Urticaria and angioedema

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

While acute urticaria is generally short-lived, chronic urticaria is prolonged and can lead to significant lifestyle disturbance. Regardless of the duration of urticaria, antihistamines are the mainstay of therapy. More than 90% of patients with urticaria (both acute and chronic) will respond well to antihistamine therapy. Patients with chronic urticaria may require additional measures for adequate disease control.

Acute urticaria with or without angioedema

Acute urticaria is generally self-limited. Triggers can often be identified and need to be strictly avoided. This can involve dietary modifications, the discontinuation or substitution of causative drugs (with a drug from a different class), or the removal of physical stimuli.

Nonsedating, second-generation antihistamines tend to work well in patients with acute urticaria.

If an episode of urticaria is severe, a short course of corticosteroids can be considered in addition to antihistamines. However, the addition of prednisone to an antihistamine failed to improve symptomatic and clinical response of acute urticaria to antihistamine alone in one randomized controlled study.[41] The use of systemic corticosteroids is limited by their adverse effects. It is imperative that all efforts are made to treat patients with other agents first. Topical corticosteroids have no role in the management of urticaria.

Episodes of urticaria with associated angioedema require prompt and aggressive management. Although angioedema usually develops over a matter of hours, sudden and rapid progression can occur. Patients require hospitalization and prompt administration of epinephrine (adrenaline), especially if the angioedema affects the neck, face, lips, or tongue.

If available, flexible fiberoptic laryngoscopy can rapidly determine the extent of involvement of the base of the tongue or the larynx. This can determine the most appropriate airway management strategy.[26]

If stridor is apparent, or respiratory arrest is imminent, emergency intubation is indicated. Even if emergency intubation is not indicated, rapid consideration for an elective airway intervention should be made, rather than allowing an emergency situation to develop. Consultation with an anesthesiologist may be appropriate. Any attempt at intubation should be performed by a clinician experienced in difficult intubations and in a setting equipped for conversion to fiberoptic intubation, tracheostomy, or emergent cricothyroidotomy, in case standard methods fail. If angioedema does not appear severe, patients still require hospitalization for close observation and monitoring.

Patients who have administered epinephrine outside a medical setting will often require immediate medical attention at an emergency facility, although this may not be required if the patient experiences prompt, complete, and durable response to treatment.[28]

Patients with a history of urticaria associated with angioedema of the head and neck should be prescribed two self-injectable epinephrine devices and instructed on their use.[27] Beta-blockers can interfere with the action of epinephrine, and discontinuing this class of drug in patients with known urticaria and angioedema can be considered if comorbid conditions allow. However, for most medical indications, the risk of stopping or changing the drug may exceed the risk of more severe anaphylaxis if the drug is continued, particularly in patients with insect sting anaphylaxis.[28]

Chronic urticaria with or without angioedema

As with acute urticaria, the management of chronic urticaria should include the avoidance of known triggers. This strategy is particularly important for patients with an inducible urticaria.

Psychosocial stress may play a role in patients with chronic urticaria, although the mechanism is unclear.[42] Patients are encouraged and educated on how to manage their stresses in the hope of achieving better symptom control.

Management of any other underlying illness should be optimized, while also providing symptomatic relief for the urticaria. Although underlying conditions do not cause the urticaria directly, they are generally felt to play a role in exacerbating the disease and making symptomatic management more difficult.

Second-generation antihistamines

Second-generation, nonsedating antihistamines are the mainstay of treatment.[37] Examples of this class of drug include loratadine, desloratadine, cetirizine, levocetirizine, and fexofenadine. It should be stressed to patients that antihistamines have their greatest efficacy if taken prophylactically, rather than reactively after lesions develop.

One study showed cetirizine to be more effective than fexofenadine in clearing symptoms of urticaria after 1 month of therapy.[43] Similar comparisons for loratadine versus cetirizine or loratadine versus fexofenadine do not exist.

