Four Systemic Lupus Erythematosus Subgroups, Defined by Autoantibodies Status, Differ Regarding HLA‐DRB1 Genotype Associations and Immunological and Clinical Manifestations

Abstract

Objective. 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.Methods. 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, and β 2 glycoprotein I [β 2 GPI]-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).Results. 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-ß 2 GPI-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.Conclusion. 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.

Antibodies to Porphyromonas gingivalis Are Increased in Patients with Severe Periodontitis, and Associate with Presence of Specific Autoantibodies and Myocardial Infarction

“…However, in contrast to the other study [30], we did not observe any association between anti-Pg antibodies and SLE per se or SLE disease activity. This discrepancy may be related to statistical power, since the other study was larger than ours (n = 303 versus n = 101), or to the type of SLE patients included, as SLE is a notoriously heterogenous disease [46]. We found no association between elevated anti-Rgp IgG levels and presence of autoantibodies in general, including RF, ANA and aPL antibodies, in any of the two cohorts investigated.…”

Remission and clinical patterns of systemic lupus erythematosus (SLE) in Pakistan: a retrospective cohort study

“…We show using factor analysis that SLE in our cohort demonstrated 4 clinical and 3 antibody-based subtypes. Recently, Diaz-Gallo et al showed that 4 SLE subgroups based on autoantibody profile could be distinguished (13). Idborg et al showed that there were differences at the proteomic level based on SLE antibody profile (15).…”

“…Given the complex heterogeneity of SLE, several studies have attempted to classify the disease into subgroups for purposes of improved clinical management. These subgroups have been based on clinical patterns (13,14), auto-antibody profiling (13)(14)(15), organ domains (16), flares (17,18), remission patterns (19), and treatment response (20). Using unsupervised cluster analysis, Diaz-Gallo et al (13) identified four distinct subgroups based on auto-antibody profiling.…”

“…These subgroups have been based on clinical patterns (13,14), auto-antibody profiling (13)(14)(15), organ domains (16), flares (17,18), remission patterns (19), and treatment response (20). Using unsupervised cluster analysis, Diaz-Gallo et al (13) identified four distinct subgroups based on auto-antibody profiling. Interestingly, these subgroups also had differential clinical patterns indicating that SLE may exist as distinct sub-phenotypes.…”

The long and winding road: From mouse linkage studies to a novel human therapeutic pathway in type 1 diabetes

“…Different ADs share risk factors (e.g., environmental and genetic) and immunological mechanisms (4). A single autoimmune disease may manifest with autoantibodies of diverse organ specificities (i.e., latent polyautoimmunity) (5)(6)(7). Polymorphisms in HLA-DRB1, HLA-DQB1, CD226, PTPN22, STAT4, GPR103, TNFAIP3, and LRP1/STAT6 are associated with multiple ADs (8,9), including systemic and organ-specific ADs (10).…”