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PubMed2004

Ischaemic stroke in progressive systemic sclerosis.

Progressive systemic sclerosis (PSS) or scleroderma is a multisystem disease affecting the skin, lungs, myocardium, kidneys and gastrointestinal tract. Primary involvement of cerebral arteries in PSS has been reported but is very rare. A 61-year-old woman suffering from scleroderma for six years was hospitalised for two subsequent episodes of transient acute dysarthria and left hemiparesis. After five hours from the first onset of symptoms, she was submitted to brain magnetic resonance (MR) protocol that showed a right subinsular ischaemic lesion and whole right middle cerebral artery (MCA) territory hypoperfusion. Intracranial and epiaortic MR angiography reported a focal stenosis in the M2 portion of MCA. She was immediately treated with i.v. high dose steroids and oral acetylsalicylic acid. At one-month follow up, MR findings were confirmed. We have documented a cerebral infarct in a PSS patient. In our opinion, the ischaemic stroke was caused by a localised autoimmune angiopathy.

Aspirin↗

PubMed2003

Pulmonary functional abnormalities in asymptomatic patients with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a disease characterized by widespread fibrosis of the skin and multiple organs, including the lungs. This study was designed to evaluate pulmonary function in SSc patients without symptoms of lung involvement. METHODS: Spirometric measurements were done in 26 female SSC patients without symptoms of pulmonary involvement. RESULTS: Maximal voluntary ventilation was found to be decreased in half of the patients, and forced vital capacity was decreased in 23% of the patients. Forced expiratory flow rate was impaired in about half of the SSc patients, especially the flow at 50-75% of forced vital capacity. Peak expiratory flow rate was decreased in 77% of asymptomatic patients. CONCLUSIONS: A functional defect, mainly of the restrictive type, was observed in the majority of asymptomatic patients with SSc. Pulmonary function testing is recommended for all SSc patients.

Journal Article↗

PubMed2024

Adeno-Associated Virus Type 5 Infection via PDGFRα Is Associated With Interstitial Lung Disease in Systemic Sclerosis and Generates Composite Peptides and Epitopes Recognized by the Agonistic Immunoglobulins Present in Patients With Systemic Sclerosis.

OBJECTIVE: The etiopathogenesis of systemic sclerosis (SSc) is unknown. Platelet-derived growth factor receptors (PDGFRs) are overexpressed in patients with SSc. Because PDGFRα is targeted by the adeno-associated virus type 5 (AAV5), we investigated whether AAV5 forms a complex with PDGFRα exposing epitopes that may induce the immune responses to the virus-PDGFRα complex. METHODS: The binding of monomeric human PDGFRα to the AAV5 capsid was analyzed by in silico molecular docking, surface plasmon resonance (SPR), and genome editing of the PDGFRα locus. AAV5 was detected in SSc lungs by in situ hybridization, immunohistochemistry, confocal microscopy, and molecular analysis of bronchoalveolar lavage (BAL) fluid. Immune responses to AAV5 and PDGFRα were evaluated by SPR using SSc monoclonal anti-PDGFRα antibodies and immunoaffinity-purified anti-PDGFRα antibodies from sera of patients with SSc. RESULTS: AAV5 was detected in the BAL fluid of 41 of 66 patients with SSc with interstitial lung disease (62.1%) and in 17 of 66 controls (25.75%) (P < 0.001). In SSc lungs, AAV5 localized in type II pneumocytes and in interstitial cells. A molecular complex formed of spatially contiguous epitopes of the AAV5 capsid and of PDGFRα was identified and characterized. In silico molecular docking analysis and binding to the agonistic anti-PDGFRα antibodies identified spatially contiguous epitopes derived from PDGFRα and AAV5 that interacted with SSc agonistic antibodies to PDGFRα. These peptides were also able to bind total IgG isolated from patients with SSc, not from healthy controls. CONCLUSION: These data link AVV5 with the immune reactivity to endogenous antigens in SSc and provide a novel element in the pathogenesis of SSc.

Humans↗

PubMed2005

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.

Animals↗

PubMed1996

Heterogeneity of collagen synthesis in normal and systemic sclerosis skin fibroblasts. Increased proportion of high collagen-producing cells in systemic sclerosis fibroblasts.

