CANDLE syndrome case highlights key features of this type 1 interferonopathy

BOSTON – Annular erythematous plaques in a child with fever and dense, atypical, mixed mononuclear and neutrophilic dermal infiltrate on biopsy could signal the recently described autoinflammatory disorder known as CANDLE Syndrome, according to Raegan Hunt, MD.

CANDLE, which stands for chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature, is a proteasome-associated autoinflammatory syndrome characterized by dysregulation of type 1 interferon signaling, Dr. Hunt of Baylor College of Medicine and Texas Children’s Hospital said during a presentation at the American Academy of Dermatology summer meeting.

She described a case involving a 12-year-old girl with erythematous, warm, tender, nonpruritic papules and plaques on the superior chest, neck, and upper back. Most had an annular configuration with central clearing and occasionally central duskiness and ulceration.

The child also sometimes had violaceous swelling of the eyelid, nodules on the ear, and figurate erythematous plaques on the upper arm.

“She’s been having these since she was an infant in periodic bursts, and carried a diagnosis of annular erythema of infancy,” Dr. Hunt said.

Other symptoms included recurrent fevers, myalgias, transient and migratory arthritis, elevated C-reactive protein and erythrocyte sedimentation rate, and aseptic meningitis requiring hospitalization.

She had no family history of autoimmune disease, immune deficiency, or other genetic diseases, Dr. Hunt said.

Courtesy Dr. Raegan Hunt

“She was treated with methotrexate and prednisone, as well as IVIG [intravenous immunoglobulin] every 4 weeks. Her prednisone was never weaned successfully below 0.8 mg/kg. She had complications of chronic corticosteroid disease, including many fractures,” she said.

A biopsy showed a dense infiltrate of atypical, mixed mononuclear and neutrophilic dermal infiltrate.

“These taken together are suggestive of ... CANDLE,” she said.

Genetic testing confirmed the presence of a compound heterozygous mutation in the proteasome subunit beta type 9, or PSMB8 gene.

Key features of CANDLE syndrome, first described in a 2010 article and further described by Liu, et al in 2012, include early disease onset, recurrent febrile episodes, skin lesions – including recurrent attacks of erythematous annular plaques and violaceous swelling of the eyelids, delayed physical development, progressive lipodystrophy, arthralgias, systemic inflammation, and aseptic meningitis episodes.

“Our patient did have very, very subtle lipodystrophy, but overall not as quick onset as some other [cases in children] that have been described,” Dr. Hunt said.

The type 1 interferonopathy is of autosomal recessive inheritance, and involves either homozygous or compound heterozygous mutations in PSMB8, as found in this patient. PSMB8 is an immunoproteasome unit involved in proteolysis and maintenance of cell homeostasis, she explained.

Treatment of the syndrome involves high-dose corticosteroids (usually 1-2 mg/kg day), which helps improve cutaneous eruptions, joint pain, and fever, but it is important to remember that disease flares can occur with tapering, Dr. Hunt noted.

Response is typically poor in patients treated with steroid-sparing agents, such as methotrexate, cyclosporine, azathioprine, or IVIG, as well as with tumor necrosis factor–alpha inhibitors and interleukin-1 receptor antagonists.

“But there is an interesting molecule on the horizon for possibly treating this more specifically and that’s JAK inhibitors,” she said, noting that a National Institutes of Health compassionate use clinical research trial is evaluating the JAK 1/2 inhibitor, baricitinib.

Dr. Hunt reported having no relevant disclosures.

[email protected]

BOSTON – Annular erythematous plaques in a child with fever and dense, atypical, mixed mononuclear and neutrophilic dermal infiltrate on biopsy could signal the recently described autoinflammatory disorder known as CANDLE Syndrome, according to Raegan Hunt, MD.

CANDLE, which stands for chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature, is a proteasome-associated autoinflammatory syndrome characterized by dysregulation of type 1 interferon signaling, Dr. Hunt of Baylor College of Medicine and Texas Children’s Hospital said during a presentation at the American Academy of Dermatology summer meeting.

She described a case involving a 12-year-old girl with erythematous, warm, tender, nonpruritic papules and plaques on the superior chest, neck, and upper back. Most had an annular configuration with central clearing and occasionally central duskiness and ulceration.

The child also sometimes had violaceous swelling of the eyelid, nodules on the ear, and figurate erythematous plaques on the upper arm.

“She’s been having these since she was an infant in periodic bursts, and carried a diagnosis of annular erythema of infancy,” Dr. Hunt said.

Other symptoms included recurrent fevers, myalgias, transient and migratory arthritis, elevated C-reactive protein and erythrocyte sedimentation rate, and aseptic meningitis requiring hospitalization.

She had no family history of autoimmune disease, immune deficiency, or other genetic diseases, Dr. Hunt said.

Courtesy Dr. Raegan Hunt

“She was treated with methotrexate and prednisone, as well as IVIG [intravenous immunoglobulin] every 4 weeks. Her prednisone was never weaned successfully below 0.8 mg/kg. She had complications of chronic corticosteroid disease, including many fractures,” she said.

A biopsy showed a dense infiltrate of atypical, mixed mononuclear and neutrophilic dermal infiltrate.

