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

Leandro Ladislau; Xavier Suárez-Calvet; Ségolène Toquet; Océane Landon-Cardinal; Damien Amelin; Marine Depp; Mathieu Rodéro; Denisa Hathazi; Darragh Duffy; Vincent Bondet; Corinna Preusse; Boris Bienvenu; Flore Rozenberg; Andreas Roos; Claudia Benjamim; Eduard Gallardo; Isabel Illa; Vincent Mouly; Werner Stenzel; Gillian Butler-Browne; Olivier Benveniste; Yves Allenbach

doi:10.1093/brain/awy105

Journal articles

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

Leandro Ladislau ^{1, 2} Xavier Suárez-Calvet ^{2, 3, 4} Ségolène Toquet ² Océane Landon-Cardinal ² Damien Amelin ² Marine Depp ⁵ Mathieu Rodéro ⁵ Denisa Hathazi ⁶ Darragh Duffy ⁷ Vincent Bondet ⁷ Corinna Preusse ⁸ Boris Bienvenu ⁹ Flore Rozenberg ¹⁰ Andreas Roos ^{6, 11} Claudia Benjamim ¹ Eduard Gallardo ^{3, 4} Isabel Illa ^{3, 4} Vincent Mouly ² Werner Stenzel ⁸ Gillian Butler-Browne ² Olivier Benveniste ² Yves Allenbach ^{2, *}

* Corresponding author

1 IBCCF / UFRJ - Instituto de Biofísica Carlos Chagas Filho [Rio de Janeiro]

2 Institut de Myologie

3 UAB - Universitat Autònoma de Barcelona [Barcelona]

4 CIBER de Enfermedades Raras (CIBERER)

5 IMAGINE - U1163 - Imagine - Institut des maladies génétiques

6 Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V.

7 Immunobiologie des Cellules dendritiques

8 Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin

9 Hôpital Saint-Joseph [Marseille]

10 AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris]

11 Institute of Genetic Medicine, International Centre for Life,

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.

Keywords : JAK inhibitor autoimmune diseases type I interferon dermatomyositis

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Immunology

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Submitted on : Wednesday, June 20, 2018 - 10:51:59 AM
Last modification on : Monday, October 19, 2020 - 2:34:03 PM

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

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

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