Treatment Of Hereditary Angioedema Research Articles

Prophylaxis in hereditary angioedema: a United Kingdom Delphi consensus.

Hereditary angioedema (HAE) is a rare inherited disorder causing recurrent episodes of swelling that can be potentially life threatening. Treatment of HAE can be divided into on-demand treatment for swelling, and prophylaxis. The last UK consensus on HAE was in 2014 and since then, new medications for prophylaxis have been developed, with more drugs in the pipeline. International guidelines currently recommend the use of long-term prophylaxis (LTP) as the only way of achieving disease control and normalizing patient lives. Modern prophylactic medications are available in the UK, although access is restricted primarily by HAE attack frequency. To establish an updated view of UK clinicians and patients, a Delphi process was used to develop statements regarding LTP as well as other aspects of HAE management. There was consensus that UK access criteria for modern LTP agents based on numerical frequency of attacks alone are too simplistic and potentially disadvantage a cohort of patients who may benefit from LTP. Additionally, there was agreement that patients should be seen in expert centres, remote monitoring of patients is popular post-pandemic, and that the use of patient-reported outcome measures has the potential to improve patient care. Psychological health is an area in which patients may benefit, and recognition of this is important for future research and development.

Hereditary Angioedema: Novel Molecules for Treatment of Acute Attacks and Long-Term Prophylaxis

Hereditary angioedema (HAE) is a rare disease caused by a genetic alteration of the SERPING1 gene and characterized by recurrent attacks of angioedema that involve the skin, and the mucosae of the gastrointestinal tract and upper airways, which significantly affect the quality of life of patients. Nowadays there are effective drugs for both 1. treating acute attacks and 2. preventing attacks with a long-term prophylaxis. However, there are some unmet needs for HAE treatment, and therefore several novel molecules are under active testing for this clinical condition. Novel drugs will simplify the mode of administration (oral versus parenteral for both on demand treatment or long-term prophylaxis), prolong the interval between administrations (up to 3–6 months of efficacy with a single administration), target more specifically the central enzymes involved in the generation of bradykinin, the ultimate mediator of angioedema (prekallikrein, activated plasma kallikrein or activated factor XII), and potentially determine a definitive cure for the disease by genetic manipulation of the altered gene (SERPING1) or other downstream genes (KLKB1). In this review we provide a panoramic view of all new medications that are under active experimentation and will probably transform and enrich all of the therapeutic armamentarium for treating this disease.

Hereditary C1-inhibitor deficiency angioedema (C1-INH-HAE) in children – practical considerations

Hereditary angioedema is a rare, autosomal dominant, potentially life-threatening disorder usually resulting from C1-esterase deficiency or dysfunction. Clinical manifestations include unpredictable, acute, recurrent episodes of well-demarcated oedema occurring without pruritus, most commonly affecting the face, trunk, extremities, but also, due to mucosal involvement, the respiratory and gastrointestinal systems. Although oedema resolves spontaneously within 2–5 days, the skin lesions are disfiguring, painful and disrupt daily functioning, while abdominal attacks are very painful and often lead to hospital admissions and unnecessary surgery. In addition, laryngeal oedema, which affects at least half of patients, is life-threatening and, in many cases, leads to fatal asphyxia. Therefore, early diagnosis and implementation of proper therapeutic management as soon as possible are crucial. In recent years, significant advances have been made in the treatment of hereditary angioedema. Initially, only intravenous drugs administered during attacks were available in medical facilities. Patient education has allowed for home therapy. The next step was the introduction of subcutaneous injections, which were more convenient for patients. Finally, long-term prophylactic treatment, which completely relieves symptoms and allows for a normal life, has gained importance. Unfortunately, the high cost of these therapies remains a problem. This paper reviews in detail the clinical picture and differential diagnosis of the disorder, as well as modern treatment approaches, with special focus on the distinctive features in children.

