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PubMed1998

Different patterns of endothelial cell activation in renal and pulmonary vascular disease in scleroderma.

Abnormal endothelial cell function is implicated in the development of scleroderma, and in major life-threatening complications of the disease. The nature of the stimulus leading to abnormal endothelial cell function in scleroderma, scleroderma renal crisis, and scleroderma-associated pulmonary hypertension was investigated by measurement of soluble adhesion molecules, shed by activated endothelial cells, in sera from patients with these conditions. In scleroderma renal crisis, mean levels of soluble E-selectin (p < 0.05 limited scleroderma, p < 0.0001 diffuse scleroderma), sVCAM-1 (soluble vascular cell adhesion molecule-1) (p < 0.05 limited scleroderma, p < 0.05 diffuse scleroderma), and sICAM-1 (soluble intercellular adhesion molecule-1) (p < 0.0001 limited scleroderma, p < 0.0001 diffuse scleroderma) were raised, supporting a model of endothelial cell activation in this complication. Evidence for endothelial cell activation in scleroderma-associated pulmonary hypertension was inconsistent, with normal sE-selectin and normal sVCAM-1 in sera from patients with limited scleroderma and pulmonary hypertension. The endothelial cell phenotype in scleroderma-associated pulmonary hypertension may resemble that of unstimulated cells. The pulmonary vascular and renal vascular lesions associated with scleroderma may arise by distinct pathogenic mechanisms.

Acute Kidney Injury↗
PubMed1986

[Systemic scleroderma. Contribution of esophageal manometry].

Oesophageal motor function was studied by oesophageal manometry in 48 patients with progressive systemic sclerosis: 25 with proximal scleroderma and 23 with diffuse scleroderma. Oesophageal lesions were noted in 70% (74% in diffuse scleroderma; 64% in proximal scleroderma). Classical manometric signs of scleroderma were found in only 31% of patients. Peristaltic modifications might begin at the junction of the two muscular coats, since a four centimeter long aperistaltic suspended area was noted in that region in 20% of patients, especially in the proximal scleroderma group. Oesophageal motility and low lower oesophageal sphincter pressure account for the gastro-oesophageal reflux and may compromise respiratory function, as suggested by the high frequency of concurrent oesophageal and respiratory dysfunction in diffuse scleroderma. Systematic prevention of gastro-oesophageal reflux should perhaps be advocated as soon as abnormalities in oesophageal motility are diagnosed.

Adolescent↗
PubMed1984

Factors predicting development of renal involvement in progressive systemic sclerosis.

Renal involvement or "scleroderma renal crisis" developed in 60 patients with progressive systemic sclerosis evaluated at the University of Pittsburgh during the period from 1972 to 1982. Forty-seven of these patients had progressive systemic sclerosis with diffuse scleroderma, representing 18 percent of persons with progressive systemic sclerosis and diffuse scleroderma evaluated during this time period. Ten additional patients did not have truncal scleroderma but were suspected of having incompletely developed diffuse scleroderma. Only three patients were classified as having progressive systemic sclerosis with the CREST syndrome. Renal crisis was observed early in the course of the illness, a mean of 3.2 years after onset. During May and June, this complication developed in fewer patients than expected. Thirty-six patients who had diffuse scleroderma and renal involvement after their initial Pittsburgh evaluation were compared with 212 who had diffuse scleroderma without renal involvement during follow-up. The patients with renal involvement had a shorter mean disease duration at the time of their first evaluation (2.4 versus 4.2 years, p less than 0.05) and less frequently had digital pitting scars (29 versus 54 percent), but no other significant clinical, laboratory, or serologic differences were noted. Data available for 31 patients with renal involvement during the six months preceding the onset of renal disease were analyzed. Blood pressure, serum creatinine, urine protein and red blood cells, and plasma renin levels were similar in these patients and the 212 patients without renal involvement. More patients with renal involvement had anemia or clinical evidence of cardiac involvement during this period compared with the patients without renal involvement. During the 12-month period prior to renal involvement, seven of 16 (44 percent) patients with such involvement had an impressive increase in skin thickening on physical examination compared with only 23 of 180 (14 percent) patients without renal involvement at any time during their course. Thus, the subset of patients with diffuse scleroderma who show rapid progression of their skin thickening early in the illness with development of anemia, pericardial effusion, or congestive heart failure have a high risk of "scleroderma renal crisis."

