Acute Hereditary Angioedema Attacks Research Articles

Bradykinin-Mediated Angioedema Induced by Commonly Used Cardiovascular Drugs

ACE inhibitors, sartans, and sacubitril are among the most important drugs for the prevention of cardiovascular mortality and morbidity. At the same time, they are known to cause non-allergic bradykinin-mediated angioedema, a potentially fatal swelling of the mucosa and/or submucosa and deeper skin without signs of urticaria or pruritus, occurring mainly in the head and neck region. In contrast with hereditary angioedema, which is also mediated by bradykinin, angioedema triggered by these drugs is by far the most common subtype of non-allergic angioedema. The molecular mechanisms underlying this type of angioedema, which are discussed here, are not yet sufficiently understood. There are a number of approved drugs for the prevention and treatment of acute attacks of hereditary angioedema. These include inhibitors of bradykinin synthesis that act as kallkrein inhibitors, such as the parenterally applied plasma pool, and recombinant C1 esterase inhibitor, ecallantide, lanadelumab, and the orally available berotralstat, as well as the bradykinin receptor type 2 antagonist icatibant. In contrast, no diagnostic tools, guidelines, or treatments have yet been approved for the diagnosis and treatment of acute non-allergic drug-induced angioedema, although it is more common and can take life-threatening courses. Approved specific drugs and a structured diagnostic workflow are needed for this emergency diagnosis.

Patient-level indirect treatment comparison of lanadelumab versus pdC1-INH i.v. in hereditary angioedema patients: PATCH study.

Hereditary angioedema (HAE) is an autosomal dominant inherited disease in which patients suffer from local attacks primarily affecting skin and gastrointestinal tract, and sometimes even the upper respiratory tract leading to asphyxiation. Since head-to-head trials between authorized treatments are lacking, this study compares efficacy and safety of lanadelumab and intravenous plasma-derived C1-esterase inhibitor (pdC1-INH i.v.) in HAE patients on long-term prophylaxis by means of an indirect treatment comparison. Efficacy and safety of lanadelumab against pdC1-INH i.v. were analyzed in a fully prespecified indirect comparison based on individual patient data (n = 231) from the HELP and CHANGE clinical trials. Primary and secondary efficacy endpoints were compared using a generalized linear model for count data. Confounding variables were identified a priori via systematic literature research and validated by clinical experts. Adjustment of confounders was implemented using a conditional regression model. Lanadelumab showed a statistically significant improvement in reduction of HAE attack rates compared to pdC1-INH i.v. across multiple endpoints: Monthly attack rate of patients treated with lanadelumab was less than half compared to pdC1-INH i.v. (Rate ratio: 0.486; 95% CI: 0.253, 0.932). Monthly rate of laryngeal attacks was found to be five times lower for lanadelumab (Rate ratio: 0.2; 95% CI: 0.044, 0.915) and monthly rate of acute treated HAE attacks among lanadelumab patients was about one third of the attack rate of pdC1-INH i.v. patients (Rate ratio: 0.366; 95% CI: 0.185, 0.727). This study contributes to current knowledge in the treatment of HAE by indicating a statistically significant reduction of HAE attacks under lanadelumab compared to pdC1-INH i.v.

Safety, efficacy, and pharmacokinetics of icatibant treatment in Japanese pediatric patients with hereditary angioedema: A phase 3, open-label study.

We evaluated the safety, efficacy, and pharmacokinetics of subcutaneous weight-adjusted icatibant for the treatment of acute hereditary angioedema attacks in Japanese pediatric patients. Two patients (aged 10-13 and 6-9 years) received icatibant for a total of four attacks. Each attack was abdominal and/or cutaneous and was treated with a single icatibant injection. Mild or moderate injection-site reactions were the only adverse events reported. Time to onset of symptom relief was 0.9-1.0 h. Icatibant was rapidly absorbed, with a pharmacokinetic profile consistent with previous studies. Simulated exposure levels were consistent with non-Japanese pediatric patients. These results support the safety and efficacy of icatibant in Japanese pediatric patients.

