-
Annals of the Rheumatic Diseases May 2020Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression.
METHODS
In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10-22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52.
RESULTS
At week 52, change from baseline in mRSS units was -2.09±5.66 (n=57) with riociguat and -0.77±8.24 (n=52) with placebo (difference of least squares means -2.34 (95% CI -4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud's condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths.
CONCLUSIONS
Riociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated.
Topics: Adult; Biopsy, Needle; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Enzyme Activators; Female; Follow-Up Studies; Humans; Immunohistochemistry; Internationality; Male; Middle Aged; Pyrazoles; Pyrimidines; Respiratory Function Tests; Risk Assessment; Scleroderma, Diffuse; Severity of Illness Index; Treatment Failure
PubMed: 32299845
DOI: 10.1136/annrheumdis-2019-216823 -
Annals of the Rheumatic Diseases Nov 1991Proper classification of patients into diffuse cutaneous and limited cutaneous subsets and the anticipation of complications are the keys to the management of subjects... (Review)
Review
Proper classification of patients into diffuse cutaneous and limited cutaneous subsets and the anticipation of complications are the keys to the management of subjects with systemic sclerosis (scleroderma). Patients with early diffuse disease and rapidly progressive skin thickening are at highest risk of developing serious disease of the internal organs (intestine, lung, heart, kidney) and should be considered for disease modifying treatment. The targets of the disease and sites of possible intervention are vascular endothelium (vasoprotective agents), mononuclear cell subsets (immunosuppressive agents), and fibroblasts (colchicine, D-penicillamine). A number of new agents with sound scientific rationale are currently undergoing therapeutic trials. Much can be done to improve the lifestyle of those with scleroderma. The most dramatic recent development is the ability to reverse kidney disease by the prompt use of angiotensin converting enzyme inhibitors and modern methods of renal dialysis and transplantation. Scleroderma is not a hopeless disease.
Topics: Colchicine; Humans; Immunosuppressive Agents; Penicillamine; Scleroderma, Systemic
PubMed: 1750801
DOI: 10.1136/ard.50.suppl_4.877 -
Scientific Reports May 2018Systemic sclerosis (SSc) is an autoimmune disease of unknown aetiology characterized by vascular lesions, immunological alterations and diffuse fibrosis of the skin and...
Systemic sclerosis (SSc) is an autoimmune disease of unknown aetiology characterized by vascular lesions, immunological alterations and diffuse fibrosis of the skin and internal organs. Since recent evidence suggests that there is a link between metabolomics and immune mediated disease, serum metabolic profile of SSc patients and healthy controls was investigated by H-NMR and GC-MS techniques. The results indicated a lower level of aspartate, alanine, choline, glutamate, and glutarate in SSc patients compared with healthy controls. Moreover, comparing patients affected by limited SSc (lcSSc) and diffuse SSc (dcSSc), 6 discriminant metabolites were identified. The multivariate analysis performed using all the metabolites significantly different revealed glycolysis, gluconeogenesis, energetic pathways, glutamate metabolism, degradation of ketone bodies and pyruvate metabolism as the most important networks. Aspartate, alanine and citrate yielded a high area under receiver-operating characteristic (ROC) curves (AUC of 0.81; CI 0.726-0.93) for discriminating SSc patients from controls, whereas ROC curve generated with acetate, fructose, glutamate, glutamine, glycerol and glutarate (AUC of 0.84; CI 0.7-0.98) discriminated between lcSSc and dcSSc. These results indicated that serum NMR-based metabolomics profiling method is sensitive and specific enough to distinguish SSc from healthy controls and provided a feasible diagnostic tool for the diagnosis and classification of the disease.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Disease Progression; Female; Humans; Male; Metabolome; Middle Aged; Scleroderma, Systemic; Young Adult
PubMed: 29769578
DOI: 10.1038/s41598-018-25992-7 -
Clinical and Experimental Rheumatology 2013Diffuse systemic sclerosis carries a high morbidity and mortality. The Prospective Registry of Early Systemic Sclerosis (PRESS), a multicentre incident cohort study of... (Review)
Review
Diffuse systemic sclerosis carries a high morbidity and mortality. The Prospective Registry of Early Systemic Sclerosis (PRESS), a multicentre incident cohort study of patients with early diffuse cutaneous systemic sclerosis, has the goal of advancing the understanding of disease pathogenesis and identifying novel biomarkers. In this review, PRESS investigators discuss the evidence pertaining to the more commonly used treatments for early diffuse SSc skin disease including methotrexate, mycophenolate, cyclophosphamide, azathioprine, and intravenous immunoglobulin. This review highlights the unmet need for effective treatment in early diffuse SSc as well as its more rigorous study. Nonetheless, the PRESS investigators aim to decrease intra- and inter-institutional variability in prescribing in order to improve the understanding of the clinical course of early diffuse SSc skin disease.
