New treatment hope for systemic sclerosis
Study suggests potential of inhibitory molecule to prevent development of fibrosis
Systemic sclerosis (SSc) is a chronic autoimmune disorder marked by early skin lesions and the progressive tissue fibrosis. More than skin deep, this thickening and hardening of connective tissue affects the blood capillaries, the gastrointestinal tract, the lungs, and the heart. 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. Featured in the January 2007 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), 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."
Article: "Imatinib Mesylate Reduces Production of Extracellular Matrix and Prevents Development of Experimental Dermal Fibrosis," Jörg H. W. Distler, Astrid Jüngel, Lars C. Huber, Ursula Schulze-Horsel, Jochen Zwerina, Renate F. Gay, Beat A. Michel, Thomas Hauser, Georg Schett, Steffen Gay, and Oliver Distler, Arthritis & Rheumatism, January 2007; (DOI: 10.1002/art.22314).
Editorial: "Treatment of Pulmonary Fibrosis in Systemic Sclerosis: Light at the End of the Tunnel?," Frank A. Wollheim, Arthritis & Rheumatism, January 2007; (DOI: 10.1002/art.22315).
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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