title: Biologic predictors of extension of oligoarticular juvenile idiopathic arthritis as determined from synovial fluid cellular composition and gene expression.
abstract: OBJECTIVE
  To identify biomarkers in the first synovial fluid (SF) aspirate obtained from children with oligoarticular juvenile idiopathic arthritis (JIA), which could be used to identify children whose disease is likely to extend to a more severe phenotype.
  
  
  METHODS
  Patients with recent-onset oligoarticular JIA were identified and grouped according to those whose mild disease persisted (persistent disease) or those whose disease would extend from a mild to more severe phenotype (extended-to-be disease) at 1 year after diagnosis. Flow cytometry was used to delineate differences in the mononuclear cell populations between the first blood sample and first SF aspirate from the same patient and between outcome (persistent versus extended-to-be) groups. Proportions of lymphocytes in the joint were modeled on chemotaxis of lymphocytes to CCL5, using Transwell migration assays. Levels of CCL5 in the SF were quantified by enzyme-linked immunosorbent assay. RNA profiles of SF mononuclear cells were compared between groups using the Affymetrix GeneChip hybridization protocol and hierarchical clustering analyses.
  
  
  RESULTS
  Compared with peripheral blood mononuclear cells, SF mononuclear cells displayed an expansion of CD8+ T cells, reduced proportion of B cells, and expansion of CD16- natural killer cells. The lower CD4:CD8 ratio in the SF was recapitulated in vitro by the observed migration of blood T cells in response to CCL5. Synovial CCL5 levels were higher in children whose disease extended to a more severe phenotype. The CD4:CD8 ratio in the SF was significantly lower in patients with extended-to-be oligoarticular JIA (0.57 compared with 0.90 in the persistent disease group, difference 0.33, 95% confidence interval 0.04-0.62; P = 0.009). Gene expression profiling revealed that 344 genes were >1.5-fold differentially expressed between outcome groups (P < 0.05), and these included genes associated with inflammation and macrophage differentiation, which showed increased levels in patients with extended disease at 1 year, and genes associated with immune regulation, which showed increased levels in patients with persistent disease at 1 year.
  
  
  CONCLUSIONS
  Analyses of the proportions of synovial lymphocytes, levels of CCL5, and differential gene expression yielded potential biomarkers with which to predict the likelihood of extension of oligoarticular JIA to a more severe disease phenotype.
authors.affiliation: Rheumatology Unit, University College London Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. p.hunter@ich.ucl.ac.uk
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Hunter
authors.forename: Kiran
authors.initials: K
authors.lastname: Nistala
authors.forename: Nipurna
authors.initials: N
authors.lastname: Jina
authors.forename: Ayad
authors.initials: A
authors.lastname: Eddaoudi
authors.forename: Wendy
authors.initials: W
authors.lastname: Thomson
authors.forename: Mike
authors.initials: M
authors.lastname: Hubank
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Wedderburn
mesh_terms: D001171:Arthritis, Juvenile / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D015415:Biomarkers / Q000032:analysis*; D016516:CD4-CD8 Ratio; D018946:Chemokine CCL5 / Q000032:analysis; D002648:Child; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology*; D016131:Lymphocyte Subsets; D008297:Male; D013582:Synovial Fluid / Q000166:cytology*
chemical_list: D015415:Biomarkers; D018946:Chemokine CCL5