Abstract
Rheumatoid arthritis (RA) is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability. Though prior studies have demonstrated the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear. To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA. To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1–12 years prior to disease onset. We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines. We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing). We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes. At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA. Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-α, IL-6, IL-12p70, and IFN-γ. Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread. Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis.
Highlights
Rheumatoid arthritis (RA) is the most common inflammatory arthritis worldwide affecting 0.5–1% of the population
Of 81 subjects included in the analysis, 27 had no autoantibodies detected in their earliest serum specimen and of these all demonstrated at least one autoantibody at a future preclinical RA timepoint. 55 patients were anti-CCP2+ at any timepoint, of which 26 were anti-CCP2+ at outset and 29 converted from anti-CCP22 to anti-CCP2+ during the period of study observation
We identified the presence of anti-citrulline autoimmunity years before clinical diagnosis, and demonstrate that preclinical epitope spreading of anti-citrullinated protein antibodies (ACPA) responses is associated with the emergence of subclinical inflammation and the onset of clinical RA
Summary
Rheumatoid arthritis (RA) is the most common inflammatory arthritis worldwide affecting 0.5–1% of the population. 70% of cases of established RA are characterized by the presence of autoantibodies, either rheumatoid factor (RF) or antibodies directed against citrullinated proteins (ACPA), of which antibodies to cyclic citrullinated peptides (anti-CCP) are the most specific clinical test currently available [3,4,5]. These antibodies and inflammatory cytokines [6,7,8] are present years prior to the onset of symptoms in RA, suggesting that the autoimmune processes leading to arthritis are present long before overt disease manifestations
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