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Advances in Clinical and Experimental... Aug 2017Systemic sclerosis is a rare generalized disease with scleroderma, i.e. skin thickening as one of the most common symptoms. The disease has 2 main subsets, diffuse and... (Review)
Review
Systemic sclerosis is a rare generalized disease with scleroderma, i.e. skin thickening as one of the most common symptoms. The disease has 2 main subsets, diffuse and limited forms. The subset known as systemic sclerosis sine scleroderma (ssSSc) is a very rare subset characterized by the total or partial absence of cutaneous manifestations of systemic sclerosis with the occurrence of internal organ involvement and serologic abnormalities. The classification of ssSSc into 3 groups was proposed. Type I (complete) is characterized by the lack of any cutaneous changes typical for the disease at least until systemic sclerosis-related insufficiency of any internal organ occurs. Type II (incomplete) is characterized by the absence of sclerodactyly, but other cutaneous involvements (e.g. calcifications, telangiectasies, pitting scars) can be found. Type III (delayed) is characterized by clinical internal organ involvement typical for systemic sclerosis that has appeared before skin changes (complete or incomplete). In general, the demographic and clinical characteristics of the ssSSc patients suggest that they are similar to those with diffuse or limited form of the disease. Diagnosis of ssSSc still remains difficult and this disease form should be considered in all cases of unexplained fibrotic involvement of the internal organs.
Topics: Disease Progression; Fibrosis; Humans; Prevalence; Prognosis; Scleroderma, Systemic; Severity of Illness Index; Terminology as Topic
PubMed: 29068586
DOI: 10.17219/acem/64334 -
Journal Der Deutschen Dermatologischen... Aug 2013Microscopy of the nailfold capillaries has found increasing use in dermatology, rheumatology and angiology particularly as an important tool to distinguish between... (Review)
Review
Microscopy of the nailfold capillaries has found increasing use in dermatology, rheumatology and angiology particularly as an important tool to distinguish between primary and secondary Raynaud disease. The best evidence is available in systemic sclerosis where specific capillaroscopic patterns have a high positive predictive value for the development of the disease. Conversely, a regular capillary pattern rules out systemic sclerosis with high degree of probability. PRINCE (prognostic index for nailfold capillaroscopic examination) was developed to identify patients at high risk of developing systemic sclerosis. CSURI (capillaroscopic skin ulcer risk index) should predict the risk of developing digital ulcers in patients with systemic sclerosis with high specificity and sensitivity. As a consequence of recent results a pathologic capillary pattern was integrated by the EULAR Scleroderma Trials and Research Group (EUSTAR) in the diagnostic algorithm of the VEDOSS-Project (very early diagnosis of systemic sclerosis). Capillary patterns may correlate with visceral involvement and capillaroscopy thus has the potential as a screening tool to enable early diagnosis of organ involvement in systemic sclerosis.
Topics: Angiography; Diagnosis, Differential; Humans; Microscopic Angioscopy; Microscopy; Raynaud Disease; Scleroderma, Diffuse; Skin Ulcer
PubMed: 23738531
DOI: 10.1111/ddg.12137 -
Annals of the Rheumatic Diseases Nov 2021Although T cells have been implicated in the pathogenesis of systemic sclerosis (SSc), a comprehensive study of T-cell-mediated immune responses in the affected skin of...
OBJECTIVES
Although T cells have been implicated in the pathogenesis of systemic sclerosis (SSc), a comprehensive study of T-cell-mediated immune responses in the affected skin of patients with progressive SSc is lacking. Droplet-based single-cell transcriptome analysis of SSc skin biopsies opens avenues for dissecting patient-specific T-cell heterogeneity, providing a basis for identifying novel gene expression related to functional pathways associated with severity of SSc skin disease.
METHODS
Single-cell RNA sequencing was performed by droplet-based sequencing (10x Genomics), focusing on 3729 CD3 lymphocytes (867 cells from normal and 2862 cells from SSc skin samples) from skin biopsies of 27 patients with active SSc and 10 healthy donors. Confocal immunofluorescence microscopy of progressive SSc skin samples validated transcriptional results and visualised spatial localisations of T-cell subsets.
RESULTS
We identified several subsets of recirculating and tissue-resident T cells in healthy and SSc skin that were associated with distinct signalling pathways. While most clusters shared a common gene expression signature between patients and controls, we identified a unique cluster of recirculating CXCL13 T cells in SSc skin which expressed a T helper follicular-like gene expression signature and that appears to be poised to promote B-cell responses within the inflamed skin of patients.
