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PubMed1990

Is there a link between dendrocytes, fibrosis and sclerosis?

In a series of fibrotic and sclerotic diseases including scars, keloids, fibromas, scleroderma and lichen sclerosus et atrophicus, we found modifications in the dendrocyte population. Dendrocytes were numerous in fibrotic diseases associated with little deposits of collagen. Conversely, they were almost absent in sclerotic diseases when the lay-down of collagen was prominent. We hypothesize that dendrocytes, by their content in factor XIIIa, may limit the accumulation of collagen in the skin.

Dendritic Cells↗
PubMed1991

Anti-neutrophil cytoplasmic antibodies and anti-endothelial cell antibodies.

Anti-neutrophil cytosolic antibodies (ANCA) and anti-endothelial cell antibodies (AECA) have been identified in a wide variety of disorders, but their pathophysiological role remains unclear. ANCA appear to be particularly associated with various forms of vasculitis including Wegener's granulomatosis. Kawasaki disease and microscopic polyarteritis. Cytoplasmic staining (cANCA) on indirect immunofluorescence is associated with extrarenal disease and a perinuclear pattern (pANCA) with renal limited disease. The cANCA antigen appears to be proteinase 3 and that for pANCA myeloperoxidase. AECA have been detected in systemic lupus erythematosus, scleroderma and dermatomyositis but are also found in systemic vasculitis, Kawasaki disease, haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura and renal allograft recipients at the time of rejection. Their presence appears to be correlated with disease activity and they may be directed against epitopes on as yet unidentified infective agents that precipitate some of the diseases in which they are found that cross-react with antigenic sites exposed on endothelial cells. Measurement of these antibodies has a diagnostic role, facilitates monitoring of disease activity and may prove valuable in understanding the pathogenesis of the diseases in which they are found.

Autoantibodies↗
PubMed2002

Increased circulating concentrations of the counteradhesive proteins SPARC and thrombospondin-1 in systemic sclerosis (scleroderma). Relationship to platelet and endothelial cell activation.

OBJECTIVE: To determine whether circulating concentrations of the counteradhesive proteins SPARC (secreted protein acidic and rich in cysteine) and thrombospondin-1 (TSP-1) are elevated in scleroderma (systemic sclerosis, SSc). The relationship of these counteradhesive proteins to measures of platelet and endothelial cell activation was examined. METHODS: Plasma from 45 patients with SSc (26 limited form, 19 diffuse) and 22 age and sex matched controls was assayed for SPARC, TSP-1, beta-thromboglobulin (betaTG), and platelet factor 4 (PF4), 2 distinct platelet a-granule products, and soluble E-selectin, a marker of endothelial cell activation. RESULTS: The mean (+/- SE) SPARC concentration was greater in patients with limited SSc (124.0 +/- 9.6 ng/ml) compared to controls (66.8 +/- 8.0 ng/ml) (p = 0.0005), whereas in patients with diffuse SSc (74.1 +/- 7.9 ng/ml) it was not. Elevated SPARC concentrations in the limited SSc group could not be ascribed to either platelet or endothelial cell activation. TSP-1 concentrations were also increased in SSc patients (n = 29) compared to controls (n = 11) (2.98 +/- 0.12 vs 2.4 +/- 0.21 log transformed ng/ml; p < 0.02). Unlike SPARC, TSP-1 concentrations correlated with both betaTG (r = 0.57, p = 0.0014) and PF4 (r = 0.41, p = 0.026) levels, indicating that increased TSP-1 could, in part, be explained through elevated platelet a-granule release in SSc patients. Plasma levels of betaTG, PF4, and E-selectin were each similarly elevated (p < 0.003) in patients with both limited and diffuse SSc compared to controls. CONCLUSION: That circulating SPARC and TSP-1 are elevated in patients with SSc raises the possibility that counteradhesive proteins, which regulate vascular organization and remodeling, might contribute to the pathogenesis of SSc vasculopathy.

Adult↗
PubMed2002

Vascular and connective tissue histopathologic alterations of the female lower genital tract in scleroderma.

