Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare autosomal dominant genetic disorder that usual results from a decreased level of functional C1-INH and clinically manifests with intermittent attacks of swelling of the subcutaneous tissue or submucosal layers of the respiratory or gastrointestinal tracts. Laboratory studies and radiographic imaging have limited roles in evaluation of patients with acute attacks of HAE except when the diagnosis is uncertain and other processes must be ruled out. Treatment begins with assessment of the airway to determine the need for immediate intervention. Emergency physicians should understand the pathophysiology of HAE to help guide management decisions.

Acquired Angioedema in Selected Neoplastic Diseases.

Background and Objectives. Acquired angioedema is a relatively common revelation accompanying some diseases such as autoimmune or cancer. The study aimed to assess the incidence of one subtype of angioedema-C1-INH-AAE (acquired angioedema with C1 inhibitor deficiency). Material and methods. The study was retrospective and based on 1 312 patients with a final diagnosis of breast cancer, colorectal cancer, or lung cancer: 723 women and 589 men with a mean age of 58.2 ± 13.5 years. The cancer diagnosis according to the ICD (International Classification of Diseases)-10 code, medical history including TNM (Tumour, Node, Metastasis) staging, histopathology, and assessment of the occurrence of C1-INH-AAE angioedema were analysed. Results. C1-INH-AAE occurred more often in patients with cancer than in the control group, as follows: 327 (29%) vs. 53 (6%) for p < 0.05. C1-INH-AAEs were observed most often in the group of patients diagnosed with breast cancer compared to colorectal and lung groups: 197 (37%) vs. 108 (26%) vs. 22 (16%) (p < 0.05). A higher incidence of C1-INH-AAE was observed in the early stages of breast cancer. However, there was no relationship between the occurrence of C1-INH-AAE and the BRCA1 (Breast Cancer gene 1)/BRCA2 (Breast Cancer gene 2) mutation or histopathological types of breast cancer. Conclusion. Angioedema type C1-INH-AAE occurs more often in patients with selected neoplastic diseases, especially in the early stages of breast cancer.

Hereditary Angioedema During Pregnancy: Considerations in Management.

In recent years, hereditary angioedema (HAE) management has substantially advanced but also become more complex with additional therapeutic options. Pregnancy significantly influences the clinical symptoms of HAE in many women because of estrogen effects or other physiologic factors, and also introduces important safety concerns related to HAE medications. Management of HAE during pregnancy requires clinicians to be familiar with the potential clinical course, triggers, and recommended treatment strategies to provide guidance and optimal medical management to women and families affected by the condition. This review provides an overview of data, considerations, and recommendations related to HAE and pregnancy.

Periodic Severe Angioedema without Exogenous Hormone Exposure.

Hereditary angioedema (HAE) is characterized by recurrent attacks of skin and mucosal swelling in any part of the body including the digestive and respiratory tract which generally improve spontaneously within 12-72 hours. The underlying mechanism in HAE is related to bradykinin dysregulation which causes these attacks not to respond to common treatment strategies including epinephrine/corticosteroid or adrenaline. There are several types of HAE with different etiology but with the same clinical picture. Type 1 is due to the deficiency of C1 Inhibitor (C1-INH) protein and type 2 is related to dysfunctional C1-INH protein. The third type of HAE which comprises the minority of cases is associated with the normal amount and function of C1-INH protein. The presented case in this report was a 15-years old girl with a history of spontaneous angioedema attacks from the age of 14. The frequency of attacks was initially every two months but consequently increased to every two weeks after using some hormonal medications for ovarian cyst. Each episode has lasted around 10 days without any symptoms in between. Complement studies including C4, C1q, and C1-INH protein, both quantitative and qualitative, were reported as normal. A genetic assessment revealed a mutation in the exon 9 on the gene related to factor XII, hence the diagnosis of HAE type 3 was confirmed. This was a rare type of angioedema with normal amount and function of C1-INH protein which is predominantly seen in women during periods of imbalanced estrogen increments like pregnancy, lactation, and menopause, and hence it is responsive to hormonal manipulation strategies such as the use of progesterone containing medications.

Acquired Angioedema with C1 Inhibitor Deficiency: Occurrence, Clinical Features, and Management: A Nationwide Retrospective Study in the Czech Republic Patients.

