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

Guðný Ella Thorlacius; Lina Hultin-Rosenberg; Johanna K. Sandling; Matteo Bianchi; Juliana Imgenberg-Kreuz; Pascal Pucholt; Elke Theander; Marika Kvarnström; Helena Forsblad-D'elia; Sara Magnusson Bucher; Katrine B. Norheim; Svein Joar Auglænd Johnsen; Daniel Hammenfors; Kathrine Skarstein; Malin V. Jonsson; Eva Baecklund; Lara A. Aqrawi; Janicke Liaaen Jensen; Øyvind Palm; Andrew P. Morris; Andrei Alexsson; Pascal Pucholt; Carin Backlin; Eva Baecklund; Johanna K. Sandling; Juliana Imgenberg-Kreuz; Lars Rönnblom; Lilian Vasaitis; Maija Leena Eloranta; Ann Christine Syvänen; Argyri Mathioudaki; Fabiana H.G. Farias; Jennifer Meadows; Jessika Nordin; Lina Hultin-Rosenberg; Matteo Bianchi; Kerstin Lindblad-Toh; Albin Björk; Guðný Ella Thorlacius; Ingrid E. Lundberg; Jorge I.Ramírez Sepúlveda; Marie Wahren-Herlenius; Marika Kvarnström; Daniel Eriksson; Helena Forsblad-D'elia; Per Eriksson; Christopher Sjöwall; Elke Theander; Thomas Mandl; Solbritt Rantapaä¨-Dahlqvist; Sara Magnusson Bucher; Daniel Hammenfors; Karl A. Brokstad; Kathrine Skarstein; Roland Jonsson; Silke Appel; Malin V. Jonsson; Johan G. Brun; Katrine Brække Norheim; Roald Omdal; Svein Joar Auglænd Johnsen; Øyvind Palm; Janicke Liaaen Jensen; Lara Adnan Aqrawi; Kerstin Lindblad-Toh; Gerli Rosengren Pielberg; Eva Murén; Åsa Karlsson; Göran Andersson; Kerstin M. Ahlgren; Anna Lobell; Lars Rönnblom; Maija Leena Eloranta; Peter Söderkvist; Olle Kämpe; Nils Landegren; Jennifer R.S. Meadows; Solbritt Rantapaä¨-Dahlqvist; Thomas Mandl; Per Eriksson; Lars Lind; Roald Omdal; Roland Jonsson; Kerstin Lindblad-Toh; Lars Rönnblom; Marie Wahren-Herlenius; Gunnel Nordmark

doi:10.1093/rheumatology/keaa367

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

Guðný Ella Thorlacius, Lina Hultin-Rosenberg, Johanna K. Sandling, Matteo Bianchi, Juliana Imgenberg-Kreuz, Pascal Pucholt, Elke Theander, Marika Kvarnström, Helena Forsblad-D'elia, Sara Magnusson Bucher, Katrine B. Norheim, Svein Joar Auglænd Johnsen, Daniel Hammenfors, Kathrine Skarstein, Malin V. Jonsson, Eva Baecklund, Lara A. Aqrawi, Janicke Liaaen Jensen, Øyvind Palm, Andrew P. MorrisAndrei Alexsson, Pascal Pucholt, Carin Backlin, Eva Baecklund, Johanna K. Sandling, Juliana Imgenberg-Kreuz, Lars Rönnblom, Lilian Vasaitis, Maija Leena Eloranta, Ann Christine Syvänen, Argyri Mathioudaki, Fabiana H.G. Farias, Jennifer Meadows, Jessika Nordin, Lina Hultin-Rosenberg, Matteo Bianchi, Kerstin Lindblad-Toh, Albin Björk, Guðný Ella Thorlacius, Ingrid E. Lundberg, Jorge I.Ramírez Sepúlveda, Marie Wahren-Herlenius, Marika Kvarnström, Daniel Eriksson, Helena Forsblad-D'elia, Per Eriksson, Christopher Sjöwall, Elke Theander, Thomas Mandl, Solbritt Rantapaä¨-Dahlqvist, Sara Magnusson Bucher, Daniel Hammenfors, Karl A. Brokstad, Kathrine Skarstein, Roland Jonsson, Silke Appel, Malin V. Jonsson, Johan G. Brun, Katrine Brække Norheim, Roald Omdal, Svein Joar Auglænd Johnsen, Øyvind Palm, Janicke Liaaen Jensen, Lara Adnan Aqrawi, Kerstin Lindblad-Toh, Gerli Rosengren Pielberg, Eva Murén, Åsa Karlsson, Göran Andersson, Kerstin M. Ahlgren, Anna Lobell, Lars Rönnblom, Maija Leena Eloranta, Peter Söderkvist, Olle Kämpe, Nils Landegren, Jennifer R.S. Meadows, Solbritt Rantapaä¨-Dahlqvist, Thomas Mandl, Per Eriksson, Lars Lind, Roald Omdal, Roland Jonsson, Kerstin Lindblad-Toh, Lars Rönnblom, Marie Wahren-Herlenius, Gunnel Nordmark^*

^*Corresponding author for this work

Division of Musculoskeletal & Dermatological Sciences (L5)

Research output: Contribution to journal › Article › peer-review

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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 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.

Original language	English
Pages (from-to)	837-848
Number of pages	12
Journal	Rheumatology (United Kingdom)
Volume	60
Issue number	2
Early online date	21 Aug 2020
DOIs	https://doi.org/10.1093/rheumatology/keaa367
Publication status	Published - 1 Feb 2021

Keywords

autoantibodies
autoimmunity
gene polymorphism
Sjögren's syndrome

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Thorlacius, G. E., Hultin-Rosenberg, L., Sandling, J. K., Bianchi, M., Imgenberg-Kreuz, J., Pucholt, P., Theander, E., Kvarnström, M., Forsblad-D'elia, H., Bucher, S. M., Norheim, K. B., Johnsen, S. J. A., Hammenfors, D., Skarstein, K., Jonsson, M. V., Baecklund, E., Aqrawi, L. A., Jensen, J. L., Palm, Ø., ... Nordmark, G. (2021). Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome. Rheumatology (United Kingdom), 60(2), 837-848. https://doi.org/10.1093/rheumatology/keaa367

@article{aa0cfa72038c4febb67872da076a20c1,

title = "Genetic and clinical basis for two distinct subtypes of primary Sj{\"o}gren's syndrome",

abstract = "Objectives: Clinical presentation of primary Sj{\"o}gren'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.",

keywords = "autoantibodies, autoimmunity, gene polymorphism, Sj{\"o}gren's syndrome",

