Clinical implications of soluble intercellular adhesion molecule-1 levels in systemic sclerosis (original) (raw)
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Skin involvement in systemic sclerosis
Rheumatology, 2008
Skin thickening is a characteristic feature of SSc. More extensive skin involvement coincides with more severe internal organ manifestation(s), poor prognosis and increased disability, at least in the early phase of the diffuse cutaneous scleroderma subset. The fully validated, feasible method ('gold standard') for measuring the dermal skin thickness is the modified Rodnan skin score (mRSS). The responsiveness of mRSS was somewhat modest in clinical trials, and a careful teaching process is necessary. Parallel method(s) for measuring skin thickness need to be used in the future. Ultrasound (US) measurement of the dermis with a 20-30 MHz probe is a valid, reproducible and responsive method in patients with dcSSc. However, US is time-consuming and requires a training process. Of the mechanical instruments available, only the durometer, which measures the hardness of skin, has been validated. The inter-and intraobserver reproducibility and sensitivity to change of durometry were good, and correlated with mRSS and US-measured skin thickness. Several further mechanical instruments exist including the elastometer, twistometer, cutometer and plicometer. They seem to distinguish between involved and non-involved skin, and therefore merit further evaluation. The measurement of late-stage, irreversible skin damage/ atrophy should be resolved in the future through the development and validation of new instruments.
Saturday, 16 JUNE 2018
Background: Macrovascular damages of systemic sclerosis (SSc) were poorly investigated, and the link between macrovasculopathy and microvasculopathy of SSc, cardiovascular disease, and mortality remain unclear. Objectives: To evaluate if macrovascular damage in SSc predicts the occurrence of new digital ulcers (DU), cardiovascular events and mortality, and to further assess the relationship between micro and macrovascular damages in SSc. Methods: All consecutive SSc patients followed in our SSc National Reference Centre, who underwent an arterial doppler ultrasonography (aDUS) of the upper limbs, were included and prospectively followed up until October 2017. Inclusion criteria were: 1) adults; 2) a diagnosis of SSc according to 2013 ACR/EULAR criteria; 3) aDUS performed in our vascular exploration department. Results: Ninety-nine SSc patients were included. Median follow-up duration was 35 (IQR, 21 to 39) months. Macrovascular damages mainly affected ulnar arteries, with ulnar artery occlusion (UAO) in 28 (28.3%) patients (bilateral 60.7%). New DU occurred in 26 (27.1%) patients, new cardiovascular event in 10 (10.4%) patients, and 11 patients died during the study period. Interestingly, UAO was not associated with traditional cardiovascular risk factors (except dyslipidemia) nor with history of cardiovascular diseases, and was not predictive of new cardiovascular events. Conversely, UAO was associated with makers of microvascular damages, such as late nailfold capillaroscopy pattern (33.3% vs 6.8%; OR=6.88, 95% CI=1.76 to 26.82; p=0.03) and was predictive of new ischaemic DU (44.5% vs 24.8%; HR=2.23, 95%CI=1.02 to 4.86; p=0.037), pleading for a SSc specific vasculopathy. Conclusions: Our study confirms that macrovascular damages are frequent in SSc patients and mainly affect ulnar arteries. Interestingly, UAO was associated with severe microvasculopathy, but not with markers of cardiovascular diseases.
Assessment of skin involvement in systemic sclerosis
Rheumatology, 2017
Skin involvement in SSc is an important marker of disease activity, severity and prognosis, making the assessment of skin a key issue in SSc clinical research. We reviewed the published data assessing skin involvement in clinical trials and summarized the major conclusions important in SSc clinical research. A systematic literature review identified randomized controlled trials using skin outcomes in SSc. Analysis examined the validity of the different skin measures based on literature findings. Twenty-two randomized controlled trials were found. The average study duration was 10.2 (S.D. 4.5) months, mean (S.D.) sample size 32.4 (32.6) and 26.7 (27.8) in intervention and control arms, respectively. The 17-site modified Rodnan skin score is a fully validated primary outcome measure in diffuse cutaneous SSc. Skin histology seems to be an appropriate method for evaluation of skin thickness. These findings have important implications for clinical trial design targeting skin involvement in SSc.
