Environmental Epidemiology and Risk Factors for Autoimmune Disease

M. A. Dooley, MD, MPH, S. L. Hogan, PhD, MPH

Disclosures

Curr Opin Rheumatol. 2003;15(2) 

In This Article

Abstract and Introduction

It has long been recognized that environmental influences play an important role in the risk of developing chronic rheumatic disease. Defining specific pathogenic environmental mediators that may trigger the development or progression of autoimmune disease remains a focus of increasing investigative effort. Factors promoting disease may not be identical to factors that influence the severity or progression of the disorder. Human monozygotic twin studies, animal studies, and genetic models demonstrate that genetic influences strongly determine whether one will develop autoimmunity, however, genes affecting the metabolism of exogenous agents that may trigger disease expression have only recently drawn attention. In this article the authors review recent reports that advance our understanding of previously recognized environmental risk factors and challenge accepted beliefs that increased estrogenic exposures predate the incidence of autoimmune disorders, systemic lupus erythematosus in particular.

The cause(s) of autoimmune disorders remain largely unknown. Considerable evidence supports a role for environmental agents in inducing autoimmune disorders.[1,2*] An estimated 3% of the population in the United States is affected by a tissue-specific or systemic autoimmune disorder.[3] Most autoimmune disorders affect women more frequently, including 85% of patients with systemic lupus erythematosus (SLE), scleroderma, or thyroiditis. Autoimmune diseases thus contribute disproportionately to morbidity and mortality among young to middle-aged women.[4] Rather than disease-specific genes for individual autoimmune disorders, there may be "autoimmunity genes" that increase the risk for development of autoimmune disorders in families.[5] Autoimmune disorders may result from multiple interactions of genes and environmental factors.[6]

The evaluation of genetic contributions in human autoimmunity has frequently relied on family studies, and particularly, twin studies. Twin studies have been criticized for including a higher proportion of monozygotic, female, and disease concordant volunteers.[7,8,9] Previous twin studies have reported significantly higher concordance rates of 24 to 50% in autoimmune diseases such as rheumatoid arthritis (RA) and SLE among monozygotic twins.[7,10,11,12] However, recent population-based twin studies in RA detect at most a 12 to 15% concordance rate among monozygotic twins, though are criticized for their lack of validated classification criteria for disease confirmation.[13,14,15]

A recent nationwide study among twins in Denmark reports only a minor contribution of genetic factors to the risk of developing RA.[16*] Subjects were ascertained by questionnaire; those reporting RA provided a detailed clinical profile and a confirmatory phone interview. Record linkage with the Danish discharge registry was employed to locate additional subjects. Both twins were invited to a clinical examination, structured interview, and blood sampling for zygosity, rheumatoid factor, and HLA typing. The response rate was 75% in older and 86% in younger twins. A total of 13 monozygotic and 36 dizygotic RA concordant twin pairs participated. No significant differences between monozygotic and dizygotic twins were found in sex, age at onset of RA, mean discordance time, presence of rheumatoid factor, bony erosions, or shared epitopes. Given the small number of twins pairs included, the study is not sufficiently powered to conclude that genetics contributes little to the risk of developing RA. A recent population-based study of risks of autoimmune thyroid disease stresses the increasing importance of environmental contributions to the development of autoimmunity.[17*]

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