Occupational Medicine 2014;64:387–390 Advance Access publication 10 June 2014 doi:10.1093/occmed/kqu060
Case report
Systemic lupus erythematosus complicating simple silicosis C. D. Lucas1, N. Amft2 and P. T. Reid3 Department of Respiratory Medicine, University of Edinburgh, Edinburgh EH16 4TJ, UK, 2Department of Rheumatology, Western General Hospital, Edinburgh EH4 2XU, UK, 3Department of Respiratory Medicine, Western General Hospital, Edinburgh EH4 2XU, UK. 1
Abstract
Inhalation of crystalline silica is known to result in silicosis: an irreversible, disabling and potentially fatal occupational lung disease, which is associated with a variety of pulmonary and non-pulmonary complications including autoimmunity. A potential link between silicosis and systemic lupus erythematosus (SLE) is currently recognized only in cases of acute or accelerated silicosis. We report a case of SLE, a disease which usually affects young females, arising in a male former stonemason with simple silicosis. Epidemiological and clinical literature on the association of silica exposure and development of SLE are briefly reviewed. This case report and literature review highlight the link between occupational silica exposure and autoimmune disease including SLE, establishes that even simple silicosis appears linked to development of autoimmunity and emphasizes the importance of an occupational history, especially in male patients who develop SLE.
Key words
Autoimmunity; silica; silicosis; systemic lupus erythematosus.
Introduction
Case report
Inhalation of crystalline silica is known to result in silicosis: an irreversible, disabling and potentially fatal occupational lung disease (Table 1). Crystalline silica is found in substantial quantities in sand, sandstone and granite and often forms a significant proportion of clay, shale and slate. Workers at highest risk of exposure include those involved in mining, construction, masonry and the manufacture of glass and ceramics [1]. The association between silica inhalation and developing connective tissue disease is less well recognized, but an increasing body of experimental and observational literature has drawn attention to the potential role of silica exposure in the subsequent development of several conditions, including systemic sclerosis, rheumatoid arthritis and systemic lupus erythematosus (SLE) [2]. The American Thoracic Society (ATS) recognizes a potential link between silicosis and SLE, although only in cases of acute or accelerated silicosis [2]. Here, we report a case of SLE, a disease which usually affects young females, arising in a male former stonemason with simple silicosis.
A 64-year-old male was initially admitted with pleuritic chest pain and an acute worsening of breathlessness against a background of slowly progressive mild exertional dyspnoea for several years. There was no cough, sputum or haemoptysis. He had a 70 pack year history of cigarette smoking and had undergone coronary artery bypass grafting 8 months previously. He had recently retired and his occupational history included 13 years as a marble mason, working predominantly with marble, granite and slate. He had used no personal protective equipment (PPE), but always cut stone outside. His subsequent employment was as a general stone mason for >30 years, working with a wide variety of stone types. He used PPE intermittently, particularly when cutting or carving stone within confined spaces. There was no personal or family history of tuberculosis or autoimmunity. Examination was unremarkable. Computed tomography (CT) scanning excluded pulmonary embolism but showed bilateral apical nodularity and calcified hilar and mediastinal lymph nodes consistent with simple silicosis (Figure 1).