author = "Thorlacius, {Gu{\dh}n{\'y} Ella} and Lina Hultin-Rosenberg and Sandling, {Johanna K.} and Matteo Bianchi and Juliana Imgenberg-Kreuz and Pascal Pucholt and Elke Theander and Marika Kvarnstr{\"o}m and Helena Forsblad-D'elia and Bucher, {Sara Magnusson} and Norheim, {Katrine B.} and Johnsen, {Svein Joar Augl{\ae}nd} and Daniel Hammenfors and Kathrine Skarstein and Jonsson, {Malin V.} and Eva Baecklund and Aqrawi, {Lara A.} and Jensen, {Janicke Liaaen} and {\O}yvind Palm and Morris, {Andrew P.} and Andrei Alexsson and Pascal Pucholt and Carin Backlin and Eva Baecklund and Sandling, {Johanna K.} and Juliana Imgenberg-Kreuz and Lars R{\"o}nnblom and Lilian Vasaitis and Eloranta, {Maija Leena} and Syv{\"a}nen, {Ann Christine} and Argyri Mathioudaki and Farias, {Fabiana H.G.} and Jennifer Meadows and Jessika Nordin and Lina Hultin-Rosenberg and Matteo Bianchi and Kerstin Lindblad-Toh and Albin Bj{\"o}rk and Thorlacius, {Gu{\dh}n{\'y} Ella} and Lundberg, {Ingrid E.} and Sep{\'u}lveda, {Jorge I.Ram{\'i}rez} and Marie Wahren-Herlenius and Marika Kvarnstr{\"o}m and Daniel Eriksson and Helena Forsblad-D'elia and Per Eriksson and Christopher Sj{\"o}wall and Elke Theander and Thomas Mandl and Solbritt Rantapa{\"a}¨-Dahlqvist and Bucher, {Sara Magnusson} and Daniel Hammenfors and Brokstad, {Karl A.} and Kathrine Skarstein and Roland Jonsson and Silke Appel and Jonsson, {Malin V.} and Brun, {Johan G.} and Norheim, {Katrine Br{\ae}kke} and Roald Omdal and Johnsen, {Svein Joar Augl{\ae}nd} and {\O}yvind Palm and Jensen, {Janicke Liaaen} and Aqrawi, {Lara Adnan} and Kerstin Lindblad-Toh and Pielberg, {Gerli Rosengren} and Eva Mur{\'e}n and {\AA}sa Karlsson and G{\"o}ran Andersson and Ahlgren, {Kerstin M.} and Anna Lobell and Lars R{\"o}nnblom and Eloranta, {Maija Leena} and Peter S{\"o}derkvist and Olle K{\"a}mpe and Nils Landegren and Meadows, {Jennifer R.S.} and Solbritt Rantapa{\"a}¨-Dahlqvist and Thomas Mandl and Per Eriksson and Lars Lind and Roald Omdal and Roland Jonsson and Kerstin Lindblad-Toh and Lars R{\"o}nnblom and Marie Wahren-Herlenius and Gunnel Nordmark",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s). Published by Oxford University Press on behalf of the British Society for Rheumatology.",

year = "2021",

month = feb,

day = "1",

doi = "10.1093/rheumatology/keaa367",

language = "English",

volume = "60",

pages = "837--848",

journal = "Rheumatology (United Kingdom)",

issn = "1462-0324",

publisher = "Oxford University Press",

number = "2",

}

Thorlacius, GE, Hultin-Rosenberg, L, Sandling, JK, Bianchi, M, Imgenberg-Kreuz, J, Pucholt, P, Theander, E, Kvarnström, M, Forsblad-D'elia, H, Bucher, SM, Norheim, KB, Johnsen, SJA, Hammenfors, D, Skarstein, K, Jonsson, MV, Baecklund, E, Aqrawi, LA, Jensen, JL, Palm, Ø, Morris, AP, Alexsson, A, Pucholt, P, Backlin, C, Baecklund, E, Sandling, JK, Imgenberg-Kreuz, J, Rönnblom, L, Vasaitis, L, Eloranta, ML, Syvänen, AC, Mathioudaki, A, Farias, FHG, Meadows, J, Nordin, J, Hultin-Rosenberg, L, Bianchi, M, Lindblad-Toh, K, Björk, A, Thorlacius, GE, Lundberg, IE, Sepúlveda, JIR, Wahren-Herlenius, M, Kvarnström, M, Eriksson, D, Forsblad-D'elia, H, Eriksson, P, Sjöwall, C, Theander, E, Mandl, T, Rantapaä¨-Dahlqvist, S, Bucher, SM, Hammenfors, D, Brokstad, KA, Skarstein, K, Jonsson, R, Appel, S, Jonsson, MV, Brun, JG, Norheim, KB, Omdal, R, Johnsen, SJA, Palm, Ø, Jensen, JL, Aqrawi, LA, Lindblad-Toh, K, Pielberg, GR, Murén, E, Karlsson, Å, Andersson, G, Ahlgren, KM, Lobell, A, Rönnblom, L, Eloranta, ML, Söderkvist, P, Kämpe, O, Landegren, N, Meadows, JRS, Rantapaä¨-Dahlqvist, S, Mandl, T, Eriksson, P, Lind, L, Omdal, R, Jonsson, R, Lindblad-Toh, K, Rönnblom, L, Wahren-Herlenius, M & Nordmark, G 2021, 'Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome', Rheumatology (United Kingdom), vol. 60, no. 2, pp. 837-848. https://doi.org/10.1093/rheumatology/keaa367

TY - JOUR

T1 - Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome

AU - Thorlacius, Guðný Ella

AU - Hultin-Rosenberg, Lina

AU - Sandling, Johanna K.

