Are environmental factors important in primary ... - Wiley Online Library

ARTHRITIS & RHEUMATISM Vol. 48, No. 3, March 2003, pp 814–823 DOI 10.1002/art.10830 © 2003, American College of Rheumatology

Are Environmental Factors Important in Primary Systemic Vasculitis? A Case–Control Study Suzanne E. Lane,1 Richard A. Watts,2 Graham Bentham,3 Nicholas J. Innes,2 and David G. I. Scott1 Farming during working lifetime was associated with PSV (2.2 [1.2–3.8]) and with WG (2.7 [1.3–5.7]). Significant associations were found for high occupational silica exposure in the index year (with PSV 3.0 [1.0–8.4], with CSS 5.6 [1.3–23.5], and with ANCA 4.9 [1.3–18.6]), high occupational solvent exposure in the index year (with PSV 3.4 [0.9–12.5], with WG 4.8 [1.2–19.8], and with classic ANCA [cANCA] 3.9 [1.6–9.5]), high occupational solvent exposure during working lifetime (with PSV 2.7 [1.1–6.6], with WG 3.4 [1.3–8.9], and with cANCA 3.3 [1.0–10.8]), drug allergy (with PSV 3.6 [1.8–7.0], with WG 4.0 [1.8–8.7], and with cANCA 4.7 [1.9–11.7]), and allergy overall (with PSV 2.2 [1.2–3.9], with WG 2.7 [1.4–5.7]). No other significant associations were found. Conclusion. A significant association between farming and PSV has been identified for the first time. Results also support previously reported associations with silica, solvents, and allergy.

Objective. To investigate the association between primary systemic vasculitis (PSV) and environmental risk factors. Methods. Seventy-five PSV cases and 273 controls (220 nonvasculitis, 19 secondary vasculitis, and 34 asthma controls) were interviewed using a structured questionnaire. Factors investigated were social class, occupational and residential history, smoking, pets, allergies, vaccinations, medications, hepatitis, tuberculosis, and farm exposure in the year before symptom onset (index year). The Standard Occupational Classification 2000 and job-exposure matrices were used to assess occupational silica, solvent, and metal exposure. Stepwise multiple logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) adjusted for potential confounders. Total PSV, subgroups (47 Wegener’s granulomatosis [WG], 12 microscopic polyangiitis, 16 Churg-Strauss syndrome [CSS]), and antineutrophil cytoplasmic antibody (ANCA)–positive cases were compared with control groups. Results. Farming in the index year was significantly associated with PSV (OR 2.3 [95% CI 1.2–4.6]), with WG (2.7 [1.2–5.8]), with MPA (6.3 [1.9–21.6]), and with perinuclear ANCA (pANCA) (4.3 [1.5–12.7]).

The primary systemic vasculitides (PSV) are a group of relatively rare diseases of unknown etiology (1). A number of potential environmental risk factors have been reported. Systemic vasculitis has been associated with exposure to particulate silica (e.g., quartz, granite, sandstone, and grain dust) (2–5). There has been conflicting evidence regarding a link between occupational exposure to hydrocarbons (e.g., paints, glues) and Wegener’s granulomatosis (WG) and microscopic polyangiitis (MPA), and the association with glomerulonephritis is stronger (6–8). A case–control study carried out at the National Institutes of Health (NIH) revealed an association with exposure to fumes or particulates and pesticides in patients with WG compared with healthy or rheumatic disease controls but not respiratory disease

Supported by a grant from the Arthritis Research Campaign. 1 Suzanne E. Lane, MD, MRCP, David G. I. Scott, MD, FRCP: Norfolk and Norwich University Hospital, Norwich, UK; 2 Richard A. Watts, DM, FRCP, Nicholas J. Innes, MB, ChB: Ipswich Hospital, NHS Trust, Ipswich, UK; 3Graham Bentham, MA: University of East Anglia, Norwich, UK. Address correspondence and reprint requests to Suzanne E. Lane, MD, MRCP, Department of Rheumatology, PO Box 204, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK. E-mail: [email protected]. Submitted for publication March 18, 2002; accepted in revised form November 22, 2002. 814

ENVIRONMENTAL FACTORS IN PRIMARY SYSTEMIC VASCULITIS

controls (9); however, exposure to metal and welding fumes has been reported to increase the risk of chronic renal failure, glomerulonephritis, WG, and pulmonary vasculitis (5,10,11). Allergies and a family history of atopy were associated with WG, Churg-Strauss syndrome (CSS), and polyarteritis nodosa in a case–control study (12). Reports also suggest that desensitization procedures, vaccinations (e.g., influenza and hepatitis), drugs (e.g., propylthiouracil and hydralazine), and withdrawal of steroids can precipitate PSV in some individuals (13,14). Hepatitis B and hepatitis C are strongly associated with polyarteritis nodosa and cryoglobulinemic vasculitis, respectively, and infections (e.g., parvovirus B19 and chlamydia) might be important in other types of PSV (15–17). We designed a case–control study to investigate the role of environmental factors in PSV. Norfolk, in eastern England, is favorable for epidemiologic study because of its geographic location, partially bordered by coastline. The Norfolk and Norwich University Hospital (NNUH) is the single central referral center for the Norwich Health Authority (NHA) population of ⬃415,000 adults. This population has also been used for prospective studies of rheumatoid arthritis (by the Norfolk Arthritis Register) (18) and of the epidemiology of PSV (19). Patients living in the area surrounding the former NHA are also referred to the NNUH. Few patients are referred out of district without first attending this hospital. PATIENTS AND METHODS Cases. All adult patients (⬎15 years old) diagnosed as having PSV at the NNUH between May 1988 and July 2000 were identified from a prospective vasculitis register and were invited to participate. The register has been maintained since January 1988 through direct referral by hospital physicians and review of the hospital histopathologic and inpatient discharge records. Details of the methods for patient identification have been reported previously (19). Case ascertainment is thought to be complete because general practitioners (the first point of contact for patients in the UK) serving the denominator population refer all PSV cases to the NNUH. The register benefits from good communication between primary and secondary care providers, between practitioners in different hospital specialties, and between adjacent health districts. Potentially, cases with mild disease (e.g., limited WG) could remain undetected and severe cases could have been undiagnosed at the time of death. Case notes were reviewed for clinical and laboratory details including antineutrophil cytoplasmic antibody (ANCA) findings. Cases were classified as follows: WG according to the American College of Rheumatology (ACR) criteria (20) and the Chapel Hill Consensus Conference (CHCC) definition

