wegener's granulomatosis: possible role of environmental agents in its pathogenesis

Wegener’s Granulomatosis: Possible Role ofEnvironmental Agents in Its PathogenesisDANIEL ALBERT, CHERYL CLARKIN, JODI KOMOROSKI, COLLEEN M. BRENSINGER, AND

JESSE A. BERLIN

Objective. To investigate the possibility that environmental agents contribute to the pathogenesis of Wegener’s granu-lomatosis (WG).Methods. We undertook an extensive search for possible environmental exposures by developing a comprehensive question-naire that was administered by telephone interview to 53 patients with WG and 2 control groups: one with osteoarthritis andthe other with gout. Questions focused on hobbies and vocations, work, home, and allergies. Exact logistic regression was usedto calculate odds ratios and 95% confidence intervals after adjusting for potential confounders. After adjusting for age and sex,data are reported for all exposures with odds ratios >2.0 against either control group or for any allergic propensity.Results. Results suggest that mercury and perhaps lead exposure were positively associated with WG as compared witheither control group, although the number of patients exposed was small. A prior history of allergy was also associatedwith WG as compared with either control group.Conclusion. We conclude that heavy metal exposure and a prior history of allergy may play a role in the etiopathogenesisof Wegener’s granulomatosis.

KEY WORDS. Heavy metal exposure; Allergy; Lead; Mercury; Wegener’s granulomatosis; Environmental toxins.

INTRODUCTION

Wegener’s granulomatosis (WG) is a chronic granuloma-tous inflammatory vasculitis primarily involving the respi-ratory system, but also affecting multiple organs. Althoughit is of unknown etiology, an autoimmune component hasbeen established with the discovery of antineutrophil cy-toplasmic antibodies (ANCA). The mechanism that gener-ates these antibodies has not been identified, nor has theirrole in the pathogenesis of WG been identified.

The disease affects 3 of every 100,000 people in theUnited States (1); however, a recent increase in annualincidence was found in studies conducted in the UnitedKingdom (2) and Norway (3). Although it is possible thatthe rising incidence is due to improved detection of ill-ness, it has been hypothesized that an increase in indus-trial pollutants may be responsible.

Other studies have linked WG with multiple exogenous

factors, including cadmium (4); silica, which is usually inthe form of sand dust (5–8); and volatile hydrocarbons (9).In animal studies, Luzina and Handwerger induced vascu-litis with the administration of ANCA, estrogen, and mer-curic chloride, but the pathogenesis of the vascular inflam-mation was unclear (10). Using questionnaires, Duna et alinvestigated possible inhaled environmental exposures inpatients diagnosed with WG, but they failed to identify aspecific agent (11). A recent study suggests exposures ac-quired through farming in England are etiologic to sys-temic vasculitides, including WG (12). Thus, there is noconclusive association between any environmental expo-sure and the onset of WG, although there are a number ofsuggestive factors.

We report here the results of our study that was designedto further explore environmental agents in the pathogene-sis of WG. We used an investigator derived and adminis-tered questionnaire using gout and osteoarthritis patientgroups as separate controls. The questionnaire addressescommon recreational exposures, occupational exposures,and allergic symptoms.

SUBJECTS AND METHODS

Exposure questionnaire. We modified a general ques-tionnaire containing commonly encountered environmen-

Daniel Albert, MD, Cheryl Clarkin, PhD, Jodi Komoroski,MD, Colleen M. Brensinger, MS, Jesse A. Berlin, ScD: Uni-versity of Pennsylvania, Philadelphia.

Address correspondence to Daniel Albert, MD, 503 Ma-loney Building, University of Pennsylvania, 3400 SpruceStreet, Philadelphia, PA 19104. E-mail: [email protected].

Submitted for publication June 6, 2003; accepted in re-vised form November 26, 2003.

