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ORIGINAL ARTICLES

Silica Dust Exposure Increases Risk for Rheumatoid Arthritis

A Swedish National Registry Case–Control Study

Wrangel, Oscar MSc; Graff, Pål PhD; Bryngelsson, Ing-Liss BSc; Fornander, Louise PhD; Wiebert, Pernilla PhD; Vihlborg, Per MD

Author Information

Department of Occupational and Environmental Medicine, Faculty of Medicine and Health, Örebro University, Sweden (Mr Wrangel, Bryngelsson, Dr Fornander, and Dr Vihlborg); National Institute of Occupational Health (STAMI), Oslo, Norway (Dr Graff); Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (Dr Wiebert); Centre for Occupational and Environmental Medicine, Region Stockholm, Sweden (Dr Wiebert); Department of Geriatrics, Faculty of Medicine and Health, Örebro University, Sweden (Dr Vihlborg).

Address correspondence to: Pål Graff, PhD, National Institute of Occupational Health (STAMI), Pb 5330, 0304 Oslo, Norway ([email protected]).

Pål Graff (the manuscript's guarantor) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported, no important aspects of the study have been omitted; any discrepancies from the study as planned (and, if relevant, registered) have been explained.

The Corresponding Author has the right to on behalf of all authors and does grant on behalf of all authors.

The study had financial support from Region Örebro County for the submitted work. No financial relationships with any organizations that might have an interest in the submitted work existed in the previous 3 years, nor did any other relationships or activities that could appear to have influenced the submitted work.

The authors report no conflicts of interest.

The study was approved by the Swedish Ethical Review Authority; DNR 2017/252.

Clinical significance: The clinical significance of this paper is the finding that silica dust exposure is associated with a statistically significant increased risk for Rheumatoid Arthritis among silica-exposed men. Our findings suggest that the risk for seronegative and seropositive RA risk is equal. This underlines the possible health hazards regarding silica exposure.

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

Journal of Occupational and Environmental Medicine: November 2021 - Volume 63 - Issue 11 - p 951-955
doi: 10.1097/JOM.0000000000002281
  • Open

Abstract

Rheumatoid arthritis (RA) is an inflammatory joint disease characterized by pain and swelling in the joints. RA is a chronic disease that can lead to decreased quality of life and, ultimately, joint destruction. It may also lead to premature death if not properly treated.1 The disease affects somewhere between 0.5% and 1% of the population in the industrialized world.2 Currently, the exact etiology remains unknown. Previous studies have suggested a combination of genetic risks and possible environmental triggers. Certain known HLA shared epitope alleles, HLA-DRB1∗01, and HLA-DRB1∗4, are known to increase susceptibility for RA.3,4 Previous research points to smoking as an environmental trigger.4–6 The combined effects of the HLA-DRB1 alleles and smoking could initiate an immune response to anti-citrullinated peptide antibody (ACPA) and thereby lead to the development of seropositive RA.7,8 Infections of the respiratory system have also been linked to RA.9,10 These possible triggers point toward the lung being an initiating site of injury in ACPA-positive RA.11 Occupational exposure to possibly inflammatory types of dust has also been linked to the development of RA. Textile dust, traffic pollution, and silica dust are all agents that have, in earlier research, been shown to increase the risk for ACPA-positive RA.12–14 These studies have not shown the same level of risk increase for ACPA-negative RA, suggesting either a difference in the pathogenesis or environmental triggers.

A recent meta-study on occupational exposure to silica found an association with an increased risk of developing RA.15 Professions with high silica exposure include foundry fettlers, miners, and stonemasons. It is estimated that more than 3.2 million workers in the EU are exposed to silica dust in their professions.16 Inhaled silica dust has been linked to silicosis, sarcoidosis, and COPD.17–19 In certain cases, silica has also been suspected of causing lung cancer and is currently classed as a carcinogen by the IARC.20 Silica dust exposure can also increase the risk of chronic kidney disease.21

There have been several articles investigating the role of silica dust and RA. One of the larger studies, containing 18,335 cases, found modest support for an association between crystalline silica exposure and rheumatoid arthritis.22 However, this study used death certificates to determine if cases had RA. A recent Danish register study also found an incidence rate ratio for RA among silica-exposed men.23

This study aimed to examine if silica dust exposure increases the risk for RA and if there was a difference in risk for developing seropositive RA and seronegative RA.

