The heterogeneity of systemic lupus erythematosus (SLE) constitutes clinical and therapeutical challenges. We therefore studied whether unrecognized disease subgroups can be identified by using autoantibody profiling together with HLA‐DRB1 alleles and immunological and clinical data.

An unsupervised cluster analysis was performed based on detection of 13 SLE‐associated autoantibodies (double‐stranded DNA, nucleosomes, ribosomal P, ribonucleoprotein [RNP] 68, RNPA, Smith [Sm], Sm/RNP, Sjögren's syndrome antigen A [SSA]/Ro52, SSA/Ro60, Sjögren's syndrome antigen B [SSB]/La, cardiolipin [CL]‐Immunoglobulin G [IgG], CL–Immunoglobulin M [IgM], and β₂ glycoprotein I [β₂GPI]–IgG) in 911 patients with SLE from two cohorts. We evaluated whether each SLE subgroup is associated with HLA‐DRB1 alleles, clinical manifestations (n = 743), and cytokine levels in circulation (n = 446).

Our analysis identified four subgroups among the patients with SLE. Subgroup 1 (29.3%) was dominated by anti‐SSA/Ro60/Ro52/SSB autoantibodies and was strongly associated with HLA‐DRB1*03 (odds ratio [OR] = 4.73; 95% confidence interval [CI] = 4.52‐4.94). Discoid lesions were more common for this disease subgroup (OR = 1.71, 95% CI = 1.18‐2.47). Subgroup 2 (28.7%) was dominated by anti‐nucleosome/SmRNP/DNA/RNPA autoantibodies and associated with HLA‐DRB1*15 (OR = 1.62, 95% CI = 1.41‐1.84). Nephritis was most common in this subgroup (OR = 1.61, 95% CI = 1.14‐2.26). Subgroup 3 (23.8%) was characterized by anti‐ß₂GPI‐IgG/anti‐CL–IgG/IgM autoantibodies and a higher frequency of HLA‐DRB1*04 compared with the other patients with SLE. Vascular events were more common in Subgroup 3 (OR = 1.74, 95% CI = 1.2‐2.5). Subgroup 4 (18.2%) was negative for the investigated autoantibodies, and this subgroup was not associated with HLA‐DRB1. Additionally, the levels of eight cytokines significantly differed among the disease subgroups.

Our findings suggest that four fairly distinct subgroups can be identified on the basis of the autoantibody profile in SLE. These four SLE subgroups differ regarding associations with HLA‐DRB1 alleles and immunological and clinical features, suggesting dissimilar disease pathways.