BEU, Alm.del - 2020-21 - Bilag 213: Orientering om videnskabelig artikel om sammenhæng mellem udsættelse for kvartsstøv og øget risiko for autoimmune gigtsygdomme i Danmark, fra beskæftigelsesministeren

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IEA

International Journal of Epidemiology,

2021, 1–14

doi: 10.1093/ije/dyaa287

Original Article

International Epidemiological Association

Original Article

Occupational exposure to respirable crystalline

silica and risk of autoimmune rheumatic

diseases: a nationwide cohort study

Signe Hjuler Boudigaard ,

* Vivi Schlunssen,

2,3

Jesper Medom Vestergaard,

Klaus Søndergaard,

Kjell Toren,

Susan Peters , Hans Kromhout and Henrik A Kolstad

Department of Occupational Medicine, Danish Ramazzini Centre, Aarhus University Hospital, Aarhus,

Denmark,

Department of Public Health, Danish Ramazzini Centre, Aarhus University, Aarhus,

Denmark,

National Research Center for the Working Environment, Copenhagen, Denmark,

Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark,

Occupational and

Environmental Medicine, School of Public Health and Community Medicine, Sahlgrenska Academy,

University of Goteborg, Goteborg, Sweden and

Division of Environmental Epidemiology, Institute for

Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands

*Corresponding author.Department of Occupational Medicine, Danish Ramazzini Centre, Aarhus University Hospital,

Palle Juul Jensens Boulevard 99, 8210 Aarhus N, Denmark. E-mail: [email protected]

Received 4 September 2020; editorial decision 26 November 2020;

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Abstract

Background:

Exposure to respirable crystalline silica is suggested to increase the risk of

autoimmune rheumatic diseases. We examined the association between respirable

crystalline silica exposure and systemic sclerosis, rheumatoid arthritis, systemic lupus

erythematosus and small vessel vasculitis.

Methods:

In a cohort study of the total Danish working population, we included 1 541

505 male and 1 470 769 female workers followed since entering the labour market

1979–2015. Each worker was annually assigned a level of respirable crystalline silica

exposure estimated with a quantitative job exposure matrix. We identiﬁed cases of

autoimmune rheumatic diseases in a national patient register and examined sex-speciﬁc

exposure-response relations by cumulative exposure and other exposure metrics.

Results:

We identiﬁed 4673 male and 12 268 female cases. Adjusted for age and calendar

year, men exposed to high levels of respirable crystalline silica compared with non-

exposed showed increased incidence rate ratio (IRR) for the four diseases combined of

1.53 [95% conﬁdence interval (CI): 1.39–1.69], for systemic sclerosis of 1.62 (1.08–2.44)

and rheumatoid arthritis of 1.57 (1.41–1.75). The overall risk increased with increasing

cumulative exposure attained since entering the workforce [IRR: 1.07 (1.05–1.09) per

mg/m

-years]. Female workers were less exposed to respirable crystalline silica, but

showed comparable risk patterns with overall increased risk with increasing cumulative

exposure [IRR: 1.04 (0.99–1.10) per 50

mg/m

-years].

The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-

nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way,

and that the work is properly cited. For commercial re-use, please contact [email protected]

BEU, Alm.del - 2020-21 - Bilag 213: Orientering om videnskabelig artikel om sammenhæng mellem udsættelse for kvartsstøv og øget risiko for autoimmune gigtsygdomme i Danmark, fra beskæftigelsesministeren

International Journal of Epidemiology,

2021, Vol. 00, No. 00

Conclusions:

This study shows an exposure-dependent association between occupa-

tional exposure to respirable crystalline silica and autoimmune rheumatic diseases and

thus suggests causal effects, most evident for systemic sclerosis and rheumatoid

arthritis.

Key words:

Respirable crystalline silica, autoimmune, systemic sclerosis, rheumatoid arthritis, cohort

Key Messages

•

Inhalation of respirable crystalline silica has since the 1930s repeatedly been suggested in the aetiology of

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rheumatoid arthritis and other autoimmune rheumatic diseases.

•

In a cohort of 3 million workers, we show an exposure-dependent association between respirable crystalline silica

and systemic sclerosis, rheumatoid arthritis and possibly also systemic lupus erythematosus and small vessel

vasculitis, supporting a causal role of this widespread occupational exposure.

Introduction

Crystalline silica (SiO

) is a major element of earth’s crust

and found in soil, sand and rocks, and in concrete,

ceramics, glass and other industrial materials. Worldwide,

a considerable number of especially male workers

employed in construction, the metal industry, farming and

other industries are exposed at high levels, whenever these

materials are used, moved, crushed, drilled in or processed

in the production of new materials.

1,2

Since 1997, silica

has been classified as a group 1 human lung carcinogen by

the International Agency for Research on Cancer (IARC)

and inhalation of fine particles of silica is furthermore a

well-recognized risk factor for silicosis.

A causal link of rheumatic diseases with occupational

exposure to crystalline silica was already suggested from

the 1930s.

More recently, respirable crystalline silica has

repeatedly been reported to increase the risk of several au-

toimmune rheumatic diseases: systemic sclerosis in men

and women

6–9

and rheumatoid arthritis in men;

9–15

how-

ever, findings for women are unclear and based on few

studies.

12,15

Exposure to respirable crystalline silica may

also increase the risk of systemic lupus erythematosus

16–18

and small vessel vasculitis in men and women.

19–24

These

diseases affect people of working age, women more often

than men.

25–29

Low concordances between monozygotic

twins indicate environmental factors as of aetiological im-

portance.

30,31

Thus we have much to learn about the com-

plex pathogenesis, which potentially includes interaction

between genetic, environmental and epigenetic factors.

30,32

Limited quantitative information on silica exposure lev-

els characterizes most studies, and only few have examined

exposure-response relations,

13,17,18,20

which are important

before any conclusions on causation can be drawn. We

combined a large and detailed nationwide occupational

cohort with workplace surveillance exposure measure-

ments, and examined the risk of systemic sclerosis,

rheumatoid arthritis, systemic lupus erythematosus and

small vessel vasculitis, following occupational exposure to

respirable crystalline silica in men and women.