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(21), MPA according to the CHCC definition (21), and CSS according to the ACR criteria (22) and the Hammersmith criteria (23). Several cases fulfilled definitions/criteria for both MPA and WG. For the purposes of the case–control study, those with ear, nose, and throat (ENT) involvement, nodules or cavitation seen on chest radiograph, or positive classic ANCA (cANCA) (and/or specificity for proteinase 3 [PR3]) were classified as having WG; remaining patients with predominantly renal vasculitis and no ENT symptoms were classified as having MPA. Patients with primary vasculitis who did not fulfill these criteria or who had secondary vasculitis (e.g., systemic lupus erythematosus, infection, cryoglobulinemia, or malignancy) were excluded. One hundred three cases of PSV were identified, of whom 27 had died prior to the start of the study, 1 declined to participate, and 75 were recruited (98.7% response rate of available cases, 72.8% of incident cases). Forty-seven patients were classified as having WG, 12 MPA, and 16 CSS. Thirty PSV cases were cANCA and/or PR3 positive, 19 were perinuclear ANCA (pANCA) and/or myeloperoxidase (MPO) positive, 9 had positive ANCA by radioimmunoassay, 16 were ANCA negative, and in 1 case there was no recorded ANCA result. Fifty-eight patients had renal involvement (defined as hematuria, increased creatinine level, or renal biopsy findings consistent with vasculitis), and 45 had respiratory involvement (defined as hemoptysis, persistent cough or dyspnea, or chest radiography findings consistent with vasculitis). Controls. Nonvasculitis controls. Two hundred twenty hospital inpatients and outpatients of the orthopedic and rheumatology departments with noninflammatory musculoskeletal disease (e.g., osteoarthritis, fracture, osteomyelitis) and common symptoms (e.g., cellulitis, deep vein thrombosis, skin lesion excision) were recruited as nonvasculitis controls (3 controls per case). Fifteen additional patients declined to participate (93.6% response rate). All nonvasculitis controls were matched for sex and age at vasculitis onset (within 3 years) to the case. The first 83 controls were matched to the age that cases had been when they first experienced a symptom attributable to vasculitis (index date) and were asked to recall events in the year immediately preceding the interview. All other controls were matched to the age of the case at the time of interview and were asked to think back to events that occurred prior to the index date of the matched case (the change was made to minimize recall bias). Age-matched controls were not obtained for 1 17-year-old WG patient who presented at the end of the data collection period. Patients were excluded if they had a personal history of any of the following: autoimmune disease including rheumatoid arthritis, thyroid disease, diabetes, vitiligo, or pernicious anemia; connective tissue disease including systemic lupus erythematosus, scleroderma, myositis, Sjo ¨gren’s syndrome, or undifferentiated connective tissue disease, seronegative spondylarthropathy, or inflammatory bowel disease. The rationale for their exclusion was that many studies have linked autoimmune diseases to some of the environmental factors under investigation, so bias could have been introduced and real associations overlooked. In addition, patients with dementia, mental handicap, or cognitive impairment caused by acute illness or medication, as well as severely ill patients, were excluded due to a likely reduction in ability to complete the questionnaire accurately.

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Table 1. Characteristics of the study participants Age, years Diagnosis*

Mean

Median

Range

Rural residence, %†

Norfolk history, %‡

Manual occupation, %§

PSV WG (n ⫽ 47) CSS (n ⫽ 16) MPA (n ⫽ 12) Controls¶ Nonvasculitis (n ⫽ 220) Asthma (n ⫽ 34) SRV (n ⫽ 19)

60.2 58.9 59.4 66.3

61 59 60.5 67.5

17–89 17–89 31–84 42–76

61.3 61.7 62.5 58.3

52.0 46.8 62.5 58.3

32.4 34.0 20.0 41.7

60.7 57.9 55.8

62 58 56

28–87 21–84 22–74

57.6 37.5 61.1

56.4 52.9 52.6

31.8 32.4 21.1

* PSV ⫽ primary systemic vasculitis; WG ⫽ Wegener’s granulomatosis; CSS ⫽ Churg-Strauss syndrome; MPA ⫽ microscopic polyangiitis; SRV ⫽ systemic rheumatoid vasculitis. † Defined according to postal code. ‡ Main area of residence during lifetime, and either birth in Norfolk or history of generations of family living in Norfolk. § Social classes IIIM, IV, V (ref. 24). ¶ Controls age matched to cases to within 3 years, except in 1 case (see text).

