Environmental and Gene-Environment Interactions and Risk of Rheumatoid Arthritis

Multiple environmental factors including hormones, dietary factors, infections, and exposure to tobacco smoke, as well as gene-environment interactions, have been associated with increased risk for rheumatoid arthritis (RA). The growing understanding of the prolonged period before the first onset of symptoms of RA suggests that these environmental and genetic factors are likely acting to drive the development of RA-related autoimmunity long before the appearance of the first joint symptoms and clinical findings that are characteristic of RA. This article reviews these factors and interactions, especially those that have been investigated in a prospective fashion before the symptomatic onset of RA.

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Individuals with inherited genetic risk factors who are exposed to environmental triggers are at higher risk of rheumatoid arthritis (RA).
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Multiple environmental factors, including exposure to tobacco smoke, occupational exposures, hormones, infections and dietary factors, are associated with RA risk.
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Circulating RA-related autoimmunity is evident in some patients before the appearance of the first joint symptoms and clinical findings of RA. This asymptomatic phase of disease development suggests that important gene and environmental interactions leading to initiation of RA-related autoimmunity occur long before the onset of clinically apparent disease.
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Natural history studies of the asymptomatic phase of RA development are needed to determine the mechanistic role(s) that environmental factors play in the initiation of RA.
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Animal studies link autoantibodies to RA pathogenesis, and going forward may provide insight to the mechanisms of environmental and genetic factors in the pathogenesis of RA.

Key Points

Introduction

Although the etiology of rheumatoid arthritis (RA) is unknown, a growing body of evidence suggests that it develops in individuals with inherited genetic risk factors after exposure to environmental triggers. The identification of autoantibodies and cytokines in the serum many years before the diagnosis of RA led to conceptualization of the development of RA as occurring in phases ( Fig. 1 ). In this model of RA development there is an asymptomatic period of genetic risk in which environmental exposures are encountered, followed by an asymptomatic immune-activation phase in which autoantibodies and inflammatory markers are found, likely followed by a phase of articular symptoms in the absence of clearly definable arthritis, which is finally followed by the phase with signs of inflammatory arthritis (IA) that is perhaps initially unclassifiable but over time evolves to the point at which it is classifiable as RA by established criteria such as the 1987 American College of Rheumatology (ACR) criteria or the 2010 ACR/European League Against Rheumatism (EULAR) criteria. Similar phases of development have been proposed in other autoimmune diseases such as type 1 diabetes and systemic lupus erythematosus (SLE). This pattern suggests a complex series of events in which a genetically susceptible host is exposed to environmental risk factors that trigger autoimmunity with autoantibody production, and a second or more event(s) or exposure(s) that might drive further immune dysregulation and eventual development of symptomatic IA. The interaction between genetic and environmental factors such as cigarette smoking within the subtype of anticitrullinated protein antibody (ACPA)-positive RA provides clues to disease pathogenesis, but much of the complexity of RA etiopathogenesis has yet to be delineated.