A case of STING-associated vasculopathy with onset in infancy highlighting the pathogenetic role of interferon regulatory factor 5

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Objectives To elucidate the pathophysiology of stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI), we evaluated interferon-stimulated gene (ISG) expression and nuclear translocation of interferon regulatory factors 3 and 5 (IRF3 and IRF5) in patient-derived cells before and after Janus kinase (JAK) inhibitor treatment. Methods A 3-year-old girl presenting with refractory eczema, polyarthritis, and interstitial lung disease (ILD) was confirmed to have SAVI. Baricitinib, a JAK1/2 inhibitor, was initiated for refractory ILD, and peripheral blood samples were analysed before and 4 months after baricitinib initiation. Expression of representative ISGs (IFI27, MX1, and OAS1) was quantified by reverse-transcription quantitative polymerase chain reaction. Nuclear localization of IRF3 and IRF5 was examined in sorted monocytes and B cells using confocal microscopy after intracellular staining. Activation was quantified by the nuclear-to-cytoplasmic mean fluorescence intensity ratio. Results ISG expression was markedly elevated at baseline and decreased to levels comparable to those in a healthy control subject after 4 months of treatment. IRF3 localization remained unchanged, whereas IRF5 showed pronounced nuclear enrichment in monocytes at baseline, an effect that diminished after treatment. This reduction paralleled clinical improvement, including resolution of lung involvement and rash, and seroreversion of autoantibodies. Conclusion IRF5 activation may sustain chronic inflammation in SAVI independently of IRF3. The observed reduction in IRF5 nuclear translocation paralleled the improvement in disease activity, suggesting that targeting IRF5 may help suppress inflammatory processes not adequately controlled by existing treatments.