Correspondence Environmental Autoimmunity Group, National Institutes of Health, DHHS, Clinical Research Center, Room 4-2352, Bethesda, MD 20892-1301, USA

Email millerf@mail.nih.gov

Original article

Sverdrup B et al. (2005) Association between occupational exposure to mineral oil and rheumatoid arthritis: results from the Swedish EIRA case-control study. Arthritis Res Ther 7: R1296–R1303   PubMed

Synopsis

Background

Although rheumatoid arthritis (RA) is known to be dependent on both genetic and non-genetic factors, little is known about the extent to which environmental influences, such as exposure to mineral oils, affect disease occurrence.

Objectives

The object of this study was to explore the relationship between occupational exposure to mineral oil and the potential risk of RA. Other objectives included the investigation of a link between exposure to mineral oil and increased risk of rheumatoid factor (RF)-positive RA, RF-negative RA, anti-citrulline-protein antibody (anti-CP)-positive RA, and anti-CP-negative RA.

Design and intervention

This was a population-based, case–control study that included patients aged between 18 and 70 who were newly diagnosed with RA based on the American College of Rheumatology criteria, and randomly-selected, healthy controls. Selection criteria for patient controls were based on age, sex and geographical area. Patients with undifferentiated arthritis were not included in this study. All patients completed a questionnaire on lifestyle factors, occupational exposures, health, socioeconomic factors and demographic data in order to determine the effect on relative risk of developing RA attributable to exposure to mineral oils. Patients were then tested for rheumatoid factor, anti-CP antibody and human leukocyte antigen DRB1 (HLA-DRB1) allele. Results were adjusted for possible confounding factors, such as age, geographical location, smoking status and occupation.

Outcome measures

The primary outcome measure of this trial was increased prevalence of RA in patients exposed to mineral oils. Secondary outcome measures were the prevalence of RF-positive RA, RF-negative RA, anti-CP-positive RA or anti-CP-negative RA in patients exposed to mineral oils.

Results

A total of 1,419 patients participated in this study. The mean disease duration at the beginning of the study was 10 months. Tests for rheumatoid factor showed that 65.5% of women and 66.3% of men included in the study were RF-positive. Occupational exposure to mineral oils, most commonly motor oil and hydraulic oil, was predominant in men (135 male cases and 132 controls, compared with 21 female cases and 21 controls). Analyses including only the male patients showed that exposure to any mineral oil was directly associated with increased risk of RA (30%, relative risk = 1.3, 95% CI 1.0–1.7). Further analyses dividing the RA cases in terms of RF-positive RA and RF-negative RA showed that patients who were positive for RF had an increased risk of RA when exposed to mineral oils (relative risk = 1.4, 95% CI 1.0–2.0). Upon further division of RA cases into patients positive for anti-CP antibody and patients negative for anti-CP antibody, it was shown that patients positive for anti-CP antibody had a 60% increased risk of RA associated with exposure to any mineral oil (relative risk = 1.6, 95% CI 1.1–2.2). No strong interaction was found between the presence of HLA-DR shared epitope genes and exposure to mineral oil. Analyses of potential interactions between smoking and exposure to mineral oils were inconclusive, owing to the small numbers of patients involved.

Conclusion

Occupational exposure to mineral oil is directly linked with both an increased risk of RF-positive RA and an increased risk of anticitrulline antibody-positive RA.

Commentary

Some of the most common questions rheumatologists are asked by new patients relate to the cause of disease: how the patient got their disease, whether exposure to a given environmental agent of their concern was implicated, and what the potential consequences for them or their family are if exposure to that agent is continued. Although these questions appear straightforward, the answers are certainly not. Several lines of evidence support the hypothesis that many rheumatic diseases result from environmental exposures in genetically susceptible individuals;¹ yet, few appropriately designed and adequately powered investigations have been conducted to address these issues. Although the mysteries of the genetics of RA and other immune-mediated disorders are being unravelled by recent molecular and statistical advances,² studies of environmental risk factors—which are hampered by inadequately validated biomarkers and clinical tools to assess exposures—have been scarce.

Mineral oils, including motor oils and other lubricating oils, are complex mixtures of straight chain and polycyclic aromatic hydrocarbons. They are distilled from crude oil and might include additives to improve their performance. Selected mineral oils have been shown to induce arthritis and other autoimmune diseases in genetically susceptible animal models,^{3, 4} but the mechanisms of these effects and whether or not they relate to human disease have not been elucidated.

This population-based, case–control study of incident RA cases from Sweden by Sverdrup and colleagues directly addresses the question of a relationship between mineral oils and autoimmune disease. These results are the first to suggest that occupational exposure to mineral oils is associated with an increased risk of RA in men. This association pertained only for patients with RA who were either positive for RF or had antibodies to citrulline-containing peptides, and there was no evidence of a gene–environment interaction between HLA genes with the shared epitope and mineral oil exposure.

Though this study was carefully performed and attempts were made to limit confounders, some shortcomings remain. One is that of study power to detect changes; although 1,419 cases and 1,674 controls were evaluated, less than 10% reported any mineral oil exposure, possibly resulting in the rather low effect sizes and borderline significance of the associations. There was no investigation of possible dose-response effects, in which longer periods of exposure or greater exposures might have been found to be even more strongly associated with RA. Another problem with this, and other studies that rely on questionnaires of past events that do not have a confirmatory exposure biomarker, is the possible misclassification of exposure because of recall bias.

Despite these limitations, this study is an important milestone in the understanding of environmental risk factors for RA. It supports current thinking that it is likely there are multiple subsets of RA of which some, perhaps due to genetic bias, can be initiated by one or another particular environmental agent.⁵ These results spur us on to characterize further genetic and environmental factors in the hope of eventually preventing such diseases. Whether continued exposure to mineral oils in those with past exposures alters disease outcomes remains unknown, but a cautious approach would be to minimize these exposures for such RA patients.

Acknowledgments

The synopsis was written by Jasmine Farsarakis, Associate Editor, Nature Clinical Practice.

References

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3. Kleinau S et al. (1991) Adjuvant oils induce arthritis in the DA rat. I. Characterization of the disease and evidence for an immunological involvement. J Autoimmun 4: 871–880 | Article | PubMed | ChemPort |
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Subject areas under which this article appears: Epidemiology | Rheumatoid arthritis