OBJECTIVE: It has been suggested that women with scleroderma (systemic sclerosis, SSc) have cervical changes that may lead to obstetrical or postoperative complications. We evaluate histopathologic features characteristic of SSc in cervicovaginal tissue from women with SSc and compare them to age matched controls. METHODS: Records from the Scleroderma Registry at Wayne State University were matched with surgical specimens in the anatomic pathology files at Hutzel Hospital. Five women with SSc (2 with limited SSc, 3 with diffuse SSc; mean age 49 yrs) were identified who had cervical or vaginal tissue specimens available for evaluation. Small arterioles and surrounding connective tissue in these specimens and those from 26 age matched controls (15 normotensive, 11 hypertensive) were evaluated in blinded fashion. RESULTS: The following specific histopathological features were evaluated in the SSc patients: duplication or disruption of the internal elastica in 5 (100%), medial hypertrophy in 5 (100%), adventitial changes in 3 (60%), connective tissue fibrosis in 1 (20%), and vasculitis in 1 (20%). There was no significant difference in the frequency of the histopathologic changes between SSc and control patients when evaluated independently. However, the presence of 3 or more features was significantly more frequent in the SSc patients (100%) than in the controls (38%) (p = 0.018). CONCLUSION: The histopathological features evaluated were collectively more frequent in SSc patients; however, many of the control patients also exhibited similar abnormalities. In the female lower genital tract these changes, previously attributed solely to SSc, may be related to other factors.

Adult↗
PubMed2005

Correlation of the degree of dyspnea with health-related quality of life, functional abilities, and diffusing capacity for carbon monoxide in patients with systemic sclerosis and active alveolitis: results from the Scleroderma Lung Study.

OBJECTIVE: To determine whether baseline self-assessment measures of health status and physiologic indices of disease severity in alveolitis-positive patients with systemic sclerosis (SSc) correlate with the severity of their dyspnea, and to quantify functional impairment in patients with scleroderma lung disease and compare it with that in patients with chronic obstructive pulmonary disease (COPD). METHODS: SSc patients (n = 138) with diffuse (n = 81) or limited (n = 57) cutaneous disease and active alveolitis (determined by bronchoalveolar lavage and/or high-resolution computed tomography) who participated in the National Heart, Lung, and Blood Institute-sponsored, multicenter, parallel-group, double-blind, randomized, placebo-controlled trial of oral cyclophosphamide for treatment of SSc-associated interstitial lung disease were evaluated. Pearson's univariate correlations were determined between the Short Form 36 (SF-36) physical component summary (PCS) and mental component summary (MCS) scales, functional questionnaires, and physiologic parameters of breathing (forced vital capacity [FVC] and single-breath diffusing capacity for carbon monoxide [DLCO]). Student's t-test was used to compare subgroups. Scores from 2 instruments for self-assessment of breathlessness, Mahler's baseline dyspnea index (BDI) and a visual analog scale (VAS) for breathing, were divided at the median. Values for the DLCO and FVC (% predicted) were divided based on the American Thoracic Society guidelines for mild (>70% of predicted), moderate (50-70% of predicted), and severe (<50% of predicted) physiologic impairment. RESULTS: Scores on the BDI and VAS for breathing were highly correlated (r = -0.61). The PCS and MCS were able to differentiate patients with more breathlessness (measured by BDI and VAS for breathing) and more abnormal physiologic measures (FVC and DLCO). In SSc patients with alveolitis, all 8 domains of the SF-36 were significantly impaired as compared with the healthy population and were similar to those reported by patients with COPD. CONCLUSION: The SF-36 was able to discriminate between scleroderma lung disease patients with more severe and less severe breathlessness, the primary symptom of active alveolitis. The SF-36 complements the BDI and VAS scores for breathing in scleroderma lung disease and is variably correlated with results of pulmonary function tests, suggesting that the SF-36 should be included as an outcome measure in intervention trials in this population.

Carbon Monoxide↗
PubMed2002

Pulmonary hypertension in scleroderma spectrum of disease: lack of bone morphogenetic protein receptor 2 mutations.

OBJECTIVE: To determine whether mutations in the bone morphogenetic protein receptor 2 gene (BMPR2), initially reported in primary pulmonary hypertension, were present in patients with pulmonary arterial hypertension and scleroderma spectrum of disease. Methods. BMPR2 gene mutations were determined using nucleic acid sequencing in 24 patients with pulmonary arterial hypertension and scleroderma spectrum of disease and in 2 control groups, 96 healthy North American individuals and 100 Israeli Ashkenazi Jews. The patients also had antinuclear antibody determinations and underwent right heart catheterization. RESULTS: One BMPR2 guanine to adenine (G to A) mutation in exon 13 was found in a 59-year-old Ashkenazi Jewish woman with the limited cutaneous variant, a normal chest radiograph, and positive anticentromere and rheumatoid factor autoantibodies. However, this mutation is thought to be a polymorphism because the same mutation was also found in an ethnically matched healthy Ashkenazi Jew. CONCLUSION: Pulmonary arterial hypertension in scleroderma spectrum of disease was not associated with heterogeneous germline mutations of BMPR2.