Lanadelumab demonstrates high efficacy in reducing the frequency of angioedema attacks in patients with severe HAE in real-life settings

Introduction and objective: Evaluation of lanadelumab efficacy in preventing angioedema attacks in patients with severe hereditary angioedema due to C1-inhibitor deficiency in Poland and descriptive analysis of this group of patients. Materials and methods: Retrospective analysis of patients treated with lanadelumab in Poland. Data were acquired from the electronic database of the National Health Fund, compiled from 15 hereditary angioedema centres. Only patients with severe hereditary angioedema course (at least 12 severe – abdominal, pharyngeal or laryngeal – hereditary angioedema attacks per six months, requiring on-demand medications) initiated treatment. The patients received lanadelumab 300 mg every two weeks. The efficacy of the therapy was assessed after six months. Results: Lanadelumab was initiated in a total of 43 patients (group B). Twenty of them achieved the follow-up point after six months (group A). The mean age of the patients was 44 years. The majority (76.7%) were female and 79% had a family history of hereditary angioedema. Most patients (95.3%) had HAE-1 (absolute deficiency of C1-inhibitor). On average, within six months before treatment, group A patients experienced 19.7 (95% confidence interval, CI: 16.06–23.33) severe hereditary angioedema attacks. In the six months following treatment initiation, the number of attacks decreased to an average of 0.5 (95% CI: 0–1.0), with significant reductions in all types of hereditary angioedema attacks – abdominal (p < 0.0001), pharyngeal (p < 0.005), and laryngeal (p < 0.05). Utilisation of on-demand medications dropped from an average of 23.5 (95% CI: 16.7–30.3) to 0.5 standard therapeutic dose (95% CI: 0–1.1). Conclusions: The study highlights the therapeutic potential of lanadelumab in managing hereditary angioedema, usually offering patients a complete resolution of severe hereditary angioedema attacks and release from dependence on rescue medication. Our results support the current paradigm shift in hereditary angioedema treatment.

Forms of Hereditary Angioedema That Are Independent of Kallikrein and Factor XIIa System

Hereditary angioedema (HAE) is an inherited disorder characterized by recurrent episodes of severe soft tissue swelling involving skin and mucous membranes. In most cases, edema is caused by excessive formation of the vasoactive nanopeptide bradykinin (BK) due to dysregulation of the plasma kallikrein-kinin system (KKS). The KKS consists of the zymogens prekallikrein (PK) and factor XII (FXII) and the cofactor/substrate high-molecular-weight kininogen (HK). PK and FXII reciprocally convert each other to the proteases plasma kallikrein (PKa) and FXIIa. PKa cleaves HK after Lys362 and Arg371 to release bradykinin. In most cases of HAE, increased KKS activation is due to low plasma activity of C1-Inhibitor (C1-INH), the main regulator of PKa and FXIIa. However, ~10% of HAE patients have normal C1-INH activity (HAEnC1). A relationship between fibrinolysis and kinin formation was first described in 1971. The fibrinolytic protease plasmin activates FXII and cleaves HK, although it is unclear that this results in significant bradykinin generation. Recently mutations in the PLG gene encoding plasminogen (Lys311Glu) and the KNG1 gene encoding HK and the related protein low-molecular-weight kininogen (LK, Met361Lys) were identified in patients with HAEnC1. Here we describe how the fibrinolytic system contributes to angioedema in patients with these mutations. Human Glu-plasminogen (Plg), HK and LK were expressed in HEK293 cells. Lys311 in plasminogen was changed to glutamic acid, and Met361 in HK and LK were changed to lysine, by site directed mutagenesis. Wild type (Plg-Lys311) and variant (Plg-Glu311) plasminogen were converted to plasmin (Plm-Lys311 and Plm-Glu311) with urokinase. The capacity of plasmin to cleave HK and LK were studied with SDS-PAGE, western blots and kinin ELISA. Cleavage of wild type HK-Met361 and LK-Met361 and variant HK-Lys361 and LK-Lys361 by PKa and plasmin were assessed in a similar manner. The types of kinin released during reactions were determined by mass spectroscopy. Normal plasma was supplemented with Plg-Lys311 or Plg-Glu311, and tPA was added to generate plasmin. Bradykinin release was substantially greater with Plm-Glu311 than Plm-Lys311. This held when reactions were run in plasma lacking FXII or PK, indicating activation of the KKS was not responsible for kinin production. Using plasma-derived proteins, PKa released bradykinin 100-fold faster from HK than LK, and released bradykinin from HK ~50-fold faster than did plasmin. PKa and plasmin released bradykinin at comparable relatively slow rates from LK. Plm-Glu311 released bradykinin from HK 10-fold faster, and from LK 3-fold faster, than in reactions with Plm-Lys311. In experiments in which kininogen deficient plasma was supplemented with either HK or LK to a physiologic concentration, the majority of bradykinin released by Plm-Glu311 was from LK. PKa-catalyzed release of bradykinin from wild type HK-Met361 and variant HK-Lys361 comparably. The same held for LK-Met361 and LK-Lys361. However, plasmin released kinin from HK-Lys361 and LK-Lys361 3.3-fold and 13-fold faster than from HK-Met361 and LK-Met361. While the kinin released from HK-Met361 and LK-Met361 was bradykinin, plasmin released the decapeptide Lys-bradykinin (kallidin) from HK-Lys361 and LK-Lys36. Our studies indicate that angioedema in some patients with HAEnC1 may be due to fibrinolytic activity, and not to KKS activity. Both HK and LK may be substrates in such patients. As the plasma LK concentration is ~4-fold higher than HK, it may be the main pathologic kinin source. The plasmin Lys311Glu substitution converts the protease into a more efficient kininogenase. Fibrinolytic activity is normally brisk in the mouth, perhaps explaining why patients with the Lys311Glu mutation primarily suffer from oral-lingual angioedema. The findings raise the possibility that oral-lingual edema after tPA infusion or ACE inhibitor administration may also be due to plasmin-mediated cleavage of LK and HK. The Met361Lys substitution in HK and LK introduces a novel protease cleavage site immediately upstream from a normal PKa cleavage site. The novel site is preferred over the normal site by plasmin, but not PKa. Several treatments for HAE directed at neutralizing PKa or FXIIa activity have been developed. Our results suggest that such drugs may be less effective in patients with HAEnC1 in which disease mechanisms operate independently of the KKS.

