ReviewVascular biomarkers and correlation with peripheral vasculopathy in systemic sclerosis
Section snippets
Introduction—systemic sclerosis is a vascular disease from its early onset
Systemic sclerosis (SSc; scleroderma) is a life-threatening connective tissue disorder of unknown etiology, characterized by widespread vascular injury and dysfunction, impaired angiogenesis, immune dysregulation and progressive fibrosis of the skin and numerous visceral organs [1], [2], [3], [4].
A growing body of evidence supports the concept that SSc is primarily a vascular disease mediated by autoimmunity and evolving into tissue fibrosis [5], [6]. The dysregulation of vascular tone control,
Nailfold videocapillaroscopy: an open-window for detecting microvasculopathy in SSc
The damage of the microvessels evolves progressively from the early to the late stages in SSc, with different morphological abnormalities that are clearly shown by nailfold videocapillaroscopy (NVC) changes during the disease evolution [14], [15], [16], [17], [18]. These modifications are often accompanied by abnormal levels of angiogenic/angiostatic factors and markers of EC activation and injury.
The variety of NVC changes parallel the different degree of vascular disturbances in SSc [6], [9].
Vascular biomarkers and correlations with NVC changes and DUs
Several vascular biomarkers have been studied in SSc and correlated with NVC changes and the presence of DUs (Table 2, Fig. 1).
Conclusion
Microvascular abnormalities are the earliest events and key features of SSc responsible for the clinical manifestations of peripheral vasculopathy that are among the major life-threatening complications of the disease.
SSc microangiopathy seems to be strictly related to an impairment of selective factors reflecting disturbances of angiogenesis and endothelium damage. Many of these markers have been shown to clinically correlate with disturbed NVC capillary architecture and/or the occurrence of
Take-home messages
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In SSc, microvascular abnormalities are responsible both for the earliest clinical manifestations of peripheral vasculopathy and the major life-threatening complications of the disease.
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Several vascular mediators are dysregulated in SSc, reflecting endothelial damage and disturbances of angiogenesis.
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Some of these biomarkers correlate with NVC changes and/or the occurrence of ischemic DUs.
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Vascular mediators and their pathways could become targets for novel specific therapies, aiming to prevent
Acknowledgments
IC is supported by a research grant from the Foundation for the Development of Internal Medicine in Europe (FDIME). IC acknowledges Dr. Paula Vaz Marques for the NVC pictures.
References (89)
- et al.
Raynaud's phenomenon: from molecular pathogenesis to therapy
Autoimmun Rev
(2014) - et al.
Systemic sclerosis and cryoglobulinemia: our experience with overlapping syndrome of scleroderma and severe cryoglobulinemic vasculitis and review of the literature
Autoimmun Rev
(2013) - et al.
Angiogenic cytokines and growth factors in systemic sclerosis
Autoimmun Rev
(2011) - et al.
Capillaroscopic pattern in systemic sclerosis—an association with dynamics of processes of angio- and vasculogenesis
Microvasc Res
(2010) - et al.
The role of nail-videocapillaroscopy in early diagnosis of scleroderma
Autoimmun Rev
(2013) - et al.
Circulating intercellular adhesion molecule-1 in patients with systemic sclerosis
Clin Immunol Immunopathol
(1993) - et al.
Peripheral blood mononuclear cells from patients with systemic sclerosis spontaneously secrete increased amounts of vascular endothelial growth factor (VEGF) already in the early stage of the disease
Adv Med Sci
(2011) - et al.
Impaired angiogenesis in systemic sclerosis: the emerging role of the antiangiogenic VEGF(165)b splice variant
Trends Cardiovasc Med
(2011) - et al.
Autoantibodies in systemic sclerosis
Autoimmun Rev
(2013) - et al.
Diagnostic accuracy and predictive value of extended autoantibody profile in systemic sclerosis
Autoimmun Rev
(2012)
Cellular players in angiogenesis during the course of systemic sclerosis
Autoimmun Rev
Anti-annexins autoantibodies: their role as biomarkers of autoimmune diseases
Autoimmun Rev
Anti-annexin V antibodies: are they prothrombotic?
