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PubMed1995

HLA and autoimmunity in scleroderma (systemic sclerosis).

Scleroderma or systemic sclerosis (SSc) has been associated with certain class II antigens of the major histocompatibility complex (MHC), including HLA-DR1, DR2, DR3, DR5, and DR52. In general, these earlier HLA correlations were weak and varied considerably among reporting centers and different ethnic populations. More recently, a variety of disease-specific autoantibodies have been discovered including anti-centromere, antitopoisomerase I, and a variety of anti-nucleolar antibodies. These specificities show little overlap among one another, and each are markers for certain clinical features of SSc. At the same time, molecular studies of the MHC have provided more accurate methods for defining specific HLA alleles. Now it is becoming clear that certain HLA class II alleles, especially HLA-DQ, are more strongly associated with autoantibody subsets of SSc than with the disease itself. For example, anticentromere antibodies are strongly associated with HLA-DQB1*0501 (DQ5), DQB1*0301 (DQ7) and other DQB1 alleles possessing a glycine or tyrosine residue in position 26 of the outermost domain. Anti-topoisomerase I antibodies occur in SSc patients with HLA-DQB1*0301 (DQ7), DQB1*0302 (DQ8), DQB1*0601 (DQ6 in Japanese), and other DQB1 alleles possessing a tyrosine residue in position 30. HLA-DQ alleles associated with these autoantibodies tend to be in linkage disequilibrium with the HLA-DR specificities previously associated weakly with SSc itself. Rare multiplex families with SSc also show these same HLA haplotypes co-segregating with autoantibody profiles in affected members. Thus, it appears that MHC alleles play a role in affecting the serological expression of SSc, and the implications of these recent findings are discussed.

Alleles↗

PubMed2006

DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti-topoisomerase I autoantibodies from systemic sclerosis patients.

OBJECTIVE: Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis due to excessive and dysregulated collagen production by fibroblasts. Previously, we reported that anti-DNA topoisomerase I (anti-topo I) antibodies bound specifically to fibroblast surfaces; however, we had not identified their antigenic target. We undertook this study to characterize the target of anti-topo I antibodies on fibroblasts and the effects of their binding. METHODS: Purified topo I or topo I released from apoptotic cells was tested for surface binding to a number of human cell types by cell-based enzyme-linked immunosorbent assay, flow cytometry, and indirect immunofluorescence. Antibodies purified from SSc patient and normal control sera were used to detect topo I binding. The consequences of topo I and anti-topo I binding to fibroblasts were assessed by coculture with THP-1 monocytes. RESULTS: The autoantigen topo I itself was found to bind specifically to fibroblasts in a dose-dependent and saturable manner, where it was recognized by anti-topo I from SSc patients. The binding of anti-topo I subsequently stimulated adhesion and activation of cocultured monocytes. Topo I released from apoptotic endothelial cells was also found to bind specifically to fibroblasts. CONCLUSION: The findings of this study thus confirm and extend the findings of our previous study by showing that topo I binding to fibroblast surfaces is both necessary and sufficient for anti-topo I binding. Second, topo I-anti-topo I complex binding can then trigger the adhesion and activation of monocytes, thus providing a plausible model for the amplification of the fibrogenic cascade in anti-topo I-positive SSc patients.

Apoptosis↗

PubMed1997

[Effect of diltiazem on cold-induced left ventricular dysfunction in patients with systemic sclerosis].

Patients with systemic sclerosis (SS) have cardiac dysfunction induced by cold exposure. We and others have demonstrated this finding after corporal chilling, suggesting a "coronary Raynaud phenomenon" mediated by intermittent vascular spasm. In this study we evaluated the effect of diltiazem (DTZ) in cardiac dysfunction induced by cold test in patients with SS without clinical evidence of heart disease. Twelve patients with SS were studied. One patient was excluded because he did not fulfill the prescribed treatment. Eleven patients (age of 49.9 +/- 3.8 years and illness duration of 9.3 +/- 4.8 years) were included. Gated equilibrium radionuclide ventriculography was recorded after red blood cells were labeled in vivo using an intravenous injection of stannous pirophosphate followed by 20 mc of 99 Tc (gamma camera with electrocardiographic R wave gating was used). Left ventricular injection fraction (LVEF) was calculated using computer analysis and wall motion abnormalities by visual interpretation. Patients were cooled using a thermic blanket set at 5 degrees centigrade. They were evaluated before and after a period of cooling. After corporal chilling LVEF decreased more than 10% in all of them. DTZ 270 mg a day was administered to the same patients during 48 hs. Basal and cold LVEF were repeated in all patients. The results with and without DTZ were compared by Student's t Test. The basal LVEF with and without DTZ was not different (64.8 +/- 2.6 and 63.1 +/- 1.8). After corporal chilling LVEF decreased (64.8 +/- 2.6 to 54.8 +/- 2.5 p < 0.00001) and reversible abnormalities in wall motion were noticed in patients without DTZ. When they received DTZ neither difference in LVEF (63.1 +/- 1.8 to 62.1 +/- 2.4) nor wall motion abnormalities were observed. We compared the LVEF after chilling (62.1 +/- 2.4 and 54.8 +/- 2.5) and we found an important difference with the use of DTZ (p < 0.005). It can be concluded that in patients with SS and no overt heart disease, DTZ prevents the early cardiac dysfunction induced by cold test. Probably this drug blunts the coronary spasm induced by cold test in this group of patients.