Secondary vasculitis controls. Nineteen of 20 surviving adults (⬎15 years old) who had been diagnosed in 1988 or later as having systemic rheumatoid vasculitis (SRV) and who resided in the NHA district were recruited to compare risk factors for primary and secondary vasculitis. The register was known to be complete for SRV but had not been verified for other types of secondary vasculitis, so patients with secondary vasculitis other than SRV were not recruited. Asthma controls. Thirty-four asthma controls, age- and sex-matched to PSV cases, were recruited consecutively from an asthma clinic to serve as specific controls for CSS, which is characterized by asthma. None of the patients recruited as asthma controls declined to participate. There were no significant differences in the geographic area of residence between control groups and cases. Urban areas were defined according to postal codes using details provided by the Norfolk City Council Demographic Unit, and rural areas constituted the surrounding areas in the NHA district. The percentage of PSV cases who lived in rural areas was 61.3%, compared with 57.6% of nonvasculitis controls, 61.1% of SRV controls, and 37.5% of asthma controls (Table 1). Ethics approval. Ethics approval was obtained from the Norwich District Ethics Committee, and the study was registered with the research and development office prior to recruitment. PSV and SRV patients were invited, either in person at a clinic appointment or by letter, to participate in the study. Nonvasculitis and asthma controls were invited in person at the time of their clinic appointment or inpatient admission. All participants gave informed consent. Questionnaire. A structured questionnaire to measure factors of interest and potential confounders was designed to be administered by an interviewer. It was based on 2 previously used questionnaires (9,12) and adapted for the Norfolk population. Additional questions were formulated after a literature review. A copy of the full questionnaire may be obtained from the authors on request. A single interviewer (SEL), not blinded to case/control status of interviewees or to the study hypothesis, conducted interviews with all PSV patients, SRV patients, and nonvasculitis controls, and a second interviewer (NJI) interviewed the asthma controls. NJI was trained to interview

in the same manner as SEL, by observation of technique. The first part of the questionnaire was used to establish patient details, and in PSV cases the date of the first symptom attributable to vasculitis (the index date) was estimated. All subsequent questions were related only to exposures prior to this date. Data analysis and statistical methods. Subhypotheses for particular environmental factors were formulated, and questionnaire data were used to investigate each individually. Definitions of each item investigated were as described below. Age at the index date and social class were analyzed. Social class was defined by coding the last occupation by the Standard Occupational Classification (SOC) 2000 and then deriving social class using the Office for National Statistics Occupational Support service guide 6.1 (24). Nonmanual occupations (social classes I, II, IIIN) were compared with manual occupations (social classes IIIM, IV, V). Urban/rural residence was defined by postal district as previously described, and “Norfolk history” was defined as birth and subsequent main area of residence in Norfolk or a history of generations of the family living in Norfolk. Occupational exposure to silica, solvents, and metals was investigated. Occupations were coded using the SOC 2000 and job exposure matrices used to define high, intermediate, and low exposure. Appendix A shows the actual occupations of the study participants as coded in the SOC 2000. They are categorized according to the job exposure matrices described below and in refs. 25–27. For each of silica, solvents, and metals, “any exposure,” “high exposures,” “intermediate exposures,” and “low exposures” were investigated for both the index year and any time during the working life. In addition, the duration of occupational exposure to silica and solvents was analyzed using data categorized by 5-year periods. Direct questions were asked to ascertain any history of specific jobs previously reported to be associated with silica exposure and vasculitis, i.e., coal worker (coal miner/delivery), sandblaster, mine/quarry worker, baker, dental worker, painting and decorating, working in the construction industry. The job exposure matrix of Parks et al (25) was used to define high silica exposure (including agriculture, roofing, automobile repair, cement and ceramics working, construction industry, foundry, iron, and steel working, mining, quarrying, shipbuild-


ing, paint, rubber, plastics, and abrasive industries), intermediate silica exposure (including dental occupations, baking, sculpting, occupations ancillary to occupations with high exposures, or the construction trade, e.g., carpentry, painting/ decorating, electrical work), and low exposure (all other occupations). Silica exposure was also divided into “agricultural silica exposure” (exposure to grain dust, including individuals participating in harvesting, those handling grain in other occupations, and those otherwise exposed, e.g., living within 30 feet of grain harvest) and “nonagricultural silica exposure” (exposure to other silica dust, e.g., quartz, sand, or flint in the construction industry, mining, or sandblasting). The job exposure matrix published by Steenland et al was used to define occupational solvent exposures (26). A new matrix was designed to assess occupational exposures to metals. Occupations defined as having high metal exposures were aerospace/aircraft manufacture, metal workers including smelting, milling, automobile/heavy machinery and lead battery manufacture, metal mining, and welding. Intermediate metal exposures included canning, construction, cement and ceramic production, chemical, rubber, electronics, nuclear and leather industries, boat-building, dental work, soldering, paint spraying, explosives, fertilizer and pesticides (27). All other occupations were considered to have low exposure. A detailed history about farming was obtained, and factors analyzed were “ever farm” (exposure to farm/ agriculture of any type in the index year and/or any occupational exposure to farms in a working lifetime), index farm (exposure to a farm in the index year), crop exposure in the index year, livestock exposure in the index year, and exposure to both livestock and crops in the index year. The type of farming exposure (living, working, or visiting a farm) and frequency of exposure (daily, weekly, less frequently) were also included. Although the questionnaire was not initially designed to address this, the proximity to livestock was investigated by comparing subgroups who handled livestock directly (“direct”), those who worked at or were regularly present on a farm with livestock (“close”), and those who were only exposed within 30 feet of livestock (“distant”). Allergy was investigated by comparing self-reported allergy at any time prior to the index date (any allergy, skin, drug, insect, food). Other factors investigated were allergic rhinitis (recurrent, seasonal, runny blocked nose before the index date), asthma (personal history prior to the index date), and family history of allergy or asthma in parents, siblings, or children. Other items studied included owning/regular contact with a domestic pet in the index year, any blood transfusion prior to the index date, a self-reported history of personal tuberculosis (TB) or contact with an individual with TB, infectious hepatitis (A, B, C), any vaccination within 6 months of the index date, steroid withdrawal within 6 months of the index date, smoking history (smoking ever, in the index year, and pack-years). Conditional binary logistic regression was carried out using Minitab Release 13 software for each exposure of interest to obtain odds ratios (ORs) and 95% confidence intervals (95% CIs). Stepwise multiple logistic regression was used to calculate ORs and 95% CIs adjusted for potential confounding factors. Because there are no known definite risk factors for PSV, the model included all other factors that had shown a significant association on binary regression, rural

