title: A distinct multicytokine profile is associated with anti-cyclical citrullinated peptide antibodies in patients with early untreated inflammatory arthritis.
abstract: OBJECTIVE
  Early inflammatory arthritis is clinically heterogenous and biologically-based indicators are needed to distinguish severe from self-limited disease. Anti-cyclical citrullinated peptides (CCP) have been identified as potential prognostic markers in early arthritis cohorts. Since cytokine networks are known to play a critical role in the pathogenesis of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, a panel of pro- and antiinflammatory cytokines was measured to identify biologically-based subsets of early arthritis, relating cytokine profiles to clinical measures and to the presence of RA-associated autoantibodies.
  
  
  METHODS
  Plasma concentrations of cytokines [interleukin 1beta (IL-1beta), IL-2, IL-4, IL-5, IL-6, IL-7, CXCL8 (IL-8), IL-10, IL-12p70, IL-13, IL-17, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-g (IFN-g), CCL2 (monocyte chemoattractant protein-1, MCP-1), CCL4 (MIP-1beta), and tumor necrosis factor-a (TNF-a)] were measured in patients with early, untreated inflammatory arthritis [symptom duration < or = 12 months; > or = 1 swollen joint; RA, n = 41; undifferentiated arthritis (UA), n = 23]. Cytokine expression patterns were determined using cluster analysis.
  
  
  RESULTS
  Both pro- and antiinflammatory cytokines were elevated in patients over controls (n = 21). RA clustered into subgroups based solely on cytokine profiles. The "mild" RA subgroup (n = 23) had higher CCL4 (MIP-1beta), CXCL8 (IL-8), IL-2, IL-12, IL-17, IL-5, and IL-10 levels, lower IL-6, IFN-g, GM-CSF, and IL-4 levels, less CCP positivity (52% vs 82%; p < 0.05), and lower CCP titers [71 (78) vs 153 (94); p < 0.01], but similar erythrocyte sedimentation rate, C-reactive protein, and joint counts compared to the "severe" RA groups. CCL4 (MIP-1beta), IL-13, IL-12, TNF-a, and IL-4 best distinguished the groups. Combining UA with RA samples preserved cytokine subgroups and strengthened the autoantibody associations. Fewer UA patients in the "mild" cluster (n = 16) were RF-positive (24% vs 100%; p < 0.002) or CCP-positive (24% vs 66%; p < 0.08) compared to the "severe" group.
  
  
  CONCLUSIONS
  Early untreated inflammatory arthritis can be categorized into distinct subgroups based on cytokine profiles. These subgroups are associated with CCP and RF autoantibodies. Integration of cytokine profiles with autoantibody status may assist prognostication and treatment decisions in these patients.
authors.affiliation: Arthritis Centre, University of Manitoba, 800 Sherbrook Street, Winnipeg, Manitoba R3A 1M4, Canada.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Hitchon
authors.forename: Philip
authors.initials: P
authors.lastname: Alex
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Erdile
authors.forename: Mark B
authors.initials: MB
authors.lastname: Frank
authors.forename: Igor
authors.initials: I
authors.lastname: Dozmorov
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Tang
authors.forename: Keng
authors.initials: K
authors.lastname: Wong
authors.forename: Michael
authors.initials: M
authors.lastname: Centola
authors.forename: Hani S
authors.initials: HS
authors.lastname: El-Gabalawy
mesh_terms: D000704:Analysis of Variance; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000503:physiopathology; D001323:Autoantibodies / Q000032:analysis*; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D016022:Case-Control Studies; D018925:Chemokines / Q000097:blood / Q000378:metabolism; D016000:Cluster Analysis; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000032:analysis; D007378:Interleukins / Q000097:blood / Q000378:metabolism*; D008297:Male; D011379:Prognosis; D011446:Prospective Studies; D012016:Reference Values; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D007378:Interleukins