TY - JOUR
T1 - JAK inhibitor improves type i interferon induced damage: Proof of concept in dermatomyositis
AU - Ladislau, Leandro
AU - Suárez-Calvet, Xavier
AU - Toquet, Ségolène
AU - Landon-Cardinal, Océane
AU - Amelin, Damien
AU - Depp, Marine
AU - Rodero, Mathieu P.
AU - Hathazi, Denisa
AU - Duffy, Darragh
AU - Bondet, Vincent
AU - Preusse, Corinna
AU - Bienvenu, Boris
AU - Rozenberg, Flore
AU - Roos, Andreas
AU - Benjamim, Claudia F.
AU - Gallardo, Eduard
AU - Illa, Isabel
AU - Mouly, Vincent
AU - Stenzel, Werner
AU - Butler-Browne, Gillian
AU - Benveniste, Olivier
AU - Allenbach, Yves
PY - 2018/6/1
Y1 - 2018/6/1
N2 - © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: Journals.permissions@oup.com. 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.
AB - © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: Journals.permissions@oup.com. 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.
KW - JAK inhibitor
KW - autoimmune diseases
KW - dermatomyositis
KW - type I interferon
U2 - 10.1093/brain/awy105
DO - 10.1093/brain/awy105
M3 - Article
VL - 141
SP - 1609
EP - 1621
JO - Brain
JF - Brain
SN - 0006-8950
IS - 6
ER -