for short-term prophylaxis (STP). MATERIALS & METHOD: Our prospective study analyzed the course of 544 HAE attacks experienced by the 21 C1-INH-HAE patients treated, as well as the outcome of 97 instances of STP implemented with rhC1-INH. Using a purpose-designed questionnaire, the patients recorded relevant, treatment-related information. RESULTS: Time to the administration of rhC1-INH was 90.0 min (median) after the onset of HAE attacks. The symptoms started to improve as early as 60 min after the injection of rhC1-INH, and the attack resolved 730.0 min after treatment. The interval between the onset of the HAE attack and the administration of rhC1-INH correlated with time until the onset of improvement (R = 0.2053 p < 0.0001), and with time to the complete resolution of symptoms (R = 0.2805, p < 0.0001). Nine patients received STP with rhC1-INH in 97 instances. STP successfully prevented the HAE attack within 72 h of the event on 93/97 occasions. No local and serious systemic adverse events/effects were observed. CONCLUSIONS: Treatment with rhC1-INH is effective and safe both for acute management, and for STP. Following the onset of an HAE attack, early administration of rhC1-INH may reduce time to the improvement and to the complete resolution of symptoms. Repeated administration of rhC1-INH does not impair its efficacy.

[Analysis of the relationship between vitamin D3 level and disease severity in hereditary angioedema]. / A D3-vitamin-szint és a betegség súlyossága közötti kapcsolat vizsgálata herediter angioödémában.

Introduction: In recent years, many papers analyzed the relationship between serum vitamin D3 level and the frequency and activity of various diseases at least partially attributed to immune mechanisms. Aim: We looked for correlations among the number and location of edematous episodes occurring in patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) and the quantity of the C1-inhibitor used for supplementation as well as the vitamin D3 levels of patients. Method: We measured vitamin D3 levels in 118 of the 175 C1-INH-HAE patients of the National Angioedema Reference Center during the winter-spring (n = 111) and the summer-autumn periods (n = 105) in 2013-2014. Complement levels and clinical data were extracted from the National Angioedema Registry and from patient diaries. Results: The proportion of vitamin D3 deficient patients (serum level <20 ng/ml) was approximately 59.5% during winter-spring, 27.6% in summer-autumn, and 23.5% during both periods. There was a significant difference between vitamin D3 serum levels measured in the winter-spring or in the summer-autumn months (p<0.0001). The same applies to the number of the vials of C1-inhibitor concentrate administered as acute treatment for angioedema attacks (p = 0.01). In any season, vitamin D3 level did not correlate with the number of attacks experienced by the patients during the given period or of the vials of C1-inhibitor concentrate administered. Conclusions: We could not demonstrate a relationship between vitamin D3 level and the frequency or location of edematous episodes in HAE patients. The need for treatment (as reflected by the number of the vials administered) was higher in the winter-spring period. As vitamin D3 deficiency was more severe than expected in our patients, supplementation is clearly necessary. Orv Hetil. 2019; 160(25): 987-993.

Flow-mediated vasodilation assay indicates no endothelial dysfunction in hereditary angioedema patients with C1-inhibitor deficiency.

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare, potentially life-threatening disorder characterized by recurrent edematous attacks. The edema formation is the consequence of interaction of bradykinin and various vasoactive peptides with endothelium. Besides these agents, danazol, a modified testosterone derivative used in these patients to prevent edematous attacks, can also affect the function of the endothelium, because it shifts the blood lipid profile to a pro-atherogenic phenotype. OBJECTIVE: To assess the endothelial function in C1-INH-HAE patients and in healthy matched controls. METHODS: To evaluate the endothelial function, we used the flow-mediated dilation method measured in the region of the brachial artery in 33 C1-INH-HAE patients and in 30 healthy matched controls. Laboratory measurements of standard biochemical parameters were performed on computerized laboratory analyzers. RESULTS: No difference was found in endothelial function (reactive hyperemia, RH) between patients (median, 9.0; 25%-75% percentile, 6.3-12.9) and controls (median, 7.37; 25%-75% percentile, 4.52-9.93). Although we found elevated cardiovascular risk (high body mass index and low-density lipoprotein/high-density lipoprotein ratio) in danazol-treated C1-INH-HAE patients, RH values did not differ between danazol-treated and nontreated patients. Furthermore, risk factors correlated with the endothelial function only in healthy controls and patients not treated with danazol. CONCLUSION: In summary, our results did not indicate any signs of endothelial dysfunction in C1-INH-HAE patients. Moreover, the normal endothelial function in danazol-treated patients with pro-atherogenic lipid profile suggests that elevated bradykinin level or other factor(s) involved in the pathogenesis of edematous attacks may have a protective role against endothelial dysfunction and atherosclerosis.