INTRODUCTION: Acquired angioedema with C1 inhibitor deficiency (AAE-C1-INH) is rare but a potentially life-threatening disease. There are no official prevalence data, nor approved therapies for this condition. OBJECTIVE: In this study, we aimed to collect and analyze clinical data on patients with AAE-C1-INH in the Czech Republic. METHODS: We have conducted a retrospective analysis of AAE-C1-INH patients from Czech referral centers for the treatment of hereditary angioedema with C1 inhibitor deficiency. The inclusion criteria involved recurrent episodes of angioedema with the first manifestation at or after the age of 40, negative family history of angioedema, and C1 inhibitor function 50% or less. RESULTS: A total of 14 patients (7 males and 7 females) met the inclusion criteria for AAE-C1-INH. The median age of the symptom onset was 59.5 years, and the median diagnosis delay was 1 year. The most common clinical manifestation was facial edema (100%) and upper airway swelling (85.7%). All patients responded to the acute attack treatment with icatibant and plasma-derived or recombinant C1 inhibitor concentrate. Lymphoid malignancy was identified in 9 patients (64%), monoclonal gammopathy of uncertain significance in 3 (21%), and in 1 patient autoimmune disease (ulcerative colitis) was considered causative (7%). We were not able to identify any underlying disease only in 1 patient (7%). In 6 of 7 patients (86%) treated for lymphoma, either a reduction in the frequency of angioedema attacks or both angioedema symptoms' disappearance and complement parameter normalization was observed. CONCLUSIONS: The prevalence of AAE-C1-INH in the Czech Republic is about 1:760,000. This rare condition occurs in approximately 8% of the patients with angioedema with C1 inhibitor deficiency. AAE-C1-INH is strongly associated with lymphoproliferative disorders, and treating these conditions may improve the control of angioedema symptoms.

Management of hereditary angioedema in Japan: Focus on icatibant for the treatment of acute attacks.

Hereditary angioedema (HAE) is characterized by unpredictable, recurring and painful swelling episodes that can be disabling or even life-threatening. Awareness of HAE has progressively grown worldwide, and options for treatment of acute attacks and prevention of future attacks continue to expand; however, unmet needs in diagnosis and treatment remain. In Japan, recognition of HAE within the medical community remains low, and numerous obstacles complicate diagnosis and access to treatment. Importance of timely treatment of HAE attacks with on-demand therapies is continually demonstrated; recommended agents per the WAO/EAACI treatment guidelines published in 2018 include C1 inhibitor (C1-INH) concentrate, ecallantide, and icatibant. In Japan, multiple factors contribute to delayed HAE treatment (potentially leading to life-threatening consequences), including difficulties in finding facilities at which C1-INH agents are readily available. Recognition of challenges faced in Japan can help promote efforts to address current needs and expand access to effective therapies. Icatibant, a potent, selective bradykinin B2 receptor antagonist, has demonstrated inhibition of various bradykinin-induced biological effects in preclinical studies and has shown efficacy in treating attacks in various clinical settings (e.g. clinical trials, real-world studies), and HAE patient populations (e.g. with C1-INH deficiency, normal C1-INH). Icatibant was approved in Japan for the treatment of HAE attacks in September 2018; its addition to the HAE treatment armamentarium contributes to improved patient care. In Japan, disease awareness and education campaigns are warranted to further advance the management of HAE patients in light of the unmet needs and the emerging availability of modern diagnostic approaches and therapies.

Hereditary Angioedema with and Without C1-Inhibitor Deficiency in Postmenopausal Women.

PURPOSE: Most types of hereditary angioedema (HAE) are worsened by endogenous or exogenous estrogens. Conversely, androgens can improve HAE with abnormal C1-Inhibitor (C1-INH) by increasing C1-INH concentrations. Menopause is associated with an extinction of ovarian estrogenic and androgenic secretion. There is currently insufficient information on postmenopausal women with HAE. The objective of this study was to describe the activity of HAE in postmenopausal women. METHODS: This was a French retrospective, multicenter study in postmenopausal women with HAE with or without C1-INH deficiency/dysfunction. The patients were classified before and after menopause with a previously validated HAE disease severity score. RESULTS: We included 65 women from 13 centers in France. The mean age was 62.7± 9.2 years, and the mean time between menopause and inclusion was 12.5± 9.1 years. HAE was associated with C1-INH deficiencyin 88% (n = 57) of the patients, a mutation of factor 12 in 8% (n = 5), a mutation in plasminogen gene in one, and unknown HAE for two. The HAE course was not different after menopause in 46.1% (n = 30), improved in 38.5% (n = 25), and worsened in 15.4% (n = 10). Improvement was correlated with estrogen sensitivity of angioedema before menopause (p = 0.06 for improvement vs no effect or worsening). In addition, we observed that only ten women received treatment (transdermal or oral estradiol+ progestogen) for their menopause symptoms. Among them, only 3 experienced worsening of symptoms (2 on transdermal and 1 on oral estradiol). CONCLUSION: Following menopause, most women with HAE remain stable but some worsen. Improvement was mainly observed in patients with previous estrogen sensitivity. More research is required in menopausal women with HAE to better understand how to manage climacteric symptoms.

