Unique Sjögren's syndrome patient subsets defined by molecular features.

TitleUnique Sjögren's syndrome patient subsets defined by molecular features.
Publication TypeJournal Article
Year of Publication2020
AuthorsJames 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, V Holers M, Deane KD, Sivils KL, Aberle T, Wallace DJ, McNamara J, Franchimont N, E St Clair W
JournalRheumatology (Oxford)
Date Published2020 04 01
KeywordsAdult, Antibodies, Antinuclear, Autoantibodies, B-Cell Activating Factor, Chemokine CXCL10, Chemokine CXCL13, Chemokine CXCL9, Cytokines, Enzyme-Linked Immunosorbent Assay, Female, Gene Expression, Gene Regulatory Networks, Humans, Inflammation, Interferons, Interleukin-1alpha, Interleukins, Male, Middle Aged, Models, Statistical, Phenotype, Sjogren's Syndrome, Tumor Necrosis Factor Ligand Superfamily Member 14

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.

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Alternate JournalRheumatology (Oxford)
PubMed ID31497844
PubMed Central IDPMC7188221
Grant ListU54 GM104938 / GM / NIGMS NIH HHS / United States
P30 AR053483 / AR / NIAMS NIH HHS / United States
R01 DE012354 / DE / NIDCR NIH HHS / United States
P30 AR073750 / AR / NIAMS NIH HHS / United States
UM1 AI110503 / AI / NIAID NIH HHS / United States
HHSN272200900057C / AI / NIAID NIH HHS / United States
U19 AI082714 / AI / NIAID NIH HHS / United States
P30 GM103510 / GM / NIGMS NIH HHS / United States
U19 AI056363 / AI / NIAID NIH HHS / United States
U01 AI101934 / AI / NIAID NIH HHS / United States
U19 AI110491 / AI / NIAID NIH HHS / United States
U19 AI082715 / AI / NIAID NIH HHS / United States

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