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PubMed2006

IL13RA2 gene polymorphisms are associated with systemic sclerosis.

OBJECTIVE: To investigate the influence of genetic variability on the phenotypic expression of systemic sclerosis (SSc), by testing possible associations between single nucleotide polymorphisms (SNP) in IL13RA1 and IL13RA2 genes and SSc in a Caucasian population. METHODS: As IL13RA1 and IL13RA2 are located on the X chromosome and SSc occurs far more frequently in women than in men, only women were genotyped. The study group comprised 97 women with SSc, 36 with diffuse (dcSSc) and 61 with limited (lcSSc) cutaneous forms of disease, and 109 healthy controls. Patients and controls were Caucasian. We investigated 4 SNP in IL13RA1 and 3 in IL13RA2 by polymerase chain reaction amplifications and enzymatic digestion or primer extension reactions and denaturing high-performance liquid chromatography. RESULTS: We detected an association between IL13RA2 rs638376 and patients with SSc [p = 0.004, odds ratio (OR) = 1.85, confidence interval (CI) 1.22-2.74, p corr = 0.02], as well as with dcSSc in that subgroup of patients (p = 0.01, OR 2.22, 95% CI 1.27-3.89, p corr = 0.05). The IL13RA2 rs638376G allele frequency was higher in patients with SSc (51.6%) than in controls (36.4%, p = 0.003, OR 1.86, 95% CI 1.24-2.79, p corr = 0.015) and in the subgroup with dcSSc (57.6%) than in controls (36.4%, p = 0.003, OR 2.37, 95% CI 1.35-4.15, p corr = 0.015). One other IL13RA2 SNP was only associated with the dcSSc subgroup: the IL13RA2 rs5946040G allele was more common in patients with dcSSc (33.8%) than in controls (17%, p = 0.004, OR 2.5, 95% CI 1.36-4.60, p corr = 0.02). CONCLUSION: Our data suggest that IL13RA2 gene polymorphisms may be involved in susceptibility to SSc. Further studies are under way to show that they contribute to disease.

Adult↗
PubMed2001

Pulmonary capillary endothelial dysfunction in early systemic sclerosis.

OBJECTIVE: Pulmonary capillary endothelium-bound angiotensin-converting enzyme (PCEB-ACE) activity is a sensitive and quantifiable index of endothelial function in vivo. Systemic sclerosis (SSc) is characterized by endothelial damage and excess collagen formation, causing mainly pulmonary hypertension (PH) in the limited cutaneous SSc (lcSSc) subset and interstitial lung disease with pulmonary interstitial fibrosis (PIF) in the diffuse cutaneous SSc (dcSSc) subset. This study was undertaken to investigate the hypothesis that PCEB-ACE activity is reduced early in SSc, in the absence of PH or PIF. METHODS: Applying indicator-dilution techniques, we measured single-pass transpulmonary hydrolysis and percent metabolism (%M) of a synthetic ACE substrate and calculated functional capillary surface area (FCSA) in 25 SSc patients and 11 controls. Substrate hydrolysis and %M reflect ACE activity per capillary; FCSA reflects ACE activity per vascular bed. RESULTS: PCEB-ACE activity was decreased in both SSc subsets. Among patients without PH, substrate hydrolysis and %M were decreased in patients with lcSSc and more profoundly in those with dcSSc; loss of FCSA normalized to body surface area (FCSA/BSA) was observed in dcSSc, but not in lcSSc. High-resolution computed tomography of the lung, performed in all SSc patients, revealed no correlation between substrate %M, hydrolysis, or FCSA/BSA and the degree of PIF; 5 dcSSc and 5 lcSSc patients with no detectable PIF exhibited decreases in hydrolysis and %M, while FCSA/BSA was decreased only in dcSSc. CONCLUSION: Depression of PCEB-ACE activity, indicating pulmonary endothelial dysfunction, occurs early in SSc, in the absence of PH or PIF, and is more pronounced, at this early pulmonary disease stage, in dcSSc than in lcSSc.

Adult↗
PubMed2001

European multicentre study to define disease activity criteria for systemic sclerosis. II. Identification of disease activity variables and development of preliminary activity indexes.

