The pathogenesis of rheumatoid arthritis is likely to reflect genetic as well as environmental factors. Smoking has been found to increase the risk^1–,³ but little is known about the influence of other environmental factors.⁴

Six previous epidemiological studies have investigated the association between exposure to silica through the respiratory tract and the risk of rheumatoid arthritis.^5–,¹⁰ In these studies, an increased risk for the disease was observed among silica exposed persons from certain occupations or workplaces,^5–7,9 and among persons with manifest silicosis.^5,8 The number of observed cases was, however, small (between 9 and 43) in three of the studies,^6,8,9 and only two studies defined cases according to established clinical criteria.^5,10 Furthermore, only two of the studies (one of which had a total of 43 observed cases⁶) adjusted the results for the potential confounding by smoking.^6,10

To investigate further the association between silica exposure and the risk of developing rheumatoid arthritis, we analysed data from a population based case–control study, in which information about silica exposure as well as about smoking habits had been collected, and where cases were defined according to established clinical criteria.

METHODS

This study is a part of the EIRA (“epidemiological investigation of rheumatoid arthritis”) study, which is an extensive population based case–control study, using incident cases of rheumatoid arthritis from the population aged 18 to 70 years of a geographically defined area of Sweden. The present report is based on analysis of the 276 male cases and 276 male controls included from May 1996 to June 2001. The 654 female cases and the 791 female controls gathered during the same period were excluded from this study because of the small number of silica exposed women.

RESULTS

Of the 276 male cases in this study, 41 were silica exposed. About two thirds of the silica exposed cases were found to have experience in occupations associated with the building industry (construction workers, drivers, electricians, sanitary engineers, painters, stone masons, rock drillers, gardeners, brick layers, and floor layers). The mean duration of silica exposure among the exposed cases and the exposed controls was 20 and 17 years, respectively. Thirty seven (90%) of the 41 silica exposed cases and 15 (75%) of the 20 silica exposed controls had ever been cigarette smokers (table 1⇓).

Silica exposed men had an increased risk of developing rheumatoid arthritis overall when compared with unexposed men, with an odds ratio of 2.2 (95% CI, 1.2 to 3.9), adjusted for age, residential area, and smoking. When older subjects (50 to 70 years of age) were analysed separately, the odds ratio was 2.7 (1.2 to 5.8) (table 2⇓).

The attributable proportion due to silica exposure was about 0.08 when all cases in the study were considered and about 0.55 for the silica exposed cases. When restricting the analyses to the group assumed to be highly exposed—that is, those who had worked with rock drilling or stone crushing—the odds ratio for rheumatoid arthritis overall was 3.0 (95% CI, 1.2 to 7.6) (table 2⇑). There was no significant difference between odds ratios for RF− and RF+ rheumatoid arthritis.

An increased risk of rheumatoid arthritis was only apparent among the silica exposed men who were ever smokers (table 3⇓).

The attributable proportion due to interaction between silica exposure and smoking was estimated to be 0.6 (95% CI, 0.1 to 1.1).

DISCUSSION

Silica exposed men had a twofold increased risk of developing rheumatoid arthritis compared with unexposed men. When older men (50 to 70 years) and younger men (18 to 49 years) were analysed separately, a 2.5-fold increased risk was found among silica exposed men in the older age group, while no increase in risk was seen among the younger men. A somewhat stronger association was observed among persons who had been working with rock drilling or stone crushing, who had a threefold increased risk.

Our data on exposure were reported retrospectively by the cases and controls. This strategy runs the risk of misclassification of exposure because of recall bias, which needs to be considered carefully when interpreting the results. However, the risk of misclassification of exposure because of recall bias was limited in our study because significant dust exposure, particularly when related to an occupation or a work place, has a long duration and commonly occurs in circumstances that are easy to recall. There is still a risk that some silica exposed subjects were classified as unexposed, because silica exposure may occur in the absence if visible dust. Such exposure would probably be unrelated to disease and consequently biases these estimates of relative risks towards the null value.

All potential cases in the present study were examined carefully by a rheumatologist using a structured form to specify concordance with the ACR criteria, and only subjects who fulfilled these criteria were defined as cases. The risk of a substantial misdiagnosis of disease in this study is thus very limited.

