This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rheumatoid Arthritis (RA) is an autoimmune disease that affects joints and extra-articular sites, leading to joint destruction, significant morbidity and increased mortality. Analysis of other autoimmune diseases, such as Type 1 Diabetes Mellitus (DM), has shown that the majority of individuals that are ultimately clinically affected with these conditions exhibit three sequential phases of disease progression: 1) Carriage of genetic risk primarily through HLA associations, 2) Presence of clinically silent autoantibodies for one or more years, and 3) Clinically apparent target organ injury. In Type 1 DM, by determining epidemiologic relationships in children who are clinically unaffected with hyperglycemia but are at a markedly higher risk in the next five years for development of clinically apparent disease due to the presence of multiple highly predictive Type 1 DM-related autoantibodies, important interactions between milk and other early food exposures such as cereals and gluten, viral infections, vaccinations, and other proposed causal or associated environmental factors have been able to be studied in great detail. These and related studies of autoimmune disease evolution whose primary outcome measures are disease-related autoimmunity in asymptomatic individuals, rather than clinically apparent disease itself, can provide unique insights into pathogenesis because they are accomplished without substantial recall bias or the untoward effects of clinically active disease and target organ damage. We propose that RA also exhibits these phases of disease and that, in a similar manner as Type 1 DM, analysis of epidemiologic associations within the genetically at-risk and autoantibody positive but clinically unaffected individuals will provide important insights into the pathogenesis of this disease. Importantly, previous analyses of individuals affected with RA has established a significant relationship of the 'shared epitope' that is carried within certain HLA DR4, DR1 and other DRB1 alleles with both the genetic risk and severity of RA. There is also a newly-established relationship between the presence of RA in affected individuals and highly specific RA-related autoantibodies designated anti-cyclic citrullinated peptide (CCP) antibodies. Several studies have recently demonstrated that anti-CCP and other RA-related autoantibodies, as well as alterations in inflammatory markers, may be present several years prior to the onset of clinical disease. However, with the exception of results we have recently developed that are shown below in the Preliminary Data section, little is known about the association of high-risk HLA alleles, RA-related antibodies and environmental exposures in any population that is genetically at-risk but not yet clinically affected by RA.
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