Arthritis & Rheumatism (Arthritis Care & Research)Vol. 51, No. 4, August 15, 2004, pp 656–664DOI 10.1002/art.20534© 2004, American College of Rheumatology

ORIGINAL ARTICLE

656

tal and occupational exposures from one that the Depart-ment of Environmental Medicine at the University ofCincinnati kindly provided. The questionnaire includeddemographic questions (age, race, and sex), an employ-ment history addressing potentially high-risk occupations,and a history of specific hobbies associated with chemicalexposures. The form also included questions regardingspecific chemical exposures. We enlarged this base ques-tionnaire to include a more detailed tobacco analysis aswell as a history of allergies. The Allergy–Immunologysection of the Hospital of the University of Pennsylvaniaprovided the basic questionnaire related to allergy symp-toms and exacerbating factors, which we incorporated intoour questionnaire.

Cases. We identified all patients (hospitalized and outpatients) with a billing code diagnosis of WG within theprior 3 years at the Hospital of the University of Pennsyl-vania (n � 156). Duplicate entries were eliminated andpatient charts were reviewed by one of the authors (DA).Only those patients that fulfilled the American College ofRheumatology criteria (13) for the diagnosis of Wegener’sgranulomatosis or were ANCA positive in lieu of biopsyconfirmation were included. However, the exact propor-tion that were ANCA positive is unknown because thisinformation was not collected prospectively. The majorityof the 101 billing code medical record numbers we re-jected were duplicate entries because of multiple encoun-ters for the same patient. Others were rejected because thepatients were found to have had other rheumatic diseases:either when we reviewed their charts, spoke with theirrheumatologist, or spoke with the patients directly. Wewere able to locate a total of 55 patients who had diagnos-tic confirmation. Of these 55, 2 patients refused to partic-ipate. Thus, data were collected on 53 patients who variedin age from 15 to 87 years. In the analyses, we adjusted forage and sex discrepancies.

Permission to contact patients was obtained from eachtreating physician, all of whom were faculty members ofthe University of Pennsylvania Department of Medicine.The study had the approval of the University of Pennsyl-vania Institutional Review Board. All participants gaveverbal informed consent. The University of Pennsylvaniais a major referral center for vasculitis in the DelawareValley with a catchment area of at least 6 million people.

Controls. Two control groups were contacted. Fifty-three gout patients and 50 osteoarthritis patients wereincluded. All of the control group patients were seen andfollowed at the rheumatology clinic at the University ofPennsylvania. These groups were chosen to provide infor-mation about background exposures because they repre-sent clearly definable groups of comparison patients fromapproximately the same catchment area giving rise to theWegener’s patients, although the WG patients tended tocome from a wider geographic area than the controls.Because there might be exposure patterns unique to thecontrol disease groups, we chose 2 separate groups that areindependently associated with different pathogenic mech-

anisms. Consistency between control groups would beviewed as supporting an association between a potentialrisk factor and development of WG. Inconsistencies be-tween the groups would be interpreted in light of what isknown about the characteristics of patients with each ofthese diseases. In each case, these were the most recentpatients seen with these diagnoses and represented a sim-ilar time frame as when the Wegener’s patients were seen.As with the WG patients, permission to contact patientswas obtained from each treating physician. Patients andcontrols were excluded if they had any other inflamma-tory, rheumatic, or pulmonary disorders.

Data collection. Patients were mailed the questionnaire,with a description of the study purpose and design, aminimum of 2 weeks prior to being contacted. A singleinterviewer telephoned each case and each gout control toadminister the questionnaire. A second interviewer con-tacted the osteoarthritis controls. In each case, the inter-view took �30 minutes. The patients were asked to ver-bally confirm the diagnosis and only those exposures thatpreceded the diagnosis by at least 6 months were included.The exposures we focused on were those within the de-cade prior to the diagnosis, although there was no timelimit prior to the diagnosis imposed. Only quantifiablysubstantial exposures were recorded. For example, ahobby or leisure activity had to be engaged in for morethan 80 hours per year for it to be recorded as present.Workplace responses must have been present for at least 6months to be counted as an exposure. However, we did notseek external confirmation of the responses. Data providedby proxy were excluded from analysis.

