Acute cerebral vasculopathy in systemic sclerosis

Systemic sclerosis is an autoimmune disease characterized by skin and deep organ fibrosis and obliterative microvasculopathy. Cerebral involvement is currently not recognized as a manifestation of the disease, although several morphologic and functional studies suggested a frequent cerebral involvement in systemic sclerosis. We report a new case of acute cerebral vasculopathy in a patient suffering from systemic sclerosis together with five historical cases identified through a literature review. Cerebral acute vasculopathy most often revealed the disease. Affected patients suffered often from limited or diffuse cutaneous systemic sclerosis. Reversibility of arterial lesions, absence of specific histologic findings, and association with severe peripheral vascular involvement plead for a major role of vasospasm. However, the apparent efficacy of immunosuppressive treatments suggests an association with inflammatory or immune mechanisms. Awareness should be raised because of the severity of the disease, the risk of relapse, and the possible occurrence early in the course of systemic sclerosis.     

Pleural effusion in interstitial lung disease

PURPOSE OF REVIEW: This review reports recent information on the occurrence of pleural effusions in association with disorders that produce interstitial parenchymal lung disease. RECENT FINDINGS: The occurrence of effusions has been expanded to include systemic sclerosis, polymyositis-dermatomyositis, several drugs, and several miscellaneous causes of interstitial lung disease (ILD). SUMMARY: Pleural effusions occur in patients with various forms of interstitial lung disease. The effusions require a clinical evaluation to exclude complications of therapy and coexisting conditions unrelated to the underlying ILD.     

Familial occurrence of systemic sclerosis, rheumatoid arthritis and other immunological disorders: report of two kindreds with study of HLA antigens and review of the literature

We report two Caucasian families with systemic sclerosis and other connective tissue and immunological disorders, including rheumatoid arthritis, discoid lupus erythematosus, psoriasis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, asthma, Sj?gren's syndrome, Raynaud's phenomenon and thyroid disease. In one of these families, two sisters are affected with systemic sclerosis. Clinical, serological, and HLA haplotype results are reported, along with a review of the medical literature on familial occurrence of systemic sclerosis.     

Pulmonary echography in systemic sclerosis

In systemic sclerosis patients, interstitial lung disease and pulmonary hypertension are highly associated with mortality. The time point of detecting manifestations like pulmonary hypertension and interstitial lung disease (ILD) is of vital importance. High-resolution computed tomography (HRCT) to date is the gold standard to diagnose ILD. In addition, an ultrasound of the lung is suggested as a noninvasive and radiation-free method of structural monitoring of the lung. We tested the reliability of lung sonography for the assessment of patients with systemic sclerosis. In a pilot study involving 25 patients with systemic sclerosis and 40 healthy volunteers, we screened the pleura and the pulmonary parenchyma for sonographic abnormalities. The occurrence of B lines, comet tail phenomena, and pleural irregularities was scored. All systemic sclerosis (SSc) patients were subjected to computed x-ray tomography of the chest. Forty-four percent of SSc patients showed B line phenomena and pleural thickening. The diagnosis of ILD in these patients was confirmed by HRCT scan. B line phenomena and pleural irregularities were significantly more common in SSc patients. Patients with ILD had higher pleural scores and comet scores when compared to systemic sclerosis patients without radiographic ILD. If our results are confirmed in larger studies, transthoracic ultrasound of the lung might turn out to be a suitable method for screening patients with systemic sclerosis for incipient pulmonary structural changes.     

Trigeminal and peripheral neuropathy in a patient with systemic sclerosis and silicosis

The unusual occurrence of cranial (trigeminal) and peripheral neuropathy in a case of progressive systemic sclerosis (PSS) is described. The possible association of PSS with silicosis is also discussed.     

