Familial clustering of the serum cytokine profile in the relatives of rheumatoid arthritis patients

Abstract

Objective. Rheumatoid arthritis (RA) is prevalent in North American Native populations, with a high frequency of multicase families and seropositivity in first-degree relatives. This study was undertaken to determine whether the serum cytokine profile of firstdegree relatives of North American Native patients with RA differed from that of individuals with no family history of autoimmunity and whether there was an association with RA autoantibodies.Methods. North American Native patients with RA (n ‫؍‬ 105), their first-degree relatives (n ‫؍‬ 273), healthy North American Native controls (n ‫؍‬ 200), and Caucasian controls (n ‫؍‬ 150) were studied. Serum levels of 42 cytokines were tested using a multiplex laser bead assay. Rheumatoid factor (RF), anti-cyclic citrullinated peptide 2 (anti-CCP-2), monocyte chemotactic protein 1 (MCP-l), and high-sensitivity C-reactive protein (hsCRP) were tested by enzyme-linked immunosorbent assay, and HLA-DRB1 alleles by specific primers. Discriminant analysis and logistic regression classified individuals based on their cytokine profile.Results. The prevalence of RF (cutoff level predetermined to include 5% of Caucasian controls) and anti-CCP (cutoff level of >40 units) was, respectively, 88% and 81% in the RA patients, 34% and 9% in first-degree relatives, and 9% and 4% in North American Native controls; the prevalence of anti-CCP was 0% in Caucasian controls. Levels of most cytokines were highest in RA patients; 17 of 40 cytokines (43%) were significantly higher in first-degree relatives than in controls, including multiple proinflammatory cytokines. Discriminant analysis showed a notable distinction between the groups, with 85% classification accuracy. First-degree relatives had markedly higher MCP-1 and hsCRP levels than North American Native controls, but there was no consistent association with RA autoantibodies.Conclusion. Our findings indicate that levels of multiple cytokines and hsCRP are higher in first-degree relatives of North American Native patients with RA compared to individuals from a nonautoimmune background. These data suggest that elevated baseline cytokine levels may be part of the risk profile for developing RA.

Serum Acute Phase Protein and Inflammatory Cytokine Network Correlations: Comparison of a Pre-Rheumatoid Arthritis and Non-Rheumatoid Arthritis Community Cohort

“…Mean MCP-1 levels (pg/ml) did differ by RF status (p = 0.020). Inflammatory cytokines were not indicated as independent variables in a logistic regression model discriminating first-degree relatives from NAN controls (table 3 in [13]).…”

“…The most recent comparative study of a cytokine profile primarily investigated first-degree relatives of North American Native (NAN) patients with RA [13]. Those relatives were considered to be RA susceptibles, though not classifiable as pre-RA, by EULAR definition [26].…”

“…Those relatives were considered to be RA susceptibles, though not classifiable as pre-RA, by EULAR definition [26]. Multiplex methods were used to assay serum cytokine levels of relatives, as compared to the RA patients and to NAN controls (table 2 in [13]]). Multiple serum cytokine levels were significantly higher in first-degree relatives than in controls, particularly monocyte chemotactic protein 1 (MCP-1) as well as high-sensitivity CRP levels.…”

“…Animal and basic investigations support the concept that interactions of multifunctional pro-inflammatory cytokines and APPs regulate immune responses and inflammatory reactions [5,6,7,8]. However, few reports in humans quantify either concurrent serological concentrations of inflammatory immunological profiles or their correlational patterns in normal populations [2,9,10] or in susceptible persons prior to the clinical onset of chronic disease, like rheumatoid arthritis (RA) [11,12,13]. …”

“…Multiple serum immune factors were also recently assayed in patients with RA, their first-degree relatives, and population control subjects [13]. Both of the latter reports [12,13] utilized a multiplex laser bead technique [18] to quantify the panels of APPs and inflammatory cytokines, rather than the ELISA method for individual factor measurements [19,20,21], as used in this study.…”