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Objectives Autoantibody profiling has revealed clinically meaningful systemic lupus erythematosus (SLE) subgroups in Caucasian descendant cohorts, contributing to decreased disease heterogeneity. Validation in non-European populations is essential for broader applicability. We aimed to define autoantibody-based subgroups in Malay SLE patients.Methods We studied 239 Malay patients fulfilling clinical SLE criteria. Serum samples were tested for 21 SLE-associated autoantibodies using the immunoblot and ELISA methods. Sociodemographic, lifestyle, clinical, and treatment data were collected systematically using a structured form. Subgroups were identified through unsupervised clustering, by applying the partitioning around medoids (PAM) algorithm to a Gower dissimilarity matrix constructed from 21 autoantibody positivity. Autoantibody feature importance was assessed with a random forest classifier. Associations with disease activity (SLEDAI-2K), clinical manifestations, and treatment were examined using logistic regression.Results Unsupervised clustering analysis identified four distinct subgroups: Subgroup 1 (41.4%) characterized by anti-nRNP/Sm IgM (55.6%); Subgroup 2 (26.8%) by anti-SSA/Ro60 IgG (85.9%) and anti-Ro52 IgG (75.6%); Subgroup 3 (12.1%) by anti-nucleosome IgG (93.1%), anti-histone IgG (93.1%), and anti-nRNP/Sm (86.2%); and Subgroup 4 (19.7%) was negative for the tested autoantibodies ( figure 1). Disease activity (SLEDAI-2K) was significantly higher in Subgroups 2 (Padj=0.02) and 3 (Padj<0.001) compared to Subgroup 4, while Subgroup 1 showed lower activity than Subgroup 4 (Padj=0.01). Subgroup 3 was strongly associated with mucocutaneous manifestations (OR 10.8, 95% CI 2.8–56.3) and renal involvement (OR 8.3, 95% CI 1.1–171.0). Treatment associations showed Subgroup 3 was linked to glucocorticoid use (OR 6.57, 95% CI 2.23–22.59) and methotrexate (OR 13.17, 95% CI 2.12–225.82), while Subgroup 2 was associated with glucocorticoids (OR 2.20, 95% CI 1.01–4.86) and azathioprine (OR 2.52, 95% CI 1.05–6.46). No associations were observed with hydroxychloroquine use.Abstract PO:02:032 Figure 1Conclusions Autoantibody-defined subgroups in Malay SLE patients demonstrated distinct clinical characteristics and treatment patterns. Subgroups 2 (anti-SSA/Ro60) and 3 (anti-nucleosome, anti-histone, anti-nRNP/Sm) were associated with higher disease activity and greater use of immunosuppressants. These findings support the utility of autoantibody profiling for patient stratification and management in diverse populations.