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PubMed2003

[Plasmapheresis therapy in systemic sclerosis].

BACKGROUND: Systemic sclerosis (SSc) is a polysystemic autoimmune disorder characterized by excessive production of extracellular matrix and vascular abnormalities, involving the skin and internal organs. There is currently no real disease-modifying therapy of SSc and there are only few reports on the use of plasmapheresis in SSc. OBJECTIVES: Authors present 4 cases of SSc treated with plasmapheresis within one year from disease onset. All patients had diffuse cutaneous form of SSc with rapid progression and with different internal organ manifestations. METHODS: The patients were treated with plasmapheresis performed every 3 months besides symptomatic drug treatment. Clinical symptoms, Rodnan skin score, immunolaboratory markers (serum immunoglobulin, complement, several autoantibodies, leukocyte CD markers) and soluble adhesion molecules (E-selectin, intercellular adhesion molecule 1, vascular cell adhesion molecule, which were showed as the markers of disease activity in previous works) were determined before and after the plasmapheresis. RESULTS: The progression of the disease slowed down significantly in all patients, no more new clinical manifestation appeared, Rodnan skin score significantly decreased. There was a reduction in CD4/CD8 ratio (approaching normal ratio), in expression of CD69, as early activation marker. There was a significant suppression of soluble adhesion molecules also in all patients. CONCLUSION: In patients with diffuse cutaneous form of SSc, plasmapheresis may be effective with decreasing progression of the disease and improving clinical symptoms (especially skin manifestation) in the early phase of the disease.

Adult↗

PubMed1991

Cutaneous vitamin D3 formation in progressive systemic sclerosis.

Progressive systemic sclerosis (PSS) is a predominantly dermal disorder which may be associated with epidermal atrophy. We investigated epidermal function in 8 patients with PSS and their healthy controls matched for age, sex and racial group. We measured the vitamin D3 photosynthetic response to whole body irradiation with ultraviolet light B (UVB). There were no significant differences in basal serum vitamin D3 levels (mean +/- SEM: PSS 1.2 +/- 0.2 ng/ml; controls 0.8 +/- 0.1 ng/ml; p greater than 0.1) or post UVB blood values (PSS 5.2 +/- 1.4 ng/ml; controls 6.9 +/- 1.1 ng/ml; p greater than 0.1); although the increases post-UVB were significant in both groups (p less than 0.01). In an additional group of 19 patients with PSS and their corresponding matched healthy controls, we performed determination of random levels of the active vitamin D metabolites, 25-hydroxyvitamin D (25-OH-D) and 1,25-dihydroxyvitamin D [1,25-(OH)2-D]. Similar levels were observed in both groups: 25-OH-D PSS 28 +/- 3 ng/ml, controls 29 +/- 3 ng/ml; 1,25-(OH)2-D PSS 27 +/- 2 pg/ml, controls 31 +/- 2 pg/ml (p greater than 0.1). None of the correlations between skin area involved and vitamin D3 formation or active circulating metabolites reached statistical significance (p greater than 0.1). We conclude that global epidermal synthesis of vitamin D is retained in PSS and, that the hepatic and renal vitamin D hydroxylating mechanisms function normally in that condition.

Adult↗

PubMedDate not supplied

The IL-6 promoter polymorphism is associated with disease activity and disability in systemic sclerosis.

UNLABELLED: Systemic sclerosis (SSc) is a rare, autoimmune disease characterized by cutaneous and visceral fibrosis. Interleukin- 6 (IL-6) is involved in the pathogenesis of many immune-mediated diseases. IL-6 plays an important role in the initiation and promotion of fibrosis. The polymorphism in the position -174 (G/C) of the promoter region of the IL-6 gene (IL-6pr) may alter the expression of the gene. Complete linkage disequilibrium was observed between the -174 and -597 alleles. The aim of this study is to investigate the possible influence of -597 (-174) IL-6pr polymorphism on the susceptibility and/or the clinical course of SSc in Romanian population. Genotyping of -597 variant was performed by an RFLP method on 20 SSc patients and 26 healthy subjects. Patients having the homozygous GG (-597) genotype had higher disease activity and disability scores than heterozygous GA patients: the European Scleroderma Study Group (EScSG) disease activity score was 5.0 +/- 3.3 in homozygous GG subjects vs. 2.4 +/- 3.6 in heterozygous GA patients (p < 0.05), and the Disability Index of the Health Assessment Questionnaire (HAQ-DI) was 1.42 +/- 1.04 in homozygous GG subjects vs. 0.53 +/- 0.55 in heterozygous GA patients (p < 0.05). No difference was observed in the distribution of allele frequencies between SSc patients and healthy controls. CONCLUSIONS: The GG homozygosis was found to be associated with a higher degree of illness activity and disability in SSc patients. No statistically significant differences were found between SSc patients and healthy controls with respect to the -597 allele distribution.

