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PubMed1996

Lung involvement in systemic sclerosis (scleroderma): relation to classification based on extent of skin involvement or autoantibody status.

Lung involvement accounts for significant morbidity and is a leading cause of mortality in patients with systemic sclerosis (SSc). It has been shown that different patterns of pulmonary involvement are seen in different subtypes of SSc. This paper reports a retrospective review of 72 patients with SSc to determine whether disease classification according to the extent of skin involvement alone (diffuse vs. limited) or autoantibody status was predictive of pulmonary parenchymal involvement. The diagnosis of interstitial lung disease was based on pulmonary function tests and chest radiographs. Restrictive lung disease was common in both limited SSc (lSSc) and diffuse SSc (dSSc), occurring in 30% and 50% of these patients respectively (P = 0.16). Radiographic evidence of significant interstitial disease was also comparable between the groups [nine of 32 lSSc patients (28%) vs. six of 17 dSSc patients (32%), P = n.s.]. No significant difference in mean lung function was found between patients with anti-Scl 70 antibody (n = 12) compared to those without (n = 60) (TLC 79.0 +/- SE 5.1% predicted vs. 82.8 +/- 2.2, P = n.s.; DLCO 63.0 +/- 5.1 vs. 59.7 +/- 2.5, P = n.s.). By contrast, statistically significant differences in mean lung function were found between patients with anticentromere antibody (ACA) (n = 24) and those without ACA (n = 48) (TLC 98.6 +/- SE 3.9% predicted vs. 79.7 +/- 3.1%, P < 0.001); and less frequent radiographic evidence of severe interstitial disease (0 of 17 with significant interstitial changes on chest radiograph vs. 15 of 32 (47%), P = 0.002). It is concluded that classification of SSc patients on the basis of the distribution of skin involvement poorly predicts the occurrence of interstitial lung disease. On the other hand, ACA is highly associated with the absence of interstitial lung disease.

Adult↗
PubMed1984

[Visceral scleroderma].

Visceral involvement in systemic scleroderma is frequent, the most commonly affected organs being the kidney, the lung, the heart and the gastro-intestinal tract; associating different degrees of sclerosis and vasculitis depending on which organ is involved. However, this is not always clinically obvious, and angiospastic phenomena may be assumed to be responsible for certain ischaemic lesions. The diagnosis is also difficult because some visceral lesions may occur at an early stage and appear to be of primary origin. Extensive investigation, including biopsies to demonstrate small vascular changes then becomes essential.

Digestive System Diseases↗
PubMed1995

Anti-CENP-B response in sera of uranium miners exposed to quartz dust and patients with possible development of systemic sclerosis (scleroderma).

OBJECTIVE: To look for anti-CENP-B antibodies and their diagnostic relevance in patients negative and positive for anticentromere antibodies (ACA) with different risk for the development of systemic sclerosis (SSc), including uranium miners exposed to quartz dust. METHODS: We studied sera of 107 patients with SSc, 121 patients with possible SSc, 202 uranium miners heavily exposed to quartz dust, 14 patients with vibration induced white fingers, and 240 control patients. Subjects were screened for ACA by indirect immunofluorescence on HEp-2 cells (IIF-ACA) and then for anti-CENP-B autoantibodies by an ELISA using eukaryotically expressed human full length recombinant CENP-B protein. RESULTS: All IIF-ACA positive sera of "idiopathic" SSc (N = 19), "idiopathic possible" SSc (N = 6) and other patients (N = 11), and 17 of 19 IIF-ACA positive sera of miners exposed to silica with (N = 13) and without (N = 6) symptoms of SSc reacted with CENP-B in this assay. Of the 622 IIF-ACA negative sera, 28 were found positive for anti-CENP-B. There was a significant increase of the prevalence of anti-CENP-B antibodies in IIF-ACA negative patients with possible SSc (11 of 109) and in miners exposed to silica (11 of 196) compared to a group of men older than 60 years with diseases or symptoms not related to SSc (1 of 138). CONCLUSION: (1) CENP-B is also the major target of the IIF-ACA response in diseases other than scleroderma and in the risk group of miners exposed to quartz dust. (2) Anti-CENP-B antibodies can be found in IIF-ACA-negative sera, particularly in those at risk for SSc. (3) The detection of anti-CENP-B antibodies in miners exposed to quartz dust may indicate a high risk group for developing SSc and reveals possibilities for the study of early pathogenetic changes as well as exogenic and endogenic factors involved in the development of this disease.

