Unique Sjögren's syndrome patient subsets defined by molecular features

Judith A. James; Joel M. Guthridge; Hua Chen; Rufei Lu; Rebecka L. Bourn; Krista Bean; Melissa E. Munroe; Miles Smith; Eliza Chakravarty; Alan N. Baer; Ghaith Noaiseh; Ann Parke; Karen Boyle; Lynette Keyes-Elstein; Andreea Coca; Tammy Utset; Mark C. Genovese; Virginia Pascual; Paul J. Utz; V. Michael Holers; Kevin D. Deane; Kathy L. Sivils; Teresa Aberle; Daniel J. Wallace; James McNamara; Nathalie Franchimont; E. William St Clair

doi:10.1093/rheumatology/kez335

Unique Sjögren's syndrome patient subsets defined by molecular features

Judith A. James, Joel M. Guthridge, Hua Chen, Rufei Lu, Rebecka L. Bourn, Krista Bean, Melissa E. Munroe, Miles Smith, Eliza Chakravarty, Alan N. Baer, Ghaith Noaiseh, Ann Parke, Karen Boyle, Lynette Keyes-Elstein, Andreea Coca, Tammy Utset, Mark C. Genovese, Virginia Pascual, Paul J. Utz, V. Michael HolersKevin D. Deane, Kathy L. Sivils, Teresa Aberle, Daniel J. Wallace, James McNamara, Nathalie Franchimont, E. William St Clair

School of Medicine

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

11 Scopus citations

Abstract

Objective: To address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes. Methods: pSS patients met American-European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ≥0.1 ml/min. Correlated transcriptional modules were derived from gene expression microarray data from blood (n = 47 with appropriate samples). Patients were clustered based on this molecular information using an unbiased random forest modelling approach. In addition, multiplex, bead-based assays and ELISAs were used to assess 30 serum cytokines, chemokines and soluble receptors. Eleven autoantibodies, including anti-Ro/SSA and anti-La/SSB, were measured by Bio-Rad Bioplex 2200. Results: Transcriptional modules distinguished three clusters of pSS patients. Cluster 1 showed no significant elevation of IFN or inflammation modules. Cluster 2 showed strong IFN and inflammation modular network signatures, as well as high plasma protein levels of IP-10/CXCL10, MIG/CXCL9, BLyS (BAFF) and LIGHT. Cluster 3 samples exhibited moderately elevated IFN modules, but with suppressed inflammatory modules, increased IP-10/CXCL10 and B cell-attracting chemokine 1/CXCL13 and trends toward increased MIG/CXCL9, IL-1α, and IL-21. Anti-Ro/SSA and anti-La/SSB were present in all three clusters. Conclusion: Molecular profiles encompassing IFN, inflammation and other signatures can be used to separate patients with pSS into distinct clusters. In the future, such profiles may inform patient selection for clinical trials and guide treatment decisions.

Original language	English (US)
Pages (from-to)	860-868
Number of pages	9
Journal	Rheumatology (United Kingdom)
Volume	59
Issue number	4
DOIs	https://doi.org/10.1093/rheumatology/kez335
State	Published - Apr 1 2020

Keywords

Biomarkers
Interferon
Precision medicine
Sjögren's syndrome

ASJC Scopus subject areas

Rheumatology
Pharmacology (medical)

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10.1093/rheumatology/kez335

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James, J. A., Guthridge, J. M., Chen, H., Lu, R., Bourn, R. L., Bean, K., Munroe, M. E., Smith, M., Chakravarty, E., Baer, A. N., Noaiseh, G., Parke, A., Boyle, K., Keyes-Elstein, L., Coca, A., Utset, T., Genovese, M. C., Pascual, V., Utz, P. J., ... St Clair, E. W. (2020). Unique Sjögren's syndrome patient subsets defined by molecular features. Rheumatology (United Kingdom), 59(4), 860-868. https://doi.org/10.1093/rheumatology/kez335

James, JA, Guthridge, JM, Chen, H, Lu, R, Bourn, RL, Bean, K, Munroe, ME, Smith, M, Chakravarty, E, Baer, AN, Noaiseh, G, Parke, A, Boyle, K, Keyes-Elstein, L, Coca, A, Utset, T, Genovese, MC, Pascual, V, Utz, PJ, Holers, VM, Deane, KD, Sivils, KL, Aberle, T, Wallace, DJ, McNamara, J, Franchimont, N & St Clair, EW 2020, 'Unique Sjögren's syndrome patient subsets defined by molecular features', Rheumatology (United Kingdom), vol. 59, no. 4, pp. 860-868. https://doi.org/10.1093/rheumatology/kez335