METHODS AND MATERIALS

Swedish residents all have roughly equal access to healthcare services. Each person also has a unique personal identification number. The data was collected from the National non-primary outpatient care register kept by the Swedish National Board of Health and Welfare (NBHW). All patients between the age of 20 and 65 who had been diagnosed with M05 (seropositive Rheumatoid arthritis) or M06 (seronegative Rheumatoid arthritis) according to the International Classification of Diseases, 10th Edition (ICD-10), between 2005 and 2016 were included in the study. The seropositive RA (M05) cases in the register are generally conformed as ACPA positive. The information was then matched against the register for the cause of death, kept by the NBHW. This register is maintained and validated by NBHW and contains data on registered outpatients of healthcare facilities throughout Sweden. In total, 31,139 cases were initially included. However, when investigating the annual cases, there was an elevated number of cases in the first 2 years under investigation (2005 to 2006). This high number might be a result of individuals being registered in the newly established register during follow-up medical examinations in addition to new cases. Because the first diagnosis date cannot be established for the patients registered in the follow-up medical examinations, cases from 2005 to 2006 were thus excluded (as a wash-out period), see Figure 1.

F1
FIGURE 1:
Flow chart of included and excluded cases.

Two controls were included for each patient. The controls were not first-degree relatives of the case and did not have the diagnosis M06/M05. They were the same age and sex. They resided in the same county during the time that the patient received their diagnosis. The Swedish Central Bureau of Statistics (SCB) provided the controls using their multigenerational register, which contains information regarding biological and adopted first-degree relatives of all Swedish residents since 1961 of people born 1932 or later. The individuals included in the study were then checked in the SCBs longitudinal integrated database for health insurance and labor market studies (LISA) to see what occupation the individual had and for how long they worked in that profession and the register for emigration (SCB). Occupations with exposure to silica dust were then identified using a modified version of the Finnish Information System on Occupational Exposure job-exposure matrix (FINJEM).24,25

Statistical Analysis

A CLR was used to analyze the results. Stata: Software for Statistics and Data Sciences for windows was used to run the CLRs.

The data investigated all RA and were divided into seropositive and seronegative RA (M05/M06). A separate analysis was then run, sorting cases by their years of exposure stratified into less than 1 year of employment, 1 to 5 years of employment, and 5 to 10 years of employment and more than 10 years of employment. The relevant results are displayed in tables, and those results with lesser significance are mentioned in the text.

Ethical Considerations

The Regional Ethics Commission in Uppsala, Sweden approved the study (DNR 2017/252).

RESULTS

In total, 31,139 cases were included in the study. Of these cases, 20,536 were seropositive (M05) and 10,603 were seronegative (M05). Each case had two matched controls (Fig. 1).

A higher frequency of men had been exposed compared to women in both the case and control groups. This fact was also true for both seropositive RA and seronegative RA. RA was roughly three times more common among women than men in this study. Men were more likely to be employed in professions exposed to silica. Less than a fifth of all included subjects had at any time been exposed to silica dust at their workplace. The majority of those that had been exposed had only been exposed for 1 to 5 years. The mean age at inclusion was 52 years for men and 29 years for women. For seronegative RA, the mean age was 50 for men and 48 for women. The mean age for seropositive RA was 53 for men and 50 for women (Table 1).

TABLE 1 - Descriptive Statistics of the Study Population
Total Seropositive Rheumatoid Arthritis Seronegative Rheumatoid Arthritis
Cases Controls Cases Controls Cases Controls
Number of participants (%) Men 4482 (26) 8964 (26) 2523 (25) 5046 (25) 1959 (27) 3918 (27)
Women 12,871 (74) 25,742 (74) 7672 (75) 15,344 (75) 5199 (73) 10,398 (73)
Age at inclusion (±SD) Men 52 (11) 52 (11) 53 (11) 53 (11) 50 (12) 50 (12)
Women 49 (12) 49 (12) 50 (12) 50 (12) 48 (12) 50 (12)
Number of exposed (%) Men 589 (13) 987 (11) 340 (14) 572 (11) 249 (13) 415 (11)
Women 214 (2) 407 (2) 134 (2) 231 (2) 80 (2) 176 (2)
Years with exposure (±SD) Men 6.7 (4.2) 6.4 (4.3) 6.8 (4.2) 6.5 (4.1) 6.5 (4.4) 6.2 (4.4)
Women 5.3 (3.7) 5.0 (3.8) 5.4 (3.7) 5.0 (3.6) 5.2 (3.8) 5.0 (4.1)
Diseased (%) Men 246 (6) 293 (3) 170 (7) 186 (4) 76 (4) 107 (3)
Women 366 (3) 445 (2) 250 (3) 273 (2) 116 (2) 172 (2)