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residence (an earlier study suggested that CSS was more common in rural areas) (28), social class (a potential confounder for occupational data especially), and smoking (may confound in respiratory disease in particular). A stepwise approach was used rather than using a fixed model, because a fixed model may have resulted in the loss of excessive degrees of freedom, especially where numbers of cases were small. In view of the unknown etiology and pathogenesis of the disease, the cohort was investigated in a number of ways. The whole cohort of PSV patients was compared with nonvasculitis and SRV controls. Disease subtypes (WG, MPA, and CSS) may have different triggering factors and were compared with nonvasculitis controls individually. CSS was also compared specifically with the asthma controls. Additionally, different factors may be important in triggering a particular pattern of disease (e.g., an airborne stimulant may be responsible for respiratory vasculitis and renal disease may be related to solvents), and different ANCA types may have distinct etiologies. Therefore, cases were also divided according to renal and respiratory involvement and ANCA specificity and compared with nonvasculitis controls. Cases were divided into 4 groups for the analysis of ANCA according to immunofluorescence and enzyme-linked immunosorbent assay results: cANCA- and/or PR3-positive cases, pANCA- and/or MPOpositive cases, ANCA-negative cases, and ANCA result unknown. It must be noted that the clinical use of ANCA results and laboratory methods for detection have changed over the period that cases recruited to the study were diagnosed. Therefore, unknown bias is introduced by the use of retrospective ANCA data, and results should be interpreted with this in mind.

RESULTS There were no significant differences between any pairs of groups investigated, in terms of age, sex, social class, urban/rural residence, or a personal/family history of longstanding residence within Norfolk (Table 1). Farming. PSV was significantly associated with farming exposures both during the working lifetime (ever farm) and within the index year (index farm) (Table 2). Significant ORs of index farm were found for WG (2.7 [95% CI 1.2–5.8]) and MPA (6.3 [1.9–21.6]) but not for CSS (2.1 [0.6–7.0]), and a significant OR of ever farm was found for WG (2.7 [(1.3–5.7]) but not for MPA (2.5 [0.7–9.0]) or CSS (0.8 [0.3–2.6]). This may suggest a specific association of farming with WG/MPA or may reflect the relatively small numbers of CSS and MPA cases. It was not possible to distinguish between exposures to crops, livestock, or individual animal species because most individuals were exposed to more than one type and there were no significant differences in associations between modes of exposure (Table 2) or frequencies of exposure. ORs were significant for exposure to

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Table 2.

Association of farming with PSV compared with nonvasculitis controls* PSV, no. (%)

Nonvasculitis controls, no. (%)

Adjusted OR (95% CI)

46/75 (61.3)

82/220 (37.3)

2.2 (1.2–3.8)

25/75 (33.3) 7/58 (12.1) 3/54 (5.6) 9/60 (15.0) 4/55 (7.3) 6/56 (10.7) 9/59 (15.3) 10/60 (16.7)

30/219 (13.7) 12/202 (5.9) 6/196 (3.1) 11/201 (5.5) 0/190 (0) 6/195 (3.1) 14/203 (6.9) 10/199 (5.0)

2.3 (1.2–4.6) 2.2 (0.8–6.0) 2.5 (0.5–11.7) 3.0 (1.1–7.9) – 3.7 (1.1–12.4) 1.7 (0.7–4.6) 4.4 (1.7–11.7)

Item Farm ever† Farming exposure during index year Any farming exposure‡ Living near a farm§¶ Working on a farm§ Visiting a farm§ Living & working on farm§¶ Livestock only# Crops only# Livestock and crops#

* Odds ratio (OR) was obtained by conditional logistic regression and adjusted for rural residence, manual occupations, high silica exposure (ever and index year), high solvent exposure (ever and index year), allergy, drug allergy, farming exposure (ever and index year), and smoking (with the exposure under investigation omitted from the model). PSV ⫽ primary systemic vasculitis; 95% CI ⫽ 95% confidence interval. † Farm/agricultural exposure of any type during the index year and/or any occupational exposure to farms in working lifetime. ‡ Data missing for 1 nonvasculitis control. § Data missing for 1 PSV case. Cases and controls with other modes of exposure (e.g., “visiting”) treated as “missing data” in regression model. “Living” indicates daily exposure, “working” at least monthly exposure, and “visiting” refers to any number of occasions during the year. ¶ One case also visited other farms. # Cases and controls with other farm exposures (e.g., crops only) in index year treated as missing data in regression model.

cows (3.0 [95% CI 1.1–8.0]) and chickens (4.0 [1.5– 10.9]). Silica exposure. Working in occupations with high silica exposure in the index year was associated with significantly increased ORs for PSV (3.0 [95% CI 1.0– 8.4]) (Table 3) and CSS (5.6 [1.3–23.5]), but not WG (2.5 [0.8–8.5]) or MPA (3.2 [0.8–8.5]). Working in these jobs at any time during a working lifetime did not have any positive associations. However, there was a significant association between MPA and occupations defined as

Table 3. Association of occupational exposures with PSV compared with nonvasculitis controls*

Item High silica ever† High silica index year‡ High solvent ever† High solvent index year High metal ever† High metal index year

PSV, no. (%)



18/75 (24.0) 10/72 (13.9)

42/220 (19.1) 9/211 (4.3)

1.4 (0.7–2.7) 3.0 (1.0–8.4)

11/75 (14.7) 7/75 (9.3)

15/220 (6.8) 5/220 (2.3)

2.7 (1.1–6.6) 3.4 (0.9–12.5)

5/75 (6.7) 0/75 (0)

12/220 (5.5) 3/220 (1.4)

1.0 (0.3–3.6) –

* See Table 2 for explanations and definitions. † Exposure at any time during working lifetime. ‡ Data missing for 3 PSV cases and 9 nonvasculitis controls.