Creatinine↗
PubMed1999

Interferon-alpha does not improve outcome at one year in patients with diffuse cutaneous scleroderma: results of a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To determine whether interferon-alpha (IFNalpha) reduces the severity of skin involvement in early (<3 years) diffuse scleroderma. METHODS: In a randomized, placebo-controlled, double-blind trial, 35 patients with early scleroderma received subcutaneous injections of either IFNalpha (13.5 x 10(6) units per week in divided doses) or indistinguishable placebo. Outcomes assessed were the modified Rodnan skin score, as determined by a single observer at baseline, 6 months, and 12 months, as well as data on renal, cardiac, and lung function. Pre- and posttreatment skin biopsy samples were analyzed and blood was obtained for assessment of procollagen peptide levels. RESULTS: There were 11 withdrawals from the IFNalpha group and 3 from the placebo group due to either toxicity, lack of efficacy, or death. In the intent-to-treat analysis, there was a greater improvement in the skin score in the placebo group between 0 and 12 months (mean change IFNalpha -4.7 versus placebo -7.5; P = 0.36). There was also a greater deterioration in lung function in patients receiving active therapy, as assessed by either the forced vital capacity (mean change IFNalpha -8.2 versus placebo +1.3; P = 0.01) or the diffusing capacity for carbon monoxide (mean change IFNalpha -9.3 versus placebo +4.7; P = 0.002). Skin biopsy showed no significant decrease in collagen synthesis in the IFNalpha group, and no significant differences in the levels of procollagen peptides were seen between the 2 groups. CONCLUSION: This study suggests that IFNalpha is of no value in the treatment of scleroderma, and that it may in fact be deleterious.

Adolescent↗
PubMed1998

Safety and pharmacokinetics of recombinant human relaxin in systemic sclerosis.

OBJECTIVE: To investigate the safety and pharmacokinetics of a 28 day continuous subcutaneous infusion of recombinant human relaxin in patients with systemic sclerosis with diffuse scleroderma. METHODS: Thirty patients with stable diffuse scleroderma of moderate severity received recombinant human relaxin at 6, 12, 50, 100, and 200 microg/kg/day or placebo in a double blind, sequential panel, dose escalation study. RESULTS: All patients completed 28 days of study treatment. Steady state concentrations of serum relaxin were achieved by the 3rd day of infusion and were dose proportionate. Patients receiving 200 microg/kg/day achieved levels about 50-fold those of normal pregnancy. Pharmacokinetics of relaxin were nonlinear with hyperbolic increases of both t1/2 and volume of distribution and parallel decrease of elimination rate coefficient. An elimination transport system was suggested with saturation at serum relaxin concentration of 45 ng/ml. Adverse events included local infusion site rash and pain, minor bleeding episodes, and decreased hemoglobin concentration (mean reduction 1.1 g/dl). Standard measures of scleroderma were unchanged, although global assessment favored relaxin over placebo. CONCLUSION: Recombinant human relaxin in the doses used was safe and well tolerated. Longer term controlled trials are warranted to define the potential efficacy of relaxin in patients with diffuse scleroderma.

Adult↗
PubMed1991

Immunologic markers of systemic scleroderma in children.

This study was performed on seven children with systemic scleroderma, three with the diffuse and four with the limited type. All three patients with diffuse scleroderma had high titers of clumpy pattern antinucleolar antibody on HEp-2 cells. The course of the disease was severe, and two children died. Four children with limited scleroderma had mild disease, and Scl-70 antibody, an immunologic marker that in adults is associated mostly with diffuse scleroderma. In one child Scl-70 antibody and anticentromere antibody coexisted, although previously the two were believed to be mutually exclusive. This study shows that limited scleroderma of childhood with slight cutaneous involvement may be associated with the Scl-70 marker. The findings in 10 adults in whom Raynaud's phenomenon developed in childhood and indurations appeared some years later, point to the significance of careful observation of these children, with repeated testing for immunologic markers of SSc. An important new finding is the association of different types of systemic sclerodermas with specific immunologic markers.

Adolescent↗
PubMed1976

Cutaneous antigen-stimulating lymphokine production by lymphocytes of patients with progressive systemic sclerosis (scleroderma).

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.

Adolescent↗
PubMed1980

The fascia in systemic scleroderma.

Diffuse fasciitis (DF) shares clinical and pathologic features with systemic (SS) and localized scleroderma. The distinct pathologic feature in DF is involvement of the deep fascia, but it is not known if these changes consistently occur in SS. In this study, ten patients with SS underwent deep biopsies for evaluation of the fascia. All cases showed typical dermal histologic findings of scleroderma, and five cases showed thickening and fibrosis of the fascia. This study provides evidence that fascial involvement is not distinctive of DF but may occur in SS. It appears that thickening of the fascia is another morphologic feature shared between DF and SS.

Adult↗
PubMed1985

Noninvasive evaluation of cardiac dysrhythmias, and their relationship with multisystemic symptoms, in progressive systemic sclerosis patients.