Topics: Biomarkers; Early Diagnosis; Humans; Immunosuppressive Agents; Scleroderma, Diffuse
PubMed: 23910619
DOI: No ID Found -
Annals of the Rheumatic Diseases Feb 2002Antibodies targeting DNA topoisomerase I (ATA) or centromere proteins (ACA) are associated with clinical subsets of patients with systemic sclerosis (SSc). The... (Review)
Review
BACKGROUND
Antibodies targeting DNA topoisomerase I (ATA) or centromere proteins (ACA) are associated with clinical subsets of patients with systemic sclerosis (SSc). The occurrence of those autoantibodies is considered to be mutually exclusive.
OBJECTIVE
To describe the clinical and immunogenetic data of three patients who are co-expressing both antibodies, and then review previous publications.
METHODS
Both antibodies were detected by different methods, including indirect immunofluorescence technique, enzyme linked immunosorbent assay, immunodiffusion, and immunoblot. Patients were HLA typed by serological and molecular genetic methods. Data were extracted from published reports for comparison. The search for published studies was through Medline and other database research programmes.
RESULTS
During routine laboratory diagnostics over several years three patients with scleroderma and coincidence of ATA and ACA were identified: patient 1 with diffuse SSc, Raynaud's phenomenon, puffy fingers and fingertip necrosis, contractures, and calcinosis; patient 2 with diffuse SSc, Raynaud's phenomenon, oedema of the hands, and interstitial calcinosis of hands, knees, and shoulders, and pulmonary fibrosis; patient 3 with scleroderma of hands, forearms, and face, Raynaud's phenomenon, puffy fingers, finger contractures, fingertip necrosis, and calcinosis. All three patients studied were carriers of HLA alleles known to be associated with these autoantibodies. In serial measurements the concentrations of the two antibodies showed independent or even reverse fluctuations. Screening of 100 patients with ACA for ATA and vice versa disclosed no further patients with coincidence of these antibodies. Twenty eight cases of ACA/ATA coexistence in 5423 patients (0.52%) with SSc or SSc associated symptoms were found in an analysis of published studies.
CONCLUSION
The expression of ATA and ACA is not totally mutually exclusive, but coincidence is rare (<1% of patients with SSc). Patients with both autoantibodies often have diffuse scleroderma and show immunogenetic features of both antibody defined subsets of SSc.
Topics: Adult; Autoantibodies; Centromere; DNA Topoisomerases, Type I; Humans; Immunologic Tests; Middle Aged; Scleroderma, Systemic
PubMed: 11796397
DOI: 10.1136/ard.61.2.121 -
Rheumatology (Oxford, England) Aug 2022The aim of this study was to comprehensively identify instruments within relevant domains employed to assess lcSSc since the endorsement of its consensus definition in... (Review)
Review
OBJECTIVES
The aim of this study was to comprehensively identify instruments within relevant domains employed to assess lcSSc since the endorsement of its consensus definition in 1988. The overall objective is to inform the creation of a Combined Response Index for Scleroderma Trials Assessing lcSSc (CRISTAL).
METHODS
MEDLINE and Embase were searched using terms selected to comprehensively retrieve titles and abstracts mentioning both lcSSc and dcSSc, along with those only mentioning lcSSc, SSc sine scleroderma, limited SSc and/or CREST/CRST. Because our initial assessment of the literature revealed that very few studies included only lcSSc subjects, we also assessed literature that included both cutaneous subsets. A total of 3964 titles and abstracts were screened by two reviewers, and 270 articles were selected for data extraction.
RESULTS
We identified 27 domains encompassing 459 instruments. Instruments from 'Skin involvement', 'Pulmonary involvement' and 'Health-related quality of life and general functioning' were the most frequently retrieved. Among the 15 most represented instruments announced as primary end points in efficacy or effectiveness studies, 7 were clinician-reported outcomes (ROs), 7 were patient ROs, and one was a performance outcome (6 min-walk test). The mean proportion of lcSSc patients in studies of lcSSc, including studies that mention both lcSSc and dcSSc, was 56.4%, demonstrating that this subset is underrepresented in the literature, given that the prevalence of lcSSc ranges from 60% to 80% in national registries and international cohorts.
CONCLUSION
This scoping literature review provides a comprehensive identification of domains and outcomes used to assess lcSSc. Our results also highlight that lcSSc is underrepresented in the literature.
Topics: Humans; Outcome Assessment, Health Care; Quality of Life; Reactive Oxygen Species; Scleroderma, Diffuse; Scleroderma, Limited; Scleroderma, Systemic
PubMed: 35094049
DOI: 10.1093/rheumatology/keac049 -
Journal Der Deutschen Dermatologischen... Oct 2012Systemic sclerosis is a chronic inflammatory multiorgan disease belonging to the group of collagen-vascular disorders. With a prevalence of 10/100,000 inhabitants it may... (Review)
Review
Systemic sclerosis is a chronic inflammatory multiorgan disease belonging to the group of collagen-vascular disorders. With a prevalence of 10/100,000 inhabitants it may be regarded a rather rare disease. Its etiology and pathogenesis have still not been elucidated in detail, especially with regard to the differential involvement of skin and the cause of the clinically heterogeneous disease courses. Various components of the vasculature, connective tissue as well as the immune system are involved in a yet unknown sequence and significance. Patients need to be cared for in an interdisciplinary fashion depending on the individual organ involvement. Apart from the skin, the heart, kidneys and lungs are mainly affected in addition to frequent gastrointestinal and musculoskeletal symptoms. Clinically two distinct subsets may be separated, acral (also termed limited) and diffuse scleroderma, which are characterized by anti-centromere and anti-Scl-70/topoisomerase-1 antibodies, respectively. Recent data demonstrate a poor prognosis even in limited disease when pulmonary arterial hypertension develops at an early stage. In diffuse disease sudden and rapid onset will result in a sclerosis of major internal organs and early death in many cases.
Topics: Animals; Humans; Models, Biological; Prevalence; Scleroderma, Diffuse; Skin
PubMed: 22913330
DOI: 10.1111/j.1610-0387.2012.07999.x -
Arthritis Research & Therapy Dec 2021Systemic sclerosis (SSc) is associated with a variability of mortality rates in the literature. (Observational Study)
Observational Study
BACKGROUND
Systemic sclerosis (SSc) is associated with a variability of mortality rates in the literature.
OBJECTIVE
To determine the mortality and its predictors in a long-term follow-up of a bi-centric cohort of SSc patients.
METHODS
A retrospective observational study by systematically analyzing the medical records of patients diagnosed with SSc in Toulouse University Hospital and Ducuing Hospital. Standardized Mortality Ratio (SMR), mortality at 1, 3, 5, 10, and 15 years of disease and causes of death were described. Predictors of mortality using Cox regression were assessed.
