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Silica-induced scleroderma
Silica-induced scleroderma Uwe-F. Haustein, MD,a Volker Ziegler, MD,a Konrad Herrmann, MD,a Jurgen Mehlhorn, MD,b and Claudia Schmidt, MDa Leipzig and Niederdorf, German Democratic Republic In a survey done in EastGermany between 1981 and 1988, wefound that 93 of 120male scleroderma patients hadlong-term exposure to silica dust. We describe ourfindings in 12 patients with scleroderma andsilicosis. Theexposure time to silica dust was between 3 and 34 years; theinterval between thebeginning ofexposure andthe onset ofscleroderma averaged 27.3 years (range 9 to40years). Antinuclear antibodies intiters between 80and 10,240 with nucleolar and/orspeckled patterns were found in 10patients, antibodies against double-stranded DNA in three, Scl-70 (topoisomerase I) in three, and anticentromere, antibodies infive. Thefollowing markers ofcollagen metabolism were increased in serum: f3-galactosidase in 12patients, laminin peptide-PI in 10patients, Nsterminal procollagen type III peptide in 10, and urinary sialic acid excretion in 7. We propose that crystalline particles of silica less than 5 JLm may be phagocytosed by macrophages and release lymphokines and monokines, which activate fibroblasts and enhance their collagen and glycosaminoglycan synthesis. In addition, silica may act as an adjuvant to increase immune reactivity. (J AM ACAD DERMATOL 1990;22:444-8.) Several environmental hazards have been reported as predisposing or eliciting factorsfor scleroderma-like disorders, 1-4 These include vinyl chloride, polymerizing epoxy resins, organic solvents, carbidopa, metaphenylenediamine, bleomycin, pentazocine, penicillamine, silicon, paraffin, rapeseed oil, and silica. 3,5, 6 Except for silica, however, all other substances induce changes that only mimic scleroderma andthat should be classified as "scleroderma-like" disorders, which are partly reversible after exposure is discontinued.' In 1914 Bramwell'? first reported"diffuse"scleroderma in nine patients, five of whomwere stonemasons. Erasmus'' observed 17gold minersin South Africa with scleroderma, but silicosis was found in lessthan half these cases. Additional casesweredescribed by Sluis-Cremer et a1. 9 in white miners in 1985 and by Cowie'? in black minersin 1987. Not all patients with scleroderma had silicosis, but all had been occupationally exposed to silica dust.
From the Department of Dermatology, School of Medicine, Karl MarxUniversity, Leipzig,' andtheCenterofOccupational Hygiene, Niederdorf,"
Accepted for publication May 5, 1989. Reprint requests: Prof. Dr. Uwe-F. Haustein, Department of Dermatology, School of Medicine, Liebigstr, 21, 7010 Leipzig, GDR. 16/1/13764
444
Rodnan et a1. 11 in 1967 observed an association with silicosis in 8 of 60 patients with scleroderma. Thirty-six had been exposed to silica dust in coal mines or foundries. In 1970 Gunther and Schuchardt'< reported 49 cases of silicosis associated with scleroderma. In East Germany Beck et al.13 reported several casesin 1976. In 1982Ziegleret a1.I 4 performed an epidemiologic and clinical survey of patients with scleroderma throughout the country. They found that 77%of male scleroderma patients had beenexposed to silicadust andthat 50%of them had silicosis. We now have collected 120 such patients, 93 of whomhad silicadust exposure and 49 of whomhad silicosis. 15 On the basisof thesedata, we calculatedthat the likelihood for the development of scleroderma in male silicosis patients older than 40 years of age is approximately 190 times higher than in men without silicosis and approximately 50 times higher in persons exposed to silica dust than in the nonexposed male population. All patientsin whom such an association wassuspectedwerereexamined clinically; ifreexamination was not possible, hospitalnotes or autopsy findings werereviewed. 16 Duringthe last 2 years we haveinvestigated 12patientswithscleroderma and silicosis. In this report wedescribe the clinical and laboratory findings in these patients.
