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Antitransforming growth factor- therapy in fibrosis: recent progress and implications for systemic sclerosis

Varga, John; Pasche, Boris

Current Opinion in Rheumatology:
doi: 10.1097/BOR.0b013e32830e48e8
Raynaud phenomenon, scleroderma, overlap syndromes and other fibrosing syndromes: Edited by John Varga
Abstract

Purpose of review: Transforming growth factor-β (TGF-β) is required for tissue homeostasis but is also implicated in disease processes including fibrosis, and thus represents a molecular target for therapy.

Recent findings: Multiple strategies for inhibiting excessive TGF-β function exist. The three principal platforms are RNA-based technologies, monoclonal antibodies and small molecules. Monoclonal antibodies targeting TGF-β have been used in a small clinical trial, with disappointing results to date. Antibodies to the αvβ6 integrin prevent local activation of latent TGF-β and show promise in preclinical studies. Over a dozen small molecules inhibit the kinase activity of TGF-β receptors. Several commonly used drugs appear to have unanticipated anti-TGF-β activity and may therefore have a role in antifibrotic therapy. Because TGF-β has important physiological functions, inhibiting its activity might potentially lead to aberrant immune activation, epithelial hyperplasia and impaired wound healing; spontaneous autoimmunity in particular is a concern in an autoimmune disease such as systemic sclerosis. Novel insights from DNA microarray analysis and genetic polymorphisms in TGF-β signaling will aid in defining patient populations most likely to respond to anti-TGF-β treatment.

Summary: Anti-TGF-β therapies promise to have a major impact in systemic sclerosis. Significant concerns regarding efficacy and safety need to be addresed. The identification of optimal candidates for therapy, and of biomarkers of safety and efficacy, are critical challenges ahead.

Author Information

Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

Correspondence to John Varga, MD, Section of Rheumatology, Northwestern University Feinberg School of Medicine, 240 E Huron St, Chicago, IL 60611, USA Tel: +1 312 503 0368; fax: +1 312 503 0994; e-mail: j-varga@northwestern.edu

© 2008 Lippincott Williams & Wilkins, Inc.