Pesticide use and risk of systemic autoimmune diseases in the Agricultural Health Study.

BACKGROUND: Systemic lupus erythematosus (SLE) risk has been associated with pesticide use, but evidence on specific pesticides or other agricultural exposures is lacking. We investigated history of pesticide use and risk of SLE and a related disease, Sjögren's syndrome (SS), in the Agricultural Health Study. METHODS: The study sample (N = 54,419, 52% male, enrolled in 1993-1997) included licensed pesticide applicators from North Carolina and Iowa and spouses who completed any of the follow-up questionnaires (1999-2003, 2005-2010, 2013-2015). Self-reported cases were confirmed by medical records or medication use (total: 107 incident SLE or SS, 79% female). We examined ever use of 31 pesticides and farm tasks and exposures reported at enrollment in association with SLE/SS, using Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI), with age as the timescale and adjusting for gender, state, and correlated pesticides. RESULTS: In older participants (>62 years), SLE/SS was associated with ever use of the herbicide metribuzin (HR 5.33; 95%CI 2.19, 12.96) and applying pesticides 20+ days per year (2.97; 1.20, 7.33). Inverse associations were seen for petroleum oil/distillates (0.39; 0.18, 0.87) and the insecticide carbaryl (0.56; 0.36, 0.87). SLE/SS was inversely associated with having a childhood farm residence (0.59; 0.39, 0.91), but was not associated with other farm tasks/exposures (except welding, HR 2.65; 95%CI 0.96, 7.35). CONCLUSIONS: These findings suggest that some agricultural pesticides may be associated with higher or lower risk of SLE/SS. However, the overall risk associated with farming appears complex, involving other factors and childhood exposures.

Helicobacter pylori seropositivity is associated with antinuclear antibodies in US adults, NHANES 1999-2000.

Infectious diseases, such as Helicobacter pylori, which produce systemic inflammation may be one key factor in the onset of autoimmunity. The association between H. pylori and antinuclear antibodies (ANA), a marker of autoimmunity, has been understudied. Data from the 1999-2000 National Health and Nutrition Examination Survey were used to evaluate the cross-sectional association between H. pylori seroprevalence and ANA positivity in US adults aged ≥20 years. ANA was measured in a 1:80 dilution of sera by indirect immunofluorescence using HEp-2 cells (positive ⩾3). H. pylori immunoglobulin G enzyme-linked immunosorbent assays were used to categorise individuals as seropositive or seronegative. H. pylori seropositivity and ANA positivity were common in the adult US population, with estimated prevalences of 33.3% and 9.9%, respectively. Both were associated with increasing age. H. pylori seropositivity was associated with higher odds of ANA (prevalence odds ratio = 1.89, 95% confidence interval = 1.08-3.33), adjusted for age, sex, race/ethnicity, educational attainment and body mass index. H. pylori infection may be one key factor in the loss of self-tolerance, contributing to immune dysfunction.

Pesticide exposure and risk of systemic lupus erythematosus in an urban population of predominantly African-American women.

OBJECTIVE: Past studies have reported associations between pesticide exposure and the risk of systemic lupus erythematosus (SLE). Residential pesticide exposure has been less well studied than agricultural exposure. The purpose of this study was to assess SLE risk associated with residential pesticide exposure in an urban population of predominantly African-American women. METHODS: Adult women with SLE were identified from six hospital databases and community screening in three neighborhoods in Boston, Massachusetts, USA. Controls were adult women volunteers from the same neighborhoods who were screened for the absence of connective tissue disease and anti-nuclear antibodies. Subjects were considered exposed to pesticides if they had ever had an exterminator for an ant, cockroach, or termite problem prior to SLE diagnosis or corresponding reference age in controls. Risks associated with pesticide exposure were analyzed using multivariable logistic regression models, adjusted for sociodemographic factors. RESULTS: We identified 93 SLE subjects and 170 controls with similar baseline characteristics. Eighty-three per cent were African-American. Pesticide exposure was associated with SLE, after controlling for potential confounders (odds ratio 2.24, 95% confidence interval 1.28-3.93). CONCLUSION: Residential exposure to pesticides in an urban population of predominantly African-American women was associated with increased SLE risk. Additional studies are needed to corroborate these findings.

Elevated C-reactive protein and self-reported disease activity in systemic lupus erythematosus.

