Review: Evidence That Systemic Sclerosis Is a Vascular Disease

Authors


Introduction

Systemic sclerosis (SSc; scleroderma) traditionally has been considered a disease of disordered connective tissue metabolism, presenting with varying degrees of skin or major organ fibrosis. It has been widely recognized that the tissue fibrosis seen in scleroderma patients is the end result of a complex biologic process involving immune activation and widespread vascular injury ([1]). In fact, compelling clinical and biologic evidence suggests that the primary target for both initiating and propagating the disease is blood vessels. More than 120 years ago, Dinkler suggested that skin sclerosis is due to vascular involvement ([2]). In 1975, Campbell and LeRoy emphasized this concept and presented their “vascular hypothesis,” which suggested that microvascular disease was a fundamental part of the pathogenesis of scleroderma ([3]). In this article, we will present evidence from both clinical observations and biologic studies that supports the hypothesis that vascular disease is of fundamental importance in the pathogenesis of scleroderma, from the very early onset of the disease through late clinical complications. We will also propose a novel approach to therapy that focuses on vascular disease.

Clinical evidence for vascular involvement

Raynaud's phenomenon (RP).

RP is the clinical manifestation of abnormal functioning of the cutaneous vessels involved in thermal regulation of blood flow ([4]). It occurs in almost all SSc patients, it is usually the first sign of disease, and it begins before the onset of clinical signs of tissue fibrosis. The presence of RP and the loss of normal regulation of cutaneous vascular tone is a predictor of developing scleroderma ([5]). The locations of the most severe skin fibrosis follow the same distribution patterns as typical cutaneous body sites involved in thermoregulation (e.g., the fingers, feet, face, and lower arms), suggesting some causative relationship between the vascular disease and skin fibrosis.

It has been suggested that RP in SSc patients may be triggered by endothelial injury ([6]) (Figure 1). While the exact mechanism for the initial endothelial injury is unknown, apoptosis induced by infection, immune-mediated cytotoxicity, antiendothelial antibodies, and ischemia-reperfusion injury have all been implicated ([7]). Evidence suggests that dysfunction of the endothelium results in an imbalance of vasoactive factors, including overproduction of the vasoconstrictor endothelin 1 (ET-1) and underproduction of the vasodilator nitric oxide (NO) and prostacyclin ([7]). Additional evidence suggests dysregulation of a variety of neurotransmitters and their receptors that regulate small sensory nerve fibers as well as sympathetic vasoconstrictor and vasodilator nerves ([8]). Decreased release of vasodilatory neuropeptides from sensory nerves and up-regulation of vascular smooth muscle α2C-adrenoreceptors that enhance vasoconstrictive responses to stress or cold stimuli are implicated in the dysfunction of the thermoregulatory vessels leading to RP. Patients with RP who develop scleroderma exhibit unique changes in vascular structure; these changes are characterized by intimal thickening that can eventually occlude the vessel lumen, thus causing ischemic injury and chronic tissue hypoxia (Figure 1). Skin hypoxia has been documented in SSc patients and is a potent stimulus for growth factors that mediate tissue fibrosis ([9]), suggesting that vascular damage is the primary insult, which then provokes tissue fibrosis.

Figure 1.

Masson's trichrome staining of a digital artery from a patient with systemic sclerosis (SSc) (A) and hematoxylin and eosin staining of a renal artery from a patient with SSc (B). Note the striking fibrotic intimal hyperplasia and the adventitial fibrosis in the digital artery and the onion skin–like intimal thickening composed of smooth muscle cells and increased connective tissue matrix in the renal artery. The intimal hyperplasia results in critical luminal narrowing and even occlusion.

Digital ulcers

The development of digital ulcers is a frequent and early complication in SSc. Surveys show that ∼75% of patients will have their first digital ulcer episode within 5 years of their first non-RP symptom ([10]), and 30% of patients will experience digital ulcer complications each year. In some cases, digital ulcers lead to the loss of a digit due to complications associated with infection or associated macrovascular disease. Digital ulcers have a high impact on the quality of life and the cost of patient care ([10-14]).

Telangiectasias and gastric antral vascular ectasia (GAVE).

Telangiectasias are frequently seen in SSc patients due to dilatation of the postcapillary venules located in the papillary and superficial reticular dermis ([15]). Telangiectasias are a clinical marker of widespread aberrant microvascular disease. For example, their presence is associated with underlying pulmonary arterial hypertension (PAH) ([16]). Similar vascular malformations are found on the mucosa of the gastrointestinal (GI) tract ([17-19]). GAVE (or “watermelon stomach”) and similar lesions in the small and large bowel can lead to problematic GI bleeding ([20]) prior to other internal organ involvement ([21]). It has been suggested that the pathogenesis of telangiectasias is related to a disorder of transforming growth factor β (TGFβ) receptor family signaling in the microvasculature ([22]).

Nailfold capillaries

Microvascular damage in SSc patients can be detected in structural alterations of the capillaries of the skin. These alterations include a progressive decrease in the density of the capillaries, enlargement of the capillaries, and microhemorrhages. They also include signs of both neovascularization and new avascular areas associated with a decrease in cutaneous blood flow ([23, 24]). This scleroderma pattern of nailfold capillary changes is used as a clinical diagnostic tool that enables physicians to distinguish patients with scleroderma from patients with uncomplicated primary RP. In patients with RP, the presence of enlarged/giant capillaries, capillary loss, and/or the presence of SSc-related autoantibodies (anticentromere and anti–topoisomerase I autoantibodies) predicts the evolution of RP to definite scleroderma ([25]). These microvascular alterations can be divided into an “early pattern” (few giant capillaries, few capillary microhemorrhages, no evident loss of capillaries, and relatively well-preserved capillary distribution), an “active pattern” (frequent giant capillaries, frequent capillary microhemorrhages, moderate loss of capillaries, and absence of mild ramified capillaries with mild disorganization of the capillary architecture), and a “late pattern” (relative absence of giant capillaries and microhemorrhages, severe loss of capillaries with extensive avascular areas, ramified/bushy capillaries, and intense disorganization of the normal capillary array) ([26]).

These nailfold capillary changes can be quantified using a validated scoring system ([27]) for both diagnostic purposes and as a clinical biomarker of disease activity and severity ([28]). A capillaroscopic skin ulcer risk index has been shown to identify SSc patients at high risk of developing digital ulcers ([29, 30]). There is also evidence that cardiac disease is more severe in patients with higher nailfold capillary scores. Moreover, a reduction of nailfold capillary density is correlated with the severity of PAH ([31, 32]), again suggesting an association between cutaneous microvascular changes and systemic vascular disease.

Systemic vascular disease

The vascular disease of SSc is not limited to the microcirculation of the skin but also is seen in other targeted organs including the heart, lungs, kidneys, and GI tract. In fact, macrovascular disease of the peripheral circulation occurs in conjunction with the more distal small vessel pathology. Clinical and pathologic evidence strongly supports the concept that the primary insult in targeted organs of SSc patients is directed at blood vessels, and this insult results in tissue ischemia, fibrosis, and ultimately major organ malfunction. Heart dysfunction occurs with evidence of microvascular disease, which results in ischemic events and contraction band necrosis, conditions that can be explained by both occlusive vascular disease and intermittent vasospasm (i.e., intramyocardial RP [33]). The end result is arrhythmias and cardiac dysfunction that often is clinically silent until late complications occur. Cardiac and pulmonary vascular diseases are major causes of morbidity and mortality among SSc patients.

PAH is present in 7.5–12% of patients, but evidence that pulmonary circulation has been compromised is more common ([11]). In addition, the main pathologic lesions observed in the peripheral microcirculation are also found in the pulmonary circulation ([34, 35]). This obstructive proliferative vasculopathy of the small- and medium-sized pulmonary arterial circulation leads to increased pulmonary artery pressure, with downstream progressive loss of oxygenation and upstream right heart failure ([36]). As with other forms of PAH, there is evidence of underlying endothelial injury and dysfunction, which in turn are associated with decreased production of the vasodilators NO and prostacyclin and increased production of the vasoconstrictive peptide ET-1 ([37]). These findings provide the rationale for the current vasodilator therapy used to treat patients with SSc-related PAH. While potential common molecular pathways for pulmonary vascular disease have been regularly discovered ([37]), knowledge of genes marking susceptibility to the disease is only just emerging ([38]). Recently, the first evidence for an association of the KCNA5 single-nucleotide polymorphism rs10744676 with SSc-associated PAH was reported ([39]). Still, the pathophysiologic significance of this association remains unclear.

Scleroderma renal crisis (SRC) is another dramatic representation of the systemic nature of SSc vascular disease. SRC occurs in ∼5% of patients and is still a major cause of morbidity and mortality. It is characterized by sudden onset of severe hypertension, which may be followed by acute renal failure and its accompanying complications ([40]). SRC is associated with reversible vasospasm and a vasculopathy of arcuate and interlobular renal arterial circulation. An injury to the renal endothelium is believed to initiate progressive renal vascular injury that triggers high renin levels and accelerated hypertension. Renal arterial changes are characterized histologically by onion skin–like lesions and fibrotic intimal sclerosis (Figure 1), with or without adventitial fibrosis, and by thickening of the basement membrane that can result in development of end-stage glomerulosclerosis ([41]).

Other commonly involved organs are also thought to be affected by microvascular disease. GI dysfunction is characterized by loss of smooth muscle of the bowel wall and various degrees of tissue fibrosis. One theory is that an initial vascular insult leads to neurogenic dysfunction and bowel dysmotility prior to fixed structural changes. Erectile dysfunction is a common complication of SSc and is a clinical consequence of the scleroderma microvascular disease and local tissue fibrosis.

Macrovascular involvement

Macrovascular disease, defined as involvement of blood vessels with an internal diameter of >100 microns, has been recognized in conjunction with the more distal small vessel pathology. For example, it has been well documented that frequent and severe involvement of digital arteries, palmar arch, and distal arteries of the arms and legs occurs with luminal occlusion ([42]). Evidence also suggests a unique predilection for significant occlusive disease in the ulnar artery of patients with limited SSc, and this occlusive disease also is associated with critical ischemic events ([43]). Larger muscular artery involvement can lead to large skin ulcerations or loss of a digit or limb.

Impairment of the brachial artery flow mediated by vasodilation of the brachial artery in scleroderma patients has been reported. Although controversial, evidence also suggests an association with increased carotid intima-media thickness (IMT) ([44, 45]). A correlation between the morphology and blood flow of the proper palmar digital arteries and nailfold capillary morphology has been identified ([46]), providing evidence that progression of microvascular disease is linked to macrovascular disease. Additionally, it has been demonstrated that patients with low microvascular damage (early capillaroscopic pattern) had normal morphology of the palmar arteries, but the blood flow was reduced and the vascular resistance increased. Microvascular damage (active and late capillaroscopic patterns) has been associated with a significant decrease in local blood flow.

Although macrovascular disease clearly occurs among patients with SSc, it has been well documented primarily in the peripheral circulation. Ongoing debates have continued in order to determine whether accelerated atherosclerosis is a major feature of SSc, as has been suggested by its association with other rheumatic diseases. The IMT in SSc has been related to steroid treatment ([47]), oxidized low-density lipoprotein ([48]), and angiotensin-converting enzyme polymorphism ([49]). Reduced coronary flow due to microvascular disease has been demonstrated in scleroderma patients ([50]), but the role of macrovascular involvement (epicardial coronary arteries) is still under investigation. Angiographic findings as well as computed tomography studies have generated conflicting reports about the role of coronary atherosclerosis in scleroderma. An autopsy study examined the evidence for coronary artery disease but did not identify differences between medium arteries among scleroderma patients and control groups, although researchers did identify an increase in atherosclerosis in the small arteries ([51]). An angiographic study showed that the prevalence of coronary artery disease among SSc patients was similar to that in the general population ([52]). Recent epidemiologic surveys have suggested that the risk of coronary artery disease is increased among SSc patients ([53, 54]). However, additional research is needed to determine whether premature atherosclerosis occurs among SSc patients independent of traditional risk factors.

Pathologic modification and vascular pathogenesis

Scleroderma vasculopathy is characterized by a variety of changes that affect mainly the microcirculation and small arterioles. In the capillaries, vascular disease is characterized by distorted and irregular capillary loops in all the involved organs, including the kidneys, lungs, heart, and muscles. This reflects the diffuse nature of the microvascular disorder, even in sites not affected by fibrosis ([55]). On the ultrastructural level, the earliest vascular changes in the edematous stage of the disease involve opening of the tight junctions between endothelial cells (ECs), vacuolization of cytoplasm, and an increase in the number of basal lamina–like layers. Ghost vessels consisting of basal lamina with remnants of ECs are also present, in addition to perivascular cellular infiltrates that consist of macrophages, T cells, and B cells, with a predominance of CD4+ T cells ([56]). EC apoptosis was first described on ultrastructural examination of scleroderma biopsy samples in the early stages of the disease and in association with the inflammatory stage, suggesting a causal relationship ([56]). It was later noted in the University of California at Davis that lines 200/206 chickens spontaneously developed a disease resembling human scleroderma ([57]).

The fate of apoptotic ECs in SSc has not been thoroughly examined. A possible defect in the orderly removal of apoptotic cells may lead to phagocytosis by dendritic cells and macrophages and subsequent presentation of cellular antigens to CD8+ T cells ([58]), in turn leading to immune recognition of vascular antigens. Moreover, apoptotic ECs can activate the alternative complement and coagulant cascades, leading to vascular microthrombosis and resulting in further tissue compromise ([59]). Milder vascular changes can be seen in clinically uninvolved skin, mainly in the papillary dermal layer, in addition to an increased number of platelets adhering to the vessel walls of the dermal microvasculature ([56]). These findings support the idea that EC injury is an early pathologic event and suggest that EC dysfunction occurs in the early stages of the disease, only to progressively worsen with an advanced vascular insult. Abnormal vasoreactivity is thought to result from EC malfunction, with an imbalance favoring vasoconstriction due to overexpression of ET-1 as well as reduced production of NO and prostacyclin.

Vascular wall remodeling in SSc

Vascular remodeling follows microvascular injury and damage. Intimal and medial thickening and adventitial fibrosis are the common forms of remodeling found in SSc (Figure 1). The origin of the cells that populate the intima and cause the aberrant repair is unknown; however, activated resident fibroblasts, circulating fibroblast precursors (fibrocytes), and the transformation of epithelial cells, ECs, and pericytes have all been implicated ([60]).

One theory is that vascular smooth muscle cells (VSMCs) are responsible for generating the fibrotic intimal lesions. Under normal conditions, these muscle cells assume a contractile or dedifferentiated phenotype and regulate vessel diameter and blood flow. Dysfunctional ECs, infiltrating leukocytes, and altered extracellular matrix (ECM) in scleroderma provide the biologic signals for VSMCs to migrate into the intima, differentiate, and then synthesize the matrix of the fibrotic vascular lesion.

Another theory is that diseases characterized by alterations in stromal elements and fibrosis are secondary to the transformation of epithelial cells/ECs to mesenchymal cells ([61]). It has been shown that subendothelial mesenchymal cells might contribute to disease pathogenesis through transdifferentiation of ECs into myofibroblasts via TGFβ-induced endothelial-mesenchymal transition ([62]). Following injury, mesenchymal cells and ECs are influenced by several specific stimuli (e.g., hypoxia, cytokines/growth factors). These stimuli can provoke a transition into myofibroblasts that then home to the vascular intima and lead to the formation of the “neointima” that is characteristic of SSc vascular disease.

Defective angiogenesis and vasculogenesis

The vasculopathy in SSc is systemic and progressive. This suggests that the obliteration of the microvasculature and associated structural disease is not normally repaired by either a compensatory growth of new vessels from existing vessels (angiogenesis) or de novo formation of new vessels (vasculogenesis). Defective angiogenic pathways, as well as the failed release of bone marrow–derived progenitor cells, which have the potential to initiate vascular repair, have been identified in SSc patients. An early clinical indicator of defective angiogenesis/vasculogenesis is visible in the nailfold capillaries. Profound loss of the capillaries is evident along with the absence of visible new normal vessel formation. The hypoxic/ischemic state in SSc should encourage neoangiogenesis, but new cutaneous capillaries are rarely seen. Instead, nailfold capillary examinations have shown substantial avascular areas, which suggest defective angiogenesis and abnormal vascular repair pathways. The failure to compensate for vascular injury eventually leads to cumulative loss of capillaries and arterioles, resulting in the well-known vascular complications: painful ulcers appear on the digits, SRC occurs in the kidneys, and PAH occurs in the lungs.

Tissue ischemia normally leads to the expression of angiogenic growth factors (e.g., vascular endothelial growth factor [VEGF]), which then initiate angiogenic sprouting by inducing vasodilation and then proliferation and migration of ECs. This leads to stabilization of a new tubal structure and lumina that form new vessels. Interestingly, while both pro- and antiangiogenic factors are overexpressed in SSc (Table 1), there appears to be an imbalance in the ratio of these mediators, favoring inhibition of angiogenesis and progressive vascular disease. Presumably, a critical element of angiogenesis is either absent or blocked in SSc. Surprisingly, several studies have demonstrated enhanced expression of the proangiogenic factor VEGF-A in both the skin and the circulation of SSc patients ([63, 64]). The paradox is that VEGF levels, rather than being associated with evidence of angiogenesis, actually correlate with progressive microvascular loss and disease progression.

Table 1. Up-regulated proangiogenic and antiangiogenic mediators in systemic sclerosis
AngiogenicAngiostatic
Vascular endothelial growth factorEndostatin
Basic fibroblast growth factorInterferon-γ–inducible protein 10/CXCL10
Platelet-derived growth factorAngiostatin
Interleukin-8/CXCL8Angiopoietin 2
Stromal cell–derived factor 1/CXCL12Pentraxin 3
Interleukin-6Interleukin-4
CD44Thrombospondin 1 (TSP-1) and TSP-2
Kallikrein 9, 11, and 12Platelet factor 4
Urokinase plasminogen activator receptorMonokine induced by interferon-γ/CXCL9
Matrix metalloproteinase 9 (MMP-9) and proMMP-1Soluble endoglin

One explanation is that VEGF pre–messenger RNA is differentially spliced to form messenger RNAs (mRNAs) that encode at least 6 isoforms, one of which is the antiangiogenic VEGF165b splice variant. This variant is selectively overexpressed at both the mRNA and protein levels in SSc skin. Thus, the increase in VEGF expression in SSc patients appears to be mostly due to increased levels of VEGF165b and not the proangiogenic VEGF165 ([65]). This switch in SSc from proangiogenic to antiangiogenic VEGF isoforms may play a crucial role in explaining the insufficient angiogenic response to chronic ischemia. Another theory is that the soluble VEGF receptor (soluble Flt-1 [sFlt-1]) is expressed by ECs, binds to VEGF, and decreases its activity in angiogenesis. Both elevated and depressed levels of sFlt-1 have been reported among SSc patients ([66, 67]). Functional in vitro studies of SSc have revealed reduced angiogenic properties of these ECs. This defect has been linked mainly to the cleavage by matrix metalloproteinase 12 of the urokinase plasminogen activator receptor (u-PAR), resulting in a loss of the u-PAR link to β2 integrin—a linkage that is needed for the initiation of EC-mediated angiogenic processes ([68]).

Vasculogenesis is dependent on differentiating endothelial progenitor cells (EPCs) that are mobilized from the bone marrow and home to ischemic tissues in order to initiate and restore vascular supply. Reduced numbers of circulating EPCs in SSc have been reported, particularly in the late stages of the disease ([69]). This reduction in EPCs also has been associated with capillary loss and severe internal organ involvement (predominantly cardiac) as well as the development of PAH ([70]). The exact reason for the decrease of EPCs in patients with scleroderma is not clear. However, there is evidence in support of one theory: a defect in the architecture of the bone marrow with significant reduction in vascularity and increased fibrosis, which suggests a failure to release EPCs. Alternatively, apoptosis of EPCs due to antiendothelial antibodies supports the idea that a humoral autoimmune process may mediate defective vasculogenesis ([71]). Another defect in vasculogenesis has been suggested by in vitro studies demonstrating defective migration and proliferation of mesenchymal stem cells (MSCs) in scleroderma patients, as well as decreased angiogenic potential when compared to healthy control cells ([72]).

Vascular treat to target—a possible strategy in SSc

In SSc, several pathogenetic factors have been identified as potential targets for antifibrotic therapy, such as TGFβ, Wnt ligands, Toll-like receptor–mediated signaling, and type I interferon. At present, no specific therapy that may reverse vascular injury or direct normal vascular repair has been identified. Still, the recent development of drugs that target specific molecules and pathways represents a major advance in the treatment of SSc vasculopathy.

Some of the current treatment approaches include the following:

  1. Prostacyclin analogs. The main indication for prostacyclin analog therapy in scleroderma is a severe vascular complication, with epoprostenol being used predominantly in PAH and iloprost in complicated RP.
  2. Endothelin antagonists. Both bosentan and ambrisentan improve exercise capacity, functional class, and hemodynamic parameters in patients with scleroderma and PAH. Moreover, bosentan is helpful in preventing digital ulcers in SSc, especially in patients with multiple ulcers.
  3. Phosphodiesterase inhibitors. Sildenafil and tadalafil are selective phosphodiesterase 5 inhibitors that target the NO-mediated vasodilation pathway. Both have been shown to improve exercise capacity in patients with PAH, and tadalafil has beneficial effects in treating RP.
  4. Rho/Rho-associated protein kinase signaling. This pathway is believed to be involved in the genesis of fibroproliferative vascular disorder and can be targeted by the hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and by imatinib mesylate. Preliminary data suggest improvement in blood flow and deactivation of ECs with the use of statins ([73, 74]), and the results of the first trials with imatinib are now eagerly awaited.
  5. Human MSCs. This cell type can be used as an alternative source for EPCs. Recent uncontrolled observations have provided support for the efficacy of MSCs in treating intractable digital ulcers, where autologous injection of MSCs led to a reduction in the size of the ulcers, an increase in blood flow, and the formation of new capillaries ([75, 76]).
  6. Immunosuppressive therapy. This is being considered as a potential therapy for vascular disease, given the evidence that an immune insult may initiate the EC injury. For example, rituximab is being studied for the treatment of SSc-related pulmonary hypertension.
  7. Tyrosine kinase inhibitors. These inhibitors have the potential to reverse tissue fibrosis by inhibiting the TGFβ pathway. Investigations are under way to test whether imatinib plays a role in effectively treating pulmonary hypertension.

Other vascular agents include more potent vasodilators; inhibitors of endothelial apoptosis in the early stages of the disease; inhibitors of vascular wall proliferation; and antithrombotics, including thrombolytics, anticoagulants, and antiplatelet approaches.

Relationship of vascular disease to fibrosis

Fibrosis is the clinical hallmark of SSc, which results from a switch in the tissue fibroblast to an activated state that synthesizes abnormally high levels of ECM. This excessive ECM deposition results in organ dysfunction, which is a major feature of SSc pathology. The vascular injury and defective vascular response are considered to occur before and to lead to tissue fibrosis. There are various hypotheses that have attempted to explain the mechanism by which injury to the vascular system contributes to fibrosis; one hypothesis suggests that cytokines secreted by ECs form a gradient that attracts fibroblasts to the blood vessels, which in turn stimulates fibroblast proliferation, activation, and synthesis as well as secretion of collagen. Another hypothesis is that ECs become permeable, which results in the secretion of factors that stimulate fibroblast proliferation and activation as well as collagen production. Two factors implicated as the link between ECs and fibrosis are TGFβ and connective tissue growth factor (CTGF); both may mediate fibrosis following endothelial apoptosis. In the TGFβ-dependent theory, apoptotic ECs recruit phagocytes, particularly macrophages, which engulf the apoptotic cells. This event stimulates up-regulation of TGFβ, which promotes myofibroblast differentiation ([77]). However, in the CTGF hypothesis, products of apoptotic ECs may induce fibrosis by up-regulating CTGF expression ([78]). Finally, there is evidence suggesting that endothelial injury can lead to platelet activation and release of platelet-derived growth factors.

The association between vasculopathy and tissue fibrosis is not unique to scleroderma since it is seen in many other fibrotic disorders. For example, in idiopathic pulmonary fibrosis, an aberrant vascular remodeling occurs in the lungs, whereby fibrotic areas have fewer blood vessels with almost no capillaries within the fibroblastic foci, indicating that the fibrotic process is devoid of neovascularization ([79, 80]). SSc provides a unique disease model to investigate the sequence of pathogenetic events linking vascular injury to fibrosis, especially since the vascular disease seems to precede the fibrotic disorder.

Where and when does SSc start?

Research described in this review supports the hypothesis that vascular disease is a major pathologic component of SSc and that blood vessels are likely the initial target of the disease process (Figure 2). As a consequence of the resulting vasculopathy, ischemia-reperfusion tissue injury occurs along with vascular leakage of growth factors and tissue hypoxia—all of which trigger progressive tissue fibrosis. Notable is the fact that not only is the vascular disease linked to tissue fibrosis and organ failure, but the vascular disease is also due in part to a fibrotic process. Evidence suggests that increased migration of activated myofibroblasts into the vessel wall leads to a significant increase in ECM deposition in the intima and media, resulting in vascular stiffness and dysfunction. Eventually the fibrotic vascular process reduces the vessel's lumen and results in a hypoxic effect in the involved tissue (skin, lung, kidney, heart). Indeed, one can characterize scleroderma as a “fibrosing microvascular disease.”

Figure 2.

Pathogenesis of systemic sclerosis vasculopathy. Endothelial injury and dysfunction are initiated by the actions of free radicals or chemical and microbial agents that injure the endothelium, either directly or indirectly. This injury is also initiated by the induction of immune activation and the generation of autoantibodies and activated cellular immunity. The vascular injury activates platelet and coagulation pathways, which results in vascular microthrombosis. The resulting vasculopathy is associated with intimal hyperplasia in the small arterioles, and the ensuing luminal narrowing results in tissue hypoxia and chronic ischemia. Released vascular products, in association with hypoxia and ischemia, collectively contribute to the activation of resident fibroblasts, which in turn perpetuates the vasculopathy by triggering vascular wall fibrosis.

The vascular injury likely continues throughout the disease process, thus accounting for late clinical consequences (e.g., pulmonary hypertension). We present our hypothetical view of the disease course in Figure 3, based on our expert opinion. Early recognition of the manifestations of the vascular disease can provide important diagnostic clues. It is now reasonable to conclude that patients presenting with definite RP and abnormal nailfold capillaries in the presence of an SSc-specific autoantibody indeed have SSc. Identifying patients in the very early phase of the vascular disease, before irreversible tissue injury and fibrosis occur, may therefore provide therapeutic and preventive options.

Figure 3.

Schematic depiction of the course of systemic sclerosis (SSc) with onset of the various organ system involvements. While the initial events triggering vascular disease have not been fully defined, evidence suggests that the vascular system is a major target early in the disease process and that progressive vascular disease occurs and plays a major role in late organ dysfunction. Raynaud = Raynaud's phenomenon; PAH = pulmonary arterial hypertension.

While we understand a great deal about the pathogenesis of vascular disease and its relationship to tissue fibrosis, we still do not know how SSc is initiated. Understanding the biologic events that occur prior to the onset of RP or other clinical signs of active vascular disease is critical in developing novel and effective therapies. In addition, once SSc has been diagnosed and established, attention to treatment of the vascular component is critical. While the traditional approach has been solely to use vasodilator therapy, new investigations are under way to develop novel therapies to prevent further vascular injury and to stimulate vascular repair.

AUTHOR CONTRIBUTIONS

All authors drafted the article, revised it critically for important intellectual content, and approved the final version to be published.

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