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Journal of Clinical Rheumatology :... Apr 2015Systemic sclerosis is a rare autoimmune disorder with significant morbidity and mortality due to multi-organ system involvement. Early diagnosis and screening for organ... (Review)
Review
Systemic sclerosis is a rare autoimmune disorder with significant morbidity and mortality due to multi-organ system involvement. Early diagnosis and screening for organ involvement is critical as earlier treatment appears to improve function and may impact mortality. The purpose of this article is to address some of the commonly asked questions by rheumatologists on systemic sclerosis.
Topics: Disease Management; Disease Progression; Early Diagnosis; Female; Humans; Male; Mass Screening; Pregnancy; Pregnancy Complications; Rheumatology; Scleroderma, Systemic; Specialization
PubMed: 25807095
DOI: 10.1097/RHU.0000000000000232 -
Clinical and Experimental Rheumatology 2016Systemic sclerosis is a rare acquired systemic disease characterised by a complex pathogenesis and multi organ involvement. Every year, novel insights into the... (Review)
Review
Systemic sclerosis is a rare acquired systemic disease characterised by a complex pathogenesis and multi organ involvement. Every year, novel insights into the pathogenesis, diagnosis and treatment of this severe disease are published. Herewith, we provide an overview of the most significant literature contributions published over the last year.
Topics: Animals; Disease Progression; Humans; Nutritional Status; Risk Factors; Scleroderma, Systemic; Treatment Outcome
PubMed: 27463613
DOI: No ID Found -
The Journal of Investigative Dermatology Jan 1993Scleroderma is characterized by an excessive deposition of collagen in all involved organs. This is due to an overproduction of extracellular matrix (ECM) molecules... (Review)
Review
Scleroderma is characterized by an excessive deposition of collagen in all involved organs. This is due to an overproduction of extracellular matrix (ECM) molecules following induction of gene expression, whereas there is no evidence that the composition of the connective tissue matrix is altered. Several in vivo studies and in vitro experiments suggest that a close interaction between inflammatory cells and fibroblasts is required for the initial activation of fibroblasts. TGF-beta presumably plays an important role, but other cytokines, e.g., PDGF or FGF, may also be involved. Many of the ECM molecules have been shown to interact closely with fibroblasts and provide signals that regulate fibroblast metabolism. The cellular response towards those signals is a further aspect of fibrosis that has attracted attention during recent years. The altered expression of receptor proteins on the cell surface of scleroderma fibroblasts for example might explain in part the lack of down-regulation of collagen synthesis in late phases of the disease. This review summarizes the alterations of connective tissue in scleroderma, and discusses the role of cytokines as well as the ECM for the regulation of fibroblast function and their implication for the development of fibrosis.
Topics: Cells, Cultured; Connective Tissue; Cytokines; Extracellular Matrix; Fibroblasts; Fibrosis; Gene Expression Regulation; Humans; Procollagen; Scleroderma, Systemic
PubMed: 8423407
DOI: 10.1111/1523-1747.ep12356293 -
Arthritis Research & Therapy 2007A number of genetic loci have been identified that appear to be associated with systemic sclerosis (SSc; scleroderma). There is mounting evidence suggesting that these... (Review)
Review
A number of genetic loci have been identified that appear to be associated with systemic sclerosis (SSc; scleroderma). There is mounting evidence suggesting that these genetic associations may in fact be associated with distinct phenotypes in SSc based on autoantibody pattern rather than with SSc as a single disease entity. This may ultimately have implications for approaches to therapy as well as responses to therapy. The most promising candidate genes are those involved in pathways that lead to the vascular damage and fibrosis that are the hallmarks of this disease. There is uncertainty, however, regarding the nature of the key pathological mechanisms that link these two disease processes. Recent studies have focused on Fli1 (friend leukaemia integration 1), a transcription factor that is found in immune cells, fibroblasts, and endothelial cells that regulates collagen gene function and angiogenesis. Fli1 is dysregulated in SSc skin and dermal blood vessels, and appears to play a pathological role in SSc skin fibrosis and vessel degeneration. Whether this dysregulation is due to genetic polymorphisms in the Fli1 pathway or to epigenetic mechanisms is not clear.
Topics: Animals; Fibroblasts; Gene Expression Profiling; Genetic Linkage; Humans; Scleroderma, Systemic
PubMed: 17767743
DOI: 10.1186/ar2189 -
Clinical and Experimental Rheumatology 2017Haematopoetic autologous stem cell transplantation (ASCT) has emerged as a treatment option for patients with refractory, severe autoimmune disease. This is a systematic... (Review)
Review
OBJECTIVES
Haematopoetic autologous stem cell transplantation (ASCT) has emerged as a treatment option for patients with refractory, severe autoimmune disease. This is a systematic review of the current literature on ASCT in adult patients with systemic sclerosis (SSc).
