Unmet Needs in Systemic Sclerosis Understanding and Treatment: the Knowledge Gaps from a Scientist's, Clinician's, and Patient's Perspective (original) (raw)
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Systemic Sclerosis: From Pathophysiology to Novel Therapeutic Approaches
Biomedicines, 2022
Systemic sclerosis (SSc) is a systemic, immune-mediated chronic disorder characterized by small vessel alterations and progressive fibrosis of the skin and internal organs. The combination of a predisposing genetic background and triggering factors that causes a persistent activation of immune system at microvascular and tissue level is thought to be the pathogenetic driver of SSc. Endothelial alterations with subsequent myofibroblast activation, excessive extracellular matrix (ECM) deposition, and unrestrained tissue fibrosis are the pathogenetic steps responsible for the clinical manifestations of this disease, which can be highly heterogeneous according to the different entity of each pathogenic step in individual subjects. Although substantial progress has been made in the management of SSc in recent years, disease-modifying therapies are still lacking. Several molecular pathways involved in SSc pathogenesis are currently under evaluation as possible therapeutic targets in clini...
Fibrosis in systemic sclerosis: common and unique pathobiology
Fibrogenesis & Tissue Repair, 2012
Fibrosis in systemic sclerosis (SSc), a complex polygenic disease associated with autoimmunity and proliferative/ obliterative vasculopathy, shares pathobiologic features in common with other fibrosing illnesses, but also has distinguishing characteristics. Fibroblast activation induced by transforming growth factor-β (TGF-β), Wnts and innate immune receptors, along with oxidative stress and reactive oxygen species (ROS) are implicated in pathogenesis. On the other hand, the roles of endothelial-mesenchymal differentiation and bone marrow-derived fibrocytes remain to be established. Fibrotic responses are modulated by transcriptional activators and cofactors, epigenetic factors, and microRNAs that can amplify or inhibit ligand-induced signaling. The nuclear orphan receptor PPAR-γ appears to be important in governing the duration and intensity of fibroblast activation and mesenchymal progenitor cell differentiation, and defects in PPAR-γ expression or function in SSc may underlie the uncontrolled progression of fibrosis. Identifying the perturbations in signaling pathways and cellular differentiation programs responsible for tissue damage and fibrosis in SSc allows their selective targeting using novel compounds, or by innovative uses of already-approved drugs (drug repurposing).
Systemic sclerosis: current views of its pathogenesis
Autoimmunity Reviews, 2003
Systemic sclerosis (SSc) is an autoimmune disorder of unknown etiology characterized by severe and often progressive cutaneous and visceral fibrosis, pronounced alterations in the microvasculature, and numerous cellular and humoral immune abnormalities. Clinically, SSc is very heterogeneous, encompassing a spectrum ranging from mild limited forms of skin sclerosis with minimal internal organ involvement to severe skin and multiple internal organ fibrosis. Mortality and morbidity in SSc are very high and are directly related to the extent of the fibrotic and microvascular alterations. A better understanding of the pathogenesis of this incurable disorder will help to better target and design effective therapy in the future. ᮊ
State-of-the-art evidence in the treatment of systemic sclerosis
Nature Reviews Rheumatology
Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with multi-organ involvement, fibrosis and vasculopathy. Treatment in SSc, including early diffuse cutaneous SSc (dcSSc) and the use of organspecific therapies, has improved, as evident from randomized clinical trials. Treatments for early dcSSc include immunosuppressive agents such as mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab and tocilizumab. Patients with rapidly progressive early dcSSc might be eligible for autologous haematopoietic stem cell transplantation, which can improve survival. Morbidity from interstitial lung disease and pulmonary arterial hypertension is improving with the use of proven therapies. Mycophenolate mofetil has surpassed cyclophosphamide as the initial treatment for SSc-interstitial lung disease. Nintedanib and possibly perfinidone can be considered in SSc pulmonary fibrosis. Pulmonary arterial hypertension is frequently treated with initial combination therapy (for example, with phosphodiesterase 5 inhibitors and endothelin receptor antagonists) and, if necessary, the addition of a prostacyclin analogue. Raynaud phenomenon and digital ulcers are treated with dihydropyridine calcium channel blockers (especially nifedipine), then phosphodiesterase 5 inhibitors or intravenous iloprost. Bosentan can reduce the development of new digital ulcers. Trial data for other manifestations are mostly lacking. Research is needed to develop Nature Reviews Rheumatology Review article as pulmonary arterial hypertension (PAH), inflammatory arthritis, calcinosis, myopathy and/or myositis, cardiomyopathy, sicca symptoms and scleroderma renal crisis (SRC). Owing to the relatively high frequency of certain disease complications and the fact that early intervention can change the natural history of these complications, screening for ILD and PAH is recommended (Table 1). In patients with early dcSSc, blood pressure should be monitored, especially if the patient has anti-RNA polymerase III antibodies (anti-RNAPIII), in order to detect and treat SRC early. Selected screening can also be performed when the index of suspicion of certain manifestations, such as cardiac involvement (beyond echocardiography, which is done for PAH screening, such as for arrhythmias), and paraneoplastic SSc, is high where cancer screening is performed. Several SSc clinical trials and consensus statements guide treatments, and the order of their use, for various organ-based manifestations of SSc. Of note, randomized controlled trials (RCTs) of treatments that modify the overall disease (that is, improve the natural history and pathophysiology) and skin fibrosis generally consider only patients in the dcSSc subset and often only within 2-5 years from the onset of the first non-Raynaud phenomenon features, whereas RCTs of treatments for organ-based manifestations, such as ILD, PAH, Raynaud phenomenon and digital ulcers, include patients in either subset provided that they meet the entry criteria for the trials. This article reviews