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A 61 year old female patient with diffuse scleroderma, complicated by carpal tunnel syndrome, is reported. The coexistence of carpal tunnel syndrome with dermatomyositis and lupus erythematodes is reviewed.
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OBJECTIVE: Perivascular infiltrates in skin, subcutaneous tissue, and internal organs are a characteristic feature of early systemic sclerosis (SSc). We studied the first step of migration of peripheral blood mononuclear cells (PBMC) through the vessel wall to the extravascular space, i.e., adhesion of PBMC to endothelial cells (EC), in patients with various forms of SSc (limited scleroderma, diffuse scleroderma, and the transitional form). METHODS: Radioisotope-labeled patient PBMC were coincubated with umbilical cord EC in vitro, and the percentage adhesion was measured. RESULTS: Adhesion of PBMC to EC was markedly decreased, while adhesion of isolated active rosette-forming cells (ARFC) was significantly increased, in SSc patients compared with healthy controls. Decreased adhesion of PBMC to EC was found to correlate with a diminished percentage of ARFC in the peripheral blood. Preincubation of PBMC from healthy donors with interleukin-2 (IL-2) enhanced their adhesion to EC, while preincubation of PBMC from SSc patients with this cytokine resulted in a decrease in adhesion in 10 of 14 individuals. IL-1, interferon-gamma, and transforming growth factor beta had no significant effect on adhesion of SSc patient PBMC to EC. Differences in adhesion of PBMC to EC among the SSc subgroups were not significant. CONCLUSION: Our findings suggest that in SSc, activation of subpopulations of PBMC leads to their enhanced adhesion to vascular endothelium in vivo and to migration of these cells to the extravascular space, resulting in the elimination from the peripheral blood of those PBMC with high ability to adhere to EC.
Tight skin (TSK) mice develop cutaneous hyperplasia accompanied by histopathological alterations of skin and collagen metabolism similar to those described in human scleroderma. Diffuse scleroderma, the most severe form of progressive systemic sclerosis, is associated with the production of autoantibodies specific for Scleroderma 70 antigen (topoisomerase I). Our studies show that there is an increase in the level of serum anti-topoisomerase I (topo I) autoantibodies in aged TSK mice. The monoclonal antibodies isolated from TSK mice bind to epitopes which interact with autoantibodies from scleroderma patients. A significant number of TSK monoclonal anti-topo I antibodies and serum immunoglobulin (Ig) from aged TSK mice bear a cross reactive idiotype (Id) recognized by a syngeneic monoclonal anti-Id antibody obtained from a 2 month-old TSK mouse. Analysis of V gene usage by monoclonal anti-topo I antibodies showed that the majority of these antibodies are encoded by VH genes derived from VHJ558 family pairing with VK genes from various families in a stochastic manner.
Cell-mediated immunity to skin extracts was studied by the macrophage migration inhibition test, lymphocyte transformation, and direct cytotoxicity to skin fibroblasts, in normal individuals and patients with progressive systemic sclerosis. The latter included 18 individuals with diffuse scleroderma and 12 with the CREST syndrome, a variant form of systemic sclerosis in which there is more limited involvement of the skin. Controls consisted of 13 patients with other connective tissue diseases and 16 normal individuals. Phosphate-buffered saline and 3 M KCl extracts of both normal and sclerodermatous skin were used as antigens. No evidence of lymphocyte reactivity was found by the lymphocyte transformation and direct cytotoxicity test procedures. However, the lymphocytes of patients with diffuse scleroderma did respond to extracts of both normal and sclerodermatous skin in the migration inhibition assay. 10 of 16 patients (62.5%) had migration indices below 2 SD of the normal range, 1 of 10 CREST patients and 1 of 13 patients with other connective tissue diseases showed similar reactivity. Antisera specific for immunoglobulin-bearing lymphocytes (B lymphocytes) and T lymphocytes were used to characterize the lymphocytes found in skin biopsies of patients with diffuse scleroderma. T lymphocytes made up the majority of lymphocytes in the skin infiltrates. These findings suggest that lymphocytes sensitized to skin extracts are present in patients with diffuse scleroderma. The cell-mediated immune reaction to skin antigens may be a factor in the pathogenesis of diffuse scleroderma.
