What do pesticides, farming, and dose effects have to do with the risk of developing connective tissue disease?

Could pesticide exposure in the home or in the fields lead to an increased risk of developing rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE)? It seems that potential environmental exposures that could lead to immunologic derangement and the onset of autoimmunity are almost ubiquitous—cigarette smoke, crystalline silica, asbestos, mercury, lead, viruses and other microbes, pesticides, solvents, petroleum byproducts, and more. Many of these potential risks have been examined in relation to connective tissue disease risk. Not all have been rigorously examined and such studies are challenging. In this issue of Arthritis Care & Research, Parks et al have investigated whether there is an association between residential or agricultural pesticide exposure and the subsequent development of RA or SLE using data from a large cohort of older women, the Women’s Health Initiative Observational Study (WHI-OS) (1). At the start of the multicenter WHI-OS, the 93,676 postmenopausal participants were asked whether they had worked or lived on a farm and for how long (2). At the end of the first year of followup, they were also asked about insecticide exposure since age 21 years. They were asked whether they had “poured, sprayed, or applied insecticides” at home, leisure, or work, but not to report use of insect repellents, herbicides or fungicides, or pet treatments for fleas, ticks, or mites. The questionnaire attempted to have women quantify personal use of insecticides and application by others in duration (up to 20 years) and frequency of use (up to 25 times a year). Over the last few years, there has been an effort to identify and validate new-onset cases of RA and SLE in the WHI by requesting and reviewing a subset of medical records for these women (3). A hybrid strategy combining a woman’s self-report of new-onset RA or SLE with the receipt of at least one of a list of diseasemodifying antirheumatic drugs (DMARDs) had an acceptable positive predictive value of 62.2% for RA and 40.0% for SLE. In the WHI-OS, 186 incident cases of RA and 35 cases of SLE were then identified during the first 3 years of followup. A significantly increased risk of developing RA and SLE associated with pesticide use, in particular the personal use of pesticides (but not application by others in the residential or office setting), was detected in this study. Among the women with a history of farming, those who indicated they had been exposed to the frequent application of pesticides by others had a 2.7 times increased risk of RA/SLE. The risks of both RA and SLE appeared to be elevated, although the results were reported for the most part in terms of RA/SLE risk (with the small number of SLE cases, the confidence intervals were wide and the results nonsignificant for SLE alone). The association between the personal use of pesticides and the increased risk of RA and SLE will first need to be validated. It may be a false-positive; chance, bias, or confounding might explain the association. The study has limitations, although most of these would have resulted in misclassification and muddling, therefore biasing the study toward the null or no finding. The case definition of self-reported RA or SLE and use of certain DMARDs was not very accurate, and there certainly could have been misclassification of both cases and healthy women. The wording on the WHI questionnaire was vague and may have been difficult to understand, leading to misreporting. While the exposure assessment in this study may have been a bit rough and the outcome assessment may have been a bit coarse, reported use of pesticides was clearly associated with an increased risk of RA and SLE among these older women, with a dose response! Personally mixing or applying pesticides less than once a year was associated with no increased risk, but the risk steadily increased according to the number of times a year and the number of years of personal mixing and pesticide application. Those with the highest amounts and durations of exposure had a 2.2-fold higher risk of developing RA or SLE than those with no exposure. Epidemiologists love dose responses. They point to underlying biologic mechanisms and perhaps even causaKaren Costenbader, MD, MPH, Francine Laden, ScD: Brigham and Women’s Hospital, Boston, Massachusetts. Address correspondence to Karen Costenbader, MD, MPH, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail: kcostenbader@partners.org. Submitted for publication September 15, 2010; accepted in revised form September 23, 2010. Arthritis Care & Research Vol. 63, No. 2, February 2011, pp 175–177 DOI 10.1002/acr.20356 © 2011, American College of Rheumatology