Autoimmun Rev
Biomarkers in systemic sclerosis
Biomark Med
Differential expression of junctional adhesion molecules in different stages of systemic sclerosis
Arthritis Rheum
Increased serum levels and tissue expression of matrix metalloproteinase-12 in patients with systemic sclerosis: correlation with severity of skin and pulmonary fibrosis and vascular damage
Ann Rheum Dis
Scleroderma pathogenesis: a pivotal role for fibroblasts as effector cells
Arthritis Res Ther
Clinical significance of serum levels of sCD36 in patients with systemic sclerosis: preliminary data
Rheumatology (Oxford)
Review: Evidence that systemic sclerosis is a vascular disease
Arthritis Rheum
Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis
Arthritis Rheum
The complexity of managing systemic sclerosis: screening and diagnosis
Rheumatology (Oxford)
Mechanisms in the loss of capillaries in systemic sclerosis: angiogenesis versus vasculogenesis
J Cell Mol Med
Serum levels of soluble vascular endothelial growth factor receptor-2 in patients with systemic sclerosis
Br J Dermatol
Biomarkers of vascular disease in scleroderma
Rheumatology (Oxford)
Abnormal plasma levels of different angiogenic molecules are associated with different clinical manifestations in patients with systemic sclerosis
Clin. Exp. Rheumatol.
Angiogenesis and vasculopathy in systemic sclerosis: evolving concepts
Curr Rheumatol Rep
Angiogenic and angiostatic factors in systemic sclerosis: increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcers
Arthritis Res
Diagnostic potential of in vivo capillary microscopy in scleroderma and related disorders
Arthritis Rheum
Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis
J Rheumatol
A systematic overview on the use and relevance of capillaroscopy in systemic sclerosis
Expert Rev Clin Immunol
Evaluating microangiopathy in systemic sclerosis: what have we learnt and what is left to discover?
Expert Rev Clin Immunol
Nailfold capillaroscopy abnormalities as predictors of mortality in patients with systemic sclerosis
Clinical Exp Rheumatol
Organ involvement in Argentinian systemic sclerosis patients with “late” pattern as compared to patients with “early/active” pattern by nailfold capillaroscopy
Clin Rheumatol
Digital ulcers as a sentinel sign for early internal organ involvement in very early systemic sclerosis
Rheumatology (Oxford)
Natural history of ischemic digital ulcers in systemic sclerosis: single-center retrospective longitudinal study
J Rheumatol
Digital ulcers: overt vascular disease in systemic sclerosis
Rheumatology (Oxford)
Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database
Ann Rheum Dis
Digital ulcers in scleroderma: staging, characteristics and sub-setting through observation of 1614 digital lesions
Rheumatology (Oxford)
Functional impairment of systemic scleroderma patients with digital ulcerations: results from the DUO Registry
Clin Exp Rheumatol
Angiogenic biomarkers predict the occurrence of digital ulcers in systemic sclerosis
Ann Rheum Dis
Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthritis and systemic sclerosis
Arthritis Res Ther
Soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement
Clin Rheumatol
Correlations between angiogenic factors and capillaroscopic patterns in systemic sclerosis
Arthritis Res Ther
Correlation between serum E-selectin levels and panoramic nailfold capillaroscopy in systemic sclerosis
Braz J Med Biol Res
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2019, Microvascular ResearchCitation Excerpt :It increased concentrations were strongly associated with avascular areas and tended to be elevated in patients with “Late” NVC pattern. This is in accordance with several studies that have reported markedly increased VEGF in SSc skin and serum despite clear evidence of an insufficient angiogenic response (Avouac et al., 2013; Choi et al., 2003; Chora et al., 2015; Distler et al., 2002, 2004; Mackiewicz et al., 2002; Manetti et al., 2010). This is also in agreement with notion of inverse correlation between serum VEGF levels and capillary density with significantly higher VEGF concentrations in SSc patients with the “Late” NVC pattern, compared to patients with the “Early” or “Active” NVC patterns reported by other authors (Avouac et al., 2013; Choi et al., 2003).
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