having high or intermediate exposures throughout a working lifetime (OR 4.6 [95% CI 1.3–16.5]). It is likely that these differences between diagnoses are attributable to the small numbers of exposed cases. There were no significant findings for intermediate- or low-exposure jobs alone. There was no trend toward an increased risk of PSV with duration of silica exposure, although there was a significant relationship of PSV to jobs of ⬎480 months (OR 2.63 [95% CI 1.03–6.73]). Although not a primary question in the questionnaire design, it was noted that PSV showed a weak association with agricultural silica (in the form of agricultural dust) (OR 4.4 [95% CI 1.1–18.1]) but not nonagricultural silica (e.g., brick dust) (1.2 [0.4–3.3]). Solvent exposure. A history of high solvent exposure at any time was associated with PSV (OR 2.7 [95% CI 1.1–6.6]) (Table 3) and WG (3.4 [1.3–8.9]). The association was greater for individuals working in these occupations in the index year (for PSV, OR 3.4 [0.9– 12.5]; for WG, OR 4.8 [1.2–19.8]). No significant associations were found for MPA (any exposure 1.3 [0.1– 12.9]; index year 2.7 [0.2–34.1]), for CSS (no cases exposed), or for jobs defined as having intermediate or low exposures or high/intermediate exposures combined.


Table 4. Association of other environmental exposures with PSV compared with nonvasculitis controls*

Item Allergy†‡ Drug allergy†‡§ Family history of atopy‡ Blood transfusion† Vaccination¶ Smoke ever† Smoke index year Tuberculosis†#

PSV, no. (%)



43/75 (57.3) 25/73 (34.2) 27/75 (36.0)

82/217 (37.8) 29/217 (13.4) 67/217 (30.9)

2.2 (1.2–3.9) 3.6 (1.8–7.0) 1.1 (0.6–1.9)

13/75 (17.3) 17/75 (22.7) 53/75 (70.7) 15/75 (20.0) 21/74 (28.4)

55/220 (25.0) 37/220 (16.8) 156/220 (70.9) 55/220 (25.0) 53/220 (24.1)

0.5 (0.3–1.1) 1.7 (0.8–3.4) 0.9 (0.5–1.6) 0.7 (0.4–1.5) 1.4 (0.7–2.6)

* See Table 2 for explanations and definitions. † At any time prior to the index date. ‡ Data missing for 3 nonvasculitis controls. § Data missing for 2 PSV cases. ¶ In the 6 months preceding the index date. # Self-reported personal illness with tuberculosis or exposure to another individual with active tuberculosis. Data missing for 1 PSV case.

Metal exposure. There were no significant associations of occupational metal exposure, either throughout the working lifetime or in the index year, with PSV (Table 3) (no cases exposed in the index year) or any subgroup (data not shown). There were no significant associations for any of the individual job codes investigated. This may have been due to small numbers of individuals with each job. Allergy. A history of allergy was significantly associated with PSV overall (OR 2.2 [95% CI 1.2–3.9]) (Table 4) and with WG (2.7 [1.4–5.7]), but not with MPA (1.5 [0.4–5.7]) or CSS (2.4 [0.8–7.2]). The only subtype of allergy that showed a significant association was drug allergy (for PSV, OR 3.6 [95% CI 1.8–7.0]; for WG, OR 4.0 [95% CI 1.8–8.7]). There was no association between PSV and family history of allergy or

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asthma (Table 4) but, as may be anticipated, CSS was significantly associated with rhinitis, asthma, and steroid withdrawal when compared with nonvasculitis controls but not with asthma controls (data not shown). Other exposures. There were no positive associations with previous blood transfusion, recent vaccinations, smoking, or TB history (Table 4). No significant associations were found for having domestic pets, history of hepatitis, or gardening (data not shown). Subgroup analyses. Analysis by the presence or absence of renal and respiratory involvement and ANCA type showed little difference in associations, with few exceptions. There were significant associations of pANCA/MPO with farming in the index year (OR 4.3 [95% CI 1.5–12.7]), farming ever (3.3 [1.1–9.9]), and high occupational silica exposure in the index year (4.9 [1.3–18.6]), while cANCA/PR3 showed associations with farming ever (3.9 [1.6–9.5]), and with solvent exposures (3.3 [1.0–10.8] for ever exposed; 3.9 [1.6–9.5] for exposure in the index year) and allergy (3.1 [1.3–7.4]) (Table 5). DISCUSSION This study is the first to demonstrate an association between PSV and farming. Although it was not possible to distinguish between specific farming exposures (most individuals were exposed to more than one type), the association appeared to be stronger for exposure to livestock compared with crops, with significant ORs for work with cows and chickens. Results were not biased in terms of the distribution of cases or controls living in rural areas. This part of the questionnaire used direct questions and response was virtually complete, so interviewer and response bias was minimized. In a previous study from the NIH, Duna et al, using the same

Table 5. Adjusted OR (95% CI) for association of farming, silica exposure, solvent exposure, and allergy in PSV cases according to organ involvement and ANCA status, compared with nonvasculitis controls* Item

No. of cases

Farm index year

High silica index year

High solvent ever

Allergy

Renal involvement† No renal involvement Respiratory involvement‡ No respiratory involvement cANCA/PR3 pANCA/MPO

58 17 45 30 30 19

2.9 (1.4–5.8) 3.4 (1.1–10.5) 2.3 (1.1–5.1) 4.4 (1.8–10.6) 2.5 (0.9–6.3) 4.3 (1.5–12.7)

2.8 (0.9–8.7) 6.5 (1.5–28.6) 2.8 (0.9–8.7) 4.1 (1.1–15.6) 1.8 (0.4–8.5) 4.9 (1.3–18.6)

2.4 (0.9–6.6) 2.1 (0.4–10.4) 2.3 (0.8–6.8) 3.8 (1.1–12.3) 3.3 (1.0–10.8) 0.6 (0.06–6.6)

2.1 (1.1–3.8) 3.0 (1.0–9.4) 2.1 (1.1–4.2) 2.8 (1.2–6.5) 3.1 (1.3–7.4) 1.6 (0.6–4.6)

* ANCA ⫽ antineutrophil cytoplasmic antibody; cANCA ⫽ classic ANCA; PR3 ⫽ proteinase 3; pANCA ⫽ perinuclear ANCA; MPO ⫽ myeloperoxidase (see Table 2 for other explanations and definitions). † Hematuria, increased creatinine level, or renal biopsy findings consistent with vasculitis. ‡ Hemoptysis, persistent cough or dyspnea, or chest radiography findings consistent with vasculitis.

