Occupational silica exposure has been associated with an increased risk for several autoimmune diseases (1 2 – 4 4 – 10 11 12 , 13 14 , 15 8 5 , 6 16 2 , 3 , 17
The purpose of this study was to assess the association between silica exposure and onset of biopsy-proven glomerulonephritis that resulted from anti–neutrophil cytoplasmic autoantibody (ANCA)-associated SVV (ANCA-SVV), a category of SVV that frequently involves the kidney. A population-based, case-control study in the southeastern United States was conducted to study the association.
Differential associations by gender and education were of interest because male individuals and those with lower education may have a greater opportunity for exposure given that occupations that are associated with silica exposure are generally male-dominated, working-class jobs. Associations by race were also of interest because although white individuals account for 80 to 90% of cases in United States cohorts (18 , 19 18
Materials and Methods
This was a population-based, case-control study, inclusive of North Carolina, South Carolina, Georgia, and southern Virginia. A structured telephone interview, modified from one that was used in a study of silica exposure and lupus (20
Study Participants
Participants had to be aged 18 to 84 at the time of interview. Case patients had to have resided in the study area for at least 6 months during the year before their renal biopsy diagnosis; control subjects have resided in the study area at least 6 months before a uniform reference date of January 1, 2001. This date was the approximate median biopsy date among case patients. Participants had to speak and understand English.
Nephropathologists throughout the region (see Acknowledgments) identified all patients who had an initial renal biopsy between October 1997 and October 2003 and a diagnosis of pauci-immune crescentic glomerulonephritis, with or without granulomatous inflammation and with or without ANCA positivity. ANCA positivity, determined by immunofluorescence microscopy and/or antigen-specific ELISA (21 22 – 24 25 , 26 27
Control subjects were identified through list-assisted random-digit dialing and were frequency-matched to case patients by age, gender, and state. Age groups for matching were 18 to 39, 40 to 59, and 60 to 84. A list of random residential telephone numbers that were selected using an equal probability method was purchased (Marketing Systems Group, Fort Washington, PA). This study was approved by the Biomedical Institutional Review Board at the University of North Carolina at Chapel Hill (97-MED-44 and 04-MED-663) and by the home institutions of each nephropathologist (see Acknowledgments).
Interview Participation
Overall, 214 case patients met the entry criteria according to available information. The 214 case patients were from 498 potential case patients who were identified through nephropathology laboratories. Details of eligibility criteria and nonparticipation reasons were limited because all information, including age, state of residence, and ANCA positivity, was not provided to nephropathology laboratories by clinicians who requested the renal biopsy diagnosis report. Age was <18 yr in 5% (n = 24 of 455 with known age) and >84 in 1% (n = 5 of 455). No clinic or physician could be identified for 27 (5%) patients, and 61 (12%) were outside the geographic region. Seventy-seven (15%) patients died before initiation of the interviews.
Contact was attempted for the 214 case patients to verify eligibility and recruit for the full interview. Of the 214, 129 (60%) completed and two partially completed the full interview. The two partially completed were excluded because complete assessment of silica exposure could not be conducted. Thirty-six of the 214 had died. The 47 remaining patients were living, and contact was attempted but no interview was completed; 12 were ineligible with further screening (eight lived outside the geographic requirements, three were mentally incapable, and one was non–English speaking); 15 could not be contacted (nine had disconnected numbers, three did not return call after 10 attempts, and three for unknown reasons); and 20 refused to participate in the full interview. Proxy interviews were completed in an additional 29 patients: 11 who were unable to complete the full interview and 18 who were deceased. Proxy interviews were excluded from this analysis because limited silica exposure information was obtained.