Methods

do not need approval from the National Committee of

Health Research Ethics. This study is approved by the

Danish Data Protection Agency (j.no: 1–16-02–196-17)

Study population

The study population comprised all Danish residents, born

1956 or later, with a minimum of 1 year of gainful employ-

ment 1977–2015 and a valid job code according to the

Danish version of the International Standard Classification

of Occupations from 1988 (ISCO 88) as registered in the

Danish Occupational Cohort (DOC*X).

DOC*X

includes annual, harmonized information on employment

and job code for all Danish citizens. The information is

based on several data sources, such as union membership,

self-report to the civil registration authorities, tax records

and employers’ mandatory reporting of occupation to

Statistics Denmark of all employees.

If the ISCO code

was missing in a year with active employment, we assigned

the latest valid ISCO code up to 5 years back. All Danish

International Journal of Epidemiology,

2021, Vol. 00, No. 00

Table 1

Summary of the International Classiﬁcation of Diseases (ICD) codes, 8th and 10th versions for the studied autoimmune

rheumatic diseases

Disease

Systemic sclerosis

Rheumatoid arthritis

ICD 8 (1977–93)

73400, 73401, 73402, 73408, 73409, 73491

71219, 71229, 71238, 71239

ICD 10 (1994–2015)

M34, M340, M341, M342, M342A,

M342B, M348, M348B, M349

M05, M050, M051, M051A-F, M052,

M053, M058, M059, M06, M060,

M068, M069

M05, M050, M051, M051A-F, M052,

M053, M058, M059

M06, M060, M068, M069

M32, M320, M321, M328, M329

M301, M310, M310A-B, M311, M311A,

M313, M317, M318, M318A, M319

Seropositive rheumatoid arthritis

Seronegative rheumatoid arthritis

Systemic lupus erythematosus

Small vessel vasculitis

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73419

22709, 44619, 44629, 44649, 44799,

44808, 44809

Rheumatoid arthritis is split into seropositive and seronegative rheumatoid arthritis in ICD 10.

citizens hold a unique social security number which is used

by all official authorities and allows linkage with national

registers. Through linkage with the national civil registra-

tion system

we excluded those who died, disappeared or

emigrated before the start of follow-up in 1979.

cumulative exposure divided by the number of exposed

years; (iii) highest attained exposure intensity (mg/m

); and

(iv) duration of exposure (years).

Statistical methods

Follow-up started the year following the first year of em-

ployment, because of no available information on month

or day of employment. For the same reason, all indepen-

dent variables were lagged by 1 year. We furthermore

started follow-up at the earliest in 1979, 2 years after infor-

mation on autoimmune rheumatic diseases was available

from the National Patient Registry. We included this

2-year washout period (1977–78) to reduce number of

prevalent cases. Study participants were followed until the

year of the first diagnosis of systemic sclerosis, small vessel

vasculitis, systemic lupus erythematosus or rheumatoid ar-

thritis, death, emigration or end of follow-up on 31

December 2015, whichever came first.

Associations between respirable crystalline silica expo-

sure and each of the autoimmune rheumatic diseases, as

well as the studied diseases combined, were analysed in

separate discrete time hazard models in a logistic regres-

sion procedure, with person-years as unit of analysis yield-

ing incidence rate ratios that were presented with 95%

confidence intervals (CI).

All exposures and covariates

were treated as time-varying variables.

Table 2

presents the distribution of all male and female

person-years cumulated during follow-up and classified by

time worker characteristics and cumulative respirable crys-

talline silica exposure level. Separately for each exposure

metric, study participants were grouped as exposed or

non-exposed. The exposed were further grouped into ter-

tiles based on the combined female and male distribution

of exposed person-years. We also analysed respirable

Autoimmune rheumatic diseases

Incident cases of autoimmune rheumatic diseases were

identified in the National Patient Registry. Since 1977 the

since 1995, outpatient contacts with any Danish hospi-

tals,

all coded according to the 8th (1977–93) or 10th

(1994–2015) version of the International Classification of

diseases. Cases were defined according to

Table 1.

Exposure assessment

Each worker was assigned a quantitative estimate of respi-

rable crystalline silica exposure for each year of employ-

ment, based on the SYNJEM job exposure matrix (JEM,

developed for the SYNERGI study).

36,37

The SYNJEM

originally provided time- and region-specific respirable

crystalline silica exposure estimates for all job codes in-

cluded in the 1968 version of ISCO, based on the model-

ling of 23 640 personal measurements of respirable

crystalline silica from several European countries and

Canada, together with expert assessments. For the current

study, the SYNJEM was modified to provide exposure esti-

mates for ISCO 88 job codes and was restricted to esti-

mates for the Nordic countries. For each year of follow-up,

we constructed the following exposure metrics based on

each worker’s exposure history since entry: (i) cumulative

exposure (mg/m

-year) as the sum of exposure levels for all

exposed years; (ii) mean exposure intensity (mg/m

) as

International Journal of Epidemiology,

2021, Vol. 00, No. 00

Table 2

Distribution of person-years at risk (%) by time-varying worker characteristics and cumulative respirable crystalline silica exposure

level among 1 541 505 men and 1 470 769 women, Denmark, 1979–2015

Men

Cumulative respirable crystalline silica (mg/m

-years)

28 596 448

Person-years

2.0–29.2

1 581 413

Person-years

29.3–93.9

1 644 508

Person-years

94.0–1622

1 790 255

Person-years

Women

Cumulative respirable crystalline silica (mg/m

-years)

30 957 666

Person-years

2.0–29.2

342 405

Person-years

29.3–93.9

280 298

Person-years

94.0–1622

134 819

Person-years

Worker characteristics

Occupation

Armed forces

White-collar workers

Skilled blue-collar

workers

Unskilled blue-collar

workers

Others

Missing

Age

<25

26–35

>36

Calendar year

1979–84

1985–94

1995–2004

2005–15

Probability of smoking

5–25%

26–35%

36–74%

Missing

Education

Lower secondary

Vocational or high

secondary

Short cycle higher

Medium cycle higher

Long cycle higher

Unknown

Duration (year)

2–5

6–39

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100

–

100

–

Grouped according to ISCO 88

International Standard Classiﬁcation of Occupations, 1988 revision: Armed forces (ISCO 88 codes 0110), White-collar

workers (ISCO 88 codes 1000–5999), Skilled blue-collar workers (ISCO 88 codes 6000–7999), Unskilled blue-collar workers (ISCO 88 codes 8000–9999),

Others (unemployed or retired).

