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PubMed1982

Antibodies to collagen in scleroderma.

Using the enzyme-linked immunosorbent assay (ELISA), we detected antibodies to interstitial (type I) and basement membrane (type IV) collagens in the sera of patients with scleroderma (systemic sclerosis). Antibodies against type IV collagen were found in significant levels in these patients and correlated with the presence of abnormal pulmonary diffusion capacity. Levels of antibodies to type I collagens also correlated significantly with pulmonary diffusion capacity. Absorption of sera with type I or type IV collagens before analysis in the ELISA eliminated reactivity in an antigen-specific pattern, indicating that these antibodies reacted with determinants specific for either type I or type IV collagens. The removal of immune complexes by ultracentrifugation had no effect on serum antibody levels. Autoantibodies to basement membrane and interstitial collagens may participate in the pathogenesis of scleroderma.

Adolescent↗

PubMed1990

Evaluation and management of scleroderma lung disease using bronchoalveolar lavage.

PURPOSE: Bronchoalveolar lavage (BAL) was performed in 43 nonsmoking patients with scleroderma (systemic sclerosis) to determine the frequency of alveolitis, the status of BAL findings over time, and the relationship of such findings to pulmonary status initially and at follow-up. PATIENTS AND METHODS: Forty-three nonsmoking patients with systemic sclerosis underwent extensive pulmonary evaluation including pulmonary function tests, chest radiographs, and BAL with analysis of cells, IgG, albumin, immune complexes, and fibronectin. RESULTS: Alveolitis was detected on initial BAL evaluation in 21 patients (49%). Alveolitis was characterized by hypercellular lavage fluid, due to an absolute increase in alveolar macrophages and due to an increase in both the absolute number and percentage of granulocytes (neutrophils and eosinophils). Patients with systemic sclerosis had significantly higher levels of IgG and immune complexes in BAL fluid than did control subjects, and alveolar macrophages from patients with systemic sclerosis released higher amounts of fibronectin in vitro. In serial studies, alveolitis was found to persist. Patients with alveolitis had greater dyspnea than patients without alveolitis (p = 0.02), and they had greater reductions in lung volumes and carbon monoxide diffusing capacity (DLCO) (p = 0.004). Furthermore, patients with persistent alveolitis had significantly greater reductions in pulmonary function over time than patients without alveolitis (forced vital capacity [FVC]: -0.69 L versus -0.05 L, p less than 0.001; DLCO: -2.94 mL/minute/mm Hg versus +0.16 mL/minute/mm Hg, p = 0.03). BAL was used to select patients with alveolitis and at risk of pulmonary deterioration, and treatment was instituted with cyclophosphamide and prednisone, resulting in significant improvement in dyspnea (p less than 0.001) and the rate of change of FVC (p = 0.02) and DLCO (p less than 0.001). CONCLUSION: We conclude that alveolitis occurs frequently in systemic sclerosis and that BAL is useful in identifying such patients who are at risk for a further decline in pulmonary status. Preliminary observations suggest that treatment of patients with active alveolitis may result in improvement in pulmonary status.

Adult↗

PubMed1992

[Toxic oil syndrome--an example of an exogenously-induced autoimmune disease].

In 1981 epidemic poisoning with adulterated cooking oil occurred in Spain, affecting more than 20,000 people. The condition caused has since become known as the toxic oil syndrome (TOS). About 10-15% of the patients with acute symptoms developed a chronic disease with scleroderma-like skin manifestations, polyneuropathy and myositis. While the acute phase of the TOS was characterized by eosinophilia and elevated IgE, the chronic stage involved humoral autoimmune phenomena, such as antinuclear and antinucleolar antibodies, in many cases. In women with the chronic phase of TOS there was a possible prevalence of HLA-DR3 and HLA-DR4. The recently characterized eosinophilia-myalgia syndrome (EMS), which is thought to have been induced by contaminated L-tryptophan preparations, is similar to the TOS in some particulars. Understanding of the toxicological, immunological and genetic pathways leading to these diseases might give us some insight into the pathogenesis of spontaneously occurring autoimmune diseases, such as systemic scleroderma.

Animals↗

PubMed1995

Role of T cells and cytokines in effecting fibrosis.

