OBJECTIVE: To describe a large, multicenter prospective cohort study of 
first-degree relatives (FDRs) of probands with rheumatoid arthritis (RA), and 
outline the use of such a study in investigating the natural history of RA 
development.
METHODS: A total of 1,058 FDRs, none of whom met the American College of 
Rheumatology criteria for RA, were enrolled in a prospective study investigating 
genetic and environmental influences on the development of RA-related 
autoimmunity. Demographic, epidemiologic, genetic, autoantibody, and physical 
examination data from the initial study enrollment visit were described for 
these FDRs, and the relationship was examined between genetic factors, 
autoantibodies, inflammation, and joint disease.
RESULTS: Fifty-five percent of the FDRs had > or =1 copy of the shared epitope, 
20% had > or =1 copy of the PTPN22 polymorphism, and approximately 16% were 
positive for rheumatoid factor (RF; including isotypes) and/or anti-cyclic 
citrullinated peptide antibody. IgM-RF positivity is associated with > or =1 
tender joint on examination (odds ratio [OR] 2.50, 95% confidence interval [95% 
CI] 1.27-4.89; P < 0.01) and elevated C-reactive protein (CRP) levels (OR 5.31, 
95% CI 1.45-19.52; P = 0.01).
CONCLUSION: FDRs without RA demonstrate high prevalences of genetic risk factors 
and RA-related autoantibodies. Additionally, an RF association with tender 
joints and elevated CRP levels suggests that autoantibodies are a valid 
intermediate marker of RA-related autoimmunity in this cohort. This prospective 
FDR cohort will be a valuable resource for evaluating the relationship between 
genetic and epidemiologic factors and the development of RA-related 
autoimmunity.