© The Author 2014. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://occmed.oxfordjournals.org/ at University of California, San Francisco on March 20, 2015
Correspondence to: C. D. Lucas, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK. Tel: +44 (0)131 242 6662; fax: +44 (0)131 242 6578; E-mail: [email protected]
388 OCCUPATIONAL MEDICINE
He was re-admitted 7 months later with 2 weeks of malaise, dyspnoea, fever and polyarthritis with morning stiffness. Examination revealed pyrexia and mild synovitis bilaterally over the wrists, metacarpophalangeal and proximal interphalangeal joints. There was no lymphadenopathy, and cardiovascular, respiratory, abdominal and dermatological examinations were unremarkable. Investigations revealed anaemia (haemoglobin: 109 g/l), leucopaenia and lymphopaenia (3.3 × 109/l and 0.73 × 109/l, respectively). Renal biochemistry was normal, although urinalysis revealed 1+ protein and 2+ blood with a 24 h urine protein of 0.31 g/l. C-reactive protein was elevated at 83 mg/l and erythrocyte sedimentation rate was >100. Autoantibodies revealed antinuclear antibodies >1/640 with homogenous pattern, anti-double-stranded DNA 40.9 (normal 0–15 IU/ml), anti-Ro >100 (normal 0–25 U/ml), anti-RNP >100 (normal 0–25 U/ml), with anti-La, Sm, Scl70, Jo1 negative. Lupus anticoagulant was positive; anti-cardiolipin (IgG) was negative. Cyclic citrullinated peptide and anti-neutrophil cytoplasmic antibody were negative. Echocardiogram revealed good left ventricular systolic function with no evidence of a pericardial effusion. A repeat CT scan of the chest and abdomen showed stable changes of silicosis with new small bilateral pleural effusions, with no radiological evidence of lupus-related interstitial lung disease. SLE was diagnosed, based on the American College of Rheumatology criteria [3] (Table 2) and the patient was started on prednisolone 40 mg/day and azathioprine 50 mg/day (titrated to 200 mg/ day) with a rapid improvement in arthritis.
Discussion The association between silica inhalation and connective tissue disease has been recognized for nearly a century following Bramwell’s description of scleroderma in stonemasons [4]. Later, Caplan noted that the association between rheumatoid arthritis and coal mining was ‘more than coincidental’ [5]. An increasing body of evidence also suggests a link between silicosis and the development of SLE. The population prevalence of SLE is 20–150 cases per 100 000 and typically affects young females. The first description of SLE complicating acute silicosis was reported in four male tombstone sandblasters with acute silicosis [6]. Further case reports have highlighted SLE-associated glomerulonephritis in a male sandblaster and an ex-miner, both with histologically proven silicosis, and two cases of concurrent SLE and silicosis from a cohort of 40 male patients with SLE. These case reports are strengthened by several larger case series reporting an increased prevalence of connective tissue disease and autoimmune abnormalities in people with known silica exposure. A high prevalence (64%) of autoimmune abnormalities was reported in 50 (predominantly female) workers exposed to high levels of silica in a scouring powder factory, with an overall prevalence of SLE in the workforce of 16% [7]. Similarly, high rates of autoimmunity have been described in a series of 15 000 uranium miners, with 28 definite and 15 probable cases of SLE [8], and a series of 583 silicotics revealed 26 cases of connective tissue disease (one
Downloaded from http://occmed.oxfordjournals.org/ at University of California, San Francisco on March 20, 2015
Figure 1. Radiological findings consistent with simple silicosis. (i and ii) Numerous soft tissue pulmonary nodules with an upper lobe predominance are seen (black arrows; maximum intensity projection lung windows on CT scanning). (iii and iv) Mediastinal and hilar lymphadenopathy with calcification (white arrows).
C. D. LUCAS ET AL.: SYSTEMIC LUPUS ERYTHEMATOSUS 389
Table 1. Classification, radiological and clinical manifestations of silicosis Classification Simple silicosis Often long-term exposure to low concentration silica (>10 years)
Accelerated silicosis Higher concentration silica exposure, frequently presents after 5–10 years
Radiological features
Clinical features
Small rounded opacities with an upper lobe dominance Associated calcified hilar and mediastinal lymphadenopathy
Often asymptomatic
Similar to simple silicosis
Dry cough and breathlessness, often progresses more rapidly
Cough and mild breathlessness common
May progress to PMF Diffuse airspace opacification Radiologically similar to pulmonary oedema
Rapid onset and progression of cough, breathlessness and chest tightness Respiratory failure may occur
PMF, progressive massive fibrosis.