Highest attained educational level.

crystalline silica exposure accrued during three confined

time windows (the previous 1–10, 11–20 and

>20

years).

In these analyses any silica exposure accrued outside each

time window was classified as zero, and only exposure re-

ceived in the years within the time windows were divided

by the median into two exposure groups.

All analyses were stratified by sex and adjusted for age

(25, 26–35,

years), and calendar year of follow-up

(1979-84, 1985–94, 1995–2004, 2005–15). We did not

have information on smoking at an individual level, but in

supplementary analyses we used a smoking JEM developed

for the DOC*X cohort used in this study.

This JEM pro-

vided sex- and calendar year-specific estimates of smoking

prevalence for all ISCO 88 job codes, based on self-

reported smoking habits reported in four large Danish

population-based surveys. Years without employment

International Journal of Epidemiology,

2021, Vol. 00, No. 00

were assigned the same smoking habit as in the latest job

period. We furthermore conducted analyses adjusted for

educational level (lower secondary, vocational or higher

secondary, short-, medium- or long-cycle higher education,

unknown) and analyses restricted to blue-collar workers

(ISCO major categories 6–9) as defined at baseline, to ob-

tain a more homogeneous population with respect to

smoking and socioeconomic factors.

We analysed log-linear relations between respirable

crystalline silica exposure and the autoimmune rheumatic

diseases with continuous exposure variables. These analy-

ses included the total study populations as well as the ex-

posed populations only, with the low exposed as the

reference. We fitted restricted cubic splines to the models,

placing the knots at the 40, 60 and 80 percentiles. All anal-

yses were carried out using Stata v.15 and v.16.

Results

The study population included 1 541 505 male workers cu-

mulating 4673 cases of autoimmune rheumatic diseases

during follow-up: systemic sclerosis (n

252), rheumatoid

arthritis (n

3490), systemic lupus erythematosus

255) and small vessel vasculitis (n

749). The corre-

sponding figures for 1 470 769 female workers were

12 268 cases of autoimmune rheumatic diseases: systemic

sclerosis (n

746), rheumatoid arthritis (n

9190), sys-

temic lupus erythematosus (n

1821) and small vessel vas-

culitis (n

869). Some participants were diagnosed with

more than one autoimmune rheumatic disease and hence

the number of specific diseases summed up to more than

all autoimmune rheumatic diseases. Analyses for each dis-

ease were conducted separately and the respective study

populations differed slightly. Only person-years at risk for

the analyses of the studied autoimmune diseases combined

are shown in the tables. The distribution of persons in-

cluded in each exposure stratum is shown in

Supplementary Table S3,

available as

Supplementary data

IJE

online.

Among men, 17% ever held a job with exposure to respi-

rable crystalline silica, and this was the case for 3% of the

women. Furthermore, women were less exposed than men,

with median cumulative exposure of 33

mg/m

-years

(25-75% centiles: 16-72

mg/m

-years) versus 60

mg/m

-years

(23–135

mg/m

-years) for men (Figure

1).

High exposure levels were associated with greater age,

as expected, and with a higher probability of smoking

(Table

2).

There is an increasing time trend for being

diagnosed with one of the studied autoimmune rheumatic

diseases. In the time period 2005–15 compared with 1979–

84, men had an increased risk (1.58, 95% CI: 1.30-1.92)

of being diagnosed with one the studied diseases.

Among men, we observed an increased overall incidence

rate ratio of the studied autoimmune rheumatic diseases com-

bined of 1.53 (95% CI: 1.39-1.69) in analyses comparing the

highest cumulative exposure stratum with non-exposure

(Figure

and

Table 3).

Similar results were seen for mean ex-

posure intensity, highest attained exposure intensity and du-

ration of exposure. Furthermore, in the analysis of

cumulative exposure, we observed an increasing trend of

1.07 (95% CI: 1.05-1.09) per 50

mg/m

-years. The corre-

sponding trend computed among the exposed only was 1.03

(95% CI: 1.00-1.05) per 50

mg/m

-years. Similar risk patterns

were seen for the respective diseases and most clearly for sys-

temic sclerosis and rheumatoid arthritis. Cumulative expo-

sure received more than 20 years earlier appears to be more

influential for the exposure-response relation than cumulative

exposure received more recently (Table

4).

Among women, we observed a slightly increased inci-

dence rate ratio of 1.09 (95% CI: 0.87-1.37) for all the

studied autoimmune rheumatic diseases combined, for the

highest cumulative exposure stratum compared with no ex-

posure, and a trend estimate of 1.04 (95% CI: 0.99-1.10)

per 50

mg/m

-years (Figure

and

Table 3).

Among women,

there were also indications of a latency effect of more than

20 years; however, this was less evident than among men

(Table

4).

In subanalyses of seropositive and seronegative rheuma-

toid arthritis (only possible for cases classified according to

ICD 10), we observed an equally elevated incidence rate

ratio for both serotypes in both sexes (Supplementary

Table S1,

available as

Supplementary data

IJE

online).

In additional analysis of men only, we added job-, sex-,

and calendar year-specific estimates of smoking prevalence

to the models, and observed an increased incidence rate ra-

tio of 1.44 (95% CI: 1.31-1.59) for all autoimmune rheu-

matic disease when comparing high cumulative exposure

with no exposure (Supplementary

Table S2,

available as

Supplementary data

IJE

online). In age-, calendar year-

and education-adjusted analysis, comparing the highest cu-

mulative exposed men with the unexposed, we observed a

similar increased risk ratio of 1.37 (95% CI: 1.24-1.51). A

sensitivity analysis restricted to male blue-collar

workers showed an incidence rate ratio of 1.44 (95% CI:

1.31-1.59) for high versus no cumulative silica exposure

(Supplementary

Table S2).

