A prospective study of the development of inflammatory arthritis in the family members of Indigenous North American people with rheumatoid arthritis

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.