Purpose To determine the relationship between cytokine/chemokine changes and the appearance of rheumatoid arthritis (RA)-related antibodies prior to the onset of clinically apparent RA.
Methods Sixteen military subjects with rheumatoid factor (RF) and anti-cyclic citrullinated protein (anti-CCP)-positive RA were selected from a larger cohort with stored prediagnosis serum samples. Cases were selected if they had two prediagnosis serum samples for analysis, the earliest of which (median 4.2 years prior to diagnosis) was anti-CCP negative. Nine of 16 of these earliest samples were also negative for RF (nephelometry and ELISA for IgM, IgA, IgG). The following cytokines and chemokines were measured with a bead-based multiplex assay: eotaxin (CCL11), IL-1α, GM-CSF, MCP-1 (CCL2), IL-β, FGF-2, IL-15, Flt-3 ligand, TNF-α, IL-6, IL-10, IP-10 (CXCL10), IL-12 p 70, IL-12 p40, and RANTES. Levels in RA cases were compared with military controls matched for age, gender, race, region of assignment, and length of sample storage. Wilcoxon signed-rank testing was performed for comparisons (SAS 9.1).
Results Eotaxin, IL-1α, GM-CSF, and MCP-1 levels were significantly higher in the earliest preclinical RA case samples versus controls. In the 9 cases whose initial sample was negative for anti-CCP and RF, IL-1α was elevated versus controls (p = .04).
Conclusions Cytokine/chemokine abnormalities can be detected prior to the development of anti-CCP and RF antibodies in individuals who later develop seropositive RA. These elevations may reflect asymptomatic synovial inflammation or undetected extra-articular inflammatory disease, each of which may lead to humoral autoimmune responses. Additional studies in preclinical RA are key to understanding the temporal and causal relationships between cytokine/chemokine dysregulation, RA-related autoimmunity, and development of clinically apparent disease.
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