In the course of the last three decades a gradually supplemented group of 627 patients was subjected to prognostic analysis, incl. 388 with systemic lupus erythematosus, 160 with diffuse scleroderma, 51 with dermato- and polymyositis and 28 with a mixed connective tissue syndrome. Taking into account the onset of the disease, sex, extent of organ affection and therapy as well as the survival period and mortality, the conclusions of the statistical evaluation revealed that more than 90% of patients survived for more than 5 years: 92.2% with systemic lupus erythematosus, 94.3% with diffuse scleroderma 93.3% with dermato- and polymyositis and 100% with mixed connective tissue syndrome; a ten-year survival was recorded in cca 80% patients (77.6% with systemic lupus erythematosus, 81.1% with diffuse scleroderma, 89.7% with dermato- and polymyositis); a 15-year survival was recorded still by more than 50% patients (53.4% with systemic lupus erythematosus, 58.2% with diffuse scleroderma and as many as 80.0% with dermato- and polymyositis). The above data indicate considerable improvement of the prospects of these diseases, whereby the more than treble prolongation of survival of patients as compared with the previous period is due to effective, although not causal immunotherapy, in particular in systemic lupus erythematosus and dermato- and polymyositis.
Blood levels of serotonin (5-HT) and urinary excretion of 5-hydroxyindole-acetic acid (5-HIAA), tryptamine (T), and indole-acetic acid (IAA) were determined in 39 cases of systemic scleroderma and in 7 cases of very severe cutaneous scleroderma. The T/IAA ratio was normal and serotonin elevated in mild and rather severe acrosclerosis alike, i.e. in systemic scleroderma with pronounced vascular involvement. The T/IAA ratio was increased and serotonin normal in severe acroscleroderma, representing an intermediate form or transition to diffuse scleroderma, in severe diffuse scleroderma, and in severe cutaneous scleroderma. The T/IAA ratio and serotonin level were both elevated in a few cases of systemic scleroderma and in severe generalized morphea with concomitant vascular changes. The findings suggest impaired monoamine oxidase (MAO) activity in scleroderma with consequent accumulation in the organism of biogenic amines derived from tryptophan. An increased T/IAA ratio seems to be of prognostic significance in scleroderma, suggesting an adverse course of the disease.
Upon evaluation of 40 subjects with progressive systemic sclerosis (PSS), a significant association of HLA antigens A9 and Aw24 (a subgroup of A9) was found with diffuse scleroderma. HLA-Aw23 (a second subgroup of A9) was also increased in the patients, however, this was not statistically significant. Diffuse scleroderma appears to be one of the few diseases that shows an association with the HLA-A locus.
A low molecular weight cutaneous antigen was found to stimulate the release of macrophage migration inhibition factor from circulating lymphocytes of patients with diffuse scleroderma. The antigen had a molecular weight of approximately 3,500 and contained RNA and polypeptides, but no hydroxyproline. Lymphocytes from patients with the CREST syndrome, rheumatoid arthritis, and from normal controls did not respond to the antigen. An immune response to this antigen may be a factor in the pathogenesis of diffuse scleroderma.
We studied the immunohistochemistry of the skin of scleroderma patients to determine the differences (if any) between clinically "affected" and "nonaffected" areas. We examined paired skin biopsy samples from clinically involved forearm skin ("affected") and clinically uninvolved proximal skin ("nonaffected") taken from 19 patients with diffuse scleroderma and from 15 normal control subjects. We stained the sections with antibodies to endothelial leukocyte-adherence molecule type 1 (ELAM-1; to detect endothelial activation) and to procollagen-1 (PC-1; to detect newly formed, unprocessed collagen). There was increased expression of ELAM-1 and PC-1 in sclerodermatous skin as compared with the controls, but there was no difference between clinically affected and nonaffected skin samples. In 10 of 11 patients whose condition was getting worse, endothelial and fibroblast activation preceded fibrosis. Endothelial and fibroblast activation are more widespread in the skin of scleroderma patients than is evident by inspection on physical examination. What appears to be "normal" skin in diffuse scleroderma is already pathologic, as shown by abnormal endothelial activation and procollagen production.