Characteristics and Drug Utilization of Patients with Hereditary Angioedema in Italy, a Real-World Analysis.

This real-world analysis investigated the characteristics and treatment patterns of patients with hereditary angioedema (HAE) in Italy using the administrative data of health units across Italy. Patients were identified via exemption code or HAE-specific treatments (thus, all known forms, type I, II and, III, were included). The index date was that of first prescription of HAE treatments within the inclusion period (01/2010-06/2021) or of the date of exemption. The number of HAE patients included was 148 (43.2% male, mean age 43.3 years). Gastrointestinal disorders affected 36.5% patients, hypertension affected 28.4%, hypercholesterolemia affected 11.5%, and depression affected 9.5%. The frequent gastrointestinal involvement was further confirmed by the use of antiemetics and systemic antihistamines that doubled after the index date. Among patients enrolled by treatment (n = 125), n = 105 (84%) were receiving a treatment for acute attacks. This analysis provided insights into the characterization of patients with HAE and their management in Italian clinical practice, suggesting that an unmet therapeutic need could be present for such patients in terms of the clinical burden.

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.

The disease burden and societal costs of hereditary angioedema.

According to the current treatment guidelines, the goals of treatment of patients with hereditary angioedema (HAE) are to achieve total control of the disease and to normalize patients' lives. This study aims to establish the entire burden of HAE comprising disease control, treatment satisfaction, reductions in quality of life and societal costs. Adult HAE patients under treatment at the Dutch national centre of reference completed a cross-sectional survey in 2021. The survey consisted of different questionnaires: Angioedema-specific questionnaires (4-week Angioedema Activity Score and Angioedema Control Test); quality of life questionnaires (Angioedema Quality of Life questionnaire and EQ-5D-5L); the Treatment Satisfaction Questionnaire for Medication; and societal costs questionnaires (iMTA Medical Consumption Questionnaire, and iMTA Productivity Cost Questionnaire). The response rate was 78% (69/88). The entire sample had a mean AAS score of 16.61, and 36% of participants had poorly controlled disease as expressed by the AECT. The mean quality of life in the entire sample was 30.99 as expressed by the AE-QoL and 0.873 as expressed by the EQ-5D-5L utility value. Utilities dropped by 0.320 points during an angioedema attack. TSQM scores ranged from 66.67 to 75.00 across its four domains. On average, total costs per year incurred €22,764, predominantly existing of HAE-medication costs. Total costs showed substantial variation between patients. This study describes the entire burden of HAE among Dutch patients comprising disease control, quality of life, treatment satisfaction and societal costs. These results can inform cost-effectiveness analyses which can aid reimbursement decisions for HAE treatments.

Healthcare utilization of patients with hereditary angioedema treated with lanadelumab and subcutaneous C1-inhibitor concentrate.

