What is the initial workup and treatment for a patient with Chronic Spontaneous Urticaria (CSU)?

CSU Workup and Treatment

Initial Diagnostic Approach

For chronic spontaneous urticaria (CSU), perform only limited routine laboratory testing: differential blood count, C-reactive protein or ESR, total IgE, and IgG-anti-TPO levels—this basic workup is sufficient for most patients unless specific red flags suggest underlying conditions. 1, 2

Essential History and Physical Examination Elements

• Document duration of symptoms (CSU requires >6 weeks of spontaneous wheals, angioedema, or both) 3, 4
• Assess for red flag symptoms that suggest alternative diagnoses:
  • Wheals persisting >24 hours (suggests urticarial vasculitis, not CSU) 5
  • Fever, joint/bone pain, or malaise (suggests autoinflammatory disease) 5
  • Family history of periodic fevers or early-onset disease (suggests hereditary autoinflammatory syndromes) 5
• Review patient photographs to confirm clinical presentation 1

Basic Laboratory Testing (Perform on All Patients)

• Differential blood count 1, 2
• C-reactive protein or ESR 1, 2
• Total IgE level 1, 2, 6
• IgG-anti-TPO (anti-thyroid peroxidase antibodies) 1, 2, 6
• Calculate IgG-anti-TPO to total IgE ratio (high ratio indicates Type IIb autoimmune CSU, which predicts poor response to antihistamines and omalizumab but good response to cyclosporine) 5, 2, 6

Additional Testing Only When Indicated by Red Flags

• If prominent angioedema: Test C4 complement, C1-INH levels and function, C1q, and C1-INH antibodies to exclude hereditary or acquired angioedema 5
• If wheals persist >24 hours: Perform skin biopsy to evaluate for urticarial vasculitis (look for small vessel damage in papillary and reticular dermis with fibrinoid deposits) 5
• If fever, joint pain, or systemic symptoms: Check inflammatory markers and consider gene mutation analysis for hereditary periodic fever syndromes 5

Do NOT Perform Routine Extensive Testing

• Avoid routine allergy testing, autoimmune panels, or extensive workups unless history suggests specific underlying conditions 1, 7
• The autologous serum skin test has limited clinical relevance for treatment decisions, as omalizumab efficacy is independent of test results 2

Disease Activity and Control Assessment

Use Validated Scoring Tools

• For wheals with or without angioedema: Use the 7-Day Urticaria Activity Score (UAS7, range 0-42) to assess disease activity and the Urticaria Control Test (UCT) to monitor disease control (cutoff ≥12 points indicates well-controlled disease) 1, 2
• For angioedema with or without wheals: Use the Angioedema Activity Score and Angioedema Control Test (AECT, cutoff ≥10 points indicates well-controlled disease) 1, 2
• For combined wheals and angioedema: Use both UAS7 and Angioedema Activity Score together, plus both UCT and AECT 1

Treatment Algorithm

First-Line Treatment: Second-Generation H1 Antihistamines

Start with standard-dose second-generation H1 antihistamines; approximately 40% of patients achieve partial or complete response (>50% symptom reduction). 3, 8

• Use second-generation antihistamines (e.g., cetirizine, loratadine, fexofenadine) due to better safety profile than first-generation agents 8, 3
• If inadequate response after 2-4 weeks, updose to 2-4 times the standard dose before advancing to next step 8, 3

Second-Line Treatment: Omalizumab

For patients who remain symptomatic despite updosed H1 antihistamines, advance to omalizumab 300 mg subcutaneously every 4 weeks. 9, 3, 10

• Omalizumab 300 mg every 4 weeks is the FDA-approved dose for CSU 9
• Approximately 70% of antihistamine-refractory patients do not achieve complete control with omalizumab 10
• Patients with high IgG-anti-TPO to total IgE ratio (Type IIb autoimmune CSU) respond poorly to omalizumab 5, 2, 6

Third-Line Treatment: Cyclosporine

For patients failing omalizumab, particularly those with Type IIb autoimmune CSU (high IgG-anti-TPO to total IgE ratio), advance to cyclosporine 3-5 mg/kg/day divided into two doses. 2, 3

• Cyclosporine improves symptoms in approximately 54-73% of patients, especially those with autoimmune CSU 3
• Treatment duration of 16 weeks is superior to 8 weeks for reducing therapeutic failures 2
• Monitor for adverse effects including kidney dysfunction and hypertension 3

Critical Clinical Pitfalls

Endotype Recognition Matters for Treatment Selection

• Patients who fail standard or updosed antihistamines are more likely to have non-histaminergic (Type IIb autoimmune) CSU 2, 6
• For these patients, consider earlier advancement to cyclosporine rather than prolonged omalizumab trials, as they respond poorly to antihistamines and omalizumab but well to cyclosporine 5, 2

Special Populations Requiring Different Approaches

• If autoinflammatory syndrome is suspected (fever, joint pain, family history), the primary treatment is IL-1 inhibitors, not antihistamines or omalizumab 5
• If hereditary or acquired angioedema is confirmed (low C4, abnormal C1-INH), standard CSU treatments are ineffective; specific angioedema therapies are required 5

Treatment Goals and Monitoring

• The primary treatment goal is complete disease control, not just symptom reduction 1
• Use UCT/AECT scores to guide treatment escalation decisions 1, 2
• Periodically reassess the need for continued therapy based on disease severity and control level 9