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Discussion

Principal findings

Among men, we observed increasing risk of autoimmune

rheumatic diseases following increasing occupational ex-

posure to respirable crystalline silica. Findings were

International Journal of Epidemiology,

2021, Vol. 00, No. 00

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Figure 1

Cumulative plot of the distribution of cumulative exposure level (lg/m

-years) at end of follow-up among 266 325 men and 42 914 women

ever exposed to respirable crystalline silica

Men

Incidence rate ratio

Women

1.5

100

200

300

400

500

µg/m -years

100

200

300

400

500

µg/m -years

Figure 2

Restricted cubic spline ﬁts of the age- and calendar year-adjusted overall incidence rate ratios of autoimmune rheumatic diseases by cumu-

lated respirable crystalline silica among 1 541 505 men and 1 470 769 women, 1979–2015

strongest for systemic sclerosis and rheumatoid arthritis.

Similar, but less evident, results were seen for women.

However, few women were exposed at high levels.

Strengths and weaknesses of the study

The quantitative estimates of silica exposure based on job-

exposure matrix derived from an extensive number of

measurements allowed exposure response analyses, a pre-

requisite for causal inference. The long follow-up of a na-

tional working population combined with national health

registers allowed us to study these rare diseases. However,

the study still included a relatively limited number of ex-

posed cases, especially few exposed female cases due to the

rarity of silica exposure among women, and therefore the

outcome still comes with considerable statistical uncer-

tainty. The almost complete high coverage of the health

registers precluded major selection bias. Information on

occupation obtained from national labour marked regis-

ters, combined with exposure assessment based on a job

exposure matrix, largely limited recall bias.

We identified cases in a national hospital register with

positive predictive values of 79% for rheumatoid arthri-

tis,

94% for systemic sclerosis

and 73% for systemic

International Journal of Epidemiology,

2021, Vol. 00, No. 00

Table 3.

Incidence rate ratios (IRR) of the studied autoimmune rheumatic diseases combined, systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus and small vessel vasculitis

following exposure to respirable crystalline silica among 1 541 505 men and 1 470 769 women, Denmark, 1979–2015

The studied diseases combined

Exposure

Person-years

Cases

IRR

(95% CI)

Systemic sclerosis

Cases

IRR

(95% CI)

Men

Cumulative exposure (mg/m

-years)

2.0–29.2

29.3–93.9

94.0–1622

Per 50

mg/m

-years

Per 50

mg/m

-years (exposed only)

Mean exposure (mg/m

)

2.0–10.7

10.8–18.0

18.1–122.0

Per 50

mg/m

Per 50

mg/m

(exposed only)

Highest attained exposure (mg/m

)

2.0–12.0

12.1–21.9

22.0–122

Per 50

mg/m

Per 50

mg/m

(exposed only)

Duration (years)

2–5

6–39

Per 5 year

Per 5 year (exposed only)

Rheumatoid arthritis

Cases

IRR

(95% CI)

Systemic lupus erythematosus

Cases

IRR

(95% CI)

Small vessel vasculitis

Cases

IRR

(95% CI)

28 527 938

1 576 698

1 639 692

1 784 974

3563

283

351

476

1.23 (1.09–1.39)

1.42 (1.27–1.58)

1.53 (1.39–1.69)

1.07 (1.05–1.09)

1.03 (1.00–1.05)

1.42 (1.28–1.57)

1.41 (1.26–1.57)

1.39 (1.25–1.56)

2.27 (1.88–2.74)

1.13 (0.75–1.70)

1.37 (1.23–1.53)

1.38 (1.24–1.55)

1.46 (1.31–1.62)

1.95 (1.69–2.25)

1.29 (0.98–1.70)

1.09 (0.92–1.29)

1.38 (1.24–1.53)

1.54 (1.41–1.69)

1.16 (1.13–1.20)

1.07 (1.02–1.12)

203

0.69 (0.34–1.40)

1.04 (0.60–1.79)

1.62 (1.08–2.44)

1.10 (1.03–1.18)

1.11 (1.02–1.21)

0.85 (0.46–1.57)

1.15 (0.69–1.92)

1.46 (0.94–2.27)

1.90 (0.86–4.19)

2.37 (0.44–12.72)

0.98 (0.55–1.77)

0.73 (0.39–1.38)

1.69 (1.12–2.54)

1.85 (1.02–3.39)

2.62 (0.87–7.90)

0.84 (0.37–1.89)

0.90 (0.52–1.55)

1.54 (1.03–2.29)

1.17 (1.02–1.35)

1.21 (0.98–1.49)

2630

218

267

375

1.24 (1.08–1.43)

1.42 (1.25–1.61)

1.57 (1.41–1.75)

1.07 (1.05–1.10)

1.02 (0.99–1.05)

1.45 (1.29–1.63)

1.39 (1.23–1.58)

1.43 (1.26–1.62)

2.34 (1.88–2.91)

1.03 (0.65–1.65)

1.39 (1.22–1.57)

1.44 (1.27–1.62)

1.45 (1.29–1.64)

1.97 (1.68–2.32)

1.20 (0.87–1.65)

1.08 (0.89–1.31)

1.41 (1.25–1.59)

1.56 (1.41–1.73)

1.17 (1.13–1.21)

1.07 (1.02–1.13)

198

1.42 (0.88–2.31)

1.22 (0.73–2.04)

1.46 (0.94–2.27)

1.09 (1.01–1.17)

1.06 (0.96–1.18)

1.64 (1.06–2.52)

1.60 (1.03–2.50

0.84 (0.45–1.55)

1.57 (0.65–3.79)

0.38 (0.48–2.93)

1.44 (0.90–2.28)

1.47 (0.93–2.33)

1.22 (0.74–2.01)

1.78 (0.93–3.40)

1.41 (0.39–5.06)

1.24 (0.63–2.41)

1.36 (0.86–2.13)

1.44 (0.96–2.17)

1.20 (1.04–1.37)

1.15 (0.94–1.41)

587

1.34 (0.99–1.80)

1.54 (1.17–2.02)

1.34 (1.02–1.76)

1.06 (1.01–1.11)

0.99 (0.93–1.07)

1.37 (1.03–1.83)

1.55 (1.18–2.03)

1.30 (0.98–1.74)

2.27 (1.42–3.61)

1.42 (0.50–4.04)

1.43 (1.07–1.91)

1.39 (1.04–1.84)

1.40 (1.06–1.84)

1.87 (1.29–2.70)

1.20 (0.57–2.54)

1.11 (0.73–1.69)

1.48 (1.15–1.92)

1.46 (1.14–1.87)

1.11 (1.02–1.22)

0.97 (0.84–1.11)

28 527 938

1 612 428

1 654 722

1 734 214

3563

397

366

347

203

2630

317

277

266

198

587

28 527 938

1 581 211

1 645 575

1 774 578

3563

356

357

397

203

2630

279

283

298

198

587

28 527 938

974 370

1 993 555

2 003 439

3563

145

395

570

203

2630

108

304

448

198

587

(Continued)

Downloaded from https://academic.oup.com/ije/advance-article/doi/10.1093/ije/dyaa287/6104043 by guest on 25 January 2021

Table 3.

