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PubMed1999

Monocytes of patients wiht systemic sclerosis (scleroderma spontaneously release in vitro increased amounts of superoxide anion.

It has been suggested that toxic oxygen free radicals can be involved in the pathogenesis of systemic sclerosis (scleroderma) (SSc). Because the cells that contribute to the generation of free radicals are not known, our aim was (i) to evaluate the ability of unmanipulated and phorbol 12-myristate 13-acetate-stimulated monocytes and polymorphonucleate neutrophils of SSc patients to generate superoxide anion (O2*-); and (ii) to investigate whether the O2*- produced by these cells involved the activation of nicotinamide-adenine dinucleotide diphosphate oxidase biochemical pathway. Employing the superoxide dismutase-inhibitable reduction of cytochrome c to evaluate the generation of O2*-, unmanipulated monocytes of SSc patients generated more O2*- than primary Raynaud's phenomenon patients and normal control monocytes (p = 0.0001), and the release was higher in patients with diffuse cutaneous involvement and 5 y or less disease duration (p = 0.02). The involvement of nicotinamide-adenine dinucleotide diphosphate oxidase in the enhanced 02*- production was demonstrated by the finding that the cytosolic components of the enzyme, p47phox and p67phox, were both translocated to the plasma membrane of enriched but otherwise unmanipulated monocytes of SSc patients. The involvement of mitochondrial oxidases was excluded by the lack of inhibition of O2*- production when monocytes were incubated in the presence of rotenone, a mitochondrial oxidase inhibitor. Upon stimulation with phorbol 12-myristate 13-acetate, monocytes of SSc patients produced more O2*- than controls. In SSc patients untreated polymorphonucleate neutrophils generated significantly less O2*- than monocytes (p = 0.0001) and only slightly more than polymorphonucleate neutrophils of primary Raynaud's phenomenon patients and normal controls (p = 0.03). In conclusion, we demonstrate that in patients with scleroderma, unmanipulated and phorbol 12-myristate 13-acetate-stimulated monocytes release in vitro increased amounts of superoxide anion through the activation of nicotinamide-adenine dinucleotide diphosphate oxidase and, thus, contribute to the oxidative stress found in this disease.

Adult↗
PubMed1994

Intravenous dexamethasone pulse therapy in diffuse systemic sclerosis. A randomized placebo-controlled study.

Thirty-five patients with diffuse systemic sclerosis were studied in a randomized, placebo-controlled, double-blind study. Seventeen patients received intravenous dexamethasone "pulse" therapy, while 18 patients received placebo. Each "pulse" consisted of 100 mg dexamethasone in 250 ml 5% dextrose infused intravenously over 1 h. Pulse therapy was repeated every month for 6 months. Assessment of disease status with various parameters was done at entry and at completion of trial, i.e. after 6 months. Significant improvement in skin involvement was seen in the study group, with the total skin score (TSS) decreasing from 28.5 +/- 12.2 to 25.8 +/- 12.8, while in the control group, TSS increased from 30.6 +/- 13.2 to 34.7 +/- 10. Similarly, significant improvement was noted in the flexion index. Other parametres that included extension index, maximum oral opening, range of movement of joints, functional disability score, Raynaud's phenomenon (frequency and duration), ESR, proteinuria, chest X-ray, ECG, lung function tests, barium swallow and antinuclear antibody were unchanged. Adverse effects of therapy were limited to an increased incidence of minor chest infections. It is concluded that intravenous pulse dexamethasone may be useful in the treatment of diffuse systemic sclerosis.

Adult↗
PubMed1990

Evaluation of alveolitis by studies of lung biopsies.

Immunocytochemical studies of lung biopsies from patients with cryptogenic fibrosing alveolitis and those having fibrosing alveolitis associated with scleroderma show that numerous T-cells occur in the alveolar walls and septa of all patients with these diseases, implying that cell-mediated hypersensitivity reactions are involved in the pathogenesis. However, B-lymphocytes, mainly within lymphoid follicles, are also present and, in the CFA group, such patients, and those with less than 50% T-suppressor/cytotoxic cells in the diffuse T-cell infiltrates, may have a poorer prognosis. Interleukin-2 receptor expression indicates that T-cell activation is occurring within the lungs, and there is evidence that interstitial monocytes/macrophages and alveolar epithelial cells may play a more important role in antigen presentation than alveolar macrophages. These observations on the features of the inflammatory response in the interstitial tissues of patients with fibrosing alveolitis need to be incorporated into the existing hypothesis on pathogenetic mechanisms based mainly on lavage findings of alveolar macrophages and granulocytes.