OBJECTIVE: The goal of this study was to quantitatively analyze the distribution of collagen synthesis in normal and systemic sclerosis (SSc) fibroblast populations in order to determine the extent of activation in SSc populations. METHODS: We used quantitative in situ hybridization to assess the population distribution of type I collagen synthesis. Fibroblast cultures were derived from both clinically involved and uninvolved skin regions of patients with SSc, and from healthy adults, and assessed for levels of alpha 1(I) procollagen messenger RNA (mRNA). RESULTS: Dermal fibroblasts from both patients with SSc and normal adults were heterogeneous for distribution of alpha 1(I) procollagen mRNA when assessed by in situ hybridization, with a wide range of grains per cell. In contrast, clones of neonatal fibroblasts showed a relatively homogeneous distribution of grain counts. Involved SSc skin fibroblasts had a larger proportion of cells in the high collagen-producing mRNA subpopulation (mean +/- SEM 28.4 +/- 6.85%), compared with normal fibroblasts (1.75 +/- 1.44%) and uninvolved fibroblasts (9.6 +/- 6.73%). Conversely, within the low collagen-producing mRNA subpopulation, involved fibroblasts had a smaller proportion of cells (mean +/- SEM 14.0 +/- 5.63%) than did uninvolved fibroblasts (37.8 +/- 13.69%), while normal fibroblasts had a majority of the cells in this subpopulation (53.5 +/- 8.68%). CONCLUSION: These results suggest that only a specific subset of fibroblasts are activated in SSc, as evidence by an increased proportion of cells with high levels of alpha 1(I) procollagen mRNA. Differences between the SSc and normal fibroblast populations appeared to be quantitative rather than qualitative. This may be a result of either clonal selection or selective activation in the pathogenesis of SSc.

Adult↗

PubMed2003

[Systemic sclerosis: symptomatic treatment].

Systemic sclerosis is an autoimmune connective tissue disease resulting in a fibrosis of skin and internal organs. The pathogenesis is unclear and includes genetic and environmental factors leading to an immune activation, vascular abnormalities, fibroblast proliferation and collagen deposition. The treatment of systemic sclerosis can be based on a model of its pathogenesis. Therapy includes vasoactive drugs, prevention of fibrosis or immunosuppression and symptomatic treatment. In our paper we present the proven remedies and novel therapies of systemic sclerosis--disease extremely difficult to treat because of changes in digestive, pulmonary, cardiovascular, neuromuscular and locomotor's systems.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1995

Molecular structure and function of autoantigens in systemic sclerosis.

Autoantibodies in systemic sclerosis target a limited set of nuclear proteins, principally those of the nucleolus and RNA transcription complexes. These antibodies have proved helpful in diagnosis of this disease, and have been used extensively as probes of nuclear structure and function. Despite these advances, the events that initially trigger autoantibody production in systemic sclerosis are not yet known. While these ANA are not known to disrupt cellular processes by entering living cells, or to cause tissue injury (in contrast to SLE, where autoantibodies may mediate tissue damage), it seems likely that they do not merely represent epiphenomena of the disease. Rather, it is logical to assume that their origin is in some manner tied to etiology of systemic sclerosis, since they segregate by syndrome within the spectrum of this disease (for example, anti-kinetochore antibodies occur in limited cutaneous disease, and anti-topoisomerase I and anti-RNA polymerase antibodies occur in diffuse disease), and since they are distinct from the ANA found in other connective tissue diseases in their selectivity for the nucleolus and RNA polymerases.

Antigens, Nuclear↗

PubMed1998

Molecular heterogeneity of second and fourth components of complement and their genes in systemic sclerosis and association of HLA alleles A1, B8 and DR3 with limited and DR5 with diffuse systemic sclerosis.

