Module 20

Eular On-line Course on Rheumatic Diseases module n20 Marco Matucci-Cerinic, Irene Miniati, C.P.
Denton
SYSTEMIC SCLEROSIS
Learning Outcomes At the end the of this module on Systemic Sclerosis the student will be able to do the following:: To describe and explain the principal mechanisms of the pathogenesis of the disease To acquire the competence of making a diagnosis of the disease To be able to investigate internal organ involvement through lab and instrumental examinations To prescribe an overall treatment of the disease To prescribe a treatment specific for target organs To describe and explain the main complications of the disease
Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and internal organs, pronounced alterations in the microvasculature and frequent cellular and humoral immunity abnormalities. SSc is part of a more extensive group of diseases called scleroderma spectrum (table 1) (1). Table 1 The scleroderma spectrum of disorders Raynauds phenomenon Primary Secondary (Autoimmune) Localized scleroderma Morphea Linear scleroderma En coup de sabre Systemic sclerosis Limited cutaneous systemic sclerosis Diffuse cutaneous systemic sclerosis * isolated PR with abnormal nailfold capillaries and positive antinuclear antibodies
The distinction between localized scleroderma and systemic sclerosis is based on visceral involvement. Localized scleroderma is restricted to fibrotic involvement of the skin and subcutaneous tissues, while SSc (systemic scleroderma) affects also internal organs. There are many histopathological, pathogenetic and serological features common to localized and systemic forms of scleroderma, suggesting similar pathogenic mechanisms and the possibility of a common genetic or environmental predisposition. Concerning skin involvement, SSc is divided into two major categories (subsets) defined by the extension of skin sclerosis.
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Eular On-line Course on Rheumatic Diseases module n20 Marco Matucci-Cerinic, Irene Miniati, C.P. Denton
Limited cutaneous systemic sclerosis (lcSSc) is defined by skin involvement only distal to the elbows and knees, while diffuse cutaneous systemic sclerosis (dcSSc) is characterized by presence of skin thickening proximal to the knees and elbows. SSc sine scleroderma refers to the small number of patients who demonstrate vascular and serological features of SSc without any skin involvement (2). CREST (calcinosis, Raynauds phenomenon, oesophageal dysmotility, sclerodactyly, and telangiectasis) syndrome is an outdated term for lcSSc and should not to be used as a synonym for limited SSc because many patients with lcSSc do not develop all the features of CREST. This acronym does not recognise important complications of this subset including pulmonary arterial hypertension, mid-gut disease and lung fibrosis. SSc can also overlap other autoimmune diseases such as systemic lupus erythematosus, dermatomyositis and rheumatoid arthritis (overlap syndromes). 1 Epidemiology The incidence and prevalence of SSc varies in different populations, suggesting a role for genetic predisposition and\or exposure to environmental trigger factors. SSc seems to be more prevalent in the United States (276 cases per million adults) (3), than in Europe (8-15 cases per million adults (4,5). The real prevalence of SSc has been probably underestimated because the mild disease remains often undiagnosed. The annual incidence of new cases has been reported from 1 to 20 cases per million (3,5). SSc is three times more common in women than in men (6). Several recent series estimate in different populations a prevalence of approximately 1 in 10000, with incidence rates about 1 in 100000. 2 Etiology Environmental factors such as exposure to organic solvents and toxins, have been proposed as possible causative factors (7,8).The presence of microchimerism (9), infectious agents such as cytomegalovirus (10) and the inherent propensity for oxidative stress with associated generation of free radicals (11) are also candidate factors that might contribute to disease progression.
2.1 Pathogenesis and Genetic predisposition Pathogenesis of SSc is very complex and at present there is no unifying theory that may explain all its aspects. However, there are three main mechanisms responsible for the clinical and pathologic manifestations of SSc: 1) Vascular damage, principally of microcirculation; 2) Immune system activation/Inflammation, 3) Fibrosis.
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The role of genetic factors is supported by the observation of familiar clustering of the disease; the high frequency of occurrence of other autoimmune disorders and autoantibody positivity in SSc family members; differences in SSc prevalence and clinical manifestations among different ethnic groups and the increased prevalence of certain human leukocyte antigen (HLA) and major histocompatibility complex (MHC) in various ethnic populations with SSc (12). In addition to providing a permissive environment for the development of SSc, genetic factors may also be involved in the phenotypic expression of the disease (13).
-Causative agents: Environmental and infectious agents According to the theory of molecular mimicry autoantibodies (antibodies against self-antigens) are produced because the self-antigens contain epitopes that share structural similarities with viral or bacterial proteins. In SSc, it has been hypothesized infectious agents (herpes viruses, retroviruses and human cytomegalovirus) as possible causative/co-causative agents. This hypothesis is supported by: 1) the observation of a higher prevalence of IgA antihuman cytomegalovirus antibodies in patients with SSc (14); 2) the demonstration of sequence homologies between retroviral proteins and topoisomerase I antigen which is the target of Scl-70 (15); 3) the observation that the induced expression of retroviral proteins in normal human dermal fibroblasts results in the acquisition of a SSc-like phenotype in the production of extracellular matrix proteins (15). Despite these findings more consistent evidence for the involvement of the infectious agents in the aetiology or pathogenesis of SSc is still needed. Environmental factors such as exposure to silica, metal dust, (16-18) vinyl chloride (17), organic solvents (17), certain pesticides, hair dyes and fuel-derived or industrial fumes (16,18) have also been implicated in the development of SSc.
2.2 Microchimerism Microchimerism has been defined by the presence of a low number of circulating cells transferred from one individual to another, during pregnancy, blood transfusion, blood-marrow and solid-organs transplants. An increased presence of microchimeric cells has been observed in peripheral blood and tissues of patients with SSc (19-21). It has been hypothesized that these cells may become activated by a second event, producing a graft versus-host reaction triggering SSc. However, the differences between SSc and controls are quantitative and may reflect other aspects of the disease such as treatment. Also microchimerism is seen in other diseases. It is possible that it serves as a stimulus to the host immune system rather than a true GVHD.
