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In response to: Autologous Mesenchymal Stem Cells Foster Revascularization of Ischemic Limbs in Systemic Sclerosis
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Epigenetics and Systemic Sclerosis
No full textSystemic sclerosis (SSc) is a connective-tissue disease more frequent in women than in men. Genetics have been hypothesized to have a main role in disease susceptibility, but none of the genetic factors put forward is sufficient to induce the disease. Recently, exogenous factors and epigenetic modifications have been proposed to have a role in the determination of the disease phenotype. For example, fibrotic signal transduction pathways in SSc converge on DNA methylation and histone deacetylation at the FLI1 gene. In addition, regulation of the COL1A1 gene in fibroblasts involves transcription factors (hc-Krox, Sp1, Sp3) which upregulate COL1A1 transcriptional activity and provide evidence for a profibrotic role of hc-Krox. These findings provide novel insights into the epigenetic regulation of fibrosis. They may suggest that the drugs acting on epigenetic mechanisms may be useful as antifibrotic treatments in SSc. © 2009 John Wiley & Sons Ltd
Mechanisms in the loss of capillaries in systemic sclerosis: angiogenesis versus vasculogenesis
No full textSystemic sclerosis (SSc, scleroderma) is a chronic, multisystem connective tissue disorder affecting the skin and various internal organs. Although the disease is characterized by a triad of widespread microangiopathy, fibrosis, and autoimmunity, increasing evidence indicates that vascular damage is a primary event in the pathogenesis of SSc. The progressive vascular injury includes persistent endothelial cell activation/damage and apoptosis, intimal thickening, delamination, vessel narrowing and obliteration. These profound vascular changes lead to vascular tone dysfunction and reduced capillary blood flow, with consequent tissue ischemia and severe clinical manifestations, such as digital ulceration or amputation, pulmonary arterial hypertension, and scleroderma renal crisis. The resulting tissue hypoxia induces complex cellular and molecular mechanisms in the attempt to recover endothelial cell function and tissue perfusion. Nevertheless, in SSc patients there is no evidence of significant angiogenesis and the disease evolves towards chronic tissue ischemia, with progressive and irreversible structural changes in multiple vascular beds culminating in the loss of capillaries. A severe imbalance between pro-angiogenic and angiostatic factors may also lead to impaired angiogenic response during SSc. Besides insufficient angiogenesis, defective vasculogenesis with altered numbers and functional defects of bone marrow-derived endothelial progenitor cells may contribute to the vascular pathogenesis of SSc. The purpose of this article is to review the contribution of recent studies to the understanding of the complex mechanisms of impaired vascular repair in SSc. Indeed, understanding the pathophysiology of SSc-associated vascular disease may be the key in dissecting the disease pathogenesis and developing novel therapies. Either angiogenic or vasculogenic mechanisms may potentially become in the future the target of therapeutic strategies to promote capillary regeneration in SSc
The crowded crossroad to angiogenesis in systemic sclerosis: where is the key to the problem?
Full text linkIn systemic sclerosis (SSc), peripheral vasculopathy is
characterized by a progressive and irreversible loss of
capillaries following endothelial cell injury, due to
defects in both vascular repair and expected increase
in new vessel growth (angiogenesis). The discovery of
key molecular targets may help to develop the most
effective therapeutic strategy for the SSc-related
vasculopathy. A pathway worth targeting in SSc may
include vascular endothelial growth factor, 165b
isoform, an endogenous angiogenesis inhibitor
abnormally expressed and released by different cell
types, including activated endothelial cells and platelets
The origin of the myofibroblast in fibroproliferative vasculopathy: Does the endothelial cell steer the pathophysiology of systemic sclerosis?
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Very early and early diagnosis of systemic sclerosis
No full textSystemic sclerosis (SSc) is easily diagnosed when the disease is evolved to skin fibrosis with obliterative vasculopathy and internal organs involvement. In the very early/early phase of SSc, the diagnosis remains very difficult because of the lack of validated diagnostic criteria. Actually, the American College of Rheumatology (ACR) and LeRoy classification criteria are not sufficiently sensitive to enable very early/early diagnosis of the disease, limiting the possibility of a precocious treatment. Therefore, in many cases, treatment is delayed for several years following the onset of Raynaud‘s phenomenon (RP) and even after the onset of the first non-RP symptom. For this reason, the very early/early diagnosis of SSc is today of pivotal importance. Recently, RP, puffy fingers turning into sclerodactyly and antinuclear antibody (ANA) positivity are considered the three red flags for the suspicion of a very early SSc. Further signs such as positivity of other specific autoantibodies and/or videocapillaroscopy pattern may allow very early diagnosis of SSc. This may allow follow-up of the patient and start the appropriate therapeutic regimen to arrest the disease progression when an organ involvement is detected. The time gap between the onset of signs and the diagnosis can be considered the ‘window of opportunity‘ where the disease may be stopped before skin and internal organs are irreversibly damaged. Therefore, the main topic discussed in this chapter will be ‘why we need to distinguish between a very early and an early diagnosis of SSc‘
Immunosuppression for interstitial lung disease in systemic sclerosis
No full textThe efficacy of immunosuppressors in the treatment of systemic sclerosis-interstitial lung disease is still matter of controversy. In this review we will analyse the evidence that immunosuppressors, despite not being able to reverse fibrotic changes, may help in slowing disease progression. Induction treatment with cyclophosphamide should be started as soon as possible in patients at risk for progression. Mycophenolate mofetil and rituximab have to be considered in patients who are unable to tolerate cyclophosphamide. After remission, maintenance treatment with mycophenolate mofetil or azathioprine should be started in order to preserve the benefits achieved during the induction treatment
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