A number of humoral and cellular immune abnormalities are present in patients with early scleroderma (systemic sclerosis). Most of these abnormalities reflect ongoing autoimmune reactions of the cellular and humoral types, resulting in a variety of autoantibodies to cellular and tissue constituents. Evidence exists for a defect(s) in immunoregulation favoring excessive helper T cell activity. The presence of circulating cytokines and shed interleukin-2 receptors suggest ongoing cellular immune reactions are occurring, generating cytokines and lymphokines that are capable of effecting the vascular and fibrotic lesions that are hallmarks of the disease. Future directions for research are suggested that would focus on determining if, and at what point, fibroblasts might function autonomously to generate excessive matrix components and on determining the nature of the original antigenic stimulus that starts the scleroderma process.

Cytokines↗

PubMed1990

Early immune events in scleroderma.

A number of humoral and cellular immune abnormalities are present in patients with early scleroderma (systemic sclerosis). Most of these abnormalities reflect ongoing autoimmune reactions of the cellular and humoral types, resulting in a variety of autoantibodies to cellular and tissue constituents. Evidence exists for a defect(s) in immunoregulation favoring excessive helper T-cell activity. The presence of circulating cytokines and shed interleukin-2 receptors suggest ongoing cellular immune reactions are occurring, generating cytokines and lymphokines that are capable of effecting the vascular and fibrotic lesions that are hallmarks of the disease. Future directions for research are suggested that would focus on determining if, and at what point, fibroblasts might function autonomously to generate excessive matrix components and on determining the nature of the original antigenic stimulus that starts the scleroderma process.

Antibody Formation↗

PubMed2006

Scar wars: is TGFbeta the phantom menace in scleroderma?

The autoimmune disease scleroderma (systemic sclerosis (SSc)) is characterized by extensive tissue fibrosis, causing significant morbidity. There is no therapy for the fibrosis observed in SSc; indeed, the underlying cause of the scarring observed in this disease is unknown. Transforming growth factor-beta (TGFbeta) has long been hypothesized to be a major contributor to pathological fibrotic diseases, including SSc. Recently, the signaling pathways through which TGFbeta activates a fibrotic program have been elucidated and, as a consequence, several possible points for anti-fibrotic drug intervention in SSc have emerged.

Cicatrix↗

PubMed1991

Soluble immunologic products in scleroderma sera.

To investigate the role of immune mechanisms in scleroderma (systemic sclerosis, SSc), we measured the levels of selected cytokines and soluble immune markers in patient sera. Forty-two patients and 14 matched healthy controls are the subject of this report. In the SSc group, tumor necrosis factor (TNF) was found in 8/42 (29 +/- 539 pg/ml, mean level +/- SD) and lymphotoxin in 36/42 (1:409-1:200, serum dilution). Interleukin beta (IL-1 beta) was observed in 23/42 (44 +/- 29, U/ml). IL-2 was identified in 36/42 patients with a mean level of 286 +/- 406 U/ml, soluble interleukin-2 receptor in 42/42 (1055 +/- 393, U/ml), soluble CD4 antigen in 27/42 (1:10-1:320, serum dilution), and CD8 in 42/42 (470 +/- 134, U/ml). TNF, lymphotoxin, IL-1 beta, Il-2, and CD4 were not detected in the control group. IL-2 receptor levels in control subjects were 520 +/- 171 U/ml, significantly lower than those of scleroderma (P less than 0.001), and CD8 levels (582 +/- 140) were significantly higher than in scleroderma (P less than 0.05). The data suggest an ongoing activation of immune cells, particularly the CD4+ subset in SSc and indicate a potential role for the released mediator TNF, IL-1 beta, and lymphotoxin in the disease process.

Adult↗

PubMed1996

Scleroderma and watermelon stomach.

Two patients with scleroderma (systemic sclerosis, SSc) and chronic blood loss secondary to gastric vascular ectasia--"watermelon stomach"--are presented. These cases exemplify the condition of gastric vascular ectasia and highlight the increasingly recognized association with autoimmune antibodies and connective tissue disease such as SSc. In both cases the onset of gastric blood loss coincided with the clinical manifestations of sclerodactyly by months, suggesting some temporal relationship. Although a number of different treatment modalities are available, and discussed in this report, both cases required gastrectomy.

