Littérature scientifique sur le sujet « SSc: progressive systemic sclerosi »

In systemic sclerosis (SSc), interstitial lung disease (ILD) is common (>80%) and worsens the prognosis of the disease, but severe progressive damage develops only in 8–10% of cases. Interstitial changes in the lungs occur early (within the first 3–5 years of the disease). The histological manifestations are similar to those of idiopathic ILD.The main tool for screening and diagnosing of ILD associated with SSc is high-resolution computed tomography of the lungs, resulting data influence the choice of therapy. In most patients a relatively intact and stable forced vital capacity of the lungs is recorded for a long time, but the diffusion capacity of the lungs decreases early and steadily. Pulmonary functional tests have prognostic value.The choice of the optimal therapy for SSc with lung lesions is based on general disease activity (the severity of inflammation and fibrosis) and the its severity, rate of progression of the disease in general and the leading pathology – interstitial pneumonia (IP) – in particular. In patients with SSc and severe or progressive IP, treatment with mycophenolate mofetil (MMF), cyclophosphamide, nintedanib, or nintedanib in combination with MMF if appropriate, should be considered. If this therapy is ineffective, rituximab may be used.

Systemic sclerosis (SSc) is a systemic connective tissue disorder characterized by progressive skin and visceral organ fibrosis, vasculopathy, and immune dysregulation. Interstitial lung disease (ILD) is a common manifestation and major contributor to morbidity and mortality. Immunosuppression is usually indicated for extensive or progressive SSc-ILD. Recently, antifibrotic and biological therapies have been shown to be efficacious in treating SSc-ILD in various studies. In this article, we will descriptively review the latest evidence on the treatment of SSc-ILD.

Systemic sclerosis (SSc) patients are often affected by interstitial lung disease (ILD) and, although there have been recent treatment advances, it remains the leading cause of death among SSc, with a 10-year mortality up to 40%. African Americans and subjects with diffuse cutaneous SSc or anti-topoisomerase 1 antibodies are most commonly affected. Currently, early ILD diagnosis can be made, and it is pivotal to improve the prognosis. The diagnostic mainstay test for SSc-ILD is high-resolution computed tomography for the morphology and pulmonary function tests for the functional aspects. Treatment planning and intensity are guided by the disease severity and risk of progression. Traditionally, therapy has depended on combinations of immunosuppressants, particularly cyclophosphamide and mycophenolate mofetil, which can be supplemented by targeted biological and antifibrotic therapies. Benefits have been observed in trials on hematopoietic autologous stem cell transplantation for patients with progressive SSc, whilst lung transplantation is reserved for refractory SSc-ILD cases. Herein, recent advances in SSc-ILD treatment will be explored.

Objective.Systemic sclerosis (SSc) is a connective tissue disorder characterized by microvascular and fibrotic changes in the skin and internal organs. The role of blood vessel dysfunction in the pathogenesis of SSc has been extensively investigated, but few studies have addressed the involvement of the lymphatic vascular system. Our aim was to evaluate dermal lymphatic vessels in patients with SSc according to different phases of skin involvement.Methods.Skin biopsies were obtained from the forearm of 25 SSc patients (10 early/15 late-stage disease) and 13 healthy controls. Skin sections were immunostained for podoplanin (D2-40), which is selectively expressed in lymphatic endothelial cells, and examined by confocal laser scanning microscopy. Lymphatic vessels were counted in the papillary and reticular dermis. Data were analyzed using Student’s t test.Results.The number of lymphatic vessels was significantly reduced in the papillary and reticular dermis of SSc patients compared with controls. In early SSc, lymphatic vessel counts were not different from controls in the papillary dermis, and showed a trend toward a reduction in the reticular dermis. In late SSc, a significant reduction in lymphatic vessels compared with controls was found in both the papillary and reticular dermis. The number of lymphatic vessels in the papillary dermis of late SSc was significantly lower than in early SSc.Conclusion.In SSc, lymphatic microangiopathy is linked to the progression of skin involvement. The progressive disappearance of lymphatic vessels may have a critical pathogenetic role in the progression of SSc from an early edematous phase to overt fibrosis.

