What is the recommended treatment for urticaria and angioedema?

Treatment of Urticaria and Angioedema

Start with a standard dose of a second-generation H1-antihistamine (cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, or mizolastine) as first-line therapy for all forms of urticaria and histamine-mediated angioedema. 1

First-Line Treatment: Second-Generation Antihistamines

• Begin with a standard daily dose of a non-sedating second-generation H1-antihistamine. 1
• Offer patients at least two different second-generation antihistamines because individual response and tolerance vary widely between patients. 1
• Cetirizine reaches peak plasma concentration fastest and should be selected when rapid symptom relief is required. 1
• Avoid first-generation sedating antihistamines (diphenhydramine, hydroxyzine) as first-line therapy because they cause significant sedation and cognitive impairment without superior efficacy. 2

Step-Up Approach When Standard Dosing Fails

• If symptoms remain inadequately controlled after 2-4 weeks of standard-dose treatment, increase the second-generation H1-antihistamine dose up to four times the standard dose. 1, 2
• This up-dosing achieves sufficient response in approximately 23% of patients who failed standard dosing. 1
• Continue the increased dose for 2-4 weeks before determining inadequate response. 3

Second-Line Treatment: Omalizumab

• Add omalizumab 300 mg subcutaneously every 4 weeks if symptoms remain inadequately controlled despite up-dosed antihistamines. 1, 4
• Allow up to 6 months for patients to demonstrate a response to omalizumab before considering it a failure and moving to alternative therapies. 1
• Omalizumab is FDA-approved for chronic spontaneous urticaria in adults and adolescents 12 years and older who remain symptomatic despite H1-antihistamine treatment. 4

Third-Line Treatment: Cyclosporine

• Add cyclosporine (up to 5 mg/kg body weight per day) to the antihistamine regimen if inadequate control persists after 6 months of omalizumab. 1
• Monitor blood pressure and renal function every 6 weeks while on cyclosporine due to potential nephrotoxicity and hypertension. 1
• Cyclosporine is effective in approximately two-thirds of patients with severe autoimmune urticaria at 4 mg/kg daily for up to 2 months. 2

Adjunctive Therapies for Resistant Cases

• Consider adding an H2-antihistamine (cimetidine) in combination with H1-antihistamines for resistant cases, particularly when dyspeptic symptoms coexist, though evidence is limited. 1
• Adding an antileukotriene (montelukast) can be considered for resistant cases as add-on therapy, but efficacy data are sparse. 1
• A sedating antihistamine at night (chlorphenamine 4-12 mg or hydroxyzine 10-50 mg) may improve sleep quality but provides minimal additional urticaria control when H1 receptors are already saturated. 1

Role of Systemic Corticosteroids: Severely Limited

• Systemic corticosteroids should NOT be used as first-line therapy or maintenance treatment for chronic urticaria. 1
• Restrict oral corticosteroids to short courses (3-10 days) only for severe acute exacerbations or life-threatening angioedema affecting the mouth, and only after antihistamines have been optimized. 1, 3
• Prolonged corticosteroid use causes cumulative toxicity including adrenal suppression, osteoporosis, diabetes, hypertension, Cushing syndrome, and does not address the underlying pathophysiology. 1
• In chronic urticaria, steroids can make symptoms worse and long-lasting because of corticosteroid dependence. 5
• Short courses of adjunctive corticosteroids may be used as bridge therapy to other systemic treatments in acute severe exacerbations, but only after antihistamines have been optimized. 1

Critical Distinction: Angioedema Without Wheals

• When angioedema occurs without accompanying wheals, a distinct diagnostic work-up is required to rule out bradykinin-mediated angioedema. 1
• Obtain a serum C4 level as the initial screen for hereditary or acquired C1-esterase inhibitor deficiency; the test is highly sensitive when C4 is <30% of mean normal. 1
• If C4 is reduced, follow with quantitative and functional C1-inhibitor assays and a C1q level. 1
• Permanently discontinue ACE-inhibitor therapy if it is identified as the likely cause of angioedema. 1