Aged↗

PubMed1998

Antiendothelial cell antibodies in scleroderma correlate with severe digital ischemia and pulmonary arterial hypertension.

OBJECTIVE: To determine the prevalence of IgG antiendothelial cell antibodies (AECA) in patients with scleroderma (systemic sclerosis, SSc) and to correlate it with clinical spectrum and autoantibody profile. METHODS: Seventy-six patients with SSc and 50 matched healthy controls were studied. Immunological variables were antinuclear antibody (ANA), rheumatoid factor (RF), and Scl-70. IgG-AECA was measured by cellular ELISA. RESULTS: The prevalence of IgG-AECA was 27.6% in patients with SSc compared to 6% in controls (p < 0.01). Forty percent of patients with diffuse disease had this antibody, versus 13.5% of those with limited cutaneous involvement (p < 0.05). Patients with AECA had significantly higher incidence of digital infarcts and gangrene (p < 0.01) and pulmonary arterial hypertension (p < 0.001) than those without. In the AECA positive group, mean IgG-AECA levels (measured by absorbance values) were significantly higher in patients with digital infarcts (0.91+/-0.31 vs 0.60+/-0.05; p < 0.01) and pulmonary arterial hypertension (1.14+/-0.37 vs 0.68+/-0.13; p < 0.001) compared to those without these features. CONCLUSION: IgG-AECA appears to be an important marker for disease severity in scleroderma.

Adolescent↗

PubMed1993

[Physiopathology of scleroderma].

Scleroderma (systemic sclerosis) is a connective tissue disease characterized by an excessive accumulation of collage in the main body organs. The subsequent progressive fibrosis may result in severe functional impairment of the tissue(s) involved. In this paper, recent advances in the understanding of the disease are reviewed. Particular emphasis is placed on the role played by vascular lesions, inflammatory cell infiltrates, autoimmunity and possibly abnormal secretion of cytokines in the disturbance of connective tissue production. A better knowledge of the pathophysiological process involved in scleroma might lead to the development of new therapeutic approaches.

Antibody Formation↗

PubMed1991

Lung function abnormalities and decline of spirometry in scleroderma: an overrated danger?

To document the prevalence and progression of pulmonary involvement in scleroderma (systemic sclerosis including the CREST syndrome), the clinical notes and lung function records of 113 cases were reviewed. Lung function was normal in 39 cases, isolated impairment of DLCO was found in 38 patients, a restrictive defect was present in 27 cases and there was evidence of airflow obstruction in 9 cases. The median duration of symptoms was 10 years. Dyspnoea and an interstitial pattern on chest X-ray were associated with impaired lung function. Death during the period of review was significantly related to initial impairment of the DLCO. Sixty-six patients (53 women and 13 men) underwent repeat spirometry at least 1 year after initial testing. The rates of change in VC and FEV1 were no more rapid than would be expected for normal subjects. There was no significant difference in rates of change between men and women or between dyspnoeic patients and those who were asymptomatic. The extent of skin involvement and the presence of interstitial fibrosis on chest X-ray were unrelated to the rate of loss of lung function. It is concluded that most scleroderma patients in this study had abnormal lung function when first tested, but overall significant worsening of spirometry was not found.

Adolescent↗

PubMed1994

Scleroderma bronchoalveolar lavage fluid contains thrombin, a mediator of human lung fibroblast proliferation via induction of platelet-derived growth factor alpha-receptor.

In addition to its procoagulant properties, the serine protease thrombin increases endothelial permeability, stimulates granulocyte adherence, and serves as a fibroblast mitogen. We demonstrate that thrombin is mitogenic for human lung fibroblasts in vitro. The mitogenic effect of thrombin is associated with an increase in the expression of the ligand PDGF-AA and up-regulation of PDGF alpha-receptor. Since scleroderma (systemic sclerosis; SSc) is characterized by widespread microvascular injury and is frequently complicated by pulmonary fibrosis, we sought to determine the level of thrombin activity in bronchoalveolar lavage (BAL) fluid from SSc patients and normal controls. We report a significantly higher level of thrombin activity in BAL fluid from SSc patients compared with normal controls (P < 0.001). Taken together, the high levels of thrombin in BAL fluid and its demonstrated mitogenicity for lung fibroblasts suggest an important role for thrombin in the pathogenesis of SSc and perhaps other fibrotic lung diseases.

