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PubMed2006

A randomized, double-blind, placebo-controlled trial of photopheresis in systemic sclerosis.

BACKGROUND: Systemic sclerosis is a multisystemic connective tissue disease with marked involvement of the skin and joints for which few effective evidence based therapies are available. To further investigate the efficacy of extracorporeal photochemotherapy on early aggressive cutaneous disease, a randomized, double-blind, placebo-controlled trial was performed. OBJECTIVE: Our aim was to evaluate the efficacy of photopheresis in the treatment of patients with systemic sclerosis (scleroderma). METHODS: This randomized, double-blind, placebo-controlled clinical trial was conducted at 16 investigational sites in the United States, Canada, and Europe. Sixty-four patients with typical clinical and histologic findings of scleroderma, of less than 2 years' duration, were studied. Patients did not receive any other concomitant treatment for scleroderma. Patients were randomized to receive either active or sham photopheresis treatment on two consecutive days monthly for 12 months. Severity of skin (skin scores assessed in 22 body regions) and joint involvement (60 joints examined for contractures) were assessed on a monthly basis. RESULTS: A statistically significant improvement in skin scores as compared with baseline was observed at 6 months (P = .0024) and 12 months (P = .008) among those who received active photopheresis, but not among those who received sham photopheresis. Comparison of skin scores between the two study arms did not achieve statistical significance because of the small sample size of the study arms. Joint involvement was also significantly improved after 6 months (P = .002) and 12 months (P = .001) of active photopheresis when compared with baseline. LIMITATIONS: The study lacks sufficient statistical power to reveal a significant difference in skin and joint manifestations between the active and sham photopheresis arms. CONCLUSION: Photopheresis induced significant improvement of skin and joint involvement in patients with scleroderma of recent onset; however, any effect when compared with sham treatment and a possible placebo effect may be modest.

Adult↗

PubMed1987

Progressive systemic sclerosis and nervous system involvement. A review of 14 cases.

Nervous system involvement in progressive systemic sclerosis (PSS) has been considered rare compared to other collagen diseases. We present 14 additional cases of PSS with neurological manifestations. Primary involvement of the peripheral nerves could be detected in 4 of 14 patients and is documented by electromyo- and electroneurographical examinations. Central nervous system (CNS) manifestations directly related to PSS are a rarity, which may reflect the lack of collagen in the brain, histological differences between cerebral and other arteries and the immunological particularity of the brain. There may have been a direct relationship between CNS involvement and PSS in only one patient presenting with an overlap-syndrome.

Aged↗

PubMed2006

Vasoactive therapies in systemic sclerosis.

In systemic sclerosis (SSc), vasculopathy is a central mechanism and is a major initial event in the process of sclerosis and causing different complications such as Raynaud's phenomenon, ulcer(s) or pulmonary hypertension, the latter being life threatening. Therefore, vasoactive therapies are important when taking care of patients with SSc. However, as treatment has been difficult, numerous therapeutic modalities have been suggested. Until now, the interpretation of most studies is limited due to the heterogeneity of patient groups, the low number of patients, the short duration of the treatments and, possibly, further pathogenic mechanisms such as autoimmunity. Several drugs are now available with effects on vasculopathy and, furthermore, on specific pathogenic mechanisms in SSc. Prostacyclins, endothelin receptor antagonists and phosphodiesterase-5 inhibitors have potential effects on fibrosis, inflammation and endothelial cells, suggesting a disease-modifying capacity in systemic sclerosis. This review summarizes evidence-based therapy recommendations.

Endothelin Receptor Antagonists↗

PubMed1985

Pulmonary vascular response during Raynaud's phenomenon in progressive systemic sclerosis.