Deficiency of the complement component C4 at the functional, protein and gene level and deficiency of complement component C2 at the functional level were investigated and HLA analysis was performed on patients with limited and diffuse systemic sclerosis (SSc). One of the patients with limited SSc (n = 15) had subnormal C4, 1 subnormal C2 and 1 subnormal C4 and C2 activities; the latter patient had HLA alleles A11;B35;Dw1 associated with type II C2 deficiency and therefore most likely had a defect at the C2 locus. One of the patients with diffuse SSC (n = 12) had subnormal C4 and 1 subnormal C4 and C2 activities. C2 deficiencies in patients other than the one with the haplotype associated with C2 deficiency appeared not to be determined by the gene at the C2 locus. The incidence of partial C2 deficiency in a normal Caucasian population is reported to be 16 in 10,000, and that of partial C4 deficiency also appears to be very low. The percentages of C4A*Q0 and C4B*Q0 alleles in normal controls (n = 45) were within the reported range. Seven patients with limited SSc (n = 14) had one or two C4A*Q0 alleles and 2 with diffuse SSc (n = 13) had one C4A*Q0 allele. Thus, the incidence of C4A*Q0 was higher than normal in limited SSc and within the normal range in diffuse SSc. The two-sided Fisher's exact test applied on these data revealed that the association of C4A*Q0 with limited SSc did not reach a significant level (p = 0.10). Two of the 3 patients with limited SSc, who had two C4A*Q0 alleles, carried a heterozygous C4A-21-hydroxylase A (OHA) gene segment deletion as detected by Southern blotting. There was no correlation between the subnormal activity of C4 and the occurrence of one or two C4A*Q0 (and C4A-21-OHA segment deletion). HLA alleles A1, B8 and DR3 (p = 0.002) were associated with limited SSc (n = 23) and DR5(w11) (p = 0.018) with diffuse SSc (n = 17).

Alleles↗

PubMed2004

Soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement.

Systemic sclerosis (SSc) is a chronic, multisystemic, autoimmune disease characterised by vascular changes and varying degrees of fibrosis of the skin and visceral organs. Organ systemic involvement in SSc is associated with an altered function of endothelial cells, perivascular infiltrating mononuclear cells and interstitial fibrosis. To evaluate the relationship between systemic manifestations and immunological markers of endothelial cell activation, serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) were determined by an enzyme-linked immunosorbent assay in 31 SSc patients and in 30 healthy controls. In comparison with the control group, higher serum concentrations of sVCAM-1, sE-selectin, VEGF and ET-1 were detected in SSc patients (in all cases p<0.001). Elevated concentrations of sVCAM-1 (p<0.05), sE-selectin (p<0.05), VEGF (p<0.05) and ET-1 (p<0.01) dominated in the serum of SSc patients with organ systemic involvement compared to those without systemic manifestation of the disease. These results suggest that the serum levels of sVCAM-1, sE-selectin, VEGF and ET-1 may reflect the extent of internal organ involvement in SSc patients and point to a pathogenic role of these molecules in systemic manifestation of the disease.

Biomarkers↗

PubMed1995

Guidelines for clinical trials in systemic sclerosis (scleroderma). I. Disease-modifying interventions. The American College of Rheumatology Committee on Design and Outcomes in Clinical Trials in Systemic Sclerosis.

OBJECTIVE: To develop guidelines for therapeutic trials designed to improve the overall course of systemic sclerosis (SSc), that is, to reduce the development of significant organ damage or death. METHODS: A committee developed general guidelines for patient inclusion and exclusion criteria, randomization, blinding of patients and physicians, controls, duration of the trial, investigator training, responses, samples size, study dropouts, statistical analyses, data management, and safety monitoring. Delphi and nominal group techniques were used. RESULTS: Briefly, patients with diffuse cutaneous SSc of less than 24 months' duration should be included because they are at greatest risk for the development of severe organ damage and death. Patients should be excluded if they have other connective tissue diseases, SSc-like illnesses related to exposures or ingestions, severe existing internal organ damage, an unacceptable risk of side effects, or concurrent therapies that might independently influence the outcome. Randomized, double-blind, placebo-controlled trials are preferred. The treatment and followup period must be long enough to permit observation of any disease modification, which is likely to require 18-36 months, unless an extraordinarily effective therapy is identified. Responses selected should be quantitative, consistently and accurately reflect activity of SSc in major target organs (not solely the skin), be sensitive to change, and be standardized, with limited variability. An example of a set of responses is given. Surrogate responses are desirable, but none have been validated as correlating with organ damage. CONCLUSION: Guidelines have been established for trials of disease-modifying interventions in SSc. These guidelines will need to be altered as additional information becomes available. Any given protocol will be individualized based on the nature of the intervention and objectives of the study. Nonetheless, each study team should develop a protocol that meets the spirit of these guidelines.

Clinical Protocols↗

PubMed1992

The evolution of a case of overlap syndrome with systemic sclerosis, rheumatoid arthritis and systemic lupus erythematosus.

An unusual case of overlap syndrome which evolved over a 12-year period is described. The patient initially presented with limited cutaneous systemic sclerosis. She then developed seropositive erosive rheumatoid arthritis and subsequently vasculitis with positive lupus serology. There was no evidence that she had mixed or undifferentiated connective tissue disease, and antibody to ribonuclearprotein was negative. This unusual combination of connective tissue disorders in one patient is reported and the literature is reviewed.

