Treatment of systemic sclerosis associated ILD: Lessons from clinical trials.
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ABSTRACT:
SUBMITTER: Roofeh D
PROVIDER: S-EPMC8168368 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundSystemic sclerosis (SSc) is a rare connective tissue disease with a heterogeneous clinical course. Interstitial lung disease (ILD) is a common manifestation of SSc and a leading cause of death.Main bodyAll patients newly diagnosed with SSc should receive a comprehensive clinical evaluation, including assessment of respiratory symptoms, a high-resolution computed tomography (HRCT) scan of the chest, and pulmonary function tests. ILD can develop in any patient with SSc, including those with pulmonary hypertension, but the risk is increased in those with diffuse (rather than limited) cutaneous SSc, those with anti-Scl-70/anti-topoisomerase I antibody, and in the absence of anti-centromere antibody. While it can occur at any time, the risk of developing ILD is greatest early in the course of SSc, so patients should be monitored closely in the first few years after diagnosis. An increased extent of lung fibrosis on HRCT and a low forced vital capacity (FVC) are predictors of early mortality. While not all patients will require treatment, current approaches to the treatment of progressive SSc-ILD focus on immunosuppressant therapies, including cyclophosphamide and mycophenolate mofetil. In patients with severe and/or rapidly progressive disease, both haematopoietic stem cell transplantation (HSCT) and lung transplantation have been successfully used. A number of medications, including the two drugs approved for the treatment of idiopathic pulmonary fibrosis (IPF), are under active investigation as potential new therapies for SSc-ILD.ConclusionsPhysicians managing patients with SSc should maintain a high level of suspicion and regularly monitor for ILD, particularly in the first few years after diagnosis.
| S-EPMC6339436 | biostudies-literature
Project description:Pulmonary involvement including interstitial lung disease (ILD) is the leading cause of mortality in patients with systemic sclerosis (scleroderma; SSc). This article reviews the current evidence based medicine regarding available therapies for SSc-ILD ; discusses the lessons learned from recent SSc-ILD randomized controlled trials (RCTs); and proposes outcome measures and recommendations for design of future RCTs for SSc-ILD.
| S-EPMC2911794 | biostudies-literature
Project description:SSc is a rare CTD that affects multiple organ systems, resulting in substantial morbidity and mortality. Evidence of interstitial lung disease (ILD) is seen in ?80% of patients with SSc. Currently there is no approved disease-modifying treatment for ILD and few effective treatment options are available. CYC is included in treatment guidelines, but it has limited efficacy and is associated with toxicity. MMF is becoming the most commonly used medication in clinical practice in North America and the UK, but its use is not universal. Newer agents targeting the pathogenic mechanisms underlying SSc-ILD, including fibrotic and inflammatory pathways, lymphocytes, cell-cell and cell-extracellular membrane interactions, hold promise for better treatment outcomes, including improved lung function, patient-related outcomes and quality of life. Here we review ongoing trials of established and novel agents that are currently recruiting patients with SSc-ILD.
| S-EPMC6434373 | biostudies-literature
Project description:Systemic sclerosis is an autoimmune connective tissue disease characterized by vasculopathy and fibrosis of the skin and internal organs. The pathogenesis of systemic sclerosis is very complex. Mediators produced by immune cells are involved in the inflammatory processes occurring in the tissues. The currently available therapeutic options are often insufficient to halt disease progress. This article presents an overview of potential therapeutic targets and the pipeline of possible future therapeutic options. It is based on research of clinical trials involving novel, unestablished methods of treatment. Increasing knowledge of the processes and mediators involved in systemic scleroderma has led to the initiation of drug trials with therapeutic targets of CD28-CD80/86, CD19, CCL24, CD20, CD30, tumor necrosis factor (TNF), transforming growth factor β (TGF-β), B-cell activating factor (BAFF), lysophosphatidic acid receptor 1 (LPA1 receptor), soluble guanylate cyclase (sGC), Janus kinases (JAK), interleukin 6 (IL-6), endothelin receptor, and autotaxin. Data from clinical trials on these drugs indicate a significant potential for several new therapeutic options for systemic sclerosis in the upcoming future.