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questionnaire (9), failed to detect a significant association between WG and farming. The proportion of cases exposed to farms during the index year was similar in the two studies (33.3% in our study, 35.6% in the NIH study), but a greater percentage of nonvasculitis controls were exposed to farms in the NIH study. The controls and cases in that study may have been drawn from differing denominator populations leading to bias, e.g., vasculitis cases are likely to have been referred for tertiary care from a wider population than controls (sequential age- and sex-matched patients attending a general medical clinic). The NIH study did not specifically exclude autoimmune disease among controls, and similar environmental factors may be important in the initiation of autoimmunity. One explanation is that an infectious agent may play a role in the onset of PSV. Recent reports have linked a previously undescribed paramyxovirus affecting pigs with an outbreak of viral encephalitis with widespread vasculitis-induced thrombosis in Malaysian pig farmers (29). Pseudorabies virus causing vasculitis has also been noted to transfer between species, and another report suggested an association between close contact with pigs and Behc¸et’s disease (30,31). Alternatively, other factors in the care of livestock and their surroundings may be important, including animal feeds, antibiotics, and disinfectants. Duna et al also reported that exposure to pesticides and insecticides was associated with WG (9). This question was omitted from our study due to the retrospective design, because it is particularly subject to recall bias and overreporting by cases. Clearly, further investigation is needed to better establish the nature of the association with farming. Our results support published evidence that silica is associated with PSV. Most previous studies indicate that the duration of silica exposure is less important than its intensity (e.g., ORs for sandblasting are much higher than for building trades) (32–34). We also found no increased risk with duration of exposure, but the questionnaire was not designed to assess levels of exposure. A difference was noted in the relationship of WG and CSS with silica versus the relationship of MPA with silica, in terms of timing of exposure (WG and CSS were associated with recent exposures). This may reflect a difference in the role of silica, e.g., acting as a trigger of disease in WG and CSS but as an autoimmune adjuvant in MPA. However, the difference could also be explained by classification of patients, the insidious onset of MPA making determination of the index date less accurate, or the relatively small number of MPA patients. Our results suggest that silica has a stronger

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association with pANCA/MPO-positive than with cANCA/PR3-positive PSV. This is also consistent with the literature since many reports address MPO-positive vasculitis; however, our data should be interpreted with caution because the ANCA results were collected retrospectively, and clinical use of ANCA results and laboratory methods for detection developed over the study period (35–37). An association of PSV with solvents and hydrocarbons has been reported previously, but the specific association with WG has not. This may be due to differences in cases and classification between studies. The mean duration of exposure in our cases (23.7 years [range 3–50 years]) was similar to that in previous studies by Nuyts et al (⬎20 years) (5) and Steenland et al (⬃20 years [range 11–28 years]) (26). This suggests that PSV is associated with prolonged exposure to solvents. A specific link with renal vasculitis or a previously proposed association with pulmonary hemorrhage (7) was not substantiated. We failed to detect any significant relationship with metal exposure. Positive associations have previously been described for very specific exposures, e.g., welding fumes (5), whereas our study included a wider range of exposures. An association of drug allergy with WG, but not with CSS, in patients in London has previously been reported by Cuadrado et al (12), from a study using virtually the same questionnaire as the one we used. They also reported significant associations of WG and CSS with both a family history of atopy and other types of allergy, a finding we were not able to reproduce. This may be explained by their smaller number of cases (20 WG and 8 CSS) or differences between case or control groups. Because their study was conducted at a tertiary referral center, their cases are more prone to referral bias and likely to have more severe disease and to be younger than a population-based cohort such as ours. Their disease controls were selected from among rheumatology patients with common symptoms less likely to be referred for specialist consultation compared with PSV patients. The inclusion of rheumatoid arthritis patients in their control group may also have introduced a positive bias toward a hypothesis that allergy is associated with PSV, since a reduced frequency of atopy in rheumatoid arthritis has been described (38). Reports have suggested a role for a Th2 (atopic) cytokine environment in the initiation of PSV (39), and the association of allergy with PSV may support this theory. However, drug allergies are associated with heterogeneous immune responses (40), so other immunologic mechanisms may be important. The majority of


allergies described in our cohort were to antibiotics, so it is possible that drug allergy is a marker for previous exposure to infection, rendering the individual more susceptible to PSV. We recognize that the present study has limitations, and results should be interpreted with these in mind. We are confident that case recruitment was as complete as possible, but bias may have been introduced by control selection. Resource constraints meant that we were unable to recruit a random sample from the “healthy” denominator population. Use of hospital controls could introduce referral bias, but the location of the population and the fact that the NNUH is the only referral center mean that a geographically representative sample is more likely, compared with most centers. We suggest that referral bias was minimal since there was no significant difference between cases and controls when comparing urban and rural residence defined by postal code, which reflects an increasing distance from the hospital in this population. Some illnesses affecting the controls may have biased individual outcomes. For example, osteoarthritis patients may be less likely than PSV patients to have had manual jobs. This would not introduce a bias in many items of interest, e.g., allergy, and both cases and controls were required to describe events that occurred several years earlier, when their health status was likely to be different. The exclusion of autoimmune disease controls may have excluded some potential triggering factors (e.g., propylthiouracil has been linked with MPOpositive PSV), but we were unable to examine this association since patients with thyroid disease were specifically excluded. Recall bias can be a problem in retrospective case–control studies but was unavoidable. It was minimized by ensuring that both cases and controls had to recall a similar period. Although it was not possible for the interviewer to be blinded to the subject or case/control status of the interviewee, observer bias was minimized by the use of direct questions. The major selection bias was the exclusion of deceased patients from the study, who may differ from survivors in terms of some of the variables investigated. However, review of the clinical features and vasculitis activity of survivors compared with deceased cases did not reveal significant differences. In conclusion, our study has identified, for the first time, a plausible, significant association between farming and PSV, and the results support previously reported associations with silica, solvents, and allergy. Associations are sufficiently strong to warrant further