C-reactive protein (CRP), a biomarker of inflammation, has been associated with increased disease activity in rheumatoid arthritis. However, the association in systemic lupus erythematosus (SLE) remains unclear. We examined the association of CRP with self-reported disease activity in the Carolina Lupus Study and described differences by sociodemographic characteristics. The study included baseline and three-year follow-up data on 107 African-American and 69 Caucasian SLE patients enrolled at a median 13 months since diagnosis. Models estimated prevalence differences in the association of baseline CRP with self-reported flares, adjusting for age, sex, race and education. Active disease or flare was reported by 59% at baseline and 58% at follow-up. Higher CRP (>10 µg/ml vs. <3 µg/ml) was associated with a 17% (95% confidence interval (CI): -20, 53%) higher prevalence of flare at baseline and a 26% (95% CI: -9, 62%) higher prevalence of flare at follow-up. These CRP-flare associations were notably stronger in patients with lower education at baseline and in African-Americans at follow-up. These findings suggest that CRP may be a useful marker in studies of SLE health disparities.

Pesticides, chemical and industrial exposures in relation to systemic lupus erythematosus.

Growing evidence suggests exposure to chemicals and industrial pollutants may increase risk of systemic lupus erythematosus (SLE). Here we review research on SLE associations with occupational and industrial exposures, primarily drawing on studies in human populations and summarizing epidemiologic research published in the past decade. The association of occupational silica exposure with SLE is well established, but key questions remain, including the required dose and susceptibility factors, and SLE risk due to other silicate exposures. Research on SLE and other exposures is less well developed, though several potential associations merit further consideration because of the consistency of preliminary human findings, experimental animal research, and biologic plausibility. These include pesticides and solvents, for which experimental findings also support investigation of specific agents, including organochlorines and trichloroethylene. Experimental findings and biologic plausibility suggest research on SLE and occupational exposure to hydrocarbons (i.e. mineral oils) is warranted, especially given the widespread exposures in the population. Experimental and limited human findings support further investigation of SLE related to mercury exposure, especially in dental occupations. Research on environmental risk factors in risk-enriched cohorts (family-based) is recommended, as is further investigation of exposures in relation to intermediate markers of effect (e.g. antinuclear antibodies), clinical features (e.g. nephritis), and outcomes.

Employment and work schedule are related to telomere length in women.

OBJECTIVES: To examine the association of employment and work schedule with shorter DNA telomeres, a marker of cellular ageing and disease risk factor, and consider whether differences were related to health, behaviours and sociodemographic factors, or varied by stress levels or menopausal status. METHODS: This cross-sectional analysis of 608 women aged 35-74 in the Sister Study examined determinants of relative telomere length (rTL) measured by quantitative PCR in leucocyte DNA. Age-adjusted regression models estimated base pair (bp) rTL differences for current and lifetime schedule characteristics (ie, part-time, full-time or overtime hours; multiple jobs; irregular hours; shiftwork; work at night). Covariates included race, smoking, perceived stress, sleep, physical activity, health and menopausal status, education, marital status, live births, children under 18, measured body mass index and urinary stress hormones. RESULTS: Compared with non-employed women with moderate or substantial past work histories (n=190), those currently working full-time (n=247; median 40 h/week) had a shorter rTL, an age-adjusted difference of -329 bp (95% CI -110 to -548). Longer-duration full-time work was also associated with shorter rTL (age-adjusted difference of -472 bp, 95% CI -786 to -158 for 20+ vs 1-5 years). Findings were not explained by health and demographic covariates. However, rTL differences for working at least full-time were greater in women with higher stress and epinephrine levels. CONCLUSIONS: Current and long-term full-time work were associated with shorter rTL, with differences of similar magnitude to smoking and history of heart disease or diabetes. Longitudinal data with specific stress measures are needed to further evaluate the impact of work schedule on rTL.

Total serum IgE levels in systemic lupus erythematosus and associations with childhood onset allergies.