Progressive systemic sclerosis and Raynaud's phenomenon are associated with a distinctly vascular form of pulmonary involvement and pulmonary hypertension. To investigate a possible underlying vasospastic predisposition in these patients, the pulmonary vascular response to Raynaud's phenomenon induced by cold-water hand immersion was examined in nine patients. Four patients had pulmonary fibrosis and four patients had the CREST syndrome; no patient had pre-existing pulmonary hypertension. During Raynaud's phenomenon, there was no significant rise in mean pulmonary artery pressure (15 +/- 3 versus 15 +/- 2 mm Hg, p = NS) or pulmonary vascular resistance (112 +/- 38 versus 118 +/- 50 dynes X second X cm-5, p = NS) over baseline, despite a significant rise in mean aortic pressure (104 +/- 14 versus 92 +/- 11 mm Hg, p less than 0.01) and systemic vascular resistance (1,700 +/- 450 versus 1,500 +/- 470 dynes X second X cm-5, p less than 0.01). It is concluded that pulmonary vasospasm with transient pulmonary hypertension does not occur in patients with progressive systemic sclerosis and Raynaud's phenomenon during episodes of Raynaud's phenomenon. Abnormal pulmonary vasospasm in these patients in response to other stimuli, however, is not excluded.

Adult↗

PubMed1981

Abnormal colonic motility in progressive systemic sclerosis.

Progressive systemic sclerosis alters smooth muscle function throughout the gastrointestinal tract. In 10 consecutive patients with the disease, colonic spike activity and contractile activity were measured after a 1000-kcal meal, intramuscular injection of neostigmine, or intravenous injection of metoclopramide. The 1000-kcal meal stimulated a significant increase in spike and contractile activity in normal subjects. Nine of the 10 patients had no increase in motility after eating. Neostigmine or metoclopramide stimulated colonic spike (p less than 0.01) and contractile (p less than 0.02) activity in normal subjects and stimulated colonic motility (p less than 0.01) in four of 10 patients with less severe systemic manifestations of the disease (Group 1). The drugs had no effect on patients with severe progressive systemic sclerosis (Group II). The patients with severe scleroderma had significant gastrointestinal roentgenographic abnormalities and severe cardiac, renal, or pulmonary dysfunction. Four of six Group II patients died from the disease; all four had marked smooth muscle atrophy in the colonic wall. These findings suggest that the gastrocolonic response is absent early in the disease process and that the smooth muscle atrophy occurring with progression of the disease may lead to a more severe colonic motor disturbance.

Adult↗

PubMed1999

Clinical and immunological characterization of patients with systemic sclerosis overlapping primary biliary cirrhosis: a comparison with patients with systemic sclerosis alone.

Limited cutaneous systemic sclerosis (lSSc) or CREST syndrome is sometimes complicated by primary biliary cirrhosis (PBC). To characterize the clinical and immunological features of patients with SSc overlapping PBC (SSc-PBC), the clinical and laboratory data of 11 SSc-PBC were studied. Since all of the SSc-PBC were lSSc, the features of SSc-PBC were compared with those of 266 patients with lSSc alone. The sera from SSc-PBC showed a significantly higher positivity for anti-centromere antibody (ACA) (p < 0.0005) and higher reactivity to centromere protein-C. Although SSc-PBC more frequently exhibited calcinosis and telangiectasia (p < 0.05), there was no statistical difference in other features of CREST syndrome. There was no statistical difference in other scleroderma-related features either. SSc-PBC were more frequently complicated with Sjögren syndrome (p < 0.05). The most prominent feature of SSc-PBC was a higher incidence of ACA than in lSSc alone.

Adult↗

PubMed1994

HLA-DQB1 associations with anti-topoisomerase-1 antibodies in patients with systemic sclerosis and their first degree relatives. United Kingdom Systemic Sclerosis Study Group.

The frequency and functional properties of anti-topoisomerase-1 antibodies (ATA) have been studied in 58 systemic sclerosis (SSc) probands, 218 first degree relatives and 22 spouses. The dependence of ATA on the presence of certain HLA-DRB1 and HLA-DQB1 alleles was examined. ATA were detected by immunodiffusion, by absorption or inhibition of topoisomerase-1 enzymic activity, by immunoblotting of a K562 cell extract and by immunoprecipitation of 35S radiolabelled cell lines. HLA class II typing for HLA-DRB1 and HLA-DQB1 was performed by oligonucleotide typing in 49 families. Six probands and two relatives had ATA. The relatives with ATA had SSc. All eight individuals with ATA directly inhibited topoisomerase-1 function. Four of the eight had limited skin disease and four had diffuse skin involvement. The seven who were genotyped had at least one HLA-DQB1 allele encoding for tyrosine at position 30 of the first domain. Therefore, ATA are not widely dispersed within families, but rather are only present in those with SSc, and certain genetic requirements appear necessary for their generation.

