Kinga Viktória Kőhalmi

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 relationship between anxiety and quality of life in children with hereditary angioedema

The severe life‐threatening characteristics of hereditary angioedema (HAE) with C1‐inhibitor deficiency (C1‐INH‐HAE) can affect anxiety levels among pediatric patients. This emotional burden together with the physical restrictions of C1‐INH‐HAE may decrease childrens health‐related quality of life (HRQoL).

Health-related quality of life among children with hereditary angioedema

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.

Risk of thromboembolism in patients with hereditary angioedema treated with plasma-derived C1-inhibitor.

BACKGROUND Plasma-derived C1-inhibitor (C1-INH) concentrates (pdC1-INH) have been used as safe and effective treatments for hereditary angioedema with C1-INH deficiency (C1-INH-HAE) for >30 years. Notwithstanding this, sporadic reports and a study into the high-dose therapy of neonates with C1-INH concentrate administered in an off-label indication raised concerns that this drug might increase the risk of thromboembolism. OBJECTIVE To investigate the incidence of thromboembolism and the background of the risk factors related to treatment with pdC1-INH. METHODS Our retrospective cohort study of 144 patients with C1-INH-HAE compared the incidence of thromboembolism and its risk factors in patients who received pdC1-INH with those who did not receive pdC1-INH as well as with those treated with danazol or with tranexamic acid. RESULTS During the observation period (29 years), 104 of the 144 subjects received pdC1-INH. The average dose per treatment was 573.59 IU. None of the patients used an indwelling central venous catheter. Multiple risk factors for thromboembolism were identified in 93 of the 104 patients treated with pdC1-INH. The incidence rate of thromboembolism was 0.0019/100 person-years in patients treated with pdC1-INH, whereas it was 0.0211/100 person-years in the not-treated group. CONCLUSION Our cohort study did not find any evidence for an increased risk of thromboembolism during treatment with pdC1-INH, despite the presence of multiple predisposing factors.

Bacteriuria increases the risk of edematous attacks in hereditary angioedema with C1-inhibitor deficiency.

Urinary tract infections are considered among the most common infectious disorders in humans. Various infections may have a role in inducing HAE attacks. Our study intended to evaluate bacteriuria in the urinalysis of patients with C1‐INH‐HAE. Urine specimens contributed by 139 patients with C1‐INH‐HAE at the annual control visits were studied retrospectively for microorganisms. We analyzed the presence of bacteriuria in relation to the clinical symptoms. Taking into account three randomly selected urine specimens, we found that the cumulative number of edematous attacks was higher in patients with bacteriuria than in those without (P = 0.019, P = 0.022, P = 0.014). Considering the same patients, attack number was significantly higher (14.51 vs 8.63) in patients with bacteriuria than in those without (P < 0.0001). In patients with bacteriuria, we found a higher incidence of edema formation during the year before evaluation, which may suggest the triggering role of bacteriuria in the occurrence of edematous episodes.

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

ABSTRACT 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.

Complete kinetic follow-up of symptoms and complement parameters during a hereditary angioedema attack

We studied the kinetics of C1‐inhibitor (C1‐INH) and other complement parameters in a self‐limited edematous attack (EA) in a patient with hereditary angioedema due to C1‐INH deficiency to better understand the pathomechanism of the evolution, course, and complete resolution of EAs. C1‐INH concentration and functional activity (C1‐INHc+f), C1(q,r,s), C3, C4, C3a, C4a, C5a, and SC5b‐9 levels were measured in blood samples obtained during the 96‐hour observation period. The highest C1‐INHc+f, C4, and C1(q,r,s) levels were measured at baseline, and their continuous decrease was observed during the entire observation period. C4 depletion started at prodromal phase, and C4 was lowest after the maximum severity peak. Compared to baseline, C4a level was four times higher 7 hours before the onset of the attack. C1‐INH did not increase after resolution of the attack suggesting that factors other than C1‐INH may be important in this process. C4a may be a useful biomarker for the prediction of EAs.

