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PubMed2004

Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis.

Systemic sclerosis (SSc) is characterized by multi-organ fibrosis with an autoimmune background. Although autoantibodies are detected frequently in SSc patients, the role of autoantibody in the development of fibrosis remains unknown. Connective tissue homeostasis is a balance between the synthesis and degradation of the extracellular matrix (ECM); ECM degradation is regulated mainly by matrix metalloproteinases (MMPs). Anti-MMP-1 antibody is suggested to inhibit MMP-1 and be involved in the development of the fibrosis in SSc. However, the accumulation of various ECM components in the tissue of SSc cannot be explained by the anti-MMP-1 antibody alone. In this study, we examined the presence or levels of antibody to MMP-3, a protein which degrades various ECM components relevant to SSc fibrosis. Enzyme-linked immunosorbent assay (ELISA) using human recombinant MMP-3 revealed that IgG anti-MMP-3 autoantibody levels were elevated significantly in the sera from SSc patients, but not in patients with active systemic lupus erythematosus or dermatomyositis. IgG and IgM anti-MMP-3 antibody levels were significantly higher in diffuse cutaneous SSc, a severe form, than those in limited cutaneous SSc. Consistently, IgG anti-MMP-3 antibody levels correlated significantly with fibrosis of the skin, lung and renal blood vessels. The presence of IgG anti-MMP-3 autoantibody in sera from SSc patients was confirmed by immunoblotting analysis. Remarkably, MMP-3 activity was inhibited by IgG anti-MMP-3 antibody. These results suggest that anti-MMP-3 antibody is a serological marker that reflects the severity of SSc and also suggest that it may contribute to the development of fibrosis by inhibiting MMP-3 activity and reducing the ECM turnover.

Autoantibodies↗

PubMed2006

[Cyclophosphamide treatment in patients with systemic sclerosis].

Systemic sclerosis (SSc) is a chronic, multisystemic, connective tissue disease characterized by fibrosis of the skin and visceral organs and the impairment of blood vessels. The etiology of SSc is unknown and its pathogenesis unclear. Effective treatment of SSc is also unavailable. Cyclophosphamide (CFX) has been reported to exert some beneficial actions in SSc patients, in particular in those with interstitial lung disease. However, it should be kept in mind that CFX treatment is related to multiple side effects. The aim of this study was to review available literature concerning the use of CFX in SSc patients.

Cyclophosphamide↗

PubMed2005

The importance of early diagnosis of systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease which etiology and pathogenesis is still unknown. The vascular and immunological changes are the major elements of the SSc. The preliminary ACR criteria of SSc are the oldest criteria for rheumatic diseases and are not sensitive enough in respect to early SSc. Many authors suggest that these criteria should be extended by capillaroscopic and immunological changes. In 2001 LeRoy and Medsger proposed new criteria for SSc that could help to identify SSc patients with early stage of the disease. This will give the opportunity for the early and proper treatment.

Humans↗

PubMed2002

Genetic epidemiology: systemic sclerosis.

Systemic sclerosis (SSc) is a multisystem connective tissue disease characterised phenotypically by fibrosis and ischaemic atrophy. Its aetiology is most likely multifactorial. A genetic predisposition to the condition is suggested by reports of familial SSc (a positive family history is the strongest risk factor yet identified), by animal models, and by disease-association studies, in which researchers have examined a wide variety of genes including those involved in fibrosis, in vascular function and structure, and in autoimmunity - the relative rarity of SSc has precluded linkage studies, except in the Choctaw Indians. Recent advances in genetic methodologies should further our understanding of this complex disease process.