Although systemic sclerosis (SSc) is currently incurable, there have been recent advances in treatment. This review article begins by providing a brief background to SSc in terms of disease subtyping and autoantibodies, because both predict disease trajectory and help clinicians to select appropriate monitoring and treatment protocols. Broad principles of management are then described: ‘disease-modifying’ therapies and therapies directed at reducing disease burden and/or progression of SSc-related digital vascular disease and of internal organ involvement. Next, advances in the management of digital vasculopathy, pulmonary arterial hypertension (PAH), interstitial lung disease (ILD) and early diffuse cutaneous SSc are discussed in turn, for example: (a) increased use of phosphodiesterase inhibitors and endothelin receptor antagonists for digital vasculopathy; (b) early recognition and treatment of PAH, including with combination therapies; (c) increased use of mycophenolate mofetil and of nintedanib in ILD; and (d) immunosuppression now as standard practice in early diffuse cutaneous SSc, and autologous haematopoietic stem cell transplantation for highly selected patients with progressive diffuse disease. Finally, future challenges are discussed, including ensuring that all patients with SSc are monitored and treated according to best practice guidelines, and whenever possible giving patients the opportunity to participate in clinical trials.

Systemic sclerosis (SSc) is a rare chronic autoimmune disease associated with significant morbidity and mortality. Two main subsets of SSc are recognized: (i) diffuse cutaneous SSc with rapidly progressive fibrosis of the skin, lungs, and other internal organs; and (ii) limited cutaneous SSc, which is dominated by vascular manifestations, with skin and organ fibrosis generally limited and slowly progressing. In spite of intense investigation, both etiology and pathogenesis of SSc are still unknown. Genetic and environmental factors, as well as abnormalities of immune functions, are strongly suggested for etiology, while microvascular abnormalities, immune system activation, and oxidative stress are suggested for the pathogenesis. Recently, it has been found that a multitude of mediators and cytokines are implicated in the fibrotic processes observed in SSc. Among these, a central role could be exerted by “alarmins”, endogenous and constitutively expressed proteins/peptides that function as an intercellular signal defense. This review describes, in a detailed manner, the role of alarmins in the pathogenesis of scleroderma.

Systemic sclerosis (SSc) is a progressive vasculopathic, fibrosing autoimmune condition, portending significant mortality; wherein interstitial lung disease (ILD) is the leading cause of death. Although lacking a definitive cure, therapeutics for (SSc-ILD) that stave progression exist with further promising primary and adjuvant compounds in development, as well as interventions to reduce symptom burden and increase quality of life. To date, there has been a significant but varied history related to systemic sclerosis–related interstitial lung disease trial design and endpoint designation. This is especially true of endpoints measuring patient-reported perceptions of efficacy and tolerability. This article describes the underpinnings and complexity of the science, methodology, and current state of patient-reported outcome measures used in (SSc-ILD) systemic sclerosis–related interstitial lung disease in clinical practice and trials.

AbstractInterstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). SSc-ILD adversely impacts quality of life and is currently the leading cause of death in this multisystem disease. Identifying clinically significant SSc-ILD is critically important. Accurate staging and prognostication remain difficult; however, significant advances have been made in the last decade. Evidence supports the need to treat patients with extensive and/or progressive SSc-ILD, while only a subset of patients with limited ILD may require treatment. Research is urgently required to allow improved prediction of patients at risk of ILD progression at an early point in the disease, and ideally prior to its onset, to allow prevention. The last decade has seen the publication of landmark clinical trials for SSc-ILD. More effective strategies with less toxicity are under investigation. For those with refractory or very advanced disease, studies into disease-specific palliative approaches are in their infancy. Lung transplantation as an option for SSc-ILD remains patient- and center-specific, with data to suggest equivalent outcomes to other fibrotic lung diseases, in carefully selected cases. This review aims to provide a comprehensive overview of all key aspects of SSc-ILD.

