Kineret safe, effective in rare chronic inflammatory disease

BETHESDA, Md., Aug. 9 -- A fulminant inflammatory disease that develops shortly after birth, a syndrome that was only recently recognized, can be treated by blocking interleukin-1?.

Blocking interleukin-1? is safe and effective in neonatal-onset multisystem inflammatory disease (NOMID), according to Raphaela Goldbach-Mansky, M.D., of the National Institute of Arthritis and Musculoskeletal and Skin Diseases here, and colleagues.

In a small, non-randomized trial, the interleukin-1? inhibitor Kineret (ankrina) -- approved for rheumatoid arthritis -- quickly relieved symptoms of NOMID, without drug-related serious adverse events, Dr. Goldbach-Mansky reported in the Aug. 10 issue of the New England Journal of Medicine.

Symptoms recurred when the drug was stopped but resolved again when the medication was resumed, said Dr. Goldbach-Mansky and colleagues.

NOMID -- also known as chronic infantile neurologic cutaneous articular syndrome (CINCA) -- is characterized by fever and an urticaria-like rash that develops within the first six weeks of life. Also, a characteristic bony overgrowth mainly in the knees develops in most affected children.

NOMID affects the central nervous system causing chronic aseptic meningitis, increased intracranial pressure, cerebral atrophy, enlarged ventricles, and chronic papilledema. The CNS manifestations lead to optic-nerve atrophy and loss of vision, mental retardation, seizures, and hearing loss.

The syndrome also involves an elevation in serum levels of amyloid A and C-reactive protein and in the erythrocyte sedimentation rate and systemic amyloidosis is reported to occur in as many as 25% of patients, Dr. Goldbach-Mansky and colleagues said.

The researchers selected 18 patients with NOMID, ranging in age from four to 32 years; they were treated with Kineret at between 1 mg/kg to 2 mg/kg of body weight.

The clinical response to the drug was immediate, the researchers reported:

• Rash and conjunctivitis disappeared within three days in all patients.
• Daily symptoms diary scores improved significantly, at P<0.001, over baseline.
• Median serum amyloid A fell from 174 to 8 mg/L and C-reactive protein fell from a median of 5.29 mg/dL to 0.34. Both changes were significant at P<0.001.
• The erythrocyte sedimentation rate decreased significantly (P<0.001) three months after treatment started and remained low at month six.

Seventeen of the patients had cochlear enhancement at baseline; at three months, 13 showed a decrease or disappearance of the enhancement, three were unchanged, and one had worsened. Also eight patients had enlarged ventricles at baseline; all showed improvement, the researchers said. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.

NOMID is often associated with mutations in the gene for the cold-induced autoinflammatory syndrome 1 (CIAS1), which encodes a protein called cryopyrin; 12 of the patients in this study had such alterations.

There are a number of inflammatory mediators that CIAS1 could activate to cause NOMID, the researchers noted, but the current study provides solid evidence that interleukin-1? is the culprit.

The findings "suggest that peripheral, as well as CNS, manifestations of this disease are driven by interleukin-1?," Dr. Goldbach-Mansky and colleagues concluded.

The study was limited by its small size, its lack of randomization, and its relatively short follow-up of only six months, the researchers noted -- all consequences of the small number of people affected by NOMID.

However, they added, the study provides "evidence of important clinical benefits derived from interleukin-1 blockade in this condition."

The study was supported by the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the NIH. Many of the authors reported receiving consulting and lectures fees from Amgen which makes the medication evaluated in this study.