@article{5c95bb45798748da9c5c779ce5f2b083,

title = "Unique Sj{\"o}gren's syndrome patient subsets defined by molecular features",

abstract = "Objective: To address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes. Methods: pSS patients met American-European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ≥0.1 ml/min. Correlated transcriptional modules were derived from gene expression microarray data from blood (n = 47 with appropriate samples). Patients were clustered based on this molecular information using an unbiased random forest modelling approach. In addition, multiplex, bead-based assays and ELISAs were used to assess 30 serum cytokines, chemokines and soluble receptors. Eleven autoantibodies, including anti-Ro/SSA and anti-La/SSB, were measured by Bio-Rad Bioplex 2200. Results: Transcriptional modules distinguished three clusters of pSS patients. Cluster 1 showed no significant elevation of IFN or inflammation modules. Cluster 2 showed strong IFN and inflammation modular network signatures, as well as high plasma protein levels of IP-10/CXCL10, MIG/CXCL9, BLyS (BAFF) and LIGHT. Cluster 3 samples exhibited moderately elevated IFN modules, but with suppressed inflammatory modules, increased IP-10/CXCL10 and B cell-attracting chemokine 1/CXCL13 and trends toward increased MIG/CXCL9, IL-1α, and IL-21. Anti-Ro/SSA and anti-La/SSB were present in all three clusters. Conclusion: Molecular profiles encompassing IFN, inflammation and other signatures can be used to separate patients with pSS into distinct clusters. In the future, such profiles may inform patient selection for clinical trials and guide treatment decisions.",

keywords = "Biomarkers, Interferon, Precision medicine, Sj{\"o}gren's syndrome",

author = "James, {Judith A.} and Guthridge, {Joel M.} and Hua Chen and Rufei Lu and Bourn, {Rebecka L.} and Krista Bean and Munroe, {Melissa E.} and Miles Smith and Eliza Chakravarty and Baer, {Alan N.} and Ghaith Noaiseh and Ann Parke and Karen Boyle and Lynette Keyes-Elstein and Andreea Coca and Tammy Utset and Genovese, {Mark C.} and Virginia Pascual and Utz, {Paul J.} and Holers, {V. Michael} and Deane, {Kevin D.} and Sivils, {Kathy L.} and Teresa Aberle and Wallace, {Daniel J.} and James McNamara and Nathalie Franchimont and {St Clair}, {E. William}",

note = "Funding Information: This work was supported by the National Institute of Allergy and Infectious Diseases [grant numbers U19AI082714 to J.A.J., U19AI082715 to M.V.P., U19AI110491 to P.J.U., UM1AI110503 to V.M.H., U19AI056363 to E.W.St.C., U01AI101934 to J.A.J., and HHSN272200900057C]; the National Institute of Arthritis and Musculoskeletal and Skin Diseases [grant number P30AR053483 to J.A.J.]; the National Institute of Dental and Craniofacial Research [grant number R01DE12354 to A.N.B.]; and by Institutional Development Awards from the National Institute of General Medical Sciences [grant numbers U54GM104938 to J.A.J., P30GM103510 to J.A.J.] of the US National Institutes of Health Publisher Copyright: {\textcopyright} 2019 The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.",

year = "2020",

month = apr,

day = "1",

doi = "10.1093/rheumatology/kez335",

language = "English (US)",

volume = "59",

pages = "860--868",

journal = "Rheumatology (United Kingdom)",

issn = "1462-0324",

publisher = "Oxford University Press",

number = "4",

}

TY - JOUR

T1 - Unique Sjögren's syndrome patient subsets defined by molecular features

AU - James, Judith A.

AU - Guthridge, Joel M.

AU - Chen, Hua

AU - Lu, Rufei

AU - Bourn, Rebecka L.

AU - Bean, Krista

AU - Munroe, Melissa E.

AU - Smith, Miles

AU - Chakravarty, Eliza

AU - Baer, Alan N.

AU - Noaiseh, Ghaith

AU - Parke, Ann

AU - Boyle, Karen

AU - Keyes-Elstein, Lynette

AU - Coca, Andreea

AU - Utset, Tammy

AU - Genovese, Mark C.

AU - Pascual, Virginia

AU - Utz, Paul J.