New hereditary angioedema (HAE) treatments have become available in recent years for the treatment of HAE due to C1-inhibitor (C1-INH) deficiency, including two subcutaneous (SC) options: a monoclonal antibody (lanadelumab) and a plasma-derived C1-INH concentrate (SC-C1-INH). Limited real-world data on these therapies have been reported. The objective was to describe new users of lanadelumab and SC-C1-INH, including demographics, healthcareresource utilization (HCRU), costs, and treatment patterns before and after beginning treatment. This was a retrospective cohort study that used an administrative claims data base. Two mutually exclusive cohorts of adult (ages 18 years) new users of lanadelumab or SC-C1-INH with 180 days of continuous use were identified. HCRU, costs, and treatment patterns were assessed in the 180-day period before the index date (new treatment use) and up to 365 days after the index date. HCRU and costs were calculated as annualized rates. Forty-seven patients who used lanadelumab and 38 patients who used SC-C1-INH were identified. The most frequentlyused on-demand HAE treatments at baseline were the same for both cohorts: bradykinin B2 antagonists (48.9% of the patients on lanadelumab, 52.6% of the patients on SC-C1-INH) and C1-INHs (40.4% of the patients on lanadelumab, 57.9% of the patients on SC-C1-INH). More than 33% of the patients continued to fill on-demand medications after treatment initiation. Annualized angioedema-associated emergency department visits and hospitalizations decreased after initiation of treatment, from 1.8 to 0.6 for the patients on lanadelumab and from 1.3 to 0.5 for the patients on SC-C1-INH. Annualized total healthcare costs after treatment initiation in the database were $866,639 and $734,460 for the lanadelumab and SC-C1-INH cohorts, respectively. Pharmacy costs accounted for >95% of these total costs. Although HCRU decreased after the initiation of treatment, angioedema-associated emergency department visits and hospitalizations and on-demand treatment fills were not completely eliminated. This indicates ongoing disease andtreatment burden despite use of modern HAE medicines.

Real-world changes in costs over time among patients in the United States with hereditary angioedema on long-term prophylaxis with lanadelumab

AimsInvestigate trends in paid lanadelumab costs over time in a population of patients persistent for 18 months, and to understand overall hereditary angioedema (HAE) treatment cost trends, including costs of acute medication/short-term prophylaxis and supportive care. Lastly, we sought to describe the proportion of lanadelumab patients with evidence of down titration via changes in total paid amounts for lanadelumab in a fixed time period.MethodsPatients were identified in the Merative MarketScan Databases who had ≥1 claim for lanadelumab during 1/1/2018-6/30/2022 (index), a ≤ 60-d gap in days of supply over 18 months, and were enrolled for ≥6 months pre-index and 18 months post-index. Lanadelumab and HAE-specific costs were assessed during follow-up months 0–6, 7–12, and 13–18. Down titration was defined as a ≥ 25% decrease in lanadelumab costs from months 0–6 to months 7–12 or 13–18. Outcomes were compared between time periods using paired t-tests and McNemar’s test.ResultsFifty-four lanadelumab users were included; 25 (46%) had evidence of down titration. Lanadelumab costs decreased from $316,724 to $269,861 to $246,919 in months 0–6, 7–12, and 13–18, respectively (p < .01); total HAE treatment costs decreased from $377,076 to $329,855 to $286,074 in months 0–6, 7–12, and 13–18, respectively (p < .01).LimitationsPersistence was determined via days of supply on medication claims; use of the medication was not confirmed. Down titration was based on costs; the lanadelumab regimen could not be assessed. Results may not be generalizable to uninsured patients or those without commercial or Medicare insurance.ConclusionsPatients on long-term prophylaxis with lanadelumab experienced a significant reduction (24%) in HAE treatment costs over 18 months, driven by lower costs of acute medications and lanadelumab down titration. Down titration among appropriate patients with controlled HAE may lead to substantial savings in healthcare costs.

Концепция диагностики и лечения наследственного ангиоотека (по материалам международных и национальных рекомендаций)

The article analyzes recommendations for the diagnosis and treatment of hereditary angioedema (HAE) issued in the United States of America, Canada, the European Union and Russia. Based on these recommendations, a tactic for managing patients with hereditary angioedema has been developed

Are pediatricians familiar with hereditary angioedema?

BackgroundHereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent episodes of subcutaneous or mucosal edema caused by excess bradykinin. The aim of the present study was to assess the knowledge of pediatricians about hereditary angioedema. MethodsAn online survey with 12 HAE-related and 14 demographics-related questions was e-mailed to all pediatricians who were members of the Brazilian Society of Pediatrics (n = 17 145) once a week during the months of June and July 2021. The electronic questionnaire assessed clinical manifestations, diagnosis, and treatment of hereditary angioedema in children and adolescents. ResultsFour hundred and fifty-five pediatricians responded to the questionnaire (2.6%), of whom 55 (12.1%) were board certified in Allergy and Immunology (A/I), while 400 (87.9%) were not (N-A/I). Three hundred and sixty-eight (80.9%) were female, 289 (55.7%) were under 50 years of age, 286 (62.9%) graduated from Medical School more than 10 years previously, 83 (18.2%) held an MSc/PhD degree, and 253 (55.6%) were living in the Southeast Region of Brazil. The median number of correct answers to the questions related to HAE among A/I was 7 out of 12 (58.3%), with median ranging from 4.5 to 8 correct answers, while for N-A/I it was 3 (25%), with median ranging from 2.5 to 4 correct answers (p < 0.001). ConclusionKnowledge about HAE among Brazilian pediatricians, whether board certified in Allergy and Immunology or not, was unsatisfactory. HAE is a rare disease, largely unknown among physicians; therefore, increasing awareness may lead to improvement in diagnosis and treatment.

REMISSION OF HEREDITARY ANGIOEDEMA ATTACKS ASSOCIATED WITH STARTING TERIFLUNOMIDE IN A PATIENT WITH MULTIPLE SCLEROSIS.

Hereditary angioedema is a rare hereditary and potentially life-threatening disorder characterized by recurrent attacks of cutaneous and submucosal swelling. In spite of the advances made in terms of pathophysiology, underlying mechanisms are not fully clear and this, in turn, hinders the development of effective therapies. Currently, on demand treatment is considered first-class, with few cost-effective, long-term prophylactic options. Here we describe the case of a 34-year-old man diagnosed with hereditary angioedema at the age of 10, who used to suffer several angioedema attacks per month. He was given prophylactic treatment with antifibrinolytic agents and androgens without improvement. Moreover, he was treated with plasma-derived C1-INH concentrate or icatibant for on-demand treatment of moderate and severe angioedema attacks. At the age of 33, after suffering sudden vision loss and lower limb paresthesia, he was studied and diagnosed with multiple sclerosis. Teriflunomide was administered at a dosage of 14 mg/day. Angioedema attacks disappeared 40 days after starting treatment. Thus, we suggest considering the pathophysiologic mechanisms on which teriflunomide could be active and consider this drug carefully as an option for prophylaxis purposes. Yet, its effectiveness on this condition should be further studied. Underlying mechanisms in hereditary angioedema lack clarity and hence hinder the development of effective therapies.On-demand treatment of hereditary angioedema is considered first class, with few cost-effective, long-term prophylactic options.The mechanisms of action and effectiveness of teriflunomide on hereditary angioedema should be studied further.

Evaluating the Impact of Acute Versus Prophylaxis Therapy in Hereditary Angioedema

Hereditary Angioedema (HAE) is a debilitating disease consisting of unpredictable swelling attacks. We sought to determine the impact of different HAE treatments on quality of life and hypothesized that patients on long-term prophylaxis (LTP) would experience better quality of life compared to patients on acute therapy (AT).

Health and well-being implications of insurance coverage delays and denials for patients with hereditary angioedema

Hereditary angioedema (HAE) is a rare, debilitating and potentially fatal genetic disease associated with recurrent and unpredictable episodes of angioedema attacks. Modern therapies have dramatically increased quality of life. HAE treatments, similar to other rare conditions, are expensive and insurance approval is often a protracted process. This study examines the impact of delays and denials on health and well-being.

New medications to mitigate attacks of hereditary angioedema: does one size fit all?

