Association of Agricultural, Occupational, and Military Inhalants With Autoantibodies and Disease Features in US Veterans With Rheumatoid Arthritis

Abstract

Objective. To determine the association of inhalant exposures with rheumatoid arthritis (RA)-related autoantibodies and severity in US veterans. Methods. Participants in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were mailed surveys assessing occupational, agricultural, and military inhalant exposures. Demographic characteristics, disease activity, functional status, and extraarticular features were obtained from the VARA registry, while HLA-DRB1 shared epitope (SE) status, anti-cyclic citrullinated peptide (anti-CCP) antibodies, and rheumatoid factor (RF) were measured using banked DNA/ serum from enrollment. Associations between inhalant exposures and RA-related factors (autoantibodies, severity, and extraarticular features) were assessed using multivariable linear and logistic regression models adjusted for age, sex, race, and tobacco use and stratified by SE status. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Results. Questionnaires were returned by 797 of 1,566 participants (50.9%). Survey respondents were older, more often White or male, and less frequently smokers, and had lower disease activity compared to nonrespondents. Anti-CCP positivity was more common among veterans exposed to burn pits (OR 1.66 [95% CI 1.02, 2.69]) and military waste disposal (OR 1.74 [95% CI 1.04, 2.93]) independent of other factors. Among participants who were positive for SE alleles, burn pit exposure (OR 5.69 [95% CI 2.73, 11.87]) and military waste disposal exposure (OR 5.05 [95% CI 2.42, 10.54]) were numerically more strongly associated with anti-CCP positivity. Several inhalant exposures were associated with the presence of chronic lung disease, but not with the presence of RF or the level of disease activity. Conclusion. Military burn pit exposure and military waste disposal exposure were independently associated with the presence of anti-CCP antibodies in RA patients. These findings are consistent with emerging evidence that various inhalant exposures influence autoantibody expression and RA risk.

Inorganic Dust Exposure During Military Service as a Predictor of Rheumatoid Arthritis and Other Autoimmune Conditions

“…In that study, there was no significant relationship to exposure, but there were also few self-reported cases confirmed by medical records. A more recent analy sis using the VA Rheumatoid Arthritis Registry also investigated selfreported burn pit exposure and waste disposal, observing an increased risk in relation to anti-CCP positivity among persons with disease (5). Dust exposure in military occupations also was not considered in that analysis.…”

Rheumatoid Arthritis in Silica-Exposed Workers

“…It has been suggested that silica exposure exacerbates existing rheumatic diseases, resulting in hospitalization or premature death [ 17 ]. However, one study found no association between agricultural or occupational inhalant exposure and RA autoantibodies or disease severity [ 18 ].…”

Increased susceptibility to organic dust exposure-induced inflammatory lung disease with enhanced rheumatoid arthritis-associated autoantigen expression in HLA-DR4 transgenic mice

“…Multiple genetic and environmental risk factors contribute to the development of RA and RA-associated lung disease. These risk factors include the “shared epitope,” specific peptide sequences in selected type II human leukocyte antigens (HLA) such as HLA-DRB1*0401 (DR4) [ 4 , 5 ]. Whereas the association among DR4 alleles and autoimmunity is well-recognized, it is not fully understood how this shared epitope predisposes an individual to autoimmune disease.…”

“…Various airborne inflammatory exposures are recognized as shared risk factors for primary lung diseases (e.g., chronic obstructive pulmonary disease, bronchitis, asthma) and for RA and RA-associated lung disease [ 3 , 5 , 16 – 19 ]. The risk associated with these exposures appears to be disproportionately higher in men, even though RA is more common among women [ 16 ].…”

“…The risk associated with these exposures appears to be disproportionately higher in men, even though RA is more common among women [ 16 ]. Relevant exposures include not only cigarette smoke [ 3 , 5 ], but also other exposures related to ambient air pollution, military service (burn pits, organic dusts, military waste disposal), and various workplace environments (agriculture organic dusts, textiles, silica, construction, mining) [ 3 , 5 , 16 – 18 , 20 ]. The importance of environmental insults is further highlighted by emerging evidence linking the generation of autoantigens and RA-specific autoimmunity to an initial “breach” of tolerance in the respiratory mucosa [ 21 – 25 ].…”