Continued

The studied diseases combined

Exposure

Person-years

Cases

IRR

(95% CI)

Systemic sclerosis

Cases

IRR

(95% CI)

Women

Cumulative exposure (mg/m

-years)

2.0–29.2

29.3–93.9

94.0–1622

Per 50

mg/m

-years

Per 50

mg/m

-years (exposed only)

Mean exposure (mg/m

)

2.0–10.7

10.8–18.0

18.1–122.0

Per 50

mg/m

Per 50

mg/m

(exposed only)

Highest attained exposure (mg/m

)

2.0–12.0

12.1–21.9

22.0–122

Per 50

mg/m

Per 50

mg/m

(exposed only)

Duration (years)

2–5

6–39

Per 5 year

Per 5 year (exposed only)

Rheumatoid arthritis

Cases

IRR

(95% CI)

Systemic lupus erythematosus

Cases

IRR

(95% CI)

Small vessel vasculitis

Cases

IRR

(95% CI)

30 800 795

340 301

278 490

133 920

11 888

156

148

0.99 (0.84–1.16)

1.12 (0.95–1.31)

1.09 (0.87–1.37)

1.04 (0.99–1.10)

1.03 (0.96–1.12)

0.96 (0.82–1.13)

1.16 (0.99–1.37)

1.07 (0.87–1.33)

1.27 (0.91–1.77)

1.42 (0.67–2.99)

0.99 (0.85–1.16)

1.08 (0.90–1.28)

1.16 (0.93–1.44)

1.23 (0.92–1.64)

1.29 (0.68–2.45)

1.00 (0.81–1.22)

1.07 (0.93–1.24)

1.08 (0.89–1.31)

1.05 (0.97–1.14)

1.03 (0.92–1.16)

716

1.36 (0.77– 2.40)

1.56 (0.88–2.76)

1.46 (0.65–3.27)

1.14 (0.95–1.36)

1.04 (0.78–1.38)

0.86 (0.41–1.81)

1.77 (1.02–3.07)

1.92 (1.03–3.61)

3.53 (1.28–9.74)

5.05 (0.62–41.25)

0.90 (0.45–1.81)

1.69 (0.95–2.99)

2.15 (1.15–4.01)

2.90 (1.16–7.26)

3.39 (0.46–24.96)

1.86 (1.00–3.48)

1.12 (0.62–-2.04)

1.65 (0.85–3.18)

1.19 (0.89–1.59)

0.99 (0.61–1.59)

8906

114

110

0.93 (0.78– 1.12)

1.07 (0.88–1.29)

1.10 (0.85–1.42)

1.05 (0.98–1.11)

1.05 (0.97–1.15)

0.92 (0.77–1.11)

1.10 (0.91–1.33)

1.07 (0.84–1.36)

1.20 (0.82–1.75)

1.60 (0.70–3.67)

0.97 (0.81–1.15)

1.05 (0.86–1.28)

1.08 (0.84–1.39)

1.16 (0.83–1.63)

1.40 (0.68–2.89)

0.98 (0.77–1.24)

1.00 (0.84–1.18)

1.08 (0.87–1.34)

1.05 (0.95–1.15)

1.05 (0.92–1.20)

1767

1.18 (0.79–1.75)

1.26 (0.83–1.93)

0.82 (0.39–1.73)

1.04 (0.89–1.22)

0.98 (0.78–1.24)

1.01 (0.65–1.57)

1.39 (0.92–2.10)

1.01 (0.56–1.84)

1.55 (0.66–3.65)

1.42 (0.18–11.25)

1.01 (0.67–1.55)

1.19 (0.76–1.88)

1.36 (0.79–2.35)

1.46 (0.68–3.14)

1.32 (0.22–7.93)

0.86 (0.47–1.55)

1.42 (1.00–2.01)

0.93 (0.51–1.69)

0.99 (0.77–1.28)

0.82 (0.54–1.23)

846

0.87 (0.45–1.69)

0.94 (0.47–1.88)

1.38 (0.62–3.08)

1.03 (0.82–1.29)

1.10 (0.82–1.47)

1.15 (0.63–2.08)

0.99 (0.49–1.99)

0.72 (0.27–1.93)

0.67 (0.16–2.87)

0.37 (0.01–13.49)

1.15 (0.65–2.03)

0.77 (0.34–1.71)

1.01 (0.42–2.44)

0.84 (0.24–2.89)

1.10 (0.07–17.82)

0.64 (0.24–1.72)

1.18 (0.68–2.04)

1.01 (0.45–2.25)

1.11 (0.81–1.51)

1.24 (0.81–1.90)

30 800 795

300 872

266 425

185 414

11888

149

145

716

8906

113

106

1767

n.r.

30 800 795

333 072

257 420

162 219

11 888

167

129

716

8906

127

1767

846

International Journal of Epidemiology,

2021, Vol. 00, No. 00

30 800 795

210 515

363 012

179 184

11 911

181

106

716

8906

130

1767

n.r.

n.r. not reported, cells with less than ﬁve cases.

The studied diseases combined: systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and small vessel vasculitis.

Number of person-years used for each analysis of the different outcomes differed slightly. Only total person-years from the analysis of all autoimmune rheumatic disease combined are shown in the tables.

Adjusted for age (25, 26–35,36) and calendar year (1979–84, 1985–94, 1995–2004, 2005–15).