Platelet contributions to the pathogenesis of systemic sclerosis

PURPOSE OF REVIEW: The purpose of this review is to focus attention on platelet contributions, in general, to systemic sclerosis. There have also been recent advances in characterization of the phenotype of platelets in systemic sclerosis which will be reviewed. RECENT FINDINGS: An extensive literature provides strong support for varying degrees of platelet activation and aggregation in different forms and stages of systemic sclerosis. A recent finding is that systemic sclerosis platelets overexpress a specific nonintegrin 65 kDa receptor for type I collagen as well as expressing enhanced phosphilidylinositol-3 kinase as an activation signature. Overexpression of a type I collagen receptor would make systemic sclerosis platelets more susceptible to binding to exposed type I collagen in the subendothelial lining of damaged blood vessels, facilitating the cycle of platelet aggregation and release of preformed bioactive molecules that include a host of inflammatory and fibrogenic, chemokines, cytokines and growth factors. This activation phenotype of systemic sclerosis platelets may be secondary to autoimmunity and driven by cytokines from autoreactive T cells. SUMMARY: The contributions of platelets to the pathogenesis of systemic sclerosis is likely substantial and may not be adequately represented in gene profiling of systemic sclerosis tissue due to the small amounts of RNA contained in platelets.     

Identification of novel targets in scleroderma: update on population studies, cDNA arrays, SNP analysis, and mutations

PURPOSE OF REVIEW: Systemic sclerosis, or scleroderma, is an uncommon autoimmune connective tissue disease that results in systemic fibrosis. Its etiologic basis remains unclear. The pathogenesis of systemic sclerosis involves a proliferative and obliterative vasculopathy resulting from endothelial cell dysfunction, extensive fibrosis secondary to fibroblast activation, and autoimmunity as demonstrated by the presence of disease-specific autoantibodies. Although there is no clear and convincing evidence for an environmental trigger in most cases, accumulating data emphasize the role of genetic factors in systemic sclerosis. As in other complex human diseases, multiple genes likely contribute to disease susceptibility and the clinical manifestations of systemic sclerosis. This review will cover the application of genomics to the complex genetics of systemic sclerosis. RECENT FINDINGS: The following review is an update on novel targets identified in scleroderma based on published reports (May 2000-May 2003) of mutation/polymorphism analysis (using SNP and haplotyping), the results from a recent genome-wide scan on a Native American population with systemic sclerosis, and gene expression studies (microarrays). SUMMARY: The use of genomics has revealed novel targets and genetic associations that may contribute to the cause, the onset, and the subsequent pathologic changes that constitute systemic sclerosis. The identification of potential candidates for gene therapy or disease-specific targets amenable to pharmacologic intervention will benefit patients with systemic sclerosis who are currently being treated for their symptoms and not the disease process itself.     

Scleroderma renal crisis sine scleroderma during pregnancy

Renal crisis is a serious complication of systemic sclerosis. Its occurrence prior to the development of skin sclerosis is exceedingly rare. We report a patient who developed acute renal failure during pregnancy. Renal biopsy showed features compatible with scleroderma renal crisis but typical cutaneous changes were only evident 2 months after the renal episode. The relationship between pregnancy, scleroderma activity and renal crisis is discussed.     

FGF-R3 and OPG expression in patient with multiple myeloma following systemic sclerosis: case report and review of the literature

The presence of multiple myeloma (MM) in a patient with systemic sclerosis is a rare and unusual occurrence with unclear significance. We report the case of a 55-year-old woman with a 20-year history of systemic sclerosis, who subsequently presented with clinical stage IIIA IgG-λ MM. The systemic sclerosis was diagnosed and treated in 1988 with d-penicillamine and methotrexate. Twenty years later, in December 2008, she presented with symptoms of Raynaud’s phenomenon and intense facial pruritus. Immunoelectrophoresis confirmed the presence of a IgG-λ paraprotein (71.90 g/l) and Bence Jones proteinuria of the lambda light chains. Bone marrow histology revealed infiltrates of plasmocytes and lymphoplasmocytes which were on immunohistochemistry CD38+, FGF-R3+ and OPG+. An extensive X-ray skeletal survey did not show any osteolytic lesions or fractures. The patient was treated according to the CTD protocol (cyclophosphamide, thalidomide, and dexamethasone) which was effective against the myeloma as well as the systemic sclerosis and patient achieved complete remission.     

