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)

Abstract

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.

A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22

“…PBMCs were obtained from the following sources: (a) BWH PhenoGenetic Project (38); (b) Partners HealthCare Biobank, an enterprise biobank of consented patient samples at Partners HealthCare (Massachusetts General Hospital and BWH), according to IRB-approved protocols; (c) Personalized Risk Estimator for Rheumatoid Arthritis Family Study, an NIH-funded prospective, randomized, controlled trial designed to evaluate whether personalized RA risk education affects willingness to change RA-related behaviors among unaffected FDRs of RA patients (37); (d) Profiling of Cell Subsets in Human Diseases, a research initiative of BWH comparing immune cells in blood from patients with or without inflammatory diseases; and (e) Studies of the Etiology of Rheumatoid Arthritis, a multicenter study designed to examine the role of environmental and genetic factors in the development and progression of RA-related autoimmunity (63).…”

Review: Preclinical Rheumatoid Arthritis: Progress Toward Prevention

“…This increase in ACPA fine specificity is associated with an 782 MANKIA AND EMERY increase in the serum levels of cytokines and chemokines, suggesting that RA-related inflammation also begins preclinically (43). Prospective studies have corroborated these findings, both in seropositive patients with arthralgia (45) and in FDRs of patients with RA (46). Furthermore, an expanded ACPA repertoire is associated with higher anti-CCP levels and dual seropositivity (ACPAs and RF) and is predictive of arthritis development (45).…”

Interleukin-9 and T helper type 9 cells in rheumatic diseases

“…High levels of IL-9 have been also detected in patients' first-degree relatives' sera with RA or with asymptomatic RA-related autoimmunity [26,33]. Furthermore, IL-9, together with IL-6, is the most responsible in the cytokine score calculated by summing all cytokine/ chemokine levels, weighted by their regression coefficients for RA-autoantibody association [26].…”

“…This paper aims to review the evidence indicating that Th9 cells may contribute to the pathogenesis of autoimmune-related diseases, due to the recent demonstration of a possible role of Th9 T cells and of their related cytokine IL-9 in rheumatoid arthritis (RA), psoriatic arthritis (PsA), systemic vasculitis, systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) [20][21][22][23][24][25][26][27][28] (Fig. 1 shows the possible tissue target of Th9-mediated inflammation).…”