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Objective Childhood-onset systemic lupus erythematosus (cSLE) exhibits significant heterogeneity, leading to challenges in prognosis and treatment. This study aims to stratify cSLE patients into clinically distinct subgroups based on routine autoantibody profiles and to characterize these subgroups by their differences in HLA-DRB1 genotypes, cytokine signatures, clinical manifestations, and flare incidence. Methods We conducted a retrospective study of 102 cSLE patients. An unsupervised two-step cluster analysis was performed using nine routinely measured autoantibodies. The resulting subgroups were compared for clinical features, HLA-DRB1 allele frequencies, serum cytokine levels, and flare-free survival using Kaplan–Meier analysis. Results Cluster analysis identified two distinct subgroups. Subgroup 2, characterized by anti-Sm/RNP positivity, demonstrated significantly more severe disease, including higher rates of lupus nephritis, neuropsychiatric involvement, and elevated SLE disease activity index (SLEDAI) scores at diagnosis compared to subgroup 1 (anti-Sm/RNP-negative). Genetically, subgroup 2 was enriched with the HLA-DRB1*15 and * 09 alleles. Immunologically, subgroup 2 exhibited significantly elevated IFN-α levels. Despite more frequent use of belimumab, subgroup 2 had a significantly lower flare-free survival rate than subgroup 1 ( P 0.001). Conclusion Autoantibody-based stratification effectively delineates two cSLE subgroups with distinct genetic, immunological, and clinical trajectories. The anti-Sm/RNP positive subgroup, defined by HLA-DRB1*15/09 risk alleles and a high IFN-α signature, represents a more severe phenotype with a higher risk of flare, potentially explaining the suboptimal response to belimumab in this group.
Bao et al. (Mon,) studied this question.