Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the leading cause of morbidity and mortality in SSc patients. In autopsy studies, up to 70% of the SSc patients show histological evidence of lung involvement. In surgical lung biopsies from SSc-ILD patients, a pattern of non-specific interstitial pneumonia is present in a majority, while usual interstitial pneumonia is found in a more variable proportion of patients. Up to 90% of the SSc patients have lung function abnormalities, especially with respect to gas transfer. Pulmonary function testing, therefore, is a major tool of investigation of lung involvement in SSc.

Although neither lung biopsy nor bronchoalveolar lavage (BAL) is recommended for routine clinical use in patients with SSc, studies employing lung biopsy material and BAL fluid (BALF) have provided insight into the pathogenesis of scleroderma-associated interstitial lung disease (SSc-ILD). Most often, SSc-ILD is classified as a non-specific interstitial pneumonia, with abundant myofibroblasts and evidence of both epithelial cell and endothelial cell injury. Recently, SSc-ILD fibroblasts have been shown to express reduced levels of the caveolin-1 protein which, in turn, may lead to activation of the signalling molecules associated with increased collagen production and overexpression of alpha-smooth muscle cell actin (alpha-SMA). BALF often contains increased numbers of inflammatory cells as well as myofibroblasts expressing alpha-SMA. Analysis of BALF suggests an imbalance between pro-fibrotic and anti-fibrotic factors, e.g. an overabundance of TGF-beta, connective tissue growth factor (CTGF), PDGF, leucotriene B4, etc. and in some cases a deficiency of hepatocyte growth factor, 15-hydroxyeicosatetraenoic acid (15-HETE), lipoxin A, etc. Until the pathogenesis is fully understood, lung biopsy and BAL will remain useful research tools to better understand the inflammatory and fibrosing processes that underlie SSc-ILD.

High-resolution CT has now become an important part of the routine detection and evaluation of interstitial lung disease in SSc. CT now has a central role in the detection of interstitial disease, largely because other modalities have been unsatisfactory in this regard. Historically, CT has also been used to identify a high likelihood of reversible inflammatory disease in SSc, based upon studies in other diffuse lung diseases. However, accumulated evidence indicates that ground-glass attenuation on CT is not a reliable indicator of underlying alveolitis. Ground-glass attenuation on CT is common in SSc but reversible disease is found at surgical biopsy in a minority of cases, and is rare when ground glass is associated with reticular abnormalities or traction bronchiectasis. Furthermore, ground glass regresses inconsistently on serial CT evaluation, with or without treatment. CT is more useful in the staging of disease extent. Although formal CT scoring is not realistic in routine practice, rapid semi-quantitative estimation of disease extent on CT in combination with a forced vital capacity threshold has been used to stage disease as limited or extensive. The distinction between a higher and lower risk of progression of lung disease, made using this system, has important implications for both routine practice and the enrolment of higher risk patients in therapeutic studies.

Renal manifestations occur frequently in scleroderma (SSc). Commonest is a reduction in renal function due to chronic disease but most clinically important is the scleroderma renal crisis (SRC). This life-threatening complication occurs in up to 15% of the cases of dcSSc. Mortality is reduced by use of angiotensin converting enzyme (ACE) inhibitors. Renal outcome can be assessed by quantifying renal function, measuring proteinuria, exploring the frequency of renal crisis episodes and through assessment of renal outcome following SRC-such as frequency and duration of dialysis, or recovery of renal function.

Primary myocardial involvement is common in SSc. Increasing evidence strongly suggests that this involvement is related to repeat focal ischaemic injury causing irreversible myocardial fibrosis. Clinically evident cardiac involvement is recognized to be a poor prognostic factor, thus pre-clinical identification is highly encouraged. Echocardiography, if possible coupled to pulsed tissue Doppler, is the cornerstone of heart assessment even if radionuclide ventriculography remains the gold standard for evaluation of ventricular function. Myocardial perfusion may be assessed by single photon emission CT, but cardiac MRI will probably supplant this technique; it, furthermore, offers the possibility to concomitantly determine, ventricular function, myocardial perfusion and tissular parameters (i.e. myocarditis or burden of fibrosis). Conduction system abnormalities are common but not serious, while arrhythmias may be life-threatening, necessitating 24-h ambulatory Holter ECG. Natriuretic peptides have been used mainly when the heart has been involved secondary to pulmonary arterial hypertension, but may also be useful for the identification of early heart dysfunction. Their predictive value should also be investigated when there is primary heart involvement.

