Consensus Guidelines on Improving the Management of HAE

Initiative Rationale

Hereditary angioedema (HAE) is a rare and potentially fatal genetic condition involving a deficiency or dysfunction of C1 inhibitor (C1-INH). HAE is an autosomal dominant disease (Mendelian Inheritance in Man #106100) that occurs in approximately 1/10,000 to 1/50,000 individuals with no racial or gender predilection. The symptoms of HAE usually present in early childhood, worsen at puberty, persist throughout life, and are unpredictable. The frequency of attacks ranges from frequent —every 3 days— to only rarely. Trauma (including dental procedures), stress, fever, and infection are just some of a large range of HAE triggers. Many attacks, however, occur without an identifiable trigger. HAE typically manifests as cutaneous, intra-abdominal, facial, laryngeal or genital swelling. Abdominal attacks can cause severe pain, and mortality from edema-induced airway closure has been reported to be as high as 30%.

Despite its often dramatic presentation, HAE is extremely rare and tends to mimic other disease states which may delay the diagnosis or result in a misdiagnosis of HAE. In spite of increased educational efforts, the average time from the initial swelling episode to diagnosis still approaches a full decade.

The condition was described in 1876 as "giant urticaria" by John Laws Milton and fully described by William Osler in 1888 as angio-neurotic edema. In the early 1960s, Donaldson and Evans demonstrated that patients with HAE were lacking the serum inhibitor directed against the first component of the complement system, C1 esterase inhibitor, now referred to as C1 inhibitor.

At the end of the 1960s, Donaldson (et al) found that the permeability-increasing factor in the plasma of patients during acute HAE also displayed kinin-like activity. Since that time research has focused on the detailed exploration of the genetics of HAE. By the end of the twentieth century, more than 100 different C1-INH gene mutations had been described in HAE patients. Currently 150 mutations of the gene located in the q12-q13 sub-region of chromosome 11 have been identified in patients with HAE. However, specific gene mutations do not seem to correlate with disease variability or severity.

Hereditary Angioedema results from a genetic deficiency of the blood-based protein C1 inhibitor (C1-INH). Whether a low quantity of C1-INH is made or the C1-INH is defective, it doesn't perform its normal regulatory function. A biochemical imbalance occurs producing a vasoactive peptide that causes capillaries to leak into surrounding tissues, causing edema that can be incapacitating.

Historically, vast numbers of HAE patients have been misdiagnosed with histamine-mediated allergic angioedema, often resulting in unnecessary exploratory surgical procedures. Non-effective pharmacologic management results in loss of work and school time. An accurate diagnosis is crucial to the social, economic, emotional as well as physical well-being of every HAE patient. 

The treatment of hereditary angioedema (HAE) has undergone dramatic changes as newer medicines have become available in recent years. Optimal care of these patients requires a comprehensive management plan. Although several consensus papers have been published concerning the diagnosis and treatment of HAE, the HAEA's 2013 Recommendations for the Management of Hereditary Angioedema Due to C1 Inhibitor Deficiency are the first set of guidelines for a comprehensive management plan of HAE. Members of the US Hereditary Angioedema Association Medical Advisory Board began by reviewing the literature concerning treatment of HAE. Preliminary recommendations were developed based on the literature review, discussions in a face-to-face meeting, and refinements in a series of drafts. Final recommendations reflect the unanimous consensus of the medical advisory board and the US Hereditary Angioedema Association leadership. 

The US HAEA is committed to seeing patients lead a full and healthy life through research and education. It is the goal of this program to help illustrate and outline the 2013 Consensus Guidelines on Improving the Management of HAE.