OBJECTIVE: To develop criteria for disease activity in systemic sclerosis (SSc) that are valid, reliable, and easy to use. METHODS: Investigators from 19 European centres completed a standardised clinical chart for a consecutive number of patients with SSc. Three protocol management members blindly evaluated each chart and assigned a disease activity score on a semiquantitative scale of 0-10. Two of them, in addition, gave a blinded, qualitative evaluation of disease activity ("inactive to moderately active" or "active to very active" disease). Both these evaluations were found to be reliable. A final disease activity score and qualitative evaluation of disease activity were arrived at by consensus for each patient; the former represented the gold standard for subsequent analyses. The correlations between individual items in the chart and this gold standard were then analysed. RESULTS: A total of 290 patients with SSc (117 with diffuse SSc (dSSc) and 173 with limited SSc (lSSc)) were enrolled in the study. The items (including Delta-factors-that is, worsening according to the patient report) that were found to correlate with the gold standard on multiple regression were used to construct three separate 10-point indices of disease activity: (a) Delta-cardiopulmonary (4.0), Delta-skin (3.0), Delta-vascular (2.0), and Delta-articular/muscular (1.0) for patients with dSSc; (b) Delta-skin (2.5), erythrocyte sedimentation rate (ESR) >30 mm/1st h (2.5), Delta-cardiopulmonary (1.5), Delta-vascular (1.0), arthritis (1.0), hypocomplementaemia (1.0), and scleredema (0.5) for lSSc; (c) Delta-cardiopulmonary (2.0), Delta-skin (2.0), ESR >30 mm/1st h (1.5), total skin score >20 (1.0), hypocomplementaemia (1.0), scleredema (0.5), digital necrosis (0.5), Delta-vascular (0.5), arthritis (0.5), TLCO <80% (0.5) for all patients with SSc. The three indexes were validated by the jackknife technique. Finally, receiver operating characteristic curves were constructed in order to define the value of the index with the best discriminant capacity for "active to very active" patients. CONCLUSIONS: Three feasible, reliable, and valid preliminary indices to define disease activity in SSc were constructed.

Adolescent↗
PubMed1993

The predictive value of appearances on thin-section computed tomography in fibrosing alveolitis.

Fibrosing alveolitis, a condition characterized by a poor prognosis and a limited response to treatment, is readily identified by thin-section computed tomography (CT). Fibrotic and inflammatory histologic results, obtained at open lung biopsy, both have characteristic CT patterns. To evaluate whether CT could predict prognosis and response to therapy, we examined the CT appearances of 76 patients with lone cryptogenic fibrosing alveolitis and 66 patients with fibrosing alveolitis associated with systemic sclerosis. CT abnormalities were categorized as predominantly a ground-glass pattern (Grade 1), mixed (Grade 2), or predominantly a reticular pattern (Grade 3). In cryptogenic fibrosing alveolitis, 4-yr survival was highest in association with CT Grade 1 and higher with CT Grade 2 than with CT Grade 3, independent of the extent of abnormal lung on CT, duration of dyspnea, or severity of depression of DLCO or FVC, p < 0.001. A response to therapy in previously untreated cryptogenic fibrosing alveolitis was seen most frequently with CT Grade 1 and more frequently with CT Grade 2 than with CT Grade 3, p < 0.025. In systemic sclerosis, CT appearances were not predictive of 4-yr survival; a response to therapy was seen more frequently with CT Grade 2 (three of seven patients) than with CT Grade 3 (zero of six patients). These data have shown that CT appearances are of prognostic value in fibrosing alveolitis and that they are likely to play an increasing role in disease-staging in this condition.

Adult↗
PubMed2000

Serum levels of tissue inhibitor of metalloproteinases 2 in patients with systemic sclerosis.

BACKGROUND: The serum tissue inhibitor of metalloproteinases 1 (TIMP-1) level was reported to be a useful indicator of disease activity, especially of lung fibrosis in patients with systemic sclerosis. TIMP-2 is also an important inhibitor of matrix metalloproteinases (MMPs), such as interstitial collagenase, gelatinase, and stromelysin, which control the metabolism of the extracellular matrix. However, serum levels of TIMP-2 in patients with systemic sclerosis (SSc) have not been investigated. OBJECTIVE: We sought to determine the clinical significance of serum levels of TIMP-2 and MMP-2 in patients with SSc. METHODS: Serum samples were obtained from 128 patients with SSc (68 with limited cutaneous SSc and 60 with diffuse cutaneous SSc). Twenty-seven serum samples from healthy age- and sex-matched individuals were also examined as controls. The TIMP-2 and MMP-2 levels were determined by means of sandwich enzyme-linked immunosorbent assays. RESULTS: The serum TIMP-2 levels were elevated in 29 (22.7%) of the 128 patients with SSc and were significantly higher than those of the healthy control subjects. The serum TIMP-2 levels were significantly correlated with the extent of skin sclerosis in the patients with SSc. The incidence of decreased percentage of the diffusing capacity of lung for carbon monoxide (DLCO ) and that of an elevated erythrocyte sedimentation rate were significantly greater in the patients with elevated TIMP-2 levels compared with the patients with normal TIMP-2 levels (P <.05). When these patients were classified into 2 groups by disease activity, TIMP-2 levels were significantly more elevated in the high active group than in those low active group (P <.001). The serum MMP-2 levels of the patients with SSc were not significantly higher than those of the healthy control subjects. CONCLUSION: These findings suggest that the serum TIMP-2 level is a useful marker of the extent of skin sclerosis and disease activity in patients with SSc. The balance of TIMP-2 and MMP-2 may play an important role in patients with SSc. Furthermore, TIMP-2 may be thought to contribute to the development of disease in patients with SSc.

