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PubMed1998

[Vascular manifestations in systemic sclerosis (scleroderma)].

Progressive systemic sclerosis (PSS), a disease still of unknown origin, is a generalized autoimmune disorder characterized by immunological abnormalities, microvascular dysfunction, and tissue fibrosis. The mechanism leading to selective microvascular injury in PSS is not completely known, however it is now clear that neuropeptides, vascular endothelium, and disturbances in the regulation of fibroblast function are the three major contributors to the increased fibrosis of skin and internal organs. Thus, endothelial cell and fibroblast dysfunction may be linked through the paracrine activity of soluble endothelial cell products: the cytokine cascade (IL-1, TGF-beta-1, PDGF, TNF, etc.). In systemic sclerosis, the exaggerated generalized vasospastic tendency is clinically represented by Raynaud's phenomenon as shown by an early digital arterial closure after cold stimulation, and by an inadequate vasodilatory response to heat. In this review we summarize recently established data that center around the role of adhesion molecules, immune reactions, and aberrant fibroblast biology and metabolism in effecting vascular and connective tissue alterations in this disease. Only a better knowledge of the pathophysiological process involved in scleroderma might lead to the development of new therapeutic approaches.

Adult↗
PubMed2002

The impact of pain and symptoms of depression in scleroderma.

Systemic sclerosis (scleroderma) is a rare connective tissue disease that can affect multiple organ systems. Case reports and small treatment studies suggest that pain is significant in scleroderma, but few data speak of the frequency or impact of pain. This study sought to determine the frequency and impact of pain, symptoms of depression, and social network characteristics on physical functioning and social adjustment in patients with scleroderma. One hundred and forty-two scleroderma patients completed measures of pain, depressive symptoms, social network characteristics, physical functioning, and social adjustment. Sixty-three percent reported at least mild pain and 50% reported at least mild levels of depressive symptomatology. Hierarchical regression analyses revealed that pain, depressive symptoms, and employment status (disabled/unemployed vs. not) were significant, independent predictors of physical functioning, together accounting for 37% of the total variance. Pain was the single strongest predictor of physical function, accounting for 20% of the variance. Depressive symptoms, physical functioning, diversity of social network, and employment status were significant independent predictors of social adjustment, together accounting for 63% of the variance. Depressive symptoms were the single strongest predictor of social adjustment, accounting for 26% of the variance. The effects of pain and physical function on social adjustment became non-significant when depressive symptoms were entered into the model, suggesting that symptoms of depression mediate the effect of pain and physical function on social adjustment. These findings indicate that pain is common in scleroderma and that pain and depressive symptoms are significant determinants of physical functioning and social adjustment, two important components of health-related quality of life. Increased attention to effective management of pain and symptoms of depression in scleroderma will likely lead to improved functioning and quality of life.

Adult↗
PubMed2005

Chronic graft-versus-host-disease-like dermopathy in a child with CD4+ cell microchimerism.

We report the case of an 11-year-old boy suffering from a severe progressive chronic skin disease with clinical features of progressive systemic scleroderma, systemic lupus erythematosus and dermatomyositis. Skin biopsies revealed fibrosis and lichenoid changes and muscle biopsy a myositis. Immunohistology of the skin showed a lichen-ruber-like pattern. Despite repeated extensive investigations, no autoantibodies were detectable. Some of these findings looked like those described in juvenile dermatomyositis. Finally, it could be demonstrated that the boy showed microchimerism with approximately 1% maternal CD4+ lymphocytes in his peripheral blood leukocytes. Furthermore maternal cells could be demonstrated in inflamed muscle tissue. So a graft-versus-host-disease-like pathomechanism appears to be likely. Several systemic therapies have been used with limited success to improve the condition including corticosteroids, azathioprine, cyclosporine A and mycophenolate mofetil. A distinct improvement of erythemas and sclerosis could be achieved by means of low-dose UVA1 phototherapy which was applied with escalating single doses of 3-12 J/cm2 for 35 consecutive days.

CD4-Positive T-Lymphocytes↗
PubMed1993

Current therapy of systemic sclerosis (scleroderma).

Treatment of systemic sclerosis (scleroderma) presents a challenge to both the patient and the physician. Established approaches include long-term physiotherapy, disease-modifying agents such as D-penicillamine, and treatment of organ involvement. These efforts are often unsatisfactory since the results are poor. However, recent advances include treatment of Raynaud's phenomenon (plasmapheresis, stanozolol, and prostacyclin analogues), scleroderma renal crisis (angiotensin-converting enzyme inhibitors), and gastric hypomotility (cisapride). This article covers the current approaches to the disease-modifying therapy including those related to the function of collagen-producing fibroblasts, vascular alterations, and the cellular and humoral immune system, as well as treatment of involved organs.

Acute Kidney Injury↗
PubMed1998

Circulating type I collagen degradation products: a new serum marker for clinical severity in patients with scleroderma?