Second-generation antihistamines have a good safety profile and can be taken for several years continously.[1] They cross the blood-brain barrier to a lesser extent than first-generation antihistamines and may be less likely to lead to sedation and impaired cognitive function.[44][45] Cetirizine has been reported to cause a slightly greater rate of sedation compared with other agents.[46]

Choice of agent should be based on individual responses in both efficacy and adverse-effect profile.

There is some evidence to suggest that higher than typical doses of desloratadine and levocetirizine are more efficacious than typical doses.[47][48][49]

First-generation antihistamines

Not routinely recommended for the management of chronic urticaria as first line agents due to their anticholinergic and sedative effects.[1][37] If symptoms are not adequately controlled by second-generation antihistamines, addition of a nighttime dose of a first-generation antihistamine, an H2 antagonist, or doxepin should be considered.[35]

First-generation antihistamines (e.g., diphenhydramine, hydroxyzine, chlorpheniramine) are the most potent agents available. Doxepin, a tricyclic antidepressant and an antihistamine, is also used in the treatment of chronic urticaria. Although efficacious, their use is often limited by their adverse effects, particularly sedation.[50][51] If used, physicians should start at low doses and titrate as tolerated to a clinically effective dose. There is a paucity of direct comparative data regarding first-generation antihistamines. Choice of agent is dictated by individual variations in response in both efficacy and adverse-effect profile.

H2 antagonists

Roughly 15% of the histamine receptors in the skin are H2 receptors. On this basis, H2 antagonists (e.g., famotidine, cimetidine) have been used in the treatment of chronic urticaria. Although these agents have no role as monotherapy, they may provide a modest additional benefit, when used in combination with a full-dose antihistamine.[52][53] Once urticaria is controlled, H2 antagonists should be discontinued before attempting to discontinue the antihistamine.

Leukotriene receptor antagonists

Although some studies have suggested that leukotriene receptor antagonists (e.g., zafirlukast, montelukast) are superior to placebo in the treatment of patients with chronic urticaria, they have no role as monotherapy for this condition.[54][55][56]

These agents are used in addition to full-dose antihistamines, although their additional effect is marginal.[57][58] Leukotriene receptor antagonists in combination with antihistamines may be effective in patients with a history of adverse reactions to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs).[59][60]

Once urticaria is controlled, leukotriene receptor antagonists should be discontinued before attempting to discontinue the antihistamine regimen.

Montelukast has been associated with adverse neuropsychiatric events (e.g., mood changes, aggression, depression, and suicide, among others).[61] The risks and benefits should be carefully considered when prescribing this drug.

Corticosteroids

Short courses of systemic corticosteroids may be necessary for some patients to achieve symptom control during an exacerbation. However, the use of systemic corticosteroids is limited by their adverse effects. It is imperative that all efforts are made to treat patients with other agents first.

Topical corticosteroids have no role in the management of urticaria.

Omalizumab

Omalizumab is effective in chronic inducible and chronic spontaneous urticaria, can be used long term, and is effective at treating relapses after discontinuation.[62][63][64][65] It is recommended for use in patients who have persistent symptoms despite maximum antihistamine therapy.[1][35]

Cyclosporine

Cyclosporine prevents the release of histamine from mast cells.[66] Randomized controlled trials have demonstrated that it is an effective add-on therapy for patients with chronic urticaria who do not respond to maximum antihistamine therapy.[67][68][69] It is not licensed for urticaria and is associated with dose-dependent adverse effects.[69] International guidelines recommend that omalizumab is used before cyclosporine.[1][35]

Angioedema without urticaria: drug-induced or acquired

Acute episodes of angioedema without urticaria are managed on similar principles to angioedema accompanying urticaria. If the neck, face, tongue, or lips are involved, patients require hospitalization, prompt administration of epinephrine, and airway protection.

Treatment of angioedema of the neck, face, tongue, or lips is with an intravenous antihistamine; administration of an intravenous corticosteroid may be considered. If angioedema is elsewhere on the body, oral antihistamines may be used initially, with oral corticosteroids and epinephrine as adjuncts if angioedema is particularly severe.

Drug-induced angioedema without urticaria

Central to the treatment for drug-induced angioedema without urticaria is the identification and cessation of the drug responsible.