CONCLUSIONS
Current available therapies to reverse or even slow progression of SSc lead to broad killing of immune cells and consequent toxicities, including death. Identifying the precise immune mechanism(s) driving SSc pathogenesis could lead to innovative therapies that selectively target the aberrant immune response, resulting in better efficacy and less toxicity.
Topics: Case-Control Studies; Chemokine CXCL13; Gene Expression Profiling; Humans; Scleroderma, Diffuse; Sequence Analysis, RNA; Single-Cell Analysis; Skin; T-Lymphocyte Subsets; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; Transcriptome
PubMed: 34031030
DOI: 10.1136/annrheumdis-2021-220209 -
Frontiers in Immunology 2022Systemic sclerosis and autoimmune myositis are both associated with decreased quality of life and increased mortality. Their prognosis and management largely depend on... (Review)
Review
Systemic sclerosis and autoimmune myositis are both associated with decreased quality of life and increased mortality. Their prognosis and management largely depend on the disease subgroups. Indeed, systemic sclerosis is a heterogeneous disease, the two predominant forms of the disease being limited and diffuse scleroderma. Autoimmune myositis is also a heterogeneous group of myopathies that classically encompass necrotizing myopathy, antisynthetase syndrome, dermatomyositis and inclusion body myositis. Recent data revealed that an additional disease subset, denominated "scleromyositis", should be recognized within both the systemic sclerosis and the autoimmune myositis spectrum. We performed an in-depth review of the literature with the aim of better delineating scleromyositis. Our review highlights that this concept is supported by recent clinical, serological and histopathological findings that have important implications for patient management and understanding of the disease pathophysiology. As compared with other subsets of systemic sclerosis and autoimmune myositis, scleromyositis patients can present with a characteristic pattern of muscle involvement (i.e. distribution of muscle weakness) along with multisystemic involvement, and some of these extra-muscular complications are associated with poor prognosis. Several autoantibodies have been specifically associated with scleromyositis, but they are not currently integrated in diagnostic and classification criteria for systemic sclerosis and autoimmune myositis. Finally, striking vasculopathic lesions at muscle biopsy have been shown to be hallmarks of scleromyositis, providing a strong anatomopathological substratum for the concept of scleromyositis. These findings bring new insights into the pathogenesis of scleromyositis and help to diagnose this condition, in patients with subtle SSc features and/or no autoantibodies (i.e. "seronegative" scleromyositis). No guidelines are available for the management of these patients, but recent data are showing the way towards a new therapeutic approach dedicated to these patients.
Topics: Humans; Quality of Life; Myositis; Autoimmune Diseases; Scleroderma, Systemic; Myositis, Inclusion Body
PubMed: 36776390
DOI: 10.3389/fimmu.2022.974078 -
Arthritis Research & Therapy Jun 2021New molecular mechanisms that can be targeted with specific drugs have recently emerged for the treatment of systemic sclerosis (SSc) patients. Over the past 3 years,... (Review)
Review
New molecular mechanisms that can be targeted with specific drugs have recently emerged for the treatment of systemic sclerosis (SSc) patients. Over the past 3 years, the achievement of one large phase 3 trial has led to the approval by drug agencies of the first drug licenced for SSc-related interstitial lung disease. Given this exciting time in the SSc field, we aimed to perform a systemic literature review of phase 1, phase 2 and phase 3 clinical trials and large observational studies about targeted therapies in SSc. We searched MEDLINE/PubMed, EMBASE, and ClinicalTrials.gov for clinical studies from 2016 with targeted therapies as the primary treatment in patients with SSc for skin or lung involvement as the primary clinical outcome measure. Details on the study characteristics, the trial drug used, the molecular target engaged by the trial drug, the inclusion criteria of the study, the treatment dose, the possibility of concomitant immunosuppression, the endpoints of the study, the duration of the study and the results obtained were reviewed. Of the 973 references identified, 21 (4 conference abstracts and 17 articles) were included in the systematic review. A total of 15 phase 1/phase 2 clinical trials, 2 phase 3 clinical trials and 2 observation studies were analysed. The drugs studied in phase 1/phase 2 studies included the following: inebilizumab, dabigatran, C-82, pomalidomide, rilonacept, romilkimab, tocilizumab, tofacitinib, pirfenidone, lenabasum, abatacept, belimumab, riociguat, SAR100842 and lanifibranor. All but 3 studies were performed in early diffuse SSc patients with different inclusion criteria, while 3 studies were performed in SSc patients with interstitial lung disease (ILD). Phase 3 clinical trials investigated nintedanib and tocilizumab. Nintedanib was investigated in SSc-ILD patients whereas tocilizumab focused on early diffuse SSc patients with inflammatory features. Two observational studies including > 50 patients with rituximab as the targeted drug were also evaluated. All these studies offer a real hope for SSc patients. The future challenges will be to customize patient-specific therapeutics with the goal to develop precision medicine for SSc.