Adult↗

PubMed1994

Isolation and characterization of microvascular endothelial cells from the adult human dermis and from skin biopsies of patients with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a rheumatic autoimmune disease without known etiology and pathogenesis. Inflammatory processes with selective microvascular involvement seem to play an important role in the early stages of SSc. EXPERIMENTAL DESIGN: To elucidate the pathogenesis of the selective microvascular involvement in SSc, we have isolated microvascular endothelial cells from the adult human dermis (ADMEC) and for the first time from skin biopsies of patients with SSc (SSc-ADMEC) and established in cell culture. Ulex europaeus I-coated magnetic Dynabeads and the perfusion digestion technique were applied for endothelial cell isolation. RESULTS: The cultured ADMEC and SSc-ADMEC showed the endothelial cell-specific antigenic determinants of intracellular von Willebrand factor and platelet endothelial cell adhesion molecule-1 along their cell-cell borders. These cells displayed specific uptake of acetylated low-density lipoprotein. Normal ADMEC were additionally characterized for angiotensin I-converting enzyme activity. Tumor necrosis factor-alpha activated normal ADMEC and SSc-ADMEC expressed the inflammatory adhesion molecules E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, similarly to tumor necrosis factor-alpha-activated large-vessel endothelium represented by human umbilical cord vein endothelial cells. Normal ADMEC and human umbilical cord vein endothelial cells also expressed beta 1- and beta 4-integrin receptors in cell culture. CONCLUSIONS: Normal ADMEC and SSc-ADMEC express endothelial cell-specific antigenic and biochemical determinants in vitro. SSc-ADMEC were for the first time established in cell culture.

Adult↗

PubMed1985

Evidence for chronic inflammation as a component of the interstitial lung disease associated with progressive systemic sclerosis.

Progressive systemic sclerosis (PSS) is a generalized disorder characterized by fibrosis of many organs including the lung parenchyma. Unlike most other interstitial disorders, traditional concepts of the interstitial lung disease associated with PSS have held it to be a "pure" fibrotic disorder without a significant inflammatory component. To directly evaluate whether an active alveolitis is associated with this disorder, patients with chronic interstitial lung disease and PSS were studied by open lung biopsy, gallium-67 scanning, and bronchoalveolar lavage. Histologic evaluation of the biopsies demonstrated that the interstitial fibrosis of PSS is clearly associated with the presence of macrophages, lymphocytes, and polymorphonuclear leukocytes, both in the interstitium and on the alveolar epithelial surface. Gallium-67 scans were positive in 77% of the patients, showing diffuse, primarily lower zone uptake, suggestive of active inflammation. Consistent with the histologic findings, bronchoalveolar lavage studies demonstrated a mild increase in the proportions of neutrophils and eosinophils with occasional increased numbers of lymphocytes. Importantly, alveolar macrophages from patients with PSS showed increased release of fibronectin and alveolar-macrophage-derived growth factor, mediators that together stimulate lung fibroblasts to proliferate, thus suggesting at least one mechanism modulating the lung fibrosis of these patients. Thus, evidence from several different points of view together demonstrates that the interstitial lung disease associated with PSS is associated with chronic inflammation in the local milieu, leading to the hypothesis that the inflammation plays some role in the derangements to the alveolar structures that characterize this disorder.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Oligoclonal expansion of V delta 1+ gamma/delta T-cells in systemic sclerosis patients.

