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

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.

Perimysial microarteriopathy in dermatomyositis with anti‐nuclear matrix protein‐2 antibodies

“…We showed MxA expression for the first time in endothelial cells, smooth muscle cells and pericytes of the diseased arterioles, in addition to capillaries described in previous studies [22]. In-vitro studies have confirmed that the presence of type I interferon led to a reduction in the number of meshes and junctions of microvascular endothelial cells with significant upregulation of MxA [23]. In addition, extensive expression of MxA was seen in smooth muscle cells of diseased perimysial arterioles and endomysial neovessels with thick muscular coats and widely opened lumens, indicating the involvement of type I interferon signaling in smooth muscle cells.…”

Type I Interferons Suppress Anti-parasitic Immunity and Can Be Targeted to Improve Treatment of Visceral Leishmaniasis

“…Ruxolitinib (Jakafi or Jakavi) is a licensed, orally administered JAK1/JAK2 inhibitor used to treat neoplastic diseases, particularly myelofibrosis (Harrison et al, 2012;Verstovsek et al, 2012). Recently, this drug was used with some success to treat children with a type I interferonopathy (Fré mond et al, 2016) and dermatomyositis patients with type I IFN-mediated disruption of vascular endothelial networks (Ladislau et al, 2018). Therefore, we repeated the above therapeutic protocol but replaced the anti-IFNaR1 mAb with ruxolitinib.…”

Absence of sarcoplasmic myxovirus resistance protein A (MxA) expression in antisynthetase syndrome in a cohort of 194 cases

“…For this reason, ASS was suggested to be a unique myositis subtype at the European Neuromuscular Centre International Workshop [9]. Importantly, increasing number of reports suggest the therapeutic efficacy of JAK inhibitors such as tofacitinib and ruxolitinib in refractory DM [10,11]. JAK plays a key role in the expression of type 1 interferon-inducible genes, including MxA, in the target organs, by phosphorylating the transcriptional factors for interferon-inducible genes, STAT1 and STAT2.…”