What is the updated classification and treatment approach for chronic spontaneous urticaria?

Updated Classification of Chronic Spontaneous Urticaria

The classification of chronic spontaneous urticaria (CSU) remains fundamentally unchanged from prior versions, with CSU defined as itchy wheals, angioedema, or both lasting more than 6 weeks, but the updated 2022 international guidelines now emphasize endotype-based classification distinguishing Type I autoimmune (autoallergic) CSU mediated by IgE autoantibodies and Type IIb autoimmune CSU mediated by mast cell-activating IgG/IgM autoantibodies. 1, 2

Core Diagnostic Criteria

Duration and Clinical Features:

• Acute urticaria: Less than 6 weeks duration 1
• Chronic urticaria: Greater than 6 weeks duration 1
• Defining characteristics: Itchy wheals with surrounding erythema that resolve within 24 hours, angioedema lasting up to 72 hours, or both 1

Critical distinction: Individual wheals lasting more than 24 hours suggest urticarial vasculitis rather than CSU and require skin biopsy for confirmation 1, 3

Updated Endotype Classification System

The most significant update involves recognizing distinct pathogenic mechanisms rather than relying solely on clinical presentation 2:

Type I Autoimmune (Autoallergic) CSU:

• Mediated by IgE autoantibodies directed against self-antigens 2
• Represents a histaminergic endotype 4

Type IIb Autoimmune CSU:

• Mediated by IgG or IgM autoantibodies that directly activate mast cells via IgE and FcεRI 2
• Present in less than 10% of CSU patients when strict diagnostic criteria are applied 2
• Represents a non-histaminergic endotype with distinct treatment implications 4, 2
• Best identified by: High ratio of IgG-anti-TPO to total IgE 4, 2

Clinical Phenotype Classification

Beyond endotypes, CSU is classified by clinical presentation 2:

Wheals-Predominant CSU:

• Wheals with or without angioedema 2
• Disease control monitored using Urticaria Control Test (UCT) with cutoff of 12 points for well-controlled disease 2, 3

Angioedema-Predominant CSU:

• Angioedema with or without wheals 2
• Requires Angioedema Control Test (AECT) with cutoff of 10 points for well-controlled disease 2, 3

Critical pitfall: Before diagnosing CSU in patients with angioedema without wheals, exclude bradykinin-mediated angioedema (hereditary/acquired angioedema, ACE inhibitor-induced) as inflammatory markers and treatment responses differ fundamentally 1

Essential Diagnostic Workup

Basic laboratory testing for all CSU patients: 2, 3

• Complete blood count with differential
• C-reactive protein or ESR
• Total IgE level
• IgG-anti-TPO level
• Calculate IgG-anti-TPO to total IgE ratio (best surrogate marker for Type IIb autoimmune CSU) 4, 2

Differential diagnosis exclusion: 3

• Urticarial vasculitis (wheals lasting >24 hours)
• Hereditary or acquired angioedema (C4, C1-INH levels and function, C1q, C1-INH antibodies)
• ACE inhibitor-induced angioedema
• Autoinflammatory diseases (Schnitzler syndrome, cryopyrin-associated periodic syndromes)
• Chronic inducible urticaria (standardized provocation testing)

Disease Activity Assessment Tools

The 2022 guidelines strongly emphasize systematic assessment at every visit: 1, 3

7-Day Urticaria Activity Score (UAS7):

• Score ranges 0-42, with higher scores indicating greater disease activity 3
• Used to establish baseline severity and guide treatment decisions 3

Urticaria Control Test (UCT):

• Score ≥12 indicates well-controlled disease 2, 3

Angioedema Control Test (AECT):

• Score ≥10 indicates well-controlled angioedema 2, 3

Treatment Algorithm Based on Updated Classification

First-line: Second-generation H1 antihistamines at standard doses achieve partial or complete response in approximately 40% of patients 3, 5

Second-line: Updose second-generation H1 antihistamines up to 4 times standard daily dose for inadequate response 3, 5

Third-line: Omalizumab 300mg subcutaneously every 4 weeks for inadequate response to high-dose antihistamines 3, 6, 5

• Critical consideration: At least 30% of patients have insufficient response to omalizumab, especially those with IgG-mediated (Type IIb) autoimmune urticaria 3, 5
• Patients failing standard or updosed antihistamines are more likely to have non-histaminergic (Type IIb autoimmune) CSU 4, 2

Fourth-line: Cyclosporine (up to 5mg/kg body weight) for omalizumab failure, improving symptoms in 54-73% of patients, particularly effective in autoimmune CSU 3, 5

• Important caveat: Monitor for adverse effects including kidney dysfunction and hypertension 5

Key Clinical Implications of Updated Classification

Endotype-directed treatment strategy: 4, 2

• Histaminergic responders (Type I autoimmune): Progress through antihistamine updosing, potentially advancing to omalizumab
• Non-histaminergic responders (Type IIb autoimmune): May require earlier advancement to cyclosporine rather than prolonged omalizumab trials, as cyclosporine is particularly effective in this population 4, 2

The high IgG-anti-TPO to total IgE ratio serves as the most practical clinical tool for identifying patients who may benefit from alternative treatment pathways. 4, 2