麻豆传媒

Among veterans with rheumatoid arthritis (RA), environmental exposures to burn pits and military waste disposal were associated with increased risks of being seropositive for anti-cyclic citrullinated peptides (CCP), a nested case-control study found.

Anti-CCP positivity was more common among veterans exposed to burn pits -- open-air incineration pits used to dispose of various types of waste on military bases, including in Iraq and Afghanistan -- (odds ratio [OR] 1.66, 95% CI 1.02-2.69) compared with those not reporting exposure, according to Bryant R. England, MD, PhD, of Nebraska Medical Center in Omaha, and colleagues.

In addition, anti-CCP positivity was also higher among veterans with RA who reported exposure to other types of military waste disposal (OR 1.74, 95% CI 1.04-2.93), the investigators reported online in .

Complex interactions between genetic factors such as the HLA-DRB1 shared epitope alleles such as the *01 and *04 sequences and environmental exposures such as tobacco smoke result in the development of antibodies including rheumatoid factor (RF) and anti-CCP antibodies in the lung, the researchers explained.

These antibodies, particularly anti-CCP, are thought to be pathogenic in RA, contributing to disease initiation in the lung, followed by progression and the development of extra-articular manifestations such as interstitial lung disease and subcutaneous nodules. Seropositive disease is generally considered more severe overall.

Several previous studies have also implicated exposures other than smoking with RA, including occupational exposures from agriculture, bricklaying and concrete work, electronics and electrical activities, and exposure to pesticides and silica or asbestos.

Exposure to open burn pits in military settings has been linked with multiple types of lung disease, including asthma, chronic obstructive pulmonary disease, and bronchitis, the researchers noted, adding, however, that the effects of such exposures on patients with underlying RA are less well characterized, particularly with regard to autoantibody expression, shared epitope status, and disease severity.

For example, of veterans deployed to three sites in Iraq from 2003 to 2008 found inconsistent associations with new-onset RA, but the risk rose among individuals whose exposure to burn pits ranged from 132 to 211 days. The study was limited, however, by its small number of cases, short follow-up, and lack of information on autoantibody or shared epitope status.

Study Details

For the new study, designed to more fully examine the potential association between burn pits/waste exposure and RA, as well as other types of inhalant exposures, England and colleagues analyzed data from the prospective Veterans Affairs Rheumatoid Arthritis registry, using a mailed survey inquiring about exposures to military, agricultural, occupational, and household inhalants. Participants also reported smoking history and the presence of chronic pulmonary diseases, and the analyses were adjusted for age, sex, race, and smoking.

A total of 797 registry enrollees responded; mean age was 69.5 years, 82.1% were white, 86.7% were men, and 20.4% were current smokers. Anti-CCP positivity, defined as a level of 5 units/mL or higher, was reported in 77% of participants; RF positivity, defined as 15 IU/mL or higher, was reported in 76.5%; and positivity for the HLA-DRB1 shared epitope was found in 68.9%. Mean duration of RA was 17 years.

A total of 72.2% of respondents reported occupational exposure to dust, 31.1% had occupational exposure to asbestos, and 25.6% reported military asbestos exposure. Farm occupation was reported by 44.8%. Exposure to burn pits was reported by 18.6% and to waste disposal by 16%.

Respondents included those with deployments during the Vietnam War, the Persian Gulf War, the Korean War, and conflicts in Afghanistan and Iraq.

Tobacco use was associated with even higher rates of anti-CCP positivity with burn pit exposure, among both former smokers (OR 1.78, 95% CI 1.19-2.66) and current smokers (OR 3.48, 95% CI 1.88-6.44).

Burn pit exposure and waste disposal were not only more commonly associated with anti-CCP positivity, but also with higher concentrations of the autoantibodies (β 0.41, 95% CI 0.03-0.80) for burn pit exposure (β 0.20, 95% CI -0.20-0.61) and for waste disposal. In 85% of cases, individuals reported both types of exposure.

Other types of inhalant exposures such as agricultural and occupational were not associated with anti-CCP positivity, and no associations with military, occupational, or agricultural inhalant exposures were seen for RF positivity.

"The independent association of burn pits with chronic lung disease and anti-CCP but not RF, suggests the possibility that this inhalant exposure may induce the generation of citrullinated proteins and inflammatory responses within the lungs, analogous to the pathophysiologic process being identified to accompany cigarette smoking," the researchers observed.

England and co-authors then looked at the associations between burn pit and waste disposal exposures, anti-CCP positivity, and the presence of shared epitope alleles, and found that the OR for anti-CCP positivity was 5.69 (95% CI 2.73-11.87) for those with the alleles compared with those without the alleles or exposure to burn pits. This was stronger than either risk factor alone -- shared epitope positivity alone (OR 2.86, 95% CI 1.92-4.26) and burn pit exposure alone (OR 1.28, 95% CI 0.58-2.86).

Similarly, participants with the shared epitope alleles and exposure to waste disposal had an OR of 5.05 (95% CI 2.42-10.54) for anti-CCP positivity. Again, this was higher than either risk factor considered in isolation -- shared epitope positivity alone (OR 3.18, 95% CI 2.13-4.73) and waste disposal exposure alone (OR 2.19, 95% CI 0.92-5.21).

"We found burn pit and military waste exposure to be specifically associated with anti-CCP positivity in a well characterized cohort of veterans with RA, particularly in those positive for the HLA-DRB1 shared epitope," the authors wrote. "These findings support emerging evidence that various inhalant exposures may contribute to the generation of RA autoantibodies such as anti-citrullinated protein antibodies."

Burn Pit Exposure Follow-up

In 2014, the U.S. Department of Veterans Affairs established the , which allows veterans to report and document their exposures and health concerns. As of August 2020, there were 212,829 registrants.

Information on the explains that burn pits were frequently used for waste disposal at military outposts in Iraq and Afghanistan, but that "at this time, research does not show evidence of long-term health problems from exposure to burn pits. VA continues to study the health of deployed veterans."

Exposure to smoke from burn pits can have effects on multiple systems, including respiratory, cardiovascular, and gastrointestinal, as well as the eyes and skin, the site notes. The severity of health effects may depend on proximity, wind direction, and the type of waste being disposed.

"Most of the irritation is temporary and resolves once the exposure is gone," the VA's public health information continues. "This includes eye irritation and burning, coughing and throat irritation, breathing difficulties, and skin itching and rashes ... Waste products in burn pits include, but are not limited to: chemicals, paint, medical and human waste, metal/aluminum cans, munitions and other unexploded ordnance, petroleum and lubricant products, plastics, rubber, wood, and discarded food."

Limitations for their study, England and co-authors said, included the cross-sectional design and the homogeneous population.

"Prospective cohort studies comprehensively evaluating the impact of inhalant exposures, including military burn pits and waste disposal, and genetic risk factors on RA risk are needed," the team concluded.

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