Elevated serum IgE has been described in systemic lupus erythematosus (SLE), but associations with disease risk and characteristics remain unresolved. We assessed total serum IgE levels and atopy (IgE > 100 IU/ml) in recently diagnosed SLE patients (n = 228) compared with population controls (n = 293) and in relation to disease activity, autoantibodies, clinical features, total immunoglobulins, C-reactive protein, and allergy history. Multivariate models estimated determinants of IgE and atopy in patients and controls, and associations of SLE with allergy and atopy. Total IgE levels were higher in patients than controls (median = 42 vs. 29 IU/ml); 32% of patients and 25% of controls were atopic (p = 0.06). IgE levels were significantly higher in non-Whites and patients reporting childhood onset (<18 years) asthma and hives, and in controls reporting childhood asthma, hay fever, eczema, and adult onset hives. After accounting for racial differences, atopy was not associated with SLE, nephritis, or other clinical and laboratory parameters. In sum, our findings provide limited evidence of a direct association between total serum IgE and SLE overall or with other disease characteristics after adjusting for demographic characteristics and allergy history. Future studies may want to explore potentially shared risk factors for development of allergy, atopy, and SLE.

Childhood agricultural and adult occupational exposures to organic dusts in a population-based case-control study of systemic lupus erythematosus.

Organic dust exposure can influence the development and symptoms of immune-related diseases such as atopy and asthma, but has rarely been examined in relation to systemic autoimmunity. The present analyses explore the association of lifetime farm and occupational organic dust exposures with systemic lupus erythematosus (SLE) in recently diagnosed patients (n = 265) compared with controls (n = 355) frequency matched by age, sex and state. Questionnaire data included childhood farm residence, childhood and adult experience with specific crops, and adult work in textiles, hog or poultry processing and paper or furniture manufacture. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression models including age, sex, state, race, education and silica exposure. Overall childhood or adult farm contact and childhood farm residence were not associated with SLE. Farm contact with livestock was inversely associated with SLE (OR = 0.55, 95% CI 0.35, 0.88). This effect was most pronounced among those with childhood farm residence and both childhood and adult livestock exposure (OR = 0.19; 95% CI 0.06, 0.63), but was difficult to separate from adult exposure to grains or corn. Other adult occupational exposures were not associated with SLE risk overall, regardless of childhood farm residence or livestock exposure, although an inverse association was seen among non-smokers (OR = 0.59; 95% CI 0.33, 1.1), particularly for textile work (OR = 0.34; 95% CI 0.19, 0.64). These exploratory findings support the development of studies to specifically investigate the effects of organic dust exposure on SLE risk, with particular attention to exposure assessment and characterization of demographics, smoking and other occupational exposures.

Occupational exposures and risk of systemic lupus erythematosus: a review of the evidence and exposure assessment methods in population- and clinic-based studies.

Epidemiologic and experimental research suggests a potential role of occupational exposures in the development of systemic lupus erythematosus (SLE). A plausible association has been identified in studies of occupational silica exposure and SLE, complemented by experimental studies in lupus-prone mice exploring potential mechanisms related to apoptosis and immune dysregulation. Experimental studies of the solvent trichloroethylene in lupus-prone mice provide evidence of effects on immune function, including increased production of autoantibodies and activation of CD4+ T cells. However, few studies of occupational solvent exposure and SLE have been conducted, and those that are available show little evidence of an association. There is some suggestion from the available studies of the potential influence of pesticides on SLE, but as with solvents, the specific type of pesticides that may be implicated is not known. Our understanding of the role of occupational exposures in SLE could be advanced by the development of larger, multisite or parallel studies that utilize similar questionnaire and exposure evaluation methods. Multiple studies using comparable exposure measures are needed to provide sufficient sample size for examining gene-environment interactions. We provide a general overview of data requirements and methods available for the assessment and evaluation of occupational exposures in clinical and population-based studies of SLE.

CTLA-4 gene polymorphisms and systemic lupus erythematosus in a population-based study of whites and African-Americans in the southeastern United States.

Cytotoxic lymphocyte antigen-4 (CTLA-4) plays an important role in regulating T cell activation, and may help to limit T cell response under conditions of inflammation. Genetic variability in CTLA-4 has been implicated in the development of several autoimmune diseases. Some studies have described associations between CTLA-4 polymorphisms and systemic lupus erythematosus (SLE), but findings have been inconsistent. We examined polymorphisms in the CTLA-4 gene promoter region (-1722T/C, -1661 A/G, -318C/T) and exon I (+49G/A) with respect to SLE in a population-based case-control study in the southeastern US. Genotypes from 230 recently diagnosed cases and 276 controls were examined separately for African-Americans and whites. We observed no overall associations between SLE and the four CTLA-4 polymorphisms examined. Subgroup analyses revealed effect modification by age for the presence of the -1661G allele, yielding a significant positive association with SLE in younger (<35 years) African-Americans (OR = 3.3). CTLA-4 genotypes also interacted with HLA-DR2 and GM allotype to contribute to risk of SLE. These findings suggest allelic variation in this region of CTLA4 is not a major independent risk factor for SLE, but may contribute to risk of disease in younger African-Americans or in the presence of certain immunogenetic markers.