The Journal of rheumatology, 2005
Objective. Systemic sclerosis (SSc) is characterized by excessive production of collagen and other components of the extracellular matrix (ECM) by fibroblasts. The ECM receptors, integrins and CD44 (hyaluronan receptor), play a key role in the homeostasis of connective tissue and may also have a role in the pathogenesis of fibrosis. We investigated the expression of integrins and CD44 on skin fibroblasts from patients with limited and diffuse SSc. Methods. We studied 13 patients with SSc, 8 with limited SSc, and 5 with diffuse SSc, and 8 control subjects. Fibroblasts were isolated and cultured from biopsies taken from the lesional skin of the second finger of the left hand. Cell-surface expression of ß1, ß3, α1-α6, αv integrins, and CD44 was evaluated by immunofluorescence and flow cytometry analysis. Results. Fibroblasts from limited SSc showed significantly decreased expression of α2, α3, α4 integrins, while diffuse SSc fibroblasts had significantly reduced expression of α5, αv integrins, and CD44. Diffuse SSc also had significantly increased expression of α6 integrin on fibroblasts. In controls, the expression of α4 and α5 correlated positively, while in limited and diffuse SSc it did not. Conclusion. This is the first study evaluating separately the expression of adhesion molecules on skin fibroblasts from limited and diffuse subsets of SSc. We detected a distinct pattern of expression with decrease of collagen and fibronectin receptors in limited SSc, and downregulation of fibronectin and hyaluronan receptors in diffuse SSc. These results suggest that changes of fibroblasts/ECM interactions and mechanisms underlying the pathogenesis of fibrosis in SSc may differ in the single subset of the disease.
Clinical and Experimental Immunology, 2004
Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive collagen deposition in the skin and internal organs. Several cytokines and chemokines have been implicated in the induction of fibrosis, but a definitive relationship between specific cytokines and organ involvement has not been established yet. Serum samples, PBMC and T cell lines (TCL) obtained from 54 patients affected by SSc and 20 healthy donors (HD) were examined by ELISA for Interferon-g (IFN-g), interleukin (IL)-4, IL-6, IL-10, IL-18, Transforming growth factor (TGF)-b 1, Tumour necrosis factor (TNF)-a , sCD30, Macrophage derived chemokine (MDC), Monocyte chemoattractant protein (MCP)-1, Macrophage inflammatory protein (MIP)-1 a and Regulated on activation normal T-cell expressed and secreted (RANTES). In all the SSc serum samples, we found significantly increased levels of IL6, TNF a and MCP-1 but reduced amounts of g-IFN and MDC. IL6, IL10, IL18, MIP-1 a and TNF a measured in supernatants from PHA-stimulated PBMC and IL6, MCP-1 and RANTES in supernatants from stimulated TCL were also increased in patients. MDC was decreased in all the biological SSc sources studied. TGF-b 1, IL10, and sCD30 were produced at a significantly lower level by SSc TCL. Serum IL6 and sCD30 levels were significantly increased in dc-SSc patients compared to lc-SSc as were levels of MCP-1 produced by PBMC and IL10 from TCL. We observed a strict relationship between pulmonary fibrosis and IL10, MCP-1 (both from TCL) and serum IL6. Kidney involvement was related to serum MCP-1 levels and IL18 production from PBMC. Oesophageal involvement correlated with MDC production from PBMC and IL10 synthesis by TCL. We showed that IL-6, IL-10, MDC and MCP-1 are variably associated with internal organ involvement and allow the discrimination between limited and diffuse forms of the disease.
