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BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. METHODS: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses. RESULTS: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients. CONCLUSIONS: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
Assuntos
Proteína AIRE , Interferon gama , Inibidores de Janus Quinases , Poliendocrinopatias Autoimunes , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Proteína AIRE/deficiência , Proteína AIRE/genética , Proteína AIRE/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Quimiocina CXCL9/genética , Interferon gama/genética , Interferon gama/imunologia , Inibidores de Janus Quinases/uso terapêutico , Camundongos Knockout , Nitrilas/uso terapêutico , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/tratamento farmacológico , Poliendocrinopatias Autoimunes/imunologia , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Pirimidinas/uso terapêutico , Linfócitos T/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Projetos Piloto , Modelos Animais de Doenças , Criança , Adolescente , Pessoa de Meia-IdadeRESUMO
AIM: Due to the limited data from clinical trials and real-world settings in the realm of nusinersen, there is a need for further evidence. This study seeks to assess the impact of nusinersen, when combined with standard care, on bulbar function, respiratory function, and the necessity for respiratory support among pediatric patients with spinal muscular atrophy (SMA). METHODS: Prospective observational study, involving pediatric SMA patients (types 1-3) undergoing nusinersen treatment at the Hospital Universitario Virgen del Rocío in Spain over at least a 24-month period. The cohort included 11 SMA type 1 patients, comprising 6 type 1b and 5 type 1c, 12 SMA type 2 patients, and 5 SMA type 3 patients. RESULTS: 28 pediatric patients were enrolled, with a majority being male (n=20). Patients with type 1 were diagnosed and received treatment significantly earlier than those with types 2 and 3 (P<0.001). Additionally, there was a longer period between diagnosis and the start of treatment in types 2/3 (P=0.002). Follow-up revealed statistically improved functional and respiratory outcomes associated with earlier initiation of nusinersen treatment at 6, 12, and 24 months in all phenotypes. The ability to swallow and feed correctly remained unchanged throughout the study, with SMA type 1c patients maintaining oral feeding in contrast to patients with SMA type 1b. Notably, no deaths were recorded. CONCLUSIONS: This study provides important insights into the real-world clinical progress of pediatric SMA patients and their response to nusinersen treatment, highlighting the significance of early intervention for better functional and respiratory outcomes.
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