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2. 3 Vascular damage Vascular dysfunction is one of the earliest alterations considered to be one of the initiating steps in SSc pathogenesis (22). Endothelial injury, preceded by endothelial activation, involves mainly microcirculation and is mediated by cytokines produced by activated lymphocytes (23) and by antibodies against endothelial cells (AECA) (24). Activated lymphocytes secrete cytokines, such as transforming growth factor beta (TGF), which cause endothelial cell injury and expression of MHC and intercellular adhesion molecule 1 (ICAM 1) , upregulate connective tissue growth factor CTGF to increase production of the extracellular matrix, and upregulate platelet derived growth factor (PDGF). Increased PDGF expression promotes endothelial cell proliferation and downregulates vascular endothelial growth factor (VEGF), which usually promotes neovascularisation (22). Events that follow endothelial activation and endothelial damage are:
The loss of normal vasomotor tone regulation with a decrease of vasodilators as nitric oxide, and increase of vasoconstrictors as endothelin I (25)
The chemo-attraction and adhesion of inflammatory cells (26,27). The exposition of subendothelium to the blood stream: this may induce circulating platelets, to adhere to it and initiate fibrin deposition and intravascular thrombus formation .
Activation of vascular muscle cells and their migration into the intimal layer of the blood vessel where they differentiate into myofibroblasts.
These alterations lead to the enhancement of the vascular damage, with proliferation of vascular intima, narrowing of the vessel lumen and reduction of blood flow, and subsequent clinical manifestations as Raynaud's phenomenon, digital ischemia and ulcers. A later stage of the disease is characterised by vessel loss (28). In SSc, this seems to be due to an abortive neoangiogenesis. The levels of circulating endothelial progenitor cells that differentiate into endothelial cells were found significantly lower in SSc, despite the higher concentration of most angiogenic factors. These results may reflect an inadequate response of endothelial progenitor cells and their stem cells in the bone marrow to angiogenic stimuli, suggesting an intrinsecal dysfunction (29). However, endothelial progenitor cells from early SSc gave rise to some degree of in vitro endothelial differentiation and their circulating levels were significantly higher than in patients with a late disease suggesting that an altered differentiation may be a later step of the disease pathogenesis (30). Besides this, a failure of endothelial repair following SSc-related damage seems also to be linked to an alteration in endothelial differentiation of mesenchymal stem cells. These are multipotent cells present in adult bone marrow and display some features of mature endothelial cells, such as the expression of vWf, VEGFR1, VEGFR2, VE-cadherin and VCAM1. In mesenchymal stem cells of SSc patients a decreased percentage of VEGFR2+, CXCR4+, VEGFR2+/CXCR4+ cells has been found ;indeed, the angiogenic potential of endothelial like mesenchymal stem cells was reduced after being stimulated with VEGF and SDF-1, suggesting that endothelial repair may be affected in SSc starting from the bone marrow (31).
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2. 4 Immune activation\Inflammation Humoral and cellular immune system alterations and persistent tissue inflammation play an important pathogenetic role in SSc. The activation of humoral immunity is demonstrated by the numerous autoantibodies that have been described in SSc. The presence of antinuclear antibodies can be found in more than 90% of patients with SSc. Anti-Scl70 antibodies react with nuclear enzyme DNA topoisomerase I and are almost exclusively found in patient with dcSSc, but only 30-40% of these patients present anti-Scl 70. Anti-centromere antibodies are present in 80-90% of patients with lcSSc and recognize several protein components of the three-laminar kinetochore. Anti-Scl 70 and anti-centromere antibodies rarely coexist in the same patient. Other autoantibodies are less common in SSc, as anti-RNA polymerases I and II antibodies, found in patients with rapidly progressive disease and severe internal organ involvement; antifibrillarin antibodies may be found in dcSSc and anti-PM-Scl antibodies found in SSc patients without inflammatory myopathy. Although autoantibodies are very common in SSc, it is not yet demonstrated that they are directly involved in the disease pathogenesis. The cellular immune system and the consequent chronic inflammation has an important role as mononuclear cell infiltrates are found in affected skin and visceral organs of SSc patients. The mononuclear cells within the skin infiltrates are predominantly CD4+T cells and express the activation marker class II MHC antigen DR (32,33). Subsequent oligoclonal expansion of these cells within the tissues has been observed (34), suggesting an antigen-driven response, although there is no information on the putative antigen or antigens that may be involved.
2. 5 Fibrosis Fibrosis is the final step of SSc pathogenesis and is responsible of the most prominent clinical manifestations of disease. It is due to an increased fibroblast production of collagen, especially types 1 and 3, with type 1 being the most abundant. It is not known if the excessive production of connective tissue represent an altered response to an unknown injury or if is due to the primary alteration in the regulation of expression of matrix protein genes. The persistent activation of collagen genes differentiates the uncontrolled fibrosis of SSc from normal response to injury. A number of cytokines and growth factors released from the tissue inflammatory cells can stimulate collagen gene expression (35,36).
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Transforming growth factor beta (TGF), produced by activated lymphocytes and monocytes, plays a crucial role in SSc related fibrosis as it stimulates the extracellular matrix synthesis (37), but also decreases the production of collagen degrading metalloproteinases and stimulates the production of protease inhibitors (as tissue inhibitor of metalloproteinases-1), which prevent break-down of the extracellular matrix (36).The production of TGF is consistently upregulated in SSc, maintaining fibroblasts from SSc patients in an activated state. SSc fibroblasts on the other hand express increased number of TGF receptors, enhancing collagen production. The main alterations of TGF signaling that play an essential role in the persistent activation of SSc fibroblasts are represented by an up-regulation of v5 and v3 integrins, which contribute to activation of latent TGF and establishment of the autocrine TGF loop (10,11). Additional changes include alterations of the TGF_ receptor ratio (12) and the presence of persistently phosphorylated Smad3 (13). Connective tissue growth factor (CTGF) is another potentially important mediator of tissue fibrosis (38). It stimulates the synthesis of extracellular matrix components in dermal and lung fibroblasts: it is produced by fibroblasts, vascular smooth muscle cells and endothelial cells in response to TGF stimulation and in autocrine fashion CTGF can stimulate its own production (39). It has been hypothesized that CTGF might act as a downstream mediator of TGF effects, that once activated, could chronically perpetuate collagen overproduction in SSc. Besides this, oxidative stress in SSc affects fibroblasts, which show the accumulation of large amounts of reactive oxygen species (ROS); these are key cell transducers of fibroblast proliferation and collagen-gene expression. A pathway linking the signaling proteins Ha-Ras, growth-factor activated extracellular-signalregulated kinases 1 and 2 (ERK1/2), and ROS is amplified in fibroblasts from patients with scleroderma (40). Stimulatory antibodies to the PDGFR, that have been found in SSc patients, seem responsible of ROS accumulation through tyrosine phosphorylation, through a selective induction of Ha-Ras-ERK1/2 and ROS cascades (41). 3 Clinical manifestations The disease is commonly called "scleroderma" because the most visible aspect is "hard skin", however, scleroderma is a systemic disease and besides the significant aesthetic changes of the face and extremities, organ involvement leads to a functional reduction, sometimes progressing to organ or multi-organ end-stage failure. The disease has various clinical characteristics because it involves the skin as well as the internal organs. At onset, some patients present with few changes and without significant laboratory abnormalities (such as antibodies), making the diagnosis difficult to establish even for scleroderma experts. This may explain why the diagnosis is usually made once the disease has fully developed. Thus, early diagnosis is essential for starting appropriate treatment aimed at blocking disease evolution.