Adolescent↗
PubMed2004

Serum soluble CTLA-4 levels are increased in diffuse cutaneous systemic sclerosis.

OBJECTIVE: To determine serum levels of soluble cytotoxic T-lymphocyte associated molecule-4 (sCTLA-4) and clinical association in patients with systemic sclerosis (SSc). METHODS: Serum sCTLA-4 levels from 32 patients with diffuse cutaneous SSc (dSSc) and 27 patients with limited cutaneous SSc (lSSc) were examined by enzyme-linked immunosorbent assay (ELISA). For a longitudinal study, 211 sera from 30 SSc patients were analysed (follow-up 2.1-7.0 yr). RESULTS: Serum sCTLA-4 levels were elevated in dSSc patients compared with normal controls (n = 41), lSSc patients and patients with active systemic lupus erythematosus (SLE) (n = 23). By contrast, sCTLA-4 levels in patients with lSSc or SLE were normal. SSc patients with elevated sCTLA-4 levels had a shorter disease duration and more frequent presence of digital pitting scars, contracture of phalanges, diffuse pigmentation, pulmonary fibrosis and decreased percentage vital capacity (%VC) than those with normal sCTLA-4 levels. sCTLA-4 levels correlated positively with the extent of skin fibrosis, serum IgG levels and anti-topoisomerase I antibody levels. In a longitudinal study, sCTLA-4 levels decreased on a parallel with improvement of skin sclerosis in five dSSc patients. Skin sclerosis did not improve in two of six dSSc patients with high sCTLA-4 levels throughout the follow-up, while the remaining four patients showed improvement of skin sclerosis. CONCLUSION: These results suggest that sCTLA-4 correlates with disease severity and activity of SSc and that sCTLA-4 plays a role in immunological abnormalities of SSc, since sCTLA-4 may augment humoral immune responses as well as T-cell responses by interfering with B7-CTLA-4 interactions that induce negative signals in T and B cells.

Antigens, CD↗
PubMedDate not supplied

Clinical determinants of bone mass and bone ultrasonometry in patients with systemic sclerosis.

OBJECTIVE: The aim of this study was to evaluate bone mass and bone ultrasonometry in patients affected with systemic sclerosis (SSc). METHODS: Fifty-five patients (mean age 54.1 +/- 14.1 years; 25 premenopausal, and 30 postmenopausal women) affected with SSc (in a limited, intermediate or diffused form) and 60 age-matched healthy controls (30 premenopausal, and 30 postmenopausal women) were studied for Bone Mineral Density (BMD) measured by fan-beam x-ray densitometry, Stiffness Index (SI) measured by ultrasonometry of the heel, inflammation indices (erithrocyte sedimentation rate, C-reactive protein), and autoantibodies (ANA, ENA). Examinations were also carried out in order to determine any internal organ involvement. None of the patients had previously received steroid treatment. RESULTS: BMD was significantly lower in the SSc group than in the control group, whether it was expressed in g/cm2 (lumbar spine: 0.980 vs 1.241, p < 0.01; femoral neck: 0.832 vs 0.955, p < 0.05; total body 1.050 vs 1.168, p < 0.01) or by T- and Z-score (lumbar spine: T = -2.48; Z = -1.10; femoral neck: T = -1.69; Z = -0.55; total body: T = -1.11; Z = -0.48). SI was also altered (75.8 vs 96.2, p < 0.01; T = -2.10, Z = -1.12). BMD and SI were lower in women with the diffuse form of skin involvement. BMD and SI were lower in women in whom one or more internal organs were involved. CONCLUSION: SSc patients had reduced BMD and SI that was more marked in the diffuse form and in those with internal organ involvement and that became more marked with age and estrogen deficiency. This demineralisation was not related to the inflammation indices, disease duration, or to the immunological pattern.