Idiopathic Nonhistaminergic Acquired Angioedema Versus Hereditary Angioedema.

BACKGROUND: The mechanism of idiopathic nonhistaminergic acquired angioedema (InH-AAE) has not yet been precisely elucidated. This condition is characterized by recurrent angioedema without wheals. OBJECTIVE: To study the clinical features of InH-AAE, and to make, for the first time, independent comparisons with hereditary angioedema of unknown origin (U-HAE), as well as with hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE). METHODS: We compared the clinical parameters of 46 patients with InH-AAE with those of 27 patients suffering from U-HAE, as well as of 73 patients with C1-INH-HAE. RESULTS: The mean age at the onset of symptoms was 36 years in InH-AAE, 13 years in C1-INH-HAE, and 29 years in U-HAE. More than 12 edematous episodes occurred over a year in 56% of patients with InH-AAE, in 59% of those with C1-INH-HAE, and in 48% of those with U-HAE. Edema of the extremities, of the upper airways, and of the gastrointestinal tract was more common in patients with C1-INH-HAE (92%, 51%, and 75%, respectively). These manifestations occurred less frequently in patients with InH-AAE (54%, 28%, and 20%) and in patients with U-HAE (37%, 29%, and 20%). By contrast, facial edema occurred in only 15% of patients with C1-INH-HAE, but in 67% of patients with InH-AAE and in 59% of patients with U-HAE. CONCLUSIONS: The clinical manifestations of patients with InH-AAE were different from those of patients with C1-INH-HAE. This may indicate different processes underlying edema formation in these disease forms. The close resemblance of the clinical manifestations in InH-AAE and U-HAE might suggest a similarity between the pathophysiology of these conditions.

Icatibant for the treatment of hereditary angioedema with C1-inhibitor deficiency in adolescents and in children aged over 2 years.

INTRODUCTION: Hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE) is a rare disorder with life-threatening complications if untreated. It begins during childhood, and reduces the patient's quality of life. Therefore, the availability of an easily administered agent to relieve unpredictable HAE episodes is indispensable for this age group. Areas covered: Randomized, double-blind, placebo-controlled, open-label extensions and prospective observational studies have proven the safety and efficacy of the subcutaneously administered bradykinin B2 receptor antagonist, icatibant, in the acute treatment of HAE episodes in adult C1-INH-HAE patients. Recently, a Phase 3, multicenter, open-label, non-randomized, single-arm study demonstrated the efficacy, safety, and tolerability of icatibant as an acute treatment for pediatric patients aged 2 years to less than 18 years. Expert commentary: The clinical study in pediatric patients showed that icatibant undergoes rapid absorption, reaches a therapeutic level, and promptly relieves the symptoms. It is well tolerated, and the subcutaneous preparation, presented in a pre-filled syringe, ensures ease of use. It can be administered anytime, anywhere, and instantly - even by the patients themselves, or - in the case of children and adolescents - by a caregiver. Icatibant may greatly contribute to the improvement of the quality of life of pediatric patients.

Investigational drugs in phase I and phase II clinical trials for hereditary angioedema.

INTRODUCTION: Hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) is a rare bradykinin-mediated disease characterized by recurrent subcutaneous and/or submucosal angioedematous attacks (HAE attacks), which occur unpredictably. The recurrent HAE attacks do not respond to conventional treatments, and may evolve into a life-threatening condition; therefore, special therapy is required. AREAS COVERED: The agents used so far for the acute management of HAE attacks act by blocking the release of bradykinin, or its binding to its receptor. By contrast, the investigational medicinal products under evaluation in Phase I and II clinical trials are targeted at the prevention of HAE attacks. Chemically, these new drugs are small synthetic molecules, oligonucleotides, or antibodies, which inhibit either kallikrein, or Factor XII. EXPERT OPINION: The key considerations for the development of new medicinal products include more straightforward dosing, self-administration, longer duration of action, and keeping the patient attack-free. This review summarizes the status and the findings of the currently ongoing Phase I and Phase II clinical trials of C1-INH-HAE.

[Effect of danazol treatment on growth in pediatric patients with hereditary angioedema due to C1-inhibitor deficiency]. / A danazolkezelés hatása C1-inhibitor-hiány okozta hereditaer angiooedemás gyermekek növekedésére.

