Advances in Scleroderma Research

by Carol Feghali-Bostwick, Ph.D

The 2007 national meeting of the American College of Rheumatology held November 6–11, 2007, in Boston, Mass., highlighted presentations on clinical and basic research by investigators from the U.S. and abroad.  New observations on systemic sclerosis (SSc) were described in the format of posters and oral presentations.

Several presentations focused on the role of growth factors in the development of fibrosis. These growth factors, such as transforming growth factor-beta ( TGFβ) and platelet-derived growth factor (PDGF), when added to fibroblasts (cells grown from the skin of healthy donors and patients with scleroderma), signal into the cell to ‘turn on’ certain genes such as collagen, making normal fibroblasts behave like scleroderma fibroblasts. Investigators are now focusing on blocking the effect of these growth factors via a variety of approaches, thus preventing them from signaling into the cell.  New approaches include using antibodies that neutralize the activity of the growth factor, chemical inhibitors that block the ability of these factors to signal into the cell, and drugs that are currently used for the treatment of various cancers and which are also known to inhibit the signaling of these growth factors. As with any drug, there are both harmful and beneficial effects when blocking these molecules.

Several investigators reported on the results of recent clinical trials for Raynaud’s disease, pulmonary fibrosis, and pulmonary hypertension.  Findings on the epidemiology of SSc including the occurrence of autoimmune diseases in families of patients with SSc. A study conducted in the Netherlands examined the prevalence of atherosclerosis in SSc patients. Increased incidence of atherosclerosis has been observed in some rheumatic diseases such as systemic lupus erythematosus (SLE). Unlike patients with SLE, patients with SSc did not have increased signs of atherosclerosis. Investigators from Padua, Italy, and Pittsburgh, PA reported on a comparison of SSc in children and adults. Approximately 4% of SSc patients have onset of their disease in childhood.  The distribution of autoantibodies in the blood, which serve as markers of SSc, differs in children and adults. These antibodies are also associated with higher risk of involvement of particular internal organs such as kidneys and lung. For example, Anti-RNA polymerase and anti-centromere antibodies are less frequent in children while anti-U1 RNP and anti-PM-Scl antibodies are more common. As a result, kidney involvement and pulmonary arterial hypertension are less common in children with SSc while overlap with myositis (muscle involvement) is more common. Cardiac involvement seemed to occur more often in children than adults, But in spite of that, survival was found to be improved in children with SSc with 90% of patients surviving 10 years after their illness begins.

The presence of polymorphisms (individual-specific changes in the DNA) and the detection of new antibodies against self proteins and other markers that are associated with SSc or individual organ involvements such as pulmonary hypertension were also described. For example, two markers were found to correlate with pulmonary hypertension in SSc. Brain Natriuretic Peptide (BNP), has been used as a predictor of heart failure. BNP is a hormone that is released by the heart in response to stretching. A second marker, uric acid, has been used in patients with primary pulmonary hypertension (PHT)   (PHT with no underlying connective tissue disease) and correlates with pulmonary artery pressures. Both BNP and uric acid levels were found to be elevated in SSc patients with PHT compared to SSc patients without PHT suggesting that these markers may potentially predict PHT in SSc.

Both basic and clinical research conducted by investigators from many different countries have led to new insights into the mechanisms involved in the development of SSc and potential new therapies that may be effective for SSc patients.  This information has helped us add new pieces to the scleroderma puzzle.