Systemic sclerosis (SSc) is a multisystem disease characterized by T-cell infiltration of involved tissues, fibrosis, and small vessel vasculopathy. Using flow cytometric analyses, we found an increased percentage of gamma/delta T-cells expressing the T-cell antigen receptor variable (V) delta 1 gene segment in the peripheral blood and bronchoalveolar lavage fluid of patients with SSc. To estimate clonality of these V delta 1+ T-cells, the diversity of V delta 1 junctional regions (V-Diversity-Joining gene segments) was examined using a reverse transcriptase-polymerase chain reaction to amplify T-cell antigen receptor delta chain transcripts isolated from peripheral blood mononuclear cells, lung, esophagus, stomach, or skin of patients and controls. Limited diversity of V delta 1-J delta junctional regions in SSc patients was demonstrated by the finding of greater restriction in the nucleotide lengths of junctional region cDNAs in individual SSc patients than in controls. Sequence analyses confirmed that V delta 1-J delta junctional regions from the blood of SSc patients had less diversity than those from controls, in that a significantly higher proportion of sequences were repeated in patients (54.4% vs. 19.4% in controls). Evidence for selection of the V delta 1+ T-cells in tissues of individual SSc patients came from the findings that the same V delta 1-J delta junctional sequences could be isolated from the same tissue over time and that identical V delta 1-J delta junctional sequences could be isolated from multiple tissues. These data suggest that expansion of V delta 1+ gamma/delta T cells may be antigen driven in SSc patients.

Base Sequence↗

PubMed2005

Lipoprotein[a] and the lipid profile in patients with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disorder of the connective tissue characterized by widespread vascular lesions and fibrosis, associated with endothelial dysfunction, that might finally promote occlusive vascular complications. Little is known so far on the lipid profile of these patients. METHODS: To investigate the potential contribution of lipid abnormalities in genesis and progression of vascular occlusive complications, an extensive lipid profile, including total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, total cholesterol to HDL-C ratio, the atherogenic index of plasma, lipoprotein[a] (Lp[a]) and high-sensitive C Reactive Protein (Hs-CRP), was assessed in 31 consecutive female SSc patients and 33 matched healthy controls. RESULTS: When compared to healthy matched controls, SSc patients displayed statistically significant differences in median and 25-75th percentile distribution of Lp[a] (110 mg/l, 51-389 mg/l vs. 79 mg/l, 29-149 mg/l; P =0.005) and in the mean concentration of Hs-CRP (4.49 +/- 5.06 mg/l vs. 1.36 +/- 1.19 mg/l; P =0.001), but not in the other lipid parameters. When compared to the current NCEP or AHA/ACC goals, the values distributions and the relative percentage of patients with undesirable or abnormal vales were statistically different for Lp[a] (29% versus 3%) and Hs-CRP (42% vs. 12%) (both P <0.001). CONCLUSIONS: If further studies will strengthen these preliminary findings, owing to the growing evidence that Lp[a] might act in synergy with other defined prothrombotic conditions in the pathogenesis of a variety of vascular disorders, we hypothesize that Lp[a] measurement might be useful in SSc to identify and eventually treat subsets of patients more predisposed to develop thrombotic complications.

C-Reactive Protein↗

PubMed1996

Noninvasive evaluation of right ventricle systolic pressure during dynamic exercise by saline-enhanced Doppler echocardiography in progressive systemic sclerosis.

Progressive systemic sclerosis (PSS) is characterized in its first phases by vascular damage. Lungs are involved in two thirds of patients with initial progressive destruction of the capillary bed and consequent reduction of the functional reserve, which may lead to hypertension of the pulmonary circulation. For these reasons it is of great interest to have early information about the pressure of the pulmonary circulation, both at rest and during exercise, to follow the progression and the evolution of the illness independently from subjective symptoms. The aim of the study was to evaluate by a noninvasive method, saline-enhanced Doppler echocardiography, the behavior of the right ventricular systolic pressure in patients with PSS, at rest and during exercise, without clear instrumental or clinical signs of pulmonary involvement at rest. Nine patients (7 women and 2 men) with PSS, aged 55.7 +/- 8.7 years, and 9 control subjects were evaluated. All patients had normal pulmonary pressure at rest and negative history for effort dyspnea. Subjects underwent Doppler echocardiographic examination at rest and during exercise. Right ventricular systolic pressure was evaluated by saline-enhanced Doppler technique, at rest and throughout exercise. At rest the right ventricular systolic pressure was normal in all patients and controls. At the end of exercise, in 4 patients, values were still normal (40.7 +/- 2.2 mmHg); in the others pathologic values were recorded (59.8 +/- 3.9 mmHg). In the control group values were always normal (35.6 +/- 4.6 mmHg). In our study the saline-enhanced Doppler echocardiography has been demonstrated to be an important diagnostic tool for the noninvasive evaluation of right ventricular systolic pressure, both at rest and during exercise; it could be useful in monitoring the pulmonary vascular damage in patients with PSS.

