Occupational inhalable agents constitute major risk factors for rheumatoid arthritis, particularly in the context of genetic predisposition and smoking.

OBJECTIVES: To assess the effects of occupational inhalable exposures on rheumatoid arthritis (RA) development and their interactions with smoking and RA-risk genes, stratifying by presence of anticitrullinated protein antibodies (ACPA). METHODS: Data came from the Swedish Epidemiological Investigation of RA, consisting of 4033 incident RA cases and 6485 matched controls. Occupational histories were retrieved, combining with a Swedish national job-exposure matrix, to estimate exposure to 32 inhalable agents. Genetic data were used to define Genetic Risk Score (GRS) or carrying any copy of human leucocyte antigen class II shared epitope (HLA-SE) alleles. Associations were identified with unconditional logistical regression models. Attributable proportion due to interaction was estimated to evaluate presence of interaction. RESULTS: Exposure to any occupational inhalable agents was associated with increased risk for ACPA-positive RA (OR 1.25, 95% CI 1.12 to 1.38). The risk increased as number of exposed agents increased (Ptrend<0.001) or duration of exposure elongated (Ptrend<0.001). When jointly considering exposure to any occupational inhalable agents, smoking and high GRS, a markedly elevated risk for ACPA-positive RA was observed among the triple-exposed group compared with those not exposed to any (OR 18.22, 95% CI 11.77 to 28.19). Significant interactions were found between occupational inhalable agents and smoking/genetic factors (high GRS or HLA-SE) in ACPA-positive RA. CONCLUSIONS: Occupational inhalable agents could act as important environmental triggers in RA development and interact with smoking and RA-risk genes leading to excessive risk for ACPA-positive RA. Future studies are warranted to assess preventive strategies aimed at reducing occupational hazards and smoking, especially among those who are genetically vulnerable.

Occupational exposure to organic dusts and risk of developing rheumatoid arthritis: findings from a Swedish population-based case-control study.

Objectives: We estimated the association between occupational exposures to five different organic dusts: wood, animal, paper, textile and flour dust and the risk of developing rheumatoid arthritis (RA). Methods: This population-based case-control study analysed 12 582 incident cases and 129 335 controls. Participants were identified from national public authority and quality registers. Census data on occupations were collected 1960-2010 and we estimated the exposure to organic dust with the help of job-exposure matrices. We used logistic regression to assess the OR of seropositive or seronegative RA. Estimates were adjusted for the matching variables (sex, county, age and index year), education and occupational silica exposure. Results: Exposure to animal dust was associated with an increased risk of RA among both men and women. The OR was 1.2 (95% CI=1.1 to 1.4) for seropositive RA and 1.3 (95% CI=1.1 to 1.5) for seronegative RA among ever exposed participants compared with unexposed. The risk increased with duration of exposure for seropositive RA, and participants who had been exposed in five or more censuses had an OR of 1.6 (95% CI=1.1 to 2.2, p for trend=0.003). Exposure to textile dust also generated a significant dose-response relationship for seropositive RA (p for trend=0.014). We detected no association between exposure to wood, paper or flour dust and risk of RA. Conclusions: Overall, exposure to animal dust and textile dust was associated with an increased risk of developing RA. These observations give further support to the notion that airborne exposures are involved in the aetiology of RA.

Occupational exposure to asbestos and silica and risk of developing rheumatoid arthritis: findings from a Swedish population-based case-control study.

Objective: Airborne agents including cigarette smoke associate with an increased risk of rheumatoid arthritis (RA). We analysed to which extent occupational exposure to asbestos and silica confers an increased risk of developing serologically defined subsets of RA. Methods: This Swedish population-based case-control study enrolled incident RA cases between 1996 and 2013 (n=11 285), identified through national public authority and quality registers, as well as from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) Study. Controls (n=1 15 249) were randomly selected from Sweden's population register and matched on sex, age, index year and county. Occupational histories were obtained from national censuses. Exposure to asbestos and silica was assessed by job-exposure matrices. Logistic regression was used to calculate ORs adjusted for age, sex, county, index year, alcohol use and smoking. Results: Results showed that male workers exposed to asbestos had higher risk of seropositive RA (OR=1.2, 95% CI 1.0 to 1.4) and seronegative RA (OR=1.2, 95% CI 1.0 to 1.5) compared with unexposed workers. The risk was highest among workers exposed to asbestos from 1970, before a national ban was introduced. Male workers exposed to silica also had higher risk of RA (seropositive RA: OR=1.4, 95% CI 1.2 to 1.6; seronegative RA: OR=1.3, 95% CI 1.0 to 1.5). For the largest subset, seropositive RA, the OR increased with the number of years exposed to silica, up to OR=2.3 (95% CI 1.4 to 3.8, p for trend <0.0001). Women overall had lower ORs than men, but the duration and intensity of their exposure were lower. Conclusions: In conclusion, we observed an association between asbestos exposure and risk of developing RA and extended previous findings of an association between silica exposure and RA risk, where a dose-response relationship was observed.