Bradykinin receptors in GtoPdb v.2023.1

Bradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [92]) are activated by the endogenous peptides bradykinin (BK), [des-Arg9]bradykinin, Lys-BK (kallidin), [des-Arg10]kallidin, [Phospho-Ser6]-Bradykinin, T-kinin (Ile-Ser-BK), [Hyp3]bradykinin and Lys-[Hyp3]-bradykinin. Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema. Inhibition of bradykinin with icatibant in COVID-19 infection is under clinical evaluation, with trial NCT05407597 expected to complete in mid 2023.

Hereditary Angioedema: Diagnosis, Clinical Implications, and Pathophysiology.

Hereditary angioedema (HAE) is an autosomal dominant disorder caused by a mutation in the C1 esterase inhibitor gene. HAE affects 1/50,000 people worldwide. Three main types of HAE exist: type I, type II, and type III. Type I is characterized by a deficiency in C1-INH. C1-INH is important in the coagulation complement, contact systems, and fibrinolysis. Most HAE cases are type I. Type I and II HAE result from a mutation in the SERPING1 gene, which encodes C1-INH. Formally known as type III HAE is typically an estrogen-dependent or hereditary angioedema with normal C1-INH activity. Current guidelines now recommend subdividing hereditary angioedema with normal C1 esterase inhibitor gene (HAE-nl-C1-INH formerly known as HAE type III) based on underlying mutations such as in kininogen-1 (HAE-KNG1), plasminogen gene (PLG-HAE), myoferlin gene mutation (MYOF-HAE), heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6), mutation in Hageman factor (factor XII), and in angiopoietin-1 (HAE-ANGPT-1). The clinical presentation of HAE varies between patients, but it usually presents with nonpitting angioedema and occasionally abdominal pain. Young children are typically asymptomatic. Those affected by HAE usually present with symptoms in their early 20s. Symptoms can arise as a result of stress, infection, or trauma. Laboratory testing shows abnormal levels of C1-INH and high levels of bradykinin. C4 and D-dimer levels can also be monitored if an acute HAE attack is suspected. Acute treatment of HAE can include IV infusions of C1-INH, receptor antagonists, and kallikrein inhibitors. Short- and long-term prophylaxis can also be administered to patients with HAE. First-line therapies for long-term prophylaxis also include IV infusion of C1-INH. This review aims to thoroughly understand HAE, its clinical presentation, and how to treat it.

Hereditary angioedema and COVID-19 during pregnancy: Two case reports

Hereditary angioedema and COVID-19 during pregnancy: Two case reports

EE681 Costs of Treating Acute Hereditary Angioedema (HAE) Attacks With C1 Inhibitors in Five Central and Eastern European Countries

Hereditary angioedema (HAE) is a rare genetic disease caused by the deficiency or dysfunction of C1 esterase inhibitor (C1-INH), and characterized by recurring episodes of severe swelling, which can be life-threatening. Frequency and severity of attacks vary. Replacement C1-INH therapies provide effective relief; however, there is a lack of comparative data on economic outcomes in Central and Eastern European countries (CEE).

National audit of a hereditary and acquired angioedema cohort in New Zealand.

Hereditary angioedema (HAE) leads to significant morbidity and mortality from unpredictable intermittent peripheral, abdominal and laryngeal swelling. Access to appropriate healthcare and effective therapies, which can prevent and treat attacks, reduce the suffering and greatly improve quality of life. Although treatments such as C1 inhibitor (Berinert), and Icatibant are available in New Zealand (Aotearoa), there are no published data available on their use. To present a national audit of HAE and acquired angioedema (AAE) in 2019. Patients were identfied and demographical and clinical data on HAE were collected retrospectively by interview and notes review. The total number of known adult (48) and children (3) HAE and AAE (3) patients is 54. Of these, 41/54 (75%) of HAE and AAE patients were recruited to the audit. Icatibant has been available for the treatment of acute HAE attacks since 2016, and is now used in 73% of HAE patients. Icatibant is also used by patients for laryngeal attacks in the community, who may not then present to hospital. Androgens are used in half of the patients as prophylaxis, but 33% of the latter were identified as not having regular liver ultrasound screening. Tranexamic acid is used as prophylaxis in one-fifth of patients. Participants have had 40 children, half of whom may be affected. Three have been diagnosed with HAE, suggesting that the majority have not yet been tested. Corrective actions arising from this audit will improve our capacity to provide long-term care for HAE patients and their families.