RESULTS
Three hundred seventy-five patients were included: 63 with diffuse cutaneous SSc, 279 with limited cutaneous SSc, and 33 with sine scleroderma. The SMR ratio was 1.88 (95% CI 1.46-1.97). The overall survival rates were 97.6% at 1 year, 93.4% at 3 years, 87.1% at 5 years, 77.9% at 10 years, and 61.3% at 15 years. Sixty-nine deaths were recorded. 46.4% were SSc related deaths secondary to interstitial lung disease (ILD) (34.4%), pulmonary hypertension (31.2%), and digestive tract involvement (18.8%). 53.6% were non-related to SSc: cardiovascular disorders (37.8%) and various infections (35.1%) largely distanced those from cancer (13.5%). Four significant independent predictive factors were identified: carbon monoxide diffusing capacity (DLCO) < 70% (HR=3.01; p=0.0053), C-reactive protein (CRP) >5 mg/l (HR=2.13; p=0.0174), cardiac involvement (HR=2.86; p=0.0012), and the fact of being male (HR=3.25; p=0.0004).
CONCLUSION
Long-term data confirmed high mortality of SSc. Male sex, DLCO <70%, cardiac involvement, and CRP> 5mg/l were identified as independent predictors of mortality.
Topics: Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Prognosis; Scleroderma, Diffuse; Scleroderma, Limited; Scleroderma, Systemic
PubMed: 34876194
DOI: 10.1186/s13075-021-02672-y -
Biochimica Et Biophysica Acta. Gene... May 2017The CCAAT-binding factor CBF/NF-Y is needed for cell proliferation and early embryonic development. NF-Y can regulate the expression of different cell type-specific... (Review)
Review
The CCAAT-binding factor CBF/NF-Y is needed for cell proliferation and early embryonic development. NF-Y can regulate the expression of different cell type-specific genes that are activated by various physiological signaling pathways. Dysregulation of NF-Y was observed in pathogenic conditions in humans such as scleroderma, neurodegenerative disease, and cancer. Conditional inactivation of the NF-YA gene in mice demonstrated that NF-Y activity is essential for normal tissue homeostasis, survival, and metabolic function. Altogether, NF-Y is an essential transcription factor that plays a critical role in mammalian development, from the early stages to adulthood, and in human pathogenesis. This article is part of a Special Issue entitled: Nuclear Factor Y in Development and Disease, edited by Prof. Roberto Mantovani.
Topics: Animals; CCAAT-Binding Factor; Humans; Mice; Neoplasm Proteins; Neoplasms, Experimental; Neurodegenerative Diseases; Scleroderma, Diffuse
PubMed: 27815195
DOI: 10.1016/j.bbagrm.2016.10.014 -
JCI Insight Dec 2022Here, the efficacy of abatacept in patients with early diffuse systemic sclerosis (dcSSc) was analyzed to test the hypothesis that patients in the inflammatory intrinsic... (Randomized Controlled Trial)
Randomized Controlled Trial
Here, the efficacy of abatacept in patients with early diffuse systemic sclerosis (dcSSc) was analyzed to test the hypothesis that patients in the inflammatory intrinsic subset would show the most significant clinical improvement. Eighty-four participants with dcSSc were randomized to receive abatacept or placebo for 12 months. RNA-Seq was performed on 233 skin paired biopsies at baseline and at 3 and 6 months. Improvement was defined as a 5-point or more than 20% change in modified Rodnan skin score (mRSS) between baseline and 12 months. Samples were assigned to intrinsic gene expression subsets (inflammatory, fibroproliferative, or normal-like subsets). In the abatacept arm, change in mRSS was most pronounced for the inflammatory and normal-like subsets relative to the placebo subset. Gene expression for participants on placebo remained in the original molecular subset, whereas inflammatory participants treated with abatacept had gene expression that moved toward the normal-like subset. The Costimulation of the CD28 Family Reactome Pathway decreased in patients who improved on abatacept and was specific to the inflammatory subset. Patients in the inflammatory subset had elevation of the Costimulation of the CD28 Family pathway at baseline relative to that of participants in the fibroproliferative and normal-like subsets. There was a correlation between improved ΔmRSS and baseline expression of the Costimulation of the CD28 Family pathway. This study provides an example of precision medicine in systemic sclerosis clinical trials.
Topics: Humans; Abatacept; CD28 Antigens; Scleroderma, Systemic; Scleroderma, Diffuse; Skin
PubMed: 36355434
DOI: 10.1172/jci.insight.155282