Adult↗

PubMed2001

[Treatments of progressive systemic sclerosis].

Progressive Systemic Sclerosis (PSS) is still an incurable disease but there are treatments for it, and the list of proposed treatments is long. The methodology of trials concerning PSS is complex, due to the low prevalence of the disease and therefore its financial interest for pharmaceutical companies, the lack of simple end points for efficacy, and the large number of clinical expressions with various prognoses. These causes explain why most open studies are fiercely positive, and why controlled studies are so rare. The progress made during the last 10 years concern 1) the diagnosis, which is now made earlier due to capillaroscopy and antibody assays, especially of anticentromere antibodies, 2) better knowledge of the prognosis, due to the classification of PSS into limited and the diffuse forms which have different prognoses, and 3) the recognition of a serious complication of the disease, ie. pulmonary hypertension, which can now be detected by non-invasive methods. All these improvements will also improve the methodology of future trials of drugs for treating PSS. In this ocean of uncertainties, some treatments have a valid background, and 3 visceral locations of PSS can be efficiently treated: renal involvement, with angiotensin-converting enzyme inhibitors, respiratory involvement, with D-penicillamine, and pulmonary hypertension, with prostacyclin derivatives. Corticosteroids are suspected to increase the risk of renal complications. Calcium blockers are considered a useful symptomatic treatment of the associated Raynaud's phenomenon and of the risk of digital necrosis, and may also constitute a treatment of PSS itself. A recent trial conducted by the French Microcirculation Society and its acrosyndrome Study Group considered the effects of an oral derivative of prostacyclin. Beneficial effects were: a reduction of the risk of digital necroses, improved overall wellbeing, less necessity for hospitalizations, fewer giant capillaries, and a dramatic fall in the level of von-Willebrand factor.

Humans↗

PubMed2005

A randomized, blinded, parallel group, placebo controlled pilot study evaluating the effect of PVAC treatment in patients with diffuse systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is a disorder characterized by progressive thickening of the skin; there is no effective therapy. PVAC, a potential therapeutic agent derived from delipidated, deglycolipidated Mycobacterium vaccae, has shown effects on cutaneous disease in animal models of SSc. We evaluated the safety and possible biologic effect of intradermal injections of PVAC in patients with diffuse SSc. METHODS: Eighteen patients enrolled in this double blind, placebo controlled, randomized, 24 week pilot study. All patients met criteria for diffuse SSc without evidence of significant renal dysfunction, pulmonary fibrosis, pulmonary hypertension, or congestive heart failure. Patients received 8 intradermal injections of 15 microg PVAC, 50 microg PVAC, or placebo at 3 week intervals. The primary efficacy endpoint was the change in Modified Rodnan Skin Score (MRSS) at Week 24. Each of the active drug arms was compared to placebo. RESULTS: Baseline demographic and disease characteristics were similar across the 3 treatment groups. The median age was 48 years and 14 of 18 (78%) patients were female. The regimens were well tolerated with no reported serious adverse events; however, grade 1 or 2 injection site reactions occurred in the majority of patients receiving PVAC. The MRSS improved by 20.6% in the 15 microg PVAC arm, while it worsened by 29.8% in the placebo arm and by 16.7% in the 50 microg arm. Change in physician and patient global assessments followed similar trends. CONCLUSION: In this pilot study, use of PVAC in patients with SSc appeared safe and was associated with a trend toward improved skin scores in the 15 microg treatment group. Additional evaluation of this therapeutic approach is warranted.