Volume 22 Number 3 March 1990
Silica-induced scleroderma 445
MATERIAL AND METHODS
Allpatients were assessed according to theAmerican Rheumatism Association's criteria for systemic sclerosis (scleroderma),17. 18 and occupational histories were obtained. Thepatients were classified into three subsets'8. 19: Type I: Type II:
Acrosclerosis-sclerodactyly of fingers
and/ortoes
Extremity ascending form-sclerosis of
extremities proximal to fingers and to the face Type III: Diffuse form-sclerosis ofthe trunk. specimens were obtained in 10 patients. Electrocardiography; electromyography; pulmonary function tests; esophagus manometry; sonography; scintigraphy, andx-ray studies ofthejoints, chest, esophagus and gastrointestinal tract were performed. Laboratory tests to evaluate immunologic activity (blood sedimentation rate; presence and/or levels of C-reactive protein, rheumatoid factor, IgG and IgM in serum, circulating immune complexes in serum, antinuclear antibodies; presence of antibodies to double-stranded DNA with Crithidia luciliae, to Scl-70 by immunoblotting, and to centromere with HEp-2 cells) were performed. Alterations inconnective tissue metabolism (levels of.a-galactosidase, laminin peptide-PI, and N-terminal procollagen type III-peptide inserum, and excretion ofsialic acid in the urine) were also determined. Skin biopsy
RESULTS
The clinical data are listed in Table I. Seven patients had scleroderma type I, three had typeII, and two had type III. This distribution corresponds to that of idiopathic scleroderma. Skin biopsy specimens showed changes characteristic of scleroderma. The results of ourlaboratorychemical studies are shown in Table II. Increase in serum iJ-galactosidase,lamininpeptide-PI, and N-terminal procollagen type III peptide, as markers of collagen metabolism, were present in all patients. The amount of sialicacidexcreted in the urinewasincreased in 7 of 11 patients. DISCUSSION
Our clinical and laboratorydata show that silicainduced scleroderma in our patients corresponds to idiopathicscleroderma, according to the American Rheumatism Association's criteria. The incidence and significance of antibodies against various nuclear antigens,2°,21 immune complexes.P iJgalactosidase.P N-procollagen peptide,2o laminin peptide-Pl.P and urinary levels of sialic acidexcre-
_____SiOZ _____ Skin----- Vessels---- lung I I ~
IL 1
THelper
1~ ~es~ ~ I::::===='::~~rwMAF IlL 1
I
ILL 1 Fibroblasts
I
lu I
Increased collagen production With SCierOS is of invrlved organs
I
Scleroderma
\\:lscular Occlusion
I
BCeU-Sli I1Ualion
I
Immunphenomeoo
Silicosis Lung fibrosis
MAF: fl'Jacroprage activating foetor
Fig. 1. Pathogenesis ofsilica-induced scleroderma.
tion(analogous to hexuronic acid)24 werecomparabletothoseobserved inidiopathic scleroderma'" and to someextentweremarkers of the disease's activity. In addition, as previously reported in a cooperative study, the serum of our patients inhibited the release of prostacyclin 12 from endothelial cell culturestothe samedegree asserum frompatients with idiopathic scleroderma.25 Crystalline silica (a quartz) isthe majorcause of silicosis. Silica polymorphs such as cristobalite and tridymiteprobably playa minor role. Quartzparticles varywidely in size, but those less than 1 Jim are the most pathogenlc-" In silicosis theseparticles are phagocytosed by macrophages and are transported to the regional lymph nodes. Depending on theparticle size, cell plasma membranes and phagosome membranes canbedestabilized. Thisdestabilization provokes the generation offreeoxygen radicals and the release ofacidlysosomal hydrolases and neutral proteases.27,28 In both scleroderma and silicosis, fibrogenic proteins and growth factors such as interleukin 1 (ILl), platelet-derived growth factor, iJ-transforming growth factor, and fibronectin are generated. 29,30 On the otherhand, the occurrence of hypergammaglobulinemia, rheumatoid factor, antinuclear factors, and immune complexes is indicative of a nonspecific polyclonal stimulation of the humoral immune system. 31,32 Thus the ill-defined adjuvant disease (unclassified), withthe development ofrheumatoid polyarthritis-like, mixed connective.tissue disease, systemic lupus erythematosus, Sjogren's syndrome, polymyositis, and fibrositis, may be elicited by silica. 5,33-35 Recently, scleroderma-like illness has been described after augmentation mammaplasty with silicone implants. 34-38 Leakage of sil-
Journal of the American Academy of Dermatology
446 H .austein et al. Table I. Clinical data on patients with scleroderma and silicosis
Patient No.