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International Journal of Epidemiology,

2021, Vol. 00, No. 00

Table 4

Incidence rate ratios (IRR) of the studied autoimmune rheumatic diseases combined, systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus and small vessel vasculitis following respirable crystal-

line silica exposure accrued during the previous 1–10, 11–20 and

>20

years time windows among 1 541 505 men and 1 470 769 women, Denmark, 1979–2015

The studied diseases combined

Exposure

Person-years

Cases

IRR

(95% CI)

Cases

Systemic sclerosis

IRR

(95% CI)

Men

Cumulative exposure (mg/m

-years)

1–10 years

2.0–37.1

37.2–875.2

Per 50

mg/m

-years

11–20 years

03.5–47.6

47.7–875.2

Per 50

mg/m

-years

>20

years

6.1–66.6

66.7–1338.5

Per 50

mg/m

-years

Mean exposure (mg/m

)

1–10 years

0.1–9.2

9.3–122.0

Per 50

mg/m

11–20 years

0.1–8.1

8.2–110

Per 50

mg/m

>20

years

0.2–11.7

11.8–110

Per 50

mg/m

Highest attained exposure (mg/m

)

1–10 years

2.0–12.5

12.6–121.9

Per 50

mg/m

29 829 503

1 776 923

1 922 876

3975

441

257

1.41 (1.28–1.56)

1.21 (1.06–1.37)

1.91 (1.48–2.46)

217

1.05 (0.62–1.78)

1.39 (0.87–2.21)

1.69 (0.66–4.31)

2953

352

185

1.45 (1.30–1.62)

1.23 (1.05–1.42)

2.08 (1.54–2.82)

217

1.41 (0.92–2.18)

1.19 (0.70–2.03)

1.78 (0.62–5.15)

650

1.38 (1.05–1.80)

1.01 (0.72–1.40)

1.40 (0.76–2.59)

32 434 659

561 913

532 730

4242

184

247

1.56 (1.36–1.80)

1.58 (1.37–1.81)

2.95 (2.19–3.98)

230

2.37 (1.36–4.15)

1.41 (0.69–2.91)

4.86 (1.37–17.24)

3153

170

167

1.54 (1.31–1.80)

1.53 (1.31–1.80)

2.74 (1.95–3.85)

236

1.61 (0.84–3.08)

1.46 (0.74–2.88)

1.94 (0.41–9.18)

689

1.48 (0.99–2.21)

1.93 (1.35–2.76)

4.06 (1.88–8.74)

Rheumatoid arthritis

Cases

IRR

(95% CI)

Systemic lupus erythematosus

Cases

IRR

(95% CI)

Small vessel vasculitis

Cases

IRR

(95% CI)

29 829 503

1 779 056

1 920 743

31 276 025

1 081 784

1 171 493

3975

355

343

4038

302

333

1.36 (1.22–1.51)

1.30 (1.16–1.45)

1.10 (1.04–1.16)

1.42 (1.27–1.60)

1.46 (1.30–1.63)

1.13 (1.08–1.18)

217

222

1.45 (0.90–2.31)

1.02 (0.61–1.70)

1.07 (0.87–1.31)

1.64 (0.98–2.75)

1.27 (0.73–2.20)

1.16 (0.97–1.38)

2953

271

266

2986

227

277

1.36 (1.20–1.54)

1.36 (1.20–1.55)

1.12 (1.06–1.19)

1.36 (1.19–1.56)

1.54 (1.36–1.75)

1.14 (1.09–1.20)

217

223

1.26 (0.78–2.04)

1.37 (0.86–2.17)

1.14(0.93–1.39)

1.40 (0.82–2.37)

1.54 (0.93–2.55)

1.14 (0.94–1.37)

650

668

1.38 (1.05–1.82)

1.03 (0.76–1.41)

1.00 (0.87–1.16)

1.80 (1.35–2.41)

1.00 (0.69–1.45)

1.01 (0.88–1.16)

32 434 659

521 145

573 498

4242

184

247

1.42 (1.23–1.66)

1.70 (1.49–1.94)

1.13 (1.10–1.17)

230

1.28 (0.59–2.75)

2.48(1.44–4.27)

1.22 (1.09–1.36)

3153

145

192

1.40 (1.18–1.66)

1.65 (1.42–1.92)

1.12 (1.08–1.16)

236

1.72 (0.90–3.29)

1.37 (0.69–2.71)

1.15 (1.00–1.32)

689

1.52 (1.01–2.29)

1.87 (1.32–2.66)

1.17 (1.08–1.26)

29 829 503

1 836 924

1 862 875

3975

490

208

1.42 (1.29–1.56)

1.15 (1.00–1.33)

1.77 (1.24–2.53)

217

1.43 (0.91–2.23)

0.97 (0.55–1.72)

1.09 (0.28–4.17)

2953

392

145

1.45 (1.30–1.61)

1.17 (0.99–1.39)

1.96 (1.26–3.04)

217

223

1.77 (1.13–2.49)

0.77 (0.39–1.52)

1.20 (0.25–5.76)

1.95 (1.26–3.03)

0.90 (0.46–1.76)

2.02 (0.38–10.63)

650

1.19 (0.90–1.57)

1.22 (0.89–1.67)

1.57 (0.73–3.38)

31 276 025

1 148 078

1 105 199

4038

373

262

1.56 (1.40–1.74))

1.30 (1.15–1.48))

2.72 (1.90–3.88)

222

2.45 (1.55–3.87)

1.27 (0.68–2.40)

1.76 (0.32–9.54)

2986

292

212

1.55 (1.37–1.75)

1.34 (1.16–1.54)

2.90 (1.95–4.32)

668

1.40 (1.03–1.91)

1.38 (0.98–1.95)

2.49 (0.92–6.76)

(Continued)

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Table 4

Continued

The studied diseases combined

Exposure

11–20 years

3.5–15.8

15.9–121.9

Per 50

mg/m

>20

years

6.1–23.4

23.5–121.9

Per 50

mg/m

32 434 659

504 415

590 228

4242

207

224

1.60 (1.39–1.84)

1.54 (1.34–1.77)

2.04 (1.71–2.44)

230

1.49 (0.72–3.08)

2.26 (1.29–3.95)

2.97 (1.41–6.25)

Women

Cumulative exposure (mg/m

-years)

1–10 years

2.0–37.1

37.2–875.2

Per 50

mg/m

-years

11–20 years

3.5–47.6

47.7–875.2

Per 50

mg/m

-years

>20

year

6.1–66.6

66.7–1338.5

Per 50

mg/m

-years

Mean exposure (mg/m

)

1–10 years

0.1–9.2

9.3–122.0

Per 50

mg/m

11–20 years

0.1–8.1

8.2–110

Per 50

mg/m

31 252 372

128 933

172 201

12 085

100

1.11 (0.89–1.37)

1.07 (0.88–1.30)

1.24 (0.68–2.26)

n.r.