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Below is an in-depth description of the various types of internal organ involvement observed in SSc.
3 .1Vascular manifestations The earliest symptom of SSc is Raynauds phenomenon (RP) of the fingers, toes, ears, and nose: it is characterized by episodic vasospastic attacks that cause the blood vessels in the fingers and toes to constrict. RP presents with three changes in skin colour (42). Pallor (in response to spasm of the arterioles and the resulting collapse of digital arteries) followed by cyanosis (due to ischemia) and finally, as the reperfusion dilation, rubor occurs. The duration of an attack varies from less than one minute to several hours. As the attack ends, throbbing and tingling may occur in the fingers and toes. Connective tissue diseases, such as SSc, are the most common cause of secondary RP (43). Nailfold video-capillaroscopy (NVC) shows a variety of morphological changes including enlarged capillaries, bushy capillary formations, microhemorrhages, and a variable loss of capillaries with or without avascular areas. Capillaroscopic patterns in SSc may vary according to the disease stage (44-46). Some studies have described the morphological aspects of vascular damage in patients with SSc by NVC, correlating these capillary abnormalities to selected characteristics of the disease (figure I and table I from in-depth discussion 3). Figure I - Face in acute diffuse SSc
Fingertips ulcers may arise as a complication of RP and chronic ischemia and occur in up to 50% of patients with limited or diffuse systemic sclerosis (SSc). Usually ulcers heal slowly and become portals for infections that may evolve to gangrene and, as they deepen into the tissues, bone involvement can occur, which may result in osteomyelitis. In the worst refractory cases, digital amputation may be needed. (46)
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Ulcers arise as a complication of RF. In fact, chronic tissue ischemia provokes a deep tissutal sufference with formation of ulcers that may evolve to necrosis, in most severe cases affecting also muscles and bones. In SSc, digital tip ulceration occurs in about 31.871.4% (median 45.2%). Digital ulcerations are usually slow healing and 1429% progress to gangrene and autoamputation (47). The frequency of severe digital vasculopathy related complications emerged in a recent study (48) is reported in figure 1. Figure 1 - Complications of ulcers in a SSc cohort of patients (from Nihtyanova ARD 2008)
In the early phase of SSc, ulcers are localised on fingertips (figure 2.A), malleoli, heel, and great toe. With disease progression, ulcers may be found over bony prominences (figure 2.B), and may be provoked mainly by mechanical retraction of the skin as may happen to the dorsal aspect of the interphalangeal joints and elbows. Usually, these parts are exposed to repetitive trauma at sites of chronic contractures. Figure 2A and 2B - Localisation of digital ulcers in early SSc (A) and late SSc (B)
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According to morphology, ulcers may be classified as follows: 1. Digital pitting scar: these ulcers are hyperkeratotic and thick small (2-3 mm) scars localised on the fingertips. These ulcers may be white or yellow, undermined and sometimes also painful (fig. 3). 2. Loss of tissue: these ulcers are characterised by loss of tissue at different levels and at different sites, that may deepen down to the bone (fig. 4). They are frequently undermined and painful. Over joints or bony prominences are due to tissue retraction, as shown in figure 4.C. 3. Calcinosis: when ulcers develop on calcinosis . They may occur anywhere, with variable dimension and are hard, painful and are frequently complicated by infection, with or without fistulisation. (figure 5) Figure 3 - Yellow (A) and white (B) pitting scar
Figure 4 and 4C - Digital ulcers with tissue loss
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Figure 5 - Calcinosis of the knee in a patient with SSc. In the box calcium depositions that have been removed are shown.
3 .2 Gastrointestinal Tract Involvement Fibrosis can involve the entire gastrointestinal (GI) tract, making the muscle wall of these organs atrophic. Damage to the guts nervous system may cause dysmotility. Oesophageal dysmotility and its problems occur in 75-90% of SSc patients, stomach involvement in at least 50%, small bowel involvement in 40-70%, colon involvement in 20-50%, and anorectal involvement in 50-70% (49). 3 2 1 Upper Tract: Oesophageal disease is characterized by poor functioning of the muscle of the lower part of the oesophagus (50). This causes a reduction of the peristalsis and of the continence of the lower oesophageal sphincter [LES] that manifests as dysphagia and reflux episodes that are responsible of oesophagitis of lower part of oesophagus, causing heartburn, pyrosis, and regurgitation. Other less common symptoms are sore throat, laryngitis, inflammation of the gums, erosion of tooth enamel, chronic irritation in the throat, and hoarseness in the morning. Sometimes there are no symptoms, and the presence of gastro oesophageal reflux is revealed through other complications (51). Oesophageal motility is usually tested by manometry. This test evaluate the amplitude , the duration, the velocity and the presence or absence of peristaltic contractions and determines whether the measurements are within normal range 52). In a small subset of patients, Barretts oesophagus has developed as a complication of oesophagitis. This is a potentially precancerous condition in which the mucosa of the oesophagus is transformed into a specialized intestinal metaplasia. To evaluate tissue damage, upper endoscopy is recommended. If Barretts oesophagus is detected, routine endoscopic screening is advised. (53). For people with symptoms of gastro oesophageal reflux, a pH-monitoring test can be performed (54). The abnormality of the guts nervous system present in SSc also can involve the stomachs electrical rhythm, with the motility becoming weakened, spastic, or failing completely. In the most severe forms, nausea, vomiting, abdominal pain, and severe constipation are unrelenting.
