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:BACKGROUND:Systemic 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 BODY:All 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. CONCLUSIONS:Physicians 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: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:Heterogeneity in systemic sclerosis (SSc) confounds clinical trials. We previously identified "intrinsic" gene expression subsets by analysis of SSc skin. Here we test the hypotheses that skin gene expression signatures including intrinsic subset are associated with modified Rodnan skin score (MRSS) improvement during mycophenolate mofetil (MMF) treatment. Gene expression and intrinsic subset assignment were measured in 12 SSc patients' biopsies and 10 controls at baseline, and from serial biopsies of 1 cyclophosphamide-treated patient and 9 MMF-treated patients. Gene expression changes during treatment were determined using paired t-tests corrected for multiple hypothesis testing. MRSS improved in four of seven MMF-treated patients classified as the inflammatory intrinsic subset. Three patients without MRSS improvement were classified as normal-like or fibroproliferative intrinsic subsets. A total of 321 genes (false discovery rate (FDR)<5%) were differentially expressed at baseline between patients with and without MRSS improvement during treatment. The expression of 571 genes (FDR<10%) changed between pre- and post-MMF treatment biopsies for patients showing MRSS improvement. Gene expression changes in skin are only seen in patients with MRSS improvement. Baseline gene expression in skin, including intrinsic subset assignment, may identify SSc patients whose MRSS will improve during MMF treatment, suggesting that gene expression in skin may allow targeted treatment in SSc.
| S-EPMC3714324 | biostudies-literature
Project description:Introduction: Systemic sclerosis (SSc) is an autoimmune connective tissue disease that is characterized by excessive collagen deposition, vascular dysfunction, and fibrosis of cutaneous and visceral organs. Current therapeutic options are limited and provide only modest benefit.Areas covered: This review summarizes investigational agents in recent Phase I and II clinical trials evaluated for the treatment of SSc with a focus on skin in patients with early diffuse disease and interstitial lung disease. We performed a search on Pubmed and https://clinicaltrials.gov with keywords systemic sclerosis, Phase I clinical trial, and Phase II clinical trial to identify relevant studies from 2015 to 2019.Expert opinion: Therapeutic interventions in SSc should be guided by the level of disease activity and the degree of organ involvement. While most novel agents have failed to meet the primary endpoints of reducing skin thickening as measured by the modified Rodnan skin score, some have shown promise in improving the Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis (CRISS), reducing lung function decline, or improving patient-reported outcomes. However, most of the current evidence is based on small or open-label clinical trials. Well-designed, large, randomized, Phase III clinical trials are necessary to define the roles of investigational agents in treating SSc.
| S-EPMC7174094 | biostudies-literature
Project description:We sought to identify the clinical factors associated with calcinosis in an international multicenter collaborative effort with the Scleroderma Clinical Trials Consortium (SCTC).This is a retrospective cohort study of 5218 patients with systemic sclerosis (SSc). Logistic regression was used to obtain odds ratios (OR) relating calcinosis to various clinical features in multivariate analyses.A total of 1290 patients (24.7%) had calcinosis. In univariate analyses, patients with calcinosis were older than patients without calcinosis, more likely to be female, and had longer disease duration from the first non-Raynaud phenomenon symptom. Patients with calcinosis were more likely to have digital ulcers, telangiectasias, acro-osteolysis, cardiac disease, pulmonary hypertension, gastrointestinal involvement, arthritis, and osteoporosis, but less likely to have muscle disease. Anti-Scl-70, RNA-polymerase-III, and U1-RNP autoantibodies were significantly less common in patients with calcinosis, while anticentromere (ACA), anti-PM/Scl, and anticardiolipin antibodies were more frequent. In multivariate analysis, the strongest associations with calcinosis were digital ulcers (OR = 3.9; 95% CI: 2.7-5.5; p < 0.0001) and osteoporosis (OR = 4.2; 95% CI: 2.3-7.9; p < 0.0001).One quarter of patients with SSc have calcinosis at some time during their illness. Our data confirm a strong association of calcinosis with digital ulcers, and support a novel association with osteoporosis.
| S-EPMC5500288 | biostudies-literature