Hereditary angioedema has received renewed attention in the past two decades, with the elucidation of the biochemical pathways resulting in bradykinin overproduction in patients with congenital C1esterase inhibitor (C1INH) deficiency, leading to recurrent attacks of tissue swelling due to uncontrolled vascular permeability. 1 Busse PJ Christiansen SC Hereditary angioedema. N Engl J Med. 2020; 382: 1136-1148 Crossref PubMed Scopus (132) Google Scholar Oedema attacks affecting the lingual or laryngeal area can become lethal as a result of asphyxiation. 2 Minafra FG Gonçalves TR Alves TM Pinto JA The mortality from hereditary angioedema worldwide: a review of the real-world data literature. Clin Rev Allergy Immunol. 2022; 62: 232-239 Crossref PubMed Scopus (4) Google Scholar Several new treatments have emerged, 143 years after Quincke's first description of hereditary angioedema and 15 years after the introduction of the first specific bradykinin B2 receptor inhibitor (icatibant). These drugs specifically target crucial steps in the kallikrein–kinin (contact) cascade downstream of bradykinin production. 3 Fijen LM Bork K Cohn DM Current and prospective targets of pharmacologic treatment of hereditary angioedema types 1 and 2. Clin Rev Allergy Immunol. 2021; 61: 66-76 Crossref PubMed Scopus (0) Google Scholar Many of these agents have shown their efficacy and safety in acute (on-demand) treatment and prophylaxis of hereditary angioedema attacks, saving lives and revolutionising patients’ quality of life. 4 Lumry WR Settipane RA Hereditary angioedema: epidemiology and burden of disease. Allergy Asthma Proc. 2020; 41: S08-S Crossref Google Scholar These modalities fit well into the modern paradigm in hereditary angioedema treatment, supporting patients’ autonomy, recommending self-administration, and reducing reliance on hospital emergency rooms, health-care providers, and medical points of care. 5 Maurer M Magerl M Betschel S et al. The international WAO/EAACI guideline for the management of hereditary angioedema—the 2021 revision and update. Allergy. 2022; 77: 1961-1990 Crossref PubMed Scopus (32) Google Scholar An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: a two-part, randomised, double-blind, placebo-controlled, crossover phase 2 trialOral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated ( NCT05259917 ). Full-Text PDF

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

Safety Aspects and Rational Use of Lanadelumab Injections in the Treatment of Hereditary Angioedema (HAE): Clinical Insights.

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of skin/mucosal swelling, and/or attacks of severe abdominal pain when it affects the gastrointestinal tract. The disease might be unexpectedly fatal when the upper airways are compromised. HAE clinical presentation, disease course and prognosis are associated with significant disease burden and severely impaired quality of life. Lanadelumab is a breakthrough therapy for the prevention of attacks in HAE type 1 and 2 patients. This revolutionary approach to administer a single subcutaneous injection (once every two to four weeks) and achieve complete disease control has dramatically improved patient care resulting in significant change in the life of affected families. Current data support the drug's tolerability in adult and adolescent patients without notable safety concerns in both clinical research and real-world settings. Rational use of prophylactic treatments of HAE searches for a socio-economic balance, taking into account the life-long course of the disease, the public health funds who pay the monetary price, and the patients who might need to receive the therapy for a period longer than investigated during the development program. In this review, we address the current evidence on lanadelumab's tolerability, highlighting aspects of the drug's rationale use in clinical practice. Further studies need to investigate whether this therapy might be appropriate in other forms of angioedema, such as idiopathic primary angioedema and HAE with normal C1 inhibitor. Future efforts must focus to improve modern drugs' accessibility in more countries. Although modern prophylactic options lessen the risk of fatal laryngeal attacks, patients must be equipped with reliable on-demand therapies and be trained how to use them as such a risk cannot be fully diminished with potentially life-threatening attacks occurring even in subjects with successful and stable long-term prophylaxis. Notwithstanding, further studies are needed to identify early responders from non-responders and develop therapies for the latter.

Bowel obstruction secondary to internal hernia in a hereditary angioedema patient: a case report

BackgroundGastrointestinal attacks are frequent symptoms in patients diagnosed with hereditary angioedema (HAE). Cases of self-limited bowel intussusception and unneeded exploratory laparotomy due to lack of knowledge about HAE have been reported. Furthermore, after the introduction of C1-esterase inhibitor (C1-INH) concentrate, the recommended medication for HAE attacks, treatment has become typically medical in nature. We share a rare case where operative exploration was indicated to resolve a mechanical small bowel obstruction secondary to an HAE attack.Case reportAn 80-year-old woman with HAE presented with lower left abdominal pain, vomiting, and nausea. Computed tomography (CT) showed edema of the small bowel and stomach as well as possible signs of mechanical small bowel obstruction. The patient was treated with C1-INH concentrate but showed only mild signs of relief, warranting diagnostic laparoscopy. Intraoperative findings showed internal herniation and strangulation of the small bowel caused by adhesions forming a band. After surgical intervention, no bowel resection was needed.ConclusionAlthough C1-INH concentrate remains the principal treatment for HAE, gastrointestinal attacks may potentially cause surgical emergencies.