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Gastroparesis, or small bowel dysmotility, is at the extreme end of the symptom spectrum. The range of symptoms includes nausea, vomiting, belching, reflux, sensation, early satiety, abdominal pain, abdominal bloating, change in bowel habits, and weight loss (55). Gastric emptying time (GET) is the diagnostic test used for gastroparesis. 3 2 2 Lower Tract The small bowel can become dilated and often atonic, losing its propulsive function. Under these conditions bacteria that normally live in the small bowel grow enormously, damaging the mucosa that absorbs food. This leads to malabsorption, with significant loss of absorption of essential nutrients. Bacterial overgrowth syndrome (BOS) occurs when the normally low colonization of bacteria in the upper GI tract increases significantly (56). Fat, protein, carbohydrate and vitamin malabsorption result from poor enterocyte function and from bacterial transformation of nutrients into nonabsorbable and toxic metabolites, all of which contribute to damage of the intestinal mucosa. Breath tests using by-products of bacterial metabolism to identify malabsorbed substances are useful in determining the diagnosis. The most sensitive and specific is the xylose breath test, which is based on the fact that overgrowth of Gram-negative bacteria in the small bowel, which occurs during dysmotility disorders, leads to metabolization of xylose and results in the release of radioactive carbon dioxide. In the most severe cases, bowel dilatation may result in a condition known as intestinal pseudoobstruction (57). Such cases, patients should avoid oral feeding and will require the use of continuous nasogastric suction. When malnutrition is evident, total parenteral nutrition is indicated.
3. 3 Lung involvement
Pulmonary involvement is the leading cause of morbidity and mortality in SSc patients (58) as it frequently complicates SSc provoking loss of quality of life and a poor expectation of survival. Alveolitis, membrane thickening and/or the modification of microvascular structure are the main hallmarks of lung involvement that may lead, with the progression of the disease, to ILD and to pulmonary artery hypertension. Non-specific interstitial pneumonia (NSIP) is the most histopathological pattern found in SSc lung, although usual interstitial pneumonia (UIP) can be present (59,60). NSIP is characterized by varying degrees of inflammation and fibrosis but does not present the heterogeneity of UIP (it lacks fibroblast foci and honeycombing) (61). In idiopathic lung fibrosis patients with NSIP have better prognosis than those with UIP (62). This difference has not been observed in SSc, although overall all forms of lung fibrosis have a better outcome in SSc.
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Dyspnoea on exertion, hypoxemia and non productive cough are the most common manifestations of pulmonary fibrosis even in patients without radiological evidence of pulmonary damage. Haemoptysis, airway and lung inflammation can also be observed in advanced fibrosis. Fine bibasilar crackles at chest auscultation are characteristic. In the early stages there are often no clinical signs to suggest the development of pulmonary arterial hypertension. Increased and palpable pulmonary components of the second heart sound, right ventricular gallops, murmurs of pulmonary and tricuspid insufficiency, jugular distension, hepatojugular distension and feet oedema can reflect signs of pulmonary hypertension. Chest X-rays detect lung volumes, the distribution of infiltrates, pleural disease and lymphadenopathy. Chest radiography is not sufficiently sensitive to exclude lung fibrosis in SSc. 10% of symptomatic patients may have a normal chest radiograph as CXR have a low sensitivity for early lung involvement. The pulmonary function test (PFT) in SSc may show a restrictive pattern with decrease of forced vital capacity (FVC) or total lung volume (TLC) (which is less effort dependent and so can be more reliable than FVC) and diffusion capacity for carbon monoxide (DLCO) (63 ). Restrictive ventilatory defects are the most common finding ( 64). However, by the time these defects are diagnosed on spirometry the pulmonary disease is fairly advanced. A reduction in pulmonary carbon monoxide diffusion capacity (DLCO) is reportedly to be an early sign of pulmonary disease in SSc, as well as an important predictor of mortality (65).Even so, diffusion across the alveolar capillary units may be altered by parameters other than interstitial fibrosis. The reduction of DLCO alone may also suggest the presence of pulmonary hypertension (66). Assessment of PFT is recommended in SSc since chest radiography or respiratory symptoms cannot predict early lung involvement. Chest HRCT is the non invasive gold standard technique for the diagnosis of SSc ILD (67). HRCT is recognised as a sensitive tool for predicting the histological characteristics of lung parenchymal abnormalities, in patients with idiopathic pulmonary fibrosis. It allows imaging of the lung parenchyma in remarkable detail that is very useful in the diagnosis of fibrosing alveolitis, providing a non-invasive alternative to open lung biopsy. Ground glass opacification may reflect alveolitis but when there is associated traction bronchiectasis it is more likely due to finer fibrosis. Likewise, inflammatory change cannot be excluded by honeycomb reticular shadowing as there my be sites of inflammation within established disease. Treatment decisions should be based upon clinical evidence of declining lung function in the context of significant HRCT change. Also in cases with abnormal chest X-ray, HRCT was a more sensitive detector of the extent or severity of interstitial involvement (68).In patients with pulmonary fibrosis, the cell population in the BAL fluid, from different lung sections, is not uniform, and HRCT scanning appears to be a useful method to identify pulmonary areas with different inflammatory activity (69).Typical interstitial abnormalities identified on HRCT include thickened interlobular septa, subpleural cysts, and honeycombing lung formation. Additional findings may include subpleural micronodules, small airway ectasia (bronchiectasis and bronchioloectasis) and ground glass opacification (70).
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Ground glass opacification on HRCT correlates to the presence of air space inflammation in the lung (alveolitis) and decreased DLCO (71). HRCT allows a qualitative assessment (Normal/groundglass/fibrosis) or semi-quantitative assessment (Wellsor Warricks scoring systems). Clearance of inhaled 99mT-DTPA is an index of lung epithelial permeability (72). Increased 99mTDTPA clearance may be a sensitive marker of inflammation (73) and normal clearance certifies absence of inflammation (74). Rapid clearance of 99mT-DTPA can be useful in patients with an isolated reduction in DLCO to differentiate between those with early fibrosing alveolitis and to those with pulmonary vascular disease (75). A variety of cell types are increased in BAL fluid from SSc patients with pulmonary involvement, including alveolar macrophages, CD8 T cells, mast cells, basophils, eosinophils and neutrophils. In idiopathic pulmonary fibrosis a higher percentage of lymphocytes and neutrophils on BAL has been shown to predict those patients more likely to respond to immunosuppressive treatment, but cellularity may be a reflection of the extent of fibrosis (which also predicts decline). BAL may not add to the results of HRCT in making treatment decisions. The presence of active alveolitis may be used to predict future loss of FVC (76,77) A significant and direct correlation between the extent of disease seen on HRCT and the percentage of neutrophils and eosinophils on BAL has been demonstrated, suggesting that greater radiological evidence of disease seen on lung tissue should correlate with more intensive alveolitis . In order to detect the inflammatory process in the alveolar wall, BAL should be performed as early as possible, even when the DLCO and CT scan are negative in order to start a prompt immunosuppressive treatment.
3 .4 Pulmonary arterial hypertension (PAH)
PAH is a serious and potentially life-threatening condition that can develop in patients with scleroderma(78). It occurs when the blood vessels supplying the lungs constrict and then become stiffer and thicker because of irreversible fibrosis. The increased resistance in pulmonary circulation makes it difficult for blood to flow through to the lung vessels, and thus the heart must pump harder (79). Some patients may have both interstitial lung disease and PAH; the first usually develops early in the disease, whereas PAH tends to occur later, often in the second decade of disease. The precise cause of PAH is unknown, but it is associated with dysregulation of blood flow that results in vasoconstriction, as is observed in Raynauds phenomenon.. Many factors may play a role in this process; one of them is the elevation of endothelin, a potent vasoconstrictor that has been shown to be elevated in the blood of scleroderma patients and in lung tissue affected by scleroderma (80). In the earliest stages of PAH, the patient is asymptomatic. Then dyspnoea begins on exertion and later during ordinary activity. Non-specific symptoms such as chest pain, dizziness and fainting may also occur (81). Because of the poor outcome, it is critical to diagnose PAH in an early phase, so that prompt therapy can be initiated while the condition is still reversible.
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For this reason Doppler echocardiography should be performed periodically also in asymptomatic SSc patients. This technique can not only determine the size of the cardiac chambers of the heart and the state of the valves but may also estimate pulmonary arterial pressure by using the tricuspid regurgitant jet velocity to estimate right ventricular systolic pressure. An estimate of right atrial pressure must be added to estimate PAH. Although there is a strong statistical correlation between estimated systolic PAP and mean PAP this can be misleading. Especially in the important estimated range of 30 to 50 mmHg. Therefore, once PAH is suspected, right-heart catheterization must confirm the diagnosis (82). During this procedure, vasodilator drugs can be tested to determine whether they can significantly reduce pulmonary pressure, which may lead to their use as a treatment modality. A longitudinal study investigating survival, risk factors and causes of death in a cohort of patients with SSc without severe pulmonary fibrosis or severe left heart disease at baseline, showed that PAH increased the mortality risk in patients with SSc, suggesting that a yearly echocardiographic screening should be performed in order to make an early diagnosis (83). Subclinical PAH may be evaluated through exercise echocardiography, measuring PAP during exercise and allowing to differentiate physiologic from altered PAP responses; this may identify patients that may develop PAH (84).
3. 5 Cardiac involvement
Cardiac involvement is common in SSc and contributes to symptoms such as shortness of breath, fatigue, and palpitations (85). The heart is often subclinically affected by fibrosis involving both the myocardium and the conducting system. This involves both ventricles with a patchy distribution and can be distinguished from that occurring in atherosclerotic coronary artery disease by a number of histological features, such as the absence of a link to any single coronary artery and of typical hemosiderin deposits and involvement of the subendocardial layers (86-87). Cardiac involvement in SSc is likely to result from the general pathogenetic mechanism(s) thought to play a role in the disease . A myocardial Raynauds phenomenon involving unaltered small arteries has been hypothesized, but conflicting results have been reported. On the one hand, reversible perfusion defects have been detected in a significant percentage of SSc patients. On the other hand, coronary vasodilator reserve has been found to be markedly reduced in SSc (8889). Autonomic neuropathy in SSc has been reported by various authors using conventional laboratory tests (90). Tachyarrhythmias are excessively rapid and irregular heartbeats. They usually dont cause any symptoms, but they are often fatal, and SSc patients with heart involvement are susceptible to them (91). The worst prognosis in severe cardiac arrhythmias is significantly more frequent in those patients with both skeletal and cardiac muscle involvement (92). Early recognition of cardiac involvement and diagnosis of cardiotoxicity allow early treatment, prevention of cardiomyopathy and improvement in prognosis, due to the impact of heart disease on final outcome in patients affected by autoimmune diseases.
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Thus, a thorough heart-function screening and appropriate follow-up monitoring are mandatory for all SSc patients. The screening consists of various simple, noninvasive investigations: -physical examination -electrocardiogram that may show confirm conduction abnormalities and arrhythmias; a 24 hour monitoring should be performed since the incidence and prevalence of ECG disturbances increases when the patients are monitored with 24-h ambulatory ECG. -chest X ray to investigate pericardial effusion and/or alteration of cardiothoracic ratio. -Doppler 2-dimensional echocardiogram that provide information left ventricular ejection fraction (LVEF), diastolic function, tricuspid gradient, pulmonary acceleration time, right ventricular diameter and pericardial effusion, wall motion and the possible presence of PAH. -ProBNP may be useful for the diagnosis of cardiomyopathy because its concentration is altered in patients with myocardial structural impairment, even if asymptomatic, while troponin I is an accurate index of myocytolysis (93). When needed, additional tests may be performed, including long-term ambulatory electrocardiographic recording, assessment of cardiopulmonary performance by the six-minute walking test or cardiopulmonary stress test, cardiac catheterization (mandatory to confirm and better estimate PAH), cardiac magnetic resonance imaging, and nuclear studies of myocardialfunction and perfusion (94). In particular Tc-99 SPECT using vasodilators (dipyridamole) allows to demonstrate the presence of inducible ischemia. Dipyridamole causes vasodilation though the increase of adenosine locally. This vasodilation occurs in healthy arteries, whereas stenosed arteries remain narrowed. This creates a "steal" phenomenon where the coronary blood supply will increase in the dilated healthy vessels compared to the stenosed arteries. Cardiac MRI allows to evaluate coronary reserve and may also demonstrate the presence of inflammatory oedema and fibrosis.