1 2 3 4 5 6
7
8 9
10 11
12 Average
Age (yr)
57 71 59 62 57 56 58 40 58 57 63 64 58.5
Time to manifestation (yr)
Silica exposure (yr)
Occupation
Hewer Hewer Hewer Hewer Drawer and hauler Geophysicist Hewer Stove fitter Hewer Hewer Hewer Hewer
Duration of disease (yr)
18 30 22 40 15 34 25 9 32 33 35 34 27.3
6 6
11
3 30 6 14 11
34 11
3 33 14
Subset type
I I I I I III II I II III
19 10 19 2
18 2 14 3 6 7 6 7 9.4
I II
*Mainlyesophagus.
Table II. Laboratory findings of patients with scleroderma and silicosis BSR Patient No.
(mm/ hr)
1 2 3 4 5 6 7 8 9 10
3/6 22/50 28/54 25/48 4/14 48/83 3/8 2/4 20/39 20/32 42/84 18/44
11
12 Normal value ± SD
CRP
+ +
Rheumatoid factor
Immune complexes
IgG
IgM
(gm/L)
(gm/L)
(gm/ L)
0.90 ND 1.35 2.55 1.15 4.50 0.90 4.60 ND 0.45 4.60 5.60 2.2-4.7
16.00 1.90 ND ND 13.70 2.61 38.00 1.18 34.40 1.53 35.00 2.34 20.60 1.60 9.80 3.42 ND ND 25.00 1.16 12.80 1.60 29.80 3.40 9-15 0.7-2.8
+ +
+ +
+ + +
+ + +
ANA Titer
1:80 1:1280 1:100 1:80 Neg. 1:512 Neg. 1:320 1:10240 1:640 1:5120 1:80
I
Pattern
Nucleolar Speckled Nucleolar, speckled Speckled Nucleolar Speckled Nucleolar Nucleolar Nucleolar, speckled N ucleolar, speckled
BSR. Bloodsedimentation rate; CRP, C-reactiveprotein; ds-DN A, double-stranded DNA; {3-gal. {3-galactosidase; N D, not done.
icone (dimethylpolysiloxane) into lymphoid tissue has been confirmed by the demonstration of silicon in the macrophage inclusions. Whether silica is released from silicon is still unknown. In patients with occupational scleroderma, we have found, by phase contrast and polarizing microscopy,silica particles between 1 and 20 ,urn in the skin ofthe arms. This findingindicates that silicacan
penetrate the skin of heavily exposed areas . Silica is phagocytosed by macrophages that release IL-l. 39 IL- ~ also acts on helper T cells that liberate IL-2. IL- 2 may stimulate B cells that are responsible for the immunoglobulin production . Activated T cells may also produce other lymphokines (e.g., macrophage activating factor) that are able to stimulate macrophages and fibroblasts; such stimulation
Volume 22 Number 3 March 1990
Silica-induced scleroderma 447
Organinvolvement Lung Raynaud's phenomenon
Joints
+ + + + + + + + + +
+ + + + + + + + + + +
+
GI tract*
+ + + +
+ +
+
+ + +
Silicosis
+ + + + + + + + + + + +
Fibrotic signs
Heart
+ + + +
+ + +
I
Anti-ScI-70
Anti-Centromere
+
+
+
+ +
+ +
+
+
+
+ + +
Peptldes
ND
+
Kidney
+
+ + +
Antibodies Anti-ds-DNA
Muscle
+ +
p-gal (nmol/sec . L)
17.40 16.80 19.20 15.60 18.00 24.00 9.60 10.80 13.50 30.00 13.50 18.20 7.0 ± 2.0
establishes a chronic cycle that is triggered by silica. Silica is chemically inert, cannot be digested, and remains in the tissue. In addition, it is toxicto macrophages in a dose-dependent manner. After the death of macrophages, silicais again exposed for ingestion and the phagocytotic process starts again. Thus fibroblasts are permanently stimulated by Iymphokines and monokines, which enhance
Laminin p.] (kat/mI)
2.06
ND
I
ProcoUagen 1U (ng/mI)
Sialic acid (nmol/L)
55.0
2.20 2.35 6.40 2.60 2.20 3.90 2.20 6.20
ND
2.10 2.93 1.63 2.84 2.71 1.61 2.46 2.62
62.7 87.0 ·47.8 168.1 145.7 62.8 82.5 73.4
2.51 1.42 ± 0.19
74.3 38.4 ± 14.2
ND
ND
ND
2.80 3.80 1.90 2.00 ± 0.3 nmol