Exposure to silica dust gave a statistically higher risk of being diagnosed with RA, odds ratio (OR) of 1.17 (CI 95% 1.07 to 1.28) (Table 2). The risk was highest among those people exposed for more than 10 years, OR of 1.33 (CI 95% 1.10 to 1.61), but an increased risk was also found with shorter exposure time. The same trend was found for men but not women (Table 2) when the study population was stratified according to sex.

TABLE 2 - All Included Cases and Controls of Rheumatoid Arthritis (RA)
Cases, N Controls, N OR 95% CI
Total
 Unexposed 16,550 33,312 1
 Exposed 803 1394 1.17 1.07–1.28
Number of years with exposure
 0 years 16,550 33,312 1
 ≤1 years 136 286 0.96 0.78–1.18
 1.01–5 years 213 353 1.22 1.03–1.46
 5.01–10 years 266 467 1.16 0.99–1.35
 >10 years 188 288 1.33 1.10–1.61
Men
 Unexposed 3893 589 1
 Exposed 7977 987 1.22 1.10–1.36
Number of years with exposure
 0 years 3893 7977 1
 ≤1 years 95 184 1.05 0.82–1.35
 1.01–5 years 136 220 1.27 1.02–1.58
 5.01–10 years 205 355 1.18 0.99–1.41
 >10 years 153 288 1.38 1.12–1.71
Women
 Unexposed 12,657 25,335 1
 Exposed 214 407 1.05 0.89–1.25
Number of years with exposure
 0 years 12,657 25,335 1
 ≤1 years 41 102 0.81 0.56–1.16
 1.01–5 years 77 133 1.16 0.87–1.54
 5.01–10 years 61 112 1.09 0.80–1.50
 >10 years 35 60 1.17 0.77–1.77
Bold numbers indicate statistical significance (P < 0.05).The data are also shown for both men and women and grouped according to years of silica dust exposure. OR, odds ratio.

Exposure to silica dust gave an increased risk for seropositive RA, OR of 1.20 (CI 95% 1.07 to 1.35) when the cases were stratified into seropositive or seronegative RA (Table 3). However, no increased risk was found for seronegative RA for the total population.

TABLE 3 - All Included Cases and Controls Stratified Into Seropositive and Seronegative Rheumatoid Arthritis (RA) and Sorted by Sex and Years of Silica Dust Exposure
Exposed to Quartz Within 5 yrs Before Diagnosis 2007–2016
Seropositive Rheumatoid Arthritis Seronegative Rheumatoid Arthritis
Cases Controls OR CI 95% Cases Controls OR CI 95%
Total
 Unexposed 9721 19,587 1 6829 13,725 1
 Exposed 474 803 1.20 1.07–1.35 329 591 1.13 0.98–1.30
Number of years with exposure
 0 years 9721 19,587 1 6829 13,725 1
 ≤1 year 75 150 1.01 0.77–4.34 61 136 0.90 0.66–1.23
 1.01–5 years 121 204 1.21 0.96–1.52 92 149 1.25 0.96–1.63
 5.01–10 years 166 282 1.20 0.98–1.46 100 185 1.10 0.85–1.41
 >10 years 112 167 1.37 1.07–1.76 76 121 1.27 0.95–1.71
Men
 Unexposed 2183 4474 1 1710 3503 1
 Exposed 340 572 1.22 1.05–1.40 249 415 1.23 1.04–1.46
Number of years with exposure
 0 years 2183 4474 1 1710 3503 1
 ≤1 year 51 95 1.09 0.78–1.54 44 89 1.00 0.70–1.45
 1.01–5 years 73 128 1.17 0.87–1.57 63 92 1.40 1.00–1.94
 5.01–10 years 126 210 1.23 0.98–1.54 79 145 1.12 0.84–1.49
 >10 years 90 139 1.33 1.01–1.75 63 89 1.46 1.04–2.03
Women
 Unexposed 7538 15,113 1 5119 10,222 1
 Exposed 134 231 1.16 0.94–1.44 80 176 0.91 0.69–1.19
Number of years with exposure
 0 years 7538 15,113 1 5119 10,222 1
 ≤1 year 24 55 0.88 0.54–1.42 17 47 0.72 0.41–1.26
 1.01–5 years 48 76 1.26 0.88–1.81 29 57 1.01 0.64–1.60
 5.01–10 years 40 72 1.12 0.76–1.64 21 40 1.05 0.62–1.79
 >10 years 22 28 1.57 0.90–2.75 13 32 0.81 0.43–1.54
Bold numbers indicate statistical significance (P < 0.05).OR, odds ratio.

