Hereditary angioedema (HAE) is a rare but serious autosomal dominant disorder marked by swelling attacks in the extremities, face, trunk, airways, or abdominal areas that can be spontaneous or the result of trauma [1
). Attacks can be serious; the risk of dying from airway obstruction, if left untreated, has been estimated at 30
]. Attack frequency is described in the literature as ranging from rarely to once every 3
]. Untreated, patients on average experience attacks every one to two weeks [5
HAE patient experiencing HAE attacks.
The prevalence of HAE is estimated to be approximately 1 in every 50,000 persons, with no marked differences among ethnic groups [6
]. The rarity of the disease, together with the fact that 6.1–13.7
% of patients may be asymptomatic or have delayed symptom onset [7
], means that, while HAE symptoms often begin in early childhood and persist throughout patients’ lives, awareness of the condition is extremely low, and diagnosis is frequently delayed. As observed in a Danish study, the mean delay to diagnosis can be as great as 16
]. There is therefore an urgent need to raise awareness of the disease and its appropriate diagnosis and treatment among clinicians and families who have a hereditary predisposition to the condition.
Improvements in our understanding of the disease process have led to the recent availability of an increased range of treatment options for HAE. Disease management takes the form of treatment of acute attacks, short-term prophylactic treatment for the prevention of attacks (for example, before a surgical procedure), and long-term prophylactic treatment (prevention) to minimize the frequency and severity of ongoing attacks [5
]. Treatments currently approved in Europe for acute attacks include plasma derived (pd) C1-inhibitor [human] concentrate (Berinert, Cetor), pd nano-filtered C1-inhibitor [human] (Cinryze), recombinant C1-inhibitor (Ruconest/Rhucin), and use of a bradykinin B2 receptor antagonist (Firazyr). Long-term prophylaxis (prevention) options have traditionally involved androgens (such as danazol or stanozolol), although their approval status for HAE varies among European countries. Cinryze is the only agent to have received European approval for both the treatment and pre-procedure prevention of angioedema attacks in adults and adolescents with HAE, as well as for the routine prevention of angioedema attacks in adults and adolescents.
The mechanisms underlying what prompts HAE attacks to start and resolve are relatively unknown. Moreover, the severity of symptoms is highly variable both from one patient to another and within a given patient [5
]. The uncertainty surrounding the onset of an attack can cause great anxiety for patients given that the swelling—especially when affecting the airways—can be fatal. HAE may, therefore, have a substantial emotional impact on the patient as well as on his or her family. In a cross-sectional survey using the Hamilton Depression Inventory – Short Form questionnaire (HDI-SF), 42.5
% of HAE patients had scores indicative of depressive symptomatology [12
]. Such findings suggest the importance of considering potential mental health impacts like stress, in addition to traditional treatment, in the clinical management of these patients in order to reduce the burden of HAE on daily life.
Some studies, including both interventional and case studies, have explored the health-related quality of life (HRQoL) impacts of HAE. Interventional studies have used general health status measures like the SF-36 and SF-12, and the Dermatology Life Quality Index (DLQI), which focuses on dermatological quality of life issues, and have found them to be associated with improvements in several quality of life areas, including both physical and psychological parameters [13
]. However, authors noted limitations of the DLQI, as it was originally created for use in patients with chronic dermatological diseases with exacerbations such as psoriasis and refers to symptoms that may not be relevant for HAE. Also, it does not take acute attacks into consideration and therefore does not allow to measure patients’ HRQoL both during an attack and in between attacks.
The SF-36 and SF-12 and general HRQoL measures are useful for making comparisons across disease areas, but they may fail to capture specific HRQoL manifestations of HAE. As Lumry and colleagues (2010) showed, HAE was associated with detriments in HRQoL across physical and mental health domains and in each subscale of both the SF-12 and HDI-SF [12
]. However, without in-depth elaboration from patients, the interpretation of these impacts, particularly those that are primarily physical, is limited. Second, while depression was assessed by way of the HDI-SF, anxiety, arguably an important emotional marker for any chronic condition marked by sudden attacks, was not captured in this measure. Prior and colleagues are developing an international multi-language HAE-specific HRQoL measure for adults, the IHAE-QoL [17
]. The pilot study has been completed in 12 countries (Argentina, Austria, Brazil, Canada, Denmark, France, Germany, Hungary, Israel, Poland, Romania, and Spain) and the psychometric study is being performed in order to validate this instrument (T Caballero, personal communication). This disease-specific questionnaire is expected to give more detailed and relevant data on HRQoL in HAE patients in the years ahead. However, this measure is, as of the publishing of the present article, still unavailable.
While there have been advances in our understanding of the burden of illness in HAE, significant gaps in our knowledge remain, particularly with regards to the humanistic and economic burden of the disease (Figure
). There is a dearth of data on: the economic impact of HAE; comparisons of HAE treatment patterns, patient characteristics, and outcomes in different countries; the impact of HAE on adolescents; and qualitative research, including interviews and/or focus group studies with HAE patients. In addition, utility weights (preference values) have not been published for HAE. Such weights may be used to quality-adjust life expectancy for use in economic evaluations of medical interventions. Finally, no-one has yet developed a conceptual model visually depicting the relationships between HAE disease symptoms and more distal impacts, such as impact on career advancement and educational attainment.
Gaps in the literature with regard to the humanistic and economic burden of HAE.
There is also a critical need for better epidemiological data on HAE generally. The data from this study will help further inform such data. In addition, the findings likely can be compared with those from other studies, including HAE registries, such as the Sweha-Reg [19
], the European Register of HAE [20
], and observational studies such as the HAE nationwide survey conducted in Denmark [7
Given the aforementioned gaps in our knowledge of HAE, the objective of the HAE Burden of Illness Study-Europe (HAE-BOIS-Europe) is to characterize the humanistic and economic burden of HAE from the patient perspective. This large-scale, scientifically robust, multi-country European study evaluates the real-world experience of HAE patients with respect to resource utilization and HRQoL burden of HAE in Germany, Denmark, and Spain. It collects qualitative data in addition to quantitative data to support a conceptual model of the patient-perceived impacts of HAE on HRQoL, showing the quality of life and economic burden of HAE both in relation to acute attacks as well as the long-term experience of HAE. The present paper describes the development and plans for implementation of this multi-country European study, the initial findings of which will be publicly available in 2012.