For identification of control subjects, 1825 random telephone numbers were used. Of these, 913 (50%) numbers were nonresidential, nonworking, or not answered and 912 were answered. Of the answered numbers, 109 (12%) participated (99 completed and 10 partially completed), 480 (53%) declined participation (five were determined to be eligible, and 475 did not provide eligibility information), and 323 (35%) did not have an eligible participant in the household (84% did not fit the age criteria; 10% had a language barrier; and 2% each did not meet geographic criteria, were mentally incapable, or had renal disease). Although the overall response rate for control subjects among answered telephone calls was only 12%, the response rate among control subjects who were known to be eligible was 97% (109 of 114). The high frequency of households with ineligible participants (35%) suggests that if eligibility information were known, then the response rate among eligible participants would be considerably higher than 12%, albeit lower than 97%.
Exposure Assessment
A lifetime history of jobs that were held for 12 months or longer was assessed. Participants were also asked whether they ever worked in a number of specific silica-related occupations or performed specific silica-associated tasks, irrespective of duration and even if they overlapped with the overall list of occupations. Occupations and tasks that are known to be associated with silica exposure were enumerated by an occupational hygienist (L.A.N.-F.) and an epidemiologist experienced in silica assessment (C.G.P.) (28 – 30 28
Silica exposure was scored as described in a recent case-control study of silica in ANCA-positive patients (11 30 31
Exposure evaluation also included agricultural exposure to silica that has been documented, especially from harvesting crops, including but not limited to sweet potatoes and rice (32 – 34 32 32 35
Statistical Analyses
Demographics and other measures were compared between case patients and control subjects using continuity-adjusted χ2 and Wilcoxon rank-sum tests. Logistic regression was used to evaluate the association of silica exposure with disease, relative to control subjects. Results are expressed as odds ratios (OR) with 95 percent confidence intervals (CI) and P values. Silica exposure scores and duration of exposure were evaluated as continuous measures using quartile ranks to evaluate the trend for a dosage response. Silica exposure was then evaluated using predefined categories and modeled such that a linear association was not assumed. All reported models were adjusted for frequency-matched variables (age, gender, and state). Models that controlled for race had similar results, so reported models do not control for race.
Multiplicative interaction of silica exposure scores with gender, education, and race was explored using logistic regression models. Interaction terms with P < 0.20 were considered important stratification measures and were explored further using separate logistic regression models, controlling for frequency-matched variables.
Results
A total of 129 case patients and 109 control subjects participated in the interview and had data available for the assessment of silica exposure. With respect to frequency-matched variables, the state distributions were similar, but case patients were significantly older and more frequently male than control subjects (Table 1 ). Racial distribution was similar between case patients and control subjects. Case patients had significantly lower education (Table 1 ), although when age was controlled for, this difference was less pronounced (P = 0.08). Smoking history was similar between case patients and control subjects.
Sixty percent (n = 78) of case patients were ever exposed to silica, compared with 45% (n = 49) of control subjects (OR 1.6; 95% CI 0.9 to 2.8; P = 0.13; Table 2 ). Among those who were exposed, case patients had a median duration of 8 years longer than control subjects (13 versus 5 years, respectively). Compared with those who were never exposed, there was a trend for each ranked tertile of exposure duration to be associated with a 20% increased risk for the disease (OR 1.2 per tertile; 95% CI 1.0 to 1.5; P = 0.062). When evaluated by categories, duration of silica exposure was in the positive direction across all tertiles, with the largest effect among those in the highest tertile of exposure (>21 years; OR 2.3; 95% CI 1.0 to 5.3; P = 0.05; Table 2 ). Taking into consideration the cumulative duration in conjunction with intensity and probability of exposure, there was no evidence for increased risk for the disease from low or medium lifetime exposure (OR 1.0; 95% CI 0.4 to 2.2; P = 0.98), which were grouped together because of small sample sizes in these exposure categories. However, there was an increased risk for the disease with high lifetime exposure (OR 1.9; 95% CI 1.0 to 3.5; P = 0.05). Any history of harvesting potatoes, peanuts, and/or tobacco was associated with an increased risk for the disease (OR 2.5; 95% CI 1.1 to 5.4; P = 0.03), but history of work in other specific occupational exposure categories that are known to be associated with silica did not show evidence of an increased disease risk (Table 2 ). However, both agricultural and nonagricultural sources of silica exposure contributed to cumulative exposure scores, and the overall effect could not be attributed to agricultural exposures alone.
