Double-Negative B Cell Expansion Defines a Relapse-Prone Immunophenotype in Newly Diagnosed Giant Cell Arteritis

Background: Giant cell arteritis (GCA), traditionally considered T cell-driven, exhibits vascular B/plasma-cell infiltrates and altered circulating B-cell homeostasis, suggesting a pathogenic role for B cells. Relapse is common in newly diagnosed GCA (nGCA), yet predictive biomarkers remain elusive. Objective: To characterize circulating B-cell subpopulations in nGCA and assess their association with 12-month relapse. Methods: Baseline multiparametric flow cytometry was performed on peripheral blood samples from consecutive patients with nGCA and sex/age-matched healthy controls (HC). Patients received standard treatment per 2018 EULAR recommendations and were followed longitudinally. Results: 102 patients with nGCA and 102 matched HC were included. One-year outcome data were available for 55 patients, of whom 34 relapsed and 21 remained relapse-free. Baseline B-cell homeostasis differed by disease course. Non-relapsers showed reduced total CD19+ B-cell counts and contraction of most B-cell subsets, while CD27-IgD-double-negative (DN) B-cell counts remained comparable to HC. Conversely, relapsers maintained total B-cell numbers above HC despite reduced memory compartments, driven by expanded naive and DN B cells, alongside preserved plasmablast and transitional B-cell counts. At 6 months, total B-cell counts increased only in non-relapsers. DN B cells showed the greatest divergence between groups and independently predicted relapse. DN B-cell counts also correlated with circulating T peripheral helper cell numbers, supporting extrafollicular immune pathway activation. Conclusion: nGCA is characterized by outcome-dependent disturbances in B-cell homeostasis. Expansion of the DN B-cell compartment identifies a relapse-prone immunophenotype and represents a clinically relevant biomarker for early risk stratification.