Angioedema

BackgroundHereditary angioedema (HAE) is a rare, debilitating, genetic disease characterized by unpredictable, recurrent, and potentially fatal swelling of the skin and mucous membranes. We conducted a noninterventional, cross-sectional, web-based survey of patients with a self-reported diagnosis of HAE type 1/2 in Australia, Austria, Canada, France, Germany, Spain, Switzerland, and the United Kingdom to gain a comprehensive real-world understanding of the characteristics of HAE and its burden from the perspective of the patient. The survey included questions on clinical and demographic characteristics, burden of disease, and treatment. Instruments used to measure patient-reported outcomes included the Angioedema Quality of Life questionnaire (AE-QoL), 12-Item Short-Form Health Survey (SF-12v2), Angioedema Control Test (AECT), Hospital Anxiety and Depression Scale (HADS), and Work Productivity and Impairment questionnaire (WPAI). Data were analyzed with descriptive statistics.ResultsA total of 242 patients (67.4% female; mean [range] age 43.8 [18-92] years) completed the survey. The mean (SD) age at first symptoms was 11.5 (8.9) years, while diagnosis occurred at 20.8 (13.2) years. Patients reported a mean (SD) of 12.5 (14.1) attacks in the past 6 months. The most recent attack occurred within the past month in 79.7% of patients; most were of moderate severity, 6.6% affected the larynx, 21.9% lasted ≥ 3 days, and 76.4% were treated with on-demand medication. Hospitalizations and emergency/urgent care visits were highest for patients with more attacks. At the time of the survey, 62.4% of patients were using long-term prophylaxis, including 34.4% using androgens. Moderate to severe anxiety and depression were reported in 38.0% and 17.4% of patients, respectively, as measured using the HADS. The severity of anxiety and depression was associated with poorer quality of life and productivity, measured using the AECT (mean overall score 8.00 [moderate perceived disease control]), AE-QoL, WPAI, and SF-12v2. Scores for AECT, AE-QoL, and WPAI were also worse with a higher number of attacks.ConclusionsThis survey study of a broad international sample of patients with HAE showed that despite the availability of on-demand treatment and long-term prophylaxis for the prevention of attacks, patients across a wide geographical area continue to have high disease activity, likely due to restrictions in the availability of medications or incorrect use. Subsequently, significant disease burden, including impaired quality of life and mental health and decreased productivity, was evident. Increased patient education and access to newer, more effective therapies are needed.

Hereditary angioedema (HAE) has been recognized for almost 150 years. The newest form of HAE, where C1 inhibitor levels are normal (HAE-nC1INH), was first described in 2000. Over the last two decades, new types of apparent non-mast cell-mediated angioedema with normal quantity and activity of C1INH have been described, in some cases with proven genetic pathogenic variants that co-segregate with angioedema expression within families. Like HAE due to C1INH deficiency, HAE-nC1INH patients are at risk of serious morbidity and mortality. Therefore, proactive management and treatment of HAE-nC1INH patients after an expert physician diagnosis is critically important. The underlying pathophysiology responsible for the angioedema has also been clarified in some of the HAE-nC1INH types. While several clinical guidelines and practice parameters including HAE-nC1INH have been published, we have made substantial progress in our understanding encompassing diagnostic criteria, pathophysiology, and treatment outcomes. HAE International (HAEi) and the US HAE Association (HAEA) convened a symposium of global HAE-nC1INH experts to synthesize our current knowledge in the area. Given the paucity of high-level evidence in HAE-nC1INH, all recommendations are based on expert opinion. This review and expert opinion on the best practice approach to diagnosing and treating HAE-nC1INH will support physicians to better manage patients with HAE-nC1INH.

BackgroundThis systematic study aims to assess the global epidemiologic, economic, and humanistic burden of illness associated with all types of hereditary angioedema.MethodsA systematic search for articles reporting the epidemiologic, economic, and humanistic burden associated with patients with HAE was conducted using English and Chinese literature databases from the inception to May 23, 2022. The selected studies were assessed for their quality and risk of bias. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022352377).ResultsIn total, 65 articles that met the search inclusion criteria reported 10,310 patients with HAE, of whom 5861 were female patients. Altogether, 4312 patients (81%) and 479 patients (9%) had type 1 and type 2 HAE, respectively, whereas 422 patients (8%) had HAE-normal C1-INH. The overall prevalence of all types of HAE was between 0.13 and 1.6 cases per 100,000. The mean or median delay from the first onset of a symptom of HAE to confirmed diagnosis ranged from 3.9 to 26 years. The estimated risk of death from asphyxiation was 8.6% for patients with HAE. Hospitalization, medication, unnecessary surgeries, doctor visits, specialist services, and nursing costs are direct expenses that contribute to the growing economic burden. The indirect cost accounted mostly due to missing work ($3402/year) and loss of productivity ($5750/year). Furthermore, impairment of QoL as reported by patient-reported outcomes was observed. QoL measures identified depression, anxiety, and stress to be the most common symptoms for adult patients and children.ConclusionThis study highlights the importance of early diagnosis and the need for improving awareness among health care professionals to reduce the burden of HAE on patients and society.

IntroductionHereditary angioedema (HAE) and mast cell-mediated angioedema are characterized by episodic swelling. Yet, atypical variants, such as HAE with normal C1 inhibitor, remain poorly understood and diagnostically challenging. Although advances in diagnosis and therapy have improved patient outcomes, investigating the role of the endothelial glycocalyx in regulating vascular permeability may uncover novel biomarkers and enhance both diagnostic and prognostic strategies.Materials and methodsHuman umbilical vein endothelial cells (HUVEC) were treated with enzymes for glycocalyx degradation. Glycocalyx quantification was performed using wheat germ agglutinin (WGA) assays, enzyme-linked immunosorbent assays, and real time-polymerase chain reaction. Endothelial barrier function was evaluated through measurements of transendothelial electrical resistance (TEER), and permeability for dextrans. Water flux across the endothelium was determined using the D2O dilution method.ResultsHUVEC expressed a functional glycocalyx. Enzymatic glycocalyx degradation reduced barrier integrity. Bradykinin and serotonin did not affect glycocalyx integrity, while histamine reduced WGA binding. Bradykinin and histamine also decreased hyaluronidase activity. Barrier function analysis showed that glycocalyx degradation and compound exposure led to increased water permeability, with no additive effects on TEER and permeability.DiscussionGlycocalyx degradation increased endothelial permeability, with possible implication for edema development. Bradykinin and serotonin did not affect glycocalyx composition, but histamine reduced its integrity. Glycocalyx degradation led to a further increase in mediator-induced water permeability. This suggests a protective role of the glycocalyx endothelial dysfunction. This highlights its potential as a biomarker for angioedema.