Successful perioperative management of three patients with hereditary angioedema without C1 esterase inhibitor therapy: A developing country perspective.

BACKGROUND: Hereditary angioedema (HAE) is a rare inherited disorder characterized by sudden and unpredictable appearance of swelling. Surgical procedures, even minor ones, are known to precipitate an attack in these patients. C1 esterase inhibitor (C1-INH) therapy may be effective for short term prophylaxis in such situations. However, there is limited experience with short term prophylaxis in countries where C1-INH therapy is not available. METHODS: To report our experience of using short term prophylaxis for a dental procedure, a Cesarean section and a major hip surgery in one patient each with HAE in resource constrained settings. RESULTS: All 3 patients were given FFP before and during the procedure. While the first (a 6-year-old girl) and third patient (a 60-year-old male) were already taking stanozolol and the dose was doubled 5 days before the surgery, the second patient (28-year-old woman) was not taking any prophylaxis and she was initiated on stanozolol on the day of Cesarean section. The first patient was also given additional FFP one day after the dental procedure. After the procedure, the dose of stanozolol was decreased to baseline in patient 1 and 3 while it was discontinued in patient 3. All 3 patients tolerated the procedures well and had no related episodes of angioedema. CONCLUSIONS: Dental and other major surgical procedures in patients with HAE are known to precipitate an episode of angioedema. In countries where C1-INH therapy is not available, attenuated androgens and FFP may be used to prevent these episodes.

Monoclonal gammopathy with significance: case series and literature review.

Monoclonal gammopathy of undetermined significance (MGUS) is considered an asymptomatic precursor of malignant lymphoid disorders. This case series and literature review shows that these monoclonal gammopathies can cause significant morbidity. We describe a patient with angioedema due to acquired C1-esterase inhibitor deficiency, a patient with cryoglobulinemia type II causing skin vasculitis and glomerulonephritis, and a patient with glomerulonephritis and nephrotic syndrome - all caused by a monoclonal gammopathy that can be classified as MGUS. Clinicians should be familiar with these consequences of monoclonal gammopathies. The term MGUS should only be used in patients without organ damage caused by monoclonal gammopathies.

Exogenous hormones and hereditary angioedema.

Gonadal hormones, estrogen and androgen are strongly involved in the control of the bradykinin production. Estrogen may worsen whereas androgen can be part of the long-term prophylactic treatment. In this review, we will describe the potential impact of estrogen in the pathophysiology of hereditary angioedema (HAE). Then we will review the different hormone treatments and their implication on the course of HAE in women and men: contraception, Assisted Reproductive Technology (ART), menopause, hormone dependent cancers in women and men, treatment of hyperandrogenism in women.

Hereditary and acquired angioedema.

Hereditary angioedema (HAE) is an autosomal dominant disorder defined by a deficiency of functional C1 esterase inhibitor (C1-INH). Acquired angioedema is due to either consumption (type 1) or inactivation (type 2) of CI-INH. Both HAE and acquired angioedema can be life-threatening. Of the three types of HAE, type 1 is most common, occurring in approximately 85% of patients and characterized by decreased production of C1-INH, which results in reduced functional activity to 5-40% of normal. Type 2 occurs in 15% of cases; C1-INH is detectable in normal or elevated quantities but is dysfunctional. Also, HAE with normal CI-INH (previously called type 3 HAE) is rare and characterized by normal complement studies. Specific genetic mutations have been linked to factor XII, angiopoietin-1, and plasminogen gene. Patients with unknown mutations are classified as unknown. The screening test for types 1 and 2 is complement component C4, which is low to absent at times of angioedema and during quiescent periods. A useful test to differentiate HAE from acquired angioedema is C1q protein, which is normal in HAE and low in acquired angioedema. The management of HAE has been transformed with the advent of disease-specific therapies. On-demand therapy options include plasma and recombinant C1-INH for intravenous infusion; ecallantide, an inhibitor of kallikrein; and icatibant, a bradykinin ß2 receptor antagonist, both administered subcutaneously. For long-term prophylaxis, intravenous or subcutaneous C1-INH enzyme replacement and lanadelumab, a monoclonal antibody against kallikrein that is administered subcutaneously, are effective agents.

