Efficacy of JAK1/2 inhibitors in AGS genes-related interferonopathies: A multicenter retrospective observational study with treated vs untreated comparison.

Aicardi-Goutières syndrome (AGS) and genes-related interferonopathies are a group of multisystem disorders involving the central nervous system, caused by pathogenic variants in genes regulating nucleic acid metabolism and type I interferon signaling, leading to chronic interferon overproduction. This retrospective multicenter study analyzed the efficacy and safety of Janus kinase 1/2 (JAK1/2) inhibitors in 12 patients treated with Baricitinib or Ruxolitinib, compared with 20 untreated patients. Treatment showed improvement in immunological and dermatological symptoms, while the impact on neurological manifestations was limited and heterogeneous, with greater benefits in patients with mild or intermediate phenotypes and earlier treatment initiation. Neuroroimaging analyses in untreated patients showed radiological improvements equal to or greater than those treated, raising doubts about the true impact of JAK 1/2 inhibitors on the neuroradiological course. Adverse events were rare and mild, confirming the favorable safety profile of this treatment. The results suggest that the pathogenetic complexity of AGS goes beyond the JAK-STAT pathway, highlighting the need for larger prospective studies to identify subgroups most likely to benefit from this therapeutic approach and to refine treatment strategies.