Alleles↗

PubMed1996

Cardiorespiratory responses to incremental exercise in patients with systemic sclerosis.

Patients with systemic sclerosis are known to have histologic pulmonary abnormalities despite normal chest radiograph or conventional pulmonary function or both. In an attempt to detect early features of lung involvement in progressive systemic sclerosis, we investigated patients with systemic sclerosis using cardiopulmonary exercise testing. We have studied 78 patients who fulfilled the American Rheumatism Association criteria for the classification of systemic sclerosis, and according to the classification of LeRoy, 44 had limited cutaneous systemic sclerosis and 34 had diffuse cutaneous systemic sclerosis. A significantly decreased diffusing capacity (65 +/- 3% of that predicted) was present only in the group with diffuse cutaneous systemic sclerosis. The patients with lung involvement showed a significant reduction in exercise capacity (54 +/- 3% of that predicted) and in oxygen uptake (70 +/- 3% of that predicted). Additionally, we could demonstrate an increased functional dead space ventilation (0.34 +/- 0.02) and widened alveolar-arterial oxygen difference during exercise (44 +/- 3 mm Hg). By cardiopulmonary exercise testing, 12 of the 78 patients (15%) with normal single-breath diffusing capacity for carbon monoxide had increased dead space to tidal volume ratio. Our results suggest that occult pulmonary impairment may be present in patients with normal pulmonary function and that cardiopulmonary exercise testing enables detection of such impairment. Our study results show the limitations of resting data in predicting abnormalities during exercise in patients with systemic sclerosis.

Adult↗

PubMed1999

Familial risk estimation in systemic sclerosis.

BACKGROUND: Familial systemic sclerosis has been rarely reported. Assumptions have therefore been made implying no familial disease aggregation. This study critically challenges the assumption using a methodical population-based epidemiological approach to quantify the prevalence and characteristics of familial systemic sclerosis. METHODS: In this retrospective cohort study the systemic sclerosis prevalence in first degree family members was compared between 715 systemic sclerosis patients (710 families) and 371 randomly ascertained age and gender group-matched general practice controls (371 families). These data, obtained by telephone questionnaire (living patients) or medical records review (deceased patients and untraceable patients of unknown living status), were validated, where necessary, and expressed in terms of relative risk, absolute risk and population point prevalence. RESULTS: Systemic sclerosis affecting first degree members was validated in ten of 710 families. Reporting of systemic disease in another four more distant family members, and the co-occurrence of systemic and localised disease in three families was also documented. Observed and expected disease subtype concordance was 80% (44-97%) and 68% respectively and the female predominance among familial cases was similar to that for non-familial disease. The risk of disease in a subsequent first degree relative was compared to the risk in an initial first degree family member. Its estimated magnitude was wide (11-158). However, use of population prevalence data to determine the expected number of systemic sclerosis patients in the negative cohorts' families suggests the higher estimate is more realistic. Despite the high magnitude, the absolute disease risk in first degree family members remained low--approximating 1%. The population prevalence of familial systemic sclerosis approximated 1.4/million. CONCLUSIONS: This study substantially increases the otherwise small list of documented instances of familial systemic sclerosis. More importantly, it quantifies the risk for the first time, ranking it as the disease's most powerful determinant identified to date.

Cohort Studies↗

PubMed1995

Plasma endothelin-1 levels in patients with systemic sclerosis: influence of pulmonary or systemic arterial hypertension.

