A newly identified autoinflammatory condition called CANDLE syndrome (chronic atypical neutrophilic dermatosis with lipodystrophy and increased temperature) is characterized by early onset, recurring fever, skin lesions, and multisystemic inflammatory symptoms. It has been demonstrated that the majority of patients had PSMB8 gene mutations. It leads to dysfunction in the proteasome/immunoproteasome system and subsequent overproduction of type 1 interferons. Patients usually exhibit lipodystrophy, fever, rashes on the skin, and malnutrition in the early stages of infancy. The results of skin biopsies, laboratory tests, and clinical symptoms all support the diagnosis of CANDLE syndrome. Although there isn't a specific treatment for CANDLE syndrome, JAK inhibitors like baricitinib have demonstrated some effectiveness in treating its symptoms. For CANDLE syndrome patients to receive the right therapeutic interventions, early diagnosis and molecular testing are essential. A positive interferon signature has also been found to be a diagnostic indicator for the condition. Although there are no particular treatments for CANDLE syndrome, research is still being done to determine how well immunosuppressive medications, biological agents, and glucocorticoids work in treating the condition. Current research generally aims to improve the quality of life for individuals with CANDLE syndrome through the development of targeted medications, the elucidation of genetic determinants, and the advancement of diagnostic methods.

Genetic mutations affecting proteasome function can result in multi-organ diseases, such as Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. Neurological symptoms associated with CANDLE suggest that proteasomal mutations may impact neuronal development and/or function. We generated cerebral organoids (COs) from CANDLE patient induced pluripotent stem cells (iPSCs), which exhibited impaired neuronal development when compared to COs from healthy control iPSCs. Impaired neuronal maturation in CANDLE COs was correlated with increased polyamines, which were also elevated in CANDLE patient CSF. The proteasome-regulated Ornithine decarboxylase (ODC), a rate limiting enzyme for polyamines, was elevated in CANDLE neurons. Inhibition of ODC reversed polyamine overproduction and repaired neuronal maturation in CANDLE COs, suggesting a potential therapeutic avenue for intervention. These findings demonstrate that dysfunction of the proteasome affects neuronal development through overproduction of polyamines via dysregulation of ODC and offer insight into potential therapeutic strategies for CNS-related proteasomal dysfunction.

CANDLE syndrome (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature) is an autoinflammatory disorder characterized by recurrent fever, skin lesions, and other symptoms caused by a mutation in the PSMB8 gene. This case report aims to describe the clinical features of a 3-year-old male patient with this syndrome. The patient, of Syrian origin, presented with recurrent fever and widespread skin lesions since the age of 7 months. There was a family history of similar skin lesions. On examination, erythematous eruptions and generalized lymphadenopathy were noted. Genetic studies confirmed a homozygous nonsense mutation in PSMB8, a diagnostic of CANDLE syndrome. The patient showed symptomatic improvement with oral prednisolone. The mutation associated with CANDLE syndrome is in PSMB8 (proteasome subunit β type 8), activated by interferon γ, and produces cytokines. This case is significant as it is the first reported CANDLE syndrome in Syria and the Middle East. We highlight the variability in symptoms and responses to treatment and emphasize the noticeable improvement observed following treatment with corticosteroids alone.

A causal role of type-I interferons (IFN-I) in autoinflammatory type-I interferonopathies such as SAVI (STING-associated vasculopathy with onset in infancy) and CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures) is suggested by elevated expression of IFN-I stimulated genes (ISGs). Hitherto, the lack of specific inhibitors of IFN-I signaling has prevented the verification of a causal role for IFN-I in these conditions. Commonly used inhibitors of the JAK/STAT pathway exert broad effects on multiple signaling pathways leading to more general immunosuppression beyond IFN-I signaling. Here we show in four patients with SAVI and one patient with CANDLE syndrome that blockade of the IFNAR1 receptor (Anifrolumab) exerts an additive effect over JAK-inhibitor alone. In two patients with SAVI, monotherapy with Anifrolumab is sufficient to retain a suppressed IFN-I signature and clinical improvement. Anifrolumab normalizes IFN-I signature genes and relieves symptoms beyond what is typically achieved by a JAK-inhibitor (Baricitinib) alone in patients with type-I interferonopathies. In two patients Anifrolumab was used successfully as monotherapy. Addition of Anifrolumab enabled steroid tapering and cessation with reduced overall immunosuppression and lower risks of opportunistic infections and improved metabolic states and growth which is highly beneficial in these young patients. These results verify a causal role of IFN-I signaling in type-I Interferonopathies SAVI and CANDLE and suggests Anifrolumab as an important new treatment option in autoinflammatory diseases with elevated IFN-I induced gene expression. Genia Kretzschmar, Laura Piñero Páez, and Ziyang Tan are shared-first authors. Sara Alehashemi, AnnaCarin Horne, and Petter Brodin are co-senior author.