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journal article Open Access Oct 17, 2021

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

Lina‐Marcela Diaz‐Gallo ORCID Vilija Oke ORCID Emeli Lundström Kerstin Elvin Yee Ling Wu Susanna Eketjäll Agneta Zickert Johanna T. Gustafsson Andreas Jönsen Dag Leonard Daniel J. Birmingham ORCID Gunnel Nordmark Anders A. Bengtsson Lars Rönnblom ORCID Iva Gunnarsson Chack‐Yung Yu Leonid Padyukov ORCID Elisabet Svenungsson ORCID
ACR Open Rheumatology Vol. 4 No. 1 pp. 27-39 · Wiley
View at Publisher Save 10.1002/acr2.11343
Abstract
ObjectiveThe 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.MethodsAn 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).ResultsOur 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.ConclusionOur 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.
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Details
Published
Oct 17, 2021
Vol/Issue
4(1)
Pages
27-39
License
View
Authors
L
Lina‐Marcela Diaz‐Gallo

Division of Rheumatology Department of Medicine Solna Karolinska Institutet Karolinksa University Hospital Stockholm Sweden; Center for Molecular Medicine Karolinska Institutet Karolinska University Hospital Stockholm Sweden

V
Vilija Oke

Division of Rheumatology Department of Medicine Solna Karolinska Institutet Karolinksa University Hospital Stockholm Sweden; Center for Molecular Medicine Karolinska Institutet Karolinska University Hospital Stockholm Sweden

E
Emeli Lundström

Division of Rheumatology Department of Medicine Solna Karolinska Institutet Karolinksa University Hospital Stockholm Sweden; Center for Molecular Medicine Karolinska Institutet Karolinska University Hospital Stockholm Sweden

K
Kerstin Elvin

Department of Clinical Immunology and Transfusion Medicine Unit of Clinical Immunology Karolinska Institutet Karolinska University Hospital Stockholm Sweden

Y
Yee Ling Wu

The Research Institute at Nationwide Children’s Hospital Columbus Ohio; Department of Microbiology and Immunology Loyola University Chicago lk Illinois

S
Susanna Eketjäll

Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden

A
Agneta Zickert

Division of Rheumatology Department of Medicine Solna Karolinska Institutet Karolinksa University Hospital Stockholm Sweden

J
Johanna T. Gustafsson

Division of Rheumatology Department of Medicine Solna Karolinska Institutet Karolinksa University Hospital Stockholm Sweden

A
Andreas Jönsen

Department of Clinical Sciences Section of Rheumatology Lund University Skåne University Hospital Lund Sweden

D
Dag Leonard

Department of Medical Sciences Section of Rheumatology Uppsala University Uppsala Sweden

D
Daniel J. Birmingham

Department of Internal Medicine The Ohio State University Columbus Ohio

G
Gunnel Nordmark

Department of Medical Sciences Section of Rheumatology Uppsala University Uppsala Sweden

A
Anders A. Bengtsson

Department of Clinical Sciences Section of Rheumatology Lund University Skåne University Hospital Lund Sweden

L
Lars Rönnblom

Department of Medical Sciences Section of Rheumatology Uppsala University Uppsala Sweden

I
Iva Gunnarsson

Division of Rheumatology Department of Medicine Solna Karolinska Institutet Karolinksa University Hospital Stockholm Sweden

C
Chack‐Yung Yu

The Research Institute at Nationwide Children’s Hospital Columbus Ohio

L
Leonid Padyukov

Division of Rheumatology Department of Medicine Solna Karolinska Institutet Karolinksa University Hospital Stockholm Sweden; Center for Molecular Medicine Karolinska Institutet Karolinska University Hospital Stockholm Sweden

E
Elisabet Svenungsson

Division of Rheumatology Department of Medicine Solna Karolinska Institutet Karolinksa University Hospital Stockholm Sweden

Funding
Vetenskapsrådet Award: 2014‐33867
Hjärt-Lungfonden Award: 20170257
Stockholms Läns Landsting Award: 20170038
Stiftelsen Professor Nanna Svartz Fond Award: 2019‐00318
Ulla och Gustaf af Ugglas Stiftelse Award: 2018‐02670
Cite This Article
Lina‐Marcela Diaz‐Gallo, Vilija Oke, Emeli Lundström, et al. (2021). Four Systemic Lupus Erythematosus Subgroups, Defined by Autoantibodies Status, Differ Regarding HLA‐DRB1 Genotype Associations and Immunological and Clinical Manifestations. ACR Open Rheumatology, 4(1), 27-39. https://doi.org/10.1002/acr2.11343
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