OBJECTIVES: To investigate the behaviour of circulating endothelin-1 (ET-1) in patients affected by systemic sclerosis and to elucidate the relationship between systemic and pulmonary plasma peptide and arterial pressure levels. METHODS: Plasma ET-1 concentrations were determined in 48 patients affected by systemic sclerosis (41 women, seven men; mean age 47.2 (SD 5.5) years) with or without systemic or pulmonary hypertension (or both). A group of 18 normal volunteers served as controls (15 women, three men; mean age 45.0 (10.1) years). RESULTS: Plasma ET-1 levels were significantly greater in patients affected by systemic sclerosis (1.65 (0.29) pg/ml) than in controls (0.63 (0.19) pg/ml) (p < 0.0001). Pulmonary artery systolic hypertension alone was present in 14 patients with systemic sclerosis (50.5 (8.49) mm Hg, range 37-67 mm Hg), and systemic hypertension alone (160.7 (5.9)/100.6 (3.2) mm Hg) was present in 11 patients. Both conditions were present in 12 patients, while 11 patients had systemic hypertension. There were no significant differences in plasma ET-1 levels between patients with pulmonary hypertension alone (1.62 (0.21) pg/ml) and those with systemic hypertension alone (1.65 (0.43) pg/ml). In particular, patients with normal pulmonary artery and systemic pressures (n = 11) had plasma ET-1 concentrations identical to those found in patients (n = 12) with both pulmonary and systemic hypertension (1.70 (0.15) v 1.64 (0.35) pg/ml, respectively). No correlations were observed between plasma ET-1 and either pulmonary or systemic pressures. CONCLUSION: Systemic sclerosis is characterised by increased plasma ET-1 levels, but neither pulmonary nor systemic hypertension are accompanied by further increase in plasma peptide levels.

Endothelins↗

PubMedDate not supplied

[Etiopathogenesis of progressive systemic sclerosis].

Progressive systemic sclerosis (PSS) is a systemic disease of connective tissue involving the skin and internal organs characterized by fibrotic and degenerative changes. The disease is usually progressive, incurable and always leads to death. Several hypotheses about the etiopathogenesis of PSS exist which try to explain the cause of morphological changes of the connective tissue. The first theory advocates evolution of the primary lesion within the blood vessels, the second considers the primary event to be an abnormality of collagen metabolism manifested by fibrosis. The third postulates on an autoimmune basis for the disease, and the fourth is based on the disfunction of autonomic nervous system. All the theories are partly linked and represent the morphological, biochemical and immunological aspects of the pathogenesis of this disease.

Humans↗

PubMed2001

Evidence of 5-lipoxygenase overexpression in the skin of patients with systemic sclerosis: a newly identified pathway to skin inflammation in systemic sclerosis.

OBJECTIVE: Leukotrienes are a family of arachidonic acid derivatives with potent proinflammatory and profibrotic properties, and 5-lipoxygenase (5-LOX) catalyzes two key steps in the leukotriene biosynthetic pathway. Since inflammatory cell infiltrates and excessive fibrosis are hallmarks of systemic sclerosis (SSc) skin lesions, we undertook the present study to investigate the expression of 5-LOX in skin biopsy specimens from patients with SSc. METHODS: Expression of 5-LOX in skin sections from 10 SSc patients and 8 healthy controls was examined by in situ hybridization with specific riboprobes and by immunohistochemistry analysis with 5-LOX monoclonal antibodies. Synthesis of 5-LOX by cultured dermal fibroblasts from 7 patients with SSc and 4 controls was measured by fluorescence-activated cell sorter analysis. In addition, concentrations of leukotriene B4 (LTB4) and LTE4 in fibroblast supernatants after stimulation were determined using enzyme immunoassays. RESULTS: Expression of 5-LOX was found in all skin sections from SSc patients as well as from controls. However, the number and percentage of 5-LOX-positive cells were significantly higher in SSc skin sections compared with control sections. Expression of 5-LOX was seen in cells within perivascular inflammatory infiltrates as well as in fibroblasts throughout the skin. The experiments with cultured skin fibroblasts revealed that 5-LOX was constitutively expressed in these cells, which resulted in the production of leukotrienes after cell stimulation. Whereas no difference was found for LTE4, SSc fibroblasts produced significantly higher amounts of LTB4 after stimulation, compared with healthy control fibroblasts. CONCLUSION: The results of this study suggest that the 5-LOX pathway may be of significance in the pathogenesis of SSc and may represent a target for new treatment strategies.

Arachidonate 5-Lipoxygenase↗

PubMed2003

Update on disease-modifying antirheumatic drugs in the treatment of systemic sclerosis.

