Identification of activated cytokine pathways in the blood of systemic lupus erythematosus, myositis, rheumatoid arthritis, and scleroderma patients.
OBJECTIVE
To develop genomic signatures of seven cytokines involved in the pathogenesis of rheumatic diseases such as systemic lupus erythematosus (SLE), dermatomyositis (DM), polymyositis (PM), rheumatoid arthritis (RA), or systemic scleroderma (SSc) that could potentially help identify patients likely to respond to therapies that target these individual cytokines.


METHODS
Over-expressed transcripts in the whole blood (WB) were identified from 262 SLE, 44 DM, 33 PM, 38 SSc and 89 RA subjects and compared to 24 healthy subjects using Affymetrix arrays. Cytokine-inducible gene signatures such as type I interferon (IFN), tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-10, IL-13, IL-17, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were assessed in the WB of these subjects to identify subpopulations showing activation of specific cytokine pathways.


RESULTS
Significant activation of the type I IFN pathway in a population of five diseases studied was universally observed. The TNF-α and IL-1β pathways were activated in subgroups of PM and RA subjects, respectively, with another subgroup of RA subjects showing activation of the IL-13 pathway. The GM-CSF pathway was activated in a subgroup of SSc subjects and the IL-17 pathway was activated in subgroups of all diseases except SLE.


CONCLUSIONS
A novel gene expression measurement of activated cytokines in five different rheumatic diseases is presented. Characterizing the cytokine pathways most activated in specific patient subpopulations has the potential to help target the appropriate patient populations for corresponding anti-cytokine therapies.
Translational Sciences, MedImmune, LLC, Gaithersburg, MD 20878, USA.
Brandon W
BW
Higgs
Wei
W
Zhu
Laura
L
Richman
David F
DF
Fiorentino
Steven A
SA
Greenberg
Bahija
B
Jallal
Yihong
Y
Yao
D000328:Adult; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D016207:Cytokines / Q000097:blood* / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000097:blood; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D007370:Interferon Type I / Q000097:blood; D007378:Interleukins / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D009220:Myositis / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000097:blood; D012595:Scleroderma, Systemic / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D015854:Up-Regulation; D055815:Young Adult
D015415:Biomarkers; D016207:Cytokines; D007155:Immunologic Factors; D007370:Interferon Type I; D007378:Interleukins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor