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Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome

Thorlacius, Guðný Ella ; Hultin-Rosenberg, Lina ; Sandling, Johanna K ; Bianchi, Matteo ; Imgenberg-Kreuz, Juliana ; Pucholt, Pascal ; Theander, Elke LU ; Kvarnström, Marika ; Forsblad-d'Elia, Helena and Bucher, Sara Magnusson , et al. (2020) In Rheumatology (Oxford, England)
Abstract

OBJECTIVES: Clinical presentation of primary Sjögren's syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints.

METHODS: We performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls.

RESULTS: We found strong signals of association with pSS in the HLA region. Principal component analysis... (More)

OBJECTIVES: Clinical presentation of primary Sjögren's syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints.

METHODS: We performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls.

RESULTS: We found strong signals of association with pSS in the HLA region. Principal component analysis of clinical data distinguished two patient subgroups defined by the presence of SSA/SSB antibodies. We observed an unprecedented high risk of pSS for an association in the HLA-DQA1 locus of odds ratio 6.10 (95% CI: 4.93, 7.54, P=2.2×10-62) in the SSA/SSB-positive subgroup, while absent in the antibody negative group. Three independent signals within the MHC were observed. The two most significant variants in MHC class I and II respectively, identified patients with a higher risk of hypergammaglobulinaemia, leukopenia, anaemia, purpura, major salivary gland swelling and lymphadenopathy. Replication confirmed the association with both MHC class I and II signals confined to SSA/SSB antibody positive pSS.

CONCLUSION: Two subgroups of patients with pSS with distinct clinical manifestations can be defined by the presence or absence of SSA/SSB antibodies and genetic markers in the HLA locus. These subgroups should be considered in clinical follow-up, drug development and trial outcomes, for the benefit of both subgroups.

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publishing date
type
Contribution to journal
publication status
epub
subject
in
Rheumatology (Oxford, England)
publisher
Oxford University Press
external identifiers
  • scopus:85102212000
  • pmid:32889544
ISSN
1462-0332
DOI
10.1093/rheumatology/keaa367
language
English
LU publication?
no
additional info
© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.
id
3646e536-15d2-4a73-8292-3d59accc268b
date added to LUP
2020-09-09 19:23:07
date last changed
2022-06-28 22:59:03
@article{3646e536-15d2-4a73-8292-3d59accc268b,
  abstract     = {{<p>OBJECTIVES: Clinical presentation of primary Sjögren's syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints.</p><p>METHODS: We performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls.</p><p>RESULTS: We found strong signals of association with pSS in the HLA region. Principal component analysis of clinical data distinguished two patient subgroups defined by the presence of SSA/SSB antibodies. We observed an unprecedented high risk of pSS for an association in the HLA-DQA1 locus of odds ratio 6.10 (95% CI: 4.93, 7.54, P=2.2×10-62) in the SSA/SSB-positive subgroup, while absent in the antibody negative group. Three independent signals within the MHC were observed. The two most significant variants in MHC class I and II respectively, identified patients with a higher risk of hypergammaglobulinaemia, leukopenia, anaemia, purpura, major salivary gland swelling and lymphadenopathy. Replication confirmed the association with both MHC class I and II signals confined to SSA/SSB antibody positive pSS.</p><p>CONCLUSION: Two subgroups of patients with pSS with distinct clinical manifestations can be defined by the presence or absence of SSA/SSB antibodies and genetic markers in the HLA locus. These subgroups should be considered in clinical follow-up, drug development and trial outcomes, for the benefit of both subgroups.</p>}},
  author       = {{Thorlacius, Guðný Ella and Hultin-Rosenberg, Lina and Sandling, Johanna K and Bianchi, Matteo and Imgenberg-Kreuz, Juliana and Pucholt, Pascal and Theander, Elke and Kvarnström, Marika and Forsblad-d'Elia, Helena and Bucher, Sara Magnusson and Norheim, Katrine B and Johnsen, Svein Joar Auglænd and Hammenfors, Daniel and Skarstein, Kathrine and Jonsson, Malin V and Baecklund, Eva and Aqrawi, Lara A and Jensen, Janicke Liaaen and Palm, Øyvind and Morris, Andrew P and Meadows, Jennifer R S and Rantapää-Dahlqvist, Solbritt and Mandl, Thomas and Eriksson, Per and Lind, Lars and Omdal, Roald and Jonsson, Roland and Lindblad-Toh, Kerstin and Rönnblom, Lars and Wahren-Herlenius, Marie and Nordmark, Gunnel}},
  issn         = {{1462-0332}},
  language     = {{eng}},
  month        = {{08}},
  publisher    = {{Oxford University Press}},
  series       = {{Rheumatology (Oxford, England)}},
  title        = {{Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome}},
  url          = {{http://dx.doi.org/10.1093/rheumatology/keaa367}},
  doi          = {{10.1093/rheumatology/keaa367}},
  year         = {{2020}},
}