Absorptiometry, Photon↗
PubMed2006

Hemorheologic profile in systemic sclerosis: role of NOS3 -786T > C and 894G >T polymorphisms in modulating both the hemorheologic parameters and the susceptibility to the disease.

OBJECTIVE: Microvascular disorders are relevant in systemic sclerosis (SSc). Hyperviscosity, due to alterations of blood cells and plasma components, may play a role in the pathogenesis of microcirculatory disorders. An impaired availability of nitric oxide, related to polymorphisms in NOS3, the gene for endothelial cell nitric oxide synthase, might influence erythrocyte deformability. We undertook this study to investigate the hemorheologic profile in SSc and the role of NOS3 polymorphisms in modulating the hemorheologic status of SSc patients. METHODS: We studied 113 consecutive SSc patients (75 with limited cutaneous SSc [lcSSc] and 38 with diffuse cutaneous SSc [dcSSc]) and 113 healthy controls. The hemorheologic profile was obtained by assessing whole blood viscosity (WBV; at shear rates of 0.512 and 94.5 seconds(-1)), plasma viscosity (PLV; at a shear rate of 94.5 seconds(-1)), and erythrocyte deformability index (DI). We determined NOS3 polymorphisms by molecular analysis. RESULTS: A marked alteration of hemorheologic parameters was found both in patients with lcSSc and in those with dcSSc compared with controls (P < 0.0001). In multivariate analysis, rheologic variables were significantly associated with the disease (for WBV at a shear rate of 94.5 seconds(-1), odds ratio [OR] 5.4, 95% confidence interval [95% CI] 1.4-19.9, P = 0.01; for PLV, OR 2.8, 95% CI 1.2-6.5, P = 0.01; for DI, OR 3.9, 95% CI 1.4-10.8, P = 0.007), and NOS3 -786C and 894T alleles significantly affected the DI (for -786C allele, OR 2.3, 95% CI 1.01-5.4, P = 0.04; for 894T allele, OR 2.2, 95% CI 1.01-4.8, P = 0.04). The simultaneous presence of the -786C and 894T alleles represented a susceptibility factor for SSc (OR 2.8, 95% CI 1.4-5.7, P = 0.004). CONCLUSION: Our findings document an altered rheologic profile in SSc and demonstrate a relationship between this alteration and NOS3 polymorphisms, thus shedding light on a potential novel mechanism influencing the microcirculation in this disease.

Aged↗
PubMed2003

N-terminal pro-brain natriuretic peptide as a diagnostic marker of early pulmonary artery hypertension in patients with systemic sclerosis and effects of calcium-channel blockers.

OBJECTIVE: To evaluate N-terminal pro-brain natriuretic peptide (NT-proBNP) as a marker of early pulmonary artery hypertension (PAH) and to study changes in the levels of this marker following treatment with dihydropyridine-type calcium-channel blocker (DTCCB) in patients with systemic sclerosis (SSc). METHODS: We evaluated 40 consecutive SSc patients who had been hospitalized for followup care (mean +/- SD age 56 +/- 11 years and mean +/- SD duration of cutaneous disease 9 +/- 9 years; 27 with limited cutaneous and 13 with diffuse cutaneous disease) but who had no clinical symptoms of heart failure and had a normal left ventricular ejection fraction. At baseline, 10 patients had PAH, defined as a systolic pulmonary artery pressure (sPAP) >40 mm Hg, as measured by echocardiography. Levels of NT-proBNP were determined at baseline (after discontinuation of DTCCB treatment for 72 hours), after taking 3 doses of DTCCB following treatment reinitiation (assessment 1), and after 6-9 months of continuous DTCCB treatment (assessment 2) in the 20 patients who attended regular appointments (including the 10 patients with PAH at baseline). RESULTS: At baseline, 13 patients had high NT-proBNP values for their ages. High NT-proBNP levels identified patients with PAH with a sensitivity of 90%, a specificity of 90.3%, a positive predictive value of 69.2%, and a negative predictive value of 96%. The NT-proBNP level correlated with the sPAP (r = 0.44; P = 0.006). By assessment 1, the number of patients with PAH and high levels of NT-proBNP had decreased from 9 of 10 to 2 of 10 (P = 0.02). This decrease was partially sustained at assessment 2 (4 of 10 patients; P = 0.06). CONCLUSION: NT-proBNP is a useful biologic marker that can be used to diagnose early PAH in SSc patients without clinical heart failure. Measurement of NT-proBNP may be valuable for the evaluation of treatment with DTCCB and vasodilators in patients with PAH.

