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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. …
Handling editor Josef S Smolen
Contributors Conceptualisation: DMS and AKO. Methodology: DMS and AKO. Investigation: DMS, SB, NS-M, AB, SR, DS, PH, TR, AJ, IA and KSB. Formal analysis: DMS and SB. Writing: DMS, SB and AKO. Supervision: DLK, JDM and AKO.
Funding This study was supported by the Intramural Research Programs of the National Human Genome Research Institute, the National Institute for Allergy and Infectious Diseases, the National Institute for Arthritis and Musculoskeletal and Skin Diseases, and the NIH Transitional Program for Clinical Research.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval NIH Institutional Review Board, 94-HG-0105, IRB00000006.
Provenance and peer review Not commissioned; externally peer reviewed.
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