their collagen, fibronectin, and glycosaminoglycan synthesis l , 19, 40 and/or act as an adjuvant in increasing immune reactivity. 41 The pathomechanism of silica-induced scleroderma is shown in Fig. 1.5 In East Germanyscleroderma has beenacknowledged since1979 as an occupational disease notonly in cases with associated silicosis but also in cases in which silicaexposure had beendeemed longenough
448 H austein et al.
to causesilicosis, even ifclinical silicosis had not yet occurred.f REFERENCES 1. Haustein UF, Herrmann K, Bohme H1. Pathogenesis of progressive systemic sclerosis. Int J DermatoI1986;25:28693. 2. BlackC, Pereira S, McWhirter A, et al. Genetic susceptibility to scleroderma-like syndrome in symptomatic and asymptomatic workers exposed to vinyl chloride. J RheumatoI1986;13:1059-62. 3. Haustein UF, Ziegler Y. Environmentally induced systemicsclerosis-like disorders. Int J DermatoI1985;24:14751. 4. Bernstein R, Prinsloo I, Zwi S. Chromosomal aberrations in occupation-associated progressive systemic sclerosis. South Afr Med J 1980;58:235-7. 5. Ziegler Y, Kipping D, Herrmann K, et al. Quarz: seine Relevanz fiir die Dermatologie. Derm Beruf Umwelt 1987;35:199-204. 6. Owens GR, MedsgerTA. Systemic sclerosis secondary to occupational exposure. Am J Med 1988;85:114-6. 7. Bramwell B. Diffuse scleroderma: its frequency, its occurrencein stonemasons, its treatment by fibrinolysin, elevation of temperature due to fibrinolysin injections. Edinburgh Med J 1914;12:387-401. 8. ErasmusLD. Scleroderma in gold-miners on the Witwadersrandwithparticularreference to pulmonary manifestations. South Afr J Labor Clin Med 1957;3:209-31. 9. Sluis-Crerner GK, Hessel PA, HnizdoE, et al. Silica, silicosis and progressive systemic sclerosis. Br J Ind Med 1985;42:838-43. 10. Cowie RL. Silica dust-exposed mineworkers withscleroderma (systemic sclerosis). Chest 1987;92:260-2. 11. RodnanGP, BenedekTG, MedsgerTA, et al.The association of progressive systemic sclerosis (scleroderma) with coalminerpneumoconiosis and otherforms ofsilicosis. Ann Intern Med 1967;66:323-34. 12. GuntherG, SchuchardtE.Silikose undprogressive Sklerodermie. Dtsch Moo Wochenschr 1970;95:467-8. 13. BeckB, IrmscherG, Zschunke E. Silikose und Sklerodermie: Versuch einer Synopsis. Z Gesamte Inn Med 1976; 31:493-96. 14. Ziegler Y, Pampel W, Zschunke E, Kristalliner Quarz: (eine) Ursache der progressiven Sklerodermie? Dermatol Monatsschr 1982;168:398-401. 15. Zschunke E, Ziegler Y, Haustein UFo Occupationallyinduced connective tissuedisorders. In: AdamRA, ed. Occupational skin disease. 2nd ed, Orlando: Grune & Stratton, 1989. 16. Ziegler Y, Haustein UF, Mehlhorn J, Quarzinduzierte Sklerodermie, Sklerodermie-ahnliches Syndrom oderechte progressive Sklerodermie? Dermatol Monatsschr 1986; 172:86-90. 17. MasiAT, RodnanGP, Medsger TA, et al. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581-90. 18. Masi AT. Classification of systemic sclerosis (scleroderrna):relationship ofcutaneous subgroups inearlydisease to outcome and serologic reactivity. J Rheumatol 1988;15: 894-8. 19. Krieg T, Meurer M. Systemic scleroderma: clinical and pathophysiologic aspects. J AM ACAD DERMATOL 1988; 18:457-81. 20. Haustein UF, Herrmann K. Pathogenetische, diagnostische und therapeutische Gesichtspunkte der progressiven Sklerodermie. Z Klin Med (In press.)