Objective.Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc) and causes death. Once lung fibrosis occurs, disease course may become stable or decline. Little is known about risks for progression. We studied SSc–gastroesophageal (GE) involvement in relation to worsening forced vital capacity (FVC) on pulmonary function tests (PFT) to investigate whether it was related to progression. Our objective was to determine whether GE reflux and dysphagia are associated with progressive moderate/severe ILD as measured by PFT over 3 years.Methods.The Canadian Scleroderma Research Group is a multicenter SSc database that collects data annually. Using indicators of GE involvement and annual PFT, comparisons were made between no/mild ILD, stable moderate/severe ILD, and progressive moderate/severe ILD groups based on changes of FVC. Multivariate analyses determined associations between GE factors and ILD development and progression.Results.There were 1043 patients with SSc (mean age 55.7 yrs, mean disease duration 10.8 yrs); one-quarter had pulmonary fibrosis on chest radiograph that was related to FVC percentage predicted (Spearman’s rho −0.39; p < 0.01). Physician indicators such as esophageal dysmotility (p = 0.009) and postesophageal dilatation (p = 0.041), and patient indicators such as difficulty swallowing (p = 0.016) and waking up choking (p = 0.026) were associated with low FVC. In comparing progressive and stable moderate/severe FVC (< 70% predicted), early satiety (p = 0.018) and a combination term of postdilatation and choking (p = 0.042) increased risk of progression of ILD. Topoisomerase I was not associated with progression over followup.Conclusion.Symptoms of esophageal dysmotility were associated with worsening FVC in SSc, especially if both need for esophageal dilatation and choking were present.

Interstitial lung disease (ILD) is the leading cause of mortality in systemic sclerosis (SSc). Progressive pulmonary fibrosis (PPF) is defined as progression in 2 domains including clinical, radiological or lung-function parameters. Our aim was to assess predictors of functional decline in SSc-ILD patients and compare disease behavior to that in idiopathic pulmonary fibrosis (IPF) patients. Patients with normal forced vital capacity (FVC > 80% predicted; SSc-ILD: n = 31; IPF: n = 53) were followed for at least 1 year. Predictors of functional decline including clinical symptoms, comorbidities, lung-function values, high-resolution CT pattern, and treatment data were analyzed. SSc-ILD patents were significantly younger (59.8 ± 13.1) and more often women (93 %) than IPF patients. The median yearly FVC decline was similar in both groups (SSc-ILD = −67.5 and IPF = −65.3 mL/year). A total of 11 SSc-ILD patients met the PPF criteria for functional deterioration, presenting an FVC decline of −153.9 mL/year. Cough and pulmonary hypertension were significant prognostic factors for SSc-ILD functional progression. SSc-ILD patients with normal initial spirometry presenting with cough and PH are at higher risk for showing progressive functional decline.