Autoantibodies↗
PubMed1992

Antibodies to mycobacterial 65 kDa heat shock protein in systemic sclerosis (scleroderma).

It has been reported that immunity to the 65 kDa heat shock protein of Mycobacterium tuberculosis (MT-hsp65) not only accompanies rheumatoid arthritis (RA), but may also be characteristic of chronic inflammation. We now report serum antibodies to MT-hsp65 in 47% of systemic sclerosis (SSc), 38% of primary Raynaud's phenomenon (PRP) and 5% of systemic lupus erythematosus (SLE). Antibody levels were higher in patients with active or progressive SSc and correlated with the degree of skin fibrosis. Thus, immunity to MT-hsp65 appears in SSc and is not limited to RA. However, it does show some degree of specificity beyond chronic inflammation: PRP patients have a higher reactivity than do SLE patients.

Adolescent↗
PubMed1985

The clinical significance of coagulation abnormalities in systemic sclerosis (scleroderma).

A coagulation screen and measurement of circulating factor VIII related antigen (VIII-RAg), factor VIII coagulant activity (VIII-C) and beta-thromboglobulin (beta TG) levels were carried out in 25 patients with systemic sclerosis and 25 age and sex matched controls. Both VIII-RAg and beta TG levels were significantly higher in the systemic sclerosis patients than controls. Fibrin degradation products were increased in 11 (44%) of the patients. There was a significant correlation between the VIII RAg/VIII-C ratio and severity of the vascular abnormalities noted on nailfold capillary microscopy. Those with VIII-RAg levels in excess of 200% of controls (10 of 25) had more severe disease with greater mean number of organ systems involved.

Adolescent↗
PubMed2000

Microsatellites and intragenic polymorphisms of transforming growth factor beta and platelet-derived growth factor and their receptor genes in Native Americans with systemic sclerosis (scleroderma): a preliminary analysis showing no genetic association.

OBJECTIVE: Abnormalities of transforming growth factor beta (TGFbeta) and platelet-derived growth factor (PDGF) alpha and beta and/or their receptors have been demonstrated in systemic sclerosis (SSc). This study aimed to determine whether genetic polymorphisms in or near the TGFbeta and PDGF gene families were associated with susceptibility to SSc in a Native American population with a high disease prevalence. METHODS: Genotyping of 5 intragenic polymorphisms within the TGFbeta1 gene and mapping of 35 microsatellites near the genes for TGFbeta1, latent TGFbeta1 binding protein (LTBP1), TGFbeta receptors I and II, PDGFalpha, PDGFbeta, PDGF receptor alpha, and PDGF receptor beta was performed in 19 SSc patients, 76 controls, and 42 family members. Allele distributions and frequencies were examined between SSc patients and controls, and marker haplotypes were examined in families when allele frequencies appeared to be different between patients and controls. RESULTS: Although 1 polymorphism within the TGFbeta1 gene (TGFbeta1) was modestly increased in the SSc patients, this did not maintain statistical significance after correction. Similarly, 1 microsatellite (D9S120) near the TGFbeta receptor I gene (TGFBR1) showed a significant disturbance of allele frequencies between patients and controls; however, it did not form a disease-associated haplotype with other nearby markers. Weak disturbances of markers near PDGFalpha (PDGFA) and PDGFbeta, (PDGFB) also failed to maintain significance after correction. Both PDGF receptor genes (PDGFRA and PDGFRB) also showed no disease associations. CONCLUSION: The results of these preliminary analyses suggest that genetic anomalies of the TGFbeta1 and PDGF gene families are not likely to explain the dysregulation seen in SSc or to account for the susceptibility to SSc in this population.