Systemic sclerosis (SSc; scleroderma) results in the excessive deposition of extracellular matrix components in affected organs. This is partly due to enhanced synthesis; however, the role of degradative processes in this disease is still poorly understood. Sera of 32 patients with SSc (22 with the diffuse, 10 with the limited form) and of six patients with morphoea were assessed using radioimmunoassays for the cross-linked carboxy terminal telopeptide of type I collagen (ICTP) and for the amino terminal propeptide of type I procollagen (PINP) reflecting type I collagen degradation and synthesis, respectively. In 27 of the 32 patients with SSc, the concentration of ICTP was above the upper limit of the normal value (4.6 micrograms/L) and the mean level was clearly elevated at 7.92 micrograms/L. The ICTP concentration correlated with the skin score measuring the extent of the lesions, whereas no such correlation was found for PINP. The ICTP antigen in serum, studied by immunoblotting, had a molecular weight of about twice that of the trypsin-generated fragment isolated from human bone collagen. The mean concentration of serum PINP was 43.9 micrograms/L and no patient exceeded the upper limit of the normal range (80 micrograms/L). We report here for the first time that the concentration of the type I collagen degradation product ICTP in serum shows a close correlation with the extent of skin fibrosis in patients with SSc. We conclude that the increased deposition of type I collagen in this disease is accompanied by an increased turnover of this molecule, indicating a more complex derangement of synthetic and degradative processes than previously acknowledged.

Adult↗
PubMed1992

Occupationally-induced scleroderma.

Systemic sclerosis or scleroderma is an uncommon multisystem disease with a reported incidence of 2 to 12 cases per million people per year. The clinical and pathological features can be grouped into three main categories: those related to fibrosis, to vascular abnormalities, and to immunological abnormalities. Cutaneous features dominate the patients' appearance, and Raynaud's phenomenon is an early symptom. A possible association between scleroderma and workers exposed to hand-arm vibration and/or silica has been suggested by reports in the literature since the turn of the century. A further four patients with collagen disease are reported here. Three were occupationally exposed to both hand-arm vibration and silica, the fourth to hand-arm vibration alone. In conjunction with previously reported cases, this supports the hypothesis that collagen disease may be work attributable in hypersusceptible persons.

Adult↗
PubMed1981

Renal vasoactive hormones in scleroderma (progressive systemic sclerosis).

Plasma renin activity and the urinary excretions of kallikrein, kinin, immunoreactive PGE (iPGE) and aldosterone were determined in 23 patients with progressive systemic sclerosis (PSS) on a fixed sodium and potassium intake who had no clinically apparent renal disease. Urinary excretions of kallikrein and kinin in the PSS patients were not significantly different from those of a group of sex and race-matched normal controls. In the female PSS patients urinary excretion of iPGE was also found to be normal. Upright PRA was appropriate for the urinary sodium excretion in 18 PSS patients (13 normotensive and 5 hypertensives) but was significantly elevated in the remaining 5 (all normotensive). The data suggest that the renal kallikrein-kinin and prostaglandin systems are unaltered in PSS patients without clinical evidence of renal disease.

Adult↗
PubMed1986

The cardiovascular manifestations of systemic sclerosis (scleroderma).

In conclusion, systemic sclerosis is both a fascinating and frustrating affliction. It is a systemic disease of multiple stages. Prognosis is dependent on the site and extent of visceral involvement. There is evidence to implicate the vascular system as the primary target organ of the disease. The cardiovascular manifestations include myocardial fibrosis, pericarditis, and a variety of arrhythmias and conduction abnormalities. Intractable heart failure or sudden cardiac death can ensue. Cardiac involvement in systemic sclerosis portends an ominous prognosis, and is probably most directly related to the extent of myocardial fibrosis which is present. The pathogenesis of myocardial fibrosis has not been determined, but it appears to be a result of an impairment of myocardial perfusion at both the small artery and microvasculature level. Obstructive, vasospastic, and devascularization factors all may be playing a role.

Blood Vessels↗
PubMed1997

Impaired quantitative cerebral blood flow in scleroderma patients.

