Emerging evidence supports that mitochondrial dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis. Here we show that programmed mitochondrial removal, a hallmark of mammalian erythropoiesis, is defective in SLE. Specifically, we demonstrate that during human erythroid cell maturation, a hypoxia-inducible factor (HIF)-mediated metabolic switch is responsible for the activation of the ubiquitin-proteasome system (UPS), which precedes and is necessary for the autophagic removal of mitochondria. A defect in this pathway leads to accumulation of red blood cells (RBCs) carrying mitochondria (Mito+ RBCs) in SLE patients and in correlation with disease activity. Antibody-mediated internalization of Mito+ RBCs induces type I interferon (IFN) production through activation of cGAS in macrophages. Accordingly, SLE patients carrying both Mito+ RBCs and opsonizing antibodies display the highest levels of blood IFN-stimulated gene (ISG) signatures, a distinctive feature of SLE.

BACKGROUND: CANDLE syndrome (an acronym for Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature) is a recently described rare autosomal recessive disorder charaterized by systemic autoinflammation. Clinical manifestations include presentation in the first year of life, episodes of fever accompanied by erythematous skin lesions, progressive lipodystrophy, violaceous periorbital swelling and failure to thrive. This syndrome is caused by loss of function mutations and malfunction of the immunoproteasome complex. Most patients have biallelic mutations in the PSMB8 gene that encodes the β5i catalytic subunit of the immunoproteasome. Examples of digenic inheritance have been also described in CANDLE. CANDLE patients have strong type I interferon gene expression signature and they are responsive to treatment with JAK inhibitors. However, possible serious side-effects remain a concern. Here, we report another patient with CANDLE whose disease activity was well controlled by the treatment with baricitinib.
METHODS: We report a Bulgarian patient of the Turkish ancestry who carries biallelic mutations in the PSMB8 gene: p.Ala92Val and p.Lys105Gln. The pathogenic variant p.Ala92Val has not been previously described in patients with CANDLE. We also comment on the unusual feature in this patient, nephrolithiasis, that has not been described in other patients, however it might be related to the positive family history for kidney stones. We have treated the patient with the JAK inhibitor baricitinib for the past year and we observed a significant amelioration of his inflammatory episodes, skin and joint manifestations, and improvements in physical activities and growth. The treatment with glucocorticoids (GC) was completely discontinued. No side effects have been observed, however they remain in consideration for a life-long therapy of this disease.
CONCLUSIONS: CANDLE should be suspected in patients with early-onset systemic inflammatory disease and prominent skin manifestations. Molecular testing can confirm the clinical diagnosis and is very important in guiding therapies. Treatment with JAK inhibitors is highly efficacious and appears to be safe in children with CANDLE and other intereforonopathies.

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OBJECTIVE: To report the clinical and genetic features of the first cases of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome in an Arab population and to compare them with patients of C1q deficient systemic lupus erythematosus (SLE).
METHODS: This is a retrospective case series of patients with CANDLE syndrome and C1q deficient SLE seen at a single tertiary hospital. Medical records were reviewed for demographic data, clinical and laboratory features, histopathology and imaging findings, and response to therapeutic intervention. Descriptive data were summarized.
RESULTS: Three patients from unrelated families fulfilled the clinical manifestations of CANDLE syndrome. The disease onset was within the first 4 months of age. Two patients had uncommon features including uveitis, pulmonary involvement, aseptic meningitis and global delay. Skin biopsy showed heterogeneous findings. Genomic DNA screening was homozygous for mutation in PSMB8, (NM_004159.4:c.212C>T, p.T71M) in one patient and inconclusive for the other two patients. The comparison group was three patients with familial C1q deficient SLE from three unrelated families, who were born to consanguineous parents with at least one affected sibling. They presented with extensive mucocutaneous lesions, discoid rash and scarring alopecia. They required frequent admissions due to infections.
CONCLUSIONS: This is the first report of CANDLE syndrome in an Arab population; our patients had heterogeneous phenotypic and genetic features with overlap manifestations with C1q deficient SLE. Both are monogenic interferonopathies. However, C1q deficient SLE had more systemic inflammatory disease.

We described herein a patient with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome and a novel mutation in PSMB8 gene. This patient had multiple visceral inflammatory involvements, including rare manifestations, such as Sweet syndrome and pericarditis. A 3-year-old male, Caucasian, was born to consanguineous healthy parents. At the age of 11 months, he presented daily fever (temperature >40 °C), irritability, hepatomegaly, splenomegaly; and tender and itching, erythematous papular and edematous plaque lesions. Echocardiogram showed mild pericarditis. Skin biopsy revealed a neutrophil infiltrate without vasculitis suggesting Sweet syndrome. Mutational screening of PSMB8 gene revealed homozygous c.280G>C, p.A94P mutation. He responded partially to high doses of oral glucorticoid and intravenous methylprednisolone. Colchicine, azathioprine, methotrexate, cyclosporine, and intravenous immunoglobulin were not efficacious. At the age of 3 years and 1 month, tocilizumab was administered resulting in remission of daily fever and irritability. However, there was no improvement of the skin tenderness and itching lesions.
CONCLUSIONS: A new mutation in a CANDLE syndrome patient was reported with pericarditis and mimicking Sweet syndrome. The disease manifestations were refractory to immunosuppressive agents and partially responsive to tocilizumab therapy.
BACKGROUND: • Proteasome-associated autoinflammatory syndromes (PRAAS) include four rare diseases. • Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome was seldom reported. What is New: • We described a Brazilian patient with CANDLE syndrome possessing a novel mutation in the PSMB8 gene. • This patient had multiple visceral inflammatory involvements, including rare manifestations, such as pericarditis and mimicking Sweet syndrome.

BACKGROUND: Alopecia areata (AA) is an autoimmune disease resulting in hair loss with devastating psychosocial consequences. Despite its high prevalence, there are no FDA-approved treatments for AA. Prior studies have identified a prominent interferon signature in AA, which signals through JAK molecules.
METHODS: A patient with AA was enrolled in a clinical trial to examine the efficacy of baricitinib, a JAK1/2 inhibitor, to treat concomitant CANDLE syndrome. In vivo, preclinical studies were conducted using the C3H/HeJ AA mouse model to assess the mechanism of clinical improvement by baricitinib.
RESULTS: The patient exhibited a striking improvement of his AA on baricitinib over several months. In vivo studies using the C3H/HeJ mouse model demonstrated a strong correlation between resolution of the interferon signature and clinical improvement during baricitinib treatment.
CONCLUSIONS: Baricitinib may be an effective treatment for AA and warrants further investigation in clinical trials.