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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)
  1. Jan M Hughes-Austin1,
  2. Kevin D Deane2,
  3. Lezlie A Derber2,
  4. Jason R Kolfenbach2,
  5. Gary O Zerbe3,
  6. Jeremy Sokolove4,
  7. Lauren J Lahey4,
  8. Michael H Weisman5,
  9. Jane H Buckner6,
  10. Ted R Mikuls7,
  11. James R O'Dell7,
  12. Richard M Keating8,
  13. Peter K Gregersen9,
  14. William H Robinson4,
  15. V Michael Holers2,
  16. Jill M Norris1
  1. 1Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA
  2. 2Division of Rheumatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
  3. 3Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado, USA
  4. 4VA Palo Alto Health Care System, Palo Alto, California and the Division of Rheumatology, Stanford University School of Medicine, Stanford, California, USA
  5. 5Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, USA
  6. 6Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA
  7. 7Division of Rheumatology and Immunology, Omaha VA and University of Nebraska Medical Center, Omaha, Nebraska, USA
  8. 8Section of Rheumatology, University of Chicago, Chicago, Illinois, USA
  9. 9Robert S Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA
  1. Correspondence to Jill M Norris, Department of Epidemiology, Colorado School of Public Health, 13001 E 17th Place, B119, Building 500, Room W3139, Anschutz Medical Campus, Aurora, CO 80045, USA; Jill.norris{at}


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.

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