Among case patients and control subjects who were exposed to silica, there was no difference in time from last exposure to the reference date (P = 0.765). Sixty percent of case patients were still being exposed to silica at their biopsy diagnosis versus 45% of control subjects at the reference date. Among those with exposure before the diagnosis or reference date, time since last exposure ranged from 1 to 59 years among case patients and from 1 to 56 years among control subjects. There was no indication of an association between the length of time since last exposure and disease onset (Table 2 ).
There was no evidence of an interaction of silica exposure with gender (P > 0.2, interaction). Further exploration was needed for potential multiplicative interaction between silica and race (P = 0.189, interaction) as well as education (P = 0.139, interaction). When limited to white participants, the association between high silica exposure and the disease remained statistically significant (OR 2.1; 95% CI 1.1 to 4.2; P = 0.03; Table 3 ). Evaluation of nonwhite individuals was limited because of sample size, but no association was suggested even at the highest exposure level. An association was observed between silica exposure and the disease among those with a high school or lower education level. Although the sample size was small, there was a trend for an increased risk for the disease among those with low to medium silica exposure (OR 2.8; 95% CI 0.7 to 11.9; P = 0.15) and a clear increased risk with high exposure (OR 3.3; 95% CI 1.2 to 9.2; P = 0.02; Table 3 ). There was no evidence of increased risk for the disease with silica exposure among those with more than a high school education.
Among the 129 cases, the most common organs involved by patient report were the lungs (47%), upper respiratory tract (46%), and skin (24%). By definition, all case patients had kidney involvement. Among case patients, 47% had MPO-ANCA specificity, 32% had PR3-ANCA specificity, and 21% were ANCA positive with no information on specificity. No patients in this cohort were ANCA negative.
Medical chart review was available for 90 (70%) patients. Among this subset with detailed clinical information, MPO-ANCA specificity (versus PR3-ANCA specificity) was more common among those who were scored as having high silica exposure compared with all other case patients (67 versus 40%, respectively; P = 0.02). Documented lung involvement was similar between case patients with high and low or no silica exposure (51 and 45%, respectively; P = 0.58), but there was a trend for less upper respiratory disease involvement (23 and 43%, respectively; P = 0.06) and more frequent skin involvement (33 and 17%, respectively; P = 0.08). The distribution of disease categories was not statistically different between those with high exposure, with Wegener granulomatosis present among 16% of those with a high silica exposure versus 29% among those with lower or no exposure; MPA among 51 and 38%, respectively; and renal-limited disease among 33 and 33%, respectively, with an overall P = 0.33 comparing case groups with high and low or no exposure. Disease activity at the time of the renal biopsy, as measured by the Birmingham Vasculitis Activity Score, was not different between the two exposure groups (14 ± 4 for each group, P = 0.79).
To evaluate the representativeness of case patients who participated in the complete interview, we compared demographics of case patients who had more severe symptoms and completed a brief interview through a proxy interviewer (n = 29) with case patients who were identified during the study period and did not participate in the study (n = 340). Case patients who were interviewed by proxy were similar to those who completed the full interview with respect to gender (men 60 versus 55%, respectively), and although there were no statistical differences, there was a trend for patients who were interviewed by proxy to be older (66 ± 13 yr) and less frequently white (69%) than those who completed the full interview (62 ± 14 yr and 85%, respectively). Case patients who were interviewed by proxy were more likely to have a high school or lower education (82%) than those who completed the full interview (53%; P = 0.0032). Only limited demographic information was available for case patients who did not participate in the full or proxy interviews, but male gender (55%), age (62 ± 15 yr), and white race (83%) were similar to those who completed the full interview.
Discussion
The present study suggests that high levels of lifetime silica exposure are associated with the onset of ANCA-SVV, using an exposure rating that incorporated the intensity, duration, and probability of exposure. The association was most notable from agricultural silica exposure through harvesting of crops. The observed association in the current study is in agreement with previous case-control studies (4 – 8 , 10 , 11 Table 4 ). This study expands on known information with respect to the impact of duration of exposure, time since last exposure to silica, and the important contribution of silica exposure from agricultural sources in the southeastern United States that may contribute to the development of this disease.
