Systemic sclerosis is a rare condition that may occur in people of any race, although it is less common in people of Asian descent. It appears to be three to four times more common in women than men and is comparatively rare in children. It usually starts between 30-40 years in women and later in men.Scleroderma can run in families, but in most cases it occurs without any known family tendency for the disease. Scleroderma isn't considered contagious or cancerous, but this chronic condition can greatly affect self-esteem and the ability to accomplish everyday tasks.
Scleroderma (sklere-o-DER-muh) is a rare, progressive disease that leads to hardening and tightening of the skin and connective tissues — the fibers that provide the framework and support for your body. Scleroderma usually starts with a few dry patches of skin on the hands or face that begin getting thicker and harder. These patches then spread to other areas of the skin. In fact, scleroderma literally means "hard skin."
Systemic sclerosis (SSc; scleroderma) is an autoimmune connective tissue disease characterized by cutaneous and visceral fibrosis and widespread vascular pathology . The most common and evident expression of the vascular involvement is Raynaud’s phenomenon, an abnormal reactivity of blood vessels to cold and other stimuli. Excessive vasoconstrictive responses lead to pallor and cyanosis of distal extremities, particularly the digits, with complications including digital ulceration and infarction.
These complications are much more common in Raynaud’s phenomenon associated with SSc than in idiopathic Raynaud’s, which occurs in 10% of the adult population. In SSc, not only is a functional abnormality, i.e., vasoconstriction, more likely, but structural changes in the blood vessel, including intimal proliferation and obstruction, are also more likely to occur. Ulcers on the fingertips and over the interphalangeal
joints cause pain, limit function, heal with scarring and digital resorption, and, when infected, can lead to osteomyelitis or other serious soft tissue infections.
Excess collagen deposits in the skin and other organs produce the symptoms. Damage to small blood vessels within the skin and affected organs also occurs. In the skin, ulceration, calcification, and changes in pigmentation may occur.Systemic features may include fibrosis and degeneration of the heart, lungs, kidneys and gastrointestinal tract.
Diffuse scleroderma is the most serious and aggressive form of scleroderma.Persons with diffuse scleroderma are at high risk for developing intestinal, lung, heart and kidney involvement along with restricted motion, discomfort and diminished quality of life. The risk of new internal problems seems to be highest during the first one or two years when the skin involvement is worsening. Once skin involvement has plateaued or started to improve, the risk of new internal organ involvement is much reduced. However, unlike skin, organ involvement does not reverse with time.
There is no cure for systemic sclerosis and treatment is aimed at controlling symptoms and preventing complications. It is absolutely essential to discontinue smoking. Medicines that treat inflammation and pain include aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or corticosteroids. Other treatments are directed at specific manifestations of systemic sclerosis: for example, antacids or intestinal motility drugs for heartburn and related symptoms, medications that increase blood flow for Raynaud's phenomenon, and blood pressure medications (particularly ACE inhibitors) for high blood pressure or kidney problems.
In SSc patients, fibrosis frequently leads to organ dysfunction, serious illness, and death. Researchers have yet to determine the underlying cause of this disfiguring, debilitating condition or find an effective anti-fibrotic remedy.
Studies of SSc suggest the central role of two cytokines, transforming growth factor ß (TGFß) and platelet-derived growth factor (PDGF), in the development of fibrosis through stimulating the synthesis of extracellular matrix (ECM) proteins. On the strength of these findings, researchers at the University of Erlangen-Nuremberg, Germany and University Hospital Zurich, Switzerland , set out to test the therapeutic potential for SSc patients of a small growth factor inhibiting molecule widely used in the treatment of leukemia. Their experiments indicate the promise of imatinib mesylate to prevent tissue fibrosis and bring meaningful advances to the treatment of SSc.
Through skin biopsies, researchers obtained fibroblast cultures from the lesions of five patients with SSc, and six healthy sex- and age-matched controls. All the specimens were stimulated with TGFß and PDGF and incubated with the inhibitory molecule, imatinib mesylate. Then, applying real-time polymerase chain reaction and various assays, researchers analyzed and compared the expression of EMC proteins in SSc and normal skin fibroblasts. In addition, they assessed the anti-fibrotic effects of imatinib mesylate on laboratory mice with bleomycin-induced dermal fibrosis compared with non-diseased controls.
On the experimental fibroblast cultures from SSc patients, imatinib mesylate strongly reduced the synthesis of EMC proteins, the number of myofibroblasts, and the thickness of skin, almost back to levels observed in the healthy control groups. Similarly, imatinib mesylate effectively suppressed the development of fibrosis in the infected mice. These results were achieved by induction of the inhibitory molecule at strengths between 50 and 150 mg/kg.
“The present study provides the molecular background for controlled clinical trials with imatinib mesylate for the treatment of SSc,” assert the leading authors, Jörg Distler , MD and Oliver Distler, MD. As they note, the oral form of this molecule has not only proven effective in the treatment of leukemia and other tumors, but also remarkably well-tolerated by patients, with a low incidence of adverse side effects.
In a related editorial, Frank A. Wollheim, M.D., a researcher with Lund University Hospital in Sweden, notes the promise of these experiments, with cautionary caveats. In his contention, the level of the molecule’s induction was far higher than the standard clinical dosage of 400 to 800 milligrams per day. “In addition, the experimental conditions enabled study of imatinib mesylate as a prevention, but not as a treatment,” Dr. Wollheim stresses. “The results are exciting and promising, considering that there is at present no effective non-toxic therapy for pulmonary fibrosis. However, more extensive animal studies of imatinib mesylate, as well as studies assessing its efficacy as a treatment of existing fibrosis in addition to its efficacy as a preventative agent, are needed.”
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