AU - Holers, V. Michael

AU - Deane, Kevin D.

AU - Sivils, Kathy L.

AU - Aberle, Teresa

AU - Wallace, Daniel J.

AU - McNamara, James

AU - Franchimont, Nathalie

AU - St Clair, E. William

N1 - Funding Information: This work was supported by the National Institute of Allergy and Infectious Diseases [grant numbers U19AI082714 to J.A.J., U19AI082715 to M.V.P., U19AI110491 to P.J.U., UM1AI110503 to V.M.H., U19AI056363 to E.W.St.C., U01AI101934 to J.A.J., and HHSN272200900057C]; the National Institute of Arthritis and Musculoskeletal and Skin Diseases [grant number P30AR053483 to J.A.J.]; the National Institute of Dental and Craniofacial Research [grant number R01DE12354 to A.N.B.]; and by Institutional Development Awards from the National Institute of General Medical Sciences [grant numbers U54GM104938 to J.A.J., P30GM103510 to J.A.J.] of the US National Institutes of Health Publisher Copyright: © 2019 The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

PY - 2020/4/1

Y1 - 2020/4/1

N2 - Objective: To address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes. Methods: pSS patients met American-European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ≥0.1 ml/min. Correlated transcriptional modules were derived from gene expression microarray data from blood (n = 47 with appropriate samples). Patients were clustered based on this molecular information using an unbiased random forest modelling approach. In addition, multiplex, bead-based assays and ELISAs were used to assess 30 serum cytokines, chemokines and soluble receptors. Eleven autoantibodies, including anti-Ro/SSA and anti-La/SSB, were measured by Bio-Rad Bioplex 2200. Results: Transcriptional modules distinguished three clusters of pSS patients. Cluster 1 showed no significant elevation of IFN or inflammation modules. Cluster 2 showed strong IFN and inflammation modular network signatures, as well as high plasma protein levels of IP-10/CXCL10, MIG/CXCL9, BLyS (BAFF) and LIGHT. Cluster 3 samples exhibited moderately elevated IFN modules, but with suppressed inflammatory modules, increased IP-10/CXCL10 and B cell-attracting chemokine 1/CXCL13 and trends toward increased MIG/CXCL9, IL-1α, and IL-21. Anti-Ro/SSA and anti-La/SSB were present in all three clusters. Conclusion: Molecular profiles encompassing IFN, inflammation and other signatures can be used to separate patients with pSS into distinct clusters. In the future, such profiles may inform patient selection for clinical trials and guide treatment decisions.

AB - Objective: To address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes. Methods: pSS patients met American-European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ≥0.1 ml/min. Correlated transcriptional modules were derived from gene expression microarray data from blood (n = 47 with appropriate samples). Patients were clustered based on this molecular information using an unbiased random forest modelling approach. In addition, multiplex, bead-based assays and ELISAs were used to assess 30 serum cytokines, chemokines and soluble receptors. Eleven autoantibodies, including anti-Ro/SSA and anti-La/SSB, were measured by Bio-Rad Bioplex 2200. Results: Transcriptional modules distinguished three clusters of pSS patients. Cluster 1 showed no significant elevation of IFN or inflammation modules. Cluster 2 showed strong IFN and inflammation modular network signatures, as well as high plasma protein levels of IP-10/CXCL10, MIG/CXCL9, BLyS (BAFF) and LIGHT. Cluster 3 samples exhibited moderately elevated IFN modules, but with suppressed inflammatory modules, increased IP-10/CXCL10 and B cell-attracting chemokine 1/CXCL13 and trends toward increased MIG/CXCL9, IL-1α, and IL-21. Anti-Ro/SSA and anti-La/SSB were present in all three clusters. Conclusion: Molecular profiles encompassing IFN, inflammation and other signatures can be used to separate patients with pSS into distinct clusters. In the future, such profiles may inform patient selection for clinical trials and guide treatment decisions.

KW - Biomarkers

KW - Interferon

KW - Precision medicine

KW - Sjögren's syndrome

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U2 - 10.1093/rheumatology/kez335

DO - 10.1093/rheumatology/kez335

M3 - Article

C2 - 31497844

AN - SCOPUS:85078440417

SN - 1462-0324

VL - 59

SP - 860

EP - 868

JO - Rheumatology (United Kingdom)

JF - Rheumatology (United Kingdom)

IS - 4

ER -

Unique Sjögren's syndrome patient subsets defined by molecular features

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Keywords

ASJC Scopus subject areas

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