Adult↗
PubMed2004

Duration of Raynaud's phenomenon is negatively correlated with serum levels of interleukin 10 (IL-10), soluble receptor of interleukin 2 (sIL2R), and sFas in systemic sclerosis patients.

BACKGROUND: Dysfunction of blood vessels and endothelial cells is regarded as a primary triggering factor of the development of autoimmunological processes in systemic sclerosis (scleroderma, SSc). Literature data suggest that the duration of Raynaud's phenomenon may correlate with disease severity. MATERIAL/METHODS: The study comprised 34 patients with SSc, 19 with limited SSc (lSSc) and 15 with diffuse SSc (dSSc). The duration of Raynaud's phenomenon (before skin fibrosis development) was correlated with the serum levels of selected markers, measured by ELISA, reflecting disturbances in autoimmunological processes, angiogenesis, apoptosis, and fibrosis. RESULTS: A shorter duration of Raynaud's phenomenon was shown to correlate with higher serum levels of interleukin-10 (IL-10) in the whole SSc group and of aminoterminal propeptide of collagen III (PIIINP) in the lSSc subgroup (p<0.05). It also correlated with higher serum levels of soluble interleukin 2 receptor (sIL2R) and the soluble protein sFas in the whole SSc group and the lSSc subgroup (p<0.05). CONCLUSIONS: The results obtained confirm the importance of vasomotor disturbance duration in triggering fibrosis in the course of systemic sclerosis.

Cell Division↗
PubMed1998

Increased expression of TGF-beta receptors by scleroderma fibroblasts: evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype.

Scleroderma fibroblasts exhibit numerous phenotypic differences when compared with healthy skin fibroblasts. Some of these differences, in particular overexpression of collagen type I and other extracellular matrix proteins, parallel the effect of transforming growth factor-beta (TGF-beta) on dermal fibroblasts, suggesting that the scleroderma fibroblast phenotype may result from activation of autocrine TGF-beta signaling. To test this hypothesis we examined the role of TGF-beta Type I and Type II receptors in regulating collagen type I transcription. We have shown that overexpression of either Type I or Type II receptors significantly (3-4-fold) increases alpha2 (I) collagen promoter activity in transient transfection assays in dermal fibroblasts. Addition of anti-TGF-beta antibody abolished, whereas addition of plasmin enhanced, the stimulatory effect of receptor overexpression on collagen promoter activity, suggesting that this effect depends on autocrine TGF-beta. Moreover, these cotransfection experiments indicated that expression levels of TGF-beta receptors is a limiting factor in the autocrine regulation of collagen type I transcription by TGF-beta. Comparison of the TGF-beta receptor Type I and Type II mRA expression levels in scleroderma and normal fibroblasts have indicated elevated expression (2-fold) of both receptor types in scleroderma cells, which correlated with increased binding of TGF-beta. Significantly, elevated TGF-beta receptor levels correlated with elevated alpha2 (I) collagen mRNA levels. These results suggest that the elevated production of collagen type I by scleroderma fibroblasts results from overexpression of TGF-beta receptors.

Collagen↗
PubMed1994

A confocal microscopy study of anticytoskeletal antibody activity in patients with connective tissue disease.

The significance of the presence of antibodies to cytoskeleton proteins in patients with connective tissue diseases is not clear, as there is a high level of these antibodies in healthy controls. In an attempt to improve the visualization of the immunofluorescence binding pattern of autoantibodies to cytoskeletal structures in cultured fibroblasts, we have used confocal microscopy. Of the 256 serum samples tested, 155 (61%) WERE reactive with cytoplasmic structures. These reactive samples could be divided into seven patterns of binding, as determined by double-blind examination of single-section confocal images. While confirming the results of previous immunofluorescence studies which have shown that autoantibodies that bind to filamentous structures in the cytoplasm of cultured cells are common in patients with connective tissue diseases, we were able to identify three patterns of cytoskeletal binding which may be useful as an adjunct to other tests for the diagnosis of some connective tissue diseases, in particular systemic sclerosis (scleroderma) and rheumatoid arthritis/Sjogren's syndrome. None of the seven patterns was exclusive to a particular disease. We conclude that confocal microscopy may be of limited use as an adjunct to other serological assays in the diagnosis of some forms of connective tissue disease.