Alleles↗
PubMed1999

Serum levels of soluble TNF alpha receptor type I and the severity of systemic sclerosis.

Several abnormalities of cytokines have been shown to occur in systemic scleroderma; however their correlation with clinical parameters is controversial. Since serum concentrations of cytokine receptors have been shown to correlate with inflammatory processes, including systemic sclerosis, the aim of our study was to compare serum concentrations of TNF alpha receptor type 1 with the concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble interleukin-2 receptor (sIL-2R) and aminoterminal propeptide of procollagen type III (PIII NP). The findings were correlated with the clinical parameters and antibody patterns, and with the disease severity. Serum samples were studied with the use of enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA) for sTNF alpha R1, sICAM-1, sIL-2R and PIII NP. The series comprised 36 patients with systemic scleroderma: 13 with diffuse variety and 23 with limited variety, and 7 with Raynaud's disease. Healthy volunteers (n = 25) were chosen from doctors and/or other laboratory staff. Increased levels of sTNF alpha-receptor type 1 were found in 77% of patients with diffuse variety and in only 30% of patients with limited form. Increased serum concentrations in patients with diffuse scleroderma and limited variety were found for sICAM-1 54% and 65%, for sIL-2R 46% and 15%, and for PIIINP 77% and 50%, respectively. There were significant correlations between serum levels of sTNF alpha-receptor type 1 and PIIINP (r = 0.653, p < 0.0001), and sTNF alpha-receptor type 1 and sIL-2R (r = 0.625, p < 0.0001), but not between sTNF alpha-receptor type 1 and sICAM-1 (r = 0.127, p < 0.526). Clinical analysis revealed that serum concentrations of sTNF alpha-RI seem to correlate best with the severity of the disease and, as the only parameter, correlated with lung involvement. The study showed that, in addition to recognized parameters of scleroderma severity (IL-2R, PIIINP), a new important marker appears to be sTNF alpha-receptor type 1.

Adult↗
PubMed1993

Immunohistochemical localization of intracellular and extracellular associated TGF beta in the skin of patients with systemic sclerosis (scleroderma) and primary Raynaud's phenomenon.

We have investigated the distribution of TGF beta using antibodies specific for its intracellular and extracellular forms in full-thickness biopsies of patients with SSc, primary Raynaud's phenomenon (PRP), systemic lupus erythematosus (SLE), and from normal subjects. Nine of 11 SSc biopsies demonstrated intracellular TGF beta in endothelial cells while only 6 exhibited extracellular TGF beta. Endothelial cells in skin biopsies of all PRP patients displayed both intracellular and extracellular TGF beta. All other control biopsies were negative. In patients with PRP, some positively staining fibroblasts were found scattered throughout the dermis. Lastly, extracellular TGF beta was localized in the papillary dermis of PRP and SSc biopsies and in all the dermal layers of SLE patients. No significant staining of TGF beta was observed in the endothelial cells, fibroblasts, or in the extracellular matrix of the majority of biopsies from normal subjects. These data suggest that TGF beta may be one of the cytokines involved in the early stages of pathogenesis of SSc, and that endothelial cells in SSc and PRP may be a source and/or a target of TGF beta.

Aged↗
PubMed1988

Cutaneous hypoxia in patients with systemic sclerosis (scleroderma).

Measurement of transcutaneous oxygen pressure (TCPO2) is an established and noninvasive way of assessing cutaneous hypoxia. Since the degree of oxygenation modulates fibroblast growth and synthesis, we investigated the presence of cutaneous hypoxia in patients with systemic sclerosis (SS). We measured TCPO2 of the involved skin of the dorsal aspect of the forearm in 33 patients with SS and 16 control individuals (normal subjects and patients with Raynaud's disease). The degree of forearm skin thickness was assessed clinically as mild, moderate, or severe. The TCPO2 measurements were obtained at a sensor temperature of 44 degrees C, which causes maximal vasodilation and eliminates the variables associated with vascular tone. Measurements were recorded while patients were breathing room air or 31% oxygen delivered by a Ventimask system (Baxter Healthcare, Ocala, Fla). We also measured the TCPO2 of the medial aspect of the arm when this site was uninvolved. We found that sclerodermatous skin is hypoxic when compared with the uninvolved skin of patients with SS or control individuals. The TCPO2 values were indirectly related to skin thickness; thus, patients whose skin was severely thickened had the lowest TCPO2 values. There was no correlation of TCPO2 values with pulmonary function tests or arterial oxygen pressure. The TCPO2 levels of patients with Raynaud's disease did not differ from other control individuals. The administration of oxygen increased TCPO2 readings in patients with SS to normal values. We conclude that the thickened skin of patients with SS is hypoxic and suggest that TCPO2 measurements may be helpful in objectively assessing the degree of skin thickness. The hypoxia demonstrated in SS skin may play a role in the modulation of dermal fibroblast proliferation and synthetic activity.