L'endotelina-1 (ET-1) gioca un ruolo fondamentale nella vasocostrizione, nella fibrosi e nell’infiammazione, tre aspetti fondamentali nella patogenesi della sclerosi sistemica (SSc) . I recettori dell’ET-1 sono ETA ed ETB. Essi sono espressi sulla maggioranza delle cellule coinvolte nella patogenesi della SSc, come le cellule endoteliali, le cellule muscolari lisce e i fibroblasti. Poco si conosce riguardo l'espressione dei recettori dell’ET-1 sui leucociti. A eccezione dei macrofagi e dei monociti, non ci sono informazioni sull'espressione di ETA e ETB su linfociti, neutrofili e le altre cellule coinvolte nella risposta immunitaria innata e acquisita. Gli antagonisti dei recettori dell’ET-1 sono utilizzati nel trattamento di pazienti con SSc e ulcere digitali e/o con ipertensione arteriosa polmonare. Essi hanno effetti benefici sulla vasocostrizione e la fibrosi, ma poco noto è il loro ruolo nell’infiammazione. Abbiamo pertanto deciso di studiare il ruolo dell’ET-1 nell’infiammazione in pazienti affetti da SSc. Poiché le cellule T e B, i monociti e i neutrofili sono tra le cellule più importanti nelle risposta infiammatoria che si osserva nella SSc , abbiamo studiato l’espressione di ETA ed ETB su queste cellule con citometria a flusso, valutando inoltre la presenza dell’mRNA codificante per ETA ed ETB sulle cellule T CD4+ e sui neutrofili mediante RT-PCR . Abbiamo studiato la diversa espressione dei recettori dell’ET-1 sui linfociti T e B e sui monociti di pazienti e controlli, nonché la correlazione tra la loro espressione e alcune caratteristiche della malattia. Abbiamo inoltre valutato la modulazione dei recettori dell’ET-1 sulle cellule T attivate. Al fine di valutare gli effetti pro-infiammatori dell’ET-1 e il ruolo antinfiammatorio del Bosentan, antagonista dei recettori dell’ET-1, abbiamo osservato come ET-1 influenzi la produzione di IFN-γ e IL-4 nelle cellule CD4+ T, in presenza o assenza del blocco recettoriale. Abbiamo studiato anche l'espressione degli mRNA codificanti per IFN-γ, IL-4, IL-6, IL-10 e IL-17 sulle cellule CD4+ T mediante Real Time PCR in tempi diversi per meglio valutare in queste cellule il timing di risposta allo stimolo. Abbiamo osservato che le cellule T e i monociti esprimono sia ETA sia ETB. Abbiamo convalidato nostri dati su una coorte di pazienti e controlli. Abbiamo confermato che non solo le cellule T e i monociti, ma anche i linfociti B e i neutrofili esprimono ETA ed ETB sulla loro superficie. Abbiamo visto che l'espressione di ETA è maggiore di quella di ETB sia per quanto riguarda i linfociti T che i monociti di pazienti e controlli, mentre per le cellule B non c'è alcuna differenza di espressione. Anche i neutrofili esprimono sia ETA sia ETB. I neutrofili partecipano alle primissime fasi della risposta infiammatoria nella SSC e contribuiscono al danno endoteliale, alla produzione di specie reattive dell'ossigeno, all’attivazione dei fibroblasti e al reclutamento dei linfociti B e T. Inoltre i neutrofili, sotto stimolo dell’ET-1 sono incoraggiati a produrre citochine proinfiammatorie, come IL-8. IL-17 e TNF. L’ET-1, attraverso l'ETA e l’ETB, può contribuire dunque a innescare l'attivazione dei neutrofili, che contribuiscono al danno vascolare . Considerando che l'espressione ETB è inferiore nei pazienti affetti dalla forma limitata si SSc piuttosto in quelli con forma diffusa di malattia, l’ETA sembrava essere importante per gli effetti profibrotici innescati dell’ET-1. Poiché la minor espressione di ETB sui monociti correla con la presenza di ipertensione arteriosa polmonare e una diminuita espressione di ETA sulle cellule T correla con la presenza di interstiziopatia polmonare, possiamo ipotizzare che un diverso pattern di espressione recettoriale è associato a una differente risposta delle cellule T o dei monociti nell'induzione dell’ipertensione arteriosa polmonare o dell’interstiziopatia polmonare. Pertanto la differente espressione di ETA o ETB può portare allo sviluppo di complicanze cliniche differenti. Considerando che l'espressione ETB è aumentata sulle cellule T attivate, ETB probabilmente giocato un ruolo importante nel processo infiammatorio. Infine, l’ET-1 ha un’azione modulante sulla risposta immune e il pattern citochinico che i linfociti producono sotto stimolo con ET-1 è diverso a seconda del recettore dell’ET-1 che è bloccato. Questi risultati confermano l'ipotesi che ET-1 possa avere un ruolo non solo sulla vasocostrizione e fibrosi ma anche sull’infiammazione .