and summarizes the current management of SSc, including screening for and treatment of organ-based manifestations such as skin, lung (ILD and PAH) and Raynaud phenomenon and digital ulcers, as well as consideration of overall disease modification with autologous haematopoietic stem cell transplantation (AHSCT). Although patients with SSc can also be affected by other symptoms, including gastrointestinal manifestations, SRC, arthritis, myopathy and cardiac involvement, these have not been included in this Review because data from RCTs are mostly lacking; we direct the reader to treatment algorithms devised by SSc experts that address these symptoms 15. In addition, several treatments can improve disease pathophysiology and thus be considered to modify the overall disease, but in this article treatments are discussed according to the outcome measures used in studies; for example, mycophenolate mofetil (MMF) and cyclophosphamide might improve ILD and skin manifestations, whereas for AHSCT data are available on improvements in survival as well as skin, function and ILD. There may be a survival advantage when treating patients with early dcSSc with immunosuppressives, especially those not eligible for AHSCT, but proof within RCTs is lacking for immunosuppressive therapies. Management of skin manifestations Skin fibrosis is one of the dominant clinical features of SSc. The designations dcSSc and lcSSc are used as surrogates of disease severity and prognosis, but both subsets are associated with high functional and psychosocial impact. The extent of skin fibrosis in SSc is most commonly assessed using the modified Rodnan skin score (mRSS), which measures skin thickness on a scale of 0 to 3 at 17 anatomical sites (score range 0-51). The minimal clinically important difference in mRSS has been estimated to range between 3.5 and 5.3 points 16. In dcSSc, mRSS generally increases over the first 4 years of the disease and regresses somewhat over time thereafter, although many patients do not follow this pattern as they may worsen later or not improve after 4 years of disease. It is difficult to predict which patients with early dcSSc will improve or worsen during a clinical trial with respect to skin involvement, but a large response to placebo (and many active therapies) is unlikely. Some prediction models Key points • Treatment of systemic sclerosis (SSc) is organ-based or aimed at disease modification. • Autologous haematopoietic stem cell transplantation can improve survival in patients with early diffuse cutaneous SSc who are at high risk of mortality, such as those with very high skin scores (as measured by the modified Rodnan skin score) or moderate skin involvement and worsening interstitial lung disease (ILD). • Immunosuppressives and some biologic agents can soften skin and change the natural history of early diffuse cutaneous SSc. • Appropriate treatment for patients with early limited cutaneous SSc is unknown, and further research is needed. • ILD is usually treated by the use of mycophenolate mofetil as the initial therapy and then other immunosuppressives or biologic agents, but if ILD is fibrotic and progressing, anti-fibrotic therapy can be added, such as nintedanib (and possibly pirfenidone). • Raynaud phenomenon in SSc is treated with calcium channel blockers and then phosphodiesterase 5 inhibitors or intravenous iloprost. 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Clinical Reviews in Allergy & Immunology, 2022
Systemic sclerosis (SSc) is a rare systemic autoimmune disease, characterized by the presence of three main actors: vasculopathy, immune activation, and fibrosis. This pathologic process is then translated in a clinical picture with great variability among different patients in terms of type of organ involvement, disease severity and prognosis. This heterogeneity is a main feature of SSc, which, in addition to the presence of early phases of the disease characterized by mild symptoms, can explain the high difficulty in establishing classification criteria, and in defining patients’ subsets and disease outcomes. The definition of disease outcomes is particularly relevant in the setting of clinical trials, where the aim is to provide reliable endpoints, able to measure the magnitude of the efficacy of a certain drug or intervention. For this reason, in the last years, increasing efforts have been done to design measures of disease activity, damage, severity, and response to treatment,...
Rheumatology Forum, 2023
Systemic sclerosis (SSc, scleroderma) is a chronic systemic connective tissue disease with a complex pathogenesis that is still not fully understood, in the course of which attention is increasingly drawn to the dynamic, sequential pathogenetic mechanisms according to disease stage. An increasing understanding of the diversity of mechanisms underlying this disease, as well as the prevalence of certain pathogenetic elements that depend i.a. on disease stage, will enable more effective therapeutic interventions in the future. Systemic sclerosis can thus be seen as a complex process, where the main players are immune cells, endothelial cells and fibroblasts, and the focal point is probably impaired function and subsequent damage to endothelial cells. Systemic sclerosis is also the final stage of a certain continuum of events, starting with a state of susceptibility to the development of the disease (dependent on genetic conditions and environmental influences), followed by disruption of homeostasis and initiation of pathological processes (e.g. as a result of viral infections), progression of pathological responses (inflammation, endothelial damage, fibrosis) and consequently organ damage. According to most authors, the key event and focal point of the cascade of phenomena is endothelial cell damage, and the mechanisms that lead to this damage are related to the activation of the immune system. There is growing acceptance of the thesis of an autoimmune origin of the disease involving mechanisms of innate and acquired immunity, both cellular and humoral.
Systemic sclerosis: assessment and treatment : tight control in a tight disease
Bulletin of The Polish Academy of Sciences Mathematics, 2008
Systemic sclerosis(SSc) is a systemic auto immune disease, resulting in a decreased life expectancy in all, but especially in patients with diffuse cutaneous SSc. The major causes of death are pulmonary fibrosis and pulmonary hypertension. In this thesis the epidemiology of SSc and its pulmonary complications are described. Also, it offers a protocol for the diagnostic and therapeutic approach for