Management of C1-Esterase Inhibitor Deficiency

• Anabolic steroids are the treatment of choice for most adults requiring maintenance therapy for symptomatic recurring angioedema, but should be avoided in children if possible. 6
• Tranexamic acid may be used for maintenance but is contraindicated in patients with a history of thrombosis. 6
• C1-inhibitor concentrate should be given for emergency treatment of serious angioedema attacks or as prophylaxis before surgery, especially when intubation or dental extractions are necessary. 6
• Fresh frozen plasma may be used as a substitute in an emergency if C1-inhibitor concentrate is not available. 6

Anaphylaxis Management

• Administer epinephrine BEFORE any antihistamine or corticosteroid when anaphylaxis is present; using antihistamines or corticosteroids first can delay essential epinephrine therapy. 1
• Epinephrine is the sole first-line medication for anaphylaxis and alleviates pruritus, urticaria, and angioedema through its action on alpha- and beta-adrenergic receptors. 7
• Systemic corticosteroids have no proven role in preventing biphasic anaphylaxis and should not be given routinely for this purpose. 1

Identifying and Avoiding Triggers

• Stop NSAIDs, aspirin, and codeine promptly as these agents can precipitate or aggravate urticaria. 1
• Remove aggravating factors such as overheating, stress, alcohol, aspirin, NSAIDs, and codeine. 1
• Apply cooling antipruritic lotions (calamine or 1% menthol in aqueous cream) for symptomatic itch control. 1

Monitoring Disease Control and Step-Down

• Use the Urticaria Control Test (UCT) every 4 weeks to objectively assess disease control. 1
• Use the Angioedema Control Test (AECT) for patients who experience angioedema. 1
• Once complete symptom control is achieved, maintain the effective dose for at least 3 consecutive months before considering step-down. 1
• When stepping down, reduce the daily dose by no more than 1 tablet per month. 1
• If symptoms recur during step-down, return to the last effective dose that provided complete control. 1

When to Suspect Urticarial Vasculitis

• Individual wheals lasting 2-24 hours are typical of ordinary urticaria, whereas lesions persisting >24 hours suggest urticarial vasculitis and warrant skin biopsy. 1
• Conduct a lesional skin biopsy if wheals last longer than 24 hours, show ecchymotic or purpuric residues, or cause pain/burning sensations. 1
• Order a full vasculitis panel, including complement C3 and C4 levels, to distinguish normocomplementemic from hypocomplementemic disease. 1

Special Populations

Renal Impairment

• In moderate renal impairment (creatinine clearance 10-20 mL/min), avoid acrivastine. 1
• Halve the dose of cetirizine, levocetirizine, and hydroxyzine in patients with moderate renal impairment. 1
• In severe renal impairment (creatinine clearance <10 mL/min), avoid cetirizine and levocetirizine altogether. 1

Hepatic Impairment

• Mizolastine is contraindicated in patients with significant hepatic impairment. 1
• Avoid chlorphenamine and hydroxyzine in severe liver disease because of inappropriate sedating effects. 1

Pregnancy

• Avoid all antihistamines during pregnancy, especially in the first trimester, unless absolutely necessary. 1
• When antihistamine therapy is required, chlorphenamine is often selected because of its long-standing safety record. 1
• Loratadine and cetirizine are classified as FDA Pregnancy Category B drugs, indicating no evidence of risk in human studies. 1

Specialist Referral Indications

• Refer patients with possible urticarial vasculitis (lesions persisting >24 hours, ecchymotic/purpuric residues, or pain/burning sensations) for biopsy and specialist evaluation. 1
• Refer patients with systemic warning signs (fever, arthralgia, or general malaise) suggesting an underlying autoinflammatory disorder or systemic vasculitis. 1
• Refer patients who require regular oral corticosteroids or who have failed third-line therapies (cyclosporine) to an allergist-immunologist or dermatologist. 1
• Refer patients with isolated or recurrent angioedema for evaluation of hereditary or acquired angioedema, paraproteinemia, or B-cell malignancies. 1