Adult↗

PubMed1987

[Fasciitis and Shulman's syndrome. A nosologic discussion].

Eosinophilic fasciitis or Shulman's syndrome is linked to scleroderma, systemic sclerodermia as various types of localized sclerodermia, by a nosological relationship analyzed by the authors. But, excluding the one concerning eosinophilic fasciitis and deep morphea, the authors seem to believe that the current differences are still justified, since the clinical picture and the levels of the histological lesions vary from one entity to the other. The nosological debate concerning eosinophilic fasciitis demonstrates also that a histologically recognized fasciitis has no complete specificity. By far, it goes beyond sclerodermia. Inflammation of the fascia is possible in the course of disseminated lupus erythematosus and other connective tissue inflammations. It is also described beyond connective tissue inflammations during rhizomelic pseudo-polyarthritis, and mostly in the course of three diseases: Texier's disease, drepanocytosis, and the spanish toxic syndrome, where it may be associated to a hypereosinophilia.

Anemia, Sickle Cell↗

PubMed1999

Novel therapeutic strategies in scleroderma.

Optimal management for scleroderma (systemic sclerosis) is likely to require treatment of the underlying disease process, which remains incompletely understood, and also of the organ-based complications of this heterogeneous condition. Clinical trials evaluating several potential agents have been completed recently, including D-penicillamine and interferon alpha. Unfortunately none of these studies has suggested significant efficacy. This article focuses on new treatment approaches using existing therapeutic agents, such as prostacyclin, and considers the potential usefulness of new agents (eg, relaxin, halofuginone) or strategies such as intensive immunosuppression with peripheral stem cell rescue. Ultimately, a better understanding of disease pathogenesis may facilitate the development of targeted therapy against key events or mediators, but for the present better evaluation of existing agents and a focus on optimizing protocols for organ-based complications, such as pulmonary vascular disease or hypertensive renal crisis, are important goals.

Clinical Trials as Topic↗

PubMed1994

Excess matrix accumulation in scleroderma is caused partly by differential regulation of stromelysin and TIMP-1 synthesis.

Scleroderma (systemic sclerosis: SSc) is an autoimmune disorder in which excessive extracellular matrix is deposited in skin and internal organs. Because of the importance of metalloproteinases in the turnover of connective tissue, in this study we have developed a novel procedure which utilises flow cytometry (FACS) to measure the production of stromelysin (MMP-3), gelatinase A (MMP-2), and the proteinase inhibitor TIMP-1, by SSc skin fibroblasts. In the presence of monensin, which prevents the secretion of these matrix proteins, there was a similar intracellular accumulation of gelatinase A in normal and SSc cells. However, whereas stromelysin levels also increased in the normal cells, no net synthesis could be detected in the SSc fibroblasts. In marked contrast, the synthesis of TIMP-1 was 50% greater in the SSc cells than in the normal fibroblasts. Our results thus show unequivocally, for the first time, that cells from SSc patients simultaneously produce less stromelysin but substantially higher amounts of TIMP-1 than do normal dermal fibroblasts, suggesting that abnormalities in the regulation of the matrix enzymes and their inhibitors play an important part in the molecular pathology of SSc.

Adolescent↗

PubMed1995

Expression of ectopeptidases in scleroderma.

OBJECTIVES: To examine the expression and concentrations of three ectopeptidases likely to be involved in regulating the functional levels of adhesion molecules and the turnover of connective tissue components, in patients with scleroderma (systemic sclerosis) (SSc) and in normal individuals. METHODS: Monoclonal antibodies against these antigens were used for immunoperoxidase staining of cryostat skin sections and for flow cytometric (fluorescence activated cell sorter) analysis of cultured dermal fibroblasts grown from SSc patients and normal controls. RESULTS: Although neutral endopeptidase-24.11 (NEP) (CD10) was not detected in either SSc or normal skin, aminopeptidase N (APN) (CD13) and dipeptidyl peptidase IV (DPPIV) (CD26) were both readily visualised. However, DPPIV appeared to be present in smaller concentrations in the SSc biopsy specimens. Moreover, while fibroblasts grown in vitro from both SSc and normal skin also had similar concentrations of APN, the expression of DPPIV in the cultured SSc cells was found to be very much less than that present in the normal fibroblasts. It is noteworthy that NEP, which was not detected in the tissue sections, was nevertheless readily detected in fibroblasts in culture. CONCLUSIONS: These results show that a number of cell surface proteases are expressed by dermal fibroblasts both in vivo and in vitro, and it is suggested that the marked downregulation of DPPIV in SSc could be at least partly responsible for the increased concentrations of adhesion molecules and matrix proteins associated with the molecular pathology of this disease.