METHODS
Original articles published between 2005 and 2016 that evaluated the use of ASCT in patients with SSc were reviewed with respect to the primary outcomes of overall and transplant related mortality (TRM) rates, and secondary outcomes of changes in modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), progression/event free survival (P/EFS) and quality of life measures. We also focussed on patient characteristics, the ASCT conditioning and mobilisation regimens used, and their relationship to patient outcome in each study.
RESULTS
Of the 155 articles found, only 9 articles were suitable for review. There were 2 placebo-controlled trials (RCTs), ASTIS and ASSIST, and 7 observational and cohort studies. In general, patients undergoing ASCT had diffuse SSc with mRSS >14, and interstitial lung disease. The 2 RCTs showed a benefit in P/EFS (80-81%), FVC and quality of life measures in ASCT compared to monthly cyclophosphamide. All the studies showed an improvement in mRSS. TRM rates varied among studies, from 0 to 23%, with a trend to higher mortality rates in studies using higher doses of cyclophosphamide or myeloablative conditioning regimens.
CONCLUSIONS
We conclude that ASCT is beneficial in some patients with SSc and that patient selection and conditioning regimens are critical determinants of prognosis and mortality post-ASCT.
Topics: Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Patient Selection; Randomized Controlled Trials as Topic; Scleroderma, Systemic; Transplantation Conditioning; Transplantation, Autologous; Vital Capacity
PubMed: 28869416
DOI: No ID Found -
Current Opinion in Rheumatology May 2020This review provides a risk-stratified and evidence-based management for subsets of systemic sclerosis (SSc) patients in the first five years from disease onset. (Review)
Review
PURPOSE OF REVIEW
This review provides a risk-stratified and evidence-based management for subsets of systemic sclerosis (SSc) patients in the first five years from disease onset.
RECENT FINDINGS
Cardiopulmonary disease remains the primary cause of mortality in SSc patients. Morbidity and mortality in SSc-associated pulmonary arterial hypertension have improved with combination treatment, in either an upfront or sequential treatment pattern. Traditional therapies for interstitial lung disease (SSc-ILD) have targeted those with clinically significant and progressive ILD with immunosuppression. New data suggest a possible paradigm shift, introducing immunosuppressive therapy to patients before they develop clinically significant or progressive ILD. The year 2019 saw the approval of the first FDA-approved therapy for SSc-associated interstitial lung disease, using an antifibrotic agent previously approved for idiopathic pulmonary fibrosis. To date, only autologous hematopoietic stem cell transplant has demonstrated a mortality benefit for SSc-ILD, albeit in a narrow spectrum of SSc-ILD patients.
SUMMARY
SSc is a highly heterogeneous autoimmune disease typified by varying clinical trajectories. Its management may be stratified within the first five years by subclassifying patients based on factors that have important prognostic significance: skin distribution and autoantibody status.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Prognosis; Scleroderma, Systemic
PubMed: 32205570
DOI: 10.1097/BOR.0000000000000711 -
American Journal of Respiratory and... Jun 2010Pulmonary arterial hypertension (PAH) is a devastating vascular complication of a number of connective tissue diseases, including systemic sclerosis (SSc), where it has... (Review)
Review
Pulmonary arterial hypertension (PAH) is a devastating vascular complication of a number of connective tissue diseases, including systemic sclerosis (SSc), where it has a dramatic impact on the clinical course and overall survival and is the single most common cause of death in patients afflicted with this syndrome. Although remarkable advances have been achieved in elucidating the pathogenesis of PAH over the past 2 decades, leading to the development of disease-targeted therapies for the idiopathic form of this condition (IPAH), the response to therapy is suboptimal in SSc-related PAH (SSc-PAH), and survival remains very poor. Factors accounting for striking clinical and prognostic differences between these two syndromes are unclear but may include a more pronounced autoimmune, cellular, and inflammatory response, and a higher prevalence of comorbidities in SSc-PAH, including cardiac and pulmonary venous and parenchymal involvement. Furthermore, currently available markers of disease severity and clinical tools to assess response to therapy, which may be reliable in IPAH, are either limited or lacking in SSc-PAH. Thus, a more focused approach, including a better understanding of the pathogenesis and genetic factors underlying the development of SSc-PAH, a search for more specific and reliable tools to adequately assess functional impairment and monitor therapy, as well as the design of novel targeted therapies, are all urgently required to alter the dismal course of this syndrome.
