What is the recommended treatment for urticaria?

Treatment of Urticaria

Start with a second-generation H1-antihistamine at standard dose, and if symptoms persist after 2-4 weeks, increase up to 4 times the standard dose before adding omalizumab or other second-line agents. 1

First-Line Treatment: Second-Generation H1-Antihistamines

Second-generation non-sedating H1-antihistamines are the cornerstone of urticaria management and should be initiated immediately. 2, 1, 3

Available agents include:

• Cetirizine (once daily) 2
• Desloratadine (once daily) 2
• Fexofenadine (once daily) 2, 4
• Levocetirizine (once daily) 2, 4
• Loratadine (once daily) 2
• Mizolastine (once daily) 2

Key prescribing principles:

• Offer at least two different second-generation antihistamines to each patient, as individual responses and tolerance vary significantly between agents 2, 1, 4
• Cetirizine reaches peak concentration fastest and may be preferred when rapid symptom control is needed 2, 4
• Desloratadine has the longest half-life (27 hours) and must be stopped 6 days before skin testing 1
• Schedule dosing so peak drug levels coincide with anticipated urticaria flares 1

Dose Escalation Strategy

If standard dosing fails after 2-4 weeks, increase the dose up to 4 times the standard dose. 1, 3 This off-label practice is widely accepted when benefits outweigh risks. 2 Approximately 23% of patients who fail standard dosing achieve sufficient response with up-dosing. 1 Patient surveys confirm that 40-54% report significant added benefit from taking 2-4 tablets daily, with no significant increase in unwanted effects or sedation compared to standard doses. 5

Second-Line Treatment: Omalizumab

For patients who remain symptomatic despite 4-fold antihistamine dosing, add omalizumab 300 mg subcutaneously every 4 weeks. 1, 4, 6 Omalizumab is FDA-approved for chronic spontaneous urticaria in patients aged 12 years and older who remain symptomatic despite H1-antihistamine treatment. 6

Critical timing considerations:

• Allow up to 6 months for patients to demonstrate response before considering treatment failure 1, 7, 4
• If insufficient response at 300 mg, increase to 600 mg every 2 weeks as the maximum dose 7

Third-Line Treatment: Cyclosporine

If symptoms remain inadequately controlled after 6 months of omalizumab, add cyclosporine up to 5 mg/kg body weight to the antihistamine regimen. 1, 7, 4 Cyclosporine is effective in approximately 65-70% of patients with severe urticaria. 7, 4

Mandatory monitoring:

• Check blood pressure and renal function every 6 weeks due to nephrotoxicity and hypertension risk 1, 7, 4
• Treatment duration of 16 weeks is superior to 8 weeks for reducing therapeutic failures 7

Adjunctive Therapies for Resistant Cases

H2-antihistamines (cimetidine) may be added to H1-antihistamines for resistant cases, though evidence is limited. 2, 1, 4

Antileukotrienes (montelukast) can be useful as add-on therapy for resistant cases, but efficacy data are sparse. 2, 1

Sedating antihistamines at night (chlorphenamine 4-12 mg or hydroxyzine 10-50 mg) may improve sleep quality but provide minimal additional urticaria control when H1 receptors are already saturated. 1

Role of Corticosteroids

Restrict oral corticosteroids to short courses of 3-10 days for severe acute exacerbations only. 1, 7, 4 Long-term use causes cumulative toxicity including adrenal suppression, osteoporosis, diabetes, hypertension, and Cushing syndrome. 1 Corticosteroids should never be used as maintenance therapy for chronic urticaria. 4

General Measures and Trigger Avoidance

Identify and minimize aggravating factors:

• Avoid overheating, stress, and alcohol 2, 7, 4
• Discontinue aspirin, NSAIDs, and codeine, which can worsen urticaria 2, 7, 4
• Avoid ACE inhibitors in patients with angioedema without wheals 2, 4
• Apply cooling antipruritic lotions (calamine or 1% menthol in aqueous cream) for symptomatic relief 2, 7, 4

Disease Monitoring

Use validated tools to assess disease control:

• Urticaria Control Test (UCT) every 4 weeks 1
• 7-Day Urticaria Activity Score (UAS7) for objective measurement 1
• Angioedema Control Test (AECT) when angioedema is present 1

Once complete symptom control is achieved, maintain the effective dose for at least 3 consecutive months before stepping down. 1 When reducing therapy, decrease by no more than 1 tablet per month. 1 If symptoms recur, return to the last effective dose. 1

Critical Diagnostic Distinctions

Distinguish chronic spontaneous urticaria from urticarial vasculitis:

• Chronic spontaneous urticaria: individual wheals last 2-24 hours 2, 1
• Urticarial vasculitis: lesions persist >24 hours and require skin biopsy for confirmation 2, 1, 4
• Urticarial vasculitis requires a full vasculitis screen including C3 and C4 complement assays 4

For angioedema without wheals, screen for C1 inhibitor deficiency:

• Use serum C4 as initial screening test 4
• If low, confirm with quantitative and functional C1 inhibitor assays 2

Special Population Considerations

Renal impairment:

• Avoid acrivastine in moderate impairment (CrCl 10-20 mL/min) 1
• Halve the dose of cetirizine, levocetirizine, and hydroxyzine in moderate impairment 1
• Avoid cetirizine and levocetirizine in severe impairment (CrCl <10 mL/min) 1

Hepatic impairment:

• Mizolastine is contraindicated in significant hepatic impairment 1
• Avoid chlorphenamine and hydroxyzine in severe liver disease 1

Pregnancy:

• Avoid all antihistamines during pregnancy, especially first trimester, unless absolutely necessary 1
• If required, chlorphenamine has the longest safety record 1
• Loratadine and cetirizine are FDA Pregnancy Category B 1

When to Refer to Specialist

Refer immediately for:

• Lesions persisting >24 hours with ecchymotic/purpuric residues or pain/burning (possible urticarial vasculitis) 1
• Fever, arthralgia, or malaise accompanying urticaria (suggests systemic vasculitis or autoinflammatory disorder) 1
• Isolated or recurrent angioedema without wheals (evaluate for hereditary/acquired angioedema) 1
• Patients requiring regular oral corticosteroids or who have failed third-line therapies 1