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investigation. It would be of interest to determine if the association with farming can be replicated in other populations. However, our study had a number of potential biases, and a prospective analysis of incident cases compared with community controls would be desirable to provide definitive results. REFERENCES 1. Watts RA, Lane SE, Bentham G, Scott DGI. Epidemiology of systemic vasculitis: a ten-year study in the United Kingdom. Arthritis Rheum 2000;43:414–9. 2. Tervaert JW, Stegeman CA, Kallenberg CG. Silicon exposure and vasculitis. Curr Opin Rheumatol 1998;10:12–7. 3. Hogan SL, Satterly KK, Dooley MA, Nachman PH, Jennette JC, Falk RJ. Silica exposure in anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and lupus nephritis. J Am Soc Nephrol 2001;12:134–42. 4. Gregorini G, Feroli A, Donato F, Tira P, Morassi L, Tardanico R, et al. Association between silica exposure and necrotizing crescentic glomerulonephritis with p-ANCA and anti-MPO antibodies: a hospital-based case-control study. Adv Exp Med Biol 1993;336: 435–40. 5. Nuyts GD, van Vlem E, de Vos A, Dademans RA, Rorive G. Wegener granulomatosis is associated to exposure to silicon compounds: a case-control study [see comments] [published erratum appears in Nephrol Dial Transplant 1995;10:2168]. Nephrol Dial Transplant 1995;10:1162–5. 6. Pai P, Stevenson A, Mason H, Bell GM. Occupational hydrocarbon exposure and nephrotoxicity: a cohort study and literature review. Postgrad Med J 1998;74:225–8. 7. Pai P, Bone JM, Bell GM. Hydrocarbon exposure and glomerulonephritis due to systemic vasculitis. Nephrol Dial Transplant 1998;13:1321–3. 8. Van Gurp EAFJ, Shorer B, van der Woude FJ, de Jong GMTH, Yaqoob M, Hermans J, et al. Hydrocarbon exposure in ANCA associated disease [abstract]. Clin Exp Immunol 2000;120 Suppl 1:60 (90O). 9. Duna GF, Cotch MF, Galperin C, Hoffman DB, Hoffman GS. Wegener’s granulomatosis: role of environmental exposures. Clin Exp Rheumatol 1998;16:669–74. 10. Voznesenskii NK, Khorobrykh VG, Chicherina EN. The morphological characteristics of the lung lesions in straighteners working with brass-bronze alloys. Gigiena i Sanitariia 1995;6:20–2. 11. Costa DL, Dreher KL. Bioavailable transition metals in particulate matter mediate cardiopulmonary injury in healthy and compromised animal models. Environ Health Perspect 1997;105 Suppl 5:1053–60. 12. Cuadrado MJ, D’Cruz D, Lloyd M, Mujic F, Khamashta MA. Allergic disorders in systemic vasculitis: a case-control study. Br J Rheumatol 1994;33:749–53. 13. Somer T, Finegold S. Vasculitides associated with infections, immunization and antimicrobial drugs. Clin Infect Dis 1995;20: 1010–36. 14. Kinoshita M, Shiraishi T, Koga T, Ayabe M, Rikimaru T, Oizumi K. Churg Strauss syndrome after corticosteroid withdrawal in an asthmatic patient treated with pranlukast. J Allergy Clin Immunol 1999;103:534–5. 15. Guillevin L, Lhote F, Gherardi R. The spectrum and treatment of virus-associated vasculitides. Curr Opin Rheumatol 1997;9:31–6. 16. Gocke DJ, Morgan C, Lockshin M, Hsu K, Bombardieri S, Christian C. Association between polyarteritis nodosa and Australia antigen. Lancet 1970;2:1149–53.

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17. Mandell BF, Calabrese L. Infections and systemic vasculitis. Curr Opin Rheumatol 1998;10:51–7. 18. Symmons DP, Barrett EM, Bankhead CR, Scott DG, Silman AJ. The incidence of rheumatoid arthritis in the United Kingdom: results from the Norfolk Arthritis Register. Br J Rheumatol 1994;33:735–9. 19. Lane SE, Scott DGI, Heaton A, Watts RA. Primary renal vasculitis in Norfolk: increasing incidence or increasing recognition? Nephrol Dial Transplant 2000;15:23–7. 20. Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 1990;33:1101–7. 21. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitides: proposal of an international consensus conference. Arthritis Rheum 1994;37: 187–92. 22. Masi AT, Hunder GG, Lie JT, Michel BA, Bloch DA, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990;33:1094–100. 23. Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg Strauss syndrome. Medicine (Baltimore) 1984;63:65–81. 24. Office for National Statistics. Statistics, standard occupational classification 2000. Vol. 1 and 2. London: The Stationery Office; 2000. 25. Parks CG, Conrad K, Cooper G. Occupational exposure to crystalline silica and autoimmune disease. Environ Health Perspect 1999;107 Suppl 5:793–802. 26. Steenland NK, Thun MJ, Ferguson W, Port FK. Occupational and other exposures associated with male end-stage renal disease: a case-control study. Am J Public Health 1990;80:153–9. 27. Lewis R. Occupational exposures: metals. In: LaDou J, editor. Occupational and environmental medicine. Hemel Hempstead, UK: Prentice-Hall; 1997. p. 405–39. 28. Watts RA, Scott DGI. Churg Strauss syndrome: possible role of environmental factors [abstract]. Clin Exp Immunol 1998;112 Suppl 1:30.