Occupation and Risk of Developing Rheumatoid Arthritis: Results From a Population-Based Case-Control Study.

OBJECTIVE: Environmental factors are of importance for the etiology of rheumatoid arthritis (RA), but much remains unknown concerning the contributions from distinct occupational hazards. We explored the association between occupation and the risk of anti-citrullinated protein antibody (ACPA)+ RA or ACPA- RA. METHODS: We analyzed 3,522 cases and 5,580 controls from the Swedish population-based Epidemiological Investigation of Rheumatoid Arthritis case-control study. A questionnaire was used to obtain information on work history and lifestyle factors. Blood samples were drawn for serologic analyses. Unconditional logistic regression was used to calculate the odds ratio (OR) of RA associated with the last occupation before study inclusion. Analyses were performed with adjustments for known environmental exposures and lifestyle factors, including pack-years of cigarette smoking, alcohol use, body mass index, and education. RESULTS: Among men, bricklayers and concrete workers (OR 2.9, 95% confidence interval [95% CI] 1.4-5.7), material handling operators (OR 2.4, 95% CI 1.3-4.4), and electrical and electronics workers (OR 2.1, 95% CI 1.1-3.8) had an increased risk of ACPA+ RA. For ACPA- RA, bricklayers and concrete workers (OR 2.4, 95% CI 1.0-5.7) and electrical and electronics workers (OR 2.6, 95% CI 1.3-5.0) had an increased risk. Among women, assistant nurses and attendants had a moderately increased risk of ACPA+ RA (OR 1.3, 95% CI 1.1-1.6). No occupations were significantly associated with ACPA- RA among women. CONCLUSION: Mainly occupations related to potential noxious airborne agents were associated with an increased risk of ACPA+ or ACPA- RA, after adjustments for previously known confounders.

Occupational exposure to diesel motor exhaust and risk of lung cancer by histological subtype: a population-based case-control study in Swedish men.

We investigated occupational exposure to diesel motor exhaust (DME) and the risk of lung cancer by histological subtype among men, using elemental carbon (EC) as a marker of DME exposure. 993 cases and 2359 controls frequency-matched on age and year of study inclusion were analyzed by unconditional logistic regression in this Swedish case-control study. Work and smoking histories were collected by a questionnaire and telephone interviews. DME was assessed by a job-exposure matrix. We adjusted for age, year of study inclusion, smoking, occupational exposure to asbestos and combustion products (other than motor exhaust), residential exposure to radon and exposure to air pollution from road traffic. The OR for lung cancer for ever vs. never exposure to DME was 1.15 (95% CI 0.94-1.41). The risk was higher for squamous and large cell, anaplastic or mixed cell carcinoma than for alveolar cell cancer, adenocarcinoma and small cell carcinoma. The OR in the highest quartile of exposure duration (≥34 years) vs. never exposed was 1.66 (95% CI 1.08-2.56; p for trend over all quartiles: 0.027) for lung cancer overall, 1.73 (95% CI 1.00-3.00; p: 0.040) for squamous cell carcinoma and 2.89 (95% CI 1.37-6.11; p: 0.005) for the group of undifferentiated, large cell, anaplastic and mixed cell carcinomas. We found no convincing association between exposure intensity and lung cancer risk. Long-term DME exposure was associated with an increased risk of lung cancer, particularly to squamous cell carcinoma and the group of undifferentiated, large cell, anaplastic or mixed carcinomas.

Occupational exposure to textile dust increases the risk of rheumatoid arthritis: results from a Malaysian population-based case-control study.

