Ania L Manson PhD MRCP,
Specialist Registrar in Clinical Immunology,
Barts and the London NHS Trust, London, UK
Hilary J Longhurst PhD FRCP FRCPath,
Consultant in Clinical Immunology,
Barts and the London NHS Trust, London, UK
Hereditary angiodema (HAE) is an autosomal dominant condition that has an estimated prevalence of 1:50,000. It occurs in both men and women with no predilection for any particular ethnic group. It is characterised by episodic, non-pruritic, localised subcutaneous and sub-mucosal swellings that, untreated, typically last for 1-5 days.
While the trigger for most attacks of angiodema is not known, minor trauma, surgery, infection, menstruation, bleeding and stress are all known to exacerbate the disease. In some cases, an attack is heralded by a prodromal rash or feeling of malaise. Untreated, patients average 1-2 attacks per month, but there is considerable variability between patients with regard to the frequency and severity of their attacks.
At its most severe HAE can be life threatening, with swelling of the larynx causing asphyxiation. Fortunately, only a minority of attacks involve the larynx, but most patients with HAE will experience at least one attack of laryngeal oedema in their lifetime. Swellings affecting the internal organs such as the intestine or bladder are extremely painful, and the resulting loss of fluid into the peritoneum can cause significant ascites and hypotension.
Consequently, abdominal attacks of HAE can be clinically indistinguishable from acute-abdominal emergencies, and many patients undergo unnecessary surgery before a diagnosis of HAE is considered. However, the less dramatic peripheral attacks can also have a significant impact, and the loss of function of the dominant hand as a result of swelling can prevent a patient from performing their job or interfere with their ability to care for dependants.
The unpredictable nature of the disease means that patients may live in fear of having an attack, and the fact that several members of the same family may have HAE is a further complication.
As a result of the above, the social burden of the disease is significant. Patients with HAE have been shown to have significantly higher levels of depression, significantly poorer quality of life and decreased work productivity. In some studies, even on prophylactic treatment, patients have an average of 7.7 attacks per year, with their most recent attack causing them to miss an average of 3.3 days of work.
In most cases, HAE is caused by mutations in the C1 inhibitor (C1INH) gene that can be transmitted through families as an autosomal dominant inherited trait. However, in around 15% of cases there is no family history, and the disease is caused by a new mutation. Most of the mutations (80%) result in a non-secreted protein and, consequently, a reduced plasma level of the C1INH protein and its function; this is called Type I HAE. The rest are predominantly point mutations within the active site resulting in normal plasma levels of C1IHN but with reduced functional activity; this is called Type II HAE.
The C1INH gene codes for a serine-protease inhibitor that negatively regulates the classical complement cascade and the contact-system and also plays a more minor role in regulating the clotting cascade. Hence, partial deficiency in C1INH shifts the equilibrium towards the activation of these pathways, resulting in the increased consumption of C4 through the classical complement cascade. Thus, low C4 serves as a biomarker for disease activity.
However, it is the accumulation of vasoactive kinins from the increased activity of the contact system that really drives the disease phenotype. Bradykinin engages with specific receptors in the vascular epithelium to cause vasodilation, endothelial leakage and, as a result, tissue oedema.
Type III HAE is a very rare form of the disease that is seen more frequently in females than males, often during pregnancy or after oestrogen administration. It is particularly difficult to diagnose because C1INH function and C4 are normal. In some pedigrees, Type III HAE has been associated with activating point mutations in the factor XII gene.
Treatment of HAE
A range of treatments are used in the medical management of hereditary angioedema (see Table 1).
The aim of treatment is to ameliorate acute attacks, to prevent attacks occurring at times of high risk, such as surgery (short-term prophylaxis), and to reduce the overall frequency and severity of attacks (long-term prophylaxis). International consensus guidelines were published in 2010 that make recommendations for the management of HAE, but the authors make the point that these should be regarded as an interim measure and will need to be updated when further results of on-going clinical trials are published.
Since potentially life-threatening swellings in HAE occur unpredictably and can progress rapidly and emergency staff may be unfamiliar with this rare condition, patients are advised to carry their own supply of rescue medication and a letter describing the indications for its use. In Europe, Berinert, Cinryze, Rhucin and icatibant are licensed for the treatment of acute attacks. The rationale for the administration of plasma derived C1 inhibitor proteins (pdC1INH) such as Berinert is to reconstitute the deficient protein. Berinert has been shown to be superior to placebo in randomised controlled trials, and a dose-finding study showed that when compared to placebo, 20u/kg had a significantly shorter time to onset of relief of symptoms, whereas 10u/kg (the dose used historically) did not.
Icatibant is a stable selective bradykinin B2 receptor antagonist that is aimed at preventing the physiological effect of increased bradykinin production. It was initially shown to be associated with a significantly quicker time to symptom relief when compared to tranexamic acid, but the reduction in time was not significant when compared to placebo. The non-significance of the latter has been attributed to problems with the study design, and while icatibant was licensed by the European Medicines Agency (EMA) on the basis of these trials, it was not licensed in the US. Icatibant has subsequently been shown to be superior to placebo in a further randomised, double-blind, placebo-controlled multi-centre study, and it has subsequently been licensed by the US Food and Drug Administration (FDA).