Exploring the patient experience of digital ulcers in systemic sclerosis

Digital ulcers are common in patients with systemic sclerosis, affecting over half of patients during the course of their disease. For some patients, digital ulcers occur as isolated phenomena; whereas, for others, digital ulceration is recurrent, and often refractory to intervention. Demonstrating treatment efficacy for digital ulcer disease has typically focussed on clinician opinion of ulcer healing and new ulcer occurrence. Advances in management have improved outcomes which may have had the unfortunate effect of rendering traditional trial endpoints less effective at demonstrating treatment efficacy. Despite recent improvements in management, our work is not complete and digital ulceration remains a major cause of morbidity for many patients with systemic sclerosis. This review shall examine the patient experience of digital ulcers in systemic sclerosis. We shall consider how a detailed understanding of the severity and burden of digital ulceration, aetiopathogenesis, and their impact on emotional health, function, work and social participation might inform the development of novel clinical trial outcomes that can support future advances in the assessment and management of digital ulceration in systemic sclerosis.     

Involvement of the small intestine in systemic scleroderma]

INTRODUCTION: Though impairment of the gastrointestinal tract is commonly encountered in patients with systemic sclerosis, the most frequent abnormalities are esophageal and anorectal disorders. Involvement of the small intestine is also common, reaching a 40-80% prevalence. It often leads to life-threatening complications. CURRENT KNOWLEDGE AND KEY POINTS: The occurrence of small intestine impairment and its potential relationships with other organ impairment is still unknown. However, it rarely indicates the existence of the disease (10%) which remains asymptomatic for a long period. As clinical symptoms are non-specific and radiological tests (upper intestinal tract barium meal, gastrointestinal transit times of radiolabeled meal, computerized tomography scan) not sensitive enough to detect the symptoms, diagnosis of small intestine impairment is delayed, i.e., when severe complications such as malabsorption or pseudo-obstruction are present. The physiopathology of small intestine disorders is still unclear, leading to both collagenous fibrosis and atrophy of muscle fibers. As well, its treatment is difficult. FUTURE PROSPECTS AND PROJECTS: Knowledge of the mechanisms at the origin of small intestine impairment in the course of systemic sclerosis is important for the development of efficacious therapies. Manometry of the small intestine would be a useful tool to assess the various motor abnormalities that may occur in patients presenting with systemic sclerosis associated with either malabsorption or pseudo-obstruction. It would also provide a useful test in selecting patients whose treatment require somatostatin analogs.     

Genetic and environmental factors in systemic sclerosis.

The occurrence of autoantibodies in patients with systemic sclerosis has suggested a role for immune dysregulation in this disease. Recent genetic studies have concentrated on the major histocompatibility complex-encoded antigens and found an association of particular HLA-DQ alleles with anticentromere antibodies. Although the role of major histocompatibility complex antigens and autoantibodies in the pathogenesis of systemic sclerosis remains unclear, determination of major histocompatibility complex alleles may have clinical value in identifying patients who are at increased risk for development of pulmonary fibrosis or rapidly advancing skin disease. A variety of environmental factors have been associated with systemic sclerosis-like skin diseases, including silica, vinyl chloride, paraffin, adulterated L-tryptophan, and "toxic" rapeseed oil. It has been suggested that silicone used during breast augmentation may be a risk factor for development of systemic sclerosis, but ascertainment bias in case reporting makes interpretation of these studies difficult. The heterogeneity of clinical features, major histocompatibility complex status, and autoantibody profiles in systemic sclerosis suggest that this disorder may actually be a group of distinct disorders, each of which has its own characteristic genetic and environmental predisposing risk factors.     

Antiubiquitin antibody in localised and systemic scleroderma.