Endothelin-1 (ET-1) plays a pivotal role in vasoconstriction, fibrosis and inflammation, the three major aspects in the pathogenesis of Systemic Sclerosis (SSc). ET-1 receptors are ETA and ETB. The receptors are expressed on the majority of cells involved in SSc, such as endothelial cells, smooth muscle cells and fibroblasts. Little is known about the expression of ET-1 receptors on leukocytes, except for macrophages and monocytes; there is no information about the expression of ETA and ETB on lymphocytes, neutrophils and other cells involved in the innate and acquired immune response. Endothelin receptors antagonists are used in the treatment of scleroderma patients with recurrent ischemic digital ulcers and/or pulmonary arterial hypertension. They have beneficial effects on vasoconstriction and fibrosis, but less is known about their anti-inflammatory role. We aimed at studying the link between ET-1 and inflammation in SSc. Since T and B cells, monocytes and neutrophils are among the most important cells in inflammatory responses in SSc, we studied ETA and ETB expression on these cells with flow cytometry, and also ETA- and ETB-coding mRNA expression in T CD4+ cells and neutrophils by RT-PCR. We have studied the different expression of receptors on T and B cell and monocytes between patients and controls, the correlations of the expression with the cutaneous form of disease, with Bosentan therapy, and ischemic digital ulcers, pulmonary arterial hypertension and interstitial lung disease. We also studied the receptors modulation on activated T cells by flow cytometry. In order to evaluate the pro-inflammatory effects of ET-1 and the anti-inflammatory role of Bosentan, we studied how ET-1 influences IFN-γ and IL-4 production by T CD4+ cells, with or without receptors blockage. We also studied the expression of IFN-γ-, IL-4- IL-6-, IL-10- and IL-17-coding mRNA in T CD4+ cells by Real Time PCR at different times in order to understand the timing of T CD4+ cells response to stimulation with ET-1. We previously described that T cells and monocytes express both ETA and ETB receptors. We have validated our data in a larger cohort of patients and controls. We confirmed that not only T cells and monocytes but also B lymphocytes and neutrophils express ETA and ETB on their surface. Moreover, the expression of ETA was greater than ETB both in patients and controls in T cells and monocytes, while for B cells there was not difference between ETA and ETB expression. Interesting, neutrophils express both ETA and ETB. Neutrophils participate in the early stages of SSc and contribute to endothelial damages, by production of reactive oxygen species, fibroblasts activation and recruitment T and B cells. ET-1, through ETA and ETB, can contribute to trigger neutrophils activation, that lead to vascular damage. Considering that ETB expression was lower in dSSc- rather than lSSc-patients, ETA signal seemed to be important in the cutaneous profibrotic effects of ET-1. Since a lower ETB expression on monocytes correlated with PAH and a lower ETA expression on T cells correlates with ILD, we can hypothesize that a different pattern of receptors expression is associated with a different response of T cells or monocytes in the preferential induction of PAH or ILD. Therefore ETA or ETB signalling may lead to different clinical features. Considering that ETB expression is increased on activated T cells, ETB signal probably played a major role in inflammation. We also show that activation of ETA and ETB receptors plays an immunomodulatory role, since the production of cytokines changes over time in relation to the stimulation by ET-1 in the presence or absence of the selective blockade of one or both receptors. Furthermore these results support the hypothesis that ET-1 system has a role not only on vasoconstriction and fibrosis but also on inflammation.