The international consensus guidelines recommend that either icatibant or C1INH is administered in the case of an acute attack associated with laryngeal swelling, swelling affecting the face or neck or for abdominal attacks. However, in the case of progressive laryngeal oedema, the onus is on maintaining a patent airway and attempts to administer these medications should not be allowed to delay securing the airway by intubation if it is necessary. For cutaneous swellings affecting other areas of the body, the assessing physician may, after consultation with the patient, still advocate administering the rescue medication if the swelling is going to cause significant social disability.
Although it will depend on the individual circumstances of the patient, in general, long-term prophylaxis is considered if the patient is having more than one attack per month. Anti-fibrinolytics, attenuated androgens and pdC1INH (Berinert and Cinryze) have all been shown to be effective for long-term prophylaxis when compared to placebo in randomised trials.
In practice, the majority of patients in Europe requiring prophylaxis are maintained on attenuated (17-alpha-alkylated) androgens (see Figure 1). Although the 17-alpha-alkylated androgens have significant side-effects, including weight gain, dyslipidaemia and liver toxicity, these are dose-related and each individual treatment is empirically titrated to the minimal clinically effective dose in order to minimise the side-effects. As a result of this approach, the currently recommended maximum treatment dose of danazol is less than was used in the original trials. Antifibrinolytics have been shown to be less effective than androgens in observational studies, but they are used when androgens are contra-indicated, for example in childhood and pregnancy. Plasma-derived C1INH is considered if these measures fail.
Certain activities such as surgery are recognised as increasing the risk of an HAE attack. The international consensus guidelines recommend that for minor procedures that do not cause significant bleeding, C1INH concentrate should be immediately available. If this is not possible, attenuated androgens should be given or the dose increased for up to five days either side of surgery.
For more major procedures that result in significant bleeding or those which require intubation, pdC1INH (10-20 u/kg) should be given prior to the procedure, and a second dose should be available for use during surgery. Most immunologists would recommend that their patients take prophylaxis prior to any dental surgery.
Future of HAE treatment in Europe
In addition to the drugs discussed above, there are some therapies that have been recently licensed for HAE treatment in Europe, and one on the horizon which may be licensed in the future:
Conestat alpha (Rhucin, Ruconest) was granted a licence by the EMA for use in the acute treatment of HAE in October 2010. It is a recombinant human C1 inhibitor protein (rhC1INH) that is extracted from the milk of transgenic rabbits, and so the possibility of the transmission of human viruses by this product is small. When compared to saline, doses of 50U/kg and 100U/kg were shown to be comparably effective for the treatment of acute attacks, and hence a recommended dose of 50U/kg was selected. However, Rhucin has a shorter plasma-half life then the natural human protein (three versus 20 hours) and is not currently recommended for prophylaxis. The short half-life of Rhucin compared to the length of an average attack of HAE means that there is a theoretical risk that a single infusion will not cure an attack. However, in practice, no relapses have been reported in clinical trials to date.
Cinryze is a plasma-derived human C1INH protein. In the production process, it is passed through a nano-filter as an extra purification step in addition to the standard pasteurisation step with the aim of improving the removal of viruses. It has been licensed by the FDA for prophylaxis of HAE and was licensed by the EMA for acute short-term and long-term treatment in June 2011. The manufacturers of Berinert have also recently introduced the nano-filtered step.
Ecallantide is a kallikrein inhibitor that has already been licensed by the FDA for the treatment of acute attacks in the US. Like icatibant, it can be administered subcutaneously.
There is some evidence that the time to complete resolution of an attack is less when effective therapy is initiated quickly, and treatment at an early or even prodromal stage may ameliorate an attack almost completely. Requirements to attend a medical facility for treatment lead inexorably to delays in receiving it. This being the case, early self-treatment may provide the best way to reduce morbidity.
Patients and their relatives have been successfully trained to administer C1INH concentrate intravenously, and self-infusion programmes have been endorsed in several countries. However, not all patients opt for home care, and it is not offered by all centres. Icatibant has recently been licensed for home administration. It is supplied in a pre-filled syringe and is given subcutaneously and hence is more amenable to self-administration and is likely to be used more widely. Ecallantride is not likely to be given as a home treatment because it has been associated with anaphylaxis in a few cases.
It remains to be seen whether increased availability of the new drugs for the acute treatment of HAE and on-demand treatment will be associated with increased usage of rescue medications and treatment costs. However, increased treatment costs are likely to be balanced, at least in part, by increased productivity and reduced usage of emergency medical services. In times of economic restraint, as doctors and pharmacists, we are increasingly involved in debates about cost-effectiveness and health benefit. Unfortunately, it appears to be easier to count the cost of treatment than to attach a monetary value to its benefits, and the two are rarely considered in the same equation. Thus, we have reached a stage in the treatment of HAE where a variety of effective treatments are available, and the challenge for us is to ensure that they are accessible to those of our patients that will benefit from them.
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