In a patient with chronic urticaria and elevated immunoglobulin E, what is the appropriate diagnostic work‑up and treatment algorithm?

Management of Chronic Urticaria with Elevated IgE

Start with standard-dose second-generation H1-antihistamines as first-line therapy, escalate to four-fold dosing if inadequate response after 2-4 weeks, then advance to omalizumab 300 mg every 4 weeks as second-line treatment, which is particularly effective in patients with elevated IgE. 1

Diagnostic Work-Up

Essential Initial Testing

• Obtain differential blood count, C-reactive protein or ESR, total IgE, and IgG-anti-TPO levels for all chronic spontaneous urticaria (CSU) patients 2
• Calculate the ratio of IgG-anti-TPO to total IgE, as a high ratio indicates Type IIb autoimmune CSU, while elevated total IgE alone suggests Type I autoallergic CSU 1, 2
• Elevated total IgE (present in up to 50% of CSU patients) predicts high disease activity, longer disease duration, and excellent response to omalizumab 3

Additional Testing When Indicated

• Perform thyroid function tests and thyroid autoantibodies, as thyroid autoimmunity occurs in 14% of chronic urticaria patients versus 6% in controls 4
• Order lesional skin biopsy if wheals persist beyond 24 hours to exclude urticarial vasculitis 4
• Check full vasculitis screen including serum complement assays if systemic features are present 4

Treatment Algorithm

Step 1: Second-Generation H1-Antihistamines (First-Line)

• Initiate standard-dose second-generation H1-antihistamines: cetirizine, desloratadine, fexofenadine, levocetirizine, or loratadine once daily 1
• Offer at least two different antihistamine options since individual responses vary 1
• Assess disease control after 2-4 weeks using the Urticaria Control Test (UCT), with a score ≥12 indicating well-controlled disease 1

Step 2: Updose Antihistamines

• Increase antihistamine dose up to 4-fold the standard dose if UCT score remains <12 after 2-4 weeks 1
• This updosing approach is common practice despite exceeding manufacturer's licensed recommendations, as benefits outweigh risks 1
• Reassess after an additional 2-4 weeks at the higher dose 1

Step 3: Omalizumab (Second-Line)

• Advance to omalizumab 300 mg subcutaneously every 4 weeks if symptoms remain inadequately controlled after updosed antihistamines 1
• Patients with elevated total IgE have high response rates to omalizumab, with rapid symptom control often occurring within days after the first injection 3, 5
• Allow up to 6 months for patients to respond to omalizumab before considering treatment failure 1
• For insufficient responders, consider updosing omalizumab by shortening intervals and/or increasing dosage, with a maximum recommended dose of 600 mg every 14 days 1

Step 4: Cyclosporine (Third-Line)

• Consider cyclosporine up to 5 mg/kg body weight for patients who fail to respond to high-dose omalizumab 1
• Important caveat: If total IgE is very low or normal with high IgG-anti-TPO to total IgE ratio, this suggests Type IIb autoimmune CSU, which responds poorly to omalizumab but well to cyclosporine 2, 3
• In such cases, consider advancing to cyclosporine earlier rather than prolonging omalizumab trials 2
• Mandatory monitoring of blood pressure and renal function every 6 weeks during cyclosporine therapy 4

Disease Monitoring Strategy

• Use the UCT at each visit to guide treatment decisions, aiming for complete disease control (UCT ≥16) 1
• For angioedema-predominant presentations, use the Angioedema Control Test (AECT) with a cutoff of 10 points for well-controlled disease 2
• Consider stepping down treatment once complete control is achieved for at least 3 consecutive months to assess for spontaneous remission 1

Critical Pitfalls to Avoid

• Avoid aspirin and NSAIDs in all urticaria patients, as they exacerbate symptoms through leukotriene formation 4
• Advise patients to avoid nonspecific aggravating factors including overheating, stress, and alcohol 1
• Reserve systemic corticosteroids for severe flares only as brief courses, not for long-term management 1, 4
• Do not rely on autologous serum skin test results to guide omalizumab decisions, as efficacy is independent of test results 2