Efficacy of the Janus Kinase 1/2 Inhibitor Ruxolitinib in the Treatment of Vasculopathy Associated with TMEM173-Activating Mutations in three children

Publication date: Available online 20 August 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Marie-Louise Frémond, Mathieu Paul Rodero, Nadia Jeremiah, Alexandre Belot, Eric Jeziorski, Darragh Duffy, Didier Bessis, Guilhem Cros, Gillian I. Rice, Bruno Charbit, Anne Hulin, Nihel Khoudour, Consuelo Modesto Caballero, Christine Bodemer, Monique Fabre, Laureline Berteloot, Muriel Le Bourgeois, Philippe Reix, Thierry Walzer, Despina Moshous, Stéphane Blanche, Alain Fischer, Brigitte Bader-Meunier, Fréderic Rieux-Laucat, Yanick Joseph Crow, Bénédicte Neven
BackgroundGain-of-function mutations in TMEM173 encoding STING (Stimulator of Interferon Genes) underlie a novel type I interferonopathy. This disease is seemingly minimally responsive to conventional immunosuppressive therapies - and thus associated with high childhood morbidity and mortality.ObjectiveOur aim was to describe the use of ruxolitinib, an oral Janus kinase (JAK) 1/2 inhibitor, in the treatment of vasculopathy associated with TMEM173-activating mutations.Design, settings, participants, and interventionsWe report three children with TMEM173-activating mutations, recruited from three institutions, treated with ruxolitinib over a period of 6 to 18 months.MethodsDuring follow-up, clinical data were collected and disease activity scores were determined. Interferon (IFN) scores and ruxolitinib concentrations were measured. The effect of ruxolitinib on JAK-STAT signaling was assessed in patients by ex vivo STAT phosphorylation assays.ResultsThe patients, aged between 5 and 12 years, variably exhibited the core features of STING-associated vasculopathy including recurrent fevers, destructive skin lesions and interstitial lung disease. We observed marked clinical improvement with treatment, mirrored by in vitro and ex vivo experiments. Tolerance was good without an obvious infectious risk.ConclusionAlthough questions of sustained efficacy and safety require longer-term evaluation, these data suggest that JAK1 inhibition represents a promising therapeutic approach to the systemic inflammation associated with constitutive type I IFN upregulation.

Teaser

This article demonstrates that JAK inhibition represents a highly promising and well-tolerated therapy for STING-associated vasculopathy, and which may also be relevant to the treatment of other type I interferonopathies.


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