Uranium Exposure Linked to High Lupus Rates in Community Living Near a Former Refinery

Newswise — WASHINGTON – High rates of systemic lupus erythematosus have been linked to living in proximity to a former uranium ore processing facility in Ohio, according to new research findings presented this week at the American College of Rheumatology Annual Meeting in Washington, D.C.

Systemic lupus erythematosus, also called SLE or lupus, is a chronic inflammatory disease that can affect the skin, joints, kidneys, lungs, nervous system, and/or other organs of the body. The most common symptoms include skin rashes and arthritis, often accompanied by fatigue and fever. Lupus occurs mostly in women, typically developing in individuals in their twenties and thirties – prime child-bearing age.

Researchers at the University of Cincinnati and Cincinnati Children’s Medical Center sought to explain an excessive number of lupus cases reported in a community five miles from a former uranium plant in Fernald, Ohio, from 1990 to 2008. They used available medical data from the Fernald Community Cohort, an 18-year study of 8,788 adult volunteers living near the plant, not including any plant workers.

“What prompted us was the knowledge that lupus patients may be sensitive to sunlight and irradiation, in addition to literature hinting that miners may be at increased risk for developing lupus,” says Pai-Yue Lu, MD, a pediatric rheumatology fellow at Cincinnati Children’s Hospital Medical Center and the lead researcher in the study. “When we learned of the Fernald cohort, how carefully the community had been followed, and the uranium exposure data collected, we were curious whether the frequency of lupus in those exposed was increased over those who had not been exposed. The availability of this cohort and carefully collected data provided a great setting to ask this question.”

Using the data from the cohort, 24 cases of lupus were confirmed. Data collected included ICD9 medical codes associated with lupus, hydroxychloroquine (Plaquenil®) prescription, and autoantibody testing. Lupus cases were confirmed using an operational definition of the disease according to ACR classification criteria and medical record documentation.

Estimated levels of uranium exposure from the plant were associated with higher rates of lupus. Among the lupus cases, 12 were in the high exposure group, seven with moderate exposure, and five in the low exposure group. Lupus was associated with the high exposure group. Typical U.S. incidence for lupus is 1.8 to 7.6 cases per 100,000 people per year, according to the Centers for Disease Control and Prevention statistics. Prevalence in this group, however, is five times higher than expected in the group exposed to higher amounts of radiation.

Although the exact connection between uranium exposure and lupus is unknown, studies in mice have shown that uranium can mimic the effects of estrogen, says Dr. Lu. “In adults, lupus is 10 times more common in women compared to men and estrogen effects have been a target of research. Also, uranium is a radioactive element, and the accompanying radiation exposure has been known to cause genetic mutations and changes in gene expression. Both genes and environment may play a role in lupus development.”

Exploring which potential environmental factors may trigger or cause lupus is making slow progress, says Dr. Lu. “There are likely many contributing environmental factors. A starting place for exposure identification is the study of well-characterized cohorts such as the Fernald cohort used in this project.”

The American College of Rheumatology is an international professional medical society that represents more than 9,000 rheumatologists and rheumatology health professionals around the world. Its mission is to advance rheumatology. The ACR/ARHP Annual Meeting is the premier meeting in rheumatology. For more information about the meeting, visit www.acrannualmeeting.org or join the conversation on Twitter by using the official hashtag: #ACR2012.

Learn more about living well with rheumatic disease as well as rheumatologists and the role they play in health care. Also, discover the ACR’s Simple Tasks campaign, which highlights the severity of rheumatic diseases and the importance of early and appropriate referral to a rheumatologist.

Editor’s Notes: Pai-Yue Lu, MD will present this research during the ACR Annual Meeting at the Walter E. Washington Convention Center at 3:00 PM on Monday, November 12 in Salon B. Dr. Lu will be available for media questions and briefing at 8:30 AM on Tuesday, November 13 in the on-site press conference room, Room 203 A–B.

Presentation Number: 1606

Identifying a Link Between Uranium Exposure and Systemic Lupus Erythematosus in a Community Living near a Uranium Plant

Pai-Yue Lu (Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio)Leah C. Kottyan (Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio)Susan M. Pinney (University of Cincinnati, Cincinnati, Ohio)Judith A. James (Oklahoma Medical Research Foundation and Oklahoma University Health Sciences Center, Oklahoma City, Okla.)Changchun Xie (University of Cincinnati, Cincinnati, Ohio)Jeanette M. Buckholz (University of Cincinnati, Cincinnati, Ohio)John B. Harley (Cincinnati Children's Hospital Medical Center; US Department of Veterans Affairs Medical Center, Cincinnati, Ohio)

Background/Purpose: Effects of environmental exposures on the development of systemic lupus erythematosus (SLE) are potentially important and relatively unexplored in SLE pathogenesis. An excess of reported SLE cases in a community surrounding a former uranium ore processing plant provided an opportunity to evaluate the relationship between uranium exposure through downstream air or water and SLE. Our specific a priori objective was to explore the hypothesis that SLE patients will be found more frequently in community members exposed to high prior uranium exposure levels in the Fernald Community Cohort (FCC).

Methods: A nested case control study was performed with data from the FCC. The FCC is comprised of voluntarily enrolled individuals who lived during plant operation within 5 miles of a uranium ore processing facility in Fernald, OH and followed from 1990 to 2008, which was after the plant ceased operations. No uranium plant workers are included in this study. Potential SLE cases were identified with searches for ICD9 codes associated with lupus (710.0 and 695.4) and a medication code search for hydroxychloroquine. Sera from potential cases were screened for autoantibodies using the Bioplex 2200 multiplex assay and anti-cardiolipin antibodies using ELISA. Cases were confirmed using an operational definition that included American College of Rheumatology classification criteria and medical record documentation. Four age-, race-, and sex-matched controls were selected for every case. Cumulative uranium exposure was calculated for each individual with a dosimetry model developed by the Centers for Disease Control and Prevention. Covariates in the analysis included smoking history, alcohol intake history, and family history of SLE. Logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI). For comparison, preliminary analysis with rheumatoid arthritis (RA, ICD9 code 714.0) was also performed.

Results: The FCC includes 4,187 individuals with low uranium exposure, 1,273 with moderate exposure, and 2,756 with high exposure. SLE was confirmed in 20 of 26 cases with an ICD9 code of 710.0, in 2 of 5 cases with an ICD9 code of 695.4, and in 2 of 43 other cases prescribed hydroxychloroquine. The female to male ratio among cases was 5 to 1. Of the SLE cases, 5 were in the low exposure group, 7 in the moderate exposure group, and 12 in the high exposure group. Following logistic regression modeling, SLE was found to be associated with high exposure (OR 4.81, 95% CI 1.38-16.75, p = 0.043). There was no association between low or moderate uranium exposure and SLE. In the FCC overall, RA occurs at the expected prevalence, while SLE is increased by 5-fold over the expected prevalence.

Conclusion: High uranium exposure is associated with SLE relative to matched controls in this sample of uranium exposed individuals, suggesting that our hypothesis is correct. Potential explanations for this relationship include the estrogen effects of uranium, somatic mutation from ionizing radiation, or effects of some other unidentified accompanying exposure. Whatever the cause for this association, understanding the basis of this relationship is likely to provide important fundamental insight into SLE pathogenesis.

Disclosure: P. Y. Lu, None; L. C. Kottyan, None; S. M. Pinney, None; J. A. James, None; C. Xie, None; J. M. Buckholz, None; J. B. Harley, None.