Antibodies, Monoclonal↗
PubMed1996

Pattern of gastric emptying in patients with systemic sclerosis.

Gastric emptying studies, using an indigenously prepared radiolabeled solid food marker in the form of Indian bread called Chapati, were performed on 13 patients with systemic sclerosis. Six patients had limited cutaneous disease and seven had diffuse cutaneous disease. Earlier, the procedure was standardized in 30 healthy volunteers. Seven of the 13 (54%) patients (five with diffuse and two with limited cutaneous disease) had delayed gastric emptying. Most of these patients had gastric symptoms. This pattern of gastric emptying may be clinically significant, particularly in patients with diffuse cutaneous disease.

Adult↗
PubMedDate not supplied

[Study of bone density in systemic scleroderma].

BACKGROUND: Osteopenia in systemic sclerosis (scleroderma) patients was reported in X-ray studies of hands and by proximal and distal forearm bone mass measurement. It has been suggested that bone loss in these patients might be due to chronic ischemia, immobilization and early menopause. Nevertheless, it is not established if these patients present generalized osteopenia. To shed light into this point we studied bone mineral density in the spine, proximal femur and total body in patients with systemic sclerosis. PATIENTS AND METHOD: Twenty-five Caucasian women were evaluated. Mean age of patients was 48 +/- 12 years and mean time of disease was 7 +/- 7 years; 13 were postmenopausal (8 +/- 8 years). Bone mass was measured in the spine, proximal femur and total body by using a dual-photon absorptiometry with X rays source (Lunar-Model DPX). RESULTS: Bone mass in different sites was not statistically different from the age-matched control healthy women. Mean bone mass of patients with limited form was not different from patients with diffuse form of systemic sclerosis. Patients with calcinosis had lower bone mass at proximal femur than those without this alteration. CONCLUSIONS: Patients with systemic sclerosis do not present bone loss and this disease in not a risk factor for generalized osteoporosis.

Adult↗
PubMed1999

[Renal disorders in patients with collagen vascular diseases].

Membranous nephropathy, mesangial proliferative glomerulonephritis and renal amyloidosis are common renal pathology in RA patients. However, IgA nephropathy and diffuse thinning of glomerular basement membrane are described as common and characteristic renal lesions in Japanese RA patients. Glomerular filtration rate may decrease significantly in active lupus nephritis, but renal plasma flow does not change or even increase. These findings seem to be characteristic of SLE patients with active renal disorders. Therefore, filtration fraction may be a useful clinical parameter to evaluate SLE patients. Scleroderma renal crisis(SRC) has been believed to be the most serious renal disorder in systemic sclerosis (SSc). Recently, the presence of an antibody to RNA polymerase has been associated with a high prevalence of SRC.

Autoantibodies↗
PubMedDate not supplied

Interstitial pneumonia in progressive systemic sclerosis: serial high-resolution CT findings with functional correlation.

PURPOSE: The aim of our study was to assess the serial high-resolution CT findings and their correlation with the results of pulmonary function tests in patients with progressive systemic sclerosis (PSS) and interstitial pneumonia. METHOD: The study included 40 patients with symptoms or signs of PSS and interstitial pneumonia, who underwent serial high-resolution CT scans (mean follow-up period 39 months). Seventeen patients simultaneously had serial pulmonary function tests (mean follow-up period 40 months). On high-resolution CT, the pattern and extent of parenchymal abnormalities were retrospectively analyzed. Serial changes on high-resolution CT were correlated with the changes of pulmonary function tests. RESULTS: On initial CT, areas of ground-glass opacity (mean +/- SD extent 17.7 +/- 12.3% in all patients), irregular linear opacity (4.4 +/- 4.4% in 36 patients), small nodules (3.9 +/- 12.5% in 28), consolidation (1.9 +/- 4.2% in 13), and honeycombing (1.9 +/- 3.8% in 12) were seen. The total disease extent (p = 0.042) and extents of ground-glass opacity (18.9 +/- 15.5%; p = 0.04) and honeycombing (5.0 +/- 7.2%; p = 0.002) increased significantly on follow-up CT. Both forced vital capacity (from 2.4 +/- 0.4 to 2.0 +/- 0.4 L; p = 0.002) and forced expiratory volume in 1 s (from 2.0 +/- 0.4 to 1.6 +/- 0.3 L; p = 0.013) decreased significantly on follow-up examination. The increase in the extent of honeycombing on CT correlated significantly with the decrease in diffusing capacity for carbon monoxide (r = -0.411, p = 0.049). CONCLUSION: In patients with PSS and interstitial pneumonia, the overall extent of disease and extents of honeycombing and ground-glass opacity increase significantly on follow-up CT. Increase of honeycombing correlates well with decrease of diffusing capacity for carbon monoxide.