The University of California at Davis 200 and 206 (UCD-200/206) lines of chickens have proven to be the animal model that best reflects the situation in human SSc. We have demonstrated a misbalance of pro-fibrotic (TGF-beta1) and anti-fibrotic (TGF-beta2 and -beta3) TGF-beta isoforms as a possible cause for fibrotic alterations in this model. This opens new avenues for diagnosis and therapy for this still intractable condition.

The indolent progression of lung disease in SSc has caused great difficulty in therapeutic studies as outcome measures need to be sensitive. Idiopathic pulmonary fibrosis (IPF) has been more widely studied and can usefully be extrapolated to SSc, but is more rapidly progressive. In IPF, forced vital capacity (FVC) trends are the most accurate serial surrogate for mortality. Serial gas transfer trends have a lower prognostic value in IPF and may be confounded by pulmonary vascular disease in SSc. Unresolved issues include the optimal time interval between pulmonary function tests and the mode of expression of change (percentage change from baseline vs absolute change). It has yet to be determined whether changes in pulmonary function variables are best analysed continuously or categorically (i.e. according to whether a threshold for 'significant change' has been reached). The 6-min walk distance has proved disappointing as an outcome variable due to major inter-test variability over the course of therapeutic studies, ascribable to extra-pulmonary factors. Serial CT is promising in principle but an optimal scoring system has proved elusive. Dyspnoea and quality of life scales provide useful ancillary information as to the likelihood that pulmonary function trends are clinically significant. For the time being, serial change in FVC appears to be the best primary end-point.

Ischaemic ulcerations of the fingertips are common in SSc and a source of pain and disability. Healing has been demonstrated with intravenous iloprost and two studies with bosentan have demonstrated reduction in the occurrence of new digital ulcers (DUs) over 4-6 months of treatment. Both bosentan studies showed no benefit in healing DU and because of this, net DU burden is no different between drug and placebo and accordingly secondary measures of outcome including pain and hand functionality are inconsistently affected. While it is likely an artefact, it remains unclear that current outcome measures including the Scleroderma Health Assessment Questionnaire (SHAQ), the UK Functional Score and the Michigan Hand Questionnaire are sensitive to change in the domain of digital ischaemia. Major events including amputation and hospitalization occur too infrequently to serve as practical measures of outcome in trials. Future studies of DU therapies will benefit from development of an ulcer-specific measure of outcome.

Skin thickening is a characteristic feature of SSc. More extensive skin involvement coincides with more severe internal organ manifestation(s), poor prognosis and increased disability, at least in the early phase of the diffuse cutaneous scleroderma subset. The fully validated, feasible method ('gold standard') for measuring the dermal skin thickness is the modified Rodnan skin score (mRSS). The responsiveness of mRSS was somewhat modest in clinical trials, and a careful teaching process is necessary. Parallel method(s) for measuring skin thickness need to be used in the future. Ultrasound (US) measurement of the dermis with a 20-30 MHz probe is a valid, reproducible and responsive method in patients with dcSSc. However, US is time-consuming and requires a training process. Of the mechanical instruments available, only the durometer, which measures the hardness of skin, has been validated. The inter- and intra-observer reproducibility and sensitivity to change of durometry were good, and correlated with mRSS and US-measured skin thickness. Several further mechanical instruments exist including the elastometer, twistometer, cutometer and plicometer. They seem to distinguish between involved and non-involved skin, and therefore merit further evaluation. The measurement of late-stage, irreversible skin damage/atrophy should be resolved in the future through the development and validation of new instruments.

