An independent association of the non-SE allele DRB1*0901 with RA was confirmed in this population, and this allele in combination with a SE allele was associated with younger age at disease onset. FDR of RA probands have a higher prevalence of anti-CCP antibodies than more distant relatives and unrelated controls, suggesting a gradient of risk for disease development. Immunogenetic risks may act early in disease pathogenesis at the level of initiation of RA autoantibody formation; however, it is not clear what additional genetic and environmental risks are involved in progression to clinical disease.

Compared to white patients, NAN patients with RA develop disease earlier, are more frequently seropositive, have greater large joint involvement, and greater disease burden, although treatment is more aggressive. These differences are present early and persist throughout the disease course.

Objective To determine the incidence of inflammatory arthritis and autoantibody prevalence in Indigenous North American people. Methods Unaffected relatives of Indigenous North Americans with rheumatoid arthritis (RA) from central Canada and Alaska were systematically monitored from 2005 to 2017. Rheumatoid factor (RF) and anti–citrullinated protein antibodies (ACPAs) were tested at every visit, and a subset was tested for ACPA fine specificity using a custom multiplex assay. Multistate models based on all available study visits were developed to determine the likelihood of transitioning between autoantibody states, or to inflammatory arthritis. Results Eighteen of 374 relatives (4.8%) developed inflammatory arthritis during follow‐up (after a mean ± SD of 4.7 ± 2.4 years), yielding a transition rate of 9.2 cases/1,000 person‐years. Thirty percent of those who developed inflammatory arthritis were seronegative at baseline, but all were seropositive at inflammatory arthritis onset. Although 30% of ACPA/RF double‐seropositive individuals developed inflammatory arthritis (after 3.2 ± 2.2 years), the majority of these individuals did not develop inflammatory arthritis. Multistate modeling indicated a 71% and 68% likelihood of ACPA and RF seropositive states, respectively, reverting to a seronegative state after 5 years, and a 39% likelihood of an ACPA/RF double‐seropositive state becoming seronegative. Fine specificity testing demonstrated an expansion of the ACPA repertoire prior to the development of inflammatory arthritis. Conclusion Despite a high incidence of inflammatory arthritis in this cohort of at‐risk relatives of Indigenous North Americans with RA, a large proportion of autoantibody‐positive individuals do not develop inflammatory arthritis and revert back to an autoantibody‐negative state.

Objective Anti–citrullinated protein antibodies (ACPAs) are disease‐specific biomarkers in rheumatoid arthritis (RA). More than 90% of IgG ACPAs harbor N‐linked glycans in the antibody variable (V) domain. The corresponding N‐glycosylation sites in ACPA V‐region sequences result from somatic hypermutation, a T cell–dependent process. As ample evidence indicates that T cells drive the maturation of the ACPA response prior to arthritis onset, we undertook this study to investigate whether the presence of glycans in IgG ACPA V domains predicts the transition from predisease autoimmunity to overt RA. Methods We analyzed 2 independent sets of serum samples obtained from 126 ACPA‐positive first‐degree relatives (FDRs) of RA patients. Both sets originated from an Indigenous North American population and comprised cross‐sectional and longitudinal samples of individuals who did or did not develop inflammatory arthritis. Serum IgG ACPAs were affinity‐purified and subjected to ultra high‐performance liquid chromatography–based glycan analysis. Results In both data sets, FDR‐derived IgG ACPA displayed markedly lower levels of V domain glycans (<50%) compared to IgG ACPA from RA patients. Notably, FDRs who later developed RA showed extensive V‐domain glycosylation before the onset of arthritis. Moreover, IgG ACPA V‐domain glycosylation was strongly associated with future development of RA (hazard ratio 6.07 [95% confidence interval 1.46–25.2]; P = 0.013). Conclusion Extensive glycosylation of the IgG ACPA V domain is present in a subset of predisposed FDRs of Indigenous North American RA patients. The presence of this feature substantially increases the risk of RA development. Based on these findings, we propose that glycosylation of the IgG ACPA V domain represents a predictive marker for RA development in ACPA‐positive individuals and may serve to better target prevention measures.

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.