Animals↗

PubMed2003

New insights into the pathogenesis of systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disorder characterized by vascular abnormalities and excessive collagen synthesis. Extracellular matrix overproduction by fibroblasts results from abnormal interactions among endothelial cells, mononuclear cells (lymphocytes and monocytes) and fibroblasts, in a setting of vascular hyperreactivity and tissue hypoxia. Many autoantibodies have been identified in the sera of SSc patients; some of them are specific to the disease, such as anti-centromere antibodies in limited SSc, anti-topoisomerase 1 and anti-RNA polymerase I/III antibodies in diffuse SSc. Their pathogenetic role(s) remains uncertain. However, genetic, environmental and possibly alloreactive factors might also contribute to disease susceptibility.

Autoantibodies↗

PubMed2006

Primary myocardial involvement in systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease characterized by diffuse vascular lesions and fibrosis. Primary myocardial involvement is common in SSc and, when clinically evident, appears as a poor prognostic factor. An increasing body of evidence suggests that myocardial involvement is due, at least in part, to microcirculation impairment with abnormal vasoreactivity, with or without associated structural abnormalities of the small coronary arteries or arterioles. Using conventional methods, myocardial perfusion impairment, systolic and diastolic left ventricular dysfunction and right ventricular dysfunction have been reported in SSc. Recently, tissue Doppler echocardiography and magnetic resonance imaging have confirmed these results. Vasodilators, such as calcium channel blockers and angiotensin converting enzyme inhibitors, improve both myocardial perfusion and function abnormalities.

Arterioles↗

PubMed1992

Serum levels of aminoterminal type III procollagen peptide and hyaluronan predict mortality in systemic sclerosis.

Systemic sclerosis (SSc) is characterized by an excessive accumulation of collagen in skin and internal organs and increased serum concentrations of different connective tissue metabolites have been reported. In this study of 82 patients with SSc, serum concentrations of aminoterminal type III procollagen peptide (PIIINP), smaller PIIINP-related antigens (Fab PIIINP) and hyaluronan (HA) were increased as compared to healthy controls matched for age and sex. Patients with a shorter disease duration (less than 3 years) had higher serum levels of PIIINP and Fab PIIINP than patients with a longer disease duration. The highest serum concentrations of PIIINP and HA were seen in seven patients who died within 2 years.

Cyclofenil↗

PubMed2006

[Treatment of systemic sclerosis].

Systemic sclerosis (SSc, scleroderma) is a multisystem disease with a bad prognosis. No drugs have been shown to cure this disease. In view of its pathogenesis, in which immune responses are presumed to play an important role, immune suppressive therapies are widely applied in the treatment of SSc. Recent placebo-controlled trials with cyclophosphamide in patients with SSc complicated by alveolitis, show a modest but significant difference in pulmonary function tests in favour for the cyclophosphamide treated group. Treatment with prostacyclin analogues and endothelin-1 receptor antagonists appear to stabilize pulmonary arterial hypertension, a thus far fatal complication of SSc.

Cyclophosphamide↗

PubMed2002

Recurrent bronchiolitis obliterans organizing pneumonia in a patient with limited cutaneous systemic sclerosis.

Systemic sclerosis (SSc) is a generalized disorder characterized by fibrosis and vascular obliteration in the skin, lung, gastrointestinal tract, and kidney. One of its two subsets is a stable, limited cutaneous group (lSSc). Pulmonary involvement in scleroderma is common, and several types of pulmonary disorders are associated with SSc. Bronchiolitis obliterans organizing pneumonia (BOOP) is a rare finding in lung disorders associated with SSc. We describe a case of lSSc with BOOP that was responsive to steroid therapy. Of interest is that the lung disorders appeared in different periods and areas. It might be important to diagnose abnormal shadows in lung fields before treatment of patients with SSc.

Aged↗

PubMed2001

Colonic transit disorders in systemic sclerosis.