Aged↗
PubMedDate not supplied

Anti-endothelial cell antibodies in systemic sclerosis: significant association with vascular involvement and alveolo-capillary impairment.

OBJECTIVE: To assess the frequency of antiendothelial cell autoantibodies (AECAs) in a group of patients with systemic sclerosis (SSc) and possible associations with clinical and serologic features of the disease. METHODS: Sera from 50 patients with SSc (38 with the limited and 12 with the diffuse form) were screened for AECA (ELISA). The reference limits were were 56.6% for the IgM isotype and 3.3.5% for the IgG isotype. AECA results were analyzed in relation to lung involvement (chest x-ray, high resolution computed tomography (HRCT), ventilation scintiscan with radioaereosol (DTPA), pulmonary pressure (echodoppler technique): heart involvement (EKG, 24 hr ambulatory EKG, echocardiography), cutaneous involvement (skin score), capillaroscopic characteristics and digital ulcers. AECA were also correlated with the erythrocyte sedimentation rate (ESR), anticentromere (ACA) and antitopoisomerase I (ATA) autoantibodies, and angiotensin converting enzyme plasma levels (ACE). RESULTS: The AECA IgG prevalence was 40% (22/50) for the SSc group as a whole, without significant differences between subsets. A significant negative correlation was shown between the AECA and ACE plasma levels in both subsets. In the diffuse form, a significant positive correlation was found between AECA and ESR and significant associations were found between AECA and the parameters reflecting alveolo-capillary involvement (DLco, DTPA), the pulmonary artery pressures, digital ulcers and capillaroscopic abnormalities. No statistically significant correlations were found between AECA and heart involvement, the skin score or pulmonary interstitial fibrosis. CONCLUSIONS: These data suggest that in SSc the anti-endothelial cell antibodies are directly linked to vascular injury and could reflect endothelial damage. Further studies are needed to verify whether AECA might identify a subgroup of patients at higher risk for the development of vascular crises and whether they might therefore be considered a predictor of outcome in SSc patients.

Autoantibodies↗
PubMed2004

Peripheral vasculopathy in patients with systemic sclerosis: difference in limited and diffuse subset of disease.

OBJECTIVE: To examine the difference in clinical signs of peripheral vasculopathy in patients (pts) with limited (lcSSc) and diffuse cutaneus systemic sclerosis (dcSSc). PATIENTS AND METHODS: Ninety one patients with systemic sclerosis (39 with lcSSc and 52 with dcSSc) have been assessed for the presence of clinical signs of vascular injury: Raynaud's phenomenon, severity of capillary damage on capillaroscopy, presence or absence of finger-tip ulcers or pitting scars, presence of telangiectasias and radiographic signs of finger-tip osteolysis. Statistical significance of difference in clinical manifestations of peripheral vasculopathy in pts with lcSSc and dcSSc was assessed using the Mann-Whitney and X2-test. RESULTS: Duration of Raynaud's phenomenon before manifestation of skin or internal organ damage, was significantly longer (z=-2.54, p=0.004) in patients with lcSSc (5.4 years) than in patients with dcSSc (1.9 years). Using the technique of nailfold capillaroscopy, we found normal capillaries or non-specific capillary change in 10.2% pts with lcSSc and only in 2.0% pts with dcSSc. Enlarged capillaries without significant loss of capillaries were found in 38.5% pts with lcSSc, and 11.5% pts with dcSSc (p=0.05). But severe capillary damage, with significant loss of capillaries, was noticed more frequently in pts with dcSSc (dcSSc/lcSSc: 86.5%/51.3%, p=0.002). Pitting scars or digital ulcers were found in 46.2% pts with lcSSc and 67.3% pts with dcSSc (p=0.04). We did not notice significant difference in frequency of finger-tip osteolysis (lcSSc/dcSSc: 23.1%/21.2%, p>0.05) and telangiectasias (lcSSc/dcSSc: 46.2%/53.8%, p>0.05). CONCLUSION: Severe capillary damage and digital ulcers are more common in patients with diffuse cutaneus systemic sclerosis, but finger-tip osteolysis and telangiectasias are equally frequent in both form of disease.

Capillaries↗
PubMed1999

Clinical and serological associations with anti-RNA polymerase antibodies in systemic sclerosis.