3.6 Kidney involvement
Kidney involvement is often clinically silent. It may progress slowly toward renal failure and thus heavily influence prognosis. In some cases, breakdown of the renal system may be abrupt, without any sentinel symptom. Sudden onset of high blood pressure and kidney failure is known as scleroderma renal crisis (SRC). Patients with diffuse cutaneous (DC) involvement, particularly those with early, rapidly progressive skin thickening and serum anti-RNA polymerase III antibody, are at highest risk to develop SRC (95). The typical presentation is that of a stable patient who abruptly develops severe arterial hypertension accompanied by headache, visual disturbance, seizures, congestive heart failure, pericardial effusion , microangiopathic haemolytic anemia, thrombocytopenia and accelerated oliguric renal failure. The optic fundi show acute hypertensive changes, including haemorrhages and exudates.
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Other findings include microscopic hematuria and proteinuria; occasionally RBC casts are seen in the urine (96). The plasma renin level is extremely high, as found in malignant essential hypertension. Renal biopsy characteristically shows changes in the small interlobular and arcuate arteries. The earliest change is intimal edema, followed by an intense proliferation of intimal cells increased mucopolysaccharide deposition. Lymphocytes and other mononuclear cells are absent. Fibrinoid necrosis in the vessel walls or subintima location is typical of severe cases in small arteries. This usually occurs in patients with diffuse scleroderma, resulting in kidney failure within a few days. Thus, to detect sudden kidney failure promptly, daily at-home monitoring of blood pressure is recommended for SSc patients, and particularly for those with diffuse scleroderma, even if they do not have high blood pressure or other renal symptoms. Chronic kidney disease other than renal crisis is not well described .Kidney abnormalities such as proteinuria, hypertension, or abnormal serum creatinine does not predict future renal crisis. It has been presumed that such abnormalities reflect the vasculopathy that occurs pathologically in patients with scleroderma even in the absence of renal crisis. Colour Doppler ultrasonography can confirm the early reduction of renal arterial blood flow in patients with SSc who have no clinical sign of renal involvement. Abnormal findings on renal function tests (serum creatinine, creatinine clearance, 24hour proteinuria) may be observed at a later stage (97,98) of the disease. It has also been demonstrated that most patients with SSc cannot increase renal filtration under the challenge of a protein overload. This defective renal response to the amino acid load test sustains the concept of the prevalence of vasoconstrictor over vasodilating factors in the kidney of these patients (99). 4 Treatment 4 . 1 Overall treatment Severe forms of the disease and rapidly progressive diffuse SSc in particular, are associated with significant mortality (estimated at 40%-50% in 5 years) secondary to pulmonary, cardiac, and renal involvement (100,101). No proven effective therapy exists to prevent disease progression. The perceived failure of immunosuppressive treatments in the reversal of established fibrosis suggests that once initiated, the fibrotic process becomes independent of the immune drive and continues as an autonomous process. Blinded randomized clinical trials of D-penicillamine failed to demonstrate a clinically significant effect (102). Low-dose oral methotrexate showed beneficial effects on skin thickening, but not on organ dysfunction, in a small placebo-controlled crossover study (103). Cyclophosphamide (Cyc) has been shown to improve skin thickening, stabilize pulmonary function, and increase survival in non randomised trials (104,105). The effects of both pulses and oral Cyc on lung involvement in SSc have been reported in double-blinded placebo controlled randomized trials, where Cyc seems moderately helpful in stabilizing lung function (106, 107).
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An improvement of the transitional dyspnea index, HAQ disability index, and the vitality- and healthtransition domains of the SF36 has also been observed in patients treated with Cyc (108). Although the efficacy of cyclophosphamide is considered moderate, this is currently the only drug with proven efficacy in SSc interstitial lung disease and for that reason should be considered as the drug of choice in progressive lung involvement (109). In the past decade, intense immunosuppression followed by autologous stem cells transplantation (HSCT) has emerged as a new therapeutic procedure for patients affected by severe SSc that is refractory to conventional treatments (1110). This procedure is intended to eliminate auto-aggressive lymphocytes by a lympho-myeloablative treatment and is followed by stem-cell rescue. A phase I-II trial showed improvement in the skin score (>25% in 69% of the patients), stabilization of lung function and pulmonary pressure, and no occurrence of renal crisis after the treatment (111). The initial procedure-related mortality observed was particularly elevated (17%), probably owing to the already advanced organ damage of most participants (112). The new criteria for patient selection, in terms of both disease stage and organ involvement, have remarkably decreased transplant-related mortality. Phase III clinical studies are currently underway in Europe (www.astistrial.com) and the United States (SCOT trial). Preliminary results indicate that HSCT can significantly improve skin involvement and stabilize lung function, thus having a positive effect on quality of life.
4. 2 Treatment of specific organs 4 . 2.1 Gastro-intestinal involvement Treatment of oesophageal disease in scleroderma is based, first of all, on modifications in lifestyle. Gravity plays an important role in controlling reflux. To minimize the possibility of heartburn, it is recommended that an upright posture be maintained until a meal is digested and avoid exertion after a meal. The medications prescribed to treat oesophagus dysmotility and reflux are promotility agents, H2 blockers, and proton pump inhibitors. Prokinetic drugs are indicated to promote emptying of the stomach and gut, and to enhance the contractions and coordination of the gut. H2 blockers reduce the amount of acid produced in the stomach, and proton pump inhibitors limit secretion of acid in the stomach. Because these agents work in different ways, combination therapy employing two or more of these drugs may be especially helpful in controlling symptoms. Malabsorption and enterocyte dysfunction further degrade the health of the gut by reducing local and systemic nutrition delivery. When bacterial overgrowth is caused by slow transit through the small bowel, broad-spectrum antibiotics are indicated for a few days per month, and patients should reduce or avoid fats and fibre in their diet in an effort to reduce abdominal symptoms such as constipation and distension. (113).
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The bowel can remain atonic and nonpropulsive, causing fermentation and bacterial overgrowth. In early phases, treatment with octreotide can stimulate small bowel function, helping to reduce bacterial overgrowth (114).