Arthritis Research & Therapy, 2013
Introduction: Systemic sclerosis (SSc) is an autoimmune disease characterized by chronic inflammation, vascular injury and excessive fibrosis. CD163 is a scavenger receptor which affects inflammatory response and may contribute to connective tissue remodelling. It has recently been demonstrated that CD163 can bind and neutralize the TNF-like weak inducer of apoptosis (TWEAK), a multifunctional cytokine which regulates inflammation, angiogenesis and tissue remodelling. We aimed to investigate the relationships between serum levels of soluble CD163 (sCD163) and soluble TWEAK (sTWEAK) in relation to disease manifestations in SSc patients. Methods: This study included 89 patients with SSc who had not received immunosuppressive drugs or steroids for at least 6 months and 48 age-and sex-matched healthy controls (HC) from four European centres. Serum concentrations of sTWEAK and sCD163 were measured using commercially available ELISA kits.
Rheumatology, 2019
Objectives. Skin improvement in diffuse cutaneous SSc (dcSSc), measured with modified Rodnan skin score (mRSS), is frequently used as a primary outcome in clinical trials, but it is uncertain whether mRSS changes reflect changes in other organ systems. This aim of this study was to explore if skin changes in early dcSSc over 1 and 2 years are associated with changes in severity of other organ involvement. Methods. Canadian Scleroderma Research Group database patients with dcSSc, disease duration of 5 years, no evidence of initial end-stage organ damage and/or significant comorbidity who had 1 year (n ¼ 154) and 2 years (n ¼ 128) of follow-up data were included. mRSS changes of 25% and/or !5 points were considered significant. Organ involvement was assessed by Medsger Disease Severity Score and Canadian Scleroderma Research Group definitions using bivariate, chi-square, ANOVA, adjusted regression and longitudinal mixed effect model analyses. Results. Improvement in mRSS was found in 41% of patients at 1 year and in 50% at 2 years. Improved patients showed less forced vital capacity decline (P ¼ 0.012) and less frequent new cardiac involvement (P ¼ 0.02) over 1 year, as well as better lung (by both Disease Severity Score, P ¼ 0.006, and Dforced vital capacity%, P ¼ 0.026), peripheral vascular (P ¼ 0.006) and joint/tendon (P ¼ 0.002) involvement over 2 years. mRSS worsening was consistently linked to less favourable lung outcomes at both 1-and 2-year follow-up visits, and more severe gastrointestinal disease at 2 years. Conclusion. Changes in lung function in early dcSSc closely parallel skin changes. mRSS improvement reflects better prognosis for visceral disease and may be a reliable outcome measure in clinical trials.
Vascular damage and lack of angiogenesis in systemic sclerosis skin
Clinical Rheumatology, 2003
The aim of this study was to analyse microvascular damage and compensatory angiogenesis in skin from patients with systemic sclerosis (SSc) compared with systemic lupus erythematosus (SLE), Raynaud's phenomenon (RP) and healthy controls. Immunohistochemistry was used for skin biopsies (9 SSc, 10 SLE, 9 RP and 12 healthy controls) using von Willebrand factor and b 3 integrin subunit specific antibodies, TechMate immunostaining robot and biotin-streptavidin protocol. In the early stages of SSc, vWF was found in the perivascular space and interstitial matrix in papillary but not in the reticular dermis, in particular around small oedematous blood vessels infiltrated by mononuclear cells. The extravascular release of vWF in SSc specimens was associated with weak or even a total lack of immunoreactivity within the associated endothelial cells. Late stages of SSc were characterised by loss of the dermal papillae, subepidermal fibrosis, hypovascularity and strong endothelial vWF expression without extravascular leakage. In all SSc patients studied only a few vascular profiles were weakly immunostained for b 3 integrin subunit. This work demonstrates that vWF is not only released into the systemic circulation, but is also leaked to the perivascular space/matrix. This local release and deposition of vWF is probably a sensitive and early marker of microvascular involvement in SSc pathogenesis. Local vWF release may play a role in platelet adhesion, aggregation, thrombogenesis and dermal connective tissue remodelling. In spite of some attempts towards compensatory angiogenesis in SSc, as evidenced by b 3 integrin subunit expression, it was evident that the angiogenic response was not able to prevent the development of hypovascularity during the advanced stages of the disease.