Mechanisms of Disease: environmental factors in the pathogenesis of rheumatic disease

Although environmental factors have been implicated as risk factors for the development of rheumatic disease, our understanding of which exposures are important in disease pathogenesis and possible mechanisms by which these factors might act remains limited, as discussed in this Review. Most rheumatic diseases are complex disorders for which pathogenetic mechanisms are poorly understood. Nonetheless, increasing evidence suggests that many of these illnesses result from one or more specific environmental exposures in genetically susceptible individuals. Although much progress has been made over the past few decades in advancing our knowledge of the genetics of rheumatic diseases, few studies have assessed environmental features and understanding of which exposures are important in pathogenesis remains limited. In this article, we review the difficulties inherent in deciphering the interacting environmental and genetic risk factors for rheumatic diseases, the current state of knowledge of infectious and noninfectious risk factors, possible mechanisms by which environmental exposures might induce pathologic processes and future directions. The advances in technologies and statistical approaches, development of collaborating consortia and focused resources that have resulted in the explosion of genetic information must now be applied to environmental studies so we can eventually interrupt pathogenesis before the onset of disease and transform the practice of medicine from curative to pre-emptive paradigms. Key Points Complementary lines of evidence point to the role of environmental factors in the pathogenesis of rheumatic diseases In addition to well-described cases of drug-induced disease, epidemiologic data support a role for inhaled silica, solvents, pesticides, tobacco smoke and DNA viruses in triggering many rheumatic diseases Mechanisms are ill-defined for all environmentally-associated rheumatic diseases Integrated collaborative approaches, focused resources and better tools, including validated exposure biomarkers and questionnaires, are needed to define additional environmental risk factors and, ultimately, prevent the development of certain forms of rheumatic disease