Systemic sclerosis (SS) alters smooth muscle function throughout the gastrointestinal tract, the oesophagus being the segment most often involved. Involvement of the colon, though less common, may lead to life-threatening complications. We studied 23 unselected patients with SS and 20 age-matched healthy controls using radionuclide colon transit studies. The geometric centre (GC) at 4 and 24 hours was used to summarise overall transit in the colon. In patients with SS, colon transit was delayed (GC4: 0.39 +/- 0.36 vs 0.85 +/- 0.45; P=0.001) (GC24: 1.68 +/- 0.9 vs 2.58 +/- 1.08; P=0.006). These findings suggest that delayed colon transit is common in patients with SS.

Adolescent↗

PubMedDate not supplied

The pathogenesis of systemic sclerosis.

Systemic sclerosis (scleroderma) is a generalized disease of the interstitial connective tissue of several organs characterized by vascular and microvascular injury and fibroblast activation leading to fibrosis. Cell culture models have been instructive in attempts to study the pathogenesis of this disorder. The scleroderma fibroblast in vitro demonstrates persistent, excessive extracellular matrix production, as well as an autocrine abnormality in cell growth regulation with persistent expression of the proto-oncogene c-myc. Since it has not yet been possible to culture scleroderma endothelial cells, human umbilical endothelial cells have been studied with regard to potential informational molecules (peptide regulatory factors, cytokines, growth factors) which selectively injure or alter the function of the endothelium. Transforming growth factor beta and tumor necrosis factor are two of these molecules which are currently under study.

Cells, Cultured↗

PubMed2002

[Psychiatric manifestations of systemic sclerosis].

Systemic sclerosis (SSc) is a rare conjuctive tissue disorder that is characterized by fibrosis of the skin and internal organs as well as vascular obliteration phenomenons. SSc is responsible for increased morbidity and mortality, and skin fibrosis may be responsible for major body changes. These phenomenons may contribute to the occurrence of psychological disturbances such as anxiety and depression, whereas the incidence of psychotic symptoms is very low in SSc patients. However, the prevalence of psychiatric symptoms during the course of SSc has not been evaluated yet with standardized evaluation scales, and an important breakthrough can be made in understanding the underlying mechanisms of psychiatric manifestations, in order to improve therapeutic management and quality of life.

Adaptation, Psychological↗

PubMed2001

Development of agents for the treatment of systemic sclerosis.

Systemic sclerosis (SSc) is a multisystem connective tissue disease characterised clinically by fibrosis and ischaemic atrophy. Internal organ involvement can be life-threatening. Although there are effective treatments for some of the organ-based manifestations of SSc, for example proton-pump inhibitors for upper gastrointestinal disease, no drug has so far been proven to modify the underlying disease process. Our increased understanding of the pathogenesis of SSc, which involves a complex interplay between excessive collagen production, vascular abnormalities and immune dysfunction, is directing development of drugs which hold promise as 'disease-modifying' agents. Some of the drugs under investigation for the treatment of SSc have already been used in other conditions which 'overlap' with SSc, for example primary pulmonary hypertension. Conversely, it is to be hoped that in the future, drugs shown to be effective in SSc might prove beneficial for other fibrotic diseases.

Humans↗

PubMed1994

CD4+ and CD8+ subsets: naive and memory cells in the peripheral blood of patients with systemic sclerosis.

Systemic Sclerosis (SSc; scleroderma) is associated with several immunological abnormalities, including altered proportion between lymphocyte subsets. Peripheral blood lymphocyte subsets from 25 patients with SSc were studied by two-colour flow cytometry using monoclonal antibodies against CD45RA and CD29 markers, which allow a dissection of CD4+ and CD8+ populations into 'naive' and 'memory' subsets. A decrease of the percentage of CD8+ (p < 0.05) and of CD8+CD29+ (p < 0.001) cells was observed compared to that in 20 age and sex-matched controls. These abnormalities were not significantly associated with the extension of cutaneous disease or other clinical features of SSc nor with treatment, pattern of autoantibodies or HLA phenotype.

Adolescent↗

PubMed2006

Targeting vascular disease in systemic sclerosis.