Treatment of systemic sclerosis has been somewhat haphazard and treatment has often been "borrowed" from the experience gained from treating other connective tissue diseases. There was a period of time that was focused mainly on organ-specific manifestations of systemic sclerosis and some advance in preventing vital organ damage (such as renal crisis) was achieved. The vast improvement in mortality from the use of ACE inhibitors raises one's hopes for other effective therapeutic interventions. At this juncture, the evidence is strong that the ACE inhibitors that are used in scleroderma renal crisis are disease-modifying, even without proving it by a randomized controlled trial. The evidence is strong that the use of epoprostenol for primary pulmonary hypertension is life-saving; however, whether epoprostenol is life-saving in the pulmonary hypertension in scleroderma remains to be proven. There are suggestions that bosentan (for the pulmonary hypertension of scleroderma), cyclophosphamide (for SSc alveolitis), stem cell transplant, interferon-gamma (for interstitial pulmonary fibrosis), and methotrexate (for the skin thickening of diffuse scleroderma) may improve organ function or functional activities, but whether they are truly disease-modifying remains to be proven. As we increase our understanding of the pathophysiology of systemic sclerosis and we learn how better to design trials for systemic sclerosis, we may be more successful in developing optimal disease-modifying therapy. Although the treatment of systemic sclerosis remains difficult, there are an increasing number of potentially effective regimens that are undergoing clinical investigations. A rational approach to therapy seems possible, based on a hypothesis of the pathogenesis of systemic sclerosis. Thus, there is accumulating evidence that supports the use of prostacyclin derivatives to treat systemic sclerosis, some evidence that antifibrotic regimens may be effective, and moderate evidence that immunosuppression also may be effective in certain stages of this disease.

Antirheumatic Agents↗

PubMed1983

Absence of positional change in pulmonary diffusing capacity in systemic sclerosis.

Patients with systemic sclerosis frequently have pulmonary function abnormalities, and recent evidence suggests that pulmonary vascular involvement is a common manifestation. To test the hypothesis that patients with systemic sclerosis have impaired ability to recruit or distend the pulmonary vascular bed, the postural change in the coefficient of carbon monoxide diffusing capacity was measured in 11 patients with systemic sclerosis, and the results were compared with results from age-, smoking-, and sex-matched control subjects with rheumatoid arthritis and with results from healthy subjects. In normal subjects and patients with rheumatoid arthritis increased, the coefficient of diffusion by 9.4 percent (p less than 0.005) and 8.4 percent (p less than 0.01), respectively, when they moved from the sitting to the supine position. In contrast, patients with systemic sclerosis did not show a significant increase in coefficient of diffusion, even those who had otherwise normal pulmonary function. Regression analyses showed that the change in coefficient of diffusion decreased with increasing age (r = -0.57) in normal subjects, and that the change in coefficient of diffusion was a function of the percent predicted forced vital capacity, both in patients with systemic sclerosis (r = 0.59) and in those with rheumatoid arthritis (r = 0.70). Thus, these findings indicate that patients with systemic sclerosis have a nondistensible pulmonary capillary bed and that the absence of positional change in the coefficient of diffusion in systemic sclerosis is a subtle indicator of pulmonary involvement.

Adult↗

PubMed1995

Enhanced production of transforming growth factor-beta (TGF-beta) during autologous mixed lymphocyte reaction of systemic sclerosis patients.

Systemic sclerosis (SSc) is characterized by systemic fibrosis and microvascular lesions. As TGF-beta is suggested to be related to skin fibrosis, we examined the production of TGF-beta from peripheral mononuclear cells (MNC) of SSc patients. Since anti-TGF-beta neutralizing antibody improved the defective proliferative response in autologous mixed lymphocyte reaction (AMLR) of SSc patients, TGF-beta was thought to participate in the decreased AMLR of SSc patients. Greater amounts of TGF-beta in the active as well as in the latent forms were produced during AMLR of SSc patients than that of normal subjects. It was suggested that TGF-beta excessively produced from the MNC of SSc patients might play a major role in the fibrosis of the patients during AMLR-like in vivo responses.

Adult↗

PubMed2006

[Causes of death of patients with systemic sclerosis].

