Dermatologic Manifestations of Hereditary Angioedema Treatment & Management

Depending on the symptoms and the sites of the angioedema, intensive support may be necessary, including intravenous fluids. In cases of serious laryngeal edema causing respiratory obstruction, intubation or tracheostomy should be performed. In hereditary angioedema (HAE) types I and II, the treatment of choice in acute attacks consists of replacement with commercially available C1-INH concentrates^[12] or kallikrein inhibitor or, if unavailable, fresh-frozen plasma. In HAE type III, infusion of C1-INH has proven to be ineffective.^{[13, 14]}

Prophylactic treatment

Prophylactic treatment is instituted if patients are afflicted with frequent and/or severe episodes.^[15]

Danazol may be used at doses that prevent attacks; normalizing the levels of C1-INH is not necessary. The most significant complication of long-term use may be arterial hypertension. The 17-alpha-alkylated androgens rarely cause hepatotoxicity and liver tumors, but they should be used at the lowest effective dosage. Regular monitoring of liver function test results, lipid levels, and liver ultrasonography findings is recommended. Although virilization may be an issue with women, keeping to the lowest possible dose usually obviates this concern. Contraindications to the use of androgens include prostate cancer, pregnancy, childhood, and breastfeeding.

Antifibrinolytic agents such as epsilon-aminocaproic acid or tranexamic acid can also be used for prophylaxis, although they have not been found to be as effective as the androgenic agents. These agents are the option for pregnant women.

Short-term prophylaxis for surgical procedures, especially dental work, is necessary. C1-INH infusions can be given 24 hours before the procedure or just prior to it. Alternatives, such as antifibrinolytics or androgens, can be used, and they should be started 5 days before the procedure and continued for 2 days afterwards.

Eradication

Eradication of the underlying cause of the attack, such as H pylori or another infectious agent, may lead to resolution of symptoms. Careful attention should be given to medications being taken by the patient that may have contributed to an attack, such as contraceptives, hormone replacement therapy, or ACE inhibitors.

Clinical trials and new treatments

Until recently, no effective agent for acute attacks from hereditary angioedema existed in the United States. Now, several agents have been approved and others are in the midst of the FDA approval process.^[16]

Rhucin, a recombinant human C1-INH produced by Pharming (Leiden, The Netherlands), is still in a dialogue with the US Food and Drug Administration (FDA) regarding the anticipated approval time for this drug.^[17] Pharming plans to provide an update regarding the status of Rhucin in the first half of 2010 (personal communication with Pharming representative).

Icatibant (Firazyr), a bradykinin B2 receptor antagonist produced by Shire Human Genetic Therapies, blocks the effects of bradykinin. This drug received FDA approval in August 2011. Approval was based on 3 double-blind, randomized, controlled clinical trials known as For Angioedema Subcutaneous Treatment (FAST) 1, 2, and 3.^{[18, 19]}

Note the following:

• FAST 3 was a placebo-controlled study of 98 adult patients with a median age of 36 years. The primary endpoint was assessed using a 3-item composite visual analog score (VAS), composed of averaged assessments of skin swelling, skin pain, and abdominal pain. The median time to 50% reduction in symptoms for patients with cutaneous or abdominal attacks treated with icatibant (n=43) compared with placebo (n=45) was 2 hours (95% confidence interval [CI], 1.5, 3.0) versus 19.8 hours (95% CI, 6.1, 26.3), respectively (P < .001). The median times to almost complete symptom relief were 8 versus 36 hours for icatibant and placebo, respectively. Additional rescue medications were used by 3 patients (7%) treated with icatibant and 18 patients (40%) treated with placebo.^[19]
• Two phase III clinical trials, EASSI and FAST-3, are enrolling patients in the United States to determine the efficacy, safety, and tolerability of icatibant.^{[20, 21]} Case reports of icatibant use have recently been published.^[6]
• In Germany, 5 patients with HAE were treated with a single dose of icatibant, 30 mg, administered subcutaneously during acute attacks. Two of these patients were experiencing abdominal attacks, and 3 were experiencing angioedema of the extremities and/or face. In all patients, significant improvement was seen and only minor adverse effects were reported.^[22]
• In France, 3 patients were similarly treated with a subcutaneous dose of icatibant, 30 mg, with resolution of symptoms. One patient required a second dose 6 hours later. The major adverse effect reported was reaction at the injection site.^[23]
• Another study by Cicardi et al reported a significant benefit of icatibant, an investigational bradykinin-beta2-receptor antagonist, when used for acute hereditary angioedema attacks compared with tranexamic acid in one trial. A second trial comparing icatibant with placebo did not show a significant difference, although the early use of rescue medication may have obscured the benefit of icatibant.^[18]

Several protease inhibitors have been found to have functional overlap with C1-INH (eg, antithrombin III, beta-macroglobulin, alpha1-antitrypsin) and may be therapeutic options in the future.^{[24, 25, 26, 27]}

Ecallantide (DX-88), a recombinant kallikrein inhibitor produced by Dyax (Cambridge, Mass), stops the generation of bradykinin by inhibiting kallikrein activation. This drug decreases the rate of C1-INH catabolism, allowing for C1-INH concentrate to be more effective. The FDA approved this drug in December 2009 for patients aged 16 years and older.^[28] Two randomized, double-blind, placebo-controlled trails, EDEMA4 and EDEMA3, established the safety and efficacy of ecallantide.^[29] After multiple drug administrations, some patients developed antidrug antibodies and experienced allergic or anaphylacticlike reactions. Thus, the FDA has issued a black box warning and recommends that the drug only be administered by a healthcare professional who can treat anaphylaxis.^[28]

Cicardi et al observed significantly better outcome scores in patients treated for acute attacks of angioedema with ecallantide compared with placebo.^[30]

Two randomized trials by Zuraw et al evaluated use of nanofiltered C1 inhibitor concentrate (Cinryze) for the management of hereditary angioedema. Nanofiltered C1 inhibitor concentrate shortened the duration of acute attacks and, when used for prophylaxis, reduced the frequency of acute attacks.^[31]

Other recent and ongoing clinical trials include the following:

• Recombinant Human C1 Inhibitor for the Treatment of Acute Attacks in Patients With Hereditary Angioedema
• A Study of Icatibant in Patients With Acute Attacks of Hereditary Angioedema (FAST-3)
• Safety and Efficacy Study of Repeated Doses of DX-88 (Ecallantide) to Treat Attacks of Hereditary Angioedema (HAE)
• Berinert P Study of Subcutaneous Versus Intravenous Administration

Intubation may be necessary in hereditary angioedema (HAE) cases complicated by laryngeal edema.

A clinical guideline summary from the American Academy of Allergy, Asthma & Immunology, Consultation and referral guidelines citing the evidence: how the allergist-immunologist can help, may be helpful.^[32]