There are three classes of RNA polymerase enzyme (RNAPs I, II and III). In systemic sclerosis (SSc), three main groups of anti-RNAP sera have been characterized by radioimmunoprecipitation techniques: anti-RNAP I/III sera, anti-RNAP I/II/III sera, and a group precipitating both RNAP II and topoisomerase I (topo I). Some sera in this third group precipitate the phosphorylated (IIO) form of RNAP II in the absence of the unphosphorylated (IIA) form. Certain other antinuclear antibodies (ANA) have also been detected in anti-RNAP IIO/IIA/topo I and anti-RNAP IIO/topo I sera. In the present study of 155 SSc patients, clinical features of individuals from each of these antibody groups were assessed and compared with those of patients from other autoantibody-defined groups. The anti-RNAP I/II/III antibody specificity was closely associated with the presence of diffuse cutaneous SSc (dc-SSc) (77.8%; cf. remaining group, 12.4%; P < 0.001; relative risk (RR) 6.3). Patients with anti-RNAP I/III antibodies also had an increased incidence of dc-SSc, but this was not significant (42.9%; cf. remainder, 15.7%). Anti-RNAP+ patients had a significantly increased incidence of renal involvement (29.0%, cf. remainder, 11.3%; P < 0.05; RR 2.6), with 40% of anti-RNAP I/II/III patients having renal disease. Meanwhile, the presence of anti-centromere antibodies (ACA) was associated with limited cutaneous SSc (lc-SSc) (100.0%; cf. remainder, 75.3%; P < 0. 005), together with reduced incidences of both renal disease (2.4%, cf. remainder, 22.1%: P < 0.01) and pulmonary fibrosis (21.4%, cf. remainder, 52.3%; P < 0.005; RR 1.9). Anti-topo I antibodies were associated with the presence of pulmonary fibrosis (69.7%; cf. remainder, 32.6%; P < 0.001; RR 2.1). A majority of anti-topo I sera were from lc-SSc patients, regardless of whether anti-topo I antibodies occurred alone (75.0%) or together with anti-RNAP IIO + IIA antibodies (75.0%), and this was similar to the remainder (86. 5%; NS). However, when anti-topo I+ patients were compared with the ACA group, and then with all anti-RNAP I+ patients (37.5% lc-SSc), significant differences were found in the occurrence of dc- versus lc-SSc (P < 0.005 and P < 0.05, respectively). In conclusion, these results confirm that there are three main groups of SSc sera, each characterized by the presence of a mutually exclusive SSc-specific autoantibody (ACA, anti-topo I or anti-RNAP I), and distinguished by patterns of cutaneous involvement and specific clinical features. It appears that, in each of the three groups of SSc patients, distinct pathological processes are occurring, which are responsible for the characteristic symptoms, for the modification of particular autoantigens and, consequently, for the production of particular autoantibodies. Based on these data, together with our previous results, it is further hypothesized that anti-RNAP II antibodies may be produced in the context of two different immune response pathways.

Antibodies, Antinuclear↗
PubMed1996

Computer based quantitative analysis of capillary abnormalities in systemic sclerosis and its relation to plasma concentration of von Willebrand factor.

OBJECTIVES: To evaluate an objective and quantitative method for assessment of capillary abnormalities in systemic sclerosis (SSc). METHODS: Nailfold capillaries were investigated by capillary microscopy and photographed in 17 consecutive SSc patients (five with diffuse cutaneous systemic sclerosis (dSSc) and 12 with limited cutaneous systemic sclerosis (lSSc)) and in 17 healthy controls. Investigators having no access to clinical data made drawings from magnified projections of coded photographs and analysed them using a computer program. Capillary density (capillary loops/mm in the distal row) and median capillary loop area were calculated. Presence of functional or organic arterial changes was evaluated by measurement of finger pressure with finger cooling. Plasma concentration of von Willebrand factor (VWF) was analysed using an enzyme linked immunosorbent assay (ELISA). RESULTS: In 16 of 17 SSc patients and 13 of 17 controls the technical quality of the photographs was sufficient for computer analysis. Capillary density was decreased in dSSc (median 6.9 loops/mm) and in lSSc (median 3.8 loops/mm) compared with healthy controls (8.9 loops/mm) and median capillary loop area was increased in dSSc (7.3 x 10(-3) mm2) and in lSSc (8.5 x 10(-3) mm2) compared with healthy controls (5.0 x 10(-3) mm2). An inverse relation was found between capillary density and median capillary loop area in SSc patients. Plasma VWF was increased in patients (median 401 IE/l in dSSc and 409 IE/l in lSSc) compared with controls matched for age and sex (median 276 IE/l). Computer based analysis showed capillary density below the control range and median capillary loop area above the control range in 14 of 16 SSc patients. Measurement of finger pressure with finger cooling showed organic vascular changes in nine of 13 SSc patients. CONCLUSION: Computer based quantitative analysis has low interobserver variability and is a quantitative and sensitive method of assessing capillary abnormalities in SSc.