Pediatric hereditary angioedema: what the otolaryngologist should know.

PURPOSE OF REVIEW: To review pediatric hereditary angioedema for otolaryngologists, with emphasis on articles within the past 12-18 months. RECENT FINDINGS: Biologic therapies are accepted for adult hereditary angioedema (HAE), but have been studied less for pediatric HAE. Recent literature supports expanded use of biologic agents in pediatrics as acute treatment and prophylaxis. Available agents include plasma-derived C1 esterase inhibitors (C1-INH) (Berinert, Haegarda, Cinryze), recombinant C1-INH (Ruconest), bradykinin B2 receptor inhibitor (Icatibant), and kallikrein inhibitors (Ecallantide and lanadelumab). Of these, only Berinert is Food and Drug Administration (FDA) approved for acute therapy for children under 12 years of age. Ruconest is approved for treatment of acute attacks over age 13. Ecallantide also has FDA approval as acute treatment for age 12 and older, while lanadelumab and Haegarda are prophylactic agents for adolescents. Icatibant lacks FDA approval in patients under 18 years of age. Cinryze has FDA approval only for prophylaxis for children as young as 6 years old. SUMMARY: Pediatric HAE is a potentially life-threatening disease. Targeted biologic agents have gained acceptance in treatment of acute attacks, and their use as prophylactic agents is changing the focus of management from acute intervention to preventive management. While intubation or surgical airway management may still be necessary, early intervention or prophylaxis can decrease morbidity and improve quality of life.

Plasminflammation-An Emerging Pathway to Bradykinin Production.

Plasminogen activation is essential for fibrinolysis-the breakdown of fibrin polymers in blood clots. Besides this important function, plasminogen activation participates in a wide variety of inflammatory conditions. One of these conditions is hereditary angioedema (HAE), a rare disease with characteristic attacks of aggressive tissue swelling due to unregulated production and activity of the inflammatory mediator bradykinin. Plasmin was already implicated in this disease decades ago, but a series of recent discoveries have made it clear that plasmin actively contributes to this pathology. Collective evidence points toward an axis in which the plasminogen activation system and the contact system (which produces bradykinin) are mechanistically coupled. This is amongst others supported by findings in subtypes of HAE that are caused by gain-of-function mutations in the genes that respectively encode factor XII or plasminogen, as well as clinical experience with the antifibrinolytic agents in HAE. The concept of a link between plasminogen activation and the contact system helps us to explain the inflammatory side effects of fibrinolytic therapy, presenting as angioedema or tissue edema. Furthermore, these observations motivate the development and characterization of therapeutic agents that disconnect plasminogen activation from bradykinin production.

Acquired C1-inhibitor deficiency presenting with nephrotic syndrome.

Acquired C1-inhibitor (C1-INH) deficiency is a rare and potentially life-threatening disorder, which presents with recurrent attacks of non-pitting oedema to the face, airway, limbs or gastrointestinal tract. It is often associated with underlying B-cell lymphoproliferative disorders. We describe a case of a 73-year-old man with acquired C1-INH deficiency who presented with nephrotic syndrome due to glomerular IgM deposition, secondary to an underlying secretory lymphoplasmacytic lymphoma. Both the acquired C1-INH deficiency and the nephrotic syndrome resolved when the underlying B-cell lymphoma was treated with rituximab and bendamustine, suggesting the underlying lymphoproliferative malignancy was driving both disorders.

Hereditary Angio-Oedema for Dermatologists.

Among angio-oedema patients, hereditary angio-oedema (HAE) should not be overlooked. Besides skin swellings, these patients might have very painful abdominal attacks and potentially life-threatening angio-oedema of the upper airway. They will not respond to traditional anti-allergic therapy with antihistamines, corticosteroids, and adrenaline, and instead need specific drugs targeting the kallikrein-kinin pathway. Classically, patients with HAE have a quantitative or qualitative deficiency of the C1 inhibitor (C1INH) due to different mutations in SERPING1, although a new subtype with normal C1INH has been recognised more recently. This latter variant is diagnosed based on clinical features, family history, or molecular genetic testing for mutations in F12, ANGPT1,or PLG.The diagnosis of HAE is often delayed due to a general unfamiliarity with this orphan disease. However, undiagnosed patients are at an increased risk of unnecessary surgical interventions or life-threatening laryngeal swellings. Within the last decade, new and effective therapies have been developed and launched for acute and prophylactic therapy. Even more drugs are under evaluation in clinical trials. It is therefore of utmost importance that patients with HAE are diagnosed as soon as possible and offered relevant therapy with orphan drugs to reduce morbidity, prevent mortality, and improve quality of life.