Fifty-three patients (34 who had diffuse scleroderma, and 19 who had CREST syndrome [calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias]) were studied by noninvasive procedures, including resting electrocardiogram (ECG), continuous 24-hour Holter ECG monitoring, M-mode echocardiography, and 2-dimensional echocardiography. Only 22 patients (42%) had abnormalities such as conduction defects, supraventricular or ventricular arrhythmias, or ST-T changes detected on resting ECG. In contrast, using Holter monitoring, the number of conduction abnormalities seen increased from 10 to 16 patients and transient ST-T changes increased from 2 to 18 patients. Forty-eight patients had ventricular arrhythmias, with multiform ventricular premature beats in 21 (40%), pairs of runs of ventricular tachycardia in 15 patients (28%), and 1 or more runs of ventricular tachycardia in 7 (13%). Echocardiography detected asymmetric septal hypertrophy in 10 patients, impaired ventricular function in 9 patients, congestive cardiomyopathy in 2, mitral prolapse in 4, and pericardial effusion in 3 patients. Multiform and/or repetitive ventricular premature beats occurred more frequently in patients with echocardiographic abnormalities, but were also present in patients who had normal findings on echocardiographic examination. Cardiac involvement was not correlated with clinical variants of scleroderma (CREST syndrome or diffuse scleroderma), nor with other signs and symptoms of the disease. Thus, cardiac involvement is found much more frequently than would be expected from clinical symptoms or from results of resting ECG alone; therefore, Holter monitoring and echocardiography should be included in the routine workup of patients who have scleroderma.

Adolescent↗
PubMed1990

Cytotoxic effects of sera from patients with systemic scleroderma: comparison of three different in vitro methods.

Sera from 93 patients with systemic scleroderma including incipient or prodromal acroscleroderma and from 43 healthy individuals were studied for cytotoxic effects on endothelial cells by means of three different in vitro methods. Inhibition of 3H-thymidine incorporation by endothelium was caused by about 33% of sera, almost exclusively from patients with diffuse scleroderma and the transitional form: acroscleroderma--diffuse scleroderma. An antibody-dependent cellular cytotoxicity assay revealed cytotoxicity of about 37% of sera from patients with diffuse scleroderma and the transitional form but also of a proportion of sera from patients with CREST syndrome with pronounced vascular changes. Serum cytotoxic activity, revealed by both methods, was related with more frequent involvement of muscle and kidney in the patients. A direct 51Cr release assay showed the cytotoxicity only in 4 of 68 cases in diffuse scleroderma with pronounced internal organ involvement. Thus, depending on the method used, various types of cytotoxicity could be detected in sera from patients with systemic scleroderma.

Adult↗
PubMed1988

Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis.

Of 397 systemic sclerosis (scleroderma) patients from the University of Pittsburgh, who had serum determinations of both anti-Scl-70 and anticentromere antibody (ACA), 26% had anti-Scl-70 and 22% had ACA. No patient had both autoantibodies. Weak associations with HLA-DR5 and HLA-DR1 were detected with anti-Scl-70 and ACA, respectively. ACA was found almost exclusively (96%) in patients with limited cutaneous scleroderma (the CREST syndrome variant), but the majority (57%) of patients with limited scleroderma did not have this antibody. Among patients with limited scleroderma, those with ACA more often had calcinosis and telangiectasias and less often had pulmonary interstitial fibrosis and restrictive lung disease. However, the frequency of pulmonary hypertension and the survival rates were similar in the ACA+ and ACA- limited scleroderma patients. Two-thirds of patients with anti-Scl-70 had diffuse scleroderma, but only 33% of all diffuse scleroderma patients had this antibody. Within the subset of diffuse scleroderma, anti-Scl-70 was associated with peripheral vascular disease (digital pitting scars) and pulmonary interstitial fibrosis, but was not predictive of cardiac or renal involvement or survival. ACA and anti-Scl-70 are useful in diagnosing and classifying systemic sclerosis variants and in predicting the natural course of the disease. Their mutually exclusive occurrence suggests either 2 separate clinical entities or important host factors determining their production.

Adult↗
PubMed1999

Pregnancy in women with systemic sclerosis.

OBJECTIVE: To determine pregnancy outcomes in women with systemic sclerosis. METHODS: Women of childbearing age with systemic sclerosis seen at the University of Pittsburgh between 1987 and 1996 were observed prospectively. Pregnancy outcomes included abortion, miscarriage, preterm and term birth, and perinatal death. Complications of pregnancy and scleroderma were determined during and after pregnancy. RESULTS: Fifty-nine women with systemic sclerosis had 91 pregnancies during the 10-year period. No increase in the frequency of miscarriage was found, except in those with long-standing diffuse scleroderma. Preterm births occurred in 29% of pregnancies, and all but one of the infants survived. Symptoms related to scleroderma, particularly Raynaud phenomenon, improved during pregnancy, but esophageal reflux became worse. After pregnancy, some women with diffuse scleroderma had increased skin thickening. There were three cases of renal crisis during pregnancy, all in women with early diffuse scleroderma. Four women had five healthy infants while taking angiotensin-converting-enzyme inhibitors. CONCLUSION: Women with systemic sclerosis can safely have healthy pregnancies. Those with early diffuse scleroderma should wait until their disease stabilizes before becoming pregnant to decrease the risk of renal crisis. High-risk pregnancy management should be standard for all scleroderma pregnancies because of the high frequency of premature births.

Adult↗