OBJECTIVES: Lung exposures including cigarette smoking and silica exposure are associated with the risk of rheumatoid arthritis (RA). We investigated the association between textile dust exposure and the risk of RA in the Malaysian population, with a focus on women who rarely smoke. METHODS: Data from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis population-based case-control study involving 910 female early RA cases and 910 female age-matched controls were analysed. Self-reported information on ever/never occupationally exposed to textile dust was used to estimate the risk of developing anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA. Interaction between textile dust and the human leucocyte antigen DR ß-1 (HLA-DRB1) shared epitope (SE) was evaluated by calculating the attributable proportion due to interaction (AP), with 95% CI. RESULTS: Occupational exposure to textile dust was significantly associated with an increased risk of developing RA in the Malaysian female population (OR 2.8, 95% CI 1.6 to 5.2). The association between occupational exposure to textile dust and risk of RA was uniformly observed for the ACPA-positive RA (OR 2.5, 95% CI 1.3 to 4.8) and ACPA-negative RA (OR 3.5, 95% CI 1.7 to 7.0) subsets, respectively. We observed a significant interaction between exposure to occupational textile dust and HLA-DRB1 SE alleles regarding the risk of ACPA-positive RA (OR for double exposed: 39.1, 95% CI 5.1 to 297.5; AP: 0.8, 95% CI 0.5 to 1.2). CONCLUSIONS: This is the first study demonstrating that textile dust exposure is associated with an increased risk for RA. In addition, a gene-environment interaction between HLA-DRB1 SE and textile dust exposure provides a high risk for ACPA-positive RA.

Associations with smoking and shared epitope differ between IgA- and IgG-class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis.

OBJECTIVE: Smoking and HLA-DRB1/shared epitope (SE) alleles are risk factors for rheumatoid arthritis (RA) characterized by seropositivity for antibodies targeting citrullinated proteins (ACPAs)/cyclic citrullinated peptides (anti-CCP). Previously, mainly IgG-class antibodies have been studied. IgA-class antibodies are to a great extent related to mucosal immunity. The aim of this study was to explore interrelations between cigarette smoking, presence of SE, and seropositivity for circulating IgA and/or IgG anti-CCP antibodies among patients with early RA, to determine whether ACPAs of the IgA subclass are regulated by different mechanisms than those of the IgG subclass. METHODS: Two cohorts of patients with early RA, from the first Epidemiological Investigations of RA trial (n = 1,663) and the second Early Intervention in RA trial (n = 199), were grouped into 4 subsets based on anti-CCP subclass status (IgG-/IgA-, IgG-/IgA+, IgG+/IgA-, and IgG+/IgA+), and each subset was compared with regard to associations with smoking (current and former) and presence of SE. Interaction between smoking and SE was calculated using the attributable proportion (AP) due to interaction (assessing deviation from additivity of effects). RESULTS: Smoking was overrepresented among IgA anti-CCP-positive RA patients, regardless of whether IgG anti-CCP were present, whereas in patients with IgG anti-CCP alone, no association with smoking was found. SE alleles were overrepresented among IgG anti-CCP-positive patients, regardless of IgA anti-CCP status, and was not seen in patients with IgA anti-CCP alone. An interaction between ever smoking and SE was found with regard to the risk of IgG+/IgA+ RA (AP 0.5, 95% confidence interval 0.4, 0.6). No significant interaction was observed with regard to the risk of IgG-/IgA+ RA or IgG+/IgA- RA. CONCLUSION: In patients with RA, a history of ever smoking was associated with seropositivity for IgA anti-CCP antibodies, whereas presence of SE was associated with seropositivity for IgG anti-CCP antibodies. An interaction between ever smoking and the SE was limited to the RA subset characterized by seropositivity for both IgG and IgA anti-CCP. These findings provide novel evidence that anti-CCP-positive RA can be divided into at least 3 serologically distinct subsets associated with different risk factors, indicating different modes of pathogenesis in RA.

Myocardial infarction and occupational exposure to motor exhaust: a population-based case-control study in Sweden.

There is a well-established association between particulate urban air pollution and cardiovascular disease, but few studies have investigated the risk associated with occupational exposure to particles from motor exhaust. This study investigated the risk of myocardial infarction (MI) after occupational exposure to motor exhaust, using elemental carbon (EC) as a marker of exposure. A population-based case-control study of first-time non-lethal MI was conducted among Swedish citizens in ages 45-70 living in Stockholm County 1992-1994, including 1,643 cases and 2,235 controls. Working histories and data on potential confounders were collected by questionnaire and medical examination. The exposure to EC was assessed through a job-exposure matrix. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated by unconditional logistic regression. We investigated various exposure metrics: intensity, cumulative exposure and years since exposure. There was an exposure-response relation between the highest average exposure intensity during the work history and the risk of MI when adjusting for smoking and alcohol drinking (p for trend 0.034), with an OR of 1.30 (95% CI 0.99-1.71) in the highest tertile of exposure compared to the unexposed. An exposure-response pattern was observed in the analysis of years since exposure cessation among formerly exposed. Additional adjustments for markers of the metabolic syndrome reduced ORs and trends to non-significant levels, although this might be an over-adjustment since the metabolic syndrome may be part of the causal pathway. Occupational exposure to motor exhaust was associated with a moderately increased risk of MI.