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29. Chua KB, Goh KB, Wong KT, Kamarulzaman A, Tan PS, Ksiazek TG, et al. Fatal encephalitis due to Nipah virus among pig-farmers in Malaysia. Lancet 1999;354:1222–3. 30. Mocsari E, Szolnoki J, Glavits R, Zsak L. Horizontal transmission of Aujeszky’s disease virus from sheep to pigs. Vet Microbiol 1989;19:245–52. 31. Larsson H, Bengtsson-Stigmar E. Behcet’s disease and close contact with pigs. Acta Med Scand 1984;216:541–3. 32. Rosenman KD, Moore-Fuller M, Reilly MJ. Connective tissue disease and silicosis. Am J Ind Med 1999;35:375–81. 33. Boujemaa W, Lauwerys R, Bernard A. Early indicators of renal dysfunction in silicotic workers. Scand J Work Environ Health 1994;20:180–3. 34. Hotz P, Gonzalez-Lorenzo J, Siles E, Trujillano G, Lauwerys R, Bernard A. Subclinical signs of kidney dysfunction following short exposure to silica in the absence of silicosis. Nephron 1995;70: 438–42. 35. Yashiro M, Muso E, Itoh-Ihara T, Oyama A, Hashimoto K, Kawamura T, et al. Significantly high regional morbidity of MPO-ANCA related angiitis and/or nephritis with respiratory tract involvement after the 1995 great earthquake in Kobe (Japan). Am J Kidney Disease 2000;35:889–95. 36. Chevailler A, Carrere F, Renier G, Hurez D, Subra JF, Reboul P, et al. Silicon nephropathy and MPO. Ann Rheum Dis 1994;53: 781–2. 37. Wichmann I, Sanchez-Roman J, Morales J, Castillo MJ, Oscana C, Nurez-Roldan A. Antimyeloperoxidase antibodies in individuals with occupational exposure to silica. Ann Rheum Dis 1996;55: 205–7. 38. Hilliquinn P, Allanore Y, Cote J, Renoux M, Kahan A, Menkes CJ. Reduced incidence and prevalence of atopy in rheumatoid arthritis: results of a case-control study. Rheumatology 2000;39: 1020–6. 39. Tomer Y, Barak V, Gilburd B, Shoenfeld Y. Cytokines in experimental autoimmune vasculitis: evidence for a Th2 type response. Clin Exp Rheumatol 1999;17:521–6. 40. Witte KW, West DP. Immunology of adverse drug reactions. Pharmacotherapy 1982;2:54–65.


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APPENDIX A. OCCUPATIONS OF STUDY PARTICIPANTS* Occupation Occupations with silica exposure High silica exposure Foundry/metal workers Arable farm workers Both farming and construction (⫹abrasive blasting in Lotus car manufacture) Construction industry/bricklayer/roofing Road worker Coal miner Cement industry worker Abrasive blaster automobiles/maltings worker Shipwright/shipyard worker Terrazzo floor polisher Total Intermediate or probable silica exposure Dentist/dental technician/dental nurse Carpenter Electrician Property maintenance Painter and decorator Coal delivery Land army Baker Fireman/railways/Navy stoker Sculptor Transport of grain Boatbuilder Paint analyzer Poultry farm/grain Industrial boiler servicing Jeweler Total Occupations with solvent exposure High solvent exposure Printer Laundry worker Aircraft fitter/aircraft fuel pumping Painter and decorator Building and roofing Factory work exposed to glues Car repair/paint sprayer/paint factory Paint analyzer Total

No. of subjects

3 26 7 21 2 4 1 1 2 1 68† 5 4 6 1 6 1 2 2 2 1 1 7 1 1 1 1 42‡ 8 3 4 9 1 1 2 1 29§

Occupation Intermediate solvent exposure Armed forces Illustrator/artist Factory worker Boatbuilder Hairdresser Health and safety consultant Window cleaner Building/roofing Cabinet/furniture maker Electronics engineer Carpenter Engineer Solvents used in cleaning Plastics industry Manufacturing chemist/laboratory technician Leather industry Car mechanic/salvage Petrol pump attendant Diesel fumes/refrigerants Paint delivery Dye manufacture Science teacher Forestry worker Total Occupational exposure to metals High metal exposure Aluminum/steel plant worker Grinding metals/abrasive work Iron molder Welding Total Intermediate metal exposure Boatyard workers Canning Cement manufacture Chemical processor/analytical chemist Dentist/dental nurse/dental technician Dye manufacture Electrical wiring manufacture Farm worker (possible fertilizer exposure) Forestry worker Gas fitter/heating engineer Leather industry Munitions factory Other factory worker Painter and decorator/paint sprayer Panel beating Pest control Plastics worker Soldering Total

No. of subjects 35 3 22 6 6 1 1 15 6 1 6 7 5 7 6 8 4 2 5 1 1 1 1 150¶ 7 7 1 7 22# 6 2 1 4 5 1 1 35 1 1 6 2 1 8 2 1 4 4 85**

* Occupation codes from ref. 24. High, medium, and low exposures defined by job exposure matrices (refs. 25–27). † Eighteen primary systemic vasculitis (PSV) (9 Wegener’s granulomatosis [WG], 5 microscopic polyangiitis [MPA], 4 Churg-Strauss syndrome [CSS]), 42 nonvasculitis controls, 3 systemic rheumatoid vasculitis (SRV), 5 asthma controls. ‡ Nine PSV (4 WG, 3 MPA, 2 CSS), 24 nonvasculitis controls, 4 SRV, 5 asthma controls. § Eleven PSV (10 WG, 1 MPA), 15 nonvasculitis controls, 1 SRV, 2 asthma controls. ¶ Twenty-three PSV (12 WG, 6 MPA, 5 CSS), 105 nonvasculitis controls, 10 SRV, 12 asthma controls. # Five PSV (3 WG, 1 MPA, 1 CSS), 12 nonvasculitis controls, 2 SRV, 3 asthma controls. ** Twenty PSV (11 WG, 6 MPA, 3 CSS), 57 nonvasculitis controls, 2 SRV, 6 asthma controls.