What is the recommended treatment for urticaria, including first‑line antihistamine dosing for acute and chronic cases and subsequent therapy options?

Treatment of Urticaria

Second-generation non-sedating H1-antihistamines are the first-line treatment for both acute and chronic urticaria, with dose escalation up to four-fold the standard dose recommended before adding second-line therapies. 1, 2

First-Line Treatment: Antihistamines

Initial Therapy

• Start with a standard dose of a second-generation H1-antihistamine (cetirizine 10 mg, desloratadine 5 mg, fexofenadine 180 mg, levocetirizine 5 mg, loratadine 10 mg, or bilastine 20 mg daily). 1, 2
• Offer patients a choice of at least two different non-sedating antihistamines, as individual responses and tolerance vary markedly between agents. 1, 2
• Cetirizine reaches peak plasma concentration fastest and is preferred when rapid symptom control is required. 2
• Schedule dosing so that peak drug levels coincide with the expected time of urticaria flares. 2

Dose Escalation Algorithm

• If symptoms persist after 2–4 weeks of standard dosing, increase to 2× standard dose. 1, 2
• If control remains inadequate after another 2–4 weeks, escalate to 4× standard dose (the maximum recommended). 1, 2, 3
• Maintain the high dose for at least 2–4 weeks before declaring treatment failure. 1
• Approximately 23% of patients who fail standard dosing achieve adequate control after up-dosing. 2

Common pitfall: Do not exceed four-fold dosing, as current international guidelines do not formally recommend higher doses due to limited high-quality evidence. 1

Safety of Up-Dosing

• Bilastine, fexofenadine, levocetirizine, and cetirizine are recommended for up-dosing with Grade A evidence. 4
• No dose-dependent increase in adverse effects occurs with up-dosing, except cetirizine may cause dose-related sedation. 4, 5
• No reports of systemic complications or cardiotoxicity at higher than licensed doses. 4
• Never use first-generation antihistamines at high doses due to significant sedation, cognitive impairment, and anticholinergic effects. 1

Second-Line Treatment: Omalizumab

• Add omalizumab 300 mg subcutaneously every 4 weeks for patients still symptomatic after four-fold antihistamine dosing. 1, 2, 6
• Allow up to 6 months of omalizumab treatment before declaring treatment failure. 1, 2
• If the 300 mg dose is insufficient, increase to a maximum of 600 mg every 2 weeks. 1, 6
• Omalizumab produces complete disease control in a high percentage of patients and has an excellent safety profile. 6, 7

Monitoring and Safety

• Observe patients for 2 hours after the first 3 doses, then 30 minutes for subsequent doses due to 0.2% anaphylaxis risk. 6
• All patients must be prescribed an epinephrine autoinjector and trained in its use. 6
• Administer only in healthcare settings with appropriate staff and equipment to treat anaphylaxis. 6
• Use the Urticaria Control Test (UCT) every 4 weeks to assess disease control; scores ≤16 indicate inadequate control. 1, 2

Third-Line Treatment: Cyclosporine

• Introduce cyclosporine (4–5 mg/kg daily) after 6 months of omalizumab if disease remains uncontrolled. 1, 2
• Cyclosporine produces clinical improvement in approximately 65–70% of patients with severe autoimmune urticaria. 1, 2
• Monitor blood pressure and renal function every 6 weeks due to nephrotoxicity and hypertension risk. 1, 2
• A treatment course of 16 weeks is more effective than 8 weeks. 2

Adjunctive Therapies

• H2-antihistamines (cimetidine) may be added to H1-antihistamine therapy, though evidence is limited. 2
• Leukotriene receptor antagonists (montelukast) can be used as add-on therapy but have minimal evidence as monotherapy. 2, 6
• Sedating antihistamines at night (chlorphenamine or hydroxyzine) may improve sleep quality but provide minimal additional urticaria control when H1 receptors are already saturated. 2

Corticosteroids: Restricted Use Only

• Reserve oral corticosteroids for short courses of 3–10 days in severe acute exacerbations only. 8, 2
• Never use corticosteroids as maintenance therapy due to cumulative toxicity (adrenal suppression, osteoporosis, diabetes, hypertension). 2
• More prolonged corticosteroid treatment may be necessary only for delayed pressure urticaria or urticarial vasculitis. 8

Trigger Identification and Avoidance

• Advise patients to avoid overheating, emotional stress, and alcohol. 1, 2
• Discontinue aspirin, NSAIDs, and codeine, which can exacerbate urticaria. 1, 2
• Avoid ACE inhibitors in individuals with angioedema without wheals. 1, 2
• Cooling antipruritic lotions (calamine or 1% menthol in aqueous cream) provide symptomatic relief. 1, 2

Special Population Considerations

Renal Impairment

• Avoid acrivastine in moderate renal impairment. 1, 2
• Halve the dose of cetirizine, levocetirizine, and hydroxyzine in moderate impairment; avoid cetirizine and levocetirizine in severe impairment. 1, 2

Hepatic Impairment

• Avoid mizolastine in significant hepatic impairment. 1, 2
• Avoid chlorphenamine and hydroxyzine in severe liver disease. 1, 2

Pregnancy

• Avoid antihistamines during pregnancy, especially in the first trimester, unless absolutely necessary. 1, 2
• If required, chlorphenamine has the longest safety record. 1, 2
• Loratadine and cetirizine are FDA Pregnancy Category B. 1, 2

Treatment Tapering

• After achieving complete symptom control (UCT ≥16), maintain the effective dose for at least 3 months before initiating dose reduction. 2, 6
• Reduce the dose by no more than one tablet per month. 2, 6
• If symptoms recur, revert to the last dose that provided adequate control. 2, 6

Diagnostic Distinctions

• Individual wheals in chronic spontaneous urticaria typically last 2–24 hours. 8, 2
• Urticarial vasculitis is characterized by lesions persisting >24 hours and requires skin biopsy for confirmation. 8, 2
• For isolated angioedema without wheals, screen for C1-inhibitor deficiency using serum C4 as the initial test. 2
• Physical urticaria wheals usually last <1 hour (except delayed pressure urticaria). 8