Angioedema hereditario. Acerca de un caso clínico / Hereditary angioedema. A clinical case / Angioedema herediário. Informe de um caso clínico

Introducción: los angioedemas son motivo de consulta frecuente en alergología. Una minoría de ellos representa un desafío diagnóstico-terapéutico y concierne a la medicina transfusional. Objetivo: reseñar la presentación clínica y el tratamiento de un paciente con angioedema hereditario. Material y método: presentación de un caso clínico incluyendo antecedentes personales, familiares, descripción y reto de la enfermedad con aportes de literatura científica actualizada. Resultados: abordaje de la patología en términos clínicos, paraclínicos, terapéuticos y preventivos a partir del caso desarrollado. Conclusiones: se logró el encare de una entidad infrecuente y poco conocida con perspectivas de mejora diagnóstico-terapéutica a favor de la calidad de vida de estos pacientes.

Introduction: angioedemas are a frequent cause of consultation in allergology. A small number of cases imply a diagnostic and therapeutic challenge and involve transfusion medicine. Objective: to outline the clinical presentation and handling of a patient with hereditary angioedema. Method: presentation of the clinical case including personal and family history, as well as a description and account of the condition's challenge with the contribution of updated scientific literature. Results: ways of approaching the condition in clinical, paraclinical, therapeutic and prophylactic terms, based on the study of a case. Conclusions: the study managed to address this rather unusual and not well known condition, with the prospect of diagnostic and therapeutic improvement for the quality of life of these patients

Introdução: os angioedemas são uma causa de consulta frequente em alergologia. Uma pequena porcentagem é um desafio diagnóstico-terapêutico e é objeto de estudo da medicina transfusional. Objetivo: descrever as características clínicas e o manejo de um paciente com angioedema hereditário. Método: apresentação de um caso clínico incluindo antecedentes pessoais, familiares, descrição e desafio da doença e revisão da literatura científica. Resultados: abordagem da patologia em termos clínicos, de exames complementares, terapêuticos e preventivos a partir do caso estudado. Conclusões: estudou-se uma entidade rara e pouco conhecida com perspectivas de melhoria diagnóstico-terapêutica com benefícios para a qualidade de vida destes pacientes.

Assessment on hereditary angioedema burden of illness in Brazil: A patient perspective.

Background: Hereditary angioedema (HAE) is an autosomal dominant disorder that affects ∼1 in 50,000 individuals. The disorder is characterized by spontaneous and gradual episodes of edema in subcutaneous tissues or mucosal membrane that may endanger the patient's life. Previous studies that concern HAE treatment and burden of illness in the United States and Europe suggest an improvement in the control of HAE. However, no similar data are available in South American patients. The purpose of the present study was to evaluate the burden of disease and compliance to therapy of patients with HAE in Brazil. Methods: We developed a structured questionnaire to assess the variables that influence the diagnosis and treatment of Brazilian patients with HAE. The questionnaire was evaluated by allergists with expertise in HAE and was reformatted before applying it. The consent form was included before survey access; approval from the ethic committee of Faculdade de Medicina do ABC (Santo André, São Paulo, Brazil) was ensured. The Brazilian association of patients with HAE distributed the survey by e-mail to associated patients all over the country, and responses were accepted within a period of 3 months after signing a consent form. Results: Ninety patients (67 women, 23 men; average age, 36.5 years) responded; the main findings were the following: 53 of 90 (64%) had no need of visiting emergency departments in the past 6 months; 71 of 90 (79%) reported life-threatening fear due to their diagnosis; 73 of 90 (83%) had other family members affected, but 54 of 73 of these affected relatives did not look for specific HAE treatment; and 26 of 90 (29%) reported death due to asphyxia or throat swelling in family members. Conclusion: Patients with HAE report understanding how severe their diagnosis represent, but they did not ponder how important their commitment to treatment may decrease the constant fear brought by the disease in its possible swelling crisis. Family data supported this conclusion.