OBJECTIVE: To determine the presence of antiubiquitin antibody (AUbA) in localised scleroderma and systemic sclerosis, as it is frequently found in the sera of patients with systemic lupus erythematosus (SLE) and has also been shown to have a close relationship with antihistone antibodies that have an important role in scleroderma. METHODS: Serum samples from patients with localised scleroderma (n = 48) and systemic sclerosis (n = 52) were examined by enzyme linked immunosorbent assay. Twenty samples from patients with SLE, 20 from patients with dermatomyositis, and 30 samples from healthy individuals were used as controls. RESULTS: AUbA was demonstrated in 44% of patients with localised scleroderma and in 42% of those with systemic sclerosis. The presence of AUbA correlated with the presence of antihistone antibodies in both localised scleroderma and systemic sclerosis. CONCLUSIONS: AUbA is frequently present in patients with localised scleroderma and systemic sclerosis. Induction of AUbA is closely associated with that of antihistone antibodies, suggesting that ubiquitinated histone may be the target in autoimmune responses of these disorders.     

Serum concentrations of soluble P-selectin glycoprotein ligand-1 are increased in patients with systemic sclerosis: association with lower frequency of pulmonary fibrosis

OBJECTIVE: To determine serum concentrations of soluble P-selectin glycoprotein ligand-1 (sPSGL-1) and its clinical associations in patients with systemic sclerosis. METHODS: Serum sPSGL-1 concentrations from 65 patients with systemic sclerosis were examined by enzyme linked immunosorbent assay. In a retrospective longitudinal study, 177 sera from 35 patients with systemic sclerosis were analysed (follow up 0.3 to 6.3 years) RESULTS: Serum sPSGL-1 was raised in patients with limited cutaneous systemic sclerosis (lSSc) (n = 34) and diffuse cutaneous systemic sclerosis (dSSc) (n = 31) compared with healthy controls (n = 22) and patients with systemic lupus erythematosus (n = 20) or dermatomyositis (n = 20). Patients with systemic sclerosis who had raised sPSGL-1 concentrations less often had pulmonary fibrosis and decreased vital capacity (%VC) than those with normal sPSGL-1 levels. sPSGL-1 concentrations were positively correlated with %VC in patients with systemic sclerosis. In the longitudinal study, patients with systemic sclerosis but without pulmonary fibrosis had consistently increased sPSGL-1 concentrations in the early phase, while those with pulmonary fibrosis had decreased sPSGL-1 throughout the follow up period. CONCLUSIONS: A raised serum sPSGL-1 is associated with a lower frequency and severity of pulmonary fibrosis in systemic sclerosis. sPSGL-1 could be a protective factor against the development of pulmonary fibrosis in this disease and as such would be a possible therapeutic target.     

Autoantibodies in systemic sclerosis and fibrosing syndromes: clinical indications and relevance

PURPOSE OF REVIEW: Systemic sclerosis, or scleroderma, is associated with a variety of autoantibodies, each of them having their own clinical associations. The fibrosing disorders, other than systemic sclerosis, represent a diverse group of diseases with systemic or localized effect and with limited understanding of their pathogenesis. The purpose of this review is to analyze the literature on the clinical usefulness of examining serum autoantibodies in patients with known or suspected scleroderma and fibrosing disorders. RECENT FINDINGS: Studies on autoantibodies within the past year highlight their clinical utility in systemic sclerosis. Anticentromere antibodies are most often seen with limited cutaneous involvement and lower frequency of pulmonary fibrosis and lower mortality (despite an increased risk for pulmonary hypertension) compared with anti-Scl-70 and antinucleolar antibodies. Anti-Scl-70 antibodies are associated with diffuse cutaneous involvement, increased frequency of pulmonary fibrosis, and higher mortality. The anti-polymyositis-scleroderma autoantibody is associated with the polymyositis-scleroderma overlap syndrome. Anti-Th/To antibodies are associated with milder skin and systemic involvement but with more severe pulmonary fibrosis and overall worse prognosis. Anti-RNA-polymerase family antibodies and antifibrillarin antibodies are predictive of diffuse cutaneous and systemic involvement and greater mortality. Less specific autoantibodies for systemic sclerosis and limited data on some other autoantibodies limit their clinical utility in patients with systemic sclerosis. For the most part, the association between autoantibodies and fibrosing disorders other than systemic sclerosis remains inconclusive. SUMMARY: Autoantibodies in systemic sclerosis provide important and prognostic information and are useful in defining clinical subsets of the disease. When used appropriately, they can be a useful instrument in the management of scleroderma.     