Adult↗

PubMed2005

Alterations of mononuclear inflammatory cells, CD4/CD8+ T cells, interleukin 1beta, and tumour necrosis factor alpha in the bronchoalveolar lavage fluid, peripheral blood, and skin of patients with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a multisystem disease with underlying immune mechanisms. AIMS: To investigate the clinicopathological characteristics of the lesions; immunological alterations in the bronchoalveolar lavage fluid (BALF), peripheral blood, and skin; and correlations between the clinicopathological characteristics and immunological alterations in SSc. MATERIALS/METHODS: Skin biopsies, BALF, and peripheral blood samples were obtained from 19 patients (18 women, one man) with SSc and six age and sex matched healthy controls (HCs). Mononuclear inflammatory cells (MICs), CD4/CD8 cells, tumour necrosis factor alpha (TNFalpha), and interleukin 1beta (IL1-1beta) concentrations were examined in all samples using histological methods, enzyme linked immunosorbent assay, and immunoperoxidase staining. RESULTS: The mean (SD) age of the patients with SSc was 34.8 (2.6) years. Proteinuria, positive rheumatoid factor, and C reactive protein were seen in 15.8%, 26.3%, and 26.3% of patients, respectively. Compared with HCs, there were significantly higher: total MICs (macrophages, lymphocytes), neutrophils, and eosinophils in BALF, blood, and skin (all p<0.05); cytokine concentrations in BALF (TNFalpha, p<0.001; IL-1, p<0.01) and peripheral blood (p<0.01 and p<0.05); and CD8/CD4+ T cells in peripheral blood (p<0.05). Compared with HCs, lesional skin had significantly higher histiocyte cell counts (p<0.05), lower lymphocyte counts (p<0.05), and higher CD4/CD8 ratios (p<0.001). There were significant correlations between cytokine concentrations and CD8+ T cells and forced vital capacity (p<0.001 and p<0.01, respectively). CONCLUSIONS: MICs, CD4/CD8+ cells, and cytokines are altered in SSc. These alterations correlated with the underlying disease process and therefore may have pathogenic, modulatory, and potential prognostic roles in SSc.

Adult↗

PubMedDate not supplied

Heart structure and function in systemic sclerosis.

INTRODUCTION: Systemic sclerosis (SSc) is a multisystem disorder characterised by connective tissue fibrosing with vascular abnormalities and autoimmune changes. Heart involvement is one of the main factors shortening the survival of SSc patients. AIM OF THE STUDY: (1) To assess structural and pathophysiological changes of the heart in SSc patients in standard echocardiographic examination. (2) To evaluate regional systolic and diastolic left ventricle disturbances in SSc patients by means of Tissue Doppler Imaging (TDI). MATERIAL AND METHODS: In 19 SSc women aged 22-72 years and 16 control healthy women aged 19-57 years M-Mode, 2D, Continuous Doppler, Colour Doppler and Tissue Doppler examinations were performed. Tissue Doppler myocardial velocities in systole and early diastole were evaluated in 14 myocardial segments in parasternal and apical views. RESULTS: No significant differences between both groups in left ventricle (LV) ejection fraction, LV end-diastolic and end-systolic diameter, LV wall thickness, valvular structure was observed. Mitral E/A ratio was significantly decreased in SSc women (p < 0.001), and pulmonary systolic pressure was significantly increased in this group (p < 0.001). In TDI examination no significant difference between the groups in systolic myocardial velocity was found. In SSc women early diastolic velocities were significantly lower than in controls (p < 0.00001). The detailed assessment of diastolic function in SSc group showed severe diastolic dysfunction of longitudinal myocardial fibers with normal function of circumflex myocardial fibers. CONCLUSIONS: In SSc patients significant left ventricle diastolic dysfunction was found. Diastolic dysfunction was observed only in longitudinal myocardial fibres and was not found in circumflex myocardial fibres. Thus, myocardial fibrosing and ischemia in SSc patients seem to be concentrated in the subendocardial region built by longitudinal muscle layer. Left ventricle diameter, walls thickness and systolic function in SSc patients are preserved.