Adult↗
PubMed1991

Cutaneous and serologic subsets of systemic sclerosis.

The relevance of the extent of skin sclerosis and of other clinicoserological features in diagnosis, severity and prognosis of disease was studied in a large number of unselected patients with systemic sclerosis (SSc). One hundred and fifty-one patients with SSc (126 F and 25 M, mean age 48 +/- 14 SD) followed for 5.3 +/- 3.2 years were included. Patients were divided into 3 cutaneous subsets: limited (68), intermediate (46) and diffuse SSc (37). Serological markers were detected in 288 patients with Raynaud's phenomenon and other connective tissue diseases (CTD). Limited and intermediate SSC prevailed in female patients while the diffuse subset was more frequent in males (p less than 0.0001). Duration of Raynaud's phenomenon before disease onset was shorter in the diffuse variant (p less than 0.0001). A wider cutaneous involvement was associated with more severe forms of SSc. Diffuse subset showed the poorest prognosis at 10 years of followup compared with intermediate (p less than 0.05) and limited variant (p less than 0.001). Intermediate SSc seems a distinct variant of SSc on the basis of clinical manifestations and survival. Among serological markers, anticentromere, anti-Scl-70 and antinucleolar antibodies were found in 21, 40 and 27% of the cases, respectively; these were statistically less frequent (p less than 0.0001) in other CTD. In 83.5% of patients with SSc at least one of these specific markers was recorded. Anticentromere antibodies were correlated to sex (female), limited SSc, calcinosis and telangiectasia. On the contrary anti-Scl-70 was associated with diffuse and intermediate subsets and with more severe SSc manifestations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Autoantibody to Th ribonucleoprotein (nucleolar 7-2 RNA protein particle) in patients with systemic sclerosis.

We studied sera of 371 consecutive new patients with systemic sclerosis (SSc; scleroderma) who were first evaluated during 1984-1988. All sera were tested for antinuclear antibodies by immunofluorescence staining using HEp-2 cells as substrate. We excluded 219 sera showing dark nucleoli and screened for antibodies to Th in the remaining 152 sera by immunoprecipitation of a 32P-labeled HeLa cell extract. Fifteen (4.0%) of 371 sera were anti-Th+. Anti-Th antibodies were present in 14 (8.4%) of 167 SSc patients with limited cutaneous involvement, in 1 of 167 with diffuse cutaneous involvement, and in 0 of 37 with SSc overlap syndrome. Among 244 controls with other connective tissue diseases, anti-Th was detected in only 3 patients, all having primary Raynaud's phenomenon of less than 2 years duration. In the subgroup with SSc with limited cutaneous involvement, the 14 anti-Th+ patients had a significantly greater frequency of puffy fingers, small bowel involvement, and hypothyroidism, and a significantly lower frequency of arthralgia and/or arthritis. Their cumulative survival rate from the time of onset of symptoms was lower than that for anti-Th- patients (78% versus 91% at 10 years), primarily due to 3 deaths from pulmonary arterial hypertension (2 from primary pulmonary hypertension and 1 from pulmonary hypertension secondary to pulmonary interstitial fibrosis). Serum anti-Th antibodies are present almost exclusively in patients with SSc with limited cutaneous involvement or in those with primary Raynaud's phenomenon whose disease may evolve to SSc with limited cutaneous involvement, and these antibodies may identify those patients who are at greater risk for reduced survival.

Autoantibodies↗
PubMed1987

Barrett's metaplasia and adenocarcinoma of the esophagus in scleroderma.

