Daily injections of the interleukin-1β antagonist anakinra significantly improved the peripheral and central nervous system manifestations of neonatal-onset multisystem inflammatory disease in patients with and without the genetic mutation that is associated with the rare systemic disease, a study found.
Neonatal-onset multisystem inflammatory disease (NOMID) often develops in patients who have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene that is associated with regulating inflammation.
Previous studies have linked interleukin-1β pathways to NOMID, and isolated case reports have suggested that by inhibiting interleukin-1β, anakinra (Kineret) may be effective in the treatment of rash and the constitutional symptoms of disease.
To assess anakinra efficacy on these manifestations, as well as those that affect the central nervous system, Dr. Raphaela Goldbach-Mansky of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Md., and colleagues enrolled 18 patients with active disease, including 12 with identifiable CIAS1 mutations, into an open-label investigation (N. Engl. J. Med. 2006;355:581-92).
All of the patients were between the ages of 4 and 32 years old (mean age 11 years) and presented with at least two of the following clinical manifestations of NOMID: urticarial rash, central nervous system involvement, or epiphyseal or patellar overgrowth on radiography. Additionally, all of the patients had undergone previous treatment with nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, and/or corticosteroids.
Each patient received daily subcutaneous anakinra injections of 1-2 mg/kg of body weight and underwent efficacy assessments at 1, 3, and 6 months.
The primary end points of the study were changes in symptom scores for fever, rash, headache, joint pain, and vomiting as measured in a daily diary, changes in acute-phase reactants, including serum amyloid A, C-reactive protein, and erythrocyte sedimentation rate from baseline to 3 months and from 3 months until a flare. Secondary end points were childhood health assessment questionnaire scores, audiography and vision assessments, MRI of the brain, and lumbar puncture results.
The initial study design included an inpatient withdrawal phase at 3 months for patients who responded to anakinra treatment in order to induce a clinical flare, followed by a reintroduction of therapy and continuation in an ongoing extension period. The withdrawal phase was discontinued after the first 11 patients because of the severity of the flares, which included pericarditis in 1 patient, corneal infiltrates in 3 patients, and uveitis in 2 patients, according to the authors.
In all of the patients, anakinra treatment produced an immediate clinical response, including disappearance of rash and conjunctivitis within 3 days, significantly decreased diary scores at 3 months, and significant decreases in C-reactive protein, serum amyloid A, and erythrocyte sedimentation rates. Of the 11 patients who underwent an inpatient withdrawal period for up to 7 days, 10 experienced a flare that met prespecified criteria at a median of 5 days. All of the patients responded to resumed anakinra therapy promptly, and the improvements were sustained at the 6-month follow-up.
Additional findings included improved hearing in six patients and stable hearing in patients relative to baseline, stable vision in all patients, and significant improvements on the pain, parent, and physician global assessment, and Childhood Health Assessment Questionnaire scores.
With respect to central nervous system manifestations, median daily headache scores decreased significantly in all patients, with complete resolution of headaches in eight patients at 3 months. Intracranial pressures, protein levels, and white cell counts decreased significantly in the 12 patients for whom cerebrospinal fluid was evaluated. Additionally, MRI showed significant improvement from baseline in cochlear and leptomeningeal lesions, the authors wrote.
Overall, anakinra was well tolerated in the patients. Eight experienced a localized, erythematous, sometimes painful injection-site skin reaction that disappeared by 6 weeks, 15 had upper respiratory events during treatment, 3 had urinary tract infections, and 1 was hospitalized for dehydration from nonbacterial diarrhea. No patients withdrew from the study because of adverse events, according to the authors.
Dr. Goldbach-Mansky reported no conflicts of interest with respect to this study. Some coinvestigators reported having received consulting fees, lecture fees, and/or research support from Amgen (maker of anakinra), Genentech, and Abbott.