4.2.2 PAH The target of therapy is to facilitate vasodilatation. In some patients, calcium channel blockers (such as nifedifine or diltiazem) are effective (115) . Bosentan, an endothelin receptor antagonist, has been proven to offer several important benefits to patients with PAH, such as reduced dyspnoea and improved ability to perform normal daily activities(116,117). Sitaxsentan, administered orally at a dose of 100 mg/day and 300 mg/day for 12 to 18 weeks, significantly improved exercise capacity and hemodynamics, NYHA functional class improvement was even greater in the subgroup of class III or IV patients, suggesting that patients with more severe PAH may achieve greatest benefit from sitaxsentan therapy (118,119). Ventavis, an inhaled-solution form of iloprost, is indicated for patients classified as having stage III or IV pulmonary hypertension (120). Other licensed therapies include sildenafil, a PDE5 inhibitor. This has shown to improve 6MWT, functional class and hemodynamics (mean PAP and PVR) and has been approved for the treatment of patients in NYHA class II, III and IV (121). Severe cases still require intravenous prostacylin analogues such as epoprostenol or iloprost. Beneficial hemodynamic effects of epoprostenol included a statistically significant decrease in pulmonary vascular resistance, mean pulmonary artery pressure and right atrial pressure, as well as a significant increase in cardiac index. However the way of administration (through a permanent indwelling central venous catheter) may favour adverse events such as infections, pneumothorax, and haemorrhage. Sudden disruption/withdrawal of i.v. eporostenol (due to catheter/vein thrombosis and/or patients decision) may lead to life-threatening PAH rebound (122). For that reason, on overall risk-to-benefit considerations, and in agreement with the current ACCP guidelines, intravenous epoprostenol is recommended for the treatment of severe, therapy resistant SSc-PAH. (109). Subcutaneous teprostinil has shown to improve the 6MWT,the dyspnea score and hemodynamic parameters in a heterogenous population of PAH patients. In a sub-group of connective tissue diseasSSc (50% SSc) treprostinil has shown to significantly improve the cardiac index and the fatiguedyspnea score and there was a trend towards improvement.Efficacy is dose related, and subcutaneous administration may be limited by infusion site reaction and pain (123). The algorhytm for the treatment of PAH according to the recent guidelines, is reported in the picture below.
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4.2.3 Kidney involvement The outcome of scleroderma renal crisis is poor despite aggressive treatment for high blood pressure. SSc patients who develop high blood pressure should immediately receive ACE inhibitors to control blood pressure. ACE inhibitors can improve the prognosis, but it is still not known if they can prevent scleroderma renal crisis. Patients with loss of renal function require dialysis (125-126).
4.2.4 Digital vasculopathy Nifedipine and i.v. iloprost have been shown to reduce the frequency and severity of SSc-related Raynauds phenomenon attacks (127,128). Dihydropiridine-type calcium channel blockers, usually oral nifedipine, should be considered for firstline therapy for SSc-related RP, and intravenous iloprost, or other available i.v. prostanoids, for severe SSc-related RP (109). Digital ulcers, a complication of chronic tissue ischemia, needs both a topic and a systemic treatment. Intravenous prostanoids (particularly i.v. iloprost) and nifedipine are efficacious in healing digital ulcers (129). The use of Bosentan has determined fewer new digital ulcers in bosentan-treated SSc patients than in patients receiving placebo. The treatment effect was most marked in preventing the development of multiple ulcers. These encouraging results have been confirmed in a further large randomised placebo-controlled clinical trial, in which bosentan demonstrate efficacy in the reduction of new digital ulcerations onsent in SSc patients.
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In this trial bosentan appears more effective in patients with more than 3 active digital ulcers at treatment outset and this reduction is associated with improved hand function (eating and dressing). Bosentan does not appear to speed healing of digital ulcers, the cardinal ulcer persisted in 50% of all subjects for up to 24 weeks. These data suggest that chronic endothelin receptor antagonism has an important effect on peripheral vascular integrity and function in systemic sclerosis (130). In the treatment of SSc ulcers, a topical treatment is needed. Firstly a wash with sterile solution and disinfection of the lesion is required, then mechanical removal of fibrin ,induction autolysis of necrotic tissue and induce repair is necessary in order to recreate an appropriate microenvironment (humidity). For that reason any medication that will block the gas exchange and formation of humidity (greenhouse effect- restore the microclimate) should be avoided: closing the ulcers may facilitate infection that spread rapidly into the tissue, and the circulation (septicemia). In case of infections it is necessary to identify the microbial agent through a biopsy, in order to establish a promt systemic antibiotic treatment. Then a frequent follow up to determine when the infection is solved to go back to standard procedure. Summary In conclusion, there have been many advances over the past 10 years in the management of SSc and controlled clinical trials are starting to confirm treatment effectiveness. This provides a strong
platform for future advance. At present organ-based complications are generally more amenable to treatment that the underlying disease. EUSTAR (EULAR Scleroderma Trials and Research) group has recently developed evidence-based recommendations for the treatment of SSc to provide guidance to rheumatologists and practitioners to correctly approach and choose the treatment for SSc patients.
