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Arthritis Res Ther. 2019 Feb 18;21(1):62. doi: 10.1186/s13075-019-1836-8.

Two subgroups in systemic lupus erythematosus with features of antiphospholipid or Sjögren's syndrome differ in molecular signatures and treatment perspectives.

Author information

1
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 171 76, Stockholm, Sweden.
2
Division of Affinity Proteomics, SciLifeLab, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.
3
Clinical Proteomics Mass Spectrometry, Department of Oncology-Pathology, Science for Life Laboratory and Karolinska Institutet, Stockholm, Sweden.
4
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
5
Unit of Clinical Immunology, Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Karolinska Institutet, Solna, Stockholm, Sweden.
6
Section of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Lund University, Lund, Sweden.
7
Patient Safety Respiratory, Inflammation, Autoimmunity, Infection and Vaccines, AstraZeneca R&D, Gothenburg, Sweden.
8
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 171 76, Stockholm, Sweden. elisabet.svenungsson@ki.se.
9
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 171 76, Stockholm, Sweden. per-johan.jakobsson@ki.se.

Abstract

BACKGROUND:

Previous studies and own clinical observations of patients with systemic lupus erythematosus (SLE) suggest that SLE harbors distinct immunophenotypes. This heterogeneity might result in differences in response to treatment in different subgroups and obstruct clinical trials. Our aim was to understand how SLE subgroups may differ regarding underlying pathophysiology and characteristic biomarkers.

METHODS:

In a cross-sectional study, including 378 well-characterized SLE patients and 316 individually matched population controls, we defined subgroups based on the patients' autoantibody profile at inclusion. We selected a core of an antiphospholipid syndrome-like SLE (aPL+ group; positive in the lupus anticoagulant (LA) test and negative for all three of SSA (Ro52 and Ro60) and SSB antibodies) and a Sjögren's syndrome-like SLE (SSA/SSB+ group; positive for all three of SSA (Ro52 and Ro60) and SSB antibodies but negative in the LA test). We applied affinity-based proteomics, targeting 281 proteins, together with well-established clinical biomarkers and complementary immunoassays to explore the difference between the two predefined SLE subgroups.

RESULTS:

The aPL+ group comprised 66 and the SSA/SSB+ group 63 patients. The protein with the highest prediction power (receiver operating characteristic (ROC) area under the curve = 0.89) for separating the aPL+ and SSA/SSB+ SLE subgroups was integrin beta-1 (ITGB1), with higher levels present in the SSA/SSB+ subgroup. Proteins with the lowest p values comparing the two SLE subgroups were ITGB1, SLC13A3, and CERS5. These three proteins, rheumatoid factor, and immunoglobulin G (IgG) were all increased in the SSA/SSB+ subgroup. This subgroup was also characterized by a possible activation of the interferon system as measured by high KRT7, TYK2, and ETV7 in plasma. In the aPL+ subgroup, complement activation was more pronounced together with several biomarkers associated with systemic inflammation (fibrinogen, α-1 antitrypsin, neutrophils, and triglycerides).

CONCLUSIONS:

Our observations indicate underlying pathogenic differences between the SSA/SSB+ and the aPL+ SLE subgroups, suggesting that the SSA/SSB+ subgroup may benefit from IFN-blocking therapies while the aPL+ subgroup is more likely to have an effect from drugs targeting the complement system. Stratifying SLE patients based on an autoantibody profile could be a way forward to understand underlying pathophysiology and to improve selection of patients for clinical trials of targeted treatments.

KEYWORDS:

Affinity-based proteomics; Antiphospholipid syndrome; Personalized medicine; Sjögren’s syndrome; Subgroups; Systemic lupus erythematosus

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