Table 2. ACR criteria for classification of SLE ACR criteria for classification of SLE
Definition
Arthritis Renal disease Positive antinuclear antibody Serositis Haematological disorder Photosensitivity Oral ulcers Immunological Neurological Malar rash Discoid rash
>2 Peripheral joints Proteinuria or cellular casts Abnormal titre of ANA Pleuritis or pericarditis Haemolytic anaemia, leucopaenia, lymphopaenia or thrombocytopaenia Abnormal skin reaction to sunlight Often painless Anti-DNA, anti-Sm or antiphospholipid antibodies Seizures or psychosis Erythema over malar eminences Raised erythematous patches
Four or more criteria are consistent with a diagnosis of SLE. ACR, American College of Rheumatology; ANA, antinuclear antibody.
of SLE) [9]. Equally, a high frequency of silica exposure and silicosis has been found in autoimmune disease with 24 patients (five with SLE) out of 764 cases of connective tissue disease having significant silica exposure [10], and a case–control study of 265 patients with SLE noted an increased frequency of silica exposure and estimated that medium-to-high level exposure to silica of any duration was associated with a 3-fold increased risk of SLE. These clinical reports suggest a link between exposure to silica and the development of autoimmune disease including SLE. In the clinical studies, SLE associated with silicosis was clinically and immunologically indistinguishable from idiopathic SLE, except for a male predominance and later age of onset. The male majority almost certainly reflects the prevalence of male workers in workplaces where silica exposure is common; in the report by Sanchez-Roman et al. [7], 90% of subjects with connective tissue disease were female, reflecting the preponderance of females (88%) in the workplace studied. Although the ATS recognizes a potential link between silicosis and SLE, it does so only in acute or accelerated
silicosis [2]. However, this report and others have documented SLE arising in subjects with simple silicosis, suggesting that in simple silicosis a risk of autoimmune disease also exists. This report highlights the link between occupational silica exposure and autoimmune disease including SLE, serves as a reminder that even simple silicosis may be linked to development of autoimmunity and emphasizes the importance of the occupational history, especially in male patients who develop SLE.
Key points
•• Occupational
silica exposure is linked to autoimmune disease, including systemic lupus erythematosus. •• Even simple silicosis appears linked to the development of autoimmune disorders. •• The occupational history is important, especially in older male patients who develop systemic lupus.
Downloaded from http://occmed.oxfordjournals.org/ at University of California, San Francisco on March 20, 2015
Acute silicosis Caused by high concentrations of inhaled silica, presents rapidly (weeks–years)
390 OCCUPATIONAL MEDICINE
References
Downloaded from http://occmed.oxfordjournals.org/ at University of California, San Francisco on March 20, 2015
1. World Health Organization. Silicosis. Hazard Prevention and Control in the Work Environment: Airborne Dust. World Health Organization 1999. http://www.who.int/ occupational_health/publications/airdust/en/ 2. American Thoracic Society Committee of the Scientific Assembly on Environmental and Occupational Health. Adverse effects of crystalline silica exposure. Am J Respir Crit Care Med 1997;155:761–768. 3. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725. 4. Bramwell B. Diffuse scleroderma: its frequency; its occurrence in stonemasons: its treatment by fibrinolysis in elevations of temperature due to fibrinolysis injections. Edinburgh Med J 1914;12:387.
5. Caplan A. Certain unusual radiological appearances in the chest of coal-miners suffering from rheumatoid arthritis. Thorax 1953;8:29–37. 6. Suratt PM, Winn WC Jr, Brody AR, Bolton WK, Giles RD. Acute silicosis in tombstone sandblasters. Am Rev Respir Dis 1977;115:521–529. 7. Sanchez-Roman J, Wichmann I, Salaberri J, Varela JM, Nuñez-Roldan A. Multiple clinical and biological autoimmune manifestations in 50 workers after occupational exposure to silica. Ann Rheum Dis 1993;52:534–538. 8. Conrad K, Mehlhorn J, Lüthke K, Dörner T, Frank KH. Systemic lupus erythematosus after heavy exposure to quartz dust in uranium mines: clinical and serological characteristics. Lupus 1996;5:62–69. 9. Rosenman KD, Moore-Fuller M, Reilly MJ. Connective tissue disease and silicosis. Am J Ind Med 1999;35:375–381. 10. Koeger AC, Lang T, Alcaix D et al. Silica-associated connective tissue disease. A study of 24 cases. Medicine (Baltimore) 1995;74:221–237.
Case report
Systemic lupus erythematosus complicating simple silicosis C. D. Lucas1, N. Amft2 and P. T. Reid3 Department of Respiratory Medicine, University of Edinburgh, Edinburgh EH16 4TJ, UK, 2Department of Rheumatology, Western General Hospital, Edinburgh EH4 2XU, UK, 3Department of Respiratory Medicine, Western General Hospital, Edinburgh EH4 2XU, UK. 1
Abstract
Inhalation of crystalline silica is known to result in silicosis: an irreversible, disabling and potentially fatal occupational lung disease, which is associated with a variety of pulmonary and non-pulmonary complications including autoimmunity. A potential link between silicosis and systemic lupus erythematosus (SLE) is currently recognized only in cases of acute or accelerated silicosis. We report a case of SLE, a disease which usually affects young females, arising in a male former stonemason with simple silicosis. Epidemiological and clinical literature on the association of silica exposure and development of SLE are briefly reviewed. This case report and literature review highlight the link between occupational silica exposure and autoimmune disease including SLE, establishes that even simple silicosis appears linked to development of autoimmunity and emphasizes the importance of an occupational history, especially in male patients who develop SLE.
Key words
Autoimmunity; silica; silicosis; systemic lupus erythematosus.
Introduction
Case report
Inhalation of crystalline silica is known to result in silicosis: an irreversible, disabling and potentially fatal occupational lung disease (Table 1). Crystalline silica is found in substantial quantities in sand, sandstone and granite and often forms a significant proportion of clay, shale and slate. Workers at highest risk of exposure include those involved in mining, construction, masonry and the manufacture of glass and ceramics [1]. The association between silica inhalation and developing connective tissue disease is less well recognized, but an increasing body of experimental and observational literature has drawn attention to the potential role of silica exposure in the subsequent development of several conditions, including systemic sclerosis, rheumatoid arthritis and systemic lupus erythematosus (SLE) [2]. The American Thoracic Society (ATS) recognizes a potential link between silicosis and SLE, although only in cases of acute or accelerated silicosis [2]. Here, we report a case of SLE, a disease which usually affects young females, arising in a male former stonemason with simple silicosis.
A 64-year-old male was initially admitted with pleuritic chest pain and an acute worsening of breathlessness against a background of slowly progressive mild exertional dyspnoea for several years. There was no cough, sputum or haemoptysis. He had a 70 pack year history of cigarette smoking and had undergone coronary artery bypass grafting 8 months previously. He had recently retired and his occupational history included 13 years as a marble mason, working predominantly with marble, granite and slate. He had used no personal protective equipment (PPE), but always cut stone outside. His subsequent employment was as a general stone mason for >30 years, working with a wide variety of stone types. He used PPE intermittently, particularly when cutting or carving stone within confined spaces. There was no personal or family history of tuberculosis or autoimmunity. Examination was unremarkable. Computed tomography (CT) scanning excluded pulmonary embolism but showed bilateral apical nodularity and calcified hilar and mediastinal lymph nodes consistent with simple silicosis (Figure 1).
© The Author 2014. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://occmed.oxfordjournals.org/ at University of California, San Francisco on March 20, 2015
Correspondence to: C. D. Lucas, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK. Tel: +44 (0)131 242 6662; fax: +44 (0)131 242 6578; E-mail: [email protected]
388 OCCUPATIONAL MEDICINE
He was re-admitted 7 months later with 2 weeks of malaise, dyspnoea, fever and polyarthritis with morning stiffness. Examination revealed pyrexia and mild synovitis bilaterally over the wrists, metacarpophalangeal and proximal interphalangeal joints. There was no lymphadenopathy, and cardiovascular, respiratory, abdominal and dermatological examinations were unremarkable. Investigations revealed anaemia (haemoglobin: 109 g/l), leucopaenia and lymphopaenia (3.3 × 109/l and 0.73 × 109/l, respectively). Renal biochemistry was normal, although urinalysis revealed 1+ protein and 2+ blood with a 24 h urine protein of 0.31 g/l. C-reactive protein was elevated at 83 mg/l and erythrocyte sedimentation rate was >100. Autoantibodies revealed antinuclear antibodies >1/640 with homogenous pattern, anti-double-stranded DNA 40.9 (normal 0–15 IU/ml), anti-Ro >100 (normal 0–25 U/ml), anti-RNP >100 (normal 0–25 U/ml), with anti-La, Sm, Scl70, Jo1 negative. Lupus anticoagulant was positive; anti-cardiolipin (IgG) was negative. Cyclic citrullinated peptide and anti-neutrophil cytoplasmic antibody were negative. Echocardiogram revealed good left ventricular systolic function with no evidence of a pericardial effusion. A repeat CT scan of the chest and abdomen showed stable changes of silicosis with new small bilateral pleural effusions, with no radiological evidence of lupus-related interstitial lung disease. SLE was diagnosed, based on the American College of Rheumatology criteria [3] (Table 2) and the patient was started on prednisolone 40 mg/day and azathioprine 50 mg/day (titrated to 200 mg/ day) with a rapid improvement in arthritis.
Discussion The association between silica inhalation and connective tissue disease has been recognized for nearly a century following Bramwell’s description of scleroderma in stonemasons [4]. Later, Caplan noted that the association between rheumatoid arthritis and coal mining was ‘more than coincidental’ [5]. An increasing body of evidence also suggests a link between silicosis and the development of SLE. The population prevalence of SLE is 20–150 cases per 100 000 and typically affects young females. The first description of SLE complicating acute silicosis was reported in four male tombstone sandblasters with acute silicosis [6]. Further case reports have highlighted SLE-associated glomerulonephritis in a male sandblaster and an ex-miner, both with histologically proven silicosis, and two cases of concurrent SLE and silicosis from a cohort of 40 male patients with SLE. These case reports are strengthened by several larger case series reporting an increased prevalence of connective tissue disease and autoimmune abnormalities in people with known silica exposure. A high prevalence (64%) of autoimmune abnormalities was reported in 50 (predominantly female) workers exposed to high levels of silica in a scouring powder factory, with an overall prevalence of SLE in the workforce of 16% [7]. Similarly, high rates of autoimmunity have been described in a series of 15 000 uranium miners, with 28 definite and 15 probable cases of SLE [8], and a series of 583 silicotics revealed 26 cases of connective tissue disease (one
Downloaded from http://occmed.oxfordjournals.org/ at University of California, San Francisco on March 20, 2015
Figure 1. Radiological findings consistent with simple silicosis. (i and ii) Numerous soft tissue pulmonary nodules with an upper lobe predominance are seen (black arrows; maximum intensity projection lung windows on CT scanning). (iii and iv) Mediastinal and hilar lymphadenopathy with calcification (white arrows).
C. D. LUCAS ET AL.: SYSTEMIC LUPUS ERYTHEMATOSUS 389
Table 1. Classification, radiological and clinical manifestations of silicosis Classification Simple silicosis Often long-term exposure to low concentration silica (>10 years)
Accelerated silicosis Higher concentration silica exposure, frequently presents after 5–10 years
Radiological features
Clinical features
Small rounded opacities with an upper lobe dominance Associated calcified hilar and mediastinal lymphadenopathy
Often asymptomatic
Similar to simple silicosis
Dry cough and breathlessness, often progresses more rapidly
Cough and mild breathlessness common
May progress to PMF Diffuse airspace opacification Radiologically similar to pulmonary oedema
Rapid onset and progression of cough, breathlessness and chest tightness Respiratory failure may occur
PMF, progressive massive fibrosis.
