Preclinical Rheumatoid Arthritis: Identification, Evaluation, and Future Directions for Investigation

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Studies of Preclinical Rheumatoid Arthritis

Multiple studies have shown that RA-related autoantibodies are present years before the diagnosis of RA (Table 1).1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 del Puente and colleagues,1 who investigated RA in the Pima Indians in the Southwestern United States, showed that rheumatoid factor was present before the onset of clinically apparent RA. Aho and colleagues,2, 12, 13, 14 who investigated preclinical RA in Finland using a biobank of stored prediagnosis samples, and Jonsson and colleagues,15 who used

Part 2. The phases of rheumatoid arthritis development: from genetic risk to clinically apparent disease

Based on the above discussion, including the presence of preclinical RA-related autoantibodies and inflammatory markers, the genetic and environmental factors associated with RA, the models of autoimmune disease development established in prospective studies of T1DM, and the animal models of disease, it is likely that RA develops 3 phases, outlined as follows and in Fig. 1A. The initial phase (Phase 1) is characterized by genetic risk for RA, during which no biomarkers of active autoimmunity

Part 3. Defining preclinical rheumatoid arthritis and transition into clinically apparent disease

A key aspect of this 3-phase model of RA development is that there is a transition period from the “preclinical” state (or Phases 1 and 2), where specific disease markers may be present but there are no symptoms or signs of active inflammatory disease, to a “clinical” period of RA, when symptoms and signs of active inflammatory disease are present. There may be agreement that RA-related autoantibody positivity, in the absence of joint symptoms or other organ injury, in subjects that eventually

Genetic and Environmental Interactions in Preclinical Rheumatoid Arthritis

As discussed earlier, the genetic and environmental influences that lead to the preclinical phase of disease development are likely key features in the development of RA-related autoimmunity. However, given the observed length of time between the appearance of autoimmunity and diagnosis of RA, standard case-control study approaches using subjects with established RA may not optimally allow for the identification of environmental risk factors for RA or at what point the risk factors influence

Part 5. Future research in preclinical rheumatoid arthritis

There are multiple approaches to investigate preclinical RA, and these are outlined in Table 2. The investigation of preclinical RA would ideally take an approach similar to the Framingham study, which followed a large population over time to investigate causes of cardiovascular disease using serial measures of biomarkers and clinical outcomes.130 However, due to the low prevalence of RA, large-scale population studies at single centers may be impractical due to the cost of screening and

Summary

Based on multiple studies in RA as well as other autoimmune diseases, RA likely develops in phases exhibited by genetic risk, asymptomatic autoimmunity and, finally, clinically apparent disease, with transformations between these phases occurring due to combinations of genetic, environmental, and immunologic factors. Investigating the preclinical phases of RA development will provide key insights into the factors that lead to disease, as well as allow for development of predictive models for

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