Nephrol Dial Transplant (1996) 11: 1835-1838
Nephrology
Dialysis
Transplantation
Case Report
Lupus-like autoimmune disease associated with silicosis
R. A. Wilke1, S. Salisbury2, E. Abdel-Rahman1 and P. C. Brazy1
Departments of 'Nephrology and 2Pathology, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA
Key words: connective tissue disease; end-stage renal
disease; silicosis; vasculitis
Introduction
Major occupational exposures to silica occur in the
mining, stone-cutting, and abrasives industries [1,2].
Estimates of the total number of exposed workers in
the US today range from 1.2 to 3 million people [2].
Although prolonged exposure to silica has long been
associated with pulmonary pathology, a growing body
of evidence suggests that the lung is not the only organ
affected by silicosis. Several recent case reports have
documented a relationship between the development
of pneumoconiosis and systemic vasculitis [3-6]. We
now report a case of end-stage renal disease occuring
within the context of a silicosis-induced connectivetissue disorder similar in many respects to systemic
lupus erythematosus.
Case report
A 58-year-old caucasion male was referred to our
institution for evaluation of new-onset renal insufficiency. He complained only of oliguria and mild exertional dyspnoea. As an employee of the chemical
industry, he had been involved in the manufacture of
abrasive cleaners for 15 years. Review of systems was
positive only for a 30-lb weight loss over the preceding year. His presenting creatinine clearance was
17 ml/min. Physical examination revealed an anaemic,
ill-appearing gentleman weighing 60 kg. His blood
pressure was 160/95. Urinalysis revealed 3+ proteinuria and 11-20 r.b.cs; no casts were observed and
the rest of the urinalysis was unremarkable. Ultrasound
demonstrated normal size kidneys and there was no
evidence of hydronephrosis. Renal biopsy showed both
glomerulosclerosis and chronic interstitial nephritis
(Figure 1). Congo-red staining for amyloid was negative. Immunofluorescence was positive for the granular
deposition of C3, fibrin, and IgM peripherally. No
IgG deposits were detected.
Despite conservative management, the patient progressed to end-stage renal disease within 4 months.
Laboratory findings at that time were as follows:
haematocrit 27%, leukocyte count 3800/ul, platelet
count 100000/ul. Serum calcium, phosphate, sodium,
potassium, and chloride were all within normal limits.
Serum creatinine had increased to 14.9mg/dl, and
albumin was 2.5 g/dl. Rheumatological studies demonstrated an elevated sedimentation rate (>100mm/h)
and an antinuclear antibody (ANA) titre of
1:2560. Serological assays were also positive for
anti-Ro, anti-La, and anticardiolipin antibodies.
Antimyeloperoxidase and perinuclear antineutrophil
cytoplasmic antibodies (P-ANCA) were present.
C-ANCA was absent. Other negative serological
markers included rheumatoid factor, anti-Smith, antimitochondrial and anti-DNA antibodies. Syphilis and
hepatitis serologies were also unremarkable, and all
complement levels were within normal limits.
Prior to placement of a peritoneal dialysis catheter,
a chest X-ray was obtained which revealed multiple
pulmonary opacities and bilateral pleural effusions
(Figure 2). Thoracentesis yielded a sterile haemorrhagic exudate. Bronchoscopy and open lung biopsy
revealed pneumoconiosis with extensive pulmonary
Correspondence and offprint requests to: Peter C. Brazy MD Chief,Fig. 1. Glomerulosclerosis and chronic interstitial nephritis. A globSection of Nephrology, Department of Medicine, University of ally sclerotic glomerulus is shown, accompanied by a mesangial
Wisconsin Hospital and Clinics, Madison, Wisconsin, USA.
lymphocytic infiltrate. (H&E x400.)
© 1996 European Renal Association-European Dialysis and Transplant Association
1836
R. A. Wilke et al.
Fig. 2. Chest X-ray; multiple opacities bilateral pleural effusion.
fibrosis and multiple well-organized granulomata
(Figure 3).
The postoperative course of this patient was long
and complicated. Following thoracotomy, he
developed generalized erythroderma and a gradually
progressive exfoliative dermatitis (Figure4). These
skin changes were accompanied by fevers, worsening
pancytopenia, and the production of voluminous,
haem-positive, maroon-coloured stool. Skin Bx at that
time revealed the presence of leukocytoclastic vasculitis
(Figure 5). Throughout his hospital stay this patient
required maintenance on haemodialysis as well as
multiple blood and platelet transfusions, raising the
Fig. 4. Dermatological changes including palmar desquamation,
twenty-nail dystrophy, and exfoliative dermatitis.
Fig. 5. Leukocytoclastic vasculitis. Beneath a normal epidermis,
there is a perivascular infiltration of lymphocytes into the vessel
walls. (H&E x400.)
