What are the current classification and phenotypes of Chronic Spontaneous Urticaria (CSU)?

Current Classification and Phenotypes of Chronic Spontaneous Urticaria

The 2022 international urticaria guidelines classify CSU into two main endotypes based on underlying pathogenic mechanisms: Type I autoimmune (autoallergic) CSU, characterized by IgE autoantibodies to self-antigens, and Type IIb autoimmune CSU, mediated by mast cell-activating IgG or IgM autoantibodies. 1, 2

Primary Endotype Classification

The most recent classification framework recognizes distinct mechanistic subtypes:

Type I Autoimmune (Autoallergic) CSU

• Driven by IgE autoantibodies directed against autoantigens such as thyroid peroxidase (TPO) and IL-24 2
• Characterized by elevated total IgE levels 3, 2
• Patients typically show better response to omalizumab 3, 4
• Associated with higher response rates to antihistamine updosing 3

Type IIb Autoimmune CSU

• Mediated by IgG or IgM autoantibodies that directly activate mast cells via IgE and FcεRI 1, 2
• Present in less than 10% of CSU patients when strict diagnostic criteria are applied (triple positivity: autologous serum skin test, IgG autoantibody immunoassays, and basophil activation tests) 2
• Distinguished by low or very low total IgE levels and elevated IgG-anti-TPO levels 1, 3
• The high ratio of IgG-anti-TPO to total IgE is currently the best surrogate marker for this endotype 1, 3, 5

Mixed and Undefined Phenotypes

• A subpopulation demonstrates both Type I and Type IIb features simultaneously 2, 6
• Some patients show evidence of neither endotype, indicating additional mechanisms remain to be elucidated 6

Clinical Phenotypes Based on Presentation

The 2022 guidelines distinguish CSU phenotypes by clinical manifestations:

Wheals-Predominant CSU

• Patients develop wheals with or without angioedema 1
• Disease control monitored using the Urticaria Control Test (UCT) with a cutoff of 12 points for well-controlled disease 1

Angioedema-Predominant CSU

• Patients present with angioedema with or without wheals 1
• Requires assessment with the Angioedema Control Test (AECT) with a cutoff of 10 points for well-controlled disease 1

Combined Phenotype

• Patients experiencing both wheals and angioedema should be monitored using both UCT and AECT 1

Biomarker-Defined Characteristics

The updated classification emphasizes laboratory markers for phenotyping:

Histaminergic Responders (Type I/Autoallergic)

• Normal to elevated total IgE levels 3
• Low IgG-anti-TPO to total IgE ratio 3, 5
• Respond to H1-antihistamine updosing 3
• Better omalizumab response rates 3, 4

Non-Histaminergic Responders (Type IIb/Autoimmune)

• Higher disease severity and longer duration 2
• Basopenia and eosinopenia 2, 4
• Concomitant autoimmune diseases more frequently present 2
• Poor response to antihistamines and omalizumab 3, 2
• Good response to cyclosporine (65-70% efficacy) 5, 2
• Positive autologous serum skin test 1, 5

Diagnostic Workup Framework: The 7 Cs

The 2022 guidelines structure CSU evaluation around seven objectives 1:

1. Confirmation: Rule out differential diagnoses and confirm CSU diagnosis
2. Causes: Identify underlying autoimmune mechanisms (Type I vs Type IIb)
3. Cofactors: Look for indicators of specific endotypes through biomarker testing
4. Comorbidities: Check for chronic inducible urticaria and autoimmune conditions
5. Consequences: Assess mental health impacts and quality of life
6. Components: Identify sleep disturbances, sexual health issues, and social performance problems
7. Course: Monitor disease activity, impact, and control over time

Essential Basic Testing

The current guidelines recommend routine measurement of differential blood count, C-reactive protein/ESR, total IgE, and IgG-anti-TPO levels for all CSU patients 1

Clinical Pitfalls and Practical Considerations

A critical caveat: The autologous serum skin test has limited clinical relevance for treatment decisions, as omalizumab efficacy is independent of test results 1. However, it remains useful for confirming Type IIb autoimmune CSU when combined with other markers 5.

Treatment implications: Patients failing standard or updosed H1-antihistamines are more likely to have non-histaminergic (Type IIb autoimmune) CSU and may require earlier advancement to cyclosporine rather than prolonged omalizumab trials 3, 5.

The CU index should be obtained in antihistamine-refractory patients to determine presence of antibodies against IgE, FcεRI, or FcεRII, as these biomarkers predict treatment outcomes with omalizumab or cyclosporine 1.