Development of new therapies for rheumatic diseases requires a series of randomized controlled trials (RCTs) progressing from phase 1, ’first-in-human’ to generate initial safety, pharmacokinetic (PK) and pharmacodynamic (PD) data; to phase 2, proof of concept for efficacy with safety and PK/PD data; and phase 3, designed to demonstrate definitive efficacy and safety to support regulatory approval. Important aspects of RCT designs include selection of patient population, sample size estimations, treatment allocation, rescue, blinding, and statistical analyses of prespecified endpoints to preserve trial integrity. Over the past 20 years, significant progress has been made in the design of RCTs in rheumatoid arthritis (RA). Similarly, development and validation of composite outcome measures in psoriatic arthritis (PsA), axial spondyloarthritis (axSpA), gout, and osteoarthritis (OA) have furthered trial design and treatment approvals. RCTs in systemic lupus erythematosus (SLE), systemic sclerosis (SSc), vasculitis and other multisystem, heterogeneous diseases pose more challenges. Trial design will continue to evolve as promising therapies are introduced into the clinic and more therapies are approved for each indication.

Services are fundamental to the provisioning of business activities. Enterprise Architecture (EA) is maintaining the relationship between strategy, business, and technology. A clear definition and agreed understanding of services is critical to realising information technology artefacts. Services, however, tend to be more complex than the mere act of interaction or working processes, and should be seen out of the cultural, organisational, and managerial factors surrounding them. This chapter uses a service model consisting of execution, context, and intention with an underlying claim that all three elements must be present to make services meaningful. EA must be seen in the light of this. This chapter addresses the issues related to combined transformation of organisations, service systems, and consequently, EA. The transformation changes loosely coupled, distributed organisations into Shared Service Centres (SSCs). A case study of a far-reaching SSC transformation from Denmark is presented where eGovernment services are moved from local government level into a national SSC structure referred to as Udbetaling Danmark (lit. PayDK). Major findings include: (1) When eGovernment reaches a certain level of maturity, it dissolves its original reason and no longer follows a progressive maturity model. Instead, it leads to a more radical reorganisation emphasising operational efficiency. (2) Development and management of complexities and uncertainties in governmental administrative services are closely associated with the development of eGovernment through ongoing refinement of EA and service frameworks. (3) The policy-driven reshaping of governmental services, originally themselves being SSCs, can lead to iterative SSC formations, each seeking to establish a professional logic of its own. (4) The systemic perception connected to EA and service science provides valuable insight into service transformation before, during, and after the transformation. This chapter aims at a deeper understanding and discussion of services in developing eGovernment policies and architectures, but findings are readily applicable in general business environments.

Services are fundamental to the provisioning of business activities. Enterprise Architecture (EA) is maintaining the relationship between strategy, business, and technology. A clear definition and agreed understanding of services is critical to realising information technology artefacts. Services, however, tend to be more complex than the mere act of interaction or working processes, and should be seen out of the cultural, organisational, and managerial factors surrounding them. This chapter uses a service model consisting of execution, context, and intention with an underlying claim that all three elements must be present to make services meaningful. EA must be seen in the light of this. This chapter addresses the issues related to combined transformation of organisations, service systems, and consequently, EA. The transformation changes loosely coupled, distributed organisations into Shared Service Centres (SSCs). A case study of a far-reaching SSC transformation from Denmark is presented where eGovernment services are moved from local government level into a national SSC structure referred to as Udbetaling Danmark (lit. PayDK). Major findings include: (1) When eGovernment reaches a certain level of maturity, it dissolves its original reason and no longer follows a progressive maturity model. Instead, it leads to a more radical reorganisation emphasising operational efficiency. (2) Development and management of complexities and uncertainties in governmental administrative services are closely associated with the development of eGovernment through ongoing refinement of EA and service frameworks. (3) The policy-driven reshaping of governmental services, originally themselves being SSCs, can lead to iterative SSC formations, each seeking to establish a professional logic of its own. (4) The systemic perception connected to EA and service science provides valuable insight into service transformation before, during, and after the transformation. This chapter aims at a deeper understanding and discussion of services in developing eGovernment policies and architectures, but findings are readily applicable in general business environments.