Systemic Sclerosis (SSc) is a multisystem disease characterised by proliferation of vascular tissue, obliterative microvascular lesions and diffuse organ fibrosis. Despite widespread vascular disease, Central Nervous System complaints are only infrequently reported and it is uncertain whether they merely derive from systemic complications or whether they may be also caused by a primary vascular process within the brain. Regional cerebral blood flow (rCBF) was quantitatively measured by the 133Xenon clearance technique in twenty-seven consecutive SSc patients without relevant systemic complications and with different severity of vascular involvement, as staged by nailfold capillary videomicroscopy (NCV). Absolute, percent, and asymmetry rCBF values were compared (z-statistics) with age- and sex-matched healthy controls. Cerebral MRI and Mini-Mental State Examination (MMSE) were also performed. Doppler sonography of neck vessels and Transcranial Doppler sonography (TCD) were performed in patients presenting rCBF reduction. Cerebral hypoperfusion was found in the 52% of patients, i.e.: in 33% of patients with the 'early' NCV pattern, in 56% of patients with the 'active' pattern, and in 67% of patients with the 'late' NCV pattern. Thirty percent were the MRIs showing focal and/or diffuse signal abnormalities in the white matter of both hemispheres with the highest rate (44%) in the 'late' NCV pattern. MMSE disclosed mild dementia in one patient in the 'late' NCV group and some mistakes in 6 more patients, in the 'active' or 'late' NCV groups, whereas TCD failed to find significant stenosis of Willis' arteries. Cerebral hypoperfusion is shown for the first time in a substantial part of SSc patients without either neurological symptoms or relevant systemic complications. It is suggested that the rCBF reduction might be related to the systemic scleroderma microangiopathy although, probably due to the paucity of connective tissue in cerebral vessels, the vast majority of patients remains in a subclinical phase.

Adult↗
PubMed1996

Decreased expression of alpha 2 beta 1 integrin in scleroderma fibroblasts.

Systemic scleroderma (SSc) is a complex connective tissue disorder of unknown etiology. In early stages of the disease, fibroblasts are activated to produce large amounts of collagen with subsequent fibrosis. Collagen metabolism of fibroblasts is modulated by their contact with the extracellular matrix (ECM), which involves distinct receptors on the cell surface, mainly belonging to the integrins. We investigated the expression of collagen receptor alpha 2 beta 1 in SSc and normal fibroblasts, since this receptor has been shown to be utilized by fibroblasts for adhesion to and reorganization of collagen I. 9 strains of scleroderma fibroblasts grown as monolayer cultures were first analyzed with respect to their collagen I expression. 6 of these strains were similar to controls "low" producers) and 3 strains showed up to 2-3 x higher levels of collage I mRNA expression ("high" producers). Northern hybridization using a cDNA probe specific for the alpha 2 integrin subunit revealed a decrease of the corresponding mRNA in SSc fibroblasts as compared to controls (75% versus 100%). "High" collagen producing cell strains displayed the lowest values for alpha 2 integrin mRNA. The decrease of alpha 2 integrin subunit expression at the mRNA level in selected fibroblasts was further substantiated by radioimmunoprecipitation using specific mAbs directed against alpha 2 integrin subunit. No significant changes in beta 1 integrin expression could be observed - neither at mRNA nor at the protein level. Our data indicate a correlation between excessive synthesis of collagen and low levels of alpha 2 integrin subunit expression in SSc fibroblasts. Further experiments should clarify whether this observation is a phenomenon specific for scleroderma or whether it reflects an "activated" state of fibroblasts.

Cells, Cultured↗
PubMed1986

[A special case: scleroderma].

Progressive systemic scleroderma is presented in an individual case of an acrosclerotic variant, the diagnosis of which was only made following a casual minor trauma. Analysis disclosed further manifestation in various organs, which had been treated for many years without knowledge of the real cause.

Adult↗
PubMed1994

Association of HLA antigens with anti-Scl-70-antibodies and clinical manifestations of systemic sclerosis (scleroderma)

Thirty patients with systemic sclerosis (scleroderma) and 188 healthy controls were studied for class I and class II MHC antigens. All patients with scleroderma fulfilled the ARA preliminary criteria for systemic sclerosis. The frequencies of HLA antigens B8, DR3 and DR52 were higher in patients with scleroderma as compared with controls. Ten patients had anti-Scl-70 antibodies, and four of them (40%) had HLA-DR5 antigen compared to 19 of 188 controls (10%), P = 0.013. The relative risk for DR5 in anti-Scl-70-positive patients was 3.6 compared to 1.6 of DQ3 suggesting the primary significance of DR5 compared to DQ related factors. Patients with neurological manifestations had higher frequencies of B8 and DR3 than those with no neurological manifestations of scleroderma. Our results support the view that immunogenetic background is associated with different clinical subsets of systemic sclerosis.

Adult↗
PubMed2004

Cytokines as therapeutic targets for the gastrointestinal manifestations of scleroderma.

Systemic sclerosis (SSc), or scleroderma, is a connective tissue disorder characterized by progressive fibrosis of the skin and internal organs. It has significance for gastroenterologists because the gastrointestinal tract is involved in 90% of SSc patients, who often present with esophageal dysfunction. Though the exact pathogenesis of SSc is unknown, there is increasing evidence supporting an immune mechanism. Cytokines are the soluble mediators of immune activation, altered fibroblast proliferation and extracellular matrix accumulation in SSc and thereby provide important therapeutic targets. In the present review, the involvement of cytokines in SSc is discussed with particular emphasis on cytokines and growth factors that have been implicated in the disease process and likely play an important role in the gastrointestinal manifestations of scleroderma. The role of cytokines as therapeutic targets in scleroderma forms the basis of this timely review.

Chemokine CCL2↗