A danazolkezelés hatása C1-inhibitor-hiány okozta hereditaer angiooedemás gyermekek növekedésére

Absztrakt: Bevezetes: Az attenualt androgeneket gyakran alkalmazzak C1-inhibitor-hianyos hereditaer angiooedema akut epizodjainak megelőzesere. Praepubertason tuli alkalmazasuk az epifizisfugak korai zarodasahoz, ezaltal novekedes-visszamaradashoz vezethet. Celkitűzes: A danazol hereditaer angiooedemas gyermekek hossznovekedesere kifejtett hatasanak felmerese. Modszer: Retrospektiv tanulmanyunk negyvenkettő, 21 evesnel idősebb hereditaer angiooedemas beteg adatait elemezte. A betegek eseteben meghataroztuk a varhato testmagassagtol valo elterest, majd azt a betegek neme, valamint a 21 eves kor előtt vegzett danazolkezeles osszdozisa es időtartama fuggvenyeben elemeztuk. Danazollal 16 eves kora előtt kezelt betegek eseteben osszefuggest kerestunk a varhato testmagassagtol valo elteres, valamint a kezeles időtartama, illetve kumulativ dozisa kozott. Eredmenyek: Nem talaltunk szignifikans kulonbseget a varhato testmagassagtol valo elteresben danazolt szedő/nem szedő, illetve fiu es leany betegek kozott. Ezt ...

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

BackgroundHereditary 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.ResultsWe 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.ConclusionsThe 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.

Short-term prophylaxis in a patient with acquired C1-INH deficiency

To the Editor: Acquired angioedema resulting from the deficiency of the C1-inhibitor (AAE-C1-INH) was first described by Caldwell et al in 1972. In 1986, Jackson et al discovered autoantibodies against the C1-inhibitor (C1-INH). AAE-C1-INH often accompanies lymphoproliferative—and occasionally—autoimmune disorders, neoplasms, and infections. Low C1-INH level is associated with activation of the kinin-bradykinin cascade, leading to the formation of bradykinin, increasing capillary permeability, and tissue swelling. AAE-C1-INH is characterized by recurrent episodes of subcutaneous or submucosal edema formation, with initial onset after the age of 40 years. The family history is negative. The diagnosis can be established from clinical symptoms and complement testing. In AAE-C1-INH, the antigenic level of C1-INH is normal or low, as well as its functional activity—along with that of C4—is low. The C1q level is reduced in 70% of the cases. In a proportion of patients, oligoclonal or monoclonal autoantibodies against C1-INH can be detected in the serum. Only case reports and smaller observational studies have been published on the treatment of AAE-C1-INH. Plasma-derived C1-INH concentrate (pdC1-INH—mostly Berinert; CSL Behring, Marburg, Germany), as well as icatibant, ecallantide, and fresh frozen plasma, has been used to good effect for the acute treatment of edematous attacks. The elimination of potential trigger factors and the therapy of underlying disease (when present) are essential. Attenuated androgens, antifibrinolytic agents, and pdC1-INH concentrate may improve the symptoms. The anti-CD20 mAb rituximab has been found beneficial in some cases. Relevant data on the short-term prophylaxis of AAE-C1INH are rare. We found just a single case report in which pdC1INH concentratewas administered as preprocedural prophylaxis. This is the first case report on short-term prophylaxis in AAE-C1-INH, with the administration of recombinant human C1-inhibitor (rhC1-INH), derived from milk of transgenic rabbits. The 66-year-old female patient had hypertension known for 15 years and treated with enalapril. During the last 10 months, abdominal symptoms (colicky abdominal pain, vomiting) recurred once a month initially and then every 10 days. During this period, she experienced edema of the shoulder, thigh, and feet on 3 occasions. Her symptoms persisted for 7 to 8 hours and then, resolved over 2 to 3 days. She required emergency medical attention several times for abdominal symptoms. Computed tomography imaging of the abdomen during the attacks depicted free peritoneal fluid on several occasions. The gastroenterology