Specific Targeting of Plasma Kallikrein for Treatment of Hereditary Angioedema: A Revolutionary Decade

Hereditary angioedema (HAE) is a rare, chronic, genetic disease that presents with nonpruritic angioedema of the face, extremities, airway (can be life-threatening), genitourinary system, and abdomen. These symptoms can significantly impair daily activities. Hereditary angioedema is classified into HAE owing to a deficiency of functional C1INH (HAE-C1INH) or HAE with normal C1INH (HAE-nl-C1INH). Both type I and II HAE-C1INH result from inherited or spontaneous mutations in the SERPING1 gene, which encodes for C1INH. These mutations result in C1INH dysfunction, leading to uncontrolled plasma kallikrein activity with excessive bradykinin production. Bradykinin receptor activation leads to vasodilation, increased vascular permeability, and smooth muscle contractions, resulting in submucosal angioedema through fluid extravasation. Hereditary angioedema nl-C1INH is caused by either a known or unknown genetic mutation. The underlying mechanism of HAE-nl-C1INH is less well understood but is thought to be related to bradykinin signaling. Plasma kallikrein inhibitors have been developed to inhibit the kallikrein-kinin pathway to prevent (prophylactic) and treat on-demand (acute) HAE attacks. Several of these medications are delivered through subcutaneous or intravenous injection, although new and emerging therapies include oral formulations. This article provides a historical review and describes the evolving landscape of available kallikrein inhibitors to treat HAE-C1INH.

Bradykinin receptors in GtoPdb v.2021.3

Bradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [91]) are activated by the endogenous peptides bradykinin (BK), [des-Arg9]bradykinin, Lys-BK (kallidin), [des-Arg10]kallidin, [Phospho-Ser6]-Bradykinin, T-kinin (Ile-Ser-BK), [Hyp3]bradykinin and Lys-[Hyp3]-bradykinin. Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema.

A novel murine in vivo model for acute hereditary angioedema attacks

Hereditary Angioedema (HAE) is a rare genetic disease generally caused by deficiency or mutations in the C1-inhibitor gene, SERPING1, a member of the Serpin family. HAE results in acute attacks of edema, vasodilation, GI pain and hypotension. C1INH is a key inhibitor of enzymes controlling complement activation, fibrinolysis and the contact system. In HAE patients, contact system activation leads to uncontrolled production of bradykinin, the vasodilator responsible for the characteristic symptoms of HAE. In this study, we present the first physiological in vivo model to mimic acute HAE attacks. We evaluate hypotension, one of the many hallmark symptoms of acute HAE attacks using Serping1 deficient mice (serping1−/−) and implanted telemetry. Attacks were induced by IV injection of a silica nanoparticle (SiNP) suspension. Blood pressure was measured in real time, in conscious and untethered mice using implanted telemetry. SiNP injection induced a rapid, reversible decrease in blood pressure, in the presence of angiotensin converting enzyme (ACE) inhibition. We also demonstrate that an HAE therapeutic, ecallantide, can prevent HAE attacks in this model. The in vivo murine model described here can facilitate the understanding of acute HAE attacks, support drug development and ultimately contribute to improved patient care.

Icatibant promotes patients' behavior modification associated with emergency room visits during an acute attack of hereditary angioedema.

Hereditary angioedema due to C1-inhibitor (C1-INH) deficiency (HAE-C1-INH) induces an acute attack of angioedema. In 2018, icatibant available for self-possession and subcutaneous self-administration was licensed for on-demand treatment in addition to intravenous C1-INH administration in Japan. We retrospectively evaluated the percentage of attacks in critical parts at emergency room (ER) visits and the time until visiting ER for C1-INH administration before and after the initial prescription of icatibant. The percentage of attacks in critical parts at ER visits before the prescription was 69.2%, but that was 80.0% when patients visited ER for additional C1-INH administration after the self-administration of icatibant. The time from the onset of an acute attack to visiting ER for the additional treatment after the self-administration of icatibant significantly increased from 6.2 h to 19.2 h (p < 0.001). Icatibant, therefore, promoted the patients' behavior modification associated with ER visits for C1-INH administration during an acute attack of HAE-C1-INH.

