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Efficacy of JAK1/2 inhibition in the treatment of chilblain lupus due to TREX1 deficiency
  1. Coralie Briand1,
  2. Marie-Louise Frémond1,2,3,
  3. Didier Bessis4,
  4. Aurélia Carbasse5,
  5. Gillian I Rice6,
  6. Vincent Bondet7,8,
  7. Darragh Duffy7,8,9,
  8. Lucienne Chatenoud2,10,11,
  9. Stéphane Blanche1,2,
  10. Yanick J Crow2,3,12,
  11. Bénédicte Neven1,2,13
  1. 1 Department of Paediatric Haematology-Immunology and Rheumatology, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
  2. 2 Paris Descartes University, Sorbonne-Paris-Cité, Paris, France
  3. 3 Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Paris, France
  4. 4 Department of Dermatology, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
  5. 5 Paediatric Rheumatology Department, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
  6. 6 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
  7. 7 Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France
  8. 8 INSERM U1223, Institut Pasteur, Paris, France
  9. 9 Centre for Translational Research, Institut Pasteur, Paris, France
  10. 10 Laboratory of Immunology, Hôpital Necker-Enfants Malades, Paris, France
  11. 11 Institut Necker-Enfants Malades, CNRS UMR8253, INSERM UMR1151, Team “Immunoregulation and Immunopathology”, Paris, France
  12. 12 Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
  13. 13 INSERM UMR 1163, Laboratory of Immunogenetics of Paediatric Autoimmunity, Institut Imagine, Paris, France
  1. Correspondence to Professor Bénédicte Neven, Department of Pediatric Immunology and Rheumatology, Necker Hospital, Paris, 75015, France; benedicte.neven{at}nck.aphp.fr

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The type I interferonopathies, Mendelian disorders characterised by constitutive upregulation of the type I interferon (IFN) pathway, are associated with a spectrum of phenotypes particularly involving the brain and the skin.1 Mutations in the 3′−5′ DNA exonuclease TREX1 were the first described cause of the severe encephalopathy Aicardi-Goutières syndrome (AGS),2 of which acral vasculitic lesions are a well-recognised feature. Familial chilblain lupus (FCL) is the name given where such lesions occur in the absence of neurological disease.3 TREX1 dysfunction, due to biallelic loss of function or dominant negative heterozygous mutations, is postulated to lead to aberrant immune recognition of self-nucleic acids inducing the production of type I IFNs. These potent cytokines drive the expression of IFN-stimulated genes (ISGs) through the engagement of a common receptor and the subsequent activation of Janus kinase 1 (JAK1) and tyrosine kinase 2. We describe, to our knowledge for the first time, the efficacy of the JAK1/2 inhibitor ruxolitinib in a patient with TREX1-related skin disease. Parental consent was obtained for the use of ruxolitinib on a compassionate basis.

The patient carried a previously recorded dominant negative heterozygous mutation in TREX1 (c.52G>A, …

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