INTRODUCTION: Attenuated androgens are used for the prevention of angioedema attacks of hereditary angioedema with C1-inhibitor deficiency. After prepuberty, their use can lead to growth retardation. AIM: We assessed the effect of danazol on the growth of pediatric patients with hereditary angioedema. METHOD: In the retrospective study on 42 patients diagnosed with hereditary angioedema, we calculated the deviation from the mid-parental target height, and analyzed it against the gender, the dose and duration of danazol treatment administered before the age of 21 years and before the age of 16 years. RESULTS: Regarding the deviation from the mid-parental target height, we did not find any significant difference between patients taking vs. not taking danazol, males vs. females taking danazol. The dose and the duration of danazol treatment did not influence that value neither before 21, nor before 16 years of age. CONCLUSIONS: Our findings suggest that treatment with the lowest effective doses of danazol does not influence growth. Orv Hetil. 2017; 158(32): 1269-1276.

A novel prophylaxis with C1-inhibitor concentrate in hereditary angioedema during erythema marginatum.

BACKGROUND: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is a rare, autosomal dominant disorder. The characteristic episodes of subcutaneous/submucosal edema formation may be preceded by erythema marginatum (EM) - the occurrence of a 'map-like' pattern on the skin. EM can occur as an isolated finding or accompanying a hereditary angiooedema (HAE) attack as well. Nevertheless, it is unknown whether a HAE attack can be prevented by the proper prophylactic treatment during EM. OBJECTIVES: Our aim was to assess the prevalence of EM in the Hungarian C1-INH-HAE population and to introduce a safe and effective novel prophylactic treatment during EM in patients who's HAE attacks are preceded by EM in a considerable proportion of the cases. RESULTS: Based on the data of the Hungarian HAE Registry, 49 among 173 C1-INH-HAE patients (28.3%) from 32 families had EM in their life. According to the clinical data and the patient's HAE diaries, two patients (Patient #1, Patient #2) were selected who frequently had EM as a prodromal symptom. Both patients were instructed to administer plasma-derived C1-inhibitor concentrate (pdC1-INH) as soon as possible after the onset of EM, in order to prevent the development of HAE attack. Interestingly, HAE attacks never developed if pdC1-INH was administered within 6h from the occurrence of EM in both patients. In contrast, without pdC1-INH treatment, in Patient 1 and Patient 2, 97.0% and 44.3% of the EM were followed by a HAE attack, respectively (p<0.0001, Fisher's exact test). CONCLUSIONS: As a novel prophylaxis in C1-INH-HAE, intravenous administration of pdC1-INH concentrate during EM might be an effective, individual therapeutic strategy in those patients who's HAE attacks are often preceded by EM. Besides it can improve the quality of life of these selected patients, pdC1-INH administration during EM provides the lowest effective dose for the prophylaxis of their HAE attacks.

Health-related quality of life among children with hereditary angioedema.

BACKGROUND: The clinical expressions of hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) and its related burden may negatively affect patient quality of life. This study aimed to assess health-related quality of life (HRQoL) in children with C1-INH-HAE. METHODS: Children (N = 98: 34 C1-INH-HAE patients, 64 healthy controls) aged 3-18 years were recruited in Israel and Hungary. All individuals completed a demographic questionnaire, a disease activity and site questionnaire, and the Pediatric Quality of Life Inventory (PedsQL™) 4.0 Generic Core Scales (child self-report and maternal proxy report) to assess HRQoL. RESULTS: Among C1-INH-HAE patients, nine (26.5%) had 1-5 attacks/year, six (17.6%) had 6-18 attacks/year, eight (23.5%) had 25-60 attacks/year, and 11 (32.4%) were asymptomatic over the previous year. Children with C1-INH-HAE attacks demonstrated lower HRQoL than healthy control children across the total score, school, and psychosocial dimensions of the PedsQL™. The number of C1-INH-HAE attacks negatively correlated with the total HRQoL score (r = -0.48, p = 0.008), school-related HRQoL (r = -0.39, p = 0.02), and psychosocial HRQoL (r = -0.43, p = 0.01). Patients with multisite laryngeal, abdominal, and peripheral C1-INH-HAE attacks had a lower HRQoL compared with those who experienced solely peripheral attacks across the total score (p = 0.04), physical (p = 0.04), and school (p = 0.02) domains. There was no significant difference between asymptomatic C1-INH-HAE patients and healthy controls. CONCLUSIONS: Children with symptomatic C1-INH-HAE demonstrate impaired HRQoL compared with healthy controls. HRQoL was affected by the frequency and site of C1-INH-HAE attacks and mostly in the school and physical domains.

Glucocorticoid receptor gene polymorphisms in hereditary angioedema with C1-inhibitor deficiency.

