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

Idborg, Helena; Zandian, Arash; Sandberg, Ann Sofi; Nilsson, Bo; Elvin, Kerstin; Truedsson, Lennart LU ; Sohrabian, Azita; Rönnelid, Johan; Mo, John and Grosso, Giorgia, et al. (2019) In Arthritis Research and Therapy 21(1).
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... (More)

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.

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keywords
Affinity-based proteomics, Antiphospholipid syndrome, Personalized medicine, Sjögren's syndrome, Subgroups, Systemic lupus erythematosus
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Arthritis Research and Therapy
volume
21
issue
1
publisher
BioMed Central
external identifiers
  • scopus:85061844312
ISSN
1478-6354
DOI
10.1186/s13075-019-1836-8
language
English
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yes
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35493e80-d840-4deb-ac5f-3e1342de9c49
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2019-03-01 13:26:01
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2019-07-21 05:13:54
@article{35493e80-d840-4deb-ac5f-3e1342de9c49,
  abstract     = {<p>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.</p>},
  articleno    = {62},
  author       = {Idborg, Helena and Zandian, Arash and Sandberg, Ann Sofi and Nilsson, Bo and Elvin, Kerstin and Truedsson, Lennart and Sohrabian, Azita and Rönnelid, Johan and Mo, John and Grosso, Giorgia and Kvarnström, Marika and Gunnarsson, Iva and Lehtiö, Janne and Nilsson, Peter and Svenungsson, Elisabet and Jakobsson, Per Johan},
  issn         = {1478-6354},
  keyword      = {Affinity-based proteomics,Antiphospholipid syndrome,Personalized medicine,Sjögren's syndrome,Subgroups,Systemic lupus erythematosus},
  language     = {eng},
  month        = {02},
  number       = {1},
  publisher    = {BioMed Central},
  series       = {Arthritis Research and Therapy},
  title        = {Two subgroups in systemic lupus erythematosus with features of antiphospholipid or Sjögren's syndrome differ in molecular signatures and treatment perspectives},
  url          = {http://dx.doi.org/10.1186/s13075-019-1836-8},
  volume       = {21},
  year         = {2019},
}