Classification and Management of Chronic Spontaneous Urticaria

Primary Endotype Classification

The American Academy of Allergy, Asthma, and Immunology classifies 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
Type IIb Autoimmune CSU is mediated by IgG or IgM autoantibodies that directly activate mast cells via IgE and FcεRI, and is present in less than 10% of CSU patients when strict diagnostic criteria are applied 1
The high ratio of IgG-anti-TPO to total IgE is currently the best surrogate marker for Type IIb autoimmune CSU 1, 2, 3

The European Academy of Allergy and Clinical Immunology distinguishes CSU phenotypes by clinical manifestations, including wheals-predominant CSU, angioedema-predominant CSU, and combined phenotype 4, 5
Patients with wheals-predominant CSU develop wheals with or without angioedema, and disease control is monitored using the Urticaria Control Test (UCT) with a cutoff of 12 points for well-controlled disease 4, 5
Patients with angioedema-predominant CSU present with angioedema with or without wheals, and requires assessment with the Angioedema Control Test (AECT) with a cutoff of 10 points for well-controlled disease 4, 5

The American Academy of Allergy, Asthma, and Immunology recommends a diagnostic workup framework for CSU evaluation, including confirmation, causes, cofactors, comorbidities, consequences, components, and course 5
Essential basic testing includes routine measurement of differential blood count, C-reactive protein/ESR, total IgE, and IgG-anti-TPO levels for all CSU patients 1, 4, 5

The autologous serum skin test has limited clinical relevance for treatment decisions, as omalizumab efficacy is independent of test results, but remains useful for confirming Type IIb autoimmune CSU when combined with other markers 1, 3
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 2, 3

The presence of elevated rheumatoid factor suggests broader autoimmune involvement, which is relevant in the diagnosis of Type IIb autoimmune chronic spontaneous urticaria (CSU) 6

A normal C4 complement level, as seen in this patient with a C4 level of 45, effectively excludes hereditary or acquired angioedema 7, 8

For patients with Type IIb autoimmune CSU, the British Journal of Dermatology recommends cyclosporine 3-5 mg/kg/day divided into two doses, with a treatment duration of 16 weeks being superior to 8 weeks for reducing therapeutic failures 9
The use of cyclosporine is recommended due to its efficacy in treating IgG-mediated mast cell activation, which is the underlying mechanism in Type IIb autoimmune CSU 9
Alternative treatments, such as tacrolimus and mycophenolate mofetil, can be considered if cyclosporine fails or is contraindicated, with omalizumab being less likely to work in Type IIb autoimmune CSU but can be trialed 8, 9