BACKGROUND: Hereditary angioedema caused by C1-inhibitor deficiency (C1-INH-HAE) is a rare, autosomal dominant disorder. C1-INH-HAE is characterized by edema-formation, which may occur in response to stress. The individual's response to stress stimuli is partly genetically determined. Activation of the hypothalamic-pituitary-adrenal axis results in the release of cortisol. In turn, the secreted gluco- and mineralocorticoids affect the metabolism, as well as the cardiovascular and immune systems. We hypothesized that changes in serum cortisol level and polymorphisms of the glucocorticoid receptor (GR) modify the individual sensitivity to stressor stimuli of C1-INH-HAE patients. RESULTS: We compared the response to stress with Rahe's Brief Stress and Coping Inventory of 43 C1-INH-HAE patients, 18 angioedema patients and 13 healthy controls. 139 C1-INH-HAE patients and 160 healthy controls were genotyped for glucocorticoid receptor polymorphisms BclI, N363S and A3669G. Serum cortisol levels were determined during attacks and during symptom-free periods in 36 C1-INH-HAE patients. The relationships between clinical, laboratory data and GR SNPs (Single Nucleotide Polymorphisms) were assessed using ANOVA. C1-INH-HAE patients have decreased coping capabilities compared to healthy controls. Cortisol levels were significantly higher during attacks than in symptom-free periods (p = 0.004). The magnitude of the elevation of cortisol levels did not show a significant correlation with any clinical or laboratory data. Among the C1-INH-HAE patients, the carriers of the A3669G allele had significantly lower cortisol levels, and increased body mass index compared with non-carriers. CONCLUSIONS: The higher cortisol level observed during attacks may reflect the effect of a stressful situation (such as of the attack itself), on the patients' neuroendocrine system. In A3669G carriers, the lower cortisol levels might reflect altered feedback to the hypothalamic-pituitary-adrenal axis, due to decreased sensitivity to glucocorticoids.

First report of icatibant treatment in a pregnant patient with hereditary angioedema.

Hereditary angioedema resulting from C1-inhibitor deficiency (C1-INH-HAE) is a rare, autosomal dominant disorder, characterized by recurrent attacks of edema formation. The management of pregnant patients with C1-INH-HAE is often a challenge for the physician. There is limited experience with novel therapies. Plasma-derived nanofiltered C1-INH (pnfC1-INH) is the only recommended therapeutic option during pregnancy. In our 26-year-old female patient with type II C1-INH-HAE, pregnancy was confirmed in the sixth week of gestation. During this period, the patient received the bradykinin B2-receptor antagonist, icatibant, on five occasions, as acute treatment. She experienced 119 attacks, for which she received 108 vials of pnfC1-INH during her pregnancy. The patient gave birth to a healthy baby. No side effects were detected with either treatment. No reports have been published to date on multiple dosing with icatibant during the first trimester of pregnancy. This therapy proved effective and free of maternal or fetal adverse effects.

The effect of long-term danazol treatment on haematological parameters in hereditary angioedema.

BACKGROUND: The 17-alpha-alkylated derivatives of testosterone are often used for the prevention of oedematous episodes in hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE). However, these agents can have many adverse effects, including erythrocytosis and polyglobulia. Our aim was to investigate occurrence of erythrocytosis and polyglobulia after long-term danazol prophylaxis in C1-INH-HAE. METHODS: During the initial stage of our retrospective study, we explored whether C1-INH-HAE is associated with susceptibility to erythrocytosis and/or polyglobulia. In the second stage, we analyzed the haematological parameters of 39 C1-INH-HAE patients before, as well as after treatment with danazol for 1, 3, or 5 years. In the third stage, we studied the incidence of erythrocytosis and of polyglobulia after dosing with danazol for more than 5 years. RESULTS: We did not find any significant difference between C1-INH-HAE patients not receiving danazol and healthy controls as regards the occurrence of erythrocytosis or polyglobulia. The haematological parameters did not change after treatment with danazol for 1, 3, or 5 years. Platelet count was an exception-it decreased significantly (p = 0.0115) versus baseline, but within the reference range. Treatment-related polyglobulia did not occur. We observed erythrocytosis in a single female patient after 1-year-and in three female patients after more than 5-year long-treatment with danazol. Erythrocytosis did not require intervention or the discontinuation of danazol therapy. CONCLUSIONS: We conclude that neither erythrocytosis, nor polyglobulia occurs more often in C1-INH-HAE patients than in healthy individuals; it can be observed only sporadically even after treatment with danazol.