Type I interferon signature predicts response to JAK inhibition in haploinsufficiency of A20

• Published in: Annals of the rheumatic diseases Vol. 79; no. 3; pp. 429 - 431
• Main Authors: Schwartz, Daniella Muallem, Blackstone, Sarah A, Sampaio-Moura, Natalia, Rosenzweig, Sofia, Burma, Aarohan M, Stone, Deborah, Hoffmann, Patrycja, Jones, Anne, Romeo, Tina, Barron, Karyl S, Waldman, Meryl A, Aksentijevich, Ivona, Kastner, Daniel L, Milner, Joshua D, Ombrello, Amanda K
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01.03.2020
• Subjects: A20 protein; Adolescent; Adult; Asymptomatic; Corticosteroids; Cytokines; Disease; Female; Haploinsufficiency; Haploinsufficiency - drug effects; Humans; Immunology; Inflammasomes; Inflammation; Interferon; Interferon Type I - metabolism; Interleukin 1; Interleukin 1 receptors; Janus kinase; Janus Kinase Inhibitors - pharmacology; Kinases; Loss of Function Mutation - drug effects; Male; Middle Aged; Mutation; NF-kappa B - metabolism; NF-κB protein; Pathology; Proteins; Signal Transduction - drug effects; TNF inhibitors; Tumor Necrosis Factor alpha-Induced Protein 3 - genetics; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Tumors; Young Adult; fever syndromes; DMARDs (synthetic); cytokines
• ISSN: 0003-4967; 1468-2060; 1468-2060
• DOI: 10.1136/annrheumdis-2019-215918

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. [...]we measured expression in the whole blood of all five patients and found elevated ISGs compared with healthy volunteers (figure 1C). Together with a recent report of HA20 treatment with the JAK1/2 inhibitor baricitinib, we provide compelling evidence that JAK inhibition is safe and effective for HA20.6 A20 directly targets NF-κB signalling and the NLRP3 inflammasome; although A20 is also described to regulate IFN signalling, the underlying mechanisms are incompletely characterised.4 7 Our data suggest that disease activity correlates with elevations of multiple proinflammatory cytokines and increased ISG expression.2 Future studies will be needed to identify the targets of A20 in various inflammatory cells, and the mechanisms through which A20 constrains type I IFN responses.