Fig. 3. Pulmonary silicosis. A granulomatous nodule is shown, with
central eosinophilic material surrounded by epithelioid monocytes
and a thin outer layer of lymphocytes. (H&E x400.)
possibility of a transfusion-related graft-versus-host
disease. However, HLA typing of both skin and peripheral blood leukocytes showed no exogenous DR
subtypes, making such a diagnosis unlikely.
Unfortunately, the patient's course was further complicated by enterococcal peritonitis, catheter-related
septicaemia, and an episode of bacterial endocarditis
which left him with aortic valve insufficiency. Because
1837
Silicosis-induced autoimmune disease
of his predisposition to recurrent infection occurring
in the context of a proliferative exfoliative dermatitis,
the possible diagnosis of cutaneous T-cell lymphoma
(CTCL) was also entertained. Although some lymphocytes on his peripheral smear did appear to contain
cerebriform nucei, a Sezary cell preparation from his
blood buffy coat was negative. Furthermore, T-cell
receptor gene rearrangement studies showed no clonality, essentially ruling out a diagnosis of CTCL.
Bone-marrow biopsy was hypercellular, but otherwise
normal with trilinear haematopoiesis (not shown).
Discussion
Recent case reports have suggested a link between
prolonged exposure to silica and various forms of
connective tissue disease [3-6]. The coexistence of
pneumoconiosis with the serological evidence of an
autoimmune process is not uncommon [5]. Estimates
of the prevalence of an elevated antinuclear antibody
titre specifically accompanying silicosis have ranged
from 26 to 44% [7,8]. Perhaps this association is the
result of an immune response evoked by destructured
components of the granulomatous silicotic nodules.
The finding of antinuclear antibodies in our patient's
serum suggests the presence of a lupus-like autoimmune process. However, anti-DNA and anti-Smith
antibodies were absent, making the diagnosis of systemic lupus erythematosus less plausible [2,5]. The
presence of antimyeloperoxidase and perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) suggest
the diagnosis of Wegener's granulomatosis. In fact, a
recent case report has implicated this disease as causative in the declining renal function observed in a
patient known to have silicotic pulmonary nodules [3].
Although our patient's open-lung biopsy did demonstrate the presence of granulomata, his renal biopsy
did not. Furthermore, his serological analysis was
negative for C-ANCA, a marker estimated to be 90%
sensitive and 95% specific for the diagnosis of
Wegener's granulomatosis. The presence of anti-Ro
and anti-La antibodies suggests an alternative diagnosis of Sjogren's syndrome; however, our patient
was remarkably negative for the common signs and
symptoms of this disease. Although he did not meet
strict diagnostic criteria for any single rheumatological
disease, a lupus-like autoimmune process had clearly
left him with end-stage renal disease.
The renal lesions documented in systemic lupus
erythematosus are characteristically pleomorphic. Four
major histological groupings are recognized: minimal
lesions, proliferative lupus nephritis (focal and diffuse),
membranous lupus nephritis, and chronic sclerosing
nephritis [9,10]. Our patient's renal pathology showed
changes most consistent with the latter grouping.
Interestingly, though, sclerotic glomeruli were not the
only outstanding feature of his renal biopsy; there was
a significant amount of lymphocytic infiltration into
the mesangium as well. Whether this observation
reflects the presence of a second discrete pathogenetic
process or a parenchymal extension of the first is
unknown.
Previous investigators have proposed the coexistence
of two distinct pathogenetic mechanisms responsible
for the collective histological changes seen in the
nephritis of systemic lupus [9]. While the diffuse sclerotic changes are probably the result of immunecomplex deposition, current evidence suggests that
focal lesions result from thrombosis-induced intracapillary necrosis and aneurysmal dilatation of the capillary
walls [11]. Formation of these microangiopathic
thromboses have been linked to the presence of autoantibodies with high affinity for negatively charged phospholipids [12], such as the anticardiolipin antibodies
noted to be present in the serum of our patient.
Evidence has suggested that bolus doses of intravenous methylprednisolone, with or without alkylating
agents, can be helpful in slowing the progression of
proliferative lupus nephritis [10]. Although our patient
had renal pathology which had clearly advanced
beyond any chance of intervention, he was given a
trial of glucocorticoids in an effort to curtail the
progression of his pancytopenia and profound exfoliative dermatitis. During an infection-free period he
was started on high-dose intravenous methylprednisolone which resulted in remarkable symptomatic
improvement. It was hypothesized that this patient's
lupus-like autoimmune disease was related to his long
occupational exposure to silica. At present he remains
clinically stable on a low maintenance dose of oral
glucocorticoids, and his end-stage renal disease is being
managed by routine haemodialysis.
As this and similar case reports continue to appear
in the renal and pulmonary literature, it becomes
increasingly evident that silicosis (more than any other
form of pneumoconiosis) is associated with the induction of a systemic autoimmune process. A thorough
occupational history is therefore critical in the evaluation of patients that present with otherwise unexplainable renal insufficiency.
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Received for publication. 1.3.96
Accepted in revised form- 8.5.96