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Introduction: Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is a rare ACP5-associated type I interferonopathy combining skeletal dysplasia with often severe systemic immune dysregulation. Although JAK inhibitors (JAKi) directly target interferon signalling, evidence in paediatric SPENCDI remains limited to small case series and individual reports.

Methods: We retrospectively analysed a genetically confirmed paediatric SPENCDI case treated at our centre and systematically reviewed all published SPENCD/SPENCDI patients receiving JAKi. Phenotype and treatment response were assessed descriptively.

Results: Our patient showed an early-onset phenotype with disproportionate short stature and progressive multisystem immune dysregulation, including constitutional symptoms, SLE-like manifestations, vasculopathic skin changes, lymphopenia, hypergammaglobulinaemia and IgA nephropathy. Initial response to ruxolitinib was limited, most likely due to underdosing in the context of advanced inflammatory disease. Following dose optimisation, however, rapid and clinically relevant improvement occurred, particularly in systemic symptoms and overall disease burden. Across the literature, we identified 14 genetically confirmed SPENCD patients, 12 of whom had been treated with JAKi. Overall, 93% experienced clinically meaningful benefit. The clearest effects were observed in immune-mediated and haematological manifestations, while skeletal disease showed little responsiveness. Haematological involvement was present in 93% of patients; partial or complete improvement was seen in most reported cases, with particularly favourable responses in AIHA, ITP and Evans syndrome. By contrast, growth remained impaired despite occasional improvement, and osteoarticular manifestations generally persisted.

Conclusion: JAK inhibition appears to be a highly promising pathway-directed treatment for immune dysregulation in SPENCDI, with the strongest effects seen in systemic and haematological disease activity rather than in the skeletal phenotype. Our findings suggest that timing and adequate dosing matter and support earlier therapeutic intervention before irreversible organ damage evolves. Given the rarity of SPENCDI, international collaborative registries are needed to better define response patterns, optimal dosing and long-term outcomes.

Disclosures: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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