AU - Bianchi, Matteo

AU - Imgenberg-Kreuz, Juliana

AU - Pucholt, Pascal

AU - Theander, Elke

AU - Kvarnström, Marika

AU - Forsblad-D'elia, Helena

AU - Bucher, Sara Magnusson

AU - Norheim, Katrine B.

AU - Johnsen, Svein Joar Auglænd

AU - Hammenfors, Daniel

AU - Skarstein, Kathrine

AU - Jonsson, Malin V.

AU - Baecklund, Eva

AU - Aqrawi, Lara A.

AU - Jensen, Janicke Liaaen

AU - Palm, Øyvind

AU - Morris, Andrew P.

AU - Alexsson, Andrei

AU - Pucholt, Pascal

AU - Backlin, Carin

AU - Baecklund, Eva

AU - Sandling, Johanna K.

AU - Imgenberg-Kreuz, Juliana

AU - Rönnblom, Lars

AU - Vasaitis, Lilian

AU - Eloranta, Maija Leena

AU - Syvänen, Ann Christine

AU - Mathioudaki, Argyri

AU - Farias, Fabiana H.G.

AU - Meadows, Jennifer

AU - Nordin, Jessika

AU - Hultin-Rosenberg, Lina

AU - Bianchi, Matteo

AU - Lindblad-Toh, Kerstin

AU - Björk, Albin

AU - Thorlacius, Guðný Ella

AU - Lundberg, Ingrid E.

AU - Sepúlveda, Jorge I.Ramírez

AU - Wahren-Herlenius, Marie

AU - Kvarnström, Marika

AU - Eriksson, Daniel

AU - Forsblad-D'elia, Helena

AU - Eriksson, Per

AU - Sjöwall, Christopher

AU - Theander, Elke

AU - Mandl, Thomas

AU - Rantapaä¨-Dahlqvist, Solbritt

AU - Bucher, Sara Magnusson

AU - Hammenfors, Daniel

AU - Brokstad, Karl A.

AU - Skarstein, Kathrine

AU - Jonsson, Roland

AU - Appel, Silke

AU - Jonsson, Malin V.

AU - Brun, Johan G.

AU - Norheim, Katrine Brække

AU - Omdal, Roald

AU - Johnsen, Svein Joar Auglænd

AU - Palm, Øyvind

AU - Jensen, Janicke Liaaen

AU - Aqrawi, Lara Adnan

AU - Lindblad-Toh, Kerstin

AU - Pielberg, Gerli Rosengren

AU - Murén, Eva

AU - Karlsson, Åsa

AU - Andersson, Göran

AU - Ahlgren, Kerstin M.

AU - Lobell, Anna

AU - Rönnblom, Lars

AU - Eloranta, Maija Leena

AU - Söderkvist, Peter

AU - Kämpe, Olle

AU - Landegren, Nils

AU - Meadows, Jennifer R.S.

AU - Rantapaä¨-Dahlqvist, Solbritt

AU - Mandl, Thomas

AU - Eriksson, Per

AU - Lind, Lars

AU - Omdal, Roald

AU - Jonsson, Roland

AU - Lindblad-Toh, Kerstin

AU - Rönnblom, Lars

AU - Wahren-Herlenius, Marie

AU - Nordmark, Gunnel

PY - 2021/2/1

Y1 - 2021/2/1

N2 - 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.

AB - 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.

KW - autoantibodies

KW - autoimmunity

KW - gene polymorphism

KW - Sjögren's syndrome

U2 - 10.1093/rheumatology/keaa367

DO - 10.1093/rheumatology/keaa367

M3 - Article

C2 - 32889544

AN - SCOPUS:85102212000

SN - 1462-0324

VL - 60

SP - 837

EP - 848

JO - Rheumatology (United Kingdom)

JF - Rheumatology (United Kingdom)

IS - 2

ER -

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

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