Body Temperature↗

PubMed2004

Electroanatomic mapping and ablation of ventricular tachycardia associated with systemic sclerosis.

Two cases of systemic sclerosis with sustained ventricular tachycardia (VT) are presented. The first patient received hydroxychloroquine for skeletal muscle disease coexisting with cardiac involvement. In both cases, 3D-electroanatomic mapping showed low-voltage areas in the right ventricle. In the first patient the tachycardia was mapped and a protected isthmus suggesting reentry was delineated and ablated. Other substrate locations were indirectly identified by pacemapping on the right and left ventricular endocardium in the second patient. VT did not reoccur during follow-up. Radiofrequency catheter ablation is safe and effective and electroanatomic mapping may be helpful in patients with systemic sclerosis.

Adult↗

PubMed1989

Isotretinoin in the treatment of systemic sclerosis.

Thirteen patients with systemic sclerosis were treated with isotretinoin. Nine patients completed between 6 and 14 months of treatment and all showed an improvement in the cutaneous manifestations of their disease. The drug did not appear to benefit internal organs affected by the disease. Most patients experienced the well-recognized side-effects of retinoids, which in three cases necessitated withdrawal from the study within 3 months. Serum levels of type III procollagen aminopropeptide did not show a consistent decline during treatment, despite a clinical improvement. The mode of action of the reported therapeutic effect of isotretinoin in systemic sclerosis is unclear. There may be a preferential suppression of the synthesis of type I collagen, or the drug may be acting by an unrelated mechanism.

Adult↗

PubMed1990

Features of systemic sclerosis (scleroderma) in South African goldminers.

Systemic sclerosis is more common among men exposed to silica-containing dust than in the general male population. The clinical features of systemic sclerosis in a group of 24 black goldminers are described. The better-known presenting features of systemic sclerosis, including Raynaud's phenomenon and dysphagia, were rare in this population. Initial presentation was usually with nonspecific features including swelling of the feet or hands, weakness, arthralgia or symptoms of respiratory or cardiac disease. Clinical evidence of pleural or pericardial involvement was more common than is usually described in non-occupational systemic sclerosis. Interstitial lung disease was frequently encountered and renal disease was rare.

Adult↗

PubMed2006

Systematic review: pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis (scleroderma).

Gastrointestinal dysmotility in systemic sclerosis (scleroderma) is prevalent in 90% of patients, increasing morbidity and in some cases mortality. The resultant gastrointestinal complications are usually extensive, involving many regions of the gut from the oesophagus to the anus. Collagen replacement of vascular and enteric smooth muscle results in hypomotility, lumen dilatation, tensile rigidity and eventual loss of organ functions. The aim of this paper is to provide an overview of systemic sclerosis-related gastrointestinal dysmotility and available/potential therapeutic options. We evaluated published data on the pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis patients using the MEDLINE database for English and non-English articles from 1966 to July 2005. Based on this systematic review, lifestyle and medical therapy approaches are preferred as they often improve and/or ameliorate symptoms. Surgery is only recommended with serious, rare complications such as bowel perforation or ischaemia. Alternative therapies such as acupuncture-based therapies are well tolerated, with clinical improvement and may be of potential therapeutic benefit for systemic sclerosis gastrointestinal dysmotility. Further elucidation of initiating and persistent mechanisms of systemic sclerosis-related gastrointestinal dysmotility will optimize the development of a multidisciplinary and more directed treatment regimen.