Gastroesophageal reflux is well documented in scleroderma, but the complications of Barrett's metaplasia and adenocarcinoma are not well described. The records of 75 patients with scleroderma seen over a four-year period at the Hospital of the University of Pennsylvania were retrospectively reviewed to determine the prevalence of Barrett's metaplasia and adenocarcinoma of the esophagus and to identify clinical, manometric, laboratory, or radiographic criteria that might predict the presence of these lesions. Twenty-four of these patients underwent endoscopy. In this group, the prevalence of Barrett's metaplasia was 37 percent (nine patients) and adenocarcinoma was also present in two of these patients. The patients with and without Barrett's metaplasia were similar in age (range, 22 to 64 compared with 28 to 79, respectively), sex (six of nine compared with 12 of 15 female, respectively), frequency of esophageal motility disorders, presence of proximal skin involvement, digital ulceration, and pulmonary involvement as measured by diffusion capacity. Barrett's metaplasia was diagnosed on the basis of double-contrast esophagographic results in only one of eight patients with Barrett's metaplasia so-studied. Patients with Barrett's metaplasia tended to have longer duration of heartburn (90 +/- 40 months compared with 11 +/- 35 months) and dysphagia (39 +/- 22 months compared with 7 +/- 3 months). Patients with Barrett's metaplasia also tended to have greater impairment of lower esophageal sphincter pressure either at end-expiration (4.0 +/- 2.1 compared with 6.1 +/- 1.8 mm Hg) or mid-respiration (13.0 +/- 3.0 compared with 16.9 +/- 2.5 mm Hg). Using chi-square analysis, however, none of these differences reached statistical significance. Discrimination did occur on the basis of the presence of the CREST (calcinosis, Raynaud's phenomenon, esophageal manifestations of scleroderma, sclerodactyly, and telangiectasis) variant (55 percent compared with 7 percent, p less than 0.01), a duration of dysphagia of more than five months (p less than 0.03), and mid-respiratory lower esophageal sphincter pressure of less than 10 mm Hg (p less than 0.05). It is suggested that: Barrett's metaplasia of the esophagus occurs in one third of patients with scleroderma; clinical, manometric, laboratory, and radiographic features are poor predictors of the presence of Barrett's metaplasia; patients with CREST syndrome, prolonged dysphagia, or a very low lower esophageal sphincter pressure may have an increased risk for the development of metaplasia; patients with scleroderma and Barrett's metaplasia have an increased risk of complications such as stricture or adenocarcinoma.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed2005

-238 and +489 TNF-alpha along with TNF-RII gene polymorphisms associate with the diffuse phenotype in patients with Systemic Sclerosis.

OBJECTIVE: To investigate possible associations of TNF-alpha and TNF-RII gene polymorphisms with diffuse or limited skin involvement phenotype in a cohort of Systemic Sclerosis (SSc) patients. METHODS: One-hundred and fourteen consecutive SSc patients attending the referral centres of three academic hospitals in Italy (University of Naples, Pavia and Udine), 56 with the diffuse (dcSSc) and 58 with limited (lcSSc) skin involvement subsets, and 170 healthy blood donors (HBDs) were included in the study. The extracted DNA was genotyped for the following polymorphisms: TNF-alpha (-238, +489) and TNF-RII (+196), using the polymerase chain reaction (PCR) and the restriction enzymes BamHI, HpyCH4 IV and NlaIII, respectively. RESULTS: The AG/AA (presence of allele A) genotypes in position -238 and the AG genotype in position +489 of the TNF-alpha gene were found significantly increased in SSc, as a whole, when compared with healthy blood donors (chi(nu=2)(2)=4.48, p=0.03 for -238 and chi(nu=2)(2)=7.82, p=0.02 for +489, respectively). The rare GG genotype in exon 6 (codon 196) of the TNF-RII gene was also found increased in SSc compared to HBDs, even though the difference did not show statistical significance (chi(nu=2)(2)=3.56, p=0.17). The strength of the association was mainly due to the dcSSc phenotype (Fisher test, p=0.04 for -238, chi(nu=2)(2)=10.07, p<0.01 for +489 and chi(nu=2)(2)=6.25, p=0.04 for the +196 TNF-RII, respectively). CONCLUSIONS: TNF-alpha and TNF-RII gene polymorphisms seem to contribute to the development of SSc and in particular to the diffuse phenotype.

Autoantibodies↗
PubMed2006

[Systemic sclerosis: epidemiology and environmental factors].

The pathophysiology of systemic sclerosis (SSc), probably multifactorial, is not yet well elucidated. Among the many endogenous and exogenous factors probably involved, environmental and occupational elements may play an essential role. SSc is a rare disease. Prevalence is estimated between 3 and 24 per 100,000 population. Reports of sporadic clusters of higher prevalence suggest environmental factors, which have not yet been defined. Silica, first suggested in 1917, plays a role in SSc development, as officially recognized in France for purposes of workers' compensation. Solvents have been associated with SSc by several rigorous case-control studies that suggest a causal role. Current data about other toxic agents (epoxy resins, vibrations, welding fumes) do not justify conclusions about their role in SSc. The severity of SSc (determined by the extent of diffuse cutaneous lesions, pulmonary involvement, and immunological profile) is probably associated with occupational exposure.

Adolescent↗
PubMed1988

Autonomic neuropathy in systemic sclerosis.

Autonomic function assessed by tests of cardiovascular reflexes was studied in 25 patients with systemic sclerosis and 10 patients with primary Raynaud's phenomenon. A comparison was made with 13 normal healthy subjects. Significant abnormalities in the cardiovascular reflexes were found in systemic sclerosis, both in the CREST (calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia) variant and also in those patients with diffuse involvement. There was sympathetic and parasympathetic dysfunction. These findings suggest that autonomic neuropathy is a feature of systemic sclerosis.

