JAK inhibitor improves type I interferon induced damage: proof of concept in dermatomyositis

Brain. 2018 Jun 1;141(6):1609-1621. doi: 10.1093/brain/awy105.

Abstract

Dermatomyositis is an acquired auto-immune disease characterized by skin lesions and muscle-specific pathological features such as perifascicular muscle fibre atrophy and vasculopathy. Dermatomyositis patients display an upregulation of type I interferon-inducible genes in muscle fibres, endothelial cells, skin and peripheral blood. However, the effect of type I interferon on muscle tissue has not yet been determined. Our aim was to study the pathogenicity of type I interferon in vitro and to evaluate the efficacy of the type I interferon pathway blockade for therapeutic purposes. The activation of type I interferon in differentiating myoblasts abolished myotube formation with reduced myogenin expression while in differentiated myotubes, we observed a reduction in surface area and an upregulation of atrophy-associated genes. In vitro endothelial cells exposure to type I interferon disrupted vascular network organization. All the pathogenic effects observed in vitro were abolished by ruxolitinib. Finally, four refractory dermatomyositis patients were treated with ruxolitinib and improvement ensued in skin lesions, muscle weakness and a reduced serum type I interferon levels and interferon-inducbile genes scores. We propose JAK inhibition as a mechanism-based treatment for dermatomyositis, a finding that is relevant for the design of future clinical trials targeting dermatomyositis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Cell Line, Transformed
  • Dermatomyositis* / chemically induced
  • Dermatomyositis* / drug therapy
  • Dermatomyositis* / pathology
  • Endothelial Cells / drug effects
  • Female
  • Humans
  • Interferon Type I / toxicity*
  • Janus Kinase Inhibitors / therapeutic use*
  • Male
  • Middle Aged
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / drug effects*
  • Myxovirus Resistance Proteins / genetics
  • Myxovirus Resistance Proteins / metabolism
  • Neovascularization, Pathologic / chemically induced
  • Pyrazoles / therapeutic use*
  • SKP Cullin F-Box Protein Ligases / genetics
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Signal Transduction / drug effects*
  • Up-Regulation / drug effects

Substances

  • INCB018424
  • Interferon Type I
  • Janus Kinase Inhibitors
  • MX1 protein, human
  • Muscle Proteins
  • Myxovirus Resistance Proteins
  • Pyrazoles
  • FBXO32 protein, human
  • SKP Cullin F-Box Protein Ligases