B lymphocytes and systemic sclerosis

PURPOSE OF REVIEW: Systemic sclerosis is characterized by fibrosis and autoimmunity. Systemic sclerosis displays a variety of abnormal immune activations, including the production of disease-specific autoantibodies, although the pathogenic relation between systemic autoimmunity and the clinical manifestations of systemic sclerosis remains unknown. Recent studies have rediscovered that B cells play critical roles in systemic autoimmunity and disease expression through various functions more than autoantibody production, such as antigen presentation and cytokine production. This review focuses on recent advances in understanding the B cell's role in systemic sclerosis. RECENT FINDINGS: Patients with systemic sclerosis have altered B-cell homeostasis characterized by expanded naive B cells and diminished memory B cells. Although memory B cells are decreased in number, they are chronically activated, possibly because of CD19 over-expression in B cells from patients with systemic sclerosis. CD19 over-expression can be genetically explained in part by a polymorphism of CD19 promoter region. Similarly, B cells from a tight-skin mouse, a genetic model of systemic sclerosis, show augmented CD19 signaling and chronic hyper-reactivity. CD19 hyper-phosphorylation in tight-skin B cells is caused by impaired function of CD22, a negative response regulator expressed on B cells. Classic roles of autoantibody secretion may also be important in systemic sclerosis because autoantibodies to matrix metalloproteinases can be pathogenic in vivo. SUMMARY: B cells may have more pathogenic roles in systemic sclerosis than had been appreciated. Further studies are required to clarify the precise molecular basis that links B cells and fibrosis. Collectively, B cells and B-cell-specific response regulators such as CD19/CD22 appear to be potential therapeutic targets of the disease.     

Bowel problems in patients with systemic sclerosis.

BACKGROUND: The impact of systemic sclerosis on bowel function is still unknown. The aim of this study was therefore to assess the frequency and severity of colorectal problems among patients with systemic sclerosis and to determine whether these problems are associated with age, gender, type of systemic sclerosis, or time since diagnosis. METHODS: A detailed questionnaire describing diarrhoea, constipation, obstructed defecation, faecal incontinence, bowel habits, social activities, and quality of life was sent to 96 consecutive patients with systemic sclerosis. RESULTS: Among 83 respondents (86%) 16% did not have a normal desire to defecate, 18% regularly needed digital stimulation or evacuation of the rectum, and 38% had faecal incontinence. Most patients (79%) had episodes of diarrhoea, and 38% had this once or more each month. Overall, 20% reported that colorectal dysfunction caused some or a major restriction of social activities or the quality of life. CONCLUSIONS: Colorectal dysfunction is very common among patients with systemic sclerosis, often restricting social activities and the quality of life. Therefore, further studies of colorectal pathophysiology in patients with systemic sclerosis are needed.     

Free radical activity and antioxidative systems in patients with systemic sclerosis

Background: Free radicals have been said to contribute to vascular damage in patients with systemic sclerosis. The aim of the study was to determine the level of lipid peroxidation products and antioxidative enzyme activity in patients with systemic sclerosis and in healthy controls. Methods: 10 women with definite systemic sclerosis and 10 age-matched healthy women were studied. Results: A significant increase in serum lipid peroxidation product levels (i.e. diene conjugates and thiobarbituric acid-reactive substances) was found in patients with systemic sclerosis. These changes were accompanied by a decrease in superoxide dismutase, catalase, and glutathione peroxidase activity in erythrocyte lysate. Furthermore, there was diminished activity of glutathione reductase and a depressed total serum level of antioxidants compared to the controls. Blood thiol group concentration in patients with systemic sclerosis was also found to be decreased. Conclusions: The results obtained indicate increased oxidative stress in patients with systemic sclerosis.