Efficacy of Dupilumab in STAT6 GOF disease: 30 months follow-up of a single patient

Abstract

Signal transducer and activator of transcription 6 (STAT6) gain-of-function (GOF) disease is a novel inborn error of immunity (IEI) characterised by early-onset severe allergic disease with dermatological, respiratory, and gastrointestinal involvement, accompanied by hypereosinophilia and hyperIgE. We diagnosed one such patient in Hong Kong, who now is a young man in his 20 s, and has had lifelong struggle with debilitating recalcitrant eczema and short stature among other issues. Exome sequencing identified a heterozygous mutation in STAT6 NM_001178078.1:c.1256A>G; p.(Asp419Gly), which we demonstrated to cause gain-of-function in luciferase promoter assays. Knowing the diagnosis, the patient was started on a biologic, Dupilumab, which is a monoclonal targeting IL4RA, the receptor upstream of STAT6. The patient experienced dramatic reduction in eczema disease activity as quantified by EASI and SCORAD scores, and had sharp reduction in peripheral eosinophilia without normalising his IgE levels. Dupilumab also potentiated the effect of his growth hormone replacement as he experienced dramatic height and weight gain since initiating Dupilumab. Transcriptomic analyses on bulk and single-cell levels also demonstrated reduced immune cell perturbation compared to healthy controls after treatment. The clinical effect of Dupilumab was sustained up to the last follow up more than 2 years after initiation. Dupilumab use was not associated with safety concerns. To conclude, Dupilumab appears to be a safe and effective treatment option for patients with STAT6 GOF disease.