Systemic lupus erythematosus and genetic variation in the interleukin 1 gene cluster: a population based study in the southeastern United States.

BACKGROUND: Interleukin (IL)1alpha and IL1beta, and their endogenous receptor antagonist (IL1Ra), have been related to the pathology of systemic lupus erythematosus (SLE), but the role of IL1 polymorphisms in the aetiology of SLE is unknown. OBJECTIVE: To examine polymorphisms at IL1alpha -889(C-->T), IL1alpha +4845(C-->T), IL1beta -511(C-->T), IL1beta +3953(G-->T), and IL1Ra (86 bp VNTR) in a population based study of SLE in North Carolina and South Carolina. METHODS: Genotypes from 230 cases who met ACR classification criteria, and from 275 controls matched for age, sex, and state, were analysed separately for African Americans and whites. Odds ratios (ORs) were estimated by logistic regression models for each locus alone and also after adjusting for polymorphisms at adjacent loci. RESULTS: An increased risk of SLE for the IL1alpha -889C/C genotype compared with carriage of the -889T allele was found in both African Americans (OR = 3.1, p = 0.001) and whites (OR = 2.9, p = 0.005). In African Americans, carriage of the IL1beta -511T allele was associated with a higher risk of SLE than carriage of the -511C/C genotype (OR = 2.4, p = 0.017), independent of variation at IL1alpha -889. CONCLUSIONS: The observed associations support the hypothesis that genetic variation in IL1 is involved in the aetiology of SLE and merit further investigation.

Occupational exposure assessment in case-control studies: opportunities for improvement.

Community based case-control studies are an efficient means to study disease aetiologies, and may be the only practical means to investigate rare diseases. However, exposure assessment remains problematic. We review the literature on the validity and reliability of common case-control exposure assessment methods: occupational histories, job-exposure matrices (JEMs), self reported exposures, and expert assessments. Given the variable quality of current exposure assessment techniques, we suggest methods to improve assessments, including the incorporation of hygiene measurements: using data from administrative exposure databases; using results of studies identifying determinants of exposure to develop questionnaires; and where reasonable given latency and biological half life considerations, directly measuring exposures of study subjects.

Differences by race, sex and age in the clinical and immunologic features of recently diagnosed systemic lupus erythematosus patients in the southeastern United States.

We examined the prevalence of clinical and immunologic features of systemic lupus erythematosus (SLE) by race, sex and age in a population-based study of 265 SLE patients. Patients fulfilled the American College of Rheumatology classification criteria. The median time between diagnosis and study enrollment was 13 months. The clinical and hematologic data were limited to occurrences up to 6 months after the diagnosis date, as documented in medical records. We used sera collected at study enrollment from 244 (92%) patients for serologic testing of autoantibodies. The associations between clinical and immunological features of SLE and age, sex and race were examined using logistic regression. The effect of each of these variables was examined adjusting for the other two demographic factors. Mean age at diagnosis was 6 years younger among African-Americans and other minorities compared with white patients (P < 0.01). Discoid lupus, proteinuria, anti-Sm and anti-RNP autoantibodies were more commonly seen in African-American patients, with odds ratios higher than 3.0. Photosensitivity and mucosal ulcers were noted less often in African-American patients. Proteinuria, leukopenia, lymphopenia and thrombocytopenia were approximately three times more common in men compared with women. The prevalence of oral or nasal ulcers and anti-DNA autoantibodies declined with age. The extent to which the differences we observed reflect genetic or environmental influences on the disease process should be investigated.

Genomic diversity of "Norwalk like viruses" (NLVs): pediatric infections in a Brazilian shantytown.