Actin Cytoskeleton↗
PubMedDate not supplied

[An electro- and vectorcardiographic study of ventricular activation in scleroderma].

Electrical ventricular activation was studied by means of electrocardiogram and vectorcardiogram in 62 patients, 55 women and 7 men, affected by systemic sclerosis of average disease duration of 10.3 years. 45% of the patients showed the "diffused form" of the disease and 55% the "limited form". The vectorcardiogram showed some alterations of the ventricular activation in 55% of the recorded cases. The previous electrocardiogram found only 18%. The alterations, which are more frequent in the diffuse form than in the limited one, are the presence of loss of forces in septal, lateral or inferior or combined areas and intraventricular conduction disorders as complete and incomplete right bundle branch block, left anterior subdivision block, left posterior subdivision block, or combination between incomplete right bundle branch block and left anterior or posterior subdivision block. The vectorcardiogram was more sensitive than the electrocardiogram in showing loss of forces, also in patients with the limited form of systemic sclerosis, when the electrocardiogram was normal. Moreover the vectorcardiogram is helpful to identify left posterior subdivision block. The vectorcardiographic investigation seems to be a useful complement of the electrocardiogram especially for the identification of cases with myocardial involvement that is clinically silent.

Adult↗
PubMed1992

Ultrastructural changes of cutaneous nerves in scleroderma.

Ultrastructural changes in cutaneous nerves of 38 patients with progressive scleroderma and eight patients with circumscribed scleroderma are described in the present study. Changes in the myelinated as well as in the unmyelinated fibers were observed in all cases. Myelinated fibers exhibited progressive disintegration of their myelin sheaths. Edema of the cytoplasm and various lesions of the organelles were observed in the Schwann cells. The basal membranes of both myelinated and unmyelinated fibers were irregularly thickened and flimsy in appearance. The axis cylinders were affected to a lesser extent. Edema of the axoplasm, and, less often, reduction of the number of neurofibrils and microtubules were observed there. Sometimes, the nerve fibers were enwrapped compactly by a considerable amount of collagen fibrils. The observed changes of the peripheral skin nerves are very often secondary. They are the morphologic basis of a limited or generalized neuropathy which sometimes develops.

Adolescent↗
PubMed1991

Scleroderma-like fasciitis without eosinophilia after L-tryptophan ingestion.

A 53-year-old man developed severe sclerodermatous skin changes and a neuromyopathic process, consistent with the eosinophilia-myalgia syndrome, 2 months after discontinuation of L-Tryptophan (L-Try). His peripheral eosinophil count was within normal limits upon presentation and remained so throughout the illness. Currently the Centers for Disease Control surveillance definition requires peripheral eosinophilia greater than 1000 cells/mm3. Eosinophilia-myalgia syndrome may need to be part of a differential diagnosis even in the absence of peripheral eosinophilia.

Diagnosis, Differential↗
PubMed2000

Pulmonary edema complicating prostacyclin therapy in pulmonary hypertension associated with scleroderma: a case of pulmonary capillary hemangiomatosis.

Continuous intravenous infusion of prostacyclin is an effective treatment for primary pulmonary hypertension (PPH), and has recently been shown to be of benefit in PH associated with scleroderma (SSc). Pulmonary capillary hemangiomatosis (PCH) is a rare cause of PPH. Prostacyclin therapy has been complicated by pulmonary edema in cases of PCH. We describe a case of PH associated with limited SSc, where treatment with prostacyclin was complicated by pulmonary edema. Autopsy revealed PCH as the pathologic basis for the PH. There were no clinical features of PCH prior to initiation of vasodilator therapy, illustrating the potential difficulty in establishing the diagnosis. This is the first reported case of PCH in SSc.

Aged↗
PubMed1994

[Lung manifestation of progressive systemic scleroderma. Computerized tomographic findings].