1.23 (0.51–2.96)

1.77 (0.91–3.42)

5.37 (0.93–31.02)

9050

1.09 (0.85–1.39)

1.01 (0.80–1.27)

1.03 (0.51–2.07)

1798

1.14 (0.61–2.12)

1.14 (0.66–1.98)

1.30 (0.24–6.87)

n.r.

858

0.33 (0.60–2.98)

0.93 (0.38–2.24)

0.28 (0.11–15.32)

31 051 236

261 915

240 355

12 066

129

0.94 (0.82–1.16)

1.03 (0.76–1.23)

0.78 (0.39–1.55)

731

1.11 (0.55–2.23)

1.31 (0.62–2.77)

2.18 (0.31–15.40)

9045

0.90 (0.74–1.10)

0.98 (0.73–1.30)

0.65 (0.28–1.54)

1790

0.81 (0.478–1.37)

1.30 (0.81–2.11)

0.99 (0.21–4.57)

n.r.

1.57 (0.91–2.72)

0.34 (0.08–1.35)

0.19 (0.1–3.64)

31 417 074

92 154

44 278

12 150

1.27 (1.01–1.58)

1.30 (0.95–1.78)

1.12 (1.02–1.24)

736

1.48 (0.61–3.57)

3.06 (1.27–7.40)

1.36 (1.06–1.74)

9096

1.22 (0.95–1.57)

1.31 (0.92–1.85)

1.14 (1.02–1.26)

n.r

1.91 (1.08–3.38)

0.66 (0.17–2.65)

1.15 (0.86–1.53)

n.r.

1.09 (0.41–2.93)

1.69 (0.54–5.27)

1.13 (0.77–1.66)

Systemic sclerosis

Cases

IRR

(95% CI)

Rheumatoid arthritis

Cases

IRR

(95% CI)

Systemic lupus erythematosus

Cases

IRR

(95% CI)

Small vessel vasculitis

Cases

IRR

(95% CI)

Person-years

Cases

IRR

(95% CI)

31 276 025

1 047 317

1 205 960

4038

352

282

1.56 (1.39–1.74)

1.32 (1.17–1.49)

2.10 (1.72–2.57)

222

1.30 (0.74–2.31)

1.58 (0.95–2.61)

2.17 (0.91–5.00)

2986

279

225

1.55 (1.37–1.76)

1.35 (1.18–1.55)

2.18 (1.74–2.74)

223

1.92 (1.21–3.04)

1.02 (0.55–1.88)

2.13 (0.89–5.11)

668

1.68 (1.25–2.27)

1.09 (0.76–1.57)

1.62 (0.91–2.89)

3153

164

173

1.59 (1.35–1.86)

1.49 (1.27–1.74)

1.95 (1.60–2.39)

236

1.71 (0.89–3.27)

1.38 (0.70–2.73)

1.85 (0.77–4.42)

689

1.80 (1.23–2.62)

1.63 (1.12–2.37)

2.26 (1.40–3.66)

31 051 236

319 807

182 463

12 066

134

0.98 (0.82–1.16)

0.97 (0.76–1.23)

1.00 (0.87–1.15)

731

1.26 (0.68–2.36)

1.08 (0.45–2.61)

0.92 (0.52–1.63)

9045

0.89 (0.72–1.09)

1.00 (0.76–1.31)

1.00 (0.85–1.19

1790

1.23 (0.82–1.83)

0.65 (0.31–1.36)

0.96 (0.67–1.38)

854

1.08 (0.58–2.02)

1.00 (0.41–2.40)

0.99 (0.60–1.65)

31 252 372

194 665

106 469

12 085

118

1.09 (0.91–1.31)

1.08 (0.84–1.38)

1.03 (0.92–1.16)

732

1.54 (0.79–2.97)

1.51 (0.62–3.64)

1.16 (0.75–1.77)

9050

1.02 (0.83–1.26)

1.08 (0.82–1.42)

1.02 (0.89–1.17)

1798

1.14 (0.69–1.90)

1.14 (0.57–2.29)

1.06 (0.76–1.48)

n.r.

1.40 (0.73–2.71)

0.58 (0.14–2.31)

0.96 (0.56–1.65)

International Journal of Epidemiology,

2021, Vol. 00, No. 00

(Continued)

Downloaded from https://academic.oup.com/ije/advance-article/doi/10.1093/ije/dyaa287/6104043 by guest on 25 January 2021

Table 4

Continued

The studied diseases combined

Exposure

>20

years

0.2–11.7

11.8–110

Per 50

mg/m

Highest attained exposure (mg/m

)

1–10 years

2.0–12.5

12.6–121.9

Per 50

mg/m

11–20 years

3.5–15.8

15.9–121.9

Per 50

mg/m

>20

years

6.1–23.4

23.5–121.9

Per 50

mg/m

31 417 074

84 633

51 799

12 150

1.26 (1.00–1.58)

1.31 (0.97–1.75)

1.66 (1.12–2.46)

n.r.

1.27 (0.47–3.40)

3.22 (1.44–7.21)

4.13 (1.19–14.32)

9096

1.27 (0.98–1.64)

1.21 (0.86–1.70)

1.62 (1.04–2.51)

1807

1.55 (0.80–2.99)

1.43 (0.59–3.45)

2.52 (0.85–7.45)

n.r.

1.16 (0.43–3.12)

1.50 (0.48–4.69)

1.75 (0.35–8.74)

31 252 372

183 189

117 945

12 085

114

1.04 (0.87–1.25)

1.17 (0.92–1.48)

1.29 (0.84–1.97)

732

1.37 (0.68–2.76)

1.80 (0.80–4.02)

2.90 (0.69–12.27)

9050

0.99 (0.80–1.23)

1.14 (0.87–1.49)

1.18 (0.72–1.93)

1798

1.19 (0.72–1.99)

1.05 (0.53–2.11)

1.62 (0.52–5.01)

n.r.