Topics: Humans; Hypertension, Pulmonary; Inflammation; Kaplan-Meier Estimate; Prognosis; Risk Factors; Scleroderma, Systemic; Severity of Illness Index
PubMed: 20194816
DOI: 10.1164/rccm.200909-1331PP -
European Respiratory Review : An... Mar 2021Interstitial lung disease (ILD) affects approximately 50% of patients with systemic sclerosis (SSc) and is the leading cause of death in SSc. Our objective was to gain... (Review)
Review
Interstitial lung disease (ILD) affects approximately 50% of patients with systemic sclerosis (SSc) and is the leading cause of death in SSc. Our objective was to gain insight into the progression of SSc-associated ILD (SSc-ILD). Using data from longitudinal clinical trials and observational studies, we assessed definitions and patterns of progression, risk factors for progression, and implications for treatment. SSc-ILD progression was commonly defined as exceeding specific thresholds of lung function worsening and/or increasing radiographic involvement. One definition used in several studies is decline in forced vital capacity (FVC) of ≥10%, or ≥5-10% plus a decline in diffusing capacity of the lung for carbon monoxide ≥15%. Based on these criteria, 20-30% of patients in observational cohorts develop progressive ILD, starting early in the disease course and progressing at a highly variable rate.Risk factors such as age, FVC, extent of fibrosis and presence of anti-topoisomerase I antibodies can help predict progression of SSc-ILD, though composite risk scores may offer greater predictive power. Whilst the variability of the disease course in SSc-ILD makes risk stratification of patients challenging, the decision to initiate, change or stop treatment should be based on a combination of the current disease state and the speed of progression.
Topics: Humans; Lung; Lung Diseases, Interstitial; Risk Factors; Scleroderma, Systemic; Vital Capacity
PubMed: 33762426
DOI: 10.1183/16000617.0340-2020 -
Arthritis Research & Therapy 2013Scleroderma (systemic sclerosis; SSc) is characterised by fibrosis of the skin and internal organs in the context of autoimmunity and vascular perturbation.... (Review)
Review
Scleroderma (systemic sclerosis; SSc) is characterised by fibrosis of the skin and internal organs in the context of autoimmunity and vascular perturbation. Overproduction of extracellular matrix components and loss of specialised epithelial structures are analogous to the process of scar formation after tissue injury. Fibroblasts are the resident cells of connective tissue that become activated at sites of damage and are likely to be important effector cells in SSc. Differentiation into myofibroblasts is a hallmark process, although the mechanisms and cellular origins of this important fibroblastic cell are still unclear. This article reviews fibroblast biology in the context of SSc and highlights the potentially important place of fibroblast effector cells in fibrosis. Moreover, the heterogeneity of fibroblast properties, multiplicity of regulatory pathways and diversity of origin for myofibroblasts may underpin clinical diversity in SSc, and provide novel avenues for targeted therapy.
Topics: Extracellular Matrix; Fibroblasts; Humans; Scleroderma, Systemic
PubMed: 23796020
DOI: 10.1186/ar4230 -
Clinical and Experimental Rheumatology 2017The low overall prevalence of systemic sclerosis (SSc) and the low proportion of male patients have resulted in a scarcity of studies assessing sex differences in Ssc... (Review)
Review
OBJECTIVES
The low overall prevalence of systemic sclerosis (SSc) and the low proportion of male patients have resulted in a scarcity of studies assessing sex differences in Ssc patients, and contradictory results have often been show among those studies that have been performed.
METHODS
A prospective study was conducted with the Spanish RESCLE register to analyse the influence of gender on survival of SSc patients.
RESULTS
In total, 1506 SSc patients (1341 women, 165 men) were recruited from 21 centres. Older age at onset (OR 1.02), shorter time from onset to diagnosis (OR 0.96), smoking (OR 2.57), interstitial lung disease (ILD) (OR 1.58), less predisposition to sicca syndrome and to antinuclear antibody positivity (OR 0.29 and 0.43, respectively), and higher compliance with the ACR 1980 criteria (OR 1.79) were independently associated with the male sex. During follow-up, 30.4% of men versus 14.6% of women died (p<0.001). Survival at 10 years from the onset of symptoms was 75.3% for men and 92.9% for women (p<0.001), and the difference remained after selecting only SSc-related deaths (85.6% vs. 96.1%, p<0.001). The mortality predictive factors were diffuse SSc (OR 2.26), ILD (OR 1.82), digital ulcers (OR 1.38), tendon friction rubs (OR 1.74), male sex (OR 1.53), increased age at onset (OR 1.13) and isolated PH (considering only deaths from diagnosis), both in the overall (OR 3.63) and female cohorts (OR 3.97). The same risk factors were observed in the male cohort, except for isolated PH and ILD.
CONCLUSIONS
The present study confirms the existence of epidemiological, clinical, laboratory and prognostic gender differences in systemic sclerosis patients.
Topics: Cause of Death; Cohort Studies; Female; Humans; Male; Prognosis; Prospective Studies; Scleroderma, Systemic; Sex Characteristics
PubMed: 28980905
DOI: No ID Found