Systemic sclerosis (scleroderma, SSc) is a chronic connective tissue disease of unknown etiology characterized by progressive fibrosis of the skin and a distinctive pattern of internal organ involvement. Excessive fibrosis, vascular injury, autoimmunity and inflammation are permanent features of the disease process leading to irreversible organ damage and significant morbidity and mortality in SSc patients. Recent progress in understanding the pathogenesis of SSc as well as diagnostic and therapeutic advances in medicine have made more effective treatment strategies possible. So far, therapies targeting vascular aspects of SSc have been most successful. This underlines the role of vascular injury in the pathogenesis of the disease and raising hopes of significant improvement in the management of SSc patients. The aim of this review is to summarize recent and potential future treatments of SSc-associated vascular disease.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2002

Systemic sclerosis.

Systemic sclerosis (SSc) presents with a great deal of variability from patient to patient and classification and subset criteria will be analysed and discussed. SSc has been reported in people from all over the world. The prevalence and incidence, however, varies from country to country and within the same country in different ethnic groups. These differences will be elucidated. Genetic and environmental factors associated with the disease will be discussed.SSc is predominantly a female disease, with the female:male ratio ranging from 3:1 to 8:1 and being higher in childbearing years. Progenitor cells acquired during pregnancy have been suggested to play a role by inducing a graft-versus-host disease (microchimerism). Recent epidemiological studies on the relationship between SSc and previous pregnancies will be discussed. SSc is associated with a significant morbidity and mortality. Survival has improved in the last 15 years. Factors associated with such improvement will be analysed.

Adult↗

PubMed2000

Bone marrow transplantation in the treatment of systemic sclerosis.

Systemic sclerosis (SSc) is an uncommon, progressive, sometimes lethal fibrotic disease whose pathogenesis probably includes immunologic elements, especially early in its course. There is no proven therapy for this disease, although some promising results have been obtained with the use of immunosuppressive drugs such as cyclophosphamide. There exists a subgroup of patients who have rapidly progressive disease or who are not responsive to conventional treatment, and who may benefit from intensive immunosuppression with stem cell rescue (stem cell transplantation). The rationale for bone marrow transplantation (BMT), and, more recently, peripheral blood stem cell transplantation (SCT), has been validated by studies on animal models of autoimmunity. Autologous transplantation has shown encouraging anecdotal results, and it is now being evaluated in phase I/II studies in patients with predictably poor outcome. In this light, reliably identifying patients early in the course of SSc is extremely important in order to establish correct eligibility criteria. For patients unable to tolerate transplant regimens, other approaches may be feasible. In this regard, nonmyeloablative approaches, such as immunosuppression without rescue and mixed chimerism, are also discussed.

Bone Marrow Transplantation↗

PubMed2006

Mechanisms and consequences of fibrosis in systemic sclerosis.

Systemic sclerosis (SSc), also known as scleroderma, is a complex connective tissue disease that is associated with a high mortality and is challenging to treat because of its clinical heterogeneity and a lack of effective antifibrotic therapies. SSc has vascular, immunologic and fibrotic components that are pathologically interconnected. A growing understanding of the molecular and cellular mechanisms that underlie SSc pathogenesis provides logical and novel approaches to treatment. At present most therapies are organ-based. Vascular and inflammatory components of the disease can also be treated, but effective antifibrotic therapies are lacking. A number of key molecular mediators have the potential to alter immune-cell, vascular and fibrotic processes and these mediators, which include transforming growth factor-beta isoforms, endothelin-1, connective-tissue growth factor, chemokines and members of the interleukin family, are attractive targets for therapeutic modulation. Key mediators can be blocked using antibodies, soluble receptors, endogenous inhibitors or small-molecule antagonists of ligands, receptors or signaling intermediates. Overall, this is an exciting time for new therapies in SSc and advances are being made in synchrony with an improved understanding of the molecular and biochemical basis of the disease.

Fibrosis↗