Progressive systemic scleroderma (PSS) is caused by generalized connective tissue disorder. The most frequent visceral manifestations are pulmonary and oesophageal involvement. Early detection of such visceral manifestations, which are sometimes life-limiting, is of paramount importance in any diagnostic procedures. The sensitivity of the methods differs and depends on the stage of the disease. Modified high-resolution computed tomographic scans (HRCT) were obtained in 28 patients with early forms of PSS and showed pulmonary involvement in 79% and signs of oesophageal involvement in 54%. HRCT is much more sensitive than chest radiography, lung scintigraphy and lung function tests even at an early stage of the disease. Classification of PSS should take account of the clinical type of sclerosis and of immunological and other parameters of prognostic importance.

Adult↗
PubMed1997

Sensitivity of secondary acute myeloid leukemia relapsing after allogeneic bone marrow transplantation to immunotherapy with interferon-alpha 2b.

A patient with acute myeloid leukemia secondary to therapy of choriocarcinoma underwent T cell non-depleted allogeneic bone marrow transplantation from an unrelated donor in first untreated relapse. Persistent/relapsed leukemia 4 months after transplantation did not respond to cessation of cyclosporine. Due to logistic difficulties in obtaining donor leukocytes, she was treated with interleukin-2 and interferon-alpha 2b. Although the interleukin could be administered for a short period only, the interferon was continued for 4 months. Interferon was stopped when limited chronic graft-versus-host disease developed, but was followed by extramedullary and early marrow relapse. Reinstitution of interferon resulted in the development of scleroderma-like extensive chronic GVHD and remission. Interferon was given for 5 months. GVHD improved slowly with treatment, but scleroderma-like changes still persist. The patient is alive with no evidence of disease and a Karnofsky score of 90% 41 months after relapse and 26 months after stopping cyclosporine. We conclude that cytokines alone may occasionally result in a durable response of acute leukemia relapsing after allografting, and should be considered in patients with a low tumor burden if it is difficult to obtain donor cells.

Adult↗
PubMedDate not supplied

Home parenteral nutrition with full-time home care nurses.

A group of patients exists who cannot manage home parenteral nutrition (HPN) due to debilitating conditions and/or lack of family resources. They are limited to either nursing home placement or extended hospitalization unless home nursing care is provided. A 58-year-old single female with malabsorption secondary to scleroderma was sent home on cyclic HPN under the supervision of full-time home care nurses. A comprehensive patient-centered nurse training program was designed to teach nursing personnel from a private nursing service the theory and practice of HPN. Each nurse must achieve at least 80% in the theory posttest and demonstrate the competent performance of central venous catheter care, mixing of parenteral nutrition solutions, use of infusion pump, and application of the heparin lock. The results of the pre- and posttests have shown that the home care nurses have been able to learn the theory necessary for implementing HPN. The mean pretest value was 46% while the mean posttest value was 90% (n = 12, p = 0.01). The patient has been doing very well at home for 5 months in this psychologically, medically, and financially effective program covered by third party payers. To the best of our knowledge, this program has never before been accomplished.

Education, Nursing↗
PubMed1984

Diffuse fasciitis with hypergammaglobulinemia and eosinophilia: a new syndrome?

Two male patients (53 and 19 years old) have been seen with a diffuse scleroderma-like illness with firm taut skin bound down to underlying structures (sparing the face in both patients and the hands and feet in one). Flexion contractures of elbows and knees and limitation of abduction at the shoulders developed in a few weeks after onset. Raynaud's phenomenon was absent and thorough evaluation failed to reveal any evidence of myositis or the visceral manifestations of systemic sclerosis. There was no loss of skin appendages. Both had circulating eosinophils (12% and 37%) without drug ingestion or parasitic infestation. Both had elevated sedimentation rates and hypergammaglobulinemia (in one, IgG = 4.1 g.%). Serologic tests for syphilis, rheumatoid factor, LE cells, antinuclear antibodies, complement and cryoglobulins were negative or normal in both patients. Bone marrow examination revealed plasmacytosis and eosinophilia. Biopsies revealed striking thickening of the fascia between the subcutis and muscle. Within the thickened connective tissue there was intense infiltration with plasma cells and lymphocytes, at times in follicles, both about and separate from vessels; eosinophils were absent. Skin biopsies revealed no changes of scleroderma; and muscle biopsies, no evidence of myositis. Prednisone therapy over 15 months in decreasing dosage, using laboratory parameters, induced in the first patient a full remission which has persisted for 5 years without therapy. In the second (more severely involved) patient prednisone therapy has reversed laboratory abnormalities; but clinical improvement to date has been minimal. The pathogenesis of this diffuse fasciitis is obscure, although unusual physical exertion antedated the onset of illness in each case.

Adolescent↗