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Type I interferon signature predicts response to JAK inhibition in haploinsufficiency of A20
  1. Daniella Muallem Schwartz1,
  2. Sarah A Blackstone1,
  3. Natalia Sampaio-Moura2,
  4. Sofia Rosenzweig2,
  5. Aarohan M Burma1,
  6. Deborah Stone2,
  7. Patrycja Hoffmann2,
  8. Anne Jones2,
  9. Tina Romeo2,
  10. Karyl S Barron1,
  11. Meryl A Waldman3,
  12. Ivona Aksentijevich2,
  13. Daniel L Kastner2,
  14. Joshua D Milner1,
  15. Amanda K Ombrello2
  1. 1 NIAID, National Institutes of Health, Bethesda, Maryland, USA
  2. 2 NHGRI, National Institutes of Health, Bethesda, Maryland, USA
  3. 3 NIDDK, National Institutes of Health, Bethesda, Maryland, USA
  1. Correspondence to Dr Daniella Muallem Schwartz, NIAID, National Institutes of Health, Bethesda, Maryland, USA; Daniella.Schwartz{at}

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The anti-inflammatory protein A20, encoded by TNFAIP3, is a ubiquitin-modifying enzyme that targets proinflammatory molecules, including those upstream of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Patients with heterozygous loss-of-function TNFAIP3 mutations develop haploinsufficiency of A20 (HA20), a systemic autoinflammatory disease that can cause severe end-organ pathology.1–3 No available medication directly targets NF-κB signalling; thus, treatment decisions are based on clinical experience. Mild cases are treated with disease-modifying antirheumatic drugs, whereas severe cases are treated with systemic corticosteroids and biological agents, including tumour necrosis factor (TNF)-α and IL-1 receptor (IL-1R) blockade.1 2 We report that a type I interferon (IFN) signature, or elevation of IFN-stimulated genes (ISGs), correlates with disease activity and predicts response to janus kinase (JAK) inhibition in HA20.

A cohort of 12 patients with HA20 is followed at the NIH Clinical Center. All patients were diagnosed by Sanger sequencing, and increased NF-κB activity was confirmed with luciferase assay.2 Five patients had disease that was treatment-refractory or caused end-organ pathology. P1 was a 15-year-old female with p.T604Rfs*93 and severe gastrointestinal ulcerations refractory to TNF-α and IL-1R inhibition. P2–P4 were members of the same extended family with p.F224Sfs*4, aged 28, 32 and 61 years. All three had incomplete responses to TNF-α and IL-1R blockade; P2 had retinal vasculopathy and neuroinflammation, whereas P3 had membranous nephropathy. …

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