Statistical analysis. Results were tabulated in a series of2 � 2 tables, resulting in unadjusted odds ratios (ORs) and95% confidence intervals. Pearson’s chi-square test, orFisher’s exact tests when cell counts were sparse, was usedto test for associations between exposures and WG. Be-cause of the small number of cases, coupled with lowvalues of exposure prevalence, exact logistic regressionwas performed to adjust the ORs for age, race, and sex.Composite scores were created to examine for dose-re-sponse relationships between the number of exposures ina category (e.g., lead) and WG. All analyses were per-formed using SAS version 8.1 (SAS Institute, Cary, NC).Our primary interest was in a broad screening of poten-tially important exposures because this was a hypothesis-generating study. We reported any exposure having an ORof �2.0 in either control group. For the allergy questions,however, we reported all the data because of our a prioribelief in the biologic importance of the role of allergy inWG. We reported all P values whether significant or not.

RESULTS

Fifty-three patients with WG, 53 patients with gout, and 50patients with osteoarthritis completed the questionnaire.The overall response rate for the WG patients was �96%,and the gout and osteoarthritis response rates were 100%.

Environmental Agents in Wegener’s Granulomatosis 657

The mean age of the WG patients was 57 years with a rangeof 15 to 87 years. The gout patients’ mean age was 65 yearswith a range of 33–89 years. The osteoarthritis patients’mean age was 64 years with a range of 31–83 years. Table1 shows comparisons in the demographic characteristicsamong the WG, gout, and osteoarthritis patients. The datapresented below represents a summary of only those asso-ciations with an OR � 2 or P � 0.05. The complete ques-tionnaire data are available in Appendix A at http://www.interscience.wiley.com/jpages/0004–3591:1/suppmat/index.html.

Hobbies and avocations. In Table 2, the hobbies thathad ORs of 2 or higher, versus either the gout or osteoar-thritis controls, are listed along with possible chemicalexposures associated with each of those hobbies. Expo-sures range from heavy metals to organic solvents andcarbon monoxide. Interestingly, indoor firing range prac-tice, (see Appendix A available at http://www.inter-science.wiley.com/jpages0004–3591:4/supmat/in-dex.html.) in which a major exposure is lead, had apositive association with WG compared with the goutgroup, and a negative association compared with the os-teoarthritis control group. On the other hand, making bul-lets, again a lead exposure, had a positive association withWG compared with either control group.

Workforce. Industry and possible associated exposuresthat were associated with elevated ORs for WG when com-pared with either control group are noted in Table 2. Theseindustrial exposures included many of the same chemicalsas in the hobby groups, as well as additional agents. Therewas a positive association between brake lining repair/change for WG when compared with either control group.

Chemical. The chemical exposures that had ORs of 2 ormore are noted in Table 3. Also listed in this table arepossible industries and other activities/places of exposure.Mercury, carbon monoxide, dibromochloropropane, andlead had positive associations with WG versus either con-trol group.

Allergy. Finally, the allergy data were analyzed andsummarized in Table 4. The Wegener’s patients frequentlyreported allergy symptoms before the onset of the WGsymptoms leading to diagnosis. Allergies to drug or med-ications had a negative association in both of the controlgroups, whereas having sinusitis �3 times in 1 year andnasal polyps were positively associated with WG. The

actual symptoms experienced, or exacerbating factors, didnot appear significant in this study.

DISCUSSION

The purpose of this study was to identify possible etiolo-gies of Wegener’s granulomatosis by using a questionnairethat would encompass a wide range of potential expo-sures. We examined inhalants, liquid solvents, solid met-als, and other chemicals associated with common hobbiesand industries. Several of the hobbies, industries, andchemical exposures that we included were found to beassociated with WG, in that they showed an OR of 2 orhigher versus at least 1 of the control groups. A previousstudy examined particular inhaled exposures associatedwith construction in industry and then in the home. Theyfailed to identify a particular inhalant as significant (11).Other case reports have suggested cadmium or silica ex-posure (4–8). A very recent study identified farming as ahigh-risk activity, presumably due to the exposure to 1 ormore of many potential environmental factors (12). Interest-ingly, in our study, farming was only positively associatedwith WG when compared with gout, and no association waspresent when compared with osteoarthritis or to the com-bined control groups. This may reflect the different basepopulations represented by the different control groups (seeAppendix A available at http://www.interscience.wiley.com/jpages/0004–3591:1/suppmat/index.html).

