Environmental Risk Factors in Systemic Sclerosis
Environmental Risk Factors in Systemic Sclerosis
Silica dust was one of the first environmental agents to be associated with the development of SSc. Initial reports identified disease clustering amongst Scottish stonemasons, South African gold miners and North American coal miners: all occupations where substantial exposure to silica is well recognized. More recently, an intriguing case report described the onset of limited cutaneous SSc in a French winegrower who frequently filtrated wine using calcined diatomaceous, which is almost 80–90% silica.
Such clinical observations have been further developed by several epidemiological investigations, the results of which have often been contradictory. However, a recent review summarised the results of all studies published between 1949 and 2009 that examined the association between silica exposure and SSc. Thirteen studies were identified of predominant European and North American origin. Of the nine case-control studies, three showed a significant positive association [relative risk (RR) ranging from 2.5 to 5.6]. A further four studies found a positive, albeit non-significant, result (RR range 1.4–5.2), the lack of significance most likely attributed to the rather small sample sizes, rather than lack of association. Perhaps most convincing, three out of four large cohorts demonstrated between a 7 and 37-fold increase in the risk of SSc associated with silica exposure. A meta-analysis was conducted, but, the high degree of heterogeneity between studies means that the findings need to be treated with caution.
Although this study was limited in its assessment of putative confounding factors, the RR estimate was higher for males compared with females [combined estimator of relative risk (CERR) 3.02, 1.24–7.35 and 1.03, 0.74–1.44, respectively], implying sex specificity. This may simply relate to the higher prevalence of occupational silica exposure in male-dominated occupations such as mining. Nevertheless, the exposure to silica occurs in a variety of other industries. For example, one study, which did identify an increased and significant risk of SSc amongst women with exposure to crystalline silica, found their cases to be employed in pottery or porcelain factories.
In general, few studies have considered the potential for confounding from demographic factors other than sex. This is especially important in any investigation of work-related exposures since occupation is an important surrogate for multiple lifestyle variables. Indeed an Australian study has previously recorded significant differences in socioeconomic status between SSc cases and population controls.
The duration between exposure to silica and onset of symptoms has previously been estimated to be 22.6 years. However, a more recent study reported the unusually early development of SSc amongst a small series of Algerian patients following heavy exposure to silica (5.8 years from exposure to disease onset). Further studies have also alluded to a dose-dependant response.
Taken together, current evidence does point towards a significant association between occupational-related silica exposure and the development of scleroderma. This would certainly seem biologically plausible since silica is known to propagate antibody production and exacerbate autoimmunity in mouse models. However, the overall effect sizes are modest and the attributable risks in population terms inevitability small due to the low prevalence of SSc.
Silica
Silica dust was one of the first environmental agents to be associated with the development of SSc. Initial reports identified disease clustering amongst Scottish stonemasons, South African gold miners and North American coal miners: all occupations where substantial exposure to silica is well recognized. More recently, an intriguing case report described the onset of limited cutaneous SSc in a French winegrower who frequently filtrated wine using calcined diatomaceous, which is almost 80–90% silica.
Such clinical observations have been further developed by several epidemiological investigations, the results of which have often been contradictory. However, a recent review summarised the results of all studies published between 1949 and 2009 that examined the association between silica exposure and SSc. Thirteen studies were identified of predominant European and North American origin. Of the nine case-control studies, three showed a significant positive association [relative risk (RR) ranging from 2.5 to 5.6]. A further four studies found a positive, albeit non-significant, result (RR range 1.4–5.2), the lack of significance most likely attributed to the rather small sample sizes, rather than lack of association. Perhaps most convincing, three out of four large cohorts demonstrated between a 7 and 37-fold increase in the risk of SSc associated with silica exposure. A meta-analysis was conducted, but, the high degree of heterogeneity between studies means that the findings need to be treated with caution.
Although this study was limited in its assessment of putative confounding factors, the RR estimate was higher for males compared with females [combined estimator of relative risk (CERR) 3.02, 1.24–7.35 and 1.03, 0.74–1.44, respectively], implying sex specificity. This may simply relate to the higher prevalence of occupational silica exposure in male-dominated occupations such as mining. Nevertheless, the exposure to silica occurs in a variety of other industries. For example, one study, which did identify an increased and significant risk of SSc amongst women with exposure to crystalline silica, found their cases to be employed in pottery or porcelain factories.
In general, few studies have considered the potential for confounding from demographic factors other than sex. This is especially important in any investigation of work-related exposures since occupation is an important surrogate for multiple lifestyle variables. Indeed an Australian study has previously recorded significant differences in socioeconomic status between SSc cases and population controls.
The duration between exposure to silica and onset of symptoms has previously been estimated to be 22.6 years. However, a more recent study reported the unusually early development of SSc amongst a small series of Algerian patients following heavy exposure to silica (5.8 years from exposure to disease onset). Further studies have also alluded to a dose-dependant response.
Taken together, current evidence does point towards a significant association between occupational-related silica exposure and the development of scleroderma. This would certainly seem biologically plausible since silica is known to propagate antibody production and exacerbate autoimmunity in mouse models. However, the overall effect sizes are modest and the attributable risks in population terms inevitability small due to the low prevalence of SSc.
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