Adult↗

PubMed2006

Impact of pain in health related quality of life of patients with systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) has an heterogenous clinical pattern, with variable organ involvement and degrees of severity. Like in other rheumatic diseases, the self-questionnaires have been used to evaluate SSc globally. The aim of the study is as to evaluate the quality of life (QoL) in patients with either diffuse or limited SSc, and to examine the impact of pain on the QoL scores. METHODS: Patients with SSc, either diffuse or limited SSc, were included in a cross-sectional study. The QoL was evaluated with the short-form 36 (SF-36) and the functional repercussion with the SSc-modified Health Assessment Questionnaire (S-HAQ). RESULTS: A total of 89 patients (67 with diffuse and 22 with limited SSc) were included. The SF-36 score values were lower in SSc patients than those reported in the general population. The physical component scores (PCS) of the SF-36 was significantly worse in diffuse compared with limited SSc (P < 0.05). The PCS was significantly negatively related to the number of clinical manifestations (ANOVA, P < 0.0001). The mental component score (MCS) was not influenced by the type of SSc or the number of clinical manifestations presented by the patient. The QoL of SSc patients was highly correlated with pain (R = 0.69) and disability (R = 0.70). Interestingly, the QoL of SSc patients was only slightly correlated with cutaneous (R = 0.42) and pulmonary involvement (R = 0.57). CONCLUSION: The QoL of patients with SSc is strongly influenced by the type of SSc, the burden of clinical manifestations, the functional disability and by the pain, whatever its cause. The treatment of pain should be considered as priority to improve the QoL of SSc patients.

Adolescent↗

PubMed2006

Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis.

BACKGROUND: Systemic sclerosis (scleroderma) is characterized by immunologic abnormalities, injury of endothelial cells, and tissue fibrosis. Abnormal oxidative stress has been documented in scleroderma and linked to fibroblast activation. Since platelet-derived growth factor (PDGF) stimulates the production of reactive oxygen species (ROS) and since IgG from patients with scleroderma reacts with human fibroblasts, we tested the hypothesis that patients with scleroderma have serum autoantibodies that stimulate the PDGF receptor (PDGFR), activating collagen-gene expression. METHODS: We analyzed serum from 46 patients with scleroderma and 75 controls, including patients with other autoimmune diseases, for stimulatory autoantibodies to PDGFR by measuring the production of ROS produced by the incubation of purified IgG with mouse-embryo fibroblasts carrying inactive copies of PDGFR alpha or beta chains or the same cells expressing PDGFR alpha or beta. Generation of ROS was assayed with and without specific PDGFR inhibitors. Antibodies were characterized by immunoprecipitation, immunoblotting, and absorption experiments. RESULTS: Stimulatory antibodies to the PDGFR were found in all the patients with scleroderma. The antibodies recognized native PDGFR, inducing tyrosine phosphorylation and ROS accumulation. Autoantibody activity was abolished by preincubation with cells expressing the PDGFR alpha chain or with recombinant PDGFR or by PDGFR tyrosine kinase inhibitors. Stimulatory PDGFR antibodies selectively induced the Ha-Ras-ERK1/2 and ROS cascades and stimulated type I collagen-gene expression and myofibroblast phenotype conversion in normal human primary fibroblasts. CONCLUSIONS: Stimulatory autoantibodies against PDGFR appear to be a specific hallmark of scleroderma. Their biologic activity on fibroblasts strongly suggests that they have a causal role in the pathogenesis of the disease.

Adult↗

PubMed1998

HLA associations in three mutually exclusive autoantibody subgroups in UK systemic sclerosis patients.