Adult↗
PubMed1984

Radiologic and histologic differentiation of neuromuscular disorders of the gastrointestinal tract: visceral myopathies, visceral neuropathies, and progressive systemic sclerosis.

Forty patients with neuromuscular disorders of the gastrointestinal tract were evaluated histologically and radiologically. Eighteen patients with progressive systemic sclerosis had predominant circular muscle thinning and fibrosis. Visceral myopathy (11 patients) was characterized by vacuolar degeneration of the smooth muscle cells with thinning and fibrosis typically affecting the longitudinal layers. Visceral neuropathy (five patients) had degeneration of myenteric plexus neurons with various patients having intranuclear inclusions, Schwann cell proliferation, or inflammatory cell infiltration. Radiologically, these syndromes had diffuse abnormalities of gastrointestinal motor function manifested by small and large intestinal dilatation, esophageal hypomotility (progressive systemic sclerosis and visceral myopathy), or disordered hypercontractility (visceral neuropathy). Marked duodenal enlargement typified visceral myopathy, and although all types may have dilated small intestine, only progressive systemic sclerosis has packing of valvulae. Colonic sacculations were found in progressive systemic sclerosis, lack of haustrations and increased colonic caliber in visceral myopathy, and hypercontractility in visceral neuropathy. Complete barium contrast examination will assist in differentiation of true obstruction from pseudoobstruction, will define the diffuse nature of the syndrome, and will help establish an accurate diagnosis by identifying features specific for these entities.

Esophagus↗
PubMedDate not supplied

[Radiology of the hand in progressive systemic sclerosis].

Radiographs and xerographs of the hands of 35 patients with progressive systemic sclerosis (PSS), as defined by the ARA, were reviewed. Patients with "overlap" syndromes (i.e., mixed connective tissue disease, systemic lupus erythematosus or rheumatoid arthritis) have been excluded. Soft tissue changes included atrophy (hide-bound skin), and dystrophic calcifications, particularly in CREST patients (calcinosis, Raynaud phenomenon, esophageal dysmobility, sclerodactily and telangectasia). The most common bony change is resorption of distal phalanges; diffuse osteoporosis is also frequent; the distal interphalangeal and first carpometacarpal joints involvement appear as a distinctive feature of this erosive arthritis.

Adult↗
PubMed2004

[Vascular changes in the pathogenesis of systemic sclerosis].

Systemic sclerosis (SSc, scleroderma) is a connective tissue disease of unknown etiology. Perivascular inflammatory infiltrates and endothelial apoptosis with an impaired angiogenesis are observed in early stages of the disease, whereas later stages are characterized by an excessive accumulation of extracellular matrix proteins in the skin and various internal organs. Consistent with the ongoing endothelial cell damage, various markers of endothelial cells such as endothelin-1, sICAM-1, s-VCAM-1 and thrombomodulin are found in high levels in the serum of SSc patients. Surprisingly, the vascular endothelial growth factor (VEGF), a potent angiogenic molecule, is overexpressed in the skin of patients with SSc despite insufficient angiogenesis. Interestingly, patients suffering from diffuse SSc and patients without finger tip ulcers show higher VEGF levels compared to age- and sex-matched controls. These results indicate that a controlled overexpression of VEGF might help to protect against the manifestation of ischemic conditions. On the other hand, data from animal models indicate that a long-term, uncontrolled overexpression of VEGF might have paradox effects on the formation of new vessels leading to capillary changes similar to those observed in SSc. In addition to the impaired angiogenesis, defective vasculogenesis might contribute to the vascular symptoms of SSc.

Capillaries↗
PubMed1989

Lyme disease: musculoskeletal manifestations.

A previously unrecognized musculoskeletal syndrome led to the recognition of this "new" infectious disease. Several distinct patterns of musculoskeletal involvement can be seen throughout the course of untreated Lyme disease. Diffuse, nonspecific muscle achiness and stiffness can be seen early to be followed by characteristically brief, recurrent episodes of LIMP and transient arthritis that help to differentiate LD from other arthropathies. Chronic oligoarticular arthritis is seen in a few. Lyme arthropathy most closely resembles the reactive arthropathies. In a few cases, LD has mimicked other connective tissue disorders such as juvenile rheumatoid arthritis, rheumatoid arthritis, myositis, and scleroderma. It would appear that the full spectrum of musculoskeletal LD is still being defined.

Arthritis↗