Colon↗

PubMed1981

Prostaglandin E1 infusions for vascular insufficiency in progressive systemic sclerosis.

Twelve patients with systemic sclerosis (SS) and severe Raynaud's phenomenon received infusions of prostaglandin E1 (PGE1) at a dose of 6-10 ng/kg/min, with either saline or 5% dextrose, for 72 hours in a single-blind cross-over study. The infusions were administered intravenously by centrally positioned catheters. Infusions were well tolerated with only mild side effects. Following the PGE1 infusion cold tolerance improved and attacks of Raynaud's phenomenon were less frequent, less severe, and shorter in duration. This subjective improvement was maintained for several weeks in most patients, and 2 noted healing of ischaemic ulcers. There was no significant change in objective measurements of hand function after either infusion. However, pain measured on a 10 cm visual analogue scale improved 2.19 cm with PGE1 and only 0.91 cm with normal saline (P less than 0.05). Temperature of the fingers and hands recorded by thermography did not change significantly with saline infusions, but did rise during PGE1 infusions (mean rise 2.0 degrees C at 48 hours, p less than 0.001), and was maintained when measured again 2 weeks later (mean rise 1.56 degrees C, p less 0.001). PGE1 may therefore be suitable treatment for Raynaud's phenomenon and the vascular insufficiency of systemic sclerosis and other connective tissue diseases.

Adult↗

PubMed1996

Treatment of ischaemic digital ulcers and prevention of gangrene with intravenous iloprost in systemic sclerosis.

Twelve patients with systemic sclerosis were treated with intravenous infusions of the prostacyclin-stable analogue iloprost 0.5-2.0 ng/kg/min for 6 h from 8 to 13 days. Imminent gangrene was stopped in 2 patients and followed by healing. In 4 of 6 patients iloprost led to complete healing of ischaemic ulcers and in the remaining 2 patients to partial healing. One patient with severe Raynaud's phenomenon discontinued the study after 3 days due to severe headache. The 2 remaining patients with Raynaud's phenomenon as an indication improved, while no improvement was recorded in a patient with vasculitis of the lower leg. Side-effects such as headache, nausea and flushing were the reason that only 5 patients reached the maximum infusion rate. No statistical differences were recorded in digital bloodflow before and after the study or in plasma endothelin in the 9 patients investigated. Three of the 6 patients with healing ulcers, however, showed a pronounced decrease in plasma endothelin. Iloprost appears useful as a treatment of imminent gangrene and ischaemic ulcers in systemic sclerosis. This reparatory capacity could also be of a more general importance in therapy of this disease.

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↗

PubMed1990

Diffusing capacity of the lung and nifedipine in systemic sclerosis.

Lung involvement in systemic sclerosis may be due in part to a functional abnormality of the pulmonary vasculature. To investigate the possible role of a pulmonary vasospastic process in this disorder, 21 non-smoking patients who had no evidence of cardiac disease or pulmonary hypertension were evaluated with pulmonary function tests prior to administration of nifedipine, 30 minutes after a single oral dose of nifedipine (20 mg), and after 4 weeks of treatment with nifedipine (10 mg 3 times daily). Treatment with nifedipine did not significantly change any of the pulmonary function values, except for the carbon monoxide diffusing capacity (DLCO). The linear trend between the individual DLCO values at baseline and their changes immediately following the initial 20-mg dose of nifedipine (r = -0.603, P = 0.02) and after 4 weeks of treatment (r = -0.636, P = 0.01) showed that the lower the DLCO value at baseline, the greater the improvement caused by nifedipine. These findings support the hypothesis of a potentially reversible pulmonary vasospasm in systemic sclerosis and suggest that nifedipine may be useful in the treatment of lung disease in these patients; however, further studies are needed.

Adult↗

PubMed1996

Neutrophil activation in fibrosing alveolitis: a comparison of lone cryptogenic fibrosing alveolitis and systemic sclerosis.