Arthritis, Rheumatoid↗

PubMed2005

The CD19-CD21 signal transduction complex of B lymphocytes regulates the balance between health and autoimmune disease: systemic sclerosis as a model system.

Cell-surface CD19 functions as a general rheostat for defining intrinsic and antigen receptor-induced signaling thresholds critical for clonal expansion of the B cell pool and humoral immunity. CD19 also governs B cell responses initiated through the CD21 receptor, where complement C3d binding to CD21 links humoral immune responses with the innate immune system. Alterations in this signaling pathway can predispose mice and humans to autoantibody production and systemic autoimmunity. Transgenic mice that overexpress CD19 by 20-170% lose tolerance and generate autoantibodies. Likewise, B cells from CD21-deficient mice overexpress CD19 by approximately 50%, which leads to autoantibody production. Autoimmune patients with systemic sclerosis also overexpress CD19 by approximately 20%, which may contribute to their intrinsic B cell abnormalities and autoantibody production. Thus, chronic B cell activation resulting from augmented CD19 expression or signaling through the CD19 pathway may reveal a prototype autoimmune disease susceptibility pathway in mice and humans.

Animals↗

PubMedDate not supplied

New ELISA kits using C3 binding glycoprotein from Cuscuta europea detect mainly IgM CIC in rheumatoid arthritis and progressive systemic sclerosis, but not in systemic lupus erythematosus.

Elevated levels of circulating immune complexes (CIC), containing IgG, IgM or IgA antibodies were detected in the sera of patients with autoimmune diseases. This might indicate a different biological meaning of the three isotypes of immunoglobulin (Ig) in the CIC. Each CIC assay detected only certain classes and subclasses of Ig in CIC material or fixed complement protein. In this study, a new method based on C3binding glycoprotein named CIF-ELISA and a well-known method ANTI-C3 ELISA, were used for quantitative assessment of IgM-CIC, IgG-CIC and IgA-CIC levels in human sera. A modified CIF-ELISA and ANTI-C3 ELISA for simultaneous detection of CIC, containing IgG, IgM and IgA, (stCIC), were also performed. The assays were evaluated on the same specially prepared samples: 55 normal sera, 99 sera from rheumatoid arthritis (RA), 88 sera from systemic lupus erythematosus (SLE), and 27 sera from progressive systemic sclerosis (PSS). We found that the sensitivity of the tests used varied depending on the diseases studied. CIF-ELISA displayed higher sensitivity of IgM-CIC when compared to ANTI-C3 ELISA in RA patients (40.0 and 20.95%, respectively) and PSS (44.43 and 37.04%, respectively). Results for the sensitivity of IgA-CIC were in adverse direction in the RA group (14.28 and 19.05%) and PSS (14.81 and 25.93%) by both methods. It was also established that the concordance of IgM-CIC positives by both methods was 48.84% in RA and 46.67% in PSS, while in SLE it was 18.78%. These results are most probably due to the different assay abilities to detect antibody isotype of the CIC material and help to explain what specific role each Ig isotype in CIC has in the course of the disease.

Antigen-Antibody Complex↗

PubMed1990

A possible role for transforming growth factor-beta in systemic sclerosis.

The cause of systemic sclerosis remains unknown, but cellular and molecular mechanisms possibly responsible for the characteristic clinical manifestations of fibrosis and vascular damage (Raynaud's phenomenon, telangiectasis, digital infection, and renal arteriopathy) are becoming understood in greater detail. One possibly important cytokine is transforming growth factor-beta (TGF-beta); its involvement is reviewed here. With regard to vascular lesions, TGF-beta has variably been shown to inhibit endothelial cell growth in vitro but to promote angiogenesis in vivo, a paradox that remains unresolved. Nonetheless, an injurious activity of TGF-beta on microvascular endothelial cells could help to explain the intimal proliferation and microvascular obliteration seen. Whether as a result of or as a cause of endothelial cell damage, platelet activation has been well documented in systemic sclerosis and the platelet alpha granule pool contains a large quantity of TGF-beta. TGF-beta is also produced by activated macrophages and T cells, both of which are known to occur within systemic sclerosis lesions. An important effect of TGF-beta is its stimulation of fibroblast collagen and fibronectin synthesis and their deposition into the extracellular matrix. Stimulation by TGF-beta may therefore account for the fibrosis seen in the dermis and in the internal organs. Direct evidence of TGF-beta involvement in systemic sclerosis is scanty, and awaits discovery of either an abnormal expression of or response to TGF-beta. The biologic effects of TGF-beta appear to be regulated at the level of activation from a latent polypeptide precursor form. Descriptions of the importance of this cytokine in pathologic conditions will need to account for this activation and its regulation. Nonetheless, the physiologic effects so far attributed to TGF-beta make its involvement in systemic sclerosis an attractive possibility to explain some of the manifestations of this enigmatic disease.