"Norwalk-like viruses" (NLVs) are a common cause of epidemic gastroenteritis in adults and children in developed countries. However, little is known about the role of NLVs in endemic pediatric gastroenteritis in developing countries. We sequenced Genogroup I and II NLV reverse transcription-polymerase chain reaction (RT-PCR) products from an 81-nucleotide region of the viral RNA polymerase gene to examine the molecular epidemiology of NLV infection in children younger than 5 years of age in Forteleza, Ceará, Brazil. NLV-positive PCR products were obtained from stool specimens collected over a 16-month period (1990-1991) from diarrhea cases and controls in a cohort of 120 children in an urban shantytown and from a study in the same city of hospitalized children with persistent diarrhea. Eight unique strains were detected in 15 specimens from 10 cohort children and in two hospital specimens. Nucleotide identity between the strains (5 Genogroup I, 3 Genogroup II) ranged from 63% to 88%. We designated these strains BraV1-8, for Brazil virus 1-8. The degree of genomic diversity of NLV strains we identified in this cohort during a short time period suggests multiple foci of infection within the community. Furthermore, sequence analysis of strains from two children with multiple symptomatic NLV infections indicates that infection with one strain was not protective against subsequent infection with a different strain in the same genogroup. These findings have implications for vaccine development and the prevention of pediatric gastroenteritis in developing countries.

Occupational exposure to crystalline silica and autoimmune disease.

Occupational exposure to silica dust has been examined as a possible risk factor with respect to several systemic autoimmune diseases, including scleroderma, rheumatoid arthritis, systemic lupus erythematosus, and some of the small vessel vasculitidies with renal involvement (e.g., Wegener granulomatosis). Crystalline silica, or quartz, is an abundant mineral found in sand, rock, and soil. High-level exposure to respirable silica dust can cause chronic inflammation and fibrosis in the lung and other organs. Studies of specific occupational groups with high-level silica exposure (e.g., miners) have shown increased rates of autoimmune diseases compared to the expected rates in the general population. However, some clinic- and population-based studies have not demonstrated an association between silica exposure and risk of autoimmune diseases. This lack of effect may be due to the limited statistical power of these studies to examine this association or because the lower- or moderate-level exposures that may be more common in the general population were not considered. Experimental studies demonstrate that silica can act as an adjuvant to nonspecifically enhance the immune response. This is one mechanism by which silica might be involved in the development of autoimmune diseases. Given that several different autoimmune diseases may be associated with silica dust exposure, silica dust may act to promote or accelerate disease development, requiring some other factor to break immune tolerance or initiate autoimmunity. The specific manifestation of this effect may depend on underlying differences in genetic susceptibility or other environmental exposures.

Wood Decay Associated with Pileated Woodpecker Roosts in Western Redcedar.

The pileated woodpecker (Dryocopus pileatus) is a species of concern to forest managers because it uses cavities in large snags and decadent trees for nesting and roosting. A radio-telemetry study of pileated woodpeckers on the Olympic Peninsula of western Washington (1) found that large western redcedar (Thuja plicata Donn ex D. Don) were frequently used for roosting. These roost trees were partially hollow or softened by internal decay. Western redcedar is thought to be less susceptible to most fungal pathogens than are other conifers. This misconception probably arose because of the high resistance to decay of cedar heartwood under service conditions. Many heartwood fungi do, however, attack living redcedar during their lifespan (often over 1,000 years), and large western redcedar have a high incidence of heartwood decay (2). Two to four wood cores were removed below openings used by radio-tagged woodpeckers at heights of 7.5 to 10.5 m on each of 10 large (200 to 300 cm diameter at 1.4 m above ground), living western redcedars. Wood samples were cultured on malt extract agar. No pure cultures of wood-decay fungi were obtained from two trees, although the samples were visually decayed. Oligoporus sericeomollis (Romell) Bondartzeva (= Poria asiatica (Pilát) Overh.) was the only wood-decay fungus isolated from the remaining eight trees. O. sericeomollis causes a brown, cubical heartrot in living western redcedar. In late stages of decay, the rot column typically forms a piped or tubular shape, can extend 25 or more meters up the bole of the tree, and can spread out into large branches (2). Pileated woodpeckers often roost in large, longitudinal tree cavities having multiple openings that provide a means of escape from potential predators. The decay columns produced by O. sericeomollis may create optimal roosting conditions in western redcedar for pileateds. During the telemetry study, woodpeckers were observed entering redcedars at one opening, but exiting from another opening some distance away. Large western redcedars that contain heartrot before they die may be particularly important to pileated woodpeckers because these trees persist in the landscape and provide potential roost sites far longer than other tree species in western Washington, perhaps even for centuries. Information from this and similar studies may be useful for developing inoculation techniques that use fungi with specific decay characteristics to create habitat for woodpeckers. References: (1) K. B. Aubry and C. M. Raley. Northwest Env. J. 6:432, 1990. (2) D. C. Buckland. Can. J. Res. C. 24:158, 1946.