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Rheumatology Advance Access originally published online on November 20, 2008
Rheumatology 2009 48(3):213-221; doi:10.1093/rheumatology/ken405
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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Pathogenesis and therapeutic approaches for improved topical treatment in localized scleroderma and systemic sclerosis

I. Badea1, M. Taylor1, A. Rosenberg2 and M. Foldvari3

1College of Pharmacy and Nutrition, 2Department of Pediatrics, College of Medicine, University of Saskatchewan, Saskatoon and 3School of Pharmacy, University of Waterloo, Waterloo, Canada.

Correspondence to: M. Foldvari, School of Pharmacy, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, Canada N2L 3G1. E-mail: foldvari{at}uwaterloo.ca


  Abstract

SSc is a chronic progressive disorder of unknown aetiology characterized by excess synthesis and deposition of collagen and other extracellular matrix components in a variety of tissues and organs. Localized scleroderma (LS) differs from SSc in that with LS only skin and occasionally subcutaneous tissues are involved. Although rarely life threatening, LS can be disfiguring and disabling and, consequently, can adversely affect quality of life. There is no known effective treatment for LS, and various options, including, as examples, corticosteroids and other immunomodulatory agents, ultraviolet radiation and vitamin D analogues, are of unproven efficacy. Clinical trials evaluating combination therapy such as corticosteroids with MTX or UVA1 exposure with psoralens have not been established as consistently effective. New immunomodulators such as tacrolimus and thalidomide are also being evaluated. A better understanding of the molecular and cellular mechanisms of LS has led to evaluation of new treatments that modulate profibrotic cytokines such as TGF-β and IL-4, regulate assembly and deposition of extracellular matrix components, and restore Th1/Th2 immune balance by administering IL-12 or IFN-{gamma}. IFN-{gamma} acts by directly inhibiting collagen synthesis and by restoring immune balance. In this review, we evaluate current and future treatment options for LS and cutaneous involvement in SSc. Recent advances in therapy focus mainly on anti-fibrotic agents. Delivery of these drugs into the skin as the target tissue might be a key factor in developing more effective and safer therapy.

KEY WORDS: Localized scleroderma, Systemic sclerosis, Cutaneous fibrosis, Autoimmunity, Skin, Collagen, Extracellular matrix, Th1/Th2 type immune response, Drug delivery

Submitted 17 March 2008; revised version accepted 18 September 2008.
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