Page 290 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

264 Elizabeth J. Brant, Julie G. McGregor, J. Charles Jennette et al.

Silica

Noted geographical differences in incidence may imply that environmental and other
geo-locational triggers play a role in disease development. Silica has been implicated as one
such trigger. The first account of a possible association of silica with autoimmune disease was
a 1914 report of systemic sclerosis occurring in Scottish stonemasons [19]. There have since
been a number of studies correlating silica exposure with the development of other
autoimmune diseases, particularly rheumatoid arthritis (RA) [20], but also systemic lupus
erythematosus (SLE) [21-23]. Data regarding the latter are conflicting [24], but differences in
results may reflect dissimilarities in study methodology and patient characteristics. Data on
the contribution of silica to the development of AAV have been inconsistent. A study of
2,288 patients from Sweden found no statistically significant association between an
occupation and development of GPA, although borderline associations were seen in miners,
paper workers, bakers, and animal keepers [25]. However, a meta-analysis of six case-control
studies examining silica exposure and risk of AAV found an overall significant summary
effect of silica exposure (summary OR 2.56; 95% confidence interval [CI] 1.51-4.36) with
development of AAV [26]. This summary OR was similar to the OR seen in studies looking
exclusively at either MPA (OR 3.95, 95% CI 1.89-8.24) or GPA (OR 3.56, 95%
CI 1.85-8.82).

Difficulties in comparing studies like these have been due largely to study heterogeneity,
with studies using different methods for ascertaining silica exposure. Negative studies have
been quite large numbering up to 2,288 patients, whereas positive studies have generally been
small, ranging from 16 to 75 patients, with variable inclusion criteria. For example, one study
included only men [27], while others differed in the age range of patients included. All but
one study [28] included only patients with glomerulonephritis, with or without other organ
system involvement. Determination of ANCA seropositivity by immunofluorescence (IF)
enzyme-linked immunosorbant assay (ELISA) or a combination thereof varies in the
literature with one study including 3 patients who were ANCA seronegative [29]. The
duration of exposure to potential silica-containing compounds, as well as the time from
exposure to clinically-evident disease has varied. No study of silica exposure included
patients with pulmonary- or otolaryngologic-limited disease, even though exposure is likely
through inhalation of crystalline particulates. However, in terms of exposure risk, the study by
Hogan and coworkers [24] did not find significant differences in patients with and without
pulmonary involvement. The geographical region of either study could have contributed to
the variable results.

Despite data inconsistencies, silica is generally accepted as having a potential role in the
development and perpetuation of AAV. Mechanisms by which silica may promote
autoimmunity have not yet been fully elucidated. One study of silica-exposed workers in
Brazil [30] found increased levels of soluble interleukin-2 receptor (sIL-2R), thought to
reflect increased immune activation in these individuals. However, investigators did not
specifically consider the role of silica in autoimmunity. Another study of slate miners
demonstrated increased and chronic T-cell activation in patients with silicosis either with or
without autoimmune disease, including one with pauci-immune glomerulonephritis [31], and
found proliferation of peripheral blood mononuclear cells (PBMC) to be 45% higher in cell
cultures of silica-exposed patients than in healthy controls. Patients had elevated levels of
both pro-inflammatory (interleukin [IL]-1ß, IL-6, tumor necrosis factor [TNF]-?, interferon

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