First reported use of anifrolumab to treat a monogenic interferonopathy (DNASE2 loss of function)

Abstract

DNASE2 loss of function resulting in DNase II deficiency has recently been described as an etiology of type I interferonopathy. DNAse II plays an important role in clearance of intracellular nucleic acids, and mice models lacking DNase II demonstrate heightened cGAS STING activation and production of type I interferon (1).We present a 14 y/o male who was referred to our clinic with a one-year history of cyclic fevers. He was born to non-consanguineous parents and had an otherwise unremarkable infancy and childhood medical history. At the age of 13, he started to develop weekly fevers (as high as 103 °F). During his initial outpatient work up, he was found to be have EBV infection and also diagnosed with autoimmune hypothyroidism, for which he was started on levothyroxine. Over the ensuing months, his cyclic fevers continued, in addition to loss of appetite, poor weight gain, and worsening fatigue. He also developed a non-hemolytic anemia & thrombocytopenia, for which he required intermittent RBC transfusions. Given his constellation of systemic symptoms with associated cytopenias he was admitted for further work up. Whole-exome sequencing revealed a homozygous missense variant in DNASE2 (NM_001375.2:c.1040G > A, p.Cys347Tyr).We validated the biochemical relevance of his DNASE2 variant with two functional assays, including a clinical assay that detects transcripts of Interferon Stimulated Genes (DxTerity) and measurement of phosphorylated STAT1 signaling (baseline and upon activation).We treated him with off-label use of a monoclonal antibody, anifrolumab, that blocks the interferon-α/β receptor. Since initiation, he has shown significant clinical improvement with cessation of fevers, improved appetite with excellent weight gain, and resolution of his cytopenias. ConclusionsThis is the first reported use of anifrolumab to treat a monogenic interferonopathy. Anifrolumab adds to our armamentarium for treatment of monogenic autoinflammatory diseases driven by excessive Type 1 interferon signaling. Anifrolumab should be considered as a treatment for autoinflammatory diseases due to STING, DNA recognition pathways (i.e. DNAase 2), RNA recognition pathways (i.e. RNASEH2A/B/C, RIG-I, etc.), COPA, and other type 1 interferonopathies.