Pemphigus vulgaris in association with silicosis

ARTICLE

Pemphigus vulgaris is an autoimmune disease, characterised by autoantibodies to desmosomal transmembrane glycoproteins such as desmogleins and desmocollins, which are involved in intercellular adhesion [1, 2]. Autoantibodies are deposited in the intercellular space and mediate acantholytic blisters in the lesions. During the clinical course of the disease their titer run in parallel to the disease activity.

During recent years we have reported on several cases of silicosis or long term silica dust exposure in association with systemic sclerosis [3, 4] and systemic lupus erythematosus [5] in accordance with other authors [6-8] who, in addition, found associations with rheumatoid arthritis, dermatomyositis and to the best of our knowledge, only in one case with pemphigus vulgaris [9]. Various signs of immune stimulation like polyclonal hypergammaglobulinemia, antinuclear antibodies, anti-ssDNA-antibodies and antitopoisomerase antibodies have been detected and, in association with genetic factors in the HLA system, interpreted as an increased risk to develop such an autoimmune disease [4]. Here we report on one patient suffering from silicosis followed by pemphigus vulgaris.

Case report

The sixty-seven year old man had been exposed to silica dust as a hawler in the uranium mining industry for 21 years from 1955 to 1978. In 1992 the patient was diagnosed as suffering from silicosis. In 1998 chest X-rays demonstrated fine stripes and granula formation all over the lungs, in particular in their upper parts (Fig. 1). The hilar lymph nodes were enlarged on both sides. Comparison with an earlier X-ray characterised by slight snow-storm like pattern in 1992, revealed a progressive course with signs of fibrosis. The diagnosis of silicosis was also confirmed by high-resolution computer tomography.

In March 1998 the patient was seen with painful oral lesions and erosions or blisters, respectively, on the trunk, axillae and extremities (Fig. 2) which had started approximately one month before. Skin biopsy from the trunk revealed an intraepidermal acantholytic blister formation at suprabasal location. Applying direct immunofluorescence an intercellular network-like pattern was seen due to deposits of IgG, IgM and C3 (Fig. 3). Using monkey esophagus the titer of the indirect immunofluorescence was 2,500. In addition, the antibodies in the serum precipitated more distinctly at 130 KD (desmoglein 3) than at 85 KD (plakoglobin) using keratinocyte extracts for immunoblotting analysis. Taken together clinical and laboratoy investigations confirmed the diagnosis of pemphigus vulgaris. Drugs known as inducers of pemphigus vulgaris had not been used by the patient in the recent past. In particular, he had not been on any continuous maintenance therapy during the last 9 months.

Routine laboratory tests were within normal limits except blood sedimentation rate (28/57 mm), leucocytosis (10,600/µl), increased serum IgG level (2,230 mg/dl) and increased C reactive protein (11 mg/dl). Autoantibodies were positive as follows: antinuclear antibodies (speckled pattern, 1,028), anti ssDNA (28 IU/ml), antitopoisomerase antibody (9.1 U/ml), while others were negative: rheumatoid factor, antimitochondrial, antimicrosomal, anticentromer, anti U1RNP, anti Sm, anti SSA/RO, anti SSB/La and anti smooth muscle antibodies.

The T-/B-lymphocyte ratio as well as CD4⁺/CD8⁺ ratio were within normal limits. The HLA-analysis revealed an association with DRB1*0301, DQB1*0201, TNFalpha2 and TNF2 alleles as shown for uranium miners with antitopoisomerase antibodies [10] and an association again with HLA DRB1*04 and DRB1*14 as shown for pemphigus vulgaris [11, 12].

The patient was treated with methylprednisolon (initially 160 mg/day) and then gradually reduced to 32 mg/day within 8 weeks. This therapy was combined with 100 and 50 mg cyclophosphamide, on alternate days. Following this treatment the skin lesions improved significantly and cleared. However, the clinical course was complicated by subsequently occurring pneumonia and sepsis. Blood cultures revealed various bacteria, in particular staphylococci and enterococci, resistant to the majority of antibiotics. Even treatment with antibiotics according to the resistogramm failed; finally the patient died from acute respiratory failure and sepsis.