Systemic sclerosis (SSc) is characterized by the presence of autoantibodies, mostly IgG, which target a limited set of nuclear proteins. These antinuclear antibodies (ANA) associate with disease subgroups and specific organ involvement. Here we show that there is mutual exclusivity of individual ANA in 130 UK SSc patients, confirm clinical associations with antibody profile and extend the analysis to include genetic data. The ANA mutual exclusivity observed leads to the possibility that SSc, in these patients, is in fact three separate diseases. An alternative explanation for exclusivity relates to the fact that optimal production of IgG antibody requires T-cell help, a process restricted by the HLA class II presentation of antigen peptide. If each autoantibody has a different and tight MHC restriction, then there is a possibility that these groups arose from a common pathway and were modified by genetics into the mutually exclusive groups observed, making the separate disease theory less tenable. In order to answer this question, we have determined MHC class II restriction precisely using high-resolution HLA genotyping (SSP) coupled with an amino acid analysis program in our 130 UK SSc patients. DRB1*11 was associated with anti-topoisomerase-I antibody (ATA)-positive patients (P = 0.007) and when combined with ATA (RR = 15.82), dcSSc (RR = 11.45), or both (RR = 21.9), represented the strongest risk factor for pulmonary fibrosis. Patients with antibodies to RNA polymerases I, II and III were associated with DQB1*0201. At the amino acid level, 20 positions in DRB1 and 20 positions in DQB1 showed some significant correlation with an ANA group. Clearly, however, the linkages to MHC class II alleles are not nearly strong enough to explain the mutually exclusive nature of the autoantibody groups and our results support, but do not prove, the separate disease theory.

Antibodies, Antinuclear↗

PubMed2003

Correlation of serum collagen I carboxyterminal telopeptide concentrations with cutaneous and pulmonary involvement in systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is characterized by fibrosis involving the skin and various internal organs. Type I collagen (Col I) is the most abundant extracellular matrix protein deposited in cutaneous involvement. We investigated Col I biochemical markers in patients with SSc. METHODS: All consecutive patients admitted for SSc over a 9 month period and a healthy control group were investigated. Serum concentrations of the C-terminal telopeptide of Col I (s-CTX-I), C-terminal type I procollagen propeptide (PICP), osteocalcin, and bone alkaline phosphatases (ALP), and urinary concentrations of deoxypyridinoline (u-DPD) and u-CTX-I were determined by ELISA. RESULTS: A total of 33 patients with SSc were included: mean age +/- SD was 54 +/- 12 yrs, with a mean disease duration of 5.4 +/- 3.9 years. Sixteen of 33 patients with SSc had s-CTX-I values exceeding the upper limit of normal values of the test and the mean +/- SEM was significantly higher (7388 +/- 1422 pmol/l) than in healthy controls (2800 +/- 1120 pmol/l; p < 0.001). s-CTX-I correlated with the Rodnan skin score (p = 0.003); it was higher in patients with diffuse disease (8459 +/- 3125; n = 14) than in patients with the limited form (6453 +/- 1235; n = 19; p < 0.02). This marker also correlated with acute phase reactants (C-reactive protein, p = 0.004; erythrocyte sedimentation rate, p = 0.02). s-CTX-I was high in patients with positive antitopoisomerase I autoantibodies (p = 0.04) and in patients with a decrease in forced vital capacity to less than 75% (p = 0.02). u-DPD concentration was high in patients with SSc (10.6 +/- 1.4 nmol/mmol creatinine vs 6.3 +/- 2.1 in controls; p < 0.01). No difference between patients and controls or correlations with the disease were found for PICP, u-CTX-I, osteocalcin, and bone ALP concentrations. CONCLUSION: s-CTX-I, a marker of Col I degradation, is correlated with cutaneous and pulmonary involvement and with acute phase reactants in patients with SSc. This marker is a good candidate for further evaluation for disease activity and treatment purposes.