Adolescent↗

PubMed1997

Tissue inhibitor of metalloproteinase 1 (TIMP-1) may be an autocrine growth factor in scleroderma fibroblasts.

In scleroderma (systemic sclerosis, SSc), an autoimmune disorder in which excessive extracellular matrix is deposited in skin and internal organs, one of the suggested contributory factors to the development of fibrosis is a decrease in collagenase activity that may be related to levels of serum tissue inhibitors of metalloproteinases 1 (TIMP-1). We recently reported that the serum TIMP-1 levels in SSc patients were elevated compared with normal controls. To determine the biologic significance of TIMP-1 in SSc, we compared the proliferative effects of TIMP-1 between normal and SSc fibroblasts. TIMP-1 showed significant mitogenic activity for both normal and SSc fibroblasts. The mitogenic responses to TIMP-1 (33-100 ng/ml) in SSc fibroblasts, however, were significantly greater than those in normal controls and were completely neutralized in the presence of anti-TIMP-1 IgG. Moreover, anti-TIMP-1 IgG partially but significantly blocked the basal mitogenic activities of SSc fibroblasts. SSc fibroblasts produced increased amounts of TIMP-1 relative to normal fibroblasts, as confirmed by western blotting, ELISA, and RT-PCR techniques. In contrast, transforming growth factor beta1 (TGF-beta1) upregulated TIMP-1 production in normal fibroblasts but not in SSc fibroblasts with elevated spontaneous secretion of TIMP-1. These observations suggest that TIMP-1 may play an important role as an autocrine growth factor in the fibrotic process in SSc.

Female↗

PubMed2005

The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists (the UNCOVER study).

OBJECTIVE: Most of the data about the prevalence of pulmonary arterial hypertension (PAH) are from tertiary centers that are biased toward seeing more severe cases; therefore, the true prevalence of PAH among patients with connective tissue disease is unknown. We sought to determine the point prevalence of undiagnosed PAH in community-based rheumatology practices. METHODS: The study design was a multicenter, prospective and retrospective survey and analysis of clinical cases in 50 community rheumatology practices. We evaluated a total of 909 patients with either scleroderma (systemic sclerosis [SSc]) or mixed connective tissue disease (MCTD). If a subject had not been diagnosed as having PAH, then a new Doppler echocardiogram was obtained to measure cardiac parameters, including estimated right ventricular systolic pressure (ERVSP), and a full review of medical records was done. RESULTS: Of 909 screened patients, 791 were evaluable and completed the study; 669 had not previously been studied for PAH. Of these 669 patients, 89 (13.3%) were found by Doppler echocardiography to have an ERVSP of > or = 40 mm Hg. Of these 89 patients, 82 (92.1%) had SSc and 7 (7.9%) had MCTD. The total prevalence of PAH in the survey was 26.7% (211 of 791 patients, including 122 with known PAH and 89 newly diagnosed as having PAH). Doppler echocardiographic data showed 20 of 89 patients (22.5%) with ERVSP of > or = 50 mm Hg, 20 of 89 patients (22.5%) with increased RV dimension, and 25 of 89 patients (28.1%) with right atrial enlargement. Patients with ERVSP > or = 40 mm Hg had decreased exercise tolerance compared with those with ERVSP <40 mm Hg (27% compared with 9.5%, respectively, were severely symptomatic). CONCLUSION: A significant number of patients with SSc or MCTD (13.3%) followed up in a community rheumatology practice setting have undiagnosed elevated ERVSP consistent with PAH.

Adolescent↗