Discussion

Pemphigus vulgaris is an autoimmune disease with pathogenetically important autoantibodies against desmosomal transmembrane glycoproteins, desmoglein 3 and desmoglein 1 [1, 2]. The formation of autoantibodies can be explained by loss of tolerance; the basis of the latter mechanism, however, remains unclear.

As a rule an interaction between endogenous genetic factors and exogenous factors is a prerequisite for the development of pemphigus vulgaris. Exogenous factors include drugs, nutritional factors, physical agents (e.g. burns, UV-radiation, X-rays), infections (viral), neoplasms, hormones and pregnancy, contact dermatitis and emotional stress [13]. In the literature, several drug-induced pemphigus cases have been reported [14], probably mediated by immune dysregulation. This refers to thiol (sulflydril) drugs (penicillamin, captopril, pyritinol, thiopronin, piroxicam, methimizol) and phenol drugs (pyritinol and 5-thiopyridoxine, cephalosporins, rifampicin, levodopa, aspirin and heroin, phenobarbital, pentachlorophenol) [14]. On the other hand, some of them may cause antibody-independent acantholysis [15].

In terms of occupational associations, gardening, typography, photographic processing, biochemistry and industrial solvent work were taken into consideration in 59 patients [16], but without any significant relationship.

According to the literature silicosis can occur in association with various autoimmune diseases such as systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis as well as dermatomyositis [3-8]. The highest prevalence has been described for systemic sclerosis, in particular in miners [4]. We were able to demonstrate that the so-called silica-induced systemic sclerosis is indistinguishable from idiopathic systemic sclerosis indicated by distinct clinical, serological and immunological features [4]. In cell culture studies we have demonstrated that silica is able to modulate the function of monocytes/macrophages [17], endothelial cells [18] and fibroblasts [19] in a fashion common with pathophysiological events known from idiopathic systemic sclerosis [4].

In addition, Ueki et al. [20] have previously shown a polyclonal human T cell activation by silicate as a super-antigen in vitro and that certain TcRVbeta repertoires, especially Vbeta5.3 were predominantly expressed in T cells activated by silicate and then fractionated flow-cytometrically. Thus, silica or silicates may activate lymphocytes polyclonally as a superantigen [20]. Furthermore this environmental factor should coincide with a certain genetic background indicating by an increased susceptibility of the immune system to xenobiotic stimuli. On one hand pemphigus vulgaris is genetically linked to two alleles of the HLA subgroup [11, 12], on the other hand silicosis, in particular in uranium miners is associated to HLA subgroup DRB1*0301, DQB1*0201, TNFalpha2 and TNF2 [10, 21]. Both subgroups of alleles were present as HLA constellation in our patient.

Taken together, we have shown in one patient suffering from pemphigus vulgaris, an association with preceding silicosis after long-term exposure. Silica as an immortal crystal incorporated by macrophages may stimulate the immune system to produce autoantibodies against various antigens such as desmoglein 3 and 1 as well as nucleoproteins and topoisomerase. In silicosis at least the occurrence of antinuclear antibodies and antitopoisomerase antibodies indicates an increased risk of developing an autoimmune disease and systemic sclerosis in particular [4]. A careful clinical investigation, however, did not reveal any features suggesting systemic sclerosis in our patient. In addition, there were no findings consistent with SLE e.g. arthritis, serositis and renal abnormalities.

It has also been shown that the genetic background favours the development of an autoimmune disease by increased susceptibility to xenobiotic stimuli or a breakdown of immune tolerance. Finally, it has recently been shown that serum soluble FAS molecule levels are elevated in silicosis patients indicating an imbalanced apoptosis of T-lymphocytes in silicosis [22]. To the best of our knowledge this is the second report of pemphigus vulgaris in association with silicosis, suggesting their pathogenetic relationship.

Article accepted on 19/7/00

REFERENCES

1. Joly P, Gilbert D, Thomine E, Zitouni M, Ghohestani R, Delpech A, Lauret P, Tron F. Identification of a new antibody population directed against a desmosomal plaque antigen in pemphigus vulgaris and pemphigus foliaceus. J Invest Dermatol 1997; 108: 469-75.