Adolescent↗
PubMed2002

Autoantibodies to fibroblasts induce a proadhesive and proinflammatory fibroblast phenotype in patients with systemic sclerosis.

OBJECTIVE: Fibroblasts play a major role in the development of systemic sclerosis (SSc), and the occurrence of serum autoantibodies reacting with fibroblast plasma membrane antigens in SSc has been reported. This study was undertaken to investigate whether IgG from SSc sera that react with human fibroblasts modulates the fibroblasts' function. METHODS: Sera from 69 patients with SSc (28 with limited cutaneous SSc [lcSSc] and 41 with diffuse cutaneous SSc [dcSSc]), 30 patients with sarcoidosis, and 50 matched healthy controls were examined. We evaluated antibody binding to human skin and lung fibroblasts by cell-based enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence, and flow cytometry. We further investigated the ability of purified IgG to modulate 1) intercellular adhesion molecule 1 (ICAM-1) expression, 2) U937 cell adhesion to fibroblasts, and 3) fibroblast steady-state messenger RNA (mRNA) levels of interleukin-1alpha (IL-1alpha), IL-beta, and IL-6, and IL-6 protein production. RESULTS: Of 69 SSc sera tested by cell-based ELISA, 58% bound to normal skin and lung fibroblasts. The prevalence of binding was significantly higher in dcSSc than in lcSSc (P < 0.05). Only IgG from SSc sera that were positive for antifibroblast antibody (AFA) induced a dose-dependent up-regulation of ICAM-1 expression and IL-6 production, enhancement of U937 cell adhesion, and increased levels of IL-1alpha, IL-1beta, and IL-6 mRNA in fibroblasts. Up-regulation of ICAM-1 mediated by AFA IgG was inhibited by the addition of IL-1 receptor antagonist, indicating an autocrine activation loop. CONCLUSION: Our findings confirm the presence of AFAs in SSc sera and demonstrate, for the first time, that autoantibodies reacting with fibroblast surface molecules act as an extrinsic stimulus inducing fibroblast activation in vitro.

Adult↗
PubMed2005

A randomized unblinded trial of cyclophosphamide versus azathioprine in the treatment of systemic sclerosis.

Current therapeutic modalities for the treatment of systemic sclerosis (SSc) have significant limitations. The window of opportunity to prevent tissue fibrosis and irreversible damage occurs during the early inflammatory phase of this condition. A drug that we believe has promise to exert a desired effect in early SSc is cyclophosphamide (CYC). However, there are only a few published reports regarding the use of cytotoxic immunosuppressive medications at the onset of the illness. The goal of this study was to test the efficacy and toxicity of CYC in patients with early diffuse SSc. The study design was a randomized, unblinded, 18 months per patient trial with a comparison group that received azathioprine (AZ). Thirty patients were assigned to receive oral CYC (2 mg/kg daily for 12 months and then maintained on 1 mg/kg daily) and 30 patients were assigned to receive oral AZ (2.5 mg/kg daily for 12 months and then maintained on 2 mg/kg daily). During first 6 months of the trial, the patients also received prednisolone, which was started at a dosage of 15 mg daily and tapered to zero by the end of the sixth month. After treatment there was a statistically significant improvement in the modified Rodnan skin score (MRSS), attack frequency of Raynaud's phenomenon (RP), and erythrocyte sedimentation rate (ESR) in the CYC-group, but not in the AZ-group. The forced vital capacity (FVC) and carbon monoxide diffusing capacity (DLCO) did not change after treatment in the CYC-group, but statistically significantly worsened in the AZ-group. No life-threatening or irreversible adverse reactions were observed in either group. This study showed that CYC is a promising disease modifying medication for SSc as it exhibited a positive influence on the evolution of disease.

Administration, Oral↗
PubMed2000

Favourable outcome in 135 children with juvenile systemic sclerosis: results of a multi-national survey.

