Neonatal-Onset Multisystem Inflammatory Disease Responsive to Interleukin-1 Inhibition

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Raphaela Goldbach-Mansky, M.D., Natalie J. Dailey, M.D., Scott W. Canna, M.D., Ana Gelabert, M.S.N., Janet Jones, B.S.N., Benjamin I. Rubin, M.D., H. Jeffrey Kim, M.D., Carmen Brewer, Ph.D., Christopher Zalewski, M.A., Edythe Wiggs, Ph.D., Suvimol Hill, M.D., Maria L. Turner, M.D., Barbara I. Karp, M.D., Ivona Aksentijevich, M.D., Frank Pucino, Pharm.D., Scott R. Penzak, Pharm.D., Margje H. Haverkamp, M.D., Leonard Stein, M.D., Barbara S. Adams, M.D., Terry L. Moore, M.D., Robert C. Fuhlbrigge, M.D., Ph.D., Bracha Shaham, M.D., James N. Jarvis, M.D., Kathleen O’Neil, M.D., Richard K. Vehe, M.D., Laurie O. Beitz, M.D., Gregory Gardner, M.D., William P. Hannan, M.D., Robert W. Warren, M.D., Ph.D., William Horn, M.D., Joe L. Cole, M.D., Scott M. Paul, M.D., Philip N. Hawkins, M.D., Tuyet Hang Pham, B.S., Christopher Snyder, B.S., Robert A. Wesley, Ph.D., Steven C. Hoffmann, M.S., Steven M. Holland, M.D., John A. Butman, M.D., Ph.D., and Daniel L. Kastner, M.D., Ph.D.


Background Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.

Methods We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations)to receive anakinra, an interleukin-1–receptor antagonist(1 to 2 mg per kilogram of body weight per day subcutaneously).In 11 patients, anakinra was withdrawn at three months untila flare occurred. The primary end points included changes inscores in a daily diary of symptoms, serum levels of amyloidA and C-reactive protein, and the erythrocyte sedimentationrate from baseline to month 3 and from month 3 until a diseaseflare.

Results All 18 patients had a rapid response to anakinra, withdisappearance of rash. Diary scores improved (P<0.001) andserum amyloid A (from a median of 174 mg to 8 mg per liter),C-reactive protein (from a median of 5.29 mg to 0.34 mg perdeciliter), and the erythrocyte sedimentation rate decreasedat month 3 (all P<0.001), and remained low at month 6. Magneticresonance imaging showed improvement in cochlear and leptomeningeallesions as compared with baseline. Withdrawal of anakinra uniformlyresulted in relapse within days; retreatment led to rapid improvement.There were no drug-related serious adverse events.

Conclusions Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations. ( number, NCT00069329 [] .)


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