Chemotactic Factors↗

PubMed2002

Early cardiovascular involvement in patients with systemic sclerosis (SSc).

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease characterized by progressive fibrosis of the skin, and by distinctive forms of internal organ involvement. Symptoms usually occur relatively late and are nonspecific, thus often unrecognized. The purpose of our study was to evaluate cardiac function in patients with SSc by means of non-invasive methods in order to detect early dysfunction of the cardiovascular system. MATERIAL/METHODS: A group of 22 patients with SSc was compared with a group of 22 healthy volunteers. Standard EKG, 24-hour Holter monitoring (HM), and echocardiography were performed in all subjects. RESULTS: In patients with SSc, HM revealed a tendency to tachycardia. Conduction disturbances were observed in 3 patients. In 6 patients significant ventricular arrhythmia was found. Silent ischemia episodes were detected in 6 patients. In HRV analysis, significantly lower values were detected in patients with SSc than in controls. LPs were present in one patient with SSc, and none in the control group. The mean values for QT interval did not exceed the range of normal values. No signs of systolic cardiac dysfunction were detected, while in 6 patients left ventricle diastolic dysfunction was recognized. Valvular lesions were observed in 8 patients, but only in 2 patients were they hemodynamically important. CONCLUSIONS: 24-hour Holter monitoring and echocardiography enable the early detection of cardiovascular dysfunction in patients with systemic sclerosis presenting without apparent cardiac impairment symptoms.

Adolescent↗

PubMed2005

[Progressive systemic sclerosis and pregnancy].

Progressive systemic sclerosis is a connective tissue disease with inflammation and fibrosis. Pregnant women with progressive systemic sclerosis have an increased risk for preterm births and probably for small-for-date babies. We report the case of a 28-year-old II G O P suffering from progressive systemic sclerosis with severe pulmonary fibrosis and affection of the oesophagus. She was admitted to hospital at 32 weeks of gestation with premature labour and cervical incompetence. At 34 weeks of gestation she was delivered by Caesarean section with spinal anaesthesia because of foetal growth arrest and decreased pulmonary function. The operation and the postoperative course were without any complications. Pregnant women with progressive systemic sclerosis have an increased risk for renal and pulmonary complications (hypertension, hypoxia). Therefore careful interdisciplinary obstetric monitoring is very important.

Adult↗

PubMed1998

[Vascular manifestations in systemic sclerosis (scleroderma)].

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

Adult↗

PubMed1988

Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis.

Of 397 systemic sclerosis (scleroderma) patients from the University of Pittsburgh, who had serum determinations of both anti-Scl-70 and anticentromere antibody (ACA), 26% had anti-Scl-70 and 22% had ACA. No patient had both autoantibodies. Weak associations with HLA-DR5 and HLA-DR1 were detected with anti-Scl-70 and ACA, respectively. ACA was found almost exclusively (96%) in patients with limited cutaneous scleroderma (the CREST syndrome variant), but the majority (57%) of patients with limited scleroderma did not have this antibody. Among patients with limited scleroderma, those with ACA more often had calcinosis and telangiectasias and less often had pulmonary interstitial fibrosis and restrictive lung disease. However, the frequency of pulmonary hypertension and the survival rates were similar in the ACA+ and ACA- limited scleroderma patients. Two-thirds of patients with anti-Scl-70 had diffuse scleroderma, but only 33% of all diffuse scleroderma patients had this antibody. Within the subset of diffuse scleroderma, anti-Scl-70 was associated with peripheral vascular disease (digital pitting scars) and pulmonary interstitial fibrosis, but was not predictive of cardiac or renal involvement or survival. ACA and anti-Scl-70 are useful in diagnosing and classifying systemic sclerosis variants and in predicting the natural course of the disease. Their mutually exclusive occurrence suggests either 2 separate clinical entities or important host factors determining their production.

Adult↗