Cytokine imbalance and immune network endotypes underlying heterogeneous response to omalizumab in chronic spontaneous urticaria.

BACKGROUND

Chronic spontaneous urticaria (CSU) exhibits marked immunologic heterogeneity, and a substantial proportion of patients show delayed or absent responses to anti-IgE therapy. While cytokines are implicated in CSU pathophysiology, their integrated network architecture in relation to treatment response remains poorly understood.

METHODS

We analyzed serum cytokine profiles in 65 antihistamine-refractory CSU patients who received omalizumab for ≥ 6 months. Fifteen cytokines were quantified at baseline and month 6 using a multiplex bead-based assay. Treatment responses were categorized as early and well-controlled (EW), late or partly controlled (LP), or no-response (NR) based on UAS7 and UCT criteria. Cytokine compositional balance, network topology, multinomial regression, and structural equation modeling were applied to delineate immune endotypes associated with treatment response.

RESULTS

Of 65 patients, 33 (50.8%) were EW, 16 (24.6%) were LP, and 16 (24.6%) were NR. Among baseline cytokines, interleukin (IL)-13 was the only analyte differing significantly in absolute concentration, being higher in LP and NR than in EW patients. Compositional analyses revealed an IL-13-dominant imbalance strongly enriched in LP and NR. Cytokine-network analysis demonstrated cohesive interactions in EW, partial disruption in LP, and fragmented innate-Th17/Th1 connectivity in NR. Multinomial regression and structural path analyses identified IL-13 as a central node linking multiple inflammatory pathways associated with inadequate response. Longitudinally, meaningful cytokine modulation was observed only in EW, whereas LP and NR exhibited minimal or no changes despite treatment.

CONCLUSION

Baseline cytokine imbalances and network architecture are closely associated with heterogeneity in omalizumab response. An IL-13-dominant, biologically rigid cytokine profile, together with persistent innate-Th17 activity in certain patients, may define CSU endotypes less amenable to anti-IgE therapy.