Divergent Gene Activation in Peripheral Blood and Tissues of Patients with Rheumatoid Arthritis, Psoriatic Arthritis and Psoriasis following Infliximab Therapy

Objective The immune inflammatory disorders rheumatoid arthritis (RA), psoriatic arthritis (PsA) and psoriasis (Ps) share common pathologic features and show responsiveness to anti-tumor necrosis factor (TNF) agents yet they are phenotypically distinct. The aim of this study was to examine if anti-TNF therapy is associated with divergent gene expression profiles in circulating cells and target tissues of patients with these diseases. Methods Peripheral blood CD14+ and CD14− cells were isolated from 9 RA, 12 PsA and 10 Ps patients before and after infliximab (IFX) treatment. Paired synovial (n = 3, RA, PsA) and skin biopsies (n = 5, Ps) were also collected. Gene expression was analyzed by microarrays. Results 26 out of 31 subjects responded to IFX. The transcriptional response of CD14+ cells to IFX was unique for the three diseases, with little overlap (<25%) in significantly changed gene lists (with PsA having the largest number of changed genes). In Ps, altered gene expression was more pronounced in lesional skin (relative to paired, healthy skin) compared to blood (relative to healthy controls). Marked suppression of up-regulated genes in affected skin was noted 2 weeks after therapy but the expression patterns differed from uninvolved skin. Divergent patterns of expression were noted between the blood cells and skin or synovial tissues in individual patients. Functions that promote cell differentiation, proliferation and apoptosis in all three diseases were enriched. RA was enriched in functions in CD14− cells, PsA in CD14+ cells and Ps in both CD14+ and CD14− cells, however, the specific functions showed little overlap in the 3 disorders. Conclusion Divergent patterns of altered gene expression are observed in RA, PsA and Ps patients in blood cells and target organs in IFX responders. Differential gene expression profiles in the blood do not correlate with those in target organs.

[1]  A. Gottlieb,et al.  Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial , 2013, The Lancet.

[2]  R. Moots,et al.  The efficacy of biologic agents in patients with rheumatoid arthritis and an inadequate response to tumour necrosis factor inhibitors: a systematic review. , 2012, Rheumatology.

[3]  P. Mease.  Is There a Role for Rituximab in the Treatment of Spondyloarthritis and Psoriatic Arthritis? , 2012, The Journal of Rheumatology.

[4]  E. Ruppin,et al.  Common and specific signatures of gene expression and protein–protein interactions in autoimmune diseases , 2012, Genes and Immunity.

[5]  G. Firestein,et al.  Pre-rheumatoid arthritis: predisposition and transition to clinical synovitis , 2012, Nature Reviews Rheumatology.

[6]  Suyan Tian,et al.  Meta-Analysis Derived (MAD) Transcriptome of Psoriasis Defines the “Core” Pathogenesis of Disease , 2012, PloS one.

[7]  Raymond K. Auerbach,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[8]  Patrick Durez,et al.  Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study , 2012, Annals of the rheumatic diseases.

[9]  J. Ortonne,et al.  Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. , 2012, The New England journal of medicine.

[10]  Subhashis Banerjee,et al.  Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. , 2012, The New England journal of medicine.

[11]  G. Kingsley,et al.  A randomized placebo-controlled trial of methotrexate in psoriatic arthritis , 2012, Rheumatology.

[12]  Jing Zhao,et al.  Inhibition of Stat3 expression induces apoptosis and suppresses proliferation in human leukemia HL-60 cells , 2011, Hematology.

[13]  D. Gladman,et al.  Abatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial. , 2011, Arthritis and rheumatism.

[14]  H. Vidal,et al.  Gene expression profiling in peripheral blood cells of patients with rheumatoid arthritis in response to anti-TNF-alpha treatments. , 2011, Physiological genomics.

[15]  M. McDermott,et al.  The early phase of psoriatic arthritis , 2011, Annals of the rheumatic diseases.

[16]  M. Suárez-Fariñas,et al.  Resolved psoriasis lesions retain expression of a subset of disease-related genes. , 2011, The Journal of investigative dermatology.

[17]  Luis Puig,et al.  Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. , 2010, The Journal of investigative dermatology.

[18]  J. Lundeberg,et al.  The Gene Expression Profile in the Synovium as a Predictor of the Clinical Response to Infliximab Treatment in Rheumatoid Arthritis , 2010, PloS one.

[19]  H. Herfarth,et al.  The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer , 2010, The Journal of experimental medicine.

[20]  Xavier Estivill,et al.  Replication of LCE3C-LCE3B CNV as a risk factor for psoriasis and analysis of interaction with other genetic risk factors. , 2010, The Journal of investigative dermatology.