Adult↗
PubMed2006

[Current pathophysiological aspects of systemic sclerosis].

Systemic scleroderma is characterized by a chronic inflammatory process of unknown etiology resulting in an increased deposition of connective tissue proteins in the involved organs. Involvement of the vascular system and the resulting fibrosis lead to atrophy and malfunction of the involved internal organs and the skin. Due to the development of new therapeutic concepts in particular with regard to the vascular involvement, the interaction between the vascular system and the connective tissue moves increasingly into focus. This review describes the major advancemades during recent years for the understanding of the pathophysiology of systemic scleroderma.

Animals↗
PubMed2000

Ultraviolet A1 (340-400 nm) phototherapy for scleroderma in systemic sclerosis.

BACKGROUND: The presence of an inflammatory infiltrate consisting of helper T cells and a dysregulated matrix metabolism leading to excessive deposition of collagen are two pathogenetic factors responsible for the developments of fibrosis and sclerosis in patients with systemic sclerosis. In previous studies, ultraviolet A1 (UVA1) radiation phototherapy was shown to deplete skin-infiltrating T cells through the induction of T-cell apoptosis and to up-regulate the expression of matrixmetalloproteinase-1 (collagenase-1) in dermal fibroblasts. OBJECTIVE: Our purpose was to determine whether UVA1 phototherapy is effective for systemic sclerosis. METHODS: Lesional skin on the forearms of patients with systemic sclerosis (diffuse type, n =3; limited type, n =1) was exposed to medium-dose UVA1 radiation (60 J/cm(2)) daily. RESULTS: In all patients studied, UVA1 phototherapy-treated skin lesions were markedly softened after 9 to 29 exposures. Clinical improvement was associated with an increase in (1) joint passive range of motion values (P <.05), (2) skin temperature (thermography, P <.05), and (3) cutaneous elasticity (cutaneous elastometry, P <.05). Histologic evaluation of skin specimens obtained before and after UVA1 phototherapy revealed loosening of collagen bundles and the appearance of small collagen fibers. CONCLUSION: These studies indicate that UVA1 phototherapy is effective for patients with systemic sclerosis.

Aged↗
PubMed1987

Systemic sclerosis (scleroderma): clinical, genetic, and serologic subsets.

Immunogenetic markers, autoantibodies, and clinical features were studied in 47 patients, 35 Caucasian and 12 black, with systemic sclerosis. Twenty-two had generalized scleroderma, while 25 had limited skin involvement. HLA-DR1 (RR = 2.1, p = 0.08) and DR5 (RR = 2.1, p = 0.08) were increased in Caucasian patients vs controls as was the supertypic specificity HLA-DRw52 (RR = 2.8, p = 0.02, pc = 0.04). HLA-DR6.1 was increased in black patients vs controls (RR = 15.4, p = 0.008, pc = 0.088). There were no significant increases in any of the complement allotypes in either racial group. Anticentromere antibody was noted in 10 patients, all Caucasian; 7 had limited disease. Anti-Scl-70 was noted in 4 patients; all had generalized disease (p = 0.036). HLA-DR2 was present in all anti-Scl-70 positive patients (RR = 22.5, p = 0.006). Our results suggest that clinical subsets of systemic sclerosis can be defined by genetic and serological markers.

Adult↗