| S-EPMC8911443 | biostudies-literature
Project description:Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is rare, poorly understood, with heterogeneous characteristics resulting in difficult diagnosis. We aimed to systematically review evidence of soluble markers in peripheral blood or bronchoalveolar lavage fluid (BALF) as biomarkers in SSc-ILD.MethodFive databases were screened for observational or interventional, peer-reviewed studies in adults published between January 2000 and September 2021 that assessed levels of biomarkers in peripheral blood or BALF of SSc-ILD patients compared with healthy controls. Qualitative assessment was performed using Critical Appraisal Skills Programme (CASP) checklists. Standardised mean difference (SMD) in biomarkers were combined in random-effects meta-analyses where multiple independent studies reported quantitative data.Results768 published studies were identified; 38 articles were included in the qualitative synthesis. Thirteen studies were included in the meta-analyses representing three biomarkers: KL6, SP-D and IL-8. Greater IL-8 levels were associated with SSc-ILD in both peripheral blood and BALF, overall SMD 0.88 (95% CI 0.61 to 1.15; I2=1%). Greater levels of SP-D and KL-6 were both estimated in SSc-ILD peripheral blood compared with healthy controls, at an SMD of 1.78 (95% CI 1.50 to 2.17; I2=8%) and 1.66 (95% CI 1.17 to 2.14; I2=76%), respectively.ConclusionWe provide robust evidence that KL-6, SP-D and IL-8 have the potential to serve as reliable biomarkers in blood/BALF for supporting the diagnosis of SSc-ILD. However, while several other biomarkers have been proposed, the evidence of their independent value in diagnosis and prognosis is currently lacking and needs further investigation.Prospero registration numberCRD42021282452.
| S-EPMC10359532 | biostudies-literature
Project description:RNA sequencing and differential expression analyses were performed to identify differentially expressed genes in SSc lung pericytes as compared to normal.
2024-05-13 | GSE222552 | GEO
Project description:Skin gene expression signatures, including intrinsic subset, are associated with skin score/MRSS improvement during mycophenolate mofetil (MMF) treatment. Gene expression and intrinsic subset assignment were measured in SSc patients amd controls at baseline, and from biopsies of MMF-treated patients.
2013-04-09 | E-GEOD-45485 | biostudies-arrayexpress
Project description:Progressive multiple sclerosis is characterised clinically by the gradual accrual of disability independent of relapses and can occur with disease onset (primary progressive) or can be preceded by a relapsing disease course (secondary progressive). An effective disease-modifying treatment for progressive multiple sclerosis has not yet been identified, and so far the results of clinical trials have generally been disappointing. Ongoing advances in the knowledge of pathogenesis, in the identification of novel targets for neuroprotection, and in improved outcome measures could lead to effective treatments for progressive multiple sclerosis. In this Series paper, we summarise the lessons learned from completed clinical trials and perspectives from trials in progress in progressive multiple sclerosis. We review promising clinical, imaging, and biological markers, along with novel designs, for clinical trials. The use of more refined outcomes and truly neuroprotective drugs, coupled with more efficient trial design, has the capacity to deliver a new era of therapeutic discovery in this challenging area.
| S-EPMC4361791 | biostudies-literature
Project description:Skin gene expression signatures, including intrinsic subset, are associated with skin score/MRSS improvement during mycophenolate mofetil (MMF) treatment.
2013-04-09 | GSE45485 | GEO
Project description:Systemic sclerosis and systemic lupus erythematosus represent two distinct autoimmune diseases belonging to the group of connective tissue disorders. Despite the great progress in the basic science, this progress has not been translated to the development of novel therapeutic approaches that can radically change the face of these diseases. The discovery of JAK kinases, which are tyrosine kinases coupled with cytokine receptors, may open a new chapter in the treatment of so far untreatable diseases. Small synthetic compounds that can block Janus kinases and interact directly with cytokine signalling may provide therapeutic potential in these diseases. In this review, we discuss the therapeutic potential of Jak kinases in light of the cytokine network that JAK kinases are able to interact with. We also provide the theoretical background for the rationale of blocking cytokines with specific JAK inhibitors.
| S-EPMC9413112 | biostudies-literature