In this study, patients with ANCA-SVV were almost two times more likely to be exposed to the highest score category for silica exposure compared with control subjects. Other studies have reported higher OR estimates ranging from 3.0 to 14.0 for associations with various case definitions of SVV (4 – 9 , 11 Table 4 ).
The two-fold association in the southeastern United States may represent a smaller effect than that observed in other regions. Traditional “dusty trades,” such as sandblasting, mining, quarrying, construction, and railroad work, were evident among those who were exposed to silica but were represented similarly between case patients and control subjects. However, harvesting crops accounted for the single highest occupational exposure among case patients and was significantly more common than among control subjects. Although harvesting of crops has been recognized as a source of silica exposure and can exceed industry standards (32 , 34 , 36 – 38 28 , 38 , 39 28 8
In this study, only the predefined level of highest exposure to silica was found to be associated with ANCA-SVV. Only two previous studies evaluated dose-response gradients of silica exposure and ANCA and/or SVV (8 , 11 8 et al. (11 P = 0.002). Exposure scores of medium or less were not associated with the disease in either study, although our study showed a trend toward a positive association of lower exposure levels within the lowest education group.
This study also suggests that duration of exposure is the primary aspect of silica exposure that is associated with the development of ANCA-SVV. This is in contrast to data from studies of association of silica with other autoimmune diseases, including scleroderma, systemic lupus erythematosus, and rheumatoid arthritis, which suggest that exposure intensity may be of equal if not greater importance than cumulative lifetime exposure (1 , 8 13 40 13
We presumed that those with less education more frequently worked in jobs that are associated with silica exposure. However, high silica exposure among control subjects was similar between those with higher education (33%) and those with lower education (29%). Given that there are effects observed among the subset with lower education, the overall effect is not due to confounding by education. Well-described associations between lower socioeconomic status and environmental risks such as poor water quality, hazardous wastes, and air pollutants suggest that multiple environmental factors contribute to disease disparities (41 42 , 43 44 , 45 5 – 9 , 11 , 17 8 9 46 – 48
The biologic mechanism of silica exposure in the development of SVV with or without glomerulonephritis is not well understood. Crushing silica yields radicals that react with water to produce a damaging hydroxyl radical (49 , 50 51 – 54 13
A noted limitation to the study is that there were differences in case patients and control subjects with respect to age and gender. However, standard statistical techniques to control for these differences likely minimize any effect on the results. Another concern is residual confounding from unknown exposures that may contribute to the development of ANCA-SVV. Traditional dusty trades and farming have a variety of hazardous exposures, although silica is common between these two occupational categories. Potential farming exposures that need further study include pesticides and fertilizers.
The study included only case patients with renal biopsy proof of disease involvement. Although this provided a definitive diagnosis date for use in referencing previous exposures, it is difficult to determine the time between true disease onset and the development of kidney involvement, which may be variable, and an unknown number of individuals may progress rapidly to kidney failure and not undergo a renal biopsy. Using a renal biopsy for the case definition may also lead to a selective case sample because of access to medical care or decisions for whether to obtain a renal biopsy, especially among patients with biopsy proof of disease in another organ. However, the renal-biopsy population is likely to represent the majority of patients with ANCA-SVV because renal involvement is reported in up to 90% of patients (16 55 56 57
ANCA-SVV that is associated with high silica exposure may convey differences in disease expression, characterized by ANCA positivity that is more frequently associated with MPO than PR3 specificity, although scores for overall disease activity were similar. Considering that silica is inhaled, there is no suggestion of more frequent ANCA-SVV disease expression in the lung and upper respiratory tract, even with high levels of silica exposure. In fact, those with high silica exposure may have less frequent upper respiratory involvement. This result is consistent with our previous report, in which no difference was found in the likelihood of silica exposure between those with and without vasculitis disease involving the airways or lungs (6
The case patients who participated in this study seem to represent the demographics of the overall population of patients who were identified during the study period and did not participate in the study. However, patients who were sicker or who had died and were interviewed by proxy were less educated than those who participated in the full interview. Attrition of case patients as a result of illness likely leads to a minimization of the association of silica exposure with ANCA-SVV from the case patients who participated in the full interview, especially given that this study suggests an increased association of silica with the disease among those with lower education. Those who are at lower socioeconomic levels may seek or obtain a diagnosis later and therefore be sicker at diagnosis, or silica exposure could contribute to more debilitating disease that is less responsive to treatment. Evaluation of the impact of silica exposure on treatment response and relapse in a future study is critical.