Journal of the American Academy of Dermatology 21. Reimer G. Zellkernantigene bei systemischen Autoimmunkrankheiten: Molekulare Charakteristika und klinische Bedeutung. Zbl Hautkr 1987;153:789-800. 22. Herrmann K, Haustein UF, Lohrisch I. Immunkomplexe bei der progressiven Sklerodermie. Dermatol Monatsschr 1982;168:531-4. 23. Herrmann K, HausteinUF, Bohme HJ, Acid lysosomal hydrolases in systemic sclerosis and other connective tissue disease. Br J Dermatol 1982;106:523-8. 24. Herrmann K, Schinagl A, Schinagl G. Glykosaminoglykanebeiderprogressiven Sklerodermie. Dermatol Monatsschr 1982;168:761-5. 25. RustinMHA, Bull HA, Ziegler Y, et al.Serologic abnormalities and clinical features of silica-associated systemic sclerosis [Abstract]. J Invest DermatoI1988;91:403. 26. Reiser KM, Last JA. Silicosis and fibrogenesis: fact and artifact. Toxicology 1979;13:51-72. 27. Goodglick LA, Kane AB. Roleof reactive oxygen metabolites in crocidolite asbestos toxicity to mouse macrophages. Cancer Res 1986;46:5558-66. 28. KaneAB,StantonRP, Raymond EG,etat.Dissociation of intracellular lysosomal rupturefrom the cell death caused by silica. J Cell BioI 1980;87:643-51. 29. Schmidt JA, Oliver CN, Lepe-Zuniga JL, et al. Silicastimulated monocytes release fibroblast proliferation factorsidentical to interleukin 1:a potential rolefor interleukin 1 in the pathogenesis of silicosis. J Clin Invest 1984;73:1462-72. 30. GritterHL, Adamson YI, KingGM. Modulation of'fibroblast activity by normal and silica-exposed alveolar macrophages. J PathoI1986;148:263-71. 31. Miller SD, Zarkower A. Silica-induced alterations of murinelymphocyte immunocompetence andsuppression of B lymphocyte immunocompetence: a possible mechanism. J Reticuloendothel Soc 1976;19:47-61. 32. Youinou P, FerecC, Cledes J, et al. Immunological effect of silica dust analyzed by monoclonal antibodies. J Clin ImmunoI1985;16:207-10. 33. Ebihara I. Clinical study on immunologic abnormalities and autoimmune diseases associated with pneumoconiosis. J Sci Labor 1982;58:329-41. 34. Kumagai Y, Shiokawa Y, Medsger TA Jr, et al. Clinical spectrum of connective tissue disease after cosmetic surgery. Arthritis Rheum 1984;27:1-12. 35. Sergott TJ, Limoli JP, Baldwin CM Jr, et al. Human adjuvant disease, possible autoimmune disease after silicone implantation: a review of the literature, case studies and speculation for the future. Plast Reconstr Surg 1986;78: 104-14. 36. SpieraH. Scleroderma after silicone augmentation mammoplasty. JAMA 1988;260:236-8. 37. Brozena SJ, Fenske NA, CruseCW,et al.Humanadjuvant disease following augmentation mammoplasty. Arch DermatoI1988;124:1383-6. 38. Kaiser W, Biesenbach G, Zazgornik 1. AutoimmunphanomenenachSilikonimplantation. DtschMed Wochenschr 1987;112:1376-9. 39. Heppleston AG, StylesFS.Activity of a macrophage factor in collagen formation bysilica. Nature 1967;214:521-2. 40. Fleischmajer R, Perlish JS, Duncan M. Scleroderma: a model for fibrosis. Arch DermatoI1983;119:957-62. 41. StalderK,Schrader R. Quarzstaub alsAdjuvans beimEntstehen einer zellvermittelten Immunitat, Naturwissenschaften 1980;67:569. 42. Mehlhorn 1. Sklerodermie auchohneSilikose eineBK? Z Erkr Atmungsorgane 1984;163:65-9.
