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We therefore studied whether unrecognized disease subgroups can be identified by using autoantibody profiling together with <jats:italic>HLA\u2010DRB1<\/jats:italic> alleles and immunological and clinical data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An unsupervised cluster analysis was performed based on detection of 13 SLE\u2010associated autoantibodies (double\u2010stranded DNA, nucleosomes, ribosomal P, ribonucleoprotein [RNP] 68, RNPA, Smith [Sm], Sm\/RNP, Sj\u00f6gren's syndrome antigen A [SSA]\/Ro52, SSA\/Ro60, Sj\u00f6gren's syndrome antigen B [SSB]\/La, cardiolipin [CL]\u2010Immunoglobulin G [IgG], CL\u2013Immunoglobulin M [IgM], and \u03b2<jats:sub>2<\/jats:sub> glycoprotein I [\u03b2<jats:sub>2<\/jats:sub>GPI]\u2013IgG) in 911 patients with SLE from two cohorts. We evaluated whether each SLE subgroup is associated with <jats:italic>HLA\u2010DRB1<\/jats:italic> alleles, clinical manifestations (n = 743), and cytokine levels in circulation (n = 446).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our analysis identified four subgroups among the patients with SLE. Subgroup 1 (29.3%) was dominated by anti\u2010SSA\/Ro60\/Ro52\/SSB autoantibodies and was strongly associated with <jats:italic>HLA\u2010DRB1*03<\/jats:italic> (odds ratio [OR] = 4.73; 95% confidence interval [CI] = 4.52\u20104.94). Discoid lesions were more common for this disease subgroup (OR = 1.71, 95% CI = 1.18\u20102.47). Subgroup 2 (28.7%) was dominated by anti\u2010nucleosome\/SmRNP\/DNA\/RNPA autoantibodies and associated with <jats:italic>HLA\u2010DRB1*15<\/jats:italic> (OR = 1.62, 95% CI = 1.41\u20101.84). Nephritis was most common in this subgroup (OR = 1.61, 95% CI = 1.14\u20102.26). Subgroup 3 (23.8%) was characterized by anti\u2010\u00df<jats:sub>2<\/jats:sub>GPI\u2010IgG\/anti\u2010CL\u2013IgG\/IgM autoantibodies and a higher frequency of <jats:italic>HLA\u2010DRB1*04<\/jats:italic> compared with the other patients with SLE. Vascular events were more common in Subgroup 3 (OR = 1.74, 95% CI = 1.2\u20102.5). Subgroup 4 (18.2%) was negative for the investigated autoantibodies, and this subgroup was not associated with <jats:italic>HLA\u2010DRB1<\/jats:italic>. Additionally, the levels of eight cytokines significantly differed among the disease subgroups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings suggest that four fairly distinct subgroups can be identified on the basis of the autoantibody profile in SLE. 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