Acquired angioedema without urticaria

For most instances of acquired idiopathic angioedema, the cornerstone of therapy remains antihistamines. A number of additional agents can be used if required. Leukotriene receptor antagonists, such as montelukast, can be used as adjunctive therapy, in addition to full-dose antihistamines, although their additional effect is marginal.[57][58] Montelukast has been associated with adverse neuropsychiatric events (e.g., mood changes, aggression, depression, and suicide, among others).[61] The risks and benefits should be carefully considered when prescribing this drug.

If chronic idiopathic angioedema proves refractory to treatment with maximal doses of antihistamines and leukotriene receptor antagonists, specialists may use one of a number of alternative anti-inflammatory and immunomodulatory agents, including omalizumab, cyclosporine, hydroxychloroquine, sulfasalazine, colchicine, dapsone, azathioprine, methotrexate, and intravenous immune globulin (IVIG).[33][70]

Hereditary angioedema

Acute attacks

Patients with hereditary angioedema (HAE) should be taught to self-administer drugs to revert their symptoms at the first sign of an attack.

Three classes of drug are approved by the Food and Drug Administration (FDA) for use in acute attacks:[38]

C1 esterase inhibitor concentrates: plasma-derived C1 esterase inhibitor concentrates significantly reduced the time to first improvement of symptoms, compared with placebo, in one randomized controlled trial.[71] One case control study demonstrated that C1 esterase inhibitor concentrate effectively relieved attacks of abdominal edema.[72] Plasma-derived and recombinant C1 esterase inhibitor is available.
Plasma kallikrein inhibitors (e.g., ecallantide): ecallantide significantly reduced the time to first improvement of symptoms, compared with placebo, in one randomized controlled trial.[73]
Bradykinin B2 receptor antagonists (e.g., icatibant): icatibant significantly reduced the time to first improvement of symptoms, compared with placebo or tranexamic acid, in one randomized controlled trial.[74]

If the neck, face, tongue, lips, or airway are involved, patients require prompt evaluation and airway protection. Depending on the areas involved, symptomatic treatment may be required. For example, extremity swelling can be disabling and may require therapy with analgesics. Gastrointestinal involvement may require antiemetics. Although epinephrine, antihistamines, and systemic corticosteroids have no proven efficacy in hereditary angioedema, they may be administered to patients if there is doubt over the type of angioedema involved.

Fresh frozen plasma (FFP) may be considered if other therapies are not readily available.[75] Its use, however, is controversial because FFP contains complement proteins that can theoretically worsen an attack.

Plasma-derived C1 esterase inhibitor may be given as a preventive measure before oral procedures that can trigger upper airway edema.[76] It rapidly reaches maximum plasma concentration and has a half-life of 33 hours in children and 39 hours in adults.[77]

Chronic treatment

The goal of long-term prophylaxis is to decrease the frequency and severity of attacks of HAE. The decision to initiate prophylaxis is made on a case-by-case basis, taking into account the frequency, location, and severity of attacks; comorbidities; and effectiveness of acute attack therapy.[78]

Options for chronic treatment include:

Plasma-derived C1 esterase inhibitor: the preferred long-term prophylaxis treatment.[38] Intravenous plasma-derived C1 esterase inhibitor, compared with placebo, significantly reduced the number of attacks over a 12-week period in one randomized controlled trial. When attacks occurred, the severity and the duration were reduced.[71] Subcutaneous C1 esterase inhibitor, compared with placebo, significantly reduced the rate of attacks and the need for rescue therapy in one randomized controlled trial.[79]
Attenuated androgens (e.g., danazol): the second-line option for long-term prophylaxis.[38][75] Androgens are thought to work by increasing hepatic production of C1 esterase inhibitor. Danazol reduces the frequency of acute attacks by 83%. However, dose-dependent adverse effects are common and include weight gain, virilization, menstrual irregularities, headache, depression, and/or liver adenomas.[80]
Tranexamic acid: primarily used when C1 esterase inhibitor is not available and attenuated androgens are contraindicated.[80] Tranexamic acid is less efficacious than C1 esterase inhibitor and attenuated androgens.

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