OBJECTIVE: To increase the current knowledge of the outcome of juvenile systemic sclerosis (jSSc), which is currently limited. METHODS: In order to investigate the patient outcome and prognostic factors, starting October 1994, we distributed questionnaires to 324 paediatric rheumatology centres. RESULTS: Until 15 May 1998 responses from 46 centres were received, 34 of which returned completed questionnaires on a total of 135 patients. One hundred and twenty-two of the 135 patients were Caucasian, 100 were female. The mean age at disease onset was 8.8 yr (S.D. +/- 3.3 yr). The mean disease duration at the last follow-up was 5 yr(S.D. +/- 3.3 yr). At the last follow-up the disease was still active and required medication in 82 patients, 36 had inactive disease on medication, and 16 were in remission. Ninety per cent of the living patients were fully active in daily life at the last follow-up. Eight of the 135 patients had died. These patients had a median age at onset of the disease of 10.5 yr (range 6.7-15.8 yr). The median disease duration until death was 2 yr (range 1-8 yr). The causes of death were heart failure (five), renal failure (one), sepsis (one) and in one case the cause was not defined. The 1 yr survival rate was 99%, the 2 yr was 97% and the 4 yr was 95%. CONCLUSIONS: At a mean follow-up of 5 yr, the current results show a favourable outcome in most patients with childhood onset jSSc and a significantly better survival than in the adult SSc patients.

Adult↗
PubMed2005

Early impairment of myocardial function in systemic sclerosis: non-invasive assessment by Doppler myocardial and strain rate imaging.

BACKGROUND: Aim of the present study was to analyze both left (LV) and right ventricular (RV) myocardial function in patients with Systemic Sclerosis (SSc), and their relation to other instrumental features of the disease. METHODS AND RESULTS: Twenty-five healthy subjects and 23 age- and sex-comparable asymptomatic patients classified as having either diffuse (11 patients) or limited form (12 patients) of SSc underwent clinical examination, serological tests, high-resolution chest-CT, standard Doppler echo, pulsed Doppler myocardial imaging (DMI) and strain rate imaging (SRI) of both LV and RV lateral walls. By chest-CT, 11 patients showed interstitial pulmonary fibrosis. Serological antibodies analysis detected anti-centromere pattern in 8 patients, and anti Scl-70 in 15 patients. LV diameters and ejection fraction were comparable between the two groups, while RV end-diastolic diameter was increased in SSc (p<0.01). Tricuspid inflow E/A ratio was slightly decreased in SSc (p<0.01), while systolic pulmonary pressure was increased (p<0.001). Pulsed DMI detected in SSc impaired myocardial RV early-diastolic (Em) peak velocity (p<0.0001), and prolonged myocardial time intervals at tricuspid annulus level. In SSc, peak systolic RV SR and strain were both reduced in basal, middle and apical RV lateral free walls, and in basal and middle LV lateral walls. By multivariate analysis, independent inverse association of RV peak Em velocity with both Rodnan Skin Score (p<0.0005) and pulmonary systolic pressure (p<0.0001), as well as independent inverse correlation of the same RV peak Em velocity with pulmonary fibrosis (<0.0005) in SSc patients were observed. In addition, RV Em was an independent predictor of the anti Scl-70 antibody pattern (p<0.001). CONCLUSIONS: Pulsed DMI and SRI are valuable non-invasive and easy-repeatable tools for detecting RV and LV myocardial involvement caused by SSc, and may therefore be useful to early identify patients with more diffused and severe form of SSc.

Autoantibodies↗
PubMedDate not supplied

A double-blind placebo-controlled trial of antioxidant therapy in limited cutaneous systemic sclerosis.

OBJECTIVE: To evaluate the effects of a combination of micronutrient antioxidants (selenium, beta-carotene, vitamin C, vitamin E and methionine) with allopurinol in patients with limited cutaneous systemic sclerosis (SSc). METHODS: The study was designed as a placebo-controlled double-blind crossover study. A carryover effect was detected retrospectively for some of the prescribed antioxidants, and so the data were analysed as: (a) a between group comparison of the first 10 week treatment period; and (b) a within group comparison of the first and second 10-week periods in those who received placebo treatment first. Study end-points were plasma von Willebrand factor (vWF), thermographic response to a standard cold challenge, frequency and duration of Raynaud's attacks, patient opinion, and specialised biochemical parameters (fatty acid profiles, antioxidants and markers of free radical injury). RESULTS: Thirty-three patients were recruited. The median duration of Raynaud's phenomenon was 10 years (range 2 to 50 years) in the active-first group and 10 years (range 4 to 53 years) in the placebo-first group. In the 10-week study, there were no differences between the active and placebo groups in the change from baseline for vWF, for the parameters of the rewarming curve, or for patients' symptoms. Despite a rise in circulating antioxidant levels, there was no fall in markers of free radical mediated injury. In the 20-week cross-over study, patients did not experience any clinical benefit from active treatment compared to placebo. CONCLUSION: No clinical benefit could be demonstrated from active treatment. There are several possible explanations for this negative result, including the short duration of therapy. It is possible that antioxidant therapy, to be effective, needs to be given early in the SSc disease process, before the onset of irreversible tissue damage.

Adult↗