SSc-associated pulmonary arterial hypertension (PAH) has a poorer prognosis than that of other types of pulmonary hypertension. Recent echocardiographic and haemodynamic studies suggest that right ventriculer (RV) pump function and filling characteristics are altered in SSc-PAH as compared with idiopathic PAH. This could be explained by intrinsic myocardial involvement of the disease, related to abnormal collagen deposition, also observed in the left ventricle, or an increased vulnerability to ischaemia due to coronary vasculopathy, abnormal collagen cross-linking and altered myocyte function. It is also possible that a relatively more important decrease in pulmonary arterial compliance as evidenced by recently reported increased characteristic impedance measurements, would contribute to RV-arterial decoupling. More pathological, imaging and haemodynamic studies are needed for a better understanding for relatively more important vulnerability of the RV in SSc-PAH.

SSc is complicated in approximately 10% of the patients by pulmonary arterial hypertension (PAH), a rare dyspnoea-fatigue syndrome caused by an increase in pulmonary vascular resistance. The prognosis of SSc-PAH is particularly poor, with estimated survival rates of approximately 50% at 2 yrs without pulmonary circulation-targeted therapies. Prostacyclins, endothelin receptor antagonists and phosphodiesterase-5 inhibitors have been shown to be efficacious in PAH, with persistent long-term benefit and approximate doubling of survival rate, and these encouraging results appear transposable to the SSc-PAH subcategory. However, PAH as well as SSc-PAH remain incurable, with insufficient functional improvement in many patients. More progress is needed, and this will require more effective drugs and adapted outcome measures.

SSc is a CTD, which may cause critical organ fibrosis. It has a highly variable clinical presentation and course. While it is more common in females, this heterogeneity has led to significant problems with classification. Biomedical (clinical) and biomolecular markers to identify diagnostic, prognostic and therapeutic response have been elusive in part as a result of difficulties with classification and also due to the rarity of the disease. Existing biomarkers have been identified largely in small cohorts and larger cross-sectional or occasional longitudinal observational cohorts. The nature of biomarkers requires well-defined clinical characteristics and/or defined clinical outcomes and this has been extremely challenging to the international SSc research community. This brief review summarizes the current level of knowledge; however, it most importantly highlights the potential now to find biomarkers through a large, multicentre, international collaborative group approach.

It is well established that patients with CTDs such as SSc carry a considerable risk of developing pulmonary arterial hypertension (PAH). Such SSc-PAH patients have an even worse prognosis than patients with only one of these two conditions. In view of the high incidence and prevalence of PAH in SSc, and the available treatment options that improve quality of life, exercise capacity and possibly survival, systematic screening has been recommended. The present article reviews current recommendations from PAH guidelines, focusing on studies that used Doppler echocardiography for screening, and describes limitations associated with the procedure. Furthermore, characteristics and parameters used to identify patients at high risk of developing PAH are summarized.

Endothelin (ET) receptors are widely expressed within the human body with one of their major functions being regulation of the vascular tone. Pulmonary arterial hypertension and other complications associated with SSc are related to the function and or dysregulation of these receptors. As ET receptors also play a crucial role in SSc, this review will discuss the expression and physiological functions of ET receptors in the human organism, their signalling pathways, the complications of diseases they are associated with and their importance as a therapeutic target in SSc.

Scleroderma-associated interstitial lung disease (SSc-ILD) occurs frequently and for many patients SSc-ILD is a significant complication of their disease. SSc-ILD is now one of the leading causes of death among patients with SSc. SSc-ILD, classified most often as a non-specific interstitial pneumonia, may culminate in interstitial pulmonary fibrosis and end-stage lung disease. Fibrosis in the lung is the net result of fibroblast proliferation and deposition of excessive amounts of extracellular matrix proteins. Among the many cytokines and growth factors involved in the pathogenesis of SSc-ILD, ET-1 may be a central mediator. In vitro and in vivo studies of animals and SSc patients support the notion that ET-1 can enhance the proliferation of pulmonary mesenchymal cells and may also enhance the fibrogenic effects of TGF-beta. Two well-designed randomized controlled trials of the dual ET receptor blocker bosentan were negative in their primary (and for SSc also secondary) endpoints, although there might be explanations for this apparent lack of efficacy.

