Author(s): Dumitru Moldovan [*] aff1 , Jonathan A Bernstein aff2 , Marco Cicardi aff3
C1-INH; C1-INH-HAE; hereditary angioedema; recombinant human C1 esterase inhibitor; Ruconest®
Patients with hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) (C1-INH-HAE) experience acute attacks of localized swelling (angioedema) due to mutations in the C1-INH gene, SERPING 1 , causing either a deficiency and decreased functionality (Type I HAE) or mutations causing a nonfunctionality of the C1-INH protein, which may be quantitatively normal or increased in the blood (Type II HAE). To date, more than 250 genetic mutations (point mutations or wide gene rearrangements) have been described (HAEdb; http://hae.enzim.hu) [1 ]. De novo mutations account for approximately 25% of C1-INH-HAE cases [2 ].
The lack of functional C1-INH results in uncontrolled activation of the contact system, leading to an excessive release of bradykinin causing increased vascular permeability (Figure 1) [3 ]. The fluid leak from the intravascular compartment into the subcutaneous or submucosal space becomes manifest as an acute episode of angioedema, which is the hallmark of an C1-INH-HAE attack.
Clinically, patients with C1-INH-HAE experience recurrent acute attacks of soft tissue swelling that can affect multiple anatomic regions, including the GI tract, facial tissues, upper airway, oropharynx, urogenital region and/or the arms and legs. These acute attacks are associated with considerable morbidity, and they often require hospitalization and immediate medical intervention. Laryngeal attacks can be life threatening, due to obstruction of the upper airway and are associated with significant morbidity and mortality [4 ]. Sudden onset of intestinal mucosa edema causes severe pain, due to the occlusion of the bowel and may mimic a surgical 'acute abdomen'. In undiagnosed C1-INH-HAE patients, this may lead to unnecessary surgical intervention. Sometimes regarded as clinically insignificant, swelling attacks in the extremities of the body are disabling, disfiguring and painful [5 ]. Such peripheral attacks account for more than half of the attacks in patients with C1-INH-HAE [6 ]. Although the majority of the published literature describing C1-INH-HAE attacks focuses on a single anatomical site, attacks can affect one or more anatomical locations simultaneously or start in one area and spread to another site [7 ].
Despite being a rare condition, C1-INH-HAE is associated with a significant healthcare and economic burden. Over a one year period in the United States, C1-INH-HAE accounted for [greater than]5000 emergency department visits, 41% of which resulted in hospitalization [8 ]. C1-INH-HAE is also associated with psychological problems, anxiety and depression resulting in high rates of absenteeism from work and school [ 9 ]. The quality of life (QoL) of C1-INH-HAE patients has been found to be significantly compromised by limited personal autonomy, and its impact on professional and leisure activities [10 ]. The low prevalence of C1-INH-HAE combined with a clinical presentation of intermittent recurrent abdominal pain and/or episodes of skin swelling, often results in a significant delay in diagnosis of patients, which further results in a decline of their QoL [11 ]. A recent study reported the average delay to diagnosis to range from...