Fibrosing alveolitis complicating systemic sclerosis (FASSc) carries a better prognosis than lone cryptogenic fibrosing alveolitis (CFA). We wanted to determine whether this improved prognosis is associated with differential neutrophil migration and activation in the lower respiratory tract. We therefore compared bronchoalveolar lavage (BAL) neutrophil numbers and levels of neutrophil-derived enzymes in FASSc, CFA and normal individuals. Bronchoalveolar lavage was performed on 45 subjects (FASSc n = 20; CFA n = 15; normals n = 10); cell counts and levels of neutrophil-derived enzymes, myeloperoxidase, elastase (total elastase and elastase/alpha 1 antitrypsin complexes), collagenase and lactoferrin were measured. Lung function testing was performed in subjects with fibrosing alveolitis. Significant differences in the levels of collagenase, myeloperoxidase and elastase/ alpha 1-antitrypsin complexes were present in the BAL fluid from the three groups. Patients with CFA had significantly higher neutrophil percentages and levels of collagenase and myeloperoxidase than those with FASSc. Disease extent, as judged by lung volumes and gas transfer, was comparable in the CFA and FASSc groups. Forced vital capacity (% predicted) was significantly lower in patients with evidence of increased neutrophil enzyme release than those without. We conclude that: 1) increased neutrophil migration to the lung is accompanied by release both of primary and secondary granule enzymes in cryptogenic fibrosing alveolitis; and 2) the lower amounts of neutrophil products in fibrosing alveolitis complicating systemic sclerosis may account for the improved prognosis, even when disease is as extensive as in cryptogenic fibrosing alveolitis.

Adult↗

PubMed2006

[Systemic sclerosis: pathophysiology of a multifaceted disease].

Systemic sclerosis is a rare disease characterized by vascular hyperreactivity and collagen deposition. Endothelial cell, fibroblast and lymphocyte abnormalities have been reported in systemic sclerosis. Fibroblast dysfunction is characterized by uncontrolled activation of the transforming growth factor-beta (TGF-beta) pathway and excess synthesis of both connective tissue growth factor (CTGF) and free radicals. These promote the accumulation of extracellular matrix. Endothelial cells produce excess quantities of endothelin 1 and inducible NO synthase. They also undergo early apoptosis. Oxidative stress appears to play a major role in disease progression. Increased levels of interleukin 4, a profibrotic cytokine, have been detected in plasma and skin of systemic sclerosis patients. Autoantibodies are detectable in the serum of almost all systemic sclerosis patients. Some are directed against well-identified ubiquitous nuclear proteins and have no demonstrated pathogenic role. Other autoantibodies bind to endothelial cells or fibroblasts and may have a pathogenic role.

Adult↗

PubMed2004

Primary B-cell lymphoma of the tongue in a patient with systemic sclerosis.

We report a patient with systemic sclerosis who had the unusual development of a large-cell B-cell lymphoma of the base of his tongue. Patients with systemic sclerosis display an increased incidence of malignant neoplasms, particularly, breast and lung carcinomas [Arthritis. Rheum. 36 (1993) 460; Ann. Rheum. Dis. 52 (1993) 531]. The description of this case adds further evidence to the possible interrelationship of systemic sclerosis and the development of malignant neoplasms. A careful review of the English medical literature disclosed that B-cell lymphoma of the tongue in a patient with systemic sclerosis is an association which has not been described previously.

Aged↗

PubMed1991

Major histocompatibility complex class II genes and systemic sclerosis.

1. In no ethnic group is the overall association between systemic sclerosis and the MHC strong enough for direct clinical use. MHC associations do support the classification of the disease into limited cutaneous systemic sclerosis and diffuse cutaneous systemic sclerosis. 2. Indications are that associations between specific subsets of patients with systemic sclerosis and genetic markers will assume greater importance both diagnostically and prognostically. The group with lung fibrosis look prime candidates, for example. 3. Genetic markers are useful means of relating chemically induced systemic sclerosis like disorders with the classical disease. Vinyl chloride disease provides an example. 4. Evidence is emerging of strong associations between certain genetic markers and autoantibody production; a similar story has emerged in systemic lupus erythematosus. We believe that, eventually, genetic tests will be used to influence treatment in at least a subset of patients with systemic sclerosis but that a dramatic breakthrough will not be made until we know how the genetics of the disease relate to the primary biochemical disease characteristic--that is, the overproduction of collagen. In this respect it has been suggested that the 5' flanking DNA of dermal collagen genes is particularly susceptible to the action of Scl-70 (topoisomerase I). A problem is how to tie this and the other observations discussed above together. The association of autoantibodies with topoisomerase I provides a tentative link between the MHC and collagen gene expression. Although the role and reason for anti-Scl-70 in systemic sclerosis is unknown, humoral autoimmunity, at least in systemic lupus erythematosus, seems to be strongly dependent on specific HLA genes. With an understanding of the function of MHC products at the molecular level, HLA and disease associations can now be analysed on a mechanistic level. For insulin dependent diabetes mellitus it has been shown that the MHC determined susceptibility to the disease is conferred by neutral residues (Val, Ser, Ala), at position 57 of the DQ beta chain, while Asp at this position correlates with resistance. A similar phenomenon has been described in rheumatoid arthritis. Although DR4 in general is associated with rheumatoid arthritis, it is heterogeneous, but a subtype of DR4 which is characterised by positively charged residues at positions 70 and 71 of the beta chains is not found in patients with rheumatoid arthritis (Wordsworth B P et al, unpublished data). A similar approach applied to the study of systemic sclerosis is likely to be similarly rewarding. The precise subtyping of the class II genes and the characterisation of their associated haplotypes is therefore required for a complete understanding of the contribution of the MHC to the disease. Additional genes linked to the MHC must not be overlooked, and are relevant to associations of haplotypes with the disease. Of particular interest are the recent reports of a new class of proteins, which are determined by genes in the MHC and which are considered to play a part in the assembly of the antigen peptide/MHC molecule complex.