Topics: Humans; Lung Diseases, Interstitial; Scleroderma, Diffuse; Scleroderma, Systemic
PubMed: 34074331
DOI: 10.1186/s13075-021-02536-5 -
JAMA Jun 2014High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials.
OBJECTIVE
To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide.
DESIGN, SETTING, AND PARTICIPANTS
The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013.
INTERVENTIONS
HSCT vs intravenous pulse cyclophosphamide.
MAIN OUTCOMES AND MEASURES
The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure.
RESULTS
A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years.
CONCLUSIONS AND RELEVANCE
Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit.
TRIAL REGISTRATION
isrctn.org Identifier: ISRCTN54371254.
Topics: Adult; Autografts; Cyclophosphamide; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Scleroderma, Diffuse; Survival Analysis
PubMed: 25058083
DOI: 10.1001/jama.2014.6368 -
Annals of the Rheumatic Diseases May 2021American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS) is a composite endpoint to assess the likelihood of improvement in diffuse...
New composite endpoint in early diffuse cutaneous systemic sclerosis: revisiting the provisional American College of Rheumatology Composite Response Index in Systemic Sclerosis.
OBJECTIVES
American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS) is a composite endpoint to assess the likelihood of improvement in diffuse systemic sclerosis. ACR-CRISS is a weighted score and includes five core set measures: modified Rodnan skin score, FVC% predicted, health assessment questionnaire-disability index, and patient and clinician global assessments.
METHODS
We analysed core set measures from 354 participants who participated in three placebo-controlled trials. We generated 10 development datasets, randomly selected from 2/3 of the participants, stratified by study and treatment group. The remaining participants (1/3 of the participants) formed the validation sets. Risk differences (RDs) between active and placebo treatments were calculated by averaging over the replicate datasets; bootstrap 95% CIs for the RDs to estimate the magnitude of treatment effects.
RESULTS
In the development sets (n=237), the proportion of participants in the active group had statistically higher improvement in >1 of 5 core set measures versus the placebo group. For example, the proportion who improved by ≥20% in ≥3 core set measures was 49.4% in the active versus338.9% in the placebo; RD: 10.5%, 95% CI4.9 % to 16.1%. In the validation sets (n=117), the proportion who improved by ≥20% in ≥3 core set measures was 50.3% in the active versus35.63% in the placebo (RD:114.8%, 95% CI 3.1% to225.7%). Similar trends were seen with larger percentage cut-offs.
CONCLUSION
Revised CRISS, as assessed by the proportion of participants who improved by a certain percentage in ≥3 of 5 core set measures, is a potential new composite outcome measure.
Topics: Adult; Antirheumatic Agents; Disability Evaluation; Double-Blind Method; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; Rheumatology; Scleroderma, Diffuse; Scleroderma, Systemic; Severity of Illness Index; Treatment Outcome; United States
PubMed: 33257497
DOI: 10.1136/annrheumdis-2020-219100 -
Rheumatic Diseases Clinics of North... Feb 1997Pregnancy in systemic sclerosis may be uneventful, with both good maternal and fetal outcomes. Because scleroderma is a multisystem disease and complications do occur,... (Review)
Review
Pregnancy in systemic sclerosis may be uneventful, with both good maternal and fetal outcomes. Because scleroderma is a multisystem disease and complications do occur, however, careful antenatal evaluations, discussion of potential problems, and participation in a high-risk obstetric monitoring program is very important to optimize the best outcome. Because women with diffuse scleroderma are at greater risk for developing serious cardiopulmonary and renal problems early in the disease, they should be encouraged to delay pregnancy until the disease stabilizes. All patients who become pregnant during this high-risk time should be monitored extremely carefully. Although there are some suggestions that there are increases in infertility and miscarriages before disease onset, recent studies show that these issues probably do not have major impact for women with established scleroderma who plan to become pregnant. The high risk of premature and small infants may be minimized with specialized obstetric and neonatal care, however. Renal crisis in scleroderma is the only truly unique aspect of these pregnant, which, unlike blood pressure elevation in nonscleroderma pregnancies, must be treated aggressively with ACE inhibitors. Other pregnancy problems may not be unique to scleroderma, but because it is a chronic illness, any complication carries higher risks for both mother and child. Careful planning, close monitoring, and aggressive management should allow women with scleroderma to have a high likelihood of a successful pregnancy.
