JAK inhibitors: a potential treatment for JDM in the context of the role of interferon-driven pathology

Abstract

Juvenile Idiopathic Inflammatory Myopathies (IIM) are a group of rare diseases that are heterogeneous in terms of pathology that can include proximal muscle weakness, associated skin changes and systemic involvement. Despite options for treatment, many patients continue to suffer resistant disease and lasting side-effects. Advances in the understanding of the immunopathology and genetics underlying IIM may specify new therapeutic targets, particularly where conventional treatment has not achieved a clinical response. An upregulated type I interferon signature is strongly associated with disease and could be a prime target for developing more specific therapeutics. There are multiple components of the IFN pathway that could be targeted for blockade therapy.Downstream of the cytokine receptor complexes are the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway, which consists of JAK1–3, TYK2, and STAT1–6. Therapeutic inhibitors have been developed to target components of this pathway. Promising results have been observed in case studies reporting the use of the JAK inhibitors, Baricitinib, Tofacitinib and Ruxolitinib in the treatment of refractory Juvenile Dermatomyositis (JDM). There is still the question of safety and efficacy for the use of JAK inhibitors in JDM that need to be addressed by clinical trials. Here we review the future for the use of JAK inhibitors as a treatment for JDM.

Is Anti-NXP2 Autoantibody a Risk Factor for Calcinosis and Poor Outcome in Juvenile Dermatomyositis Patients? Case Series

“…Recently, advances in the understanding of the immunopathology and genetics in JDM may help to specify new treatment approaches, especially when conventional therapy is not successful. An upregulated type 1 interferon signature is strongly associated with JDM, which could present the possibility for the treatment of most severe cases with JAK inhibitors ( 17 , 18 ). However, the safety and efficacy of this therapy still need to be studied in clinical trials.…”

Juvenile dermatomyositis. Where are we now?

“…Based on this evidence in a total of 49 patients (48 with refractory disease, 1 new onset), JAK kinase inhibitors appear to demonstrate efficacy for skin and muscle disease (144). The role of interferon in JDM including therapeutic interventions and comparison to interferonopathies has recently been reviewed (138,144). Monoclonal antibodies targeting IFN-α such as sifalimumab or anifrolumab may be beneficial in IIM and have been evaluated in early phase studies in adult onset disease, but not yet tested in children or young people (148,149).…”

Juvenile Dermatomyositis

“…Allerdings gibt es Anzeichen dafür, dass besonders die pädiatrische Untergruppe der Studienkohorte günstig auf die Therapie angesprochen hatte [33]. JDM dar, da diese durch eine JAK1-Inhibition direkt in Typ 1 IFN-getriebene Signalwege eingreifen [34]. Fallserien und prospektive Open-Label-Studien weisen auf eine sehr gute Effektivität bei Patienten mit schweren, refraktären Verläufen einer JDM hin [35,36].…”

“…Januskinase (JAK)-Inhibitoren, wie z. B. Baricitinib, Ruxolitinib oder Tofacitinib, stellen eine vielversprechende Therapieoption bei der JDM dar, da diese durch eine JAK1-Inhibition direkt in Typ 1 IFN-getriebene Signalwege eingreifen 34 . Fallserien und prospektive Open-Label-Studien weisen auf eine sehr gute Effektivität bei Pa-tienten mit schweren, refraktären Verläufen einer JDM hin 35 36 .…”