Table 2. ACR criteria for classification of SLE ACR criteria for classification of SLE
Definition
Arthritis Renal disease Positive antinuclear antibody Serositis Haematological disorder Photosensitivity Oral ulcers Immunological Neurological Malar rash Discoid rash
>2 Peripheral joints Proteinuria or cellular casts Abnormal titre of ANA Pleuritis or pericarditis Haemolytic anaemia, leucopaenia, lymphopaenia or thrombocytopaenia Abnormal skin reaction to sunlight Often painless Anti-DNA, anti-Sm or antiphospholipid antibodies Seizures or psychosis Erythema over malar eminences Raised erythematous patches
Four or more criteria are consistent with a diagnosis of SLE. ACR, American College of Rheumatology; ANA, antinuclear antibody.
of SLE) [9]. Equally, a high frequency of silica exposure and silicosis has been found in autoimmune disease with 24 patients (five with SLE) out of 764 cases of connective tissue disease having significant silica exposure [10], and a case–control study of 265 patients with SLE noted an increased frequency of silica exposure and estimated that medium-to-high level exposure to silica of any duration was associated with a 3-fold increased risk of SLE. These clinical reports suggest a link between exposure to silica and the development of autoimmune disease including SLE. In the clinical studies, SLE associated with silicosis was clinically and immunologically indistinguishable from idiopathic SLE, except for a male predominance and later age of onset. The male majority almost certainly reflects the prevalence of male workers in workplaces where silica exposure is common; in the report by Sanchez-Roman et al. [7], 90% of subjects with connective tissue disease were female, reflecting the preponderance of females (88%) in the workplace studied. Although the ATS recognizes a potential link between silicosis and SLE, it does so only in acute or accelerated
silicosis [2]. However, this report and others have documented SLE arising in subjects with simple silicosis, suggesting that in simple silicosis a risk of autoimmune disease also exists. This report highlights the link between occupational silica exposure and autoimmune disease including SLE, serves as a reminder that even simple silicosis may be linked to development of autoimmunity and emphasizes the importance of the occupational history, especially in male patients who develop SLE.
Key points
•• Occupational
silica exposure is linked to autoimmune disease, including systemic lupus erythematosus. •• Even simple silicosis appears linked to the development of autoimmune disorders. •• The occupational history is important, especially in older male patients who develop systemic lupus.
Downloaded from http://occmed.oxfordjournals.org/ at University of California, San Francisco on March 20, 2015
Acute silicosis Caused by high concentrations of inhaled silica, presents rapidly (weeks–years)
390 OCCUPATIONAL MEDICINE
References
Downloaded from http://occmed.oxfordjournals.org/ at University of California, San Francisco on March 20, 2015
1. World Health Organization. Silicosis. Hazard Prevention and Control in the Work Environment: Airborne Dust. World Health Organization 1999. http://www.who.int/ occupational_health/publications/airdust/en/ 2. American Thoracic Society Committee of the Scientific Assembly on Environmental and Occupational Health. Adverse effects of crystalline silica exposure. Am J Respir Crit Care Med 1997;155:761–768. 3. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725. 4. Bramwell B. Diffuse scleroderma: its frequency; its occurrence in stonemasons: its treatment by fibrinolysis in elevations of temperature due to fibrinolysis injections. Edinburgh Med J 1914;12:387.
5. Caplan A. Certain unusual radiological appearances in the chest of coal-miners suffering from rheumatoid arthritis. Thorax 1953;8:29–37. 6. Suratt PM, Winn WC Jr, Brody AR, Bolton WK, Giles RD. Acute silicosis in tombstone sandblasters. Am Rev Respir Dis 1977;115:521–529. 7. Sanchez-Roman J, Wichmann I, Salaberri J, Varela JM, Nuñez-Roldan A. Multiple clinical and biological autoimmune manifestations in 50 workers after occupational exposure to silica. Ann Rheum Dis 1993;52:534–538. 8. Conrad K, Mehlhorn J, Lüthke K, Dörner T, Frank KH. Systemic lupus erythematosus after heavy exposure to quartz dust in uranium mines: clinical and serological characteristics. Lupus 1996;5:62–69. 9. Rosenman KD, Moore-Fuller M, Reilly MJ. Connective tissue disease and silicosis. Am J Ind Med 1999;35:375–381. 10. Koeger AC, Lang T, Alcaix D et al. Silica-associated connective tissue disease. A study of 24 cases. Medicine (Baltimore) 1995;74:221–237.
