Complement C5 defines two CSU endotypes with distinct autoantibody profiles and omalizumab responses: INCA study

Complement activation has long been implicated in chronic spontaneous urticaria (CSU), but the underlying mechanisms and its clinical relevance remain unclear.

To investigate the role of complement C3, C4, C5 and C5a in CSU and their associations with immunological profiles and response to omalizumab.

We conducted a multicenter cross-sectional study involving 159 CSU patients from five Immunology and Clinical Allergology centers in Portugal. Clinical data, patient-reported outcomes, complement fractions, total IgE and IgG/IgE autoantibodies were assessed. Patients were stratified according to serum C5 levels.

Serum C5 showed a bimodal distribution identifying two distinct subgroups, that broadly aligned with the immunological features previously described for autoallergic and autoimmune CSU. The low/normal C5 group (n=61) had lower C3 and C5a, higher total IgE, lower frequencies of autoantibodies (IgG and IgE anti-TPO, and IgG anti-IgE), and an 89% response rate to standard-dose omalizumab. The high C5 group (n=98) exhibited elevated C3 and C5a, higher rates of autoimmune thyroid disease, higher prevalence of IgG and IgE autoantibodies, and a 36% response rate to standard-dose omalizumab. C5a showed a similar bimodal distribution and association with omalizumab response.

Serum C5 identifies two biologically distinct CSU subgroups: a low/normal C5 group characterized by higher total IgE, limited complement activation, and a high response rate to omalizumab; and a high C5 group characterized by lower IgE, enhanced complement activation, increased autoimmune burden, and a low response rate to omalizumab. These findings suggest that C5 may represent a clinically useful biomarker for therapeutic stratification.