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Scleroderma/Systemic Sclerosis: Important Cause of PAH

John Varga


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Conference: 2010 International PHA Conference and Scientific Sessions

Release Date: 06.22.2010

Presentation Type: Scientific Sessions

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Systemic sclerosis (SSc) is a complex autoimmune disorder of unknown cause. It is an orphan disease that occurs far more commonly in women, and peaks between the ages of 35-55. Multiple genetic associations with modest effect have been described. Fibrosis and vascular injury are prominent in most patients. However, SSc is highly heterogeneous in its clinical manifestations and natural history, with two subsets
called limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) that are characterized by partially overlapping patterns of organ involvement, and distinct rates of progression, autoantibody profiles and survival. The lung is a prominent target organ in both forms of SSc, and a majority of patients have either lung fibrosis, pulmonary hypertension, or a combination of both diatheses. SSc has a chronic and progressive course and effective treatments are lacking. Mortality is substantial, and is often due to pulmonary fibrosis or pulmonary hypertension. Fibrosis has been linked to aberrant activation of factor such as TGF-ß, Wnt, PDGF and endothelin-1 acting via intracellular pathways involving Smad2/3, Egr-1, ß-catenin and c-Abl. Pharmacological blockade of these growth factors and their downstream mediators for the treatment of SSc is under investigation. Drugs such as the tyrosine kinase inhibitor imatinib are particularly appealing, because by blocking c-Abl-mediated TGF-ß signaling as well as PDGF signaling, they might beneficially influence both TGF-ß-driven fibroblast activation and PDGF-driven vascular remodeling.

In most SSc patients, progressive vascular damage occurs in the medium and small arteries and arterioles in multiple vascular beds. Over time, chronic injury leads to obliteration of these small blood vessels, with resulant vascular rarefaction, tissue hypoxia and the generation of reactive oxygen species. Histologic examination of affected blood vessels often reveals vascular intimal hyperplasia, medial hypertrophy and loss of lumen. In contrast, vascular inflammation and vasculitis are uncommon. The vascular damage is typically most prominent in the fingers, the gut, the heart, kidneys and in the pulmonary circulation. Vascular injury and loss in these organs results in significant organ damage, manifested by Raynaud 's phenomenon and digital ischemia, watermelon stomach and GI bleeding, scleroderma renal crisis with malignant hypertension, myocardial ischemia and pulmonary arterial hypertension. The mortality of SSc is substantial, and is due in large degree to the sequelae of vascular damage, ischemia and infarction. Despite previously held views that SSc-associated PAH is indistinguishable for idiopathic PAH, it is becoming evident that these two pulmonary vascular processes are distinct. To date, mutations in the bone morphogenic protein (BMP) signaling axis have not been found in SSc patients. It is worth noting that the expression of the nuclear receptor PPAR-gamma has been shown to be reduced in the lungs of patients with idiopathic pulmonary hypertension. PPAR-gamma is relevant to pathogenesis, because its genetic deletion in the mouse is associated with spontaneous development of pulmonary hypertension. Furthermore, activating the PPARgamma receptor with insulin-sensitizing drugs such as rosiglitazone in these mice ameliorates experimental
pulmonary hypertension. In SSc, the tissue expression and activity of PPAR-gamma are reduced, and it has been suggested that activating PPAR-gamma with insulin-sensitizing drugs might be a strategy for treating both the fibrotic and the vascular complications of SSc. SSc patients with PAH typically have higher BNP levels that patients with idiopathic PAH. Furthermore, the outcome of SSc-associated PAH is worse than that of idiopathic PAH, and response to therapy less beneficial. This is due to multiple factors, including the frequent co-existence in SSc patients of pulmonary fibrosis and hypoxemia with PAH. Furthermore, recent studies indicate that myocardial damage and diastolic dysfunction are more common in SSc than previously recognized. Careful histological study indicates that compared to idiopathic PAH, in patients with SSc PAH is more commonly accompanied by vascular fibroproliferation and venous involvement; whereas plexiform lesions are infrequent.

A better understanding of the pathogenesis of SSc and its clinical heterogeneity, along with the development and validation of biomarkers of tissue damage, will lead to a greater appreciation of the unique features of SSc, and in particular the aspects of PAH that are shared with, and those that are distinct from, idiopathic PAH. This insight in turn will facilitate the development of disease-modifying therapies specific for SSc and its complications.