Aged↗

PubMed2006

Effect of small interfering RNA on the expression of connective tissue growth factor and type I and III collagen in skin fibroblasts of patients with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is characterized by an excessive production of extracellular matrix. It is widely accepted that fibrosis is induced by transforming growth factor (TGF)-beta in the early stage and is subsequently maintained by connective tissue growth factor (CTGF). CTGF is a cysteine-rich mitogenic peptide that has been involved in various fibrotic disorders and can be induced in fibroblasts by activation with TGF-beta. OBJECTIVES: To evaluate the effect of small interfering RNA (siRNA) targeting CTGF on the expression of CTGF and type I and type III collagen in SSc. METHODS: Skin fibroblasts from patients with SSc were cultured in vitro and later transfected using four CTGF-specific siRNAs and one nonspecific siRNA. The effect of CTGF-specific siRNAs on the expression of CTGF and type I and type III collagen was examined and quantified by real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blot analysis and immunocytochemistry. RESULTS: Semiquantitative RT-PCR analysis showed that the four CTGF-specific siRNAs significantly reduced CTGF mRNA expression (P < 0.001), of which siRNA742 showed the strongest inhibitory effect with an inhibitory rate of 73%. Three of the four siRNAs could also depress the transcriptional levels of type I and type III collagen mRNA (P < 0.001), of which siRNA742 showed the strongest inhibitory effect with an inhibitory rate of 37% and 29% for type I and type III collagen, respectively. Western blot analysis further demonstrated that three CTGF-specific siRNAs could significantly decrease CTGF protein level (P < 0.001). In addition, immunocytochemical analysis showed that the expression of type I collagen was significantly decreased in fibroblasts after transfection with siRNA742, whereas inhibition of expression of type III collagen was modest. CONCLUSIONS: Our data for the first time showed that CTGF RNA interference could inhibit expression of CTGF and type I and III collagen in SSc fibroblasts and indicated that CTGF might be an upstream factor regulating type I and type III collagen synthesis, particularly type I collagen. Our findings suggest that silencing CTGF expression might facilitate a potential therapeutic approach for SSc.

Blotting, Western↗

PubMed2004

Associations of right ventricular myocardial function with skin and pulmonary involvement in asymptomatic patients with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a multisystem disorder characterized by widespread vascular lesions and fibrosis of the skin and specific internal organs. Cardiac involvement is a common finding in SSc, but often clinically occult. The aim of the present study was to analyze both left and right ventricular (RV) myocardial function in patients with SSc, and their relation to other instrumental features of the disease. METHODS: Twenty-five healthy subjects and 23 age- and sex-comparable asymptomatic patients classified as having either diffuse (11 patients) or limited cutaneous (12 patients) SSc underwent clinical examination, serological analysis, high-resolution chest computed tomography, standard Doppler echocardiography and pulsed Doppler myocardial imaging (DMI) of both the mitral and tricuspid annuli. SSc was classified using the modified Rodnan skin score (mRSS) into high mRSS (score > or = 10) and low mRSS (score < 10). RESULTS: Serological antibody analysis revealed the presence of antinuclear antibody in all patients, an anticentromere pattern in 8 patients, and anti-Scl-70 antibodies in 15 patients. Eleven patients were diagnosed with interstitial pulmonary fibrosis at chest computed tomography. Standard Doppler echocardiography revealed that the left ventricular mass index and ejection fraction were comparable between the two groups, while the RV end-diastolic diameter was increased in SSc (p < 0.01). The tricuspid inflow peak E and E/A ratio were slightly decreased in SSc (p < 0.01), while the systolic pulmonary pressure was increased (p < 0.0001). DMI analysis revealed, in SSc, an impaired RV myocardial early-diastolic (Em) peak velocity (p < 0.001) as well as a prolonged myocardial relaxation time (RTm) (p < 0.001) only at the tricuspid annulus level, even after correction for age, sex, heart rate and left ventricular mass index. Independent inverse associations of the RV Em peak velocity with both the Rodnan skin score (beta coefficient = -0.62, p < 0.0005) and the pulmonary systolic pressure (beta coefficient = 0.71, p < 0.0001), as well as the independent inverse correlation of the same RV Em peak velocity with interstitial pulmonary fibrosis (odds ratio 0.68, 95% confidence interval 0.45-0.83, p < 0.0005) in SSc patients were assessed at multivariate analysis. In addition, the RV Em velocity was an independent predictor of the anti-Scl-70 antibody pattern (odds ratio 0.68, 95% confidence interval 0.45-0.83, p < 0.01). Of note, a RV Em peak velocity < 0.11 m/s well selected SSc patients with pulmonary artery pressure > 35 mmHg, pulmonary fibrosis, a high mRSS, and an anti-Scl-70 antibody pattern. CONCLUSIONS: The relationships of RV myocardial diastolic dysfunction with both skin and pulmonary involvement as well as with the serological antibody pattern emphasizes the ability of DMI to identify patients with a more diffuse and severe form of SSc. This issue may be critical for the early identification of those SSc patients who are at higher risk of cardiac impairment, ideally when they are still asymptomatic before developing severe vasculopathy.

Case-Control Studies↗