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Summary
Limited cutaneous systemic sclerosis (lcSSc) is defined by skin involvement only distal to the elbows and knees, while diffuse cutaneous systemic sclerosis (dcSSc) is characterized by the presence of skin thickening proximal to the knees and elbows. Environmental factors, such as exposure to organic solvents and toxins, have been proposed as possible causative factors. The presence of microchimerism, infectious agents such as cytomegalovirus, and the inherent propensity for oxidative stress with associated generation of free radicals, are also candidate factors that might contribute to disease progression. Activated lymphocytes secrete cytokines, such as transforming growth factor beta (TGF), which cause endothelial cell injury and expression of MHC and intercellular adhesion molecule 1 (ICAM 1) , upregulate connective tissue growth factor CTGF to increase production of the extracellular matrix, and upregulate platelet derived growth factor (PDGF). The presence of antinuclear antibodies can be found in more than 90% of patients with SSc. Anti-Scl-70 are almost exclusively found in patient with dcSSc, but only 30-40% of these patients present anti-Scl 70.Anticentromere antibodies are present in 80-90% of patients with lcSSc. Anti-Scl 70 and anticentromere antibodies rarely coexist in the same patient. Nailfold video-capillaroscopy (NVC) shows a variety of morphological changes including enlarged capillaries, bushy capillary formations, microhemorrhages, and a variable loss of capillaries with or without avascular areas. Fingertips ulcers may arise as a complication of Raynauds phenomenon and chronic ischemia and occur in up to 50% of patients with limited or diffuse SSc. Pulmonary involvement is the leading cause of morbidity and mortality in SSc patients: interstitial lung disease and pulmonary arterial hypertension (PAH). Doppler echocardiographic evaluation of velocity of tricuspid regurgitation, and right heart catheterization, enabled early detection of PAH. Sudden onset of high blood pressure and kidney failure is known as scleroderma renal crisis Autologous stem cells transplantation has emerged as a new therapeutic procedure for patients affected by severe SSc that is refractory to conventional treatments
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99m
72). O Brodovich H, Coates G, Pulmonary clearance of integrity. Lung 1987;166:1-16
TC-DTPA : a non invasive assessment of epithelial
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99m
TC predicts the clinical course of fibrosing
76). Silver RM, Miller KS et al.: Evaluation and management of scleroderma lung disease using bronchoalveolar lavage American Journal of Medicine 1990; 88: 470-476 77). Witt C, Borgess AC, John M et al Pulmonary involvement in difuse cutaneous systemic sclerosis:bronchoalveolar fluid granulocytosis predicts progression of fibrosing alveolitis Ann Rheum Dis 1999;58:635-40 78). Denton CP, Black CM. Pulmonary hypertension in systemic sclerosis. Rheum Dis Clin North Am. 2003 May;29(2):335-49, vii. 79). Yamane K: Endothelin and collagen vascular disease: a review with special reference to Raynauds phenomenon and systemic sclerosis. Intern Med 1994; 33: 579-82. 80). Vancheeswaran R, Magoulas T, Efrat G, Wheeler-Jones C, Olsen I, Penny R, Black CM. Circulating endothelin-1 levels in systemic sclerosis subsets--a marker of fibrosis or vascular dysfunction? J Rheumatol. 1994 Oct;21(10):1838-44 81). Ramirez A, Varga J. Pulmonary arterial hypertension in systemic sclerosis: clinical manifestations, pathophysiology, evaluation, and management Treat Respir Med. 2004;3(6):339-52. 82). Dentonc P, Cailes Jb, Phillips Gd, Wells Au, Black Cm, Bois Rm: Comparison of doppler echocardiography and right heart catheterization to assess pulmonary hypertension in systemic sclerosis. Br J Rheumatol 1997; 36: 239-43. 83) Hachulla E, Carpentier P, Gressin V, Diot E, Allanore Y, Sibilia J, Launay D, Mouthon L, Jego P, Cabane J, de Groote P, Chabrol A, Lazareth I, Guillevin L, Clerson P, Humbert M; ItinrAIR-Sclrodermie Study Investigators. Risk factors for death and the 3-year survival of patients with systemic sclerosis: the French ItinrAIR-Sclrodermie study. : Rheumatology (Oxford). 2009;48:304-8 84) Pignone A, Mori F, Pieri F, Oddo A, Galeota G, Fiori G, Del Rosso A, Perfetto F, Becucci A, Livi R, Tempestini A, Benvenuti C, Gramigna L, Fedi R, Generini S, Minelli M, Cinelli M, Guiducci S, Arcangeli C, Conforti ML, Bernardo P, Cerinic MM. Exercise Doppler echocardiography identifies preclinic asymptomatic pulmonary hypertension in systemic sclerosis. N Y Acad Sci. 2007 Jun;1108:291-304. 85). Deswal A , Follansbeew P : Ca rdiac invol vement in scl e ro d e rma (rev i ew). R h e u m Dis Clin North Am 1996; 22: 841-61. 86). Bulkley Bh, Ridolfi Rl, Salyer Wr, Et a l. : M yo c a rdial lesions of progre s s ive systemic sclerosis: A cause of cardiac dysfunction. Circulation 1976; 53: 483-90.
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118). Barst RJ, Langleben D, Badesch D, Frost A, Lawrence EC, Shapiro S, et al; STRIDE-2 Study Group. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol 2006;47:2049-56. 119). Langleben D, Brock T, Dixon R, Barst R; STRIDE-1 study group. STRIDE 1: Effects of the Selective ETA Receptor Antagonist, Sitaxsentan Sodium, in a Patient Population with Pulmonary Arterial Hypertension that meets Traditional Inclusion Criteria of Previous Pulmonary Arterial Hypertension Trials. J Cardiovasc Pharmacol 2004;44:S80-S84. 120) Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R, Rubin LJ, et al Aerosolized Iloprost Randomized Study Group. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322-9. 121). Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-57. 122). MacLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002;106:147782 123). Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge et al; Treprostinil Study Group. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165:800-4. 124). D.B. Badesch, S.H. Abman, G. Simonneau, L.J. Rubin and V.V. McLaughlin, Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines, Chest 2007, 131:19171928 125). Steen V D, Costantino Jp, Shapiro A P, Medsger Ta Jr: Outcome of renal crisis in systemic sclerosis: Relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med 1990; 113: 352-7. 126).Steen Vd, Medsger TA JR: Long term outcomes of scleroderma renal crisis. Ann Intern Med 2000; 133: 600-3. 127). Thompson AE, Shea B, Welch V, Fenlon D, Pope JE. Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis. Arthritis Rheum. 2001;44:1841-7 128). Pope J, Fenlon D, Thompson A, Shea B, Furst D, Wells G, et al. Iloprost and cisaprost for Raynauds phenomenon in progressive systemic sclerosis (Review). The Cochrane Library 2007; 1:I-16 129). Scorza R, Caronni M, Mascagni B, Berruti V, Bazzi S, Micallef E, et al. Effects of long-term cyclic iloprost therapy in systemic sclerosis with Raynaud's phenomenon. A randomized, controlled study. Clin Exp Rheumatol 2001;19:503-8. 130) J. H. Korn, M. Mayes, M. Matucci Cerinic, M. Rainisio, J. Pope, E. Hachulla, et al, for the RAPIDS-1 Study Group.. Digital Ulcers in Systemic Sclerosis. Prevention by Treatment With Bosentan, an Oral Endothelin Receptor Antagonist. Arthritis Rheum 2004;50:3985-93.
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Eular On-line Course on Rheumatic Diseases module n20 Marco Matucci-Cerinic, Irene Miniati, C.P.

Figure 4 and 4C - Digital ulcers with tissue loss

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72). O Brodovich H, Coates G, Pulmonary clearance of integrity. Lung 1987;166:1-16

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