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New Therapy for Neonatal-Onset Multisystem Inflammatory Disease

A rare condition with prominent cutaneous features responded immediately to treatment with an interleukin-1-receptor antagonist.

Neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic cutaneous articular syndrome, is progressive, and 20% of patients die before reaching adulthood. An urticarial rash develops in the first 6 weeks of life. Other problems ensue: a characteristic bony overgrowth, predominantly of the knees, and central nervous system abnormalities, including aseptic meningitis, increased intracranial pressure, cerebral atrophy, seizures, optic-nerve atrophy or papilledema, mental retardation, and sensorineural hearing loss. Hepatosplenomegaly and short stature are also possible outcomes. Laboratory findings include leukocytosis, an elevated erythrocyte sedimentation rate, and elevated levels of C-reactive protein and serum amyloid A. Systemic amyloidosis eventually develops in roughly 25% of cases. Sixty percent of patients have a mutation of the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, which has also been linked to Muckle-Wells syndrome and the familial cold autoinflammatory syndrome. The CIAS1 gene encodes for cryopyrin, a protein involved in interleukin-1ß pathways in the inflammatory cascade. Isolated case reports have suggested that anakinra, an interleukin-1–receptor antagonist, might be beneficial for NOMID.

These authors conducted an open-label study of anakinra in 18 patients with NOMID (12 had a mutation in CIAS1). Almost all were receiving other therapy, including methotrexate, etanercept, and prednisone. The initial dosage was 1 mg/kg/day of anakinra, increased to 2 mg/kg/day if there was no clinical response. After 3 months, the drug was withdrawn in 11 patients, who were evaluated for clinical flare; all 11 experienced severe disease flares, including pericarditis, corneal infiltrates, and uveitis. Thereafter, the protocol was changed, and all patients received continuous open-label therapy for 24 months.

All 18 patients had immediate clinical responses to therapy. Skin lesions and conjunctivitis responded within 3 days. The erythrocyte sedimentation rate and levels of serum amyloid A and C-reactive protein declined significantly. Hearing loss improved or stabilized. Headache resolved in eight patients. At baseline, mononuclear cells in the peripheral blood of these patients secreted high levels of interleukin-1ß compared with healthy controls, and these levels decreased progressively during anakinra therapy. The authors do not report whether other therapies were reducible or discontinued. Toxicity was minimal -- mostly injection-site reactions that disappeared with continued therapy.

Comment: Although NOMID occurs rarely, these findings are important because they demonstrate that therapy based on pathogenesis is often successful. This study was small, and a differential response between patients with and without the genetic mutation was not noted. In addition, the study period was not long enough to determine whether chronic therapy could prevent the development of systemic amyloidosis.

— Jeffrey P. Callen, MD

Published in Journal Watch Dermatology August 11, 2006

Citation(s):

Goldbach-Mansky R et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1ß inhibition. N Engl J Med 2006 Aug 10; 355:581-92.

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