Silica exposure may theoretically be linked to other environmental exposures as well as to lifestyle factors and socioeconomic circumstances that may in themselves be related to the possibility of developing rheumatoid arthritis. Adjustments were therefore made for potential differences in smoking habits, age, and residential area between individuals who were silica exposed and those who were not. Adjustment of all results for the potential confounding from socioeconomic class and physical workload were also made, but this affected the results only marginally and is not presented in our report.

If participation is related to silica exposure, this may introduce a selection bias in the estimated odds ratios. The risk of such bias in the present study was limited by the high participation rate (96% among cases and 77% among controls). If the observed increased risk among silica exposed subjects was entirely the result of selection bias (that is, the true odds ratio was 1.0), it can be estimated that 30% of the non-responding controls would have been exposed to silica, which is highly unlikely.

All rheumatology units linked to the general welfare system, as well as privately run rheumatology units within the study area, reported cases to the study. Nevertheless, some cases might have been unidentified. There might, for instance, be cases diagnosed at other health care facilities that were never referred to a participating unit. We consider it unlikely that these unidentified cases would differ substantially with regard to exposure from those who were identified.

Persons with occupational silica exposure generally do physically demanding work. This may increase the likelihood that they will seek help from the health care system in comparison with those doing lighter work. This potential difference between silica exposed and non-exposed individuals in attendance at health care facilities could lead to a difference in the rate of identified cases in the two groups. Adjustment for physical workload did not, however, affect the estimates of the relative risk associated with silica exposure.

In summary, we believe that the present observation of an increased risk of developing rheumatoid arthritis among subjects exposed to silica is real and not an artefact. Previous observations of a possible association between silica exposure and development of rheumatoid arthritis have been reported from different parts of the world, such as north America, South Africa, Britain, and Scandinavia.^5–,¹⁰ As previously mentioned in the introduction, only two of these studies adjusted for the potential confounding from smoking.^6,10

As smoking has been shown to be an environmental risk factor for rheumatoid arthritis,^1–,³ and considering that a correlation between silica exposure and smoking is probable in many contexts, it appears mandatory to take smoking into account when analysing the link between silica exposure and rheumatoid arthritis. In the present study silica exposure was found to be associated with an increased risk of developing rheumatoid arthritis even after adjustment for smoking. Our results were compatible with a synergistic effect of smoking and silica exposure, but did not allow a firm conclusion on this to be drawn owing to the small numbers of silica exposed subjects who had never smoked.

The mechanisms behind the biological effects of silica are still not fully understood. It has previously been proposed that increased release of inflammatory mediators from alveolar macrophages phagocytosing inhaled silica particles may activate macrophages/monocytes and lymphocytes systemically as well as in the rheumatoid synovium.^19–,²⁵ These cell types also have the potential to increase the production of matrix metalloproteinases (MMP)—enzymes involved in the degradation and remodelling of extracellular matrix, which have been shown to be associated with rheumatoid arthritis as well as with silicosis.^26–,²⁹

The production of MMP, as well as of inflammatory mediators such as tumour necrosis factor α and interleukin 1β, is regulated by the transcription factor nuclear factor κB, the activity of which appears to be influenced by silica exposure.^30–,³⁴

MEMBERS OF THE EIRA STUDY GROUP

Ingeli Andreasson, Landvetter; Eva Baecklund (Akademiska Hospital); Ann Bengtsson, Thomas Skogh (Linköping University Hospital); Johan Bratt, Ingiäld Hafström (Huddinge University Hospital); Kjell Huddenius (Rheumatology Clinic in Stockholm City); Shirani Jayawardene (Bollnäs Hospital); Ann Knight, Hudiksvall Hospital; Ido Leden (Kristianstad Hospital); Thomas Lerndal, Göran Lindahl (Danderyds Hospital); Bengt Lindell (Kalmar Hospital); Christin Lindström, Gun Sandahl (Sophiahemmet); Björn Löfström (Katrineholm Hospital); Birgitta Nordmark (Karolinska Hospital); Ingemar Petersson (Spenshult Hospital); Christoffer Schaufelberger (Sahlgrenska University Hospital); Patrik Stolt (Västerås Hospital); Berit Sverdrup (Eskilstuna Hospital); Olle Svernell (Västerviks Hospital); Tomas Weitoft (Gävle Hospital).