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.
Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado 80045, USA.
Jan M
JM
Hughes-Austin
Kevin D
KD
Deane
Lezlie A
LA
Derber
Jason R
JR
Kolfenbach
Gary O
GO
Zerbe
Jeremy
J
Sokolove
Lauren J
LJ
Lahey
Michael H
MH
Weisman
Jane H
JH
Buckner
Ted R
TR
Mikuls
James R
JR
O'Dell
Richard M
RM
Keating
Peter K
PK
Gregersen
William H
WH
Robinson
V Michael
VM
Holers
Jill M
JM
Norris
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D002097:C-Reactive Protein / Q000276:immunology; D018925:Chemokines / Q000276:immunology*; D015331:Cohort Studies; D016207:Cytokines / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D016906:Interleukin-9 / Q000276:immunology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology; D010641:Phenotype; D011446:Prospective Studies; D012217:Rheumatoid Factor / Q000276:immunology*
D001323:Autoantibodies; D018925:Chemokines; D016207:Cytokines; C573415:IFNG protein, human; C508594:IL2 protein, human; C508600:IL6 protein, human; C508607:IL9 protein, human; D007376:Interleukin-2; D015850:Interleukin-6; D016906:Interleukin-9; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002097:C-Reactive Protein; D012217:Rheumatoid Factor