INTRODUCTION

The association between silica exposure and autoimmune disease was first described by Bramwell in 1914, who observed scleroderma among stone masons [1]. Fifty years later, Erasmus found an increased incidence of systemic sclerosis (SSc) among South African gold miners, later referred to as Erasmus syndrome [2]. In 1952, Caplan described the occurrence of multiple lung nodules in coal miners who suffered from rheumatoid arthritis (RA), comorbidity known as Caplan's syndrome or rheumatoid pneumoconiosis [3]. Significant risk of developing SSc, RA, systemic lupus erythematosus (SLE), dermatomyositis/polymyositis and antineutrophil cytoplasmic antibody-positive vasculitis has been linked to silica exposure [4] and a study demonstrates that male patients with SSc have a high prevalence of occupational exposure to silica or solvents [5]. However, in a case-control study of a population including 95 patients working in 15 specific jobs likely to involve exposure to silica dust or solvents (e.g., custodial/janitorial work, dry-cleaning, construction, making pottery, or manufacturing ceramics, or computer wafers), exposure to silica was associated with SLE. The association between occupational exposure to organic solvents and SLE was not statistically significant [6].

Epidemiologic studies reveal that environmental factors may impact multiple immune system pathways within the framework of individual's genetics to potentiate the progression of specific autoimmune diseases. From particulate matter, drinking water pollutant, farming and pesticide use, environmental encounters with microbes including viruses and bacteria, gut microbiome dysbiosis, diet selection and exposure to silica in occupations such as construction, mining, and farming were studied[7▪].

We will summarize here an updated epidemiology overview of silica dust exposure related to autoimmune diseases and summarizes the evidence from human and animal studies on the possible association between silica and autoimmune diseases. We will describe the related mechanisms that may account for this association, factors for early detection and ongoing research for future therapies. 

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EPIDEMIOLOGY OF SILICA EXPOSURE ASSOCIATED AUTOIMMUNE DISEASE

Silicosis increases susceptibility to autoimmune diseases. The newer industries of sand-blasting denim and engineered stone have been associated with alarmingly high rates of silicosis

A multinational registry has documented diagnostic details related to autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, autoimmune myositis, mixed connective tissue disease, psoriasis, and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis among individuals with silicosis. The registry encompasses data from 169 engineered stone (ES) workers with silicosis: 14 workers in Australia, 125 in Israel, 20 in Spain, and 10 in the USA. Individuals were involved in the fabrication, cutting, shaping, finishing, laying, masonry, and engineering stone related industries. Workers with abnormal autoimmune serological testing without a definitive autoimmune were included [8]. Among all the ES individuals with data available, 33/154 (21.4%) were diagnosed with an autoimmune disease or had abnormal autoimmune serology. Distribution among the different diseases was as follow: rheumatoid arthritis 9 ± 5.8%, systemic sclerosis 7 ± 4.6%, psoriatic arthritis 6 ± 3.9%, abnormal autoimmune serology 7 ± 4.5%, others like Sjogren's syndrome, ANCA, SLE and mixed connective tissue diseases 8.5 ± 2%.

Lung transplantation center for advanced silica-related lung disease in Israel reported an outbreak of autoimmune disease in a group of patients with silicosis linked to artificial stone exposure [9] The data included 40 patients referred over a 15-year period (1997–2012). Nine among them were identified (23%) as suffering from various autoimmune diseases. Three of them were suffering from systemic sclerosis, 2 with minimal change disease, 2 with rheumatoid arthritis, one with Sjorgren's syndrome and one with polymyositis antisynthetase syndrome. Based on an expected autoimmune disease prevalence of 3% (based on upper-end estimate for this group of diseases in European international data), the proportion of disease in the study group represents a >7-fold excess (prevalence ratio 7.5; 99% confidence interval 2.6–16.7).

A Spanish work studied a population of 489 silicosis cases and 95 cases of silica exposure without silicosis in order to look for prevalence and clinical impact of systemic autoimmune rheumatic diseases in this group. Fifty-four (11.0%) patients with silicosis had systemic autoimmune rheumatic disease (SARD): 12 (2.4%) RA, 10 (2.0%), SLE, 10 (2.0%) SSc, 3, (0.6%) with Sjögren syndrome, 2 (0.4%), vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA+), 6 (1.2%) psoriatic arthritis, 3 (0.6%) ankylosing spondylitis, and 8 (1.6%) other autoimmune diseases with no special features. The patients with SARD visited the emergency room more often (63.0% vs. 42.5%; P = 0.004), and rapidly progressed (22.2 vs. 11.7%; P = 0.030) [10].

In Brazil, silicosis is the most frequent pneumoconiosis and represents the main cause of disability among occupational respiratory diseases [11]. A retrospective observational case series study was performed in order to detect nonmalignant silica-related diseases in a specialized outpatient clinic using primary data obtained from the medical assessments of all silica-exposed patients evaluated at the Workers Health Service of the Clinics Hospital of Federal University of Minas Gerais, from 1984 to 2021 [12]. The main occupational sectors were underground gold mining (28%), precious and semi-precious stone work (20%), and artisanal mining (9%). The group consisted of 1525 patients in patients with and without silicosis. The most common findings were chronic obstructive pulmonary diseases (COPD) (25%), active TB or sequelae (12%), and connective tissue diseases (6%). The distribution of the connective tissue diseases was as follows: inconclusive: n = 32; rheumatoid arthritis: n = 17; systemic sclerosis: n = 8; primary Sjogren syndrome: n = 4; systemic lupus erythematosus: n = 3; undifferentiated connective tissue disease: n = 2; psoriasis: n = 2; dermato-polymyositis: n = 2.

In a comprehensive nationwide cohort comprising approximately 3 million workers (1 541 505 males and 1 470 769 females), it was observed that among male workers, 17% had previously held a job involving exposure to crystalline silica with an increased overall incidence rate ratio of 1.53 (95% CI: 1.39–1.69) for the studied autoimmune rheumatic diseases combined. Among women, 3% of them held a job with exposure to crystalline silica and it was observed a slightly increased incidence rate ratio of 1.09 (95% CI: 0.87–1.37) for all the studied autoimmune rheumatic diseases combined. The exposure-dependent association between occupational exposure to respirable crystalline silica and autoimmune rheumatic was most evident for systemic sclerosis and rheumatoid arthritis [13▪▪].

A recent study elucidates that cleaning activities and dusty clothes laundry may be underestimated sources of SiO2 exposure in women with RA [14▪]. To 97 patients who were diagnosed with RA a specially trained interviewer administered DELCQ (Dust Exposure Life-Course Questionnaire). DELCQ scores related to each single source of exposure, compared between women with RA and controls. Within occupational activities, women with RA had higher exposure scores for cleaning activities (1.03 ± 1.71 vs. 0.46 ± 1.32, P = 0.02) and laundry for dusty work clothes (1.00 ± 1.86 vs. 0.19 ± 0.86, P = 0.01). This study highlights the importance of daily-life sources of exposure to crystalline silica in household products, and their association with RA in women.

MECHANISM OF SILICA INDUCED AUTOIMMUNE DISORDERS

Autoimmune disorders are induced by various environmental and occupational substances. Silica exposure is recognized as a causative factor for autoimmune disorders, with well established connections to conditions such as pulmonary fibrosis (silicosis), rheumatoid arthritis (Caplan's syndrome), systemic sclerosis, systemic lupus erythematosus, and ANCA-related vasculitis/nephritis.

Linking particulate exposure with human systemic autoimmune disease manifestations making it challenging due to the inherent limitations of epidemiological studies in establishing causality. Human populations are seldom exposed to a single xenobiotic compound, making challenging to establish a clear connection between exposure and disease. Furthermore, the specific mechanisms leading to autoimmune diseases and the effects of environmental and occupational exposures on these mechanisms remain largely unknown.

These limitations can be overcome by establishing in vitro human studies and experimental animal models in order to understand the interaction of the environment with the specific factors involved in systemic autoimmunity.

Silica-stimulated macrophages trigger the activation of pattern recognition receptors (PRRs), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, and the release of key mediators such as Interleukin 1-Beta (IL-1β), Tumor Necrosis Factor alpha (TNF-α), and interferons, playing a pivotal role in the pathogenesis of silicosis. Unlike bacteria, silica particles cannot undergo degradation, and the sustained activation of macrophages leads to NADPH oxidase (Phox) activation and production of mitochondrial reactive oxygen species (ROS). This cascade ultimately results in macrophage death and the release of silica particles, perpetuating the inflammatory response [14▪].

It was found that this cytokine inflammatory status induced by exposure to silica upregulates airway hyperreactivity and elevated antinuclear antibody levels in a bronchoalveolar lavage fluid in in a NOD/ShiLtJ mice exposed to silica [15]. In another study, it was revealed that the lung environment generated by exposure to crystalline silica (cSiO2) attracts and sustains the survival of dysregulated autoreactive B cells. These B cells exhibit aberrant regulation, escaping from normal tolerance mechanisms and demonstrating a propensity to produce autoantibodies. The study observed as well an increase in anti-DNA and antimyeloperoxidase (MPO) immunoglobulins in cultures of Toll-like receptor ligand-stimulated lung cells derived from BXSB mice exposed to silica [16].

A rapid onset of autoimmune disease pathogenesis was achieved using female lupus-prone NZBWF1 mice. After 7 days after instillation of silica particles, it was shown that there was a robust recruitment of macrophages, neutrophils, and lymphocytes into the alveoli, cell death reflected by increased protein, double-stranded DNA, and lactate dehydrogenase activity, elevated secretion of the cytokines interleukin (IL)-1α, IL-1β, IL-18, TNF-α, IL-6, MCP-1, B cell activation factor (BAFF) and upregulation of genes associated with chemokines, proinflammatory cytokines [17].

In a human in vitro study using peripheral blood mononuclear from workers with moderate to high exposure level to silica, it was found that exposure was associated with a decrease of Tregs (CD4+CD25+CD127−FoxP3+) compared to controls. Serum autoantibody detection was significantly higher in exposed workers (>10 years) compared controls. Antinuclear antibodies and ANCA were detected in 44% and 22% among expose workers as compared to 5% and 2.5% controls. This may be the mechanism of tolerance breakdown against to auto-antigens [18].

PREVENTION

Autoimmune diseases affect approximately 1/10 individuals, and their burden continues to increase over time at varying rates across individual diseases [19▪▪]. In order to prevent autoimmune diseases induced by silica exposure, it is crucial to minimize or eliminate this exposure altogether. In a comprehensive review addressing the prevention of rheumatoid arthritis, 11 strategies are discussed to reduce the disease risk. Among these strategies, one noteworthy recommendation is the avoidance of silica exposure. It is noted that 40% of rheumatoid arthritis cases are attributable to exposure to potentially modifiable factors [20].

Silica-exposed current smokers were observed to have a more than sevenfold increase in the risk of antibodies to citrullinated peptides (ACPA)-positive RA, exceeding the risk expected from the separate effects of silica exposure and smoking, suggesting that an interaction between these exposures contributes to development of ACPA-positive RA. [21].

EARLY DETECTION

Early detection of silicosis and autoimmune diseases should prioritize mitigating the risk of silica exposure, which serves as the initial trigger for the immunological cascade. This cascade first leads to silicosis and subsequently increases the susceptibility to autoimmune diseases [22▪]

Given that the histopathological onset of silicosis has no radiological signs there is a delay between histopathological onset and radiologically visible lesions. Chest X-rays, high-resolution computed tomography and pulmonary function tests, cannot detect the disease until it has significantly progressed [22▪].

For the early detection of pneumoconiosis, deep convolutional diagnosis approaches have been applied to a pneumoconiosis radiograph dataset to obtain high accuracy in pneumoconiosis detection [23]. Support vector machine (SVM)-based computer-aided silicosis diagnosis could recognize silicosis-associated opacity in several candidate regions for the radiologist's reference [24]. Thus, artificial intelligence (AI)-enabled radiology tools stand to fill the need for regulatory compliance in pneumoconiosis screening, while offering a labor-saving solution to physician workflow issues and enhancing patient safety [25].

Potential mechanism and biomarkers useful for early diagnosis have been suggested. Pro- and anti-inflammatory cytokines TNF (tumor necrosis factor-α), IL-1 IL-6, IL-10), CC16 (Clara cell protein), KL-6 (Krebs von den Lungen 6), neopterin and MUC5B gene were discussed as possible markers to bio monitor exposure and early diagnosis in silicosis. All the findings show tremendous potential for early diagnosis of silicosis, CC16 detection by immunochromatography seems the most promising and should be applied to larger groups of subjects to demonstrate on a much wider scale the sensitivity and specificity of the method for future introduction into clinical practice and screening protocols [26▪▪].

TREATMENT

Autoimmune diseases and silicosis share common pathways involving the dysregulation of autophagy, apoptosis, or pyroptosis [27▪,28,29]. Numerous studies have indicated that NLRP3 a cytosolic multiprotein complex plays a central role in the autophagy, apoptosis, or pyroptosis pathways [30–32].

In this context, the regulation of NLERP3 is a promising target for the treatment of both silicosis and silica induced autoimmune diseases.

MCC950 (originally denoted as CP-456773 or cytokine release inhibitory drug-3 [CRID3]) a selective inhibitor of NLRP3, that blocks NLRP3-mediated ASC (apoptosis-associated speck-like protein with a caspase-recruitment domain) oligomerization. Despite demonstrating great target selectivity, MCC950 did not progress in phase II clinical trials for rheumatoid arthritis, as it was shown to increase serum liver enzyme concentrations, contributing to liver toxicity. However, preliminary clinical assessment of next-generation antiNLRP3 molecules is promising, and inhalation of these small molecules, including MCC950, to directly target the lung may further limit systemic toxicity [33▪].

Another study demonstrates that serum protein C4b-binding protein (C4BP) acts as an endogenous inhibitor of the NLRP3 inflammasome signaling pathway by modulating activation of NLRP3 in response to crystalline (monosodium urate, MSU) and silica stimuli. This modulation results in the regulation of IL-1β cytokine secretion. [34].

A recent review summarized the most important NLRP3 inflammasome inhibitors currently under clinical trials. Small-molecule inhibitors of the NLRP3 inflammasome are currently being evaluated in different clinical stages for the treatment of inflammatory and autoimmune diseases. ZYIL1, selnoflast, and Emlenoflast are all derivatives of MCC950 with disclosed structures that have drawn significant interest [35▪▪].

CONCLUSION

Understanding a person's occupational history to silica is an essential aspect for evaluating potential environmental factors that may contribute to autoimmune diseases. This information can inform preventive measures and contribute to a more comprehensive approach to managing and treating these complex conditions.

Occupational health assessments may be conducted to identify and address potential hazards in the workplace. Individuals with autoimmune diseases should receive guidance on strategies to minimize exposure to specific triggers.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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