Topics: Female; Fertility; Humans; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Scleroderma, Systemic
PubMed: 9031379
DOI: 10.1016/s0889-857x(05)70319-7 -
Rheumatic Diseases Clinics of North... Feb 2008Many conditions presenting with clinical hard skin and tissue fibrosis can be confused with systemic sclerosis (scleroderma). These disorders have very diverse... (Review)
Review
Many conditions presenting with clinical hard skin and tissue fibrosis can be confused with systemic sclerosis (scleroderma). These disorders have very diverse etiologies and often an unclear pathogenetic mechanism. Distinct clinical characteristics, skin histology, and disease associations may allow one to distinguish these conditions from scleroderma and from each other. A prompt diagnosis is important to spare patients from ineffective treatments and inadequate management. This article highlights nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy), eosinophilic fasciitis (Shulman's syndrome), scleromyxedema, and scleredema. These often are detected in the primary care setting and referred to rheumatologists for further evaluation. Rheumatologists must be able to promptly recognize them to provide valuable prognostic information and appropriate treatment options for affected patients.
Topics: Diagnosis, Differential; Fasciitis; Fibrosis; Humans; Scleroderma, Diffuse; Scleromyxedema; Skin
PubMed: 18329541
DOI: 10.1016/j.rdc.2007.11.001 -
Arthritis & Rheumatology (Hoboken, N.J.) Feb 2022In this study, we sought a comprehensive understanding of myeloid cell types driving fibrosis in diffuse cutaneous systemic sclerosis (dcSSc) skin.
Expansion of Fcγ Receptor IIIa-Positive Macrophages, Ficolin 1-Positive Monocyte-Derived Dendritic Cells, and Plasmacytoid Dendritic Cells Associated With Severe Skin Disease in Systemic Sclerosis.
OBJECTIVE
In this study, we sought a comprehensive understanding of myeloid cell types driving fibrosis in diffuse cutaneous systemic sclerosis (dcSSc) skin.
METHODS
We analyzed the transcriptomes of 2,465 myeloid cells from skin biopsy specimens from 12 dcSSc patients and 10 healthy control subjects using single-cell RNA sequencing. Monocyte-derived dendritic cells (mo-DCs) were assessed using immunohistochemical staining and immunofluorescence analyses targeting ficolin-1 (FCN-1).
RESULTS
A t-distributed stochastic neighbor embedding analysis of single-cell transcriptome data revealed 12 myeloid cell clusters, 9 of which paralleled previously described healthy control macrophage/DC clusters, and 3 of which were dcSSc-specific myeloid cell clusters. One SSc-associated macrophage cluster, highly expressing Fcγ receptor IIIA, was suggested on pseudotime analysis to be derived from normal CCR1+ and MARCO+ macrophages. A second SSc-associated myeloid population highly expressed monocyte markers FCN-1, epiregulin, S100A8, and S100A9, but was closely related to type 2 conventional DCs on pseudotime analysis and identified as mo-DCs. Mo-DCs were associated with more severe skin disease. Proliferating macrophages and plasmacytoid DCs were detected almost exclusively in dcSSc skin, the latter clustering with B cells and apparently derived from lymphoid progenitors.
CONCLUSION
Transcriptional signatures in these and other myeloid populations indicate innate immune system activation, possibly through Toll-like receptors and highly up-regulated chemokines. However, the appearance and activation of myeloid cells varies between patients, indicating potential differences in the underlying pathogenesis and/or temporal disease activity in dcSSc.
Topics: Dendritic Cells; Humans; Lectins; Macrophages; Monocytes; Receptors, IgG; Scleroderma, Diffuse; Severity of Illness Index; Ficolins
PubMed: 34042322
DOI: 10.1002/art.41813