“These taken together are suggestive of ... CANDLE,” she said.

Genetic testing confirmed the presence of a compound heterozygous mutation in the proteasome subunit beta type 9, or PSMB8 gene.

Key features of CANDLE syndrome, first described in a 2010 article and further described by Liu, et al in 2012, include early disease onset, recurrent febrile episodes, skin lesions – including recurrent attacks of erythematous annular plaques and violaceous swelling of the eyelids, delayed physical development, progressive lipodystrophy, arthralgias, systemic inflammation, and aseptic meningitis episodes.

“Our patient did have very, very subtle lipodystrophy, but overall not as quick onset as some other [cases in children] that have been described,” Dr. Hunt said.

The type 1 interferonopathy is of autosomal recessive inheritance, and involves either homozygous or compound heterozygous mutations in PSMB8, as found in this patient. PSMB8 is an immunoproteasome unit involved in proteolysis and maintenance of cell homeostasis, she explained.

Treatment of the syndrome involves high-dose corticosteroids (usually 1-2 mg/kg day), which helps improve cutaneous eruptions, joint pain, and fever, but it is important to remember that disease flares can occur with tapering, Dr. Hunt noted.

Response is typically poor in patients treated with steroid-sparing agents, such as methotrexate, cyclosporine, azathioprine, or IVIG, as well as with tumor necrosis factor–alpha inhibitors and interleukin-1 receptor antagonists.

“But there is an interesting molecule on the horizon for possibly treating this more specifically and that’s JAK inhibitors,” she said, noting that a National Institutes of Health compassionate use clinical research trial is evaluating the JAK 1/2 inhibitor, baricitinib.

Dr. Hunt reported having no relevant disclosures.

[email protected]

BOSTON – Annular erythematous plaques in a child with fever and dense, atypical, mixed mononuclear and neutrophilic dermal infiltrate on biopsy could signal the recently described autoinflammatory disorder known as CANDLE Syndrome, according to Raegan Hunt, MD.

CANDLE, which stands for chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature, is a proteasome-associated autoinflammatory syndrome characterized by dysregulation of type 1 interferon signaling, Dr. Hunt of Baylor College of Medicine and Texas Children’s Hospital said during a presentation at the American Academy of Dermatology summer meeting.

She described a case involving a 12-year-old girl with erythematous, warm, tender, nonpruritic papules and plaques on the superior chest, neck, and upper back. Most had an annular configuration with central clearing and occasionally central duskiness and ulceration.

The child also sometimes had violaceous swelling of the eyelid, nodules on the ear, and figurate erythematous plaques on the upper arm.

“She’s been having these since she was an infant in periodic bursts, and carried a diagnosis of annular erythema of infancy,” Dr. Hunt said.

Other symptoms included recurrent fevers, myalgias, transient and migratory arthritis, elevated C-reactive protein and erythrocyte sedimentation rate, and aseptic meningitis requiring hospitalization.

She had no family history of autoimmune disease, immune deficiency, or other genetic diseases, Dr. Hunt said.

Courtesy Dr. Raegan Hunt

“She was treated with methotrexate and prednisone, as well as IVIG [intravenous immunoglobulin] every 4 weeks. Her prednisone was never weaned successfully below 0.8 mg/kg. She had complications of chronic corticosteroid disease, including many fractures,” she said.

A biopsy showed a dense infiltrate of atypical, mixed mononuclear and neutrophilic dermal infiltrate.

“These taken together are suggestive of ... CANDLE,” she said.

Genetic testing confirmed the presence of a compound heterozygous mutation in the proteasome subunit beta type 9, or PSMB8 gene.

Key features of CANDLE syndrome, first described in a 2010 article and further described by Liu, et al in 2012, include early disease onset, recurrent febrile episodes, skin lesions – including recurrent attacks of erythematous annular plaques and violaceous swelling of the eyelids, delayed physical development, progressive lipodystrophy, arthralgias, systemic inflammation, and aseptic meningitis episodes.

“Our patient did have very, very subtle lipodystrophy, but overall not as quick onset as some other [cases in children] that have been described,” Dr. Hunt said.

The type 1 interferonopathy is of autosomal recessive inheritance, and involves either homozygous or compound heterozygous mutations in PSMB8, as found in this patient. PSMB8 is an immunoproteasome unit involved in proteolysis and maintenance of cell homeostasis, she explained.

Treatment of the syndrome involves high-dose corticosteroids (usually 1-2 mg/kg day), which helps improve cutaneous eruptions, joint pain, and fever, but it is important to remember that disease flares can occur with tapering, Dr. Hunt noted.

Response is typically poor in patients treated with steroid-sparing agents, such as methotrexate, cyclosporine, azathioprine, or IVIG, as well as with tumor necrosis factor–alpha inhibitors and interleukin-1 receptor antagonists.

“But there is an interesting molecule on the horizon for possibly treating this more specifically and that’s JAK inhibitors,” she said, noting that a National Institutes of Health compassionate use clinical research trial is evaluating the JAK 1/2 inhibitor, baricitinib.

Dr. Hunt reported having no relevant disclosures.

[email protected]