What is the recommended management for urticaria, including first‑line non‑sedating second‑generation H1‑antihistamines, dose escalation, adjunct therapies, and treatment options for chronic spontaneous urticaria?

Management of Urticaria

Start all patients with urticaria on a standard dose of a non-sedating second-generation H1-antihistamine, and if symptoms persist after 2-4 weeks, increase the dose up to 4 times the standard dose before considering any other therapy. 1, 2

First-Line Treatment: Second-Generation H1-Antihistamines

• Non-sedating second-generation H1-antihistamines are the cornerstone of urticaria management and should be used as monotherapy initially. 2, 3

• Offer patients at least two different second-generation antihistamines to trial, as individual response and tolerance vary widely. 2

• Preferred agents include cetirizine, loratadine, desloratadine, levocetirizine, and fexofenadine due to their superior safety profile and lack of sedation compared to first-generation antihistamines. 2, 4

Pharmacokinetic Optimization

• Cetirizine reaches peak plasma concentration fastest and should be selected when rapid symptom control is needed. 2

• Schedule antihistamine dosing to coincide with anticipated urticaria flares to maximize therapeutic benefit. 2

• Desloratadine has the longest half-life (~27 hours) and must be stopped at least 6 days before skin-prick testing. 2

Dose Escalation Strategy

• If standard dosing fails after 2-4 weeks, increase the second-generation H1-antihistamine up to 4 times the standard dose. 1, 2, 3

• This up-dosing achieves adequate response in approximately 23% of patients who failed standard dosing. 2

• If one antihistamine fails at high doses, switch to a different second-generation antihistamine before adding other therapies, as individual responses vary significantly. 1

• Up-dosing is an accepted off-label practice when anticipated benefits outweigh risks. 2

Adjunctive First-Line Therapies (Limited Evidence)

• Add an H2-antihistamine (cimetidine) to the H1-antihistamine regimen for additional histamine receptor blockade in resistant cases, though evidence is limited. 1, 2

• Consider adding a leukotriene receptor antagonist (montelukast) as combination therapy for resistant cases, particularly useful when standard approaches fail. 1, 2

• Night-time administration of a sedating antihistamine (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. 2

Second-Line Treatment: Omalizumab

• If symptoms remain inadequately controlled despite 4-fold up-dosing of antihistamines, add omalizumab 300 mg subcutaneously every 4 weeks. 2, 5, 6

• Allow up to 6 months for patients to demonstrate a response to omalizumab before considering it ineffective. 2, 5

• If response is insufficient after 3 months, escalate to 600 mg every 2 weeks (maximum recommended regimen). 5

• Omalizumab has the strongest evidence base of all alternative therapies and has radically changed management of antihistamine-refractory chronic spontaneous urticaria. 6, 7

Third-Line Treatment: Cyclosporine

• If inadequate control persists after 6 months of both high-dose antihistamines and omalizumab, add cyclosporine 4-5 mg/kg daily. 2, 5

• Monitor blood pressure and renal function every 6 weeks while on cyclosporine due to nephrotoxicity risk. 2, 5

Corticosteroid Use: Severe Restrictions

• Use oral corticosteroids only for severe acute urticaria or angioedema affecting the mouth, and limit to 3-10 days maximum. 1, 2

• Do not use corticosteroids for long-term management due to cumulative toxicity including adrenal suppression, osteoporosis, diabetes, hypertension, and Cushing syndrome. 2, 7

• Corticosteroids have no role in primary therapy for acute urticaria reactions and should not delay more appropriate interventions. 5

Treatment Monitoring and Step-Down

• Use the Urticaria Control Test (UCT) every 4 weeks to objectively assess disease control. 2

• Use the 7-Day Urticaria Activity Score (UAS7) for objective measurement of wheal count and itch intensity (scores 0-42). 2

• Once complete symptom control is achieved, maintain the effective dose for at least 3 consecutive months before considering step-down. 2

• When stepping down, reduce the daily dose by no more than 1 tablet per month. 2

• If symptoms recur during step-down, return immediately to the last effective dose that provided complete control. 2

Trigger Avoidance

• Avoid medications that worsen urticaria: aspirin, NSAIDs, codeine, and ACE inhibitors. 1, 8

• Minimize aggravating factors including overheating, stress, and alcohol. 1

• Prevent skin from drying, avoid hot showers, scrubbing, and excessive sun exposure. 8

Special Populations

Renal Impairment

• In moderate renal impairment (CrCl 10-20 mL/min), avoid acrivastine and halve the dose of cetirizine, levocetirizine, and hydroxyzine. 2

• In severe renal impairment (CrCl <10 mL/min), avoid cetirizine and levocetirizine altogether. 2

Hepatic Impairment

• Mizolastine is contraindicated in significant hepatic impairment. 2

• Avoid chlorphenamine and hydroxyzine in severe liver disease due to inappropriate sedating effects. 2

Pregnancy

• Avoid all antihistamines during pregnancy, especially in the first trimester, unless absolutely necessary. 2

• When required, chlorphenamine is often selected due to its long safety record. 2

• Loratadine and cetirizine are FDA Pregnancy Category B (no evidence of risk in human studies). 2

Critical Diagnostic Distinctions

• If wheals last longer than 24 hours, perform a skin biopsy to evaluate for urticarial vasculitis, which requires different management. 1, 2

• Ordinary acute urticaria wheals last 2-24 hours, while physical urticaria wheals last less than 1 hour. 1, 2

• Distinguish urticaria from bradykinin-mediated angioedema (hereditary angioedema or ACE inhibitor-induced), as these require entirely different management. 4

Specialist Referral Indications

• Lesions persisting >24 hours with ecchymotic/purpuric residues or pain/burning sensations warrant referral for biopsy and specialist evaluation. 2

• Fever, arthralgia, or general malaise accompanying urticaria suggest underlying autoinflammatory disorder or systemic vasculitis. 2

• Patients requiring regular oral corticosteroids or who have failed third-line therapies should be referred to allergist-immunologist or dermatologist. 2

• Isolated or recurrent angioedema without wheals requires evaluation for hereditary/acquired angioedema, paraproteinemia, or B-cell malignancies. 2

Special Consideration: Cold Urticaria

• All patients with cold urticaria must carry an epinephrine autoinjector at all times due to risk of cold-induced anaphylaxis with whole-body cold exposure. 5

• Epinephrine is the only first-line treatment for anaphylaxis and must be administered immediately; antihistamines and corticosteroids have delayed onset and do not prevent anaphylaxis. 5

• Current guidelines do not recommend desensitization protocols for cold urticaria due to lack of standardized, evidence-based methods. 5

Common Pitfalls to Avoid

• Do not use first-generation sedating antihistamines as they alter REM sleep patterns and learning curves without superior efficacy compared to non-sedating agents. 4

• Do not perform routine laboratory investigation in chronic spontaneous urticaria unless clinical features suggest autoimmune disease, as it is not cost-effective. 8

• Do not delay epinephrine administration to give antihistamines or corticosteroids first in anaphylaxis, as this worsens outcomes. 5

• Do not discharge a patient after anaphylaxis without extended observation (up to 6 hours or longer) due to risk of biphasic reactions. 5

Prognosis

• Approximately 50% of patients with acute urticaria presenting with wheals alone will be clear by 6 months. 1

• Patients with both wheals and angioedema may have a more prolonged course with lower remission rates. 1, 8