Population pharmacokinetics of recombinant human C1 esterase inhibitor in children with hereditary angioedema

BackgroundRecombinant human C1 esterase inhibitor (rhC1-INH) is indicated in the United States for the treatment of acute hereditary angioedema (HAE) attacks in adolescents and adults; it is also indicated in Europe for children aged 2 years and older. A need exists for further insight into potential pharmacokinetic (PK) differences in functional C1-INH levels by age (ie, children, adolescents, and adults). ObjectiveTo perform population PK modeling to predict C1-INH levels by age after by age rhC1-INH administration. MethodsData from a phase 2 pediatric trial (children aged 4-13 years at screening) were added to a database of 6 trials in adults and adolescents. An unpublished population PK model was refined and used to simulate C1-INH exposure. ResultsAnalysis included 153 individuals (14 healthy volunteers; 139 patients with HAE) and 1788 functional C1-INH measurements (59 from 20 patients in the pediatric trial). Bodyweight (population weight, 16-128 kg) was a key predictor of C1-INH volume of distribution. Age was not a predictor of C1-INH PK after the inclusion of bodyweight in the model. Simulations of the recommended rhC1-INH dosing regimen (bodyweight <84 kg, 50 U/kg; ≥84 kg, 4200 U) revealed that overall C1-INH exposure was comparable among age groups. Predicted peak functional C1-INH concentrations were at or above the lower level of normal (≥0.7 U/mL) for 99.8% of adults (≥18 years), 99.8% of adolescents (14-17 years), and 96.0% of children (2-13 years). ConclusionThe analyses support the same weight-based rhC1-INH dosing for HAE attacks in children as currently recommended for adolescents and adults. These results support clinical trial data, which revealed similar safety and efficacy profiles across these age groups.

Hereditary angioedema: Long-term prophylactic treatment.

Hereditary Angioedema (HAE) is a potentially life-threatening condition. With episodic, unpredictable swelling, HAE negatively affect the quality of life for those affected individuals. To reduce the morbidity and mortality of HAE are the primary goal for the disease management. In addition to have access to therapeutic drugs for their acute HAE attacks, many patients require long term prophylaxis (LTP) to reduce their attack frequency and severity. Preventing HAE attack by regular administration of medicine has become an important part of HAE disease management. Over the past few years, growing number of therapeutic options for the HAE LTP have made it possible for physicians to choose the most appropriate and effective treatment for individual patients. C1 INH concentrate and plasma kallikrein inhibitors (IV or SC) have largely replaced the oder modality of treatment consisting different androgen derivatives or antifibrinolytics. Additional options, such as oral kallikrein inhibitor, antisense RNA/plasma kallikrein, anti-Factor 12a, bradykinin receptor blocker or future gene therapy are under clinical investigation. The significant cost and the uncertainty of its long term safety may be the primary limiting factors for its clinical application. The limited data for young children and pregnant women pose additional challenge for physicians to assess the risk and benefit when considering LTP treatment.

Hereditary Angioedema Due to C1-Inhibitor Deficiency in Romania: First National Study, Diagnostic and Treatment Challenges.

