OP-BRHE190339 860..868

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 50.1 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-1a, 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.

[1]  T. Radstake,et al.  Increased CCL25 and T Helper Cells Expressing CCR9 in the Salivary Glands of Patients With Primary Sjögren's Syndrome: Potential New Axis in Lymphoid Neogenesis , 2017, Arthritis & rheumatology.

[2]  R. Morita,et al.  Multiomic disease signatures converge to cytotoxic CD8 T cells in primary Sjögren’s syndrome , 2017, Annals of the rheumatic diseases.

[3]  V. Pascual,et al.  Modular transcriptional repertoire analyses identify a blood neutrophil signature as a candidate biomarker for lupus nephritis , 2016, Rheumatology.

[4]  J. Harley,et al.  Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies. , 2016, Journal of autoimmunity.

[5]  Lauren L. Ritterhouse,et al.  Autoantibody‐Positive Healthy Individuals Display Unique Immune Profiles That May Regulate Autoimmunity , 2016, Arthritis & rheumatology.

[6]  P. J. van der Spek,et al.  Contrasting expression pattern of RNA-sensing receptors TLR7, RIG-I and MDA5 in interferon-positive and interferon-negative patients with primary Sjögren's syndrome , 2016, Annals of the rheumatic diseases.

[7]  X. Mariette,et al.  Cytometry by time-of-flight immunophenotyping identifies a blood Sjögren's signature correlating with disease activity and glandular inflammation. , 2016, The Journal of allergy and clinical immunology.

[8]  Virginia Pascual,et al.  Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients , 2016, Cell.

[9]  M. Koutsilieris,et al.  Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis. , 2015, Journal of autoimmunity.

[10]  Ami A. Shah,et al.  Molecular Subsetting of Interferon Pathways in Sjögren's Syndrome , 2015, Arthritis & rheumatology.

[11]  G. Cook,et al.  Licensed human natural killer cells aid dendritic cell maturation via TNFSF14/LIGHT , 2014, Proceedings of the National Academy of Sciences.

[12]  C. Gordon,et al.  Interferon-α-induced B-lymphocyte stimulator expression and mobilization in healthy and systemic lupus erthymatosus monocytes. , 2014, Rheumatology.

[13]  Wei Wei,et al.  IL-21 acts as a promising therapeutic target in systemic lupus erythematosus by regulating plasma cell differentiation , 2014, Cellular and Molecular Immunology.

[14]  J. Guthridge,et al.  Proinflammatory Adaptive Cytokine and Shed Tumor Necrosis Factor Receptor Levels Are Elevated Preceding Systemic Lupus Erythematosus Disease Flare , 2014, Arthritis & rheumatology.

[15]  P. Schneider,et al.  The BAFF/APRIL system in SLE pathogenesis , 2014, Nature Reviews Rheumatology.

[16]  Virginia Pascual,et al.  Modular Transcriptional Repertoire Analyses of Adults With Systemic Lupus Erythematosus Reveal Distinct Type I and Type II Interferon Signatures , 2014, Arthritis & rheumatology.

[17]  Lauren L. Ritterhouse,et al.  Vitamin D Deficiency in a Multiethnic Healthy Control Cohort and Altered Immune Response in Vitamin D Deficient European-American Healthy Controls , 2014, PloS one.

[18]  Ghada S. Hassan,et al.  CD154 Is Released from T-cells by a Disintegrin and Metalloproteinase Domain-containing Protein 10 (ADAM10) and ADAM17 in a CD40 Protein-dependent Manner* , 2013, The Journal of Biological Chemistry.

[19]  H. Drexhage,et al.  MxA as a clinically applicable biomarker for identifying systemic interferon type I in primary Sjögren's syndrome , 2013, Annals of the rheumatic diseases.

[20]  I. Sanz,et al.  Updates on B-cell immunotherapies for systemic lupus erythematosus and Sjogren's syndrome , 2012, Current opinion in rheumatology.

[21]  P. Vlachoyiannopoulos,et al.  Subgroups of Sjögren syndrome patients according to serological profiles. , 2012, Journal of autoimmunity.

[22]  H. Drexhage,et al.  Prevalence of interferon type I signature in CD14 monocytes of patients with Sjögren's syndrome and association with disease activity and BAFF gene expression , 2012, Annals of the rheumatic diseases.

[23]  L. Criswell,et al.  Primary Sjögren's syndrome as a systemic disease: A study of participants enrolled in an International Sjögren's syndrome registry , 2012, Arthritis care & research.

[24]  J. Pers,et al.  Gene expression profile in the salivary glands of primary Sjögren's syndrome patients before and after treatment with rituximab. , 2010, Arthritis and rheumatism.

[25]  R. Kaaks,et al.  Validity of multiplex-based assays for cytokine measurements in serum and plasma from "non-diseased" subjects: comparison with ELISA. , 2009, Journal of immunological methods.

[26]  E. Clark,et al.  The role of CD40 and CD154/CD40L in dendritic cells. , 2009, Seminars in immunology.

[27]  G. Baron,et al.  EULAR Sjögren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjögren's syndrome , 2009, Annals of the rheumatic diseases.

[28]  Eshrat S. Emamian,et al.  Peripheral blood gene expression profiling in Sjögren’s syndrome , 2009, Genes and Immunity.

[29]  N. Kamatani,et al.  Excessive Production of IFN-γ in Patients with Systemic Lupus Erythematosus and Its Contribution to Induction of B Lymphocyte Stimulator/B Cell-Activating Factor/TNF Ligand Superfamily-13B1 , 2008, The Journal of Immunology.

[30]  Pan Du,et al.  lumi: a pipeline for processing Illumina microarray , 2008, Bioinform..

[31]  S. Horvath,et al.  Unsupervised Learning With Random Forest Predictors , 2006 .

[32]  D. Olive,et al.  LIGHT costimulates CD40 triggering and induces immunoglobulin secretion; a novel key partner in T cell‐dependent B cell terminal differentiation , 2004, European journal of immunology.

[33]  D. Olive,et al.  The TNF Superfamily Members LIGHT and CD154 (CD40 Ligand) Costimulate Induction of Dendritic Cell Maturation and Elicit Specific CTL Activity1 , 2001, The Journal of Immunology.

[34]  D. Olive,et al.  Reciprocal Expression of the TNF Family Receptor Herpes Virus Entry Mediator and Its Ligand LIGHT on Activated T Cells: LIGHT Down-Regulates Its Own Receptor1 , 2000, The Journal of Immunology.

[35]  J. Birt,et al.  Sjögren's syndrome: managed care data from a large United States population highlight real-world health care burden and lack of treatment options. , 2017, Clinical and experimental rheumatology.

[36]  Cheng Li,et al.  Adjusting batch effects in microarray expression data using empirical Bayes methods. , 2007, Biostatistics.

[37]  G. Bishop,et al.  Signaling by CD40 and its mimics in B cell activation , 2001, Immunologic research.

[38]  P. Moore,et al.  Synthesis and release of B-lymphocyte stimulator from myeloid cells. , 2001, Blood.