[21]  Andreas Radbruch,et al.  Does gene expression analysis inform us in rheumatoid arthritis? , 2009, Annals of the rheumatic diseases.

[22]  Sara Marsal,et al.  An Eight-Gene Blood Expression Profile Predicts the Response to Infliximab in Rheumatoid Arthritis , 2009, PLoS ONE.

[23]  S. Lamberts,et al.  Clinical Features Associated with Glucocorticoid Receptor Polymorphisms , 2009, Annals of the New York Academy of Sciences.

[24]  Pilar Romero,et al.  IL‐17‐producing CD8+ T lymphocytes from psoriasis skin plaques are cytotoxic effector cells that secrete Th17‐related cytokines , 2009, Journal of leukocyte biology.

[25]  Lukasz Itert,et al.  Subtype-specific peripheral blood gene expression profiles in recent-onset juvenile idiopathic arthritis. , 2009, Arthritis and rheumatism.

[26]  D. Hamilton,et al.  Periostin localizes to cells in normal skin, but is associated with the extracellular matrix during wound repair , 2009, Journal of Cell Communication and Signaling.

[27]  A. Fukamizu,et al.  Regulation of FOXO1-mediated transcription and cell proliferation by PARP-1. , 2009, Biochemical and biophysical research communications.

[28]  A. Bowcock,et al.  New insights into the pathogenesis and genetics of psoriatic arthritis , 2009, Nature Clinical Practice Rheumatology.

[29]  A. Schnerch,et al.  The Histone Demethylase KDM5b/JARID1b Plays a Role in Cell Fate Decisions by Blocking Terminal Differentiation , 2008, Molecular and Cellular Biology.

[30]  B. Franke,et al.  Gene expression profiling in rheumatoid arthritis: current concepts and future directions , 2008, Annals of the rheumatic diseases.

[31]  J. Gudjonsson,et al.  Analysis of global gene expression and genetic variation in psoriasis. , 2007, Journal of the American Academy of Dermatology.

[32]  T. Behrens,et al.  A distinct inflammatory gene expression profile in patients with psoriatic arthritis , 2006, Genes and Immunity.

[33]  Dafna Gladman,et al.  Classification criteria for psoriatic arthritis: development of new criteria from a large international study. , 2006, Arthritis and rheumatism.

[34]  N. Watanabe,et al.  N-terminal Region of CCAAT/Enhancer-binding Protein ϵ Is Critical for Cell Cycle Arrest, Apoptosis, and Functional Maturation during Myeloid Differentiation* , 2006, Journal of Biological Chemistry.

[35]  P. Nilsson,et al.  Variability in synovial inflammation in rheumatoid arthritis investigated by microarray technology , 2006, Arthritis research & therapy.

[36]  G. Firestein,et al.  Common mechanisms in immune-mediated inflammatory disease. , 2005, The Journal of rheumatology. Supplement.

[37]  K. Mitsuishi,et al.  Gene expression of enzymes for tryptophan degradation pathway is upregulated in the skin lesions of patients with atopic dermatitis or psoriasis. , 2004, Journal of dermatological science.

[38]  Pu Zhang,et al.  Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-α (C/EBPα), in acute myeloid leukemia , 2001, Nature Genetics.

[39]  A. Yang,et al.  p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. , 1998, Molecular cell.

[40]  C. Begley,et al.  musculin: a murine basic helix-loop-helix transcription factor gene expressed in embryonic skeletal muscle , 1998, Mechanisms of Development.

[41]  B. Dörken,et al.  Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells. , 1997, The Journal of clinical investigation.

[42]  M. Karin,et al.  The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. , 1991, Biochimica et biophysica acta.

[43]  F. Arnett.  Revised criteria for the classification of rheumatoid arthritis. , 1990, Orthopedic nursing.

[44]  A Y Finlay,et al.  Assessment of disease progress in psoriasis. , 1989, Archives of dermatology.

[45]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[46]  P. Gregersen,et al.  Microarray Analyses of Peripheral Blood Cells Identifies Unique Gene Expression Signature in Psoriatic Arthritis , 2005, Molecular medicine.

[47]  S. Hsu,et al.  Psoriasis is characterized by altered epidermal expression of caspase 14, a novel regulator of keratinocyte terminal differentiation and barrier formation. , 2005, Journal of dermatological science.

[48]  Gregory A. Bohach,et al.  5 – Pathogenesis of disease , 2004 .

[49]  Alex E. Lash,et al.  Gene Expression Omnibus: NCBI gene expression and hybridization array data repository , 2002, Nucleic Acids Res..

[50]  G. Behre,et al.  Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. , 2001, Nature genetics.

[51]  M. Prevoo,et al.  Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. , 1996, Arthritis and rheumatism.