Danish Researchers Call for Revised Regulations on Silica, as Increased Scleroderma Incidence at Sub-Exposure Limit Levels Are Detected

Systemic sclerosis, or scleroderma (the umbrella group of diseases), is an incurable, chronic inflammatory multisystem autoimmune disease, characterised by the excessive production of collagen, which causes diffuse tissue fibrosis, small vessel (vascular) impairment and specific autoimmune response.[1] In layman’s terms, an overactive and out of control immune system attacks the connective tissues under the skin and around internal organs and blood vessels, causing scarring and thickening of tissue, as well as fatigue, weight loss and swollen painful joints.[2]

It is thought that the over-proliferation of fibroblasts (cells) to produce collagen, with consequent interstitial fibrosis, can be triggered by a response to excess respirable crystalline silica (RCS) exposure. On average, connective tissue disease is said to develop 15-years post exposure.

Following on from Bramwell’s observations at the beginning of the 20th century,[3] one of the first links to be drawn between silica exposure and systemic sclerosis was described by Erasmus, in 1957. He found a high prevalence of progressive systemic sclerosis in gold miners in South Africa, who had been exposed to silica powder. Hence, the co-existence of silicosis and systemic sclerosis is commonly referred to as ‘Erasmus syndrome’ in case reports and modern epidemiological literature.[4]

In 2018 (here), we analysed an Industrial Injuries Advisory Council (IIAC) Position Paper, entitled: Occupational Exposure to crystalline silica and its relation to connective tissue diseases’.

This built on an earlier Position Paper, published in 2005, which found limited evidence in support of positive associations.

Of the 3 connective tissue diseases examined by the Council, the strongest evidence for prescription under the industrial injuries disablement benefit (IIDB) scheme was silica-induced systemic sclerosis. Several academic papers concluded that the risk of systemic sclerosis was doubled with RCS exposure, but this was not the case in every study.

Despite ‘reasonable evidence’ to suggest that RCS posed this specific occupational health risk, IIDB disease prescription was not invited because the Council encountered difficulties identifying individual types of hazardous workplace exposure, i.e. the evidence base for any given occupation was ‘thin’ [only Diot et al (2002)[5] offered a potential (fairly wide) range of job titles].

With the benefit of hindsight if the IIAC had had the opportunity to evaluate the latest paper by Boudigaard et al (2021) on this topic, it is unlikely that its stance would have been any different.

Earlier this year, academics at Aarhus University Hospital, Denmark[6], published the results of a nationwide cohort study in the International Journal of Epidemiology, which investigated the relationship between occupational RCS and various autoimmune rheumatic diseases, including scleroderma (but also rheumatoid arthritis, systemic lupus erythematosus, and small vessel vasculitis, with the latter being the only condition not covered by the IIAC’s Paper).

The research team analysed a group of 3 million male and female workers (commencing work between 1979 and 2015) in a ratio of roughly 1:1, making up the total Danish workforce.

Of these 3 million participants, 17% of men and 3% of women had at some point experienced job-related exposure to RCS, with the female figure being so low that it was identified as a limitation of the study. What is more, men had an almost doubled estimated annual median cumulative exposure level [60 micrograms-per-cubic meter (μg/m3-years)] than women (33 μg/m3-years).

Although it was accepted (as the IIAC commented in its Position Paper) that there was potential for false positive diagnoses (especially in the case of rheumatoid arthritis, where over-reliance on the so-called ‘rheumatoid factor’ was common[7]), there were 252 cases of scleroderma recorded in male workers and 746 cases in female workers.

For all cases examined, a latency period of 20 years unravelled.

More profoundly, the researchers concluded that there was an elevated risk of men being diagnosed with autoimmune rheumatic disease in the period of 2005 to 2015 than the period of 1979 to 1984. This could suggest that peak occurrence of silica-related scleroderma has not yet been realised and is therefore an emerging issue.

In addition, the research team detected a dose (intensity and duration)-dependent association between RCS and the development of chronic disease among men. This was most pronounced for scleroderma.

Indeed, comparing non-exposed men against those with the highest cumulative exposure (94.0–1622 μg/m3-years), there was a 53% (incidence rate ratio of 1.53) increase in risk of autoimmune rheumatic disease across the board (1.62, 1.57, 1.46, 1.34 for systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus and small vessel vasculitis, respectively.

Similar trends were seen for mean exposure intensity, highest attained exposure intensity and duration of exposure.

Not only was this cited as evidence that a causal connection exists, but also as a reason to reassess current binding exposure limits, given that disease risk was apparent at ‘mean exposure intensity levels … well below’ those prescribed by European and UK [100 µg/m3 (8-hour time-weighted average)] legislation.

Whilst this latest study does not overcome the shortcomings that prevented IIDB disease prescription in 2018 (occupations were only graded as either armed forces; white-collar worker; skilled blue-collar worker; unskilled blue-collar worker; or other), it can be described as a persuasive large-scale piece of research, which promotes associations between RCS and autoimmune rheumatic diseases.

 

[1] Machado de Miranda AA et al., Erasmus syndrome - silicosis and systemic sclerosis, Rev. Bras. Reumatol. vol.53 no.3 São Paulo May/June 2013 <https://www.scielo.br/pdf/rbr/v53n3/en_v53n3a10.pdf> accessed 12 February 2021.

[2] ‘Scleroderma’ (22 August 2018 NHS)  <https://www.nhs.uk/conditions/scleroderma/> accessed 12 February 2021.

[3] Ganguly J et al., Erasmus Syndrome: A Case Report of Silicosis-induced Scleroderma in a 26-year-old Male. Oman Med J. 2013 Sep; 28(5): e058. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669304/pdf/OMJ-D-12-00343.pdf> accessed 12 February 2021.

Bramwell B, Diffuse scleroderma: its frequency; its occurrence in stonemasons. Edinburgh Med J 1914;12:387-401.

[4] Erasmus LD, Scleroderma in gold miners on the Witzwaterzrand with particular reference to pulmonar manifestations. S Afr J Lab Clin Med. 1957;3(3):209-31. https://pubmed.ncbi.nlm.nih.gov/13495613/> accessed 12 February 2021.

[5] Diot E et al., Systemic sclerosis and occupational risk factors: a case–control study. Occup Environ Med. 2002 Aug; 59(8): 545–549. <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1740346/pdf/v059p00545.pdf> accessed 15 February 2021.

[6] Boudigaard SH et al., Occupational exposure to respirable crystalline silica and risk of autoimmune rheumatic diseases: a nationwide cohort study. International Journal of Epidemiology, 2021, 1–14, dyaa287. <https://academic.oup.com/ije/advance-article-pdf/doi/10.1093/ije/dyaa287/35920959/dyaa287.pdf> accessed 12 February 2021.

Aisha Abdullah PhD, ‘Work-related Crystalline Silica Exposure Linked to Higher Scleroderma Risk’ (4 February 2021 Scleroderma News) <https://sclerodermanews.com/2021/02/04/higher-scleroderma-risk-linked-work-related-crystalline-silica-exposure/> accessed 12 February 2021.

[7] Sluis-Cremer GK et al., Relationship between silicosis and rheumatoid arthritis. Thorax. 1986;41:596-601. <https://thorax.bmj.com/content/thoraxjnl/41/8/596.full.pdf> accessed 12 February 2021.