UNLABELLED: Systemic sclerosis (SSc) is a chronic, systemic connective tissue disease, characterized by progressive skin fibrosis, internal organs and disfunction blood vessels. THE AIM: of the study was o analyze death causes in patients with SSc and the assessment of relationship between clinical status, immunologic test results and survival/mortality of patients with SSc. MATERIAL AND METHODS: Case histories of all patients with SSc, hospitalized for six years (since 1'" October 1999 to 1It October 2005) in Department of Rheumatology and Internal Diseases, Medical University of Bialystok, were retrospectively analyzed. Current patients status at the end-point of study was estimated during control examination and phone contact in selected cases. The time and cause of death was based on autopsy results. RESULTS: In study group of 76 patients with SSc, 13 deaths were found (17,1%). Death cause analyses revealed that: interstitial lung disease was the main cause of death (4/13 - 30%). As a secondary cause of death in these patients neoplasms were recognized (3/13 - 23,1%). In all patients with neoplasms exudation in pleura was diagnosed. CONCLUSIONS: Pulmonary complications and neoplasms are predominant causes of death in patients with SSc. Risk factors of death are: pulmonary hypertension and myositis. The presence of exudation in pleura in patients with SSc is a bad prognostic symptom and a possible sign of neoplastic disease.

Adolescent↗

PubMedDate not supplied

Evaluation of abnormalities of orthostatic postural control in systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is a multi-systemic disease of unknown etiology characterized by damage to the small arteries, arterioles and capillaries. The documented occurrence of various neuropathies in SSs patients led us to hypothesize that there is a potential for postural control impairments in such disease. This study was aimed at evaluating the orthostatic postural control of SSc patients who do not manifest balance or hearing symptoms. METHODS: Postural stability was assessed in 36 female SSc patients by means of a static computerized posturography technique. Their immunological and microvascular condition were evaluated by means of blood tests and microcapillaroscopy of the digital vessels. Posturography and microcapillaroscopy were performed before and after treating the patients with Iloprost. In order to compare results, posturography was also carried out on a control group composed of 10 healthy women of similar age. Both groups were studied in two different sensory conditions, i.e. with eyes opened and with eyes closed. RESULTS: Posturography results showed relevant differences in body sway between patients and control subjects. Fourier spectral analysis of body sway showed that, independently from visual control, SSc patients exhibit a higher level of low/middle frequency oscillations (both on the lateral and the anteroposterior axis). No relationship was established between disease stage and postural performance. CONCLUSION: This study seems to indicate a subtle neurophysiological dysfunction in the orthostatic postural control of female SSc patients. Further tests on the somatosensory neurological function of SSc patients may help support the above mentioned findings.

Dizziness↗

PubMed2005

Up regulated expression of tumour necrosis factor {alpha} converting enzyme in peripheral monocytes of patients with early systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is accompanied by abnormalities in humoral and cellular immune systems. OBJECTIVE: To determine the genes specifically expressed in the immune system in SSc by analysis of the gene expression profile of peripheral blood mononuclear cells (PBMC) from patients with SSc, including those treated with haematopoietic stem cell transplantation (HSCT). Additionally, to investigate the clinical significance of the up regulation of tumour necrosis factor alpha (TNFalpha) converting enzyme (TACE). METHODS: PBMC from patients with SSc (n = 23) and other autoimmune diseases (systemic lupus erythematosus (SLE, n = 16), rheumatoid arthritis (RA, n = 29)), and from disease-free controls (n = 36) were examined. Complementary DNA arrays were used to evaluate gene expression of PBMC, in combination with real time quantitative polymerase chain reactions. TACE protein expression in PBMC was examined by fluorescence activated cell sorter (FACS). RESULTS: In patients with SSc 118 genes were down regulated after HSCT. Subsequent comparative analysis of SSc without HSCT and healthy controls indicated SSc-specific up regulation for three genes: monocyte chemoattractant protein-3 (p = 0.0015), macrophage inflammatory protein 3alpha (p = 0.0339), and TACE (p = 0.0251). In the FACS analysis, TACE protein was mainly expressed on CD14(+) monocytes both in patients with SSc and controls. TACE expression on CD14(+) cells was significantly increased in patients with early SSc (p = 0.0096), but not in those with chronic SSc, SLE, or RA. TACE protein levels in SSc monocytes correlated with the intracellular CD68 levels (p = 0.0016). CONCLUSIONS: Up regulation of TACE expression was a unique profile in early SSc, and may affect the function of TNFalpha and other immunoregulatory molecules.

ADAM Proteins↗