Stepwise Treatment of Urticaria
Start all patients with urticaria on a standard-dose second-generation H1-antihistamine immediately, 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: Second-Generation H1-Antihistamines
Initiate a non-sedating second-generation H1-antihistamine (cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, or mizolastine) at standard dosing for all patients presenting with urticaria, whether acute or chronic. 1, 2
Offer at least two different antihistamine options because individual response and tolerance vary markedly between agents—if one fails or causes side effects, switch to another. 3, 1
Cetirizine reaches peak concentration fastest and should be selected when rapid symptom control is required, such as in acute urticaria or severe flares. 1, 2
Desloratadine has the longest half-life (~27 hours) and must be discontinued at least 6 days before any skin testing to avoid false-negative results. 1, 2
Time the dose to coincide with symptom flares—schedule antihistamine administration so peak drug levels align with the expected timing of urticaria episodes. 1
Step 2: Dose Escalation (If Symptoms Persist After 2–4 Weeks)
Increase the antihistamine dose up to four-fold the standard dose before considering second-line agents; approximately 23% of patients who fail standard dosing achieve adequate control with up-dosing. 1, 2
This off-label practice is widely accepted when anticipated therapeutic benefit outweighs potential risks. 1
Step 3: Add Omalizumab (If Four-Fold Antihistamine Dosing Fails)
Add omalizumab 300 mg subcutaneously every 4 weeks for patients still symptomatic despite maximized antihistamine therapy. 1, 2
Allow up to 6 months for patients to demonstrate a response to omalizumab before declaring treatment failure. 1, 2
If 300 mg is insufficient, increase to a maximum of 600 mg every 2 weeks. 1
Omalizumab is particularly effective in non-autoimmune chronic spontaneous urticaria; at least 30% of patients—especially those with IgG-mediated autoimmune urticaria—have insufficient response. 4
Step 4: Add Cyclosporine (If Omalizumab Fails After 6 Months)
Introduce cyclosporine (up to 5 mg/kg/day) after 6 months of omalizumab if disease remains uncontrolled. 1, 2
Cyclosporine produces clinical improvement in approximately 54–73% of patients with severe urticaria, particularly those with autoimmune chronic spontaneous urticaria. 1, 4
Monitor blood pressure and renal function every 6 weeks because of nephrotoxicity and hypertension risk. 1, 2
A 16-week treatment course is superior to 8 weeks in reducing therapeutic failures. 1
Adjunctive Therapies for Resistant Cases
H2-antihistamine (cimetidine) may be added to H1-antihistamine therapy, particularly when dyspeptic symptoms coexist; evidence is limited. 1, 2
Leukotriene receptor antagonist (montelukast) can be used as add-on therapy; data on efficacy are sparse. 1, 2
Sedating antihistamines at night (e.g., 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: Short Courses Only
Reserve oral corticosteroids for short courses of 3–10 days in severe acute exacerbations only, and only after antihistamines have been optimized. 1, 2
Never use corticosteroids as maintenance therapy for chronic urticaria due to cumulative toxicity including adrenal suppression, osteoporosis, diabetes, hypertension, and Cushing syndrome. 1, 2
Evidence for corticosteroid efficacy is very low; they likely increase adverse events in approximately 15% more patients (OR 2.76; 95% CI 1.00–7.62). 1
Trigger Identification and Avoidance
Discontinue aspirin, NSAIDs, and codeine immediately—these agents can precipitate or aggravate urticaria. 3, 1, 2
Avoid ACE-inhibitors in patients with angioedema without wheals; permanently discontinue if ACE-inhibitor-related angioedema is identified. 3, 1, 2
Advise patients to minimize overheating, emotional stress, and alcohol consumption. 3, 1, 2
Recommend cooling antipruritic lotions (calamine or 1% menthol in aqueous cream) for symptomatic itch relief. 3, 1, 2
Disease Monitoring Tools
Use the Urticaria Control Test (UCT) every 4 weeks to assess disease control. 1, 2
Record the 7-Day Urticaria Activity Score (UAS7) for objective measurement of disease activity; weekly scores range from 0 to 42. 1, 2
Apply the Angioedema Control Test (AECT) when angioedema is present. 1, 2
Treatment Tapering and Relapse Management
After achieving complete symptom control, maintain the effective dose for at least 3 months before initiating dose reduction. 1, 2
If symptoms recur, revert to the last dose that provided adequate control. 1, 2
Diagnostic Distinctions and When to Refer
Individual wheals lasting 2–24 hours are typical of chronic spontaneous urticaria. 1, 2
Lesions persisting >24 hours with ecchymotic or purpuric residues, or pain/burning sensations, indicate urticarial vasculitis and require skin biopsy for confirmation. 3, 1, 2
Refer urgently for suspected urticarial vasculitis, fever, arthralgia, or malaise accompanying urticaria (suggesting systemic vasculitis or autoinflammatory disease). 1, 2
For isolated angioedema without wheals, screen for C1-inhibitor deficiency using serum C4 as the initial test; a low C4 (<30% mean normal) has very high sensitivity. 3, 1, 2
Refer any patient requiring regular oral corticosteroids or who has failed third-line therapies. 1, 2
Special Population Considerations
Renal Impairment
Avoid acrivastine in moderate renal impairment (creatinine clearance 10–20 mL/min). 1
Halve the dose of cetirizine, levocetirizine, and hydroxyzine in moderate impairment; avoid cetirizine and levocetirizine in severe impairment (creatinine clearance <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 antihistamines during pregnancy, especially in the first trimester, unless absolutely necessary. 1
If an antihistamine is required, chlorphenamine has the longest safety record. 1
Loratadine and cetirizine are FDA Pregnancy Category B. 1
Common Pitfalls to Avoid
Do not use sedating antihistamines as first-line therapy—they alter REM sleep patterns and learning curves and are not superior in efficacy to non-sedating antihistamines in head-to-head trials. 5
Do not delay epinephrine in anaphylaxis—if vascular collapse or systemic symptoms occur, administer epinephrine before any antihistamine or corticosteroid; using antihistamines or corticosteroids first can delay essential epinephrine therapy. 1
Do not confuse chronic spontaneous urticaria with urticarial vasculitis—the latter requires skin biopsy and a full vasculitis screen including C3 and C4 complement assays. 3, 1, 2
Do not perform extensive laboratory investigations in mild urticaria responsive to standard-dose antihistamines—no laboratory tests are necessary in these patients. 1