Hereditary angioedema (HAE) is a rare genetic potentially life-threatening disease characterized by episodic non-pruritic subcutaneous and submucosal edema attacks in different parts of the body. To assess the status of Romanian HAE patients after the recent introduction of a new therapy through a nationwide program. This cross-sectional observational study included patients from the Romanian HAE Registry. The study included 84 patients with HAE type I (91.7%) and type II (8.3%). The mean delay in diagnosis was 2.4 years in children and 16.7 years in adults (p=0.019). Stress and tiredness were the most frequent trigger factors. The majority of the HAE episodes involved subcutaneous (89.3%), abdominal (77.4%), genital (51.2%), facial (41.7%), and laryngeal (39.3%) symptoms during the preceding 12 months. One or several misdiagnoses were reported in 83.33% patients and 44.1 % of the patients were subjected to or proposed unnecessary surgery during abdominal episodes. Plasma-derived C1-INH (pdC1-INH) and recombinant C1-INH (rhC1-INH) were respectively used in 10 (11.9%) and 13 (15.5%) of the HAE patients for life-threatening attacks over the past 12 months. Forty-three (51.19%) patients practiced home treatment with subcutaneous injection of the bradykinin B2-receptor antagonist for acute HAE attacks. The significantly lower delay observed in children suggests an improvement in the awareness of C1-INH-HAE among physicians in recent years. The management of HAE in Romania has been somewhat enhanced as the majority of HAE patients have recently gained access to pdC1-INH, rhC1-INH, and bradykinin B2-receptor antagonist.

Patterns of Treatment and Retreatment of Acute Attacks of Hereditary Angioedema (HAE) with Standard of Care (SOC) On-Demand Medication: Results from the APeX-2 Study

Patterns of Treatment and Retreatment of Acute Attacks of Hereditary Angioedema (HAE) with Standard of Care (SOC) On-Demand Medication: Results from the APeX-2 Study

Life expectancy in Italian patients with hereditary angioedema due to C1-inhibitor deficiency

Life expectancy in Italian patients with hereditary angioedema due to C1-inhibitor deficiency

Efficacy, pharmacokinetics, and safety of icatibant for the treatment of Japanese patients with an acute attack of hereditary angioedema: A phase 3 open-label study

BackgroundHereditary angioedema (HAE) is a genetic disease characterized by recurrent swelling episodes affecting the skin, gastrointestinal mucosa, and upper respiratory tract. MethodsA phase 3, single-arm, open-label study was performed to evaluate a selective bradykinin B2 receptor antagonist, icatibant, for the treatment of acute attacks in Japanese patients with HAE Type I or II. After the onset of an acute attack, icatibant 30 mg was administered by the patient or a healthcare professional via subcutaneous injection in the abdomen. ResultsEight patients who had an attack affecting the skin (n = 4), abdomen (n = 3), or larynx (n = 1) were treated with icatibant (3 of the injections were self-administered). The median time to onset of symptom relief was 1.75 h (95% confidence interval, 1.00–2.50), and all patients had symptom relief within 5 h after administration. The time to maximum plasma concentration of icatibant was 1.79 h, and the maximum plasma concentration was 405 ng/ml. Seven patients experienced an injection site reaction, and 3 patients had adverse events (2 patients had a worsening or repeat HAE attack 29.0 and 18.3 h after icatibant administration, respectively, and 1 had headache). ConclusionsAlthough the number of patients is small, the efficacy and tolerability of icatibant for acute attacks were demonstrated in Japanese patients with HAE, regardless of self-administration or administration by healthcare professional.

Lanadelumab Injection Treatment For The Prevention Of Hereditary Angioedema (HAE): Design, Development And Place In Therapy.

Despite the efficacy of the on-demand treatment for the control of acute attacks of Hereditary Angioedema due to C1-Inhibitor Deficiency (C1-INH-HAE), the number and severity of attacks and the impairment in the quality of life of the affected patients have led to the development of a new monoclonal antibody, lanadelumab, directly addressed to the blockage of bradykinin, the principal mediator of vasodilation during angioedema attacks. It is indicated for the prophylactic treatment, it is easy to administer, highly effective and with known limited side effects. The current review summarizes the development of the drug, its clinical background and its perspectives.

Bradykinin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Bradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [76]) are activated by the endogenous peptides bradykinin (BK), [des-Arg9]bradykinin, Lys-BK (kallidin), [des-Arg10]kallidin, [Phospho-Ser6]-Bradykinin, T-kinin (Ile-Ser-BK), [Hyp3]bradykinin and Lys-[Hyp3]-bradykinin. Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema.