Laboratory Evaluation for Autoimmune Urticaria
For patients with chronic spontaneous urticaria (CSU) suspected to be autoimmune in nature, obtain a differential blood count, C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR), total IgE level, and IgG anti-thyroid peroxidase (anti-TPO) antibodies as initial screening tests. 1
Initial Basic Laboratory Tests
The 2022 international urticaria guidelines recommend a focused initial workup for all CSU patients, particularly those not responding to H1-antihistamines 1:
- Complete blood count with differential - to detect eosinophilia (suggesting parasitic infections) or leukopenia (suggesting systemic lupus erythematosus) 1
- CRP or ESR - typically normal in ordinary CSU but elevated in urticarial vasculitis and autoinflammatory syndromes 1; higher levels correlate with H1-antihistamine resistance 2
- Total IgE level - patients with autoimmune CSU characteristically have low or very low total IgE levels 1
- IgG anti-thyroid peroxidase (anti-TPO) - elevated levels suggest autoimmune CSU, especially when combined with low total IgE 1
Autoimmune-Specific Testing
The ratio of IgG anti-TPO to total IgE is currently the best surrogate marker for autoimmune CSU - a high ratio strongly suggests autoimmune etiology 1.
For patients with inadequate response to H1-antihistamines, additional autoimmune testing should include 1:
- Autologous serum skin test (ASST) - a reasonably sensitive and specific screening test for histamine-releasing autoantibodies in experienced centers 1; positive results increase the risk of comorbid autoimmune diseases 1.7-fold 3
- Basophil histamine release assay (BHRA) or basophil activation test (BAT) - the gold standard for detecting functional autoantibodies where available 1; positive results increase autoimmune disease risk 2.9-fold (BHRA) and 3.3-fold (BAT) 3
- IgG autoantibodies against FcεRIα or IgE - detected by immunoassay; all three tests (ASST, BHRA/BAT, and IgG autoantibodies) must be positive to diagnose type IIb autoimmune CSU 3
Important Caveats About Autoantibody Testing
Natural anti-FcεRIα autoantibodies exist in healthy individuals and may cause false-positive results - these natural autoantibodies only trigger histamine release after artificial IgE removal, so diagnostic assays may require signal comparison with and without IgE removal to avoid false results 4.
Additional Markers Correlating with Autoimmune CSU
Blood basophil counts are characteristically lower in autoimmune CSU patients - reduced counts correlate with positive ASST, autoimmune status, disease severity, and H1-antihistamine resistance 2. Conversely, basophil counts increase with successful omalizumab treatment 2.
D-dimer plasma levels are elevated in autoimmune CSU - higher levels correlate with H1-antihistamine resistance and presence of autoimmune disease or autoantibodies 2.
Screening for Comorbid Autoimmune Diseases
Twenty-eight percent of CSU patients have at least one comorbid autoimmune disease, most commonly Hashimoto's thyroiditis (≥21%) and vitiligo (2%) 3. Therefore:
- Thyroid function tests should be performed, especially when autoimmune etiology is suspected 1
- Thyroid autoantibodies (anti-TPO, anti-thyroglobulin) help identify thyroid autoimmunity 1
- Comorbid autoimmune diseases are strongly linked to type IIb autoimmune CSU and associate with female sex, family history of autoimmunity, and thyroid dysfunction 3
Clinical Significance
Presence of antinuclear antibodies (ANA) and/or IgG anti-thyroid antibodies predicts non-response to omalizumab treatment 3, making these markers valuable for treatment planning.
When Extensive Testing Is NOT Needed
No investigations are required for patients with mild CSU responding to H1-antihistamines 1. The diagnostic workup should be guided by clinical presentation, disease severity, and treatment response 1.