2. Hashimoto T, Amagai M, Garrod DR, Nishikawa T. Immunofluorescence and immunoblot studies on the reactivity of pemphigus vulgaris and pemphigus foliaceus sera with desmoglein 3 and desmoglein 1. Epithelial Cell Biol 1995; 4: 63-9.

3. Haustein UF, Ziegler V, Herrmann K. Silica-induced scleroderma. J Am Acad Dermatol 1990; 22: 444-8.

4. Haustein UF, Anderegg U. Silica induced scleroderma ­ clinical and experimental aspects. J Rheumatol 1998; 25: 1917-26.

5. Haustein UF. Silica-induced Lupus erythematosus. Acta Derm Venereol 1998; 78: 73-4.

6. Rodnan GP, Benedek TG, Medsger TA Jr, Cammarata RJ. The association of progressive systemic sclerosis (scleroderma) with coal miners' pneumoconiosis and other forms of silicosis. Ann Intern Med 1967; 66: 323-34.

7. Sanches RJ, Wichmann I, Salaberri J. Multiple clinical and biological autoimmune manifestations in 50 workers after occupational exposure to silica. Ann Rheum Dis 1993; 52: 534-8.

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: 62-9.

9. Yamagami Y, Kohda M, Mimura S, Ueki H. Pemphigus vulgaris associated with silicosis. Dermatology 1998; 197: 55-7.

10. Conrad K, Mehlhorn J, Frank KH. Markers of systemic autoimmune diseases in uranium miners. Clin Immunol 1998; 9: 151-2.

11. Miyagawa S, Amagai M, Niizeki H, Yamashina Y, Kaneshige T, Nishikawa T, Shirai T, Inoko H. HLA-DRB1 polymorphisms and autoimmune responses to desmogleins in Japanese patients with pemphigus. Tissue Antigens 1999; 54: 333-40.

12. Hertl M, Karr RW, Amagai M, Katz SI. Heterogeneous MHC II restriction pattern of autoreactive desmoglein 3 specific T cell responses in pemphigus vulgaris patients and normals. J Invest Dermatol 1998; 110: 388-92.

13. Goldberg I, Kashman Y, Brenner S. The induction of pemphigus by phenol drugs. Int J Dermatol 1999; 38: 888-92.

14. Brenner S, Bialy-Golan A, Ruocco V. Drug-induced pemphigus. Clin Dermatol 1998; 16: 393-7.

15. Ruocco V, De Angelis E, Lombardi ML. Drug-induced pemphigus. II. Pathomechanisms and experimental investigations. Clin Dermatol 1993; II: 507-13.

16. Krain LS. Pemphigus: epidemiologic and survival characteristics of 59 patients, 1955-1973. Arch Dermatol 1974; 110: 862-5.

17. Frank R, Giese T, Dummer R, et al. Silica-induced cytokine release in human monocyte cultures and its possible involvement in the pathophysiology of silica associated scleroderma. Eur J Dermatol 1993; 3: 304-9.

18. Anderegg U, Vorberg S, Herrmann K, Haustein UF. Silica directly induces ICAM-1 expression in cultured endothelial cells. Eur J Dermatol 1997; 7: 27-31.

19. Anderegg U, Vorberg S, Herrmann K, Haustein UF. Increased expression of interstitial collagenase in silica-treated fibroblasts. Eur J Dermatol 1996; 6: 51-5.

20. Ueki A, Yamaguchi M, Ueki H. Polyclonal human T cell activation by silicate in vitro. Immunology 1994; 82: 332-5.

21. Rihs HP, Conrad K, Mehlhorn JI. et al. Molecular analysis of HLA-DPB1 alleles in idiopathic systemic sclerosis patients and uranium miners with systemic sclerosis. Int Arch Allergy Immunol 1996; 109: 216-22.

22. Tomokuni A, Aikoh T, Ueki H, Ueki A. Elevated soluble Fas/APO-1 (CD95) levels in silicosis patients without clinical symptoms of autoimmune diseases or malignant tumours. Clin Exp Immunol 1997; 110: 303-9.