From the Department of Dermatology, School of Medicine, Karl MarxUniversity, Leipzig,' andtheCenterofOccupational Hygiene, Niederdorf,"
Accepted for publication May 5, 1989. Reprint requests: Prof. Dr. Uwe-F. Haustein, Department of Dermatology, School of Medicine, Liebigstr, 21, 7010 Leipzig, GDR. 16/1/13764
444
Rodnan et a1. 11 in 1967 observed an association with silicosis in 8 of 60 patients with scleroderma. Thirty-six had been exposed to silica dust in coal mines or foundries. In 1970 Gunther and Schuchardt'< reported 49 cases of silicosis associated with scleroderma. In East Germany Beck et al.13 reported several casesin 1976. In 1982Ziegleret a1.I 4 performed an epidemiologic and clinical survey of patients with scleroderma throughout the country. They found that 77%of male scleroderma patients had beenexposed to silicadust andthat 50%of them had silicosis. We now have collected 120 such patients, 93 of whomhad silicadust exposure and 49 of whomhad silicosis. 15 On the basisof thesedata, we calculatedthat the likelihood for the development of scleroderma in male silicosis patients older than 40 years of age is approximately 190 times higher than in men without silicosis and approximately 50 times higher in persons exposed to silica dust than in the nonexposed male population. All patientsin whom such an association wassuspectedwerereexamined clinically; ifreexamination was not possible, hospitalnotes or autopsy findings werereviewed. 16 Duringthe last 2 years we haveinvestigated 12patientswithscleroderma and silicosis. In this report wedescribe the clinical and laboratory findings in these patients.
Volume 22 Number 3 March 1990
Silica-induced scleroderma 445
MATERIAL AND METHODS
Allpatients were assessed according to theAmerican Rheumatism Association's criteria for systemic sclerosis (scleroderma),17. 18 and occupational histories were obtained. Thepatients were classified into three subsets'8. 19: Type I: Type II:
Acrosclerosis-sclerodactyly of fingers
and/ortoes
Extremity ascending form-sclerosis of
extremities proximal to fingers and to the face Type III: Diffuse form-sclerosis ofthe trunk. specimens were obtained in 10 patients. Electrocardiography; electromyography; pulmonary function tests; esophagus manometry; sonography; scintigraphy, andx-ray studies ofthejoints, chest, esophagus and gastrointestinal tract were performed. Laboratory tests to evaluate immunologic activity (blood sedimentation rate; presence and/or levels of C-reactive protein, rheumatoid factor, IgG and IgM in serum, circulating immune complexes in serum, antinuclear antibodies; presence of antibodies to double-stranded DNA with Crithidia luciliae, to Scl-70 by immunoblotting, and to centromere with HEp-2 cells) were performed. Alterations inconnective tissue metabolism (levels of.a-galactosidase, laminin peptide-PI, and N-terminal procollagen type III-peptide inserum, and excretion ofsialic acid in the urine) were also determined. Skin biopsy
RESULTS
The clinical data are listed in Table I. Seven patients had scleroderma type I, three had typeII, and two had type III. This distribution corresponds to that of idiopathic scleroderma. Skin biopsy specimens showed changes characteristic of scleroderma. The results of ourlaboratorychemical studies are shown in Table II. Increase in serum iJ-galactosidase,lamininpeptide-PI, and N-terminal procollagen type III peptide, as markers of collagen metabolism, were present in all patients. The amount of sialicacidexcreted in the urinewasincreased in 7 of 11 patients. DISCUSSION
