# Subgroups based on autoantibody status associated with clinical manifestations, HLA-DRB1 variants, cytokines, and flare of vasculitis in childhood-onset systemic lupus erythematosus

## TL;DR

This study identifies two distinct subgroups of childhood-onset lupus based on autoantibodies, with one subgroup showing more severe disease and different genetic and immune features.

## Contribution

The study introduces a novel autoantibody-based stratification method for cSLE, linking it to HLA-DRB1 alleles, cytokine profiles, and flare risk.

## Key findings

- Anti-Sm/RNP-positive subgroup has more severe disease, higher lupus nephritis, and neuropsychiatric involvement.
- Subgroup 2 is enriched with HLA-DRB1*15 and *09 alleles and has elevated IFN-α levels.
- Subgroup 2 has lower flare-free survival despite more frequent belimumab use.

## Abstract

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.

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.

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).

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.