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

BACKGROUND: Complement activation has long been implicated in chronic spontaneous urticaria (CSU), but the underlying mechanisms and its clinical relevance remain unclear. OBJECTIVE: To investigate the role of complement C3, C4, C5 and C5a in CSU and their associations with immunological profiles and response to omalizumab. METHODS: 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. RESULTS: 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. CONCLUSION: 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.