1.08 (0.51–2.28)

1.17 (0.44–3.13)

1.26 (0.22–7.36)

31 051 236

311 925

190 345

12 066

148

0.97 (0.82–1.14)

0.98 (0.75–1.29)

0.83 (0.47–1.46)

731

1.10 (0.57–2.13)

1.37 (0.61–3.08)

1.63 (0.28–9.42)

9045

109

0.91 (0.76–1.10)

0.96 (0.69–1.34)

0.73 (0.37–1.46)

1790

0.99 (0.64–1.54)

1.08 (0.59–1.95)

0.93 (0.25–3.49)

n.r.

1.38 (0.79–2.38)

0.42 (0.10–1.68)

0.40 (0.04–3.54)

31 417 074

54 240

82 192

12 150

1.37 (1.04–1.81)

1.21 (0.95–1.54)

1.91 (1.14–3.20)

n.r.

2.03 (0.76–5.43)

1.97 (0.88–4.42)

4.79 (0.94–24.47)

9096

1.31 (0.96–1.80)

1.20 (0.92–1.57)

1.95 (1.11–3.44)

1807

1.36 (0.56–3.28)

1.60 (0.83–3.09)

3.30 (0.84–12.98)

n.r.

1.89 (0.70–5.05)

0.91 (0.29–2.82)

1.11 (0.10–12.74)

Person-years

Cases

IRR

(95% CI)

Cases

Systemic sclerosis

IRR

(95% CI)

Rheumatoid arthritis

Cases

IRR

(95% CI)

Systemic lupus erythematosus

Cases

IRR

(95% CI)

Small vessel vasculitis

Cases

IRR

(95% CI)

International Journal of Epidemiology,

2021, Vol. 00, No. 00

n.r. not reported, cells with less than ﬁve cases.

The studied diseases combined: systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus, small vessel vasculitis

Adjusted for age (25, 26–35,

36)

and calendar year (1979–84, 1985–94, 1995–2004, 2005–15).

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International Journal of Epidemiology,

2021, Vol. 00, No. 00

lupus erythematosus, when compared with medical records

as the gold standard.

Thus false-positive cases, except

perhaps for systemic sclerosis, may have biased measures

of association most likely towards the null.

Smoking is a well-documented risk factor for rheuma-

toid arthritis and probably also for systemic lupus erythe-

matosus

44,45

and could have confounded our risk

estimates, as could other factors related to social class.

However, we still observed increased risks of the studied

diseases when adjusting by: estimates of smoking preva-

lence via a smoking JEM; highest attained educational

level; and in analyses restricted to blue-collar workers

expected to have fairly comparable life style patterns

across different occupations and silica exposure levels.

We observed increased risks of several of the studied au-

toimmune rheumatic diseases at mean exposure intensity

levels well below the current European occupational expo-

sure limit of 100

mg/m

indicating that this limit provides

insufficient protection of workers exposed to crystalline

silica.

Possible mechanisms

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Comparison with other studies

Our results are in line with extensive evidence linking oc-

cupational exposure to respirable crystalline silica and au-

toimmune rheumatic diseases.

44–46

To our knowledge,

only few studies have examined the association with quan-

titative exposure levels.

12,13

Vihlborg

et al.

observed a

doubled risk of seropositive rheumatoid arthritis of [stan-

dardized incidence ratio of 2.59 (95% CI: 1.24-4.76)] at

exposure levels of respirable crystalline silica above 50

mg/

and exposure-response relation in a cohort of male

foundry workers. Others have observed increasing risk

with increasing duration of exposure and semi-quantified

exposure levels (never, low, high).

6,8,17,18,20

Turner

et al.

did not, however, observe an association between quanti-

tative levels of silica exposure and rheumatoid arthritis in a

cohort of pottery, sandstone and refractory material

workers.

Whereas the prevalence of autoimmune rheumatic dis-

eases is higher among women, the association with respira-

ble crystalline silica exposure is most evident among men

in our study, most likely because fewer women were ex-

posed and when exposed their cumulative exposure was

lower. Exposure-response patterns were similar for men

and women though.

In a meta-analysis by Rubio-Rivas

et al.

of respirable

crystalline silica exposure and systemic sclerosis, they

found a slightly higher risk among men than women.

Similarly, the risk of rheumatoid arthritis among men was

slightly higher than the risk for men and women combined

in a meta-analysis by Khuder

et al.

A single study on sys-

temic lupus erythematosus found a higher risk among men

than among women.

However, an animal model with

male and female lupus-prone mice did not demonstrate

sex-related differences in outcomes after exposure to crys-

talline silica.

Following inhalation, respirable crystalline silica particles

are deposited in the alveoli.

Animal models have shown

that macrophages phagocyte the particles, activating the

immune system by secretion of cytokines, chemokines and

lysosomal enzymes, which activate antigen-presenting and

in turn antibody-producing cells.

46,51

In susceptible indi-

viduals, a disturbed control mechanism and breaking of

tolerance result in continuous production of auto-antibod-

ies.

32,51

Apoptosis of macrophages results in release of sil-

ica particles and new uptake by antigen-presenting cells,

contributing to chronic inflammation.

For silicosis it has

been shown that most of the disease progression takes

place after termination of exposure to crystalline silica.

Retained silica in lung tissue, and other similar or partly

overlapping mechanisms as for silicosis, may explain the

increased risks observed in this study more than 20 years

after exposure. Furthermore, auto-antibodies are present

years before clinical symptoms of systemic lupus erythema-

tosus develop,

53,54

and it has been suggested that triggering

exposures in susceptible individuals first lead to serological

autoimmunity and later to overt clinical disease.

This

could also explain the highest risks we observed following

exposure accrued more than 20 years earlier.

Conclusions

This study shows an exposure-dependent association be-

tween respirable crystalline silica, systemic sclerosis and

rheumatoid arthritis, and possibly also systemic lupus ery-

thematosus and small vessel vasculitis. Findings were most

evident in men, but few women were exposed at high

levels.

Supplementary data

are available at

IJE

online.

Funding

This work was supported by a grant from the Danish Working

Environment Research Fund (grant no. 34–2016-09). SP and HK re-

ceived a grant from the Deutsche Gesetzliche Unfallversicherung to

elaborate SYNJEM.

International Journal of Epidemiology,

2021, Vol. 00, No. 00

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