Multiple cytokines and chemokines are associated with rheumatoid arthritis-related autoimmunity in first-degree relatives without rheumatoid arthritis: Studies of the Aetiology of Rheumatoid Arthritis (SERA).


OBJECTIVE: We investigated whether rheumatoid arthritis (RA)-related autoantibodies were associated with systemic inflammation in a prospective cohort of first-degree relatives (FDRs) of RA probands, a population without RA but at increased risk for its future development. METHODS: We studied 44 autoantibody positive FDRs, of whom 29 were rheumatoid factor (RF) positive, 25 were positive for the high risk autoantibody profile (HRP), that is, positive for anti-cyclic citrullinated peptide and/or for at least two RF IgM, IgG or IgA isotypes, and nine FDRs who were positive for both; and 62 FDRs who were never autoantibody positive. Twenty-five cytokines/chemokines were measured using a bead-based assay in serum. As a comprehensive measure of inflammation, we calculated a Cytokine Score by summing all cytokine/chemokine levels, weighted by their regression coefficients for RA-autoantibody association. We compared C-reactive protein, individual cytokines/chemokines and Cytokine Score to the outcomes: positivity for RF and for the HRP using logistic regression. RESULTS: Adjusting for age, sex, ethnicity and ever smoking, the Cytokine Score and levels of IL-6 and IL-9 were associated with both RF and HRP. IL-2, granulocyte macrophage-colony stimulating factor (GM-CSF), and interferon (IFN)-γ were associated with HRP only. Associations between the Cytokine Score and RF and HRP positivity were replicated in an independent military personnel cohort. CONCLUSIONS: In first-degree relatives of patients with RA, RA-related autoimmunity is associated with inflammation, as evidenced by associations with multiple cytokines and chemokines.


Hughes-Austin, Jan M; Deane, Kevin D; Derber, Lezlie A; Kolfenbach, Jason R; Zerbe, Gary O; Sokolove, Jeremy; Lahey, Lauren J; Weisman, Michael H; Buckner, Jane H; Mikuls, Ted R; O'Dell, James R; Keating, Richard M; Gregersen, Peter K; Robinson, William H; Holers, V Michael; Norris, Jill M;


  • Adult
  • Aged
  • Arthritis, Rheumatoid/ genetics
  • Arthritis, Rheumatoid/ immunology
  • Autoantibodies/ immunology
  • Autoimmunity/ genetics
  • Autoimmunity/ immunology
  • C-Reactive Protein/ immunology
  • Chemokines/ immunology
  • Cohort Studies
  • Cytokines/ immunology
  • Female
  • Genetic Predisposition to Disease
  • Granulocyte-Macrophage Colony-Stimulating Factor/ immunology
  • Humans
  • Inflammation/ immunology
  • Interferon-gamma/ immunology
  • Interleukin-2/ immunology
  • Interleukin-6/ immunology
  • Interleukin-9/ immunology
  • Logistic Models
  • Male
  • Middle Aged
  • Peptides, Cyclic/ immunology
  • Phenotype
  • Prospective Studies
  • Rheumatoid Factor/ immunology

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