Using the most stringent criteria, OR �2 against eachcontrol group and P � 0.05 against the combined controlgroup, our data suggest exposure to mercury may be acausal factor. Even with mercury, when directly queried,only �10% of patients knew of this exposure. However,mercury exposure could have occurred through any of thehobby and workplace exposures that can be associatedwith mercury without the patient’s knowledge. Manyother exposures, such as other heavy metals and aromatichydrocarbons, had suggestive ORs but lacked statisticalsignificance, perhaps secondary to small numbers of cases.Some of the associations we report (e.g., lead) are sugges-tive because of their large magnitude, but they also dis-played wide confidence intervals, implying a great deal ofuncertainty around those estimates and thus requiringcaution in their interpretation.

There are many common hobbies that expose people topotentially toxic agents. We found that there is an overlapof exposures in several of the hobbies explored. Lead is anexposure in indoor firing range practice, as well as instained glass crafts, making bullets, and ceramics. In our

Table 1. Demographics*

WG group

Gout control group OA control group

Gout group P OA group P

Age, mean � SD years 57.2 � 16.2 64.7 � 12.1 0.0081 63.7 � 12.4 0.0265Sex, % male 49.1 66.0 0.0770 40.0 0.3555Race, % white 92.5 63.3 0.0003 76.0 0.0212

* P values reflect the comparison between the Wegener’s granulomatosis (WG) group and the respective control group. OA � osteoarthritis.

658 Albert et al

Tab

le2.

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pos

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s*

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s

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Tab

le3.

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(con

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660 Albert et al

Tab

le3.

Ch

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pos

ure

s*(C

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770.

562,

5.58

40.

3938


Tab

le4.

All

ergy

his

tory

*

No.

exp

osed

inW

egen

er’s

grou

p

Gou

tco

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62

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419

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942.

420.

535,

11.6

360.

3071

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eyo

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nu

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than

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year

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92.

250.

674,

8.11

20.

2235

92.

710.

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8.93

70.

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2.43

0.96

8,6.

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0.05

98

Are

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1422

0.28

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739

0.00

870.

250.

098,

0.61

60.

0013

*A

llal

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.

662 Albert et al

study, several modes of exposure to lead were suggestiveof a possible association with the development of WG.This is especially interesting because it was evident incomparison with gout patients who in some studies (butnot ours) have a higher exposure rate to lead. Although wedid not specifically test this group of gout patients for leadexposure or lead toxicity, the association of lead exposurewith gout is well recognized (14).

One proposed hypothesis to explain the increased inci-dence of WG is an increase in industrial pollutants in theenvironment. We addressed common industries associ-ated with exposure to potentially toxic agents (Table 2).Each of these industries has multiple exposures, and thepotential effects of these exposures are important. Severalworkplace or hobby exposures could be to the same chem-ical, for example farmers and individuals who are exposedto brake linings both have high silica exposure.

We examined specific exposures of individuals (Table3). Mercury, carbon monoxide, and dibromochloropro-pane each had positive associations for WG when com-pared with both of the control groups. Mercury exposureas methyl mercury was addressed specifically because it isubiquitous, has a broad spectrum of toxicity (15–19), andis a known cause of vasculitis in an animal model. Mer-cury has 3 forms in which it is found: as a metal, aninorganic salt, or an organic compound (including methylmercury).

Elemental mercury is used in common items, such asthermometers. It is liquid at room temperature and easilyvaporizes into a colorless and odorless vapor. Acute mer-cury inhalation can cause acute narcotizing bronchitis andpneumonitis, with chronic exposure resulting in centralnervous system dysfunction (16).

Methyl mercury is an organic compound containingmercury. It is an ingredient in many fungicides and disin-fectants, and is used in many industrial processes. Mercu-ric compounds are readily absorbed into the body via thegastrointestinal and respiratory tracts with toxic effects.There have been cases of mercuric poisoning with expo-sure to the compound in fish, as well as in contaminatedgrain in both Japan and Iraq. Finally, there is evidence inanimal studies that mercuric chloride can be used to in-duce autoimmune vasculitis (10).

Carbon monoxide is an indoor air pollutant that wasfound to approach statistical significance in our study.Carbon monoxide is a common pollutant resulting fromthe use of gas furnaces and heaters; gas ranges; gas clothingdryers; wood or coal heating; fireplaces; and machines thatare powered by gasoline, including automobiles, lawnmowers, snow blowers, etc. In the United States there is nouniversally agreed-upon acceptable level of carbon mon-oxide, although background levels typically range from 0to 3 ppm (20). In Canada, there is an acceptable exposurerate of 11 ppm over an 8-hour exposure time when fur-naces are functioning properly (20).

Dibromochloropropane was also found to have clinicalsignificance in both of the control groups. It is a majoringredient in many pesticides. Individuals could becomeexposed through farming, gardening, and other daily ac-tivities. It is interesting that investigators in Britain iden-

tified farming as a high-risk occupation for developingWG.

It should be noted that because of the way the question-naire was structured, we were able to obtain each categoryof exposure separately. Thus, there may be occupationalexposures that are not reflected in the specific chemicalsection. An example is silica, which is an exposure inmany of the potentially causal hobbies and occupations,but does not appear in the section on chemicals. We sus-pect that our data are consistent with other studies thatsuggest that silica is associated with WG.

Finally, allergies and allergy symptoms and exacerba-tions were also examined (Table 4). All of the questionswere specifically worded to elicit symptoms that predatedthe onset of the Wegener’s symptoms. Of note, it is inter-esting that allergy to medications had a negative associa-tion when compared with both of the control groups. Thissuggests that atopy itself is not a risk factor, but thatrespiratory symptoms that may either reflect nasal allergyor chronic bacterial sinusitis may be a risk factor, as otherinvestigators have suggested (21). There is a positive asso-ciation between sinusitis �3 times in 1 year and WG. Thisinformation cannot formally distinguish whether or notthe sinusitis is actually a precipitating factor or simply anearly symptom of WG. The same can be said for nasalpolyps. However, the way the questionnaire was struc-tured, the nasal symptoms preceded the diagnosis andthus could have been a risk factor rather than an earlymanifestation of disease.

Because we examined many different exposures, there isa strong possibility that some of the associations we iden-tified may be the product of Type I errors. In addition,some of the associations we detected could be the productof an association with or against one or both of the controlgroups (as compared with a truly general population).Thus, a larger, more focused case-control study using pop-ulation-based controls, perhaps through random-digit di-aling, would be a next step. Using data from the currentstudy, we could construct a more focused questionnaire.

We did not investigate possible infections triggers ofWG. Nasal passage colonization of Staphylococcus aureus(22) and parvovirus B19 infection (23,24) have been asso-ciated with WG. Although none of the evidence is conclu-sive for an inciting agent, there is evidence to support anincrease in symptomatic relapses associated with chroniccarriers of the Staphylococcus pathogen. There is also adecrease in relapse seen in patients placed on antimicro-bial therapy to treat colonization (22).

There is little evidence in familial studies to support acommon genetic etiology, including the absence of a dom-inant HLA genotype among WG patients (25).

In summary, this study suggests that several environ-mental exposures might be potential risk factors for devel-opment of Wegener’s granulomatosis. These are worthy offurther and more detailed consideration. It also suggeststhat a history of sinusitis (whether allergic, bacterial, orboth) is associated with WG. Testing these hypotheses willbe difficult but could be achieved through development ofan animal model, by studying geographic clusters of cases,or through a larger case-control study with population-based controls.


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