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Pomalidomide is effective for prevention and treatment of experimental skin fibrosis
  1. Simon Weingärtner1,
  2. Pawel Zerr1,
  3. Michal Tomcik1,
  4. Katrin Palumbo-Zerr1,
  5. Alfiya Distler1,
  6. Clara Dees1,
  7. Christian Beyer1,
  8. Sai L Shankar2,
  9. Dorota Cedzik2,
  10. Peter H Schafer2,
  11. Oliver Distler3,
  12. Georg Schett1,
  13. Jörg H W Distler1
  1. 1Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Celgene Corporation, Translational Development, Summit, New Jersey, USA
  3. 3Department of Rheumatology, University Hospital Zurich, Zürich, Switzerland
  1. Correspondence to Dr Jörg Distler, Department of Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen D-91054, Germany; joerg.distler{at}uk-erlangen.de

Abstract

Objectives Tissue fibrosis is a major hallmark and a leading cause of death in systemic sclerosis (SSc). Here, we investigated the antifibrotic effects of pomalidomide, an analogue of thalidomide with potent immunomodulatory effects, in preclinical models of skin fibrosis.

Methods We evaluated the antifibrotic effects of pomalidomide in preventive as well as therapeutic treatment regimes using bleomycin-induced dermal fibrosis as a model of early, inflammatory stages of fibrosis and the tight-skin mouse model as a model of later stages of fibrosis with endogenous activation of fibroblasts.

Results Treatment with pomalidomide in doses from 0.3 to 30 mg/kd/day prevented skin fibrosis in Tsk-1 mice and in bleomycin-induced dermal fibrosis in a dose-dependent manner and reduced the expression of transforming growth factor (TGF) β-target genes such as PAI-1, CTGF and col 1a1. Pomalidomide was also effective in the setting of pre-established fibrosis and reduced dermal thickness, myofibroblast counts and hydroxyproline content below pretreatment levels.

Conclusions We demonstrate for the first time that pomalidomide exerts potent antifibrotic effects in different preclinical models of skin fibrosis. These findings lend preclinical support for the clinical studies of pomalidomide in SSc.

  • Systemic Sclerosis
  • Fibroblasts
  • Treatment

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