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

Abstract

Goldbach-Mansky R, Dailey NJ, Canna SW, et al. N Engl J Med. 2006;355:581–592 PURPOSE OF THE STUDY. Neonatal-onset multisystem inflammatory disease (NOMID) is a chronic inflammatory disease that develops in infancy and is characterized by an urticarial rash, arthropathy, and central nervous system disease, including aseptic meningitis, cerebral atrophy, mental retardation, seizures, and vision and hearing loss. Approximately 60% of patients have a mutation in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, which is involved in the interleukin 1β (IL-1β) pathway. This study evaluated the effect of anakinra (Kineret, Amgen), an IL-1 receptor antagonist, on the various clinical and laboratory aspects of NOMID. STUDY POPULATION. A cohort of 18 patients aged 4 to 32 years with clinical NOMID (67% with mutations in CIAS1) who had active disease despite treatment with other antiinflammatory agents. METHODS. Patients were given a daily subcutaneous dose of anakinra. The drug was withdrawn from 11 patients at 3 months with the development of a clinical flare. Thereafter, all patients were continued on daily treatments up to 24 months. Clinical and laboratory assessments were made at 1, 3, and 6 months during therapy with anakinra. Primary end points included changes in a disease-specific daily diary score and changes in the serum levels of acute-phase reactants. RESULTS. All patients had an immediate response to anakinra with resolution of rash and conjunctivitis. There was an improvement in diary scores at 3 months that was maintained at 6 months. Serum amyloid A, C-reactive protein, and the erythrocyte sedimentation rate significantly declined with treatment. All the patients had headache at baseline, which resolved or improved with therapy, and cochlear and leptomeningeal lesions were improved on MRI. Serum levels of IL-1β, which were initially higher than those in healthy controls, decreased over the first 6 months of therapy. All the patients who underwent a treatment withdrawal experienced rapid improvement of their symptoms after resuming anakinra. Other than injection-site reactions, which resolved with continued treatment, there were no serious adverse events. CONCLUSIONS. Anakinra may be a safe and effective treatment for patients with NOMID. REVIEWER COMMENTS. This study suggests that anakinra may have a role in the treatment of other diseases in which IL-1β mediates inflammation (eg, systemic juvenile rheumatoid arthritis). Additional studies are needed to determine its long-term effects and clinical application. This study is an example of how specific immunomodulatory therapy may be useful in treating those diseases that have a defined molecular pathophysiologic profile.