It is now two decades since it was demonstrated that ET-1 is one of the most powerful vasoconstrictors in biology. ET-1 mediates its effects through two membrane G-protein coupled receptors, ET(A) and ET(B), which exhibit a wide tissue distribution including the endothelial cells, vascular smooth muscle cells and adventitial fibroblasts. In recent years, ET-1 has been identified as a key player of endothelial dysfunction in various cardiovascular, autoimmune and CTDs. Endothelial dysfunction results from endothelial cell injury subsequently leading to the generation of an inflammatory process and endothelial cell activation. Thus, beyond its known 'classical' vasoactive effects, ET-1 is additionally considered to be an important mediator in vessel remodelling ultimately leading to major changes in cellular and tissue architecture; it also appears to function in conjunction with other growth factors and cytokines. Consequently, ET-1 receptor antagonists may be useful in ameliorating progression of vascular dysfunction and vascular disease due to their ability to negatively modulate vasoconstrictor pathways, cytokines and inflammatory markers production, and growth factor effects. This review briefly summarizes the current knowledge on the role of ETs in vascular dysfunction and vascular disease, with a particular emphasis on ET-1 in CTDs.

Vascular disease is present in every patient with scleroderma and is a major source of morbidity and mortality. There is a subset of patients who will develop severe and sometimes life-threatening vascular events. We have good evidence that an insult to the microvasculature occurs early in the disease course, but there is a subset of patients who have an ongoing chronic process, the end result of which are events such as digital loss and pulmonary arterial hypertension. The ability to detect this process at an early stage by simple means would be of great value as our ability to treat these vascular complications improves with time. We have a significant amount of evidence of vascular perturbation from studies of peripheral blood in scleroderma, but know very little about the ability of these biomarkers to predict vascular outcomes. In this review, we will critically assess our current knowledge of the use of biomarkers of vascular disease in scleroderma and the possible directions of future research in this area.

PDGF functions as a primary mitogen and chemoattractant for cells of mesenchymal origin. Members of the PDGF family play an important role during embryonic development and contribute to the maintenance of connective tissue in adults. Deregulation of PDGF signalling has been linked to atherosclerosis, pulmonary hypertension and organ fibrosis. Elevated expression of PDGF and its receptors has been found in scleroderma skin and lung tissues. There is evidence for a TGF-beta and IL-1alpha-dependent autocrine PDGF-A/PDGFRalpha signalling loop in scleroderma skin and lung fibroblasts, suggesting that a cross-talk between TGF-beta and PDGF pathways may regulate chronic fibrosis in scleroderma.

Vascular abnormalities are a major component of SSc, but little is known about the events or mechanisms that initiate vascular injury and prevent its repair. In SSc, angiogenesis is incomplete or lacking despite the increased expression of a large array of pro-angiogenic factors such as VEGF. Conflicting results have recently been published concerning the presence and role of vasculogenesis and circulating endothelial progenitor cells in SSc. It remains to be established if these endothelial progenitor cells are a marker of endothelial disease or a cause of insufficient vascular repair. Human mesenchymal stem cells (MSCs) may be an alternative source for endothelial progenitor cells, and it has been observed that the angiogenic potential of endothelial-like MSCs is reduced. Other mechanisms of vascular damage include oxidative stress and factors released from activated platelets. In addition, growth factors such as ET-1 and PDGF induce proliferation of vascular smooth muscle cells resulting in intimal thickening. For the development of new therapeutic strategies, it is important to realize that the different vascular pathologies--uncompensated loss of capillaries on one hand and vascular remodelling with a proliferative vasculopathy on the other--might require different treatment approaches.

This mini review evaluates mortality in SSc and provides a literature review concluding that premature death does occur in this population. However, there has been a changing spectrum of cause of death over the past three decades, with interstitial lung disease now being the commonest cause of SSc-related mortality. Cardiovascular (CV) mortality and events also contribute to the premature mortality seen in these patients, and this contention is supported by epidemiological studies, and further underpinned by a plethora of increased biomarkers for CV disease and events. Thus, macrovascular disease does occur in these patients, and is likely to contribute to mortality. It remains to be seen whether addressing conventional risk factors will attenuate CV disease in this population.