title: Gene expression profiling in the synovium identifies a predictive signature of absence of response to adalimumab therapy in rheumatoid arthritis.
abstract: BACKGROUND
  To identify markers and mechanisms of resistance to adalimumab therapy, we studied global gene expression profiles in synovial tissue specimens obtained from severe rheumatoid arthritis (RA) patients before and after initiation of treatment.
  
  
  METHODS
  Paired synovial biopsies were obtained from the affected knee of 25 DMARD (disease-modifying antirheumatic drug)-resistant RA patients at baseline (T0) and 12 weeks (T12) after initiation of adalimumab therapy. DAS28-CRP (disease activity score using 28 joint counts-C-reactive protein) scores were computed at the same time points, and patients were categorized as good, moderate, or poor responders according to European League Against Rheumatism criteria. Global gene expression profiles were performed in a subset of patients by means of GeneChip Human Genome U133 Plus 2.0 Arrays, and confirmatory immunohistochemistry experiments were performed on the entire cohort.
  
  
  RESULTS
  Gene expression studies performed at baseline identified 439 genes associated with poor response to therapy. The majority (n = 411) of these genes were upregulated in poor responders and clustered into two specific pathways: cell division and regulation of immune responses (in particular, cytokines, chemokines, and their receptors). Immunohistochemistry experiments confirmed that high baseline synovial expression of interleukin-7 receptor alpha chain (IL-7R), chemokine (C-X-C motif) ligand 11 (CXCL11), IL-18, IL-18 receptor accessory (IL-18rap), and MKI67 is associated with poor response to adalimumab therapy. In vitro experiments indicated that genes overexpressed in poor responders could be induced in fibroblast-like synoviocytes (FLS) cultures by the addition of tumor necrosis factor-alpha (TNF-alpha) alone, IL-1beta alone, the combination of TNF-alpha and IL-17, and the combination of TNF-alpha and IL-1beta.
  
  
  CONCLUSIONS
  Gene expression studies of the RA synovium may be useful in the identification of early markers of response to TNF blockade. Genes significantly overexpressed at baseline in poor responders are induced by several cytokines in FLSs, thereby suggesting a role for these cytokines in the resistance to TNF blockade in RA.
authors.affiliation: Rheumatology Department, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium. Valerie.Badot@chu-brugmann.be
authors.forename: Valérie
authors.initials: V
authors.lastname: Badot
authors.forename: Christine
authors.initials: C
authors.lastname: Galant
authors.forename: Adrien
authors.initials: A
authors.lastname: Nzeusseu Toukap
authors.forename: Ivan
authors.initials: I
authors.lastname: Theate
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Maudoux
authors.forename: Benoît J
authors.initials: BJ
authors.lastname: Van den Eynde
authors.forename: Patrick
authors.initials: P
authors.lastname: Durez
authors.forename: Frédéric A
authors.initials: FA
authors.lastname: Houssiau
authors.forename: Bernard R
authors.initials: BR
authors.lastname: Lauwerys
mesh_terms: D000068879:Adalimumab; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000502:physiology*; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D000068879:Adalimumab