For both seropositive and seronegative RA, the same trend was observed as for total RA (Table 3), were men who had more than 10 years of exposure had the highest risk with an OR of 1.33 (CI 95% 1.01 to 1.75) for seropositive RA and OR of 1.46 (CI 95% 1.04 to 2.03) for seronegative RA. No excess risk was observed for women.

DISCUSSION

Our results are mostly in line with previous research on the subject. Several studies have shown a link between APCA positive RA and silica dust.14,26 However, the current study, which comprises all registered cases of seropositive and seronegative RA, found an increased OR for men of both seropositive and seronegative RA; OR for seropositive RA 1.22 (CI 95% 1.05 to 1.40) and OR for seronegative RA 1.23 (CI 95% 1.04 to 1.46) (Table 2).

The results indicate that silica-exposed men had a statistically significant risk for RA. When stratified into seropositive and seronegative RA, an increased risk for men was found for both. The risk was highest among those men with the longest exposure. No statistically significant risk was found for women. The reason why the risk increase was greater for men could be because of a difference in actual job exposure. For example, two people employed in the same profession could have widely different levels of exposure due to differences in the performance of tasks. One could speculate if men are more exposed than women within the same occupation.27,28

The findings in this study correlate well with what was found in a Danish study, where men exposed to silica at work had an increased incidence rate for RA, but not silica-exposed women.23

Silica dust exposure has previously been found to increase the risk for RA, even for non-smokers for specifically ACPA-positive RA.26,29 It also seems that the combination of smoking and silica dust has a synergistic relationship in RA development. However, according to other studies, this situation seems to be true only for seropositive RA.6 The finding of an equal OR for seronegative and seropositive RA for silica-exposed men might indicate that the burden of smoking has been reduced in the general population. The results presented in the current study might predominantly be attributed to silica exposure. The results also correlate with a previous Swedish study where silica-exposed men showed an increased risk for both seronegative and seropositive RA.30

This study may overestimate the total exposure since it only measured years of exposure. Consequently, the exposure of a stonemason with high levels of exposure is counted as equal to a glassblower with low levels of exposure. This approach might also underestimate the risk increase as well. The main strength of the study is the large number of cases included, which consist of all registered cases in Sweden for the time period of the study.

The main limitations of this study are that the estimations for exposure are based upon a JEM. There are no data on possible confounders, such as smoking4 in the register used. However, it is reasonable to assume that the prevalence of smoking is roughly the same in cases and controls. If there is a difference, it would most likely be that those people not exposed to silica dust are more likely to be employed in better-paid jobs and a higher socioeconomic status. Because of these factors, they are less likely to smoke.31 Generally, jobs with high silica dust are labor intensive, associated with lower socioeconomic status. Still, the majority of lower-paying occupations do not have significant levels of silica dust exposure.

CONCLUSION

Silica dust exposure is associated with a statistically significant increase in risk for seropositive and seronegative RA among silica-exposed men. The same increased risk was not seen for women. The results are in line with previous studies regarding seropositive RA or total RA. However, the finding that the OR for seronegative and seropositive RA risk was equal differs from other studies which found that seropositive RA was predominant in occupational exposure. The findings in the current study further underlines the possible health hazards regarding occupational silica exposure.

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Keywords:

case–control study; occupational exposure; rheumatoid arthritis; silica

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine.