Using autoantibodies and cutaneous subset to develop outcome-based disease classification in systemic sclerosis

OBJECTIVE: To describe the associations between autoantibodies, presentation and outcome among systemic sclerosis (SSc) patients. We propose a new SSc classification incorporating antibodies and cutaneous subset. METHODS: Survival analysis was used to assess the effect of antibodies on organ disease and death. RESULTS: The study included 1325 subjects. The ACA+ limited cutaneous (lc)SSc group (n=374) had the highest 20-year survival (65.3%), lowest incidence of clinically-significant pulmonary fibrosis (csPF, 8.5%) and scleroderma renal crisis (SRC, 0.3%), low cardiac SSc incidence (4.9%), while pulmonary hypertension (PH) frequency was similar to the cohort average. The anti-Scl70+ lcSSc (n=138) and diffuse cutaneous (dc)SSc groups (n=149) had the highest csPF incidence (86.1% and 84% at 15 years). The dcSSc group had the lowest survival (32.4%) and the second highest incidence of cardiac SSc (12.9%) at 20 years, while in the lcSSc group other complications were rare, demonstrating the lowest incidence of PH (6.9%) and second highest survival (61.8%). The anti-RNA polymerase+ group (n=147) had the highest incidence of SRC (28.1%). The anti-U3RNP+ group (n=56) had the highest PH (33.8%) and cardiac SSc incidence (13.2%). Among lcSSc patients with other autoantibodies (n=295), risk of SRC and cardiac SSc was low, while other outcomes were similar to the cohort average. DcSSc patients with other antibodies (n=166) had poor prognosis, with the second lowest survival (33.6%) and frequent organ complications. CONCLUSION: We highlight the importance of autoantibodies, cutaneous subset and disease duration when assessing SSc morbidity and mortality. Our classification may benefit disease monitoring and clinical trial design

Systemic sclerosis vasculopathy: exploration in transgenic mice

Vascular disease in systemic sclerosis (SSc) leads to significant morbidity and mortality. No robust animal model of vasculopathy in SSc has been described. The hypothesis underpinning work described in this thesis is that a primary defect in TGFβ signalling is sufficient to generate the fibrotic, vascular and inflammatory phenotype of this condition. This is explored using a novel transgenic mouse model of SSc (TβRIIΔk-fib). The transgenic mouse strain TβRIIΔk-fib carries a kinase-deficient type II TGFβ receptor which is expressed under the control of a fibroblast specific promoter leading to balanced ligand-dependent upregulation of TGFβ signalling. Consequent increased TGFβ ligand in the peri-fibroblast microenvironment modulates other cell types. The phenotype is one of ubiquitous skin and gut fibrosis and increased susceptibility to severe and persistent fibrosis in response to epithelial lung injury. In this thesis, a cardiovascular phenotype is characterised for the first time, with adventitial fibrosis and medial attenuation within the large elastic arteries of the systemic circulation resulting in systemic hypertension with cardiac fibrosis. Within the pulmonary arterial circulation, there is ubiquitous medial hypertrophy, perivascular inflammation and mild pulmonary hypertension. In both circulations, the phenotype can be exaggerated additional vascular stress: NO synthase inhibition results hypertensive renal stress and VEGFR2 inhibition results in obliterative vascular changes representative of pulmonary arterial hypertension. This thesis demonstrates a unique phenotype that is strikingly relevant to that of human SSc vasculopathy, providing compelling evidence for the role of altered TGFβ signaling in systemic and pulmonary vasculopathy and for the role of altered cell interactions and responses to injury in the development of vascular consequences. A paradigm in which a background TGFβ dependent vasculopathy renders mice susceptible to injury leading to hallmark features of SSc vasculopathy is suggested. This model provides mechanistic insight and a potential platform for preclinical interventional studies in these important complications of SSc

Endothelial injury in a transforming growth factor β-dependent mouse model of scleroderma induces pulmonary arterial hypertension.

OBJECTIVE: To delineate the constitutive pulmonary vascular phenotype of the TβRIIΔk-fib mouse model of scleroderma, and to selectively induce pulmonary endothelial cell injury using vascular endothelial growth factor (VEGF) inhibition to develop a model with features characteristic of pulmonary arterial hypertension (PAH). METHODS: The TβRIIΔk-fib mouse strain expresses a kinase-deficient transforming growth factor β (TGFβ) receptor type II driven by a fibroblast-specific promoter, leading to ligand-dependent up-regulation of TGFβ signaling, and replicates key fibrotic features of scleroderma. Structural, biochemical, and functional assessments of pulmonary vessels, including in vivo hemodynamic studies, were performed before and following VEGF inhibition, which induced pulmonary endothelial cell apoptosis. These assessments included biochemical analysis of the TGFβ and VEGF signaling axes in tissue sections and explanted smooth muscle cells. RESULTS: In the TβRIIΔk-fib mouse strain, a constitutive pulmonary vasculopathy with medial thickening, a perivascular proliferating chronic inflammatory cell infiltrate, and mildly elevated pulmonary artery pressure resembled the well-described chronic hypoxia model of pulmonary hypertension. Following administration of SU5416, the pulmonary vascular phenotype was more florid, with pulmonary arteriolar luminal obliteration by apoptosis-resistant proliferating endothelial cells. These changes resulted in right ventricular hypertrophy, confirming hemodynamically significant PAH. Altered expression of TGFβ and VEGF ligand and receptor was consistent with a scleroderma phenotype. CONCLUSION: In this study, we replicated key features of systemic sclerosis-related PAH in a mouse model. Our results suggest that pulmonary endothelial cell injury in a genetically susceptible mouse strain triggers this complication and support the underlying role of functional interplay between TGFβ and VEGF, which provides insight into the pathogenesis of this disease

Endothelial injury in a transforming growth factor β-dependent mouse model of scleroderma induces pulmonary arterial hypertension.

OBJECTIVE: To delineate the constitutive pulmonary vascular phenotype of the TβRIIΔk-fib mouse model of scleroderma, and to selectively induce pulmonary endothelial cell injury using vascular endothelial growth factor (VEGF) inhibition to develop a model with features characteristic of pulmonary arterial hypertension (PAH). METHODS: The TβRIIΔk-fib mouse strain expresses a kinase-deficient transforming growth factor β (TGFβ) receptor type II driven by a fibroblast-specific promoter, leading to ligand-dependent up-regulation of TGFβ signaling, and replicates key fibrotic features of scleroderma. Structural, biochemical, and functional assessments of pulmonary vessels, including in vivo hemodynamic studies, were performed before and following VEGF inhibition, which induced pulmonary endothelial cell apoptosis. These assessments included biochemical analysis of the TGFβ and VEGF signaling axes in tissue sections and explanted smooth muscle cells. RESULTS: In the TβRIIΔk-fib mouse strain, a constitutive pulmonary vasculopathy with medial thickening, a perivascular proliferating chronic inflammatory cell infiltrate, and mildly elevated pulmonary artery pressure resembled the well-described chronic hypoxia model of pulmonary hypertension. Following administration of SU5416, the pulmonary vascular phenotype was more florid, with pulmonary arteriolar luminal obliteration by apoptosis-resistant proliferating endothelial cells. These changes resulted in right ventricular hypertrophy, confirming hemodynamically significant PAH. Altered expression of TGFβ and VEGF ligand and receptor was consistent with a scleroderma phenotype. CONCLUSION: In this study, we replicated key features of systemic sclerosis-related PAH in a mouse model. Our results suggest that pulmonary endothelial cell injury in a genetically susceptible mouse strain triggers this complication and support the underlying role of functional interplay between TGFβ and VEGF, which provides insight into the pathogenesis of this disease

The burden and measurement of cardiovascular disease in SSc

The prognosis for patients with systemic sclerosis (SSc) has improved in the past three decades, with fewer patients succumbing to renal-crisis-related death. While pulmonary fibrosis and hypertension are currently the most frequent causes of death, there is evidence that cardiovascular disease will have an important role in the long-term prognosis of SSc in the future. Ischemia-reperfusion injury and endothelial dysfunction are cardinal features of SSc, and may predispose a patient to microvascular disease and atherosclerosis. In order to alleviate the cardiovascular burden in patients with SSc, it is important to detect endothelial dysfunction, microvascular flow disturbance and atherosclerosis. Noninvasive techniques that evaluate flow-mediated dilatation and arterial pulse waves (endothelial function measurements), microvascular blood flow (measurement of the microcirculation), carotid intima-media thickness and left ventricular hypertrophy (detection of atherosclerosis) are recommended. In addition, these measurements will facilitate trials of therapeutic strategies that, in addition to controlling conventional risk factors, prevent and treat cardiovascular disease in patients with SSc. © 2010 Macmillan Publishers Limited. All rights reserved.link_to_subscribed_fulltex

Is there evidence for vasculitis in systemic sclerosis?

Systemic sclerosis (SSc) is a devastating and potentially life-threatening multi-organ system disease. SSc is marked by skin thickening and tightening, Raynaud's phenomenon and digital ischemia with ulceration, gastrointestinal dysmotility, cardiopulmonary involvement with pulmonary fibrosis and pulmonary arterial hypertension, as well as renal failure. Fibrosis is the most obvious manifestation of SSc. Vascular involvement and inflammation are other prominent components of SSc pathology, and both features are also seen in vasculitis. This review analyzes whether there is evidence for vasculitis especially with particular organ manifestations and subgroups of patients