What investigations and biomarkers are important for diagnosing chronic spontaneous urticaria, especially its autoimmune type?

Key Investigations and Biomarkers for Diagnosing Chronic Spontaneous Urticaria, Especially Autoimmune Type

For diagnosing chronic spontaneous urticaria (CSU), especially its autoimmune type, essential investigations include a differential blood count, C-reactive protein/ESR, total IgE levels, and IgG anti-thyroid peroxidase (anti-TPO) antibodies, with a high ratio of IgG-anti-TPO to total IgE being the best current surrogate marker for autoimmune CSU. 1

Basic Diagnostic Approach

The diagnostic workup for CSU follows the "7 Cs" framework:

1. Confirm the diagnosis (wheals/angioedema lasting >6 weeks)
2. Causes (identify underlying mechanisms)
3. Cofactors (identify triggers and aggravators)
4. Comorbidities (check for associated conditions)
5. Consequences (assess impact on quality of life)
6. Components (identify problems with sleep, distress, etc.)
7. Course (monitor disease activity and control) 1

Essential Initial Investigations

For all patients with suspected CSU, the following basic tests are recommended:

• Differential blood count (may show basopenia and eosinopenia in autoimmune CSU)
• C-reactive protein (CRP) level and/or ESR (usually normal in CSU but elevated in urticarial vasculitis)
• Total IgE levels (low or very low in autoimmune CSU)
• IgG anti-thyroid peroxidase (anti-TPO) antibodies (elevated in autoimmune CSU) 1

Specific Biomarkers for Autoimmune CSU

Two main autoimmune mechanisms drive CSU pathogenesis:

1. Type I Autoimmune (Autoallergic) CSU

• IgE antibodies against autoantigens (e.g., thyroid peroxidase, IL-24)
• Patients tend to be younger
• Often responds better to omalizumab 2, 3

2. Type IIb Autoimmune CSU

• IgG autoantibodies that activate mast cells (via IgE and FcεRI)
• Present in <10% of CSU patients when strict criteria are used
• Characterized by:
  • Higher disease severity
  • Concomitant autoimmune diseases (especially Hashimoto's thyroiditis)
  • Low levels of total IgE
  • Elevated levels of IgG-anti-TPO
  • Basopenia and eosinopenia
  • Poor response to antihistamines and omalizumab
  • Good response to cyclosporine 2, 4

Triple-Positive Test for Type IIb Autoimmune CSU

To confirm Type IIb autoimmune CSU, all three of these tests should be positive:

1. Autologous Serum Skin Test (ASST) - intradermal injection of patient's own serum to detect autoantibodies
2. Basophil Activation Test (BAT) or Basophil Histamine Release Assay (BHRA) - gold standard for functional autoantibodies
3. Immunoassay for IgG autoantibodies against FcεRI/IgE 2, 4

Prognostic Indicators

• Anti-TPO positivity predicts longer disease duration (>12-18 months) 5
• Positive ASST and APST (Autologous Plasma Skin Test) correlate with:
  • More frequent urticarial attacks (>4 days/week)
  • More difficult-to-treat disease 5
• Markers for autoimmune diseases (antinuclear antibodies and/or IgG anti-thyroid antibodies) are associated with non-response to omalizumab treatment 4

Additional Tests Based on Clinical Presentation

• Thyroid function tests if thyroid autoimmunity is suspected
• CU index for patients not responsive to H1 antihistamines (detects antibodies against IgE, FcεRI, or anti-FcεRII)
• Serum C4 as screening test if hereditary or acquired C1 inhibitor deficiency is suspected
• Skin biopsy if urticarial vasculitis is suspected 1

Important Clinical Considerations

• Most patients with Type IIb autoimmune CSU (8 out of 9) also have autoallergic CSU, but only a small proportion of patients with autoallergic CSU (8 out of 64) have Type IIb autoimmune CSU 3
• Patients with autoimmune diseases have 1.7-3.3 times higher risk of having autoimmune CSU, particularly with positive ASST, BHRA, and BAT 4
• The most common autoimmune disease associated with CSU is Hashimoto's thyroiditis (≥21%), followed by vitiligo (2%) 4, 6

Monitoring Tools

• 7-Day Urticaria Activity Score (UAS7) - assesses disease activity based on wheal count and pruritus severity
• Urticaria Control Test (UCT) - evaluates disease control
• Angioedema Control Test (AECT) - for patients with angioedema 1

By systematically applying these diagnostic tests and biomarkers, clinicians can better identify autoimmune CSU subtypes, predict disease course, and select appropriate therapies based on the underlying pathophysiological mechanisms.