Environmental Exposure↗

PubMed1990

Pharmacodynamic effect of nicardipine on left ventricular function in systemic sclerosis.

Left ventricular dysfunction in systemic sclerosis may be due in part to myocardial ischemia caused by a disturbance in coronary microcirculation. We evaluated the pharmacodynamic effect of the calcium channel blocker nicardipine on left ventricular function assessed by radionuclide ventriculography in 20 patients with systemic sclerosis. Resting gated, blood-pool images were obtained at baseline and 90 min after 40 mg of oral nicardipine. The mean (+/- SEM) left ventricular ejection fraction significantly increased from 65.4 +/- 2.3% at baseline to 71.3 +/- 2.3% after nicardipine (p less than 0.005). The mean global defect score significantly decreased from 2.90 +/- 0.73 without nicardipine to 1.50 +/- 0.52 with nicardipine (p less than 0.01). The mean number of left ventricular sectors with severe hypokinesis significantly decreased from 0.80 +/- 0.24 at baseline to 0.20 +/- 0.09 after nicardipine (p less than 0.05). No significant side effects were observed with nicardipine. These results demonstrate short-term improvement in left ventricular function with nicardipine in patients with systemic sclerosis.

Adult↗

PubMed2005

[Pathophysiologic aspects of systemic sclerosis].

BACKGROUND: The pathological changes in systemic sclerosis are characterised by severe organ fibrosis, obliteration of arteries and arterioles and disturbance of immunological functions. Recent research has yielded new insight into the complex pathogenesis of systemic sclerosis, with new therapeutic options as a possible consequence. MATERIALS AND METHODS: Relevant medical literature has been reviewed. RESULTS: The pathological deposition of extracellular matrix in systemic sclerosis is most probably caused by changes in the regulation of dermal fibroblasts. The review focuses on three of the many molecules involved in the regulation of fibrosis; Transforming growth factor beta, Connective tissue growth factor and Endothelin-1. INTERPRETATION: Treatment of organ-specific disease complication has for long remained the only therapeutic option in systemic sclerosis. Based on current knowledge of the process of fibrosis, new therapeutic trials employing substances directed towards pro-fibrotic molecules are now in progress.

Connective Tissue Growth Factor↗

PubMed2001

Meta-analysis of systemic sclerosis and exposure to solvents.

BACKGROUND: Although systemic sclerosis is a rare disease, incidence rates have increased recently in the United States. This study investigated the association between systemic sclerosis and exposure to solvents. METHODS: A Medline search of articles published between 1966 and 2000 dealing with solvent exposure and systemic sclerosis identified eight studies that met inclusion criteria of the meta-analysis. The studies included seven case-control studies and one cohort study published between 1989 and 1998. A series of meta-analyses of studies on systemic sclerosis and solvent exposure were performed for all studies and for case-control studies. A random effect model was used to calculate a combined estimator of relative risk. RESULTS: The combined estimator of relative risk for all studies was 2.91, with a 95% confidence interval (CI) of 1.60 to 5.30. The combined estimator of relative risk for the seven case-control studies was 3.14 (95% CI, 1.56-6.33). CONCLUSIONS: A statistically significant increased relative risk for all studies and for case-control studies suggests that exposure to organic solvent may be a risk factor for developing systemic sclerosis. Further studies using other study designs and better control of confounders are needed.

Case-Control Studies↗