What is the recommended treatment approach for an adult with urticaria, including first‑line therapy, dosing, and options for refractory or chronic cases?

Treatment of Urticaria in Adults

Start with a standard-dose second-generation H1-antihistamine (cetirizine, desloratadine, fexofenadine, levocetirizine, or loratadine), and if symptoms persist after 2–4 weeks, increase the dose up to four-fold before adding any other therapy. 1, 2

First-Line Treatment

• Initiate a second-generation (non-sedating) H1-antihistamine at standard dosing as the cornerstone of therapy for all forms of urticaria. 1, 2
• Offer patients at least two different non-sedating antihistamine options because individual response and tolerance vary widely between agents. 1, 2
• Fexofenadine 60 mg twice daily or 180 mg once daily is FDA-approved for chronic idiopathic urticaria in adults. 3
• Cetirizine reaches peak plasma concentration fastest, making it preferable when rapid symptom control is needed. 2
• Standard-dose antihistamines achieve adequate control in approximately 40–44% of patients. 4, 5

Step-Up Approach for Inadequate Response (2–4 Weeks)

• Increase the second-generation H1-antihistamine dose up to four times the standard dose when symptoms remain inadequately controlled after 2–4 weeks of standard dosing. 1, 2
• This off-label up-dosing practice is widely accepted when anticipated therapeutic benefit outweighs potential risks. 2
• Up-dosing achieves sufficient response in approximately 23% of patients who failed standard dosing. 2

Adjunctive Therapies for Resistant Cases

• Add an H2-antihistamine (cimetidine) in combination with the H1-antihistamine for resistant cases, though evidence is limited. 4, 2
• Add a leukotriene receptor antagonist (montelukast) as adjunctive therapy; this may benefit a small subgroup of patients with chronic urticaria. 4, 1, 5
• Consider a sedating antihistamine at bedtime (chlorphenamine 4–12 mg or hydroxyzine 10–50 mg) to improve sleep quality when nocturnal itching is prominent, though it provides minimal additional urticaria control when H1 receptors are already saturated. 2

Second-Line Treatment: Omalizumab

• If symptoms remain inadequately controlled despite up-dosing of antihistamines, add omalizumab 300 mg subcutaneously every 4 weeks. 2, 6
• Omalizumab is FDA-approved for chronic spontaneous urticaria in adults and adolescents ≥12 years who remain symptomatic despite H1-antihistamine treatment. 6
• Allow up to 6 months for patients to demonstrate a response to omalizumab before considering alternative therapies. 2
• Omalizumab dosing for chronic spontaneous urticaria is not dependent on serum IgE level or body weight, unlike its use in asthma. 6

Critical Safety Warning for Omalizumab

• Anaphylaxis can occur after omalizumab administration, presenting as bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue. 6
• Anaphylaxis has occurred as early as after the first dose but also beyond 1 year of regular treatment. 6
• Initiate omalizumab therapy in a healthcare setting and closely observe patients for an appropriate period after administration; healthcare providers must be prepared to manage life-threatening anaphylaxis. 6

Third-Line Treatment: Cyclosporine

• If inadequate control persists with omalizumab, add cyclosporine (up to 5 mg/kg body weight) to the second-generation H1-antihistamine regimen. 2
• Cyclosporine is effective in approximately 75% of patients with chronic idiopathic urticaria. 7
• Monitor blood pressure and renal function every 6 weeks while on cyclosporine. 2

Role of Systemic Corticosteroids

• Restrict oral corticosteroids to short courses (3–10 days) for severe acute urticaria or angioedema affecting the mouth or airway. 4, 1, 2
• Avoid long-term corticosteroid therapy due to cumulative toxicity including adrenal suppression, osteoporosis, diabetes, hypertension, and Cushing syndrome. 2
• More prolonged corticosteroid treatment may be necessary for delayed pressure urticaria, which is uniquely resistant to antihistamines. 4

General Measures and Trigger Avoidance

• Avoid NSAIDs, aspirin, and codeine, which provoke mast-cell degranulation and can exacerbate urticaria. 1, 2, 5
• Minimize physical triggers including overheating, stress, alcohol, tight clothing, hot water, and excessive sun exposure. 1, 8, 9
• Apply cooling antipruritic lotions (calamine or 1% menthol in aqueous cream) for symptomatic itch relief. 1
• Topical steroids are not routinely recommended for urticaria. 4

Monitoring and Step-Down Strategy

• Use the Urticaria Control Test (UCT) every 4 weeks to assess disease control objectively. 2
• Use the 7-Day Urticaria Activity Score (UAS7) to track daily wheal count and itch intensity (weekly scores range 0–42). 2
• Once complete symptom control is achieved, maintain the effective dose for at least 3 consecutive months before considering step-down. 1, 2
• When stepping down, reduce the daily dose by no more than 1 tablet per month. 1, 2
• If symptoms recur during step-down, return to the last effective dose that provided complete control. 1, 2

Critical Diagnostic Distinctions

• Wheals lasting 2–24 hours are typical of chronic spontaneous urticaria; wheals persisting >24 hours indicate urticarial vasculitis and warrant skin biopsy for confirmation and different management. 4, 1, 2
• Physical urticaria wheals typically resolve within 1 hour, except delayed pressure urticaria which can last up to 48 hours. 4, 1
• Look for ecchymotic or purpuric residues, pain/burning sensations, fever, arthralgia, or general malaise—these suggest urticarial vasculitis or systemic disease and warrant specialist referral. 2

Special Considerations in Renal and Hepatic Impairment

• In moderate renal impairment (creatinine clearance 10–20 mL/min), avoid acrivastine and halve the dose of cetirizine, levocetirizine, and hydroxyzine. 2
• In severe renal impairment (creatinine clearance <10 mL/min), avoid cetirizine and levocetirizine altogether. 2
• Mizolastine is contraindicated in significant hepatic impairment; avoid chlorphenamine and hydroxyzine in severe liver disease. 2

Prognosis

• 50% of patients with chronic urticaria presenting with wheals alone are clear by 6 months, whereas >50% of patients with wheals and angioedema still have active disease after 5 years. 4, 5
• Chronic urticaria resolves spontaneously in 30–55% of patients within 5 years, but can persist for many years. 7
• Approximately 30% of chronic urticaria cases are autoimmune, with circulating functional autoantibodies against the high-affinity IgE receptor or against IgE. 4, 5, 10, 7