VIENNA — The interleukin-1 receptor antagonist anakinra (Kineret) proved “dramatically effective” in treating both the clinical and laboratory manifestations of neonatal-onset multisystem inflammatory disease in a controlled trial, Scott Canna reported at the annual European congress of rheumatology.
Particularly exciting was the observed improvement in both the CNS and cochlear abnormalities that typify neonatal-onset multisystem inflammatory disease (NOMID), indicating that these lesions are inflammatory rather than structural in origin.
“This finding raises hope that the hearing loss and possibly even the cognitive impairment could be halted or even prevented with early anakinra, although, of course, long-term treatment will be needed to prove these hypotheses,” noted Mr. Canna, who reported the results on behalf of the principal investigator of the study, Raphaela Goldbach-Mansky, M.D., a clinical investigator at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Md.
NOMID, also known as chronic infantile neurologic cutaneous and articular syndrome, or CINCA, is a severe genetic disease characterized by chronic aseptic meningitis, mental retardation, sensorineural hearing loss, uveitis, severe headaches due to increased intracranial pressure, and fevers.
Pathognomonic for NOMID is a disabling arthropathy that most often affects the knees. It is due to epiphyseal bony overgrowth that can lead to contractures and inability to walk.
Affected individuals are born with a persistent urticarial rash or develop it soon after birth. The rash is characterized by dermal infiltration of polymorphonuclear cells, histiocytes, and rare eosino-phils.
Although NOMID is rare, the NIAMS trial takes on considerable clinical import because it identifies anakinra, a drug approved for the treatment of rheumatoid arthritis, as the first highly effective and well-tolerated treatment for the diverse organ manifestations of this debilitating pediatric disease. The study also serves more broadly as a striking example of the efficacy of targeted therapy in a cytokine-mediated disease, Mr. Canna said at the congress, sponsored by the European League Against Rheumatism.
In 2001 Dr. Goldbach-Mansky and her coinvestigators at NIAMS identified the genetic defect involved in roughly 60% of NOMID cases. It involves mutations in the CIAS-1 gene, which codes for cryopyrin. It's believed the protein cryopyrin activates the IL-1 converting enzyme caspase-1, which upregulates the inflammatory cytokines IL-1 and IL-1 β and encourages apoptosis. The result is a chronic autoimmune inflammatory state. The NIAMS team reasoned that blocking IL-1 might be beneficial.
Mr. Canna, a medical student who worked on the trial, shared the results on 18 NOMID patients aged 4–18 years who were started on 1 mg/kg per day of anakinra by daily subcutaneous injection, increasing to 2 mg/kg per day as needed.
Therapeutic response was extremely rapid. Indeed, the lifelong rash disappeared within 3 days in all patients. Daily disease diary scores dropped from a baseline of 3.35 to 0.55 at 3 months. Mean intracranial pressure dropped from 294 to 201 mm H2O. CSF protein levels and WBC count decreased significantly as well.
Mean systemic corticosteroid dose fell from 0.85 to 0.44 mg/kg per day. High-resolution MRI showed improvement in the inner ear and leptomeningeal lesions. Joint pain decreased. Vision and hearing problems stabilized.
The study plan called for halting anakinra after 3 months to determine whether relapse would occur. But after the first 11 patients to stop treatment flared dramatically in a mean of just over 4 days, the drug withdrawal phase was halted for ethical reasons.
Acute phase reactant levels dropped dramatically and stayed low through the first 6 months, except during the anakinra withdrawal episode.
For example, C-reactive protein fell from a baseline of 6.79 to 0.89 mg/dL; serum amyloid A protein levels dropped from 265 to 31 mg/dL; and the ESR declined from 59.8 to 17.6 mm/hr, Mr. Canna said.
The clinical and laboratory response was equally good in NOMID patients with or without CIAS-1 mutations. No serious infections occurred during treatment, nor was there a significant increase in minor infections.
The expectation is that anakinra will be used in NOMID patients as a lifelong steroid-sparing therapy.
The plan now is to expand the study population and, with longer follow-up, learn whether early therapy prevents cognitive impairment.
One audience member rose to say he has anecdotally used anakinra in two NOMID patients who had failed high-dose etanercept (Enbrel) and many other drugs. Both children, he added, showed stunning and “virtually instantaneous” clinical benefits.
An x-ray shows the bony changes typically associated with NOMID. Courtesy Dr. Raphaela Goldbach-Mansky