Conclusion
High silica exposure, characterized by many years of exposure more than high intensity, is associated with the onset of ANCA-SVV. The importance of silica exposure from agricultural sources has not always been considered and may be a particular concern in the development of this disease, especially in the southeastern United States. Risk for disease from silica exposure may still be a possibility many years after exposure has ceased, which emphasizes the need for understanding the role of multiple exposures in inducing autoimmune dysfunction in small-vessel vasculitides, including ANCA-SVV.
Disclosures
None.
Table 1: Sociodemographic characteristics of ANCA-SVV case patients and population-based control subjectsa
Table 2: Association of silica exposure measures with ANCA-SVV with glomerulonephritis
Table 3: Association of lifetime silica exposure with ANCA-SVV with glomerulonephritis by racial group and by education
Table 4: Summary of case-control studies of silica exposure and SVV and/or ANCA-associated diseases
We acknowledge the financial support of this study by the National Institute of Diabetes and Digestive and Kidney Diseases under the Program Project “ANCA Glomerulonephritis from Molecules to Man” (P01-DK58335).
We acknowledge the time and effort required by the case patients and control subjects in this study. We are indebted to Laura Davis, MPH, for tireless efforts in the revisions of the introductory telephone scripts and interview instruments.
Two published abstracts included preliminary results that culminated in this manuscript: (1 ) J Am Soc Nephrol 15: 340A, 2004; and (2 ) Kidney Blood Press Res 28: 169, 2005.
The following nephropathologists participated in the identification of patients with biopsy-proven ANCA-SVV with glomerulonephritis: J. Charles Jennette, MD, Harsharan Singh, MD, Department of Pathology, University of North Carolina at Chapel Hill, Chapel, Hill, NC; Samy Iskandar, MBBCh, PhD, Wake Forest University School of Medicine, Winston Salem, NC; Sally Self, MD, Medical University of South Carolina, Charleston, SC; Serena Bagnasco, MD, Emory University, Atlanta, GA; Ralph C. McCoy, New Hanover Regional Medical Center, Wilmington, NC; David N. Howell, MD, Duke University Medical Center, Durham, NC; Carol Weida, MD, Carolinas Medical Center, Charlotte, NC; William F. Glass, MD, PhD, Eastern Virginia Medical School, Norfolk, VA. Institutions listed are where the nephropathologists were located at the time of the study. Biopsies reviewed at these nephropathology laboratories are from patients who received a diagnosis within their own institution as well as from private practice nephrology practices and smaller hospitals. Renal biopsies from private practices and smaller hospitals are sent to the nephropathologist of choice. The nephropathology laboratories in the region that are not represented include East Carolina University School of Medicine and the Medical College of Georgia in Augusta. Institutional review board approval was not sought at the Medical College of Georgia because no patients were identified by renal biopsy as receiving a diagnosis of ANCA-SVV during the study period. Dr. Harsharan Singh is a nephropathologist at the University of North Carolina at Chapel Hill but was responsible for reviewing renal biopsies from Eastern Carolina University School of Medicine during identification of patients for this study. Review and recruitment of case patients who were identified by Dr. Singh were approved the Biomedical Institutional Review Board at the University of North Carolina at Chapel Hill (97-MED-44 and 04-MED-663).
Published online ahead of print. Publication date available at www.cjasn.org
The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the US Environmental Protection Agency or the National Institute for Occupational Safety and Health.
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