Our clinical and laboratorydata show that silicainduced scleroderma in our patients corresponds to idiopathicscleroderma, according to the American Rheumatism Association's criteria. The incidence and significance of antibodies against various nuclear antigens,2°,21 immune complexes.P iJgalactosidase.P N-procollagen peptide,2o laminin peptide-Pl.P and urinary levels of sialic acidexcre-
_____SiOZ _____ Skin----- Vessels---- lung I I ~
IL 1
THelper
1~ ~es~ ~ I::::===='::~~rwMAF IlL 1
I
ILL 1 Fibroblasts
I
lu I
Increased collagen production With SCierOS is of invrlved organs
I
Scleroderma
\\:lscular Occlusion
I
BCeU-Sli I1Ualion
I
Immunphenomeoo
Silicosis Lung fibrosis
MAF: fl'Jacroprage activating foetor
Fig. 1. Pathogenesis ofsilica-induced scleroderma.
tion(analogous to hexuronic acid)24 werecomparabletothoseobserved inidiopathic scleroderma'" and to someextentweremarkers of the disease's activity. In addition, as previously reported in a cooperative study, the serum of our patients inhibited the release of prostacyclin 12 from endothelial cell culturestothe samedegree asserum frompatients with idiopathic scleroderma.25 Crystalline silica (a quartz) isthe majorcause of silicosis. Silica polymorphs such as cristobalite and tridymiteprobably playa minor role. Quartzparticles varywidely in size, but those less than 1 Jim are the most pathogenlc-" In silicosis theseparticles are phagocytosed by macrophages and are transported to the regional lymph nodes. Depending on theparticle size, cell plasma membranes and phagosome membranes canbedestabilized. Thisdestabilization provokes the generation offreeoxygen radicals and the release ofacidlysosomal hydrolases and neutral proteases.27,28 In both scleroderma and silicosis, fibrogenic proteins and growth factors such as interleukin 1 (ILl), platelet-derived growth factor, iJ-transforming growth factor, and fibronectin are generated. 29,30 On the otherhand, the occurrence of hypergammaglobulinemia, rheumatoid factor, antinuclear factors, and immune complexes is indicative of a nonspecific polyclonal stimulation of the humoral immune system. 31,32 Thus the ill-defined adjuvant disease (unclassified), withthe development ofrheumatoid polyarthritis-like, mixed connective.tissue disease, systemic lupus erythematosus, Sjogren's syndrome, polymyositis, and fibrositis, may be elicited by silica. 5,33-35 Recently, scleroderma-like illness has been described after augmentation mammaplasty with silicone implants. 34-38 Leakage of sil-
Journal of the American Academy of Dermatology
446 H .austein et al. Table I. Clinical data on patients with scleroderma and silicosis
Patient No.
1 2 3 4 5 6
7
8 9
10 11
12 Average
Age (yr)
57 71 59 62 57 56 58 40 58 57 63 64 58.5
Time to manifestation (yr)
Silica exposure (yr)
Occupation
Hewer Hewer Hewer Hewer Drawer and hauler Geophysicist Hewer Stove fitter Hewer Hewer Hewer Hewer
Duration of disease (yr)
18 30 22 40 15 34 25 9 32 33 35 34 27.3
6 6
11
3 30 6 14 11
34 11
3 33 14
Subset type
I I I I I III II I II III
19 10 19 2
18 2 14 3 6 7 6 7 9.4
I II
*Mainlyesophagus.
Table II. Laboratory findings of patients with scleroderma and silicosis BSR Patient No.
