Expansion of Alternative Autoantibodies Does Not Follow the Evolution of Anti–Citrullinated Protein Antibodies in Preclinical Rheumatoid Arthritis: An Analysis in At‐Risk First Degree Relatives

Abstract

Objective. Co-occurrence of autoantibodies specific for ≥1 autoimmune disease is widely prevalent in rheumatoid arthritis (RA) patients. To understand the prevalence of polyautoimmunity in preclinical RA, we performed a comprehensive autoantibody assessment in a First Nations cohort of at-risk first-degree relatives (FDR) of RA patients, a subset of whom subsequently developed RA (progressors).Methods. Venous blood was collected from all study participants (n = 50 RA patients and 64 FDR) at scheduled visits, and serum was stored at −20°C. High-sensitivity C-reactive protein level, anti-citrullinated protein antibody (ACPA) status, and autoantibody status were determined using commercially available enzyme-linked immunosorbent assay kits. Rheumatoid factor (RF) was detected by nephelometry. Antinuclear autoantibodies (ANA) were identified using Hep-2 indirect immunofluorescence assay (IFA) and classified according to international consensus nomenclature as various anti-cell (AC) patterns.Results. Of our study cohort, 78.9% had positive ANA reactivity (≥1:80), which was either a homogenous, finespeckled (AC-1 and AC-4) or mixed IFA pattern. Importantly, the AC-4 and mixed ANA patterns were also observed in progressors at the time of disease onset. While all of the RA patients showed a high prevalence of arthritis-associated autoantibodies, they also had a high prevalence of extractable nuclear antigen-positive autoantibodies to other autoantigens. In FDR, we did not observe any increase in serum autoreactivity to nonarthritis autoantigens, either cross-sectionally or in samples collected longitudinally from progressors prior to RA onset.Conclusion. While alternative autoimmunity and ANA positivity are widely prevalent in First Nations populations, including asymptomatic, seronegative FDR, expansion of alternative autoimmunity does not occur in parallel with ACPA expansion in FDR and is restricted to patients with established RA.

Increased frequency of TIGIT+ CD4 T Cell subset in autoantibody-positive first-degree relatives of patients with rheumatoid arthritis

“…The immunological mechanisms that underlie the development of the RA autoantibodies, and the progression towards pathogenic autoimmunity in specific individuals, remain unclear. Although alterations in circulating cytokines and chemokines detected in readily accessible serum/plasma samples have provided important clues in this regard ( 3 , 10 , 17 , 18 ), disturbances in immune cell populations have not been defined, primarily because of the difficulty in obtaining suitable samples from at-risk individuals. In the current study, we used multiparametric flow cytometry to profile peripheral blood T and B lymphocytes in a cohort of RA autoantibody positive at-risk individuals and compared them to autoantibody negative individuals from the same population, and to RA patients with established disease.…”

Disparities in rheumatoid arthritis outcomes for North American Indigenous populations

“…We recently demonstrated a high prevalence of ANAs in a longitudinal cohort of the first-degree relatives (FDR) of INA RA patients. Interestingly, despite this high prevalence, in those individuals who ultimately developed seropositive RA, there was a progressive expansion of the ACPA and RF autoantibodies, but not the ANAs [ 31 ]. These observations may point to unique immunoregulatory factors that broadly predispose this population to autoreactivity, while other factors determine the specificity of this autoreactivity, and in turn, the clinical manifestations.…”