ReviewThe burden of illness in patients with hereditary angioedema
Introduction
Hereditary angioedema (HAE) is a rare autosomal dominant disease characterized by recurrent attacks of subcutaneous or submucosal edema that can affect the face, respiratory tract, extremities, gastrointestinal (GI) tract, genitalia, or other areas of the body. HAE involves all ethnic groups equally, but its global prevalence is not well defined, with estimates ranging from 1 in 10,000 to 1 in 100,000.[1], [2], [3], [4] There are thought to be approximately 6,000 patients living with HAE in the United States.5
Three types of HAE have been defined based on levels and activity of plasma complement-1 esterase inhibitor (C1INH). Type I HAE, the most prevalent form (85%), is characterized by the lack of plasma C1INH.6 In type II (15%), C1INH is secreted into the plasma but is nonfunctional. These 2 types are caused by mutations in the SERPING1 gene, which codes for C1INH. Although autosomally dominant, de novo mutations are thought to occur in approximately 25% of cases.7
The third and rarest type, HAE with normal C1INH (previously referred to as type III HAE), remains poorly understood.[8], [9], [10], [11] Although attacks are similar to those of types I and II, it is characterized by normal plasma levels of functional C1INH. Symptoms frequently emerge or are worsened by estrogen therapy, and mutations in factor XII are believed to play a role in 20% to 30% of patients.8 Although the incidence does not differ between men and women for types I and II, HAE with normal C1INH predominantly affects women.8
Symptoms of types I and II usually present during childhood, with approximately 50% of patients presenting by 10 years of age and nearly all by 20 years of age,[12], [13], [14] but diagnosis is often delayed by approximately 8 years on average.[2], [15], [16] Patients with HAE with normal C1INH present at a slightly older age compared with those with types I and II. Attacks in all types of HAE are often unpredictable, painful, and potentially life threatening and significantly affect a patient's quality of life (QOL).[17], [18], [19] Depression and anxiety are prevalent.19
In the past, treatments for HAE in the United States were lacking or associated with significant side effects. Since 2008, some effective and well-tolerated prophylactic and on-demand treatments have become available in the United States, including plasma-derived C1INH concentrates (Cinryze, ViroPharma Inc, Exton, Pennsylvania; Berinert, CSL Behring LLC, Kankakee, Illinois), a recombinant plasma kallikrein inhibitor, ecallantide (Kalbitor, Dyax Corp, Burlington, Massachusetts), and a small-molecule selective bradykinin B2 receptor antagonist, icatibant (Firazyr, Shire Orphan Technologies, Lexington, Massachusetts). However, these treatments can be expensive, and their availability may be limited at some medical facilities.[20], [21]
Because of the rarity of HAE, it has been difficult to systematically assess its humanistic and economic burden to better understand the challenges facing patients, caregivers, and health care systems, to identify knowledge gaps, and to improve disease management. Recently, some retrospective and prospective studies and patient and physician surveys have begun to establish a portrait of its multifaceted burden of illness (Fig 1). The present report presents a comprehensive review of the burden of illness of HAE with respect to its diagnosis, symptoms, treatment, QOL, and costs.
Section snippets
Literature Search Methods
A Boolean search was constructed to find articles on the burden of HAE listed on MEDLINE and EMBASE. Search terms included HAE (with thesaurus terms) cross-referenced with searches on topics of interest, including patient-reported outcomes, QOL, disability, productivity, depression, questionnaires, surveys, hospitalizations, and economics. Nonhuman and non–English-language publications were excluded, as were conference and meeting abstracts. Relevant publications were selected and supplemental
Diagnosis
Hereditary angioedema is under-recognized and frequently misdiagnosed, resulting in significant morbidity and mortality. Episodes of swelling involving the skin are frequently mistaken as allergic reactions and abdominal attacks as appendicitis or irritable bowel syndrome. Misdiagnosis can lead to unnecessary treatments and surgical procedures (eg, appendectomy) and premature death.[15], [28] Some patients are misdiagnosed with psychosomatic symptoms and referred for psychiatric evaluation.4 In
Treatment
Historically, acute treatment of HAE in the United States involved supportive care with narcotic analgesics, antiemetics, and fluid replacement.17 Corticosteroids, antihistamines, and epinephrine are ineffective for HAE, but are frequently administered nonetheless.25 Fresh frozen plasma has been used for acute attacks and short-term prophylaxis, with some success, but there is concern that angioedema could worsen because of the presence of contact-system proteins, which could increase
Changing the Landscape of HAE
Unfortunately, as a rare disease, it has been difficult to systematically characterize the burden of illness associated with HAE. Nonetheless, some studies are establishing a landscape. The burden of illness is multifaceted and complex, but the tools specific to HAE to more fully understand its impact on patients, caregivers, and health care systems have not been developed. More epidemiologic data are needed to better understand the scale of the burden and how it might vary across subgroups.
Conclusions
Hereditary angioedema is a disease with a great burden of illness that can significantly affect all aspects of a patient's life. As clinical and observational data of this rare disease continue to increase, there is a better understanding of its burden, the knowledge gaps, and potential steps to improve the lives of patients. Barriers to early diagnosis and intervention clearly need to be addressed in the short term. The introduction of novel treatments is a significant advancement, but without
Acknowledgments
Medical writing and editing services were provided by Michael Raffin from PHOCUS (North Wales, PA) and were supported by Shire (Eysins, Switzerland).
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A narrative review of recent literature of the quality of life in hereditary angioedema patients
2023, World Allergy Organization JournalOptimization of care for patients with hereditary angioedema living in rural areas
2022, Annals of Allergy, Asthma and ImmunologyCitation Excerpt :There are several barriers to diagnosis in patients with HAE. For example, there may be limited recognition of HAE by hospitalists and ED physicians, and HAE may not be considered in a differential diagnosis.15 Misdiagnosis is frequent, with approximately 50% of patients (n = 185) diagnosed as having HAE type 1 or 2 reporting that they had previously been misdiagnosed, most frequently with allergic angioedema, appendicitis, or other gastrointestinal disorders.16
Preventive Treatment of Hereditary Angioedema: A Review of Phase III Clinical Trial Data for Subcutaneous C1 Inhibitor and Relevance for Patient Management
2021, Clinical TherapeuticsCitation Excerpt :The course of the disease can be more severe in women compared with men. HAE significantly impairs health-related quality of life (HRQoL), not just during an attack but also between attacks,23–27 and is associated with elevated rates of anxiety and depression.26–29 Attacks can lead to missed work, school, and daily activities, as well as decreased productivity, hindered career advancement, and lost income,26,28,30–33 which can affect caregivers in addition to the patient.
Disclosures: Dr. Banerji has served on the advisory board and received clinical research funding from Dyax, Shire, CSL, and Virpharma.
Disclaimer: All opinions expressed in this manuscript are those of the author.