(mm/ hr)
1 2 3 4 5 6 7 8 9 10
3/6 22/50 28/54 25/48 4/14 48/83 3/8 2/4 20/39 20/32 42/84 18/44
11
12 Normal value ± SD
CRP
+ +
Rheumatoid factor
Immune complexes
IgG
IgM
(gm/L)
(gm/L)
(gm/ L)
0.90 ND 1.35 2.55 1.15 4.50 0.90 4.60 ND 0.45 4.60 5.60 2.2-4.7
16.00 1.90 ND ND 13.70 2.61 38.00 1.18 34.40 1.53 35.00 2.34 20.60 1.60 9.80 3.42 ND ND 25.00 1.16 12.80 1.60 29.80 3.40 9-15 0.7-2.8
+ +
+ +
+ + +
+ + +
ANA Titer
1:80 1:1280 1:100 1:80 Neg. 1:512 Neg. 1:320 1:10240 1:640 1:5120 1:80
I
Pattern
Nucleolar Speckled Nucleolar, speckled Speckled Nucleolar Speckled Nucleolar Nucleolar Nucleolar, speckled N ucleolar, speckled
BSR. Bloodsedimentation rate; CRP, C-reactiveprotein; ds-DN A, double-stranded DNA; {3-gal. {3-galactosidase; N D, not done.
icone (dimethylpolysiloxane) into lymphoid tissue has been confirmed by the demonstration of silicon in the macrophage inclusions. Whether silica is released from silicon is still unknown. In patients with occupational scleroderma, we have found, by phase contrast and polarizing microscopy,silica particles between 1 and 20 ,urn in the skin ofthe arms. This findingindicates that silicacan
penetrate the skin of heavily exposed areas . Silica is phagocytosed by macrophages that release IL-l. 39 IL- ~ also acts on helper T cells that liberate IL-2. IL- 2 may stimulate B cells that are responsible for the immunoglobulin production . Activated T cells may also produce other lymphokines (e.g., macrophage activating factor) that are able to stimulate macrophages and fibroblasts; such stimulation
Volume 22 Number 3 March 1990
Silica-induced scleroderma 447
Organinvolvement Lung Raynaud's phenomenon
Joints
+ + + + + + + + + +
+ + + + + + + + + + +
+
GI tract*
+ + + +
+ +
+
+ + +
Silicosis
+ + + + + + + + + + + +
Fibrotic signs
Heart
+ + + +
+ + +
I
Anti-ScI-70
Anti-Centromere
+
+
+
+ +
+ +
+
+
+
+ + +
Peptldes
ND
+
Kidney
+
+ + +
Antibodies Anti-ds-DNA
Muscle
+ +
p-gal (nmol/sec . L)
17.40 16.80 19.20 15.60 18.00 24.00 9.60 10.80 13.50 30.00 13.50 18.20 7.0 ± 2.0
establishes a chronic cycle that is triggered by silica. Silica is chemically inert, cannot be digested, and remains in the tissue. In addition, it is toxicto macrophages in a dose-dependent manner. After the death of macrophages, silicais again exposed for ingestion and the phagocytotic process starts again. Thus fibroblasts are permanently stimulated by Iymphokines and monokines, which enhance
Laminin p.] (kat/mI)
2.06
ND
I
ProcoUagen 1U (ng/mI)
Sialic acid (nmol/L)
55.0
2.20 2.35 6.40 2.60 2.20 3.90 2.20 6.20
ND
2.10 2.93 1.63 2.84 2.71 1.61 2.46 2.62
62.7 87.0 ·47.8 168.1 145.7 62.8 82.5 73.4
2.51 1.42 ± 0.19
74.3 38.4 ± 14.2
ND
ND
ND
2.80 3.80 1.90 2.00 ± 0.3 nmol
their collagen, fibronectin, and glycosaminoglycan synthesis l , 19, 40 and/or act as an adjuvant in increasing immune reactivity. 41 The pathomechanism of silica-induced scleroderma is shown in Fig. 1.5 In East Germanyscleroderma has beenacknowledged since1979 as an occupational disease notonly in cases with associated silicosis but also in cases in which silicaexposure had beendeemed longenough
448 H austein et al.
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