How can histaminergic and non-histaminergic responders of Chronic Spontaneous Urticaria (CSU) be detected during a dermatological examination, and what investigations can help?

Detecting Histaminergic vs Non-Histaminergic Responders in Chronic Spontaneous Urticaria

The most reliable approach to distinguish histaminergic from non-histaminergic (autoimmune) CSU is through laboratory biomarkers: measure total IgE and IgG-anti-TPO levels, then calculate their ratio—a high IgG-anti-TPO to total IgE ratio indicates autoimmune (non-histaminergic) CSU, while normal-to-elevated total IgE suggests autoallergic (histaminergic) CSU. 1

Clinical Assessment During Dermatological Examination

Response to Antihistamines as a Clinical Clue

• Patients who fail to respond to standard or updosed H1-antihistamines are more likely to have non-histaminergic (autoimmune) CSU 1
• Document the patient's response to antihistamine therapy at standard doses and up to 4-fold updosing, as poor response suggests IgG-mediated autoimmune mechanisms rather than histamine-driven disease 1, 2

Disease Activity and Severity Markers

• High baseline disease activity, presence of angioedema, and lower Urticaria Control Test (UCT) scores correlate with non-histaminergic mechanisms 3, 4
• Patients with more severe, persistent symptoms despite antihistamines typically have autoimmune endotypes 3
• Female gender is associated with higher rates of non-response to antihistamines, suggesting autoimmune mechanisms 3

Physical Examination Findings

• Review patient photo documentation of wheals and angioedema patterns 1
• Assess for signs of systemic inflammation or autoimmune comorbidities during examination 1

Laboratory Investigations to Differentiate Endotypes

Essential Basic Tests (Recommended for All CSU Patients)

The 2022 international urticaria guidelines recommend the following basic workup 1:

• Total IgE level: Low or very low levels suggest autoimmune CSU; normal-to-elevated levels suggest autoallergic CSU 1, 5, 2
• IgG-anti-TPO (anti-thyroid peroxidase): Elevated levels indicate autoimmune CSU 1
• IgG-anti-TPO to total IgE ratio: Currently the best surrogate marker for autoimmune CSU—a high ratio identifies non-histaminergic responders 1
• Differential blood count: Look for basopenia and eosinopenia, which predict poor response to antihistamines and good response to cyclosporine 5, 2
• C-reactive protein (CRP) and/or ESR: Elevated inflammatory markers suggest autoimmune mechanisms and predict poor antihistamine response but better cyclosporine response 5, 3, 4

Advanced Testing for Antihistamine Non-Responders

For patients who remain symptomatic despite H1-antihistamines, obtain a CU index to detect autoantibodies 1:

• Antibodies against IgE, FcεRI, or anti-FcεRII: Presence indicates IgG-mediated autoimmune CSU (non-histaminergic) 1
• Autologous Serum Skin Test (ASST): A positive test suggests autoreactive disease, though its clinical utility is limited as omalizumab efficacy is independent of ASST results 1, 5
• Basophil Activation Test (BAT) or Basophil Histamine Release Assay (BHRA): Positive results indicate IgG-mediated autoimmunity and predict poor omalizumab response but good cyclosporine response 5, 2
• D-dimer levels: Elevated D-dimer indicates coagulation cascade activation, predicts poor antihistamine response, and suggests more severe disease 5, 2, 4

Clinical Algorithm for Endotype Classification

Histaminergic (Autoallergic) CSU Profile:

• Normal or elevated total IgE levels 1, 5, 2
• Normal or low IgG-anti-TPO 1
• Good response to antihistamines at standard or updosed levels 2, 4
• These patients typically respond well to omalizumab 2

Non-Histaminergic (Autoimmune) CSU Profile:

• Low or very low total IgE levels 1, 5, 2
• Elevated IgG-anti-TPO 1
• High IgG-anti-TPO to total IgE ratio 1
• Poor response to antihistamines even at 4-fold doses 1, 2, 4
• Elevated CRP/ESR 5, 3, 4
• Positive ASST, BAT, or BHRA 5, 2
• Basopenia and/or eosinopenia 5, 2
• These patients are less likely to respond to omalizumab but more likely to respond to cyclosporine 5, 2, 3

Treatment Implications Based on Endotype

For Histaminergic Responders:

• Progress through antihistamine updosing (up to 4-fold standard dose) 1
• If inadequate control, advance to omalizumab 300 mg every 4 weeks, with potential for updosing to 600 mg every 14 days if needed 1, 6

For Non-Histaminergic Responders:

• Antihistamine updosing may provide limited benefit 2, 4
• Consider earlier advancement to omalizumab, but anticipate potential need for cyclosporine if omalizumab fails 5, 2, 3
• Cyclosporine is particularly effective in this population 5, 2, 3

Common Pitfalls to Avoid

• Do not rely solely on clinical examination—laboratory biomarkers are essential for accurate endotype classification 1, 5, 2
• Do not assume all CSU is histamine-mediated—approximately 30-50% of patients have autoimmune mechanisms 1, 2, 6
• Do not delay biomarker testing until after multiple treatment failures—early identification of endotype allows for more targeted therapy 5, 3
• Do not interpret ASST results as definitive—while suggestive of autoimmunity, it does not predict omalizumab response reliably 1
• The IgG-anti-TPO to total IgE ratio is currently the most validated surrogate marker, though none of these biomarkers are yet recommended for routine use in all guidelines 1, 5