For children and young adults who suffer from a rare and debilitating disorder called neonatal-onset multisystem inflammatory disease (NOMID), a drug called anakinra brings marked improvement both in symptoms and the inflammation underlying the disease, a new study shows.

The study, published in the August 10 issue of the "New England Journal of Medicine", was conducted in the Intramural Research Programme of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a component of the National Institutes of Health.

NOMID, also known as chronic infantile neurologic cutaneous articular (CINCA) syndrome, is an inflammatory disorder that affects numerous organs and body systems, including the skin, joints, eyes and central nervous system. For most children, the first sign of the disease is a rash that develops within the first six weeks of life. Other problems, including fever, meningitis, joint damage, vision and hearing loss, and mental retardation, can follow.

NOMID is one of a group of illnesses that NIAMS Clinical Director Daniel Kastner M.D., Ph.D. has designated auto inflammatory diseases, because of their seemingly unprovoked episodes of inflammation. Despite treatment to control the inflammation -- including high-dose corticosteroids, disease-modifying antirheumatic drugs such as methotrexate, and nonsteroidal anti-inflammatory drugs such as ibuprofen or naproxen -- the disease is progressive and often fatal. As many as 20 per cent of children with NOMID don't survive to adulthood.

"This research shows the importance of studying rare but enormously instructive diseases, a unique strength of the NIH intramural science programme," says NIH director Elias A. Zerhouni, M.D. "This study provides new insights on fundamental mechanisms of inflammation. More importantly this new therapy will reduce the pain and suffering of these young patients allowing them to live a fuller life than previously possible."

While the mechanism of NOMID is not completely understood, research in recent years has revealed mutations in a gene called "CIAS1" in approximately 60 percent of patients with the disease. "CIAS1" encodes cryopyrin, which belongs to a group of interacting proteins involved in regulating inflammation and programmed cell death, which plays a crucial role in ridding the body of cells that are no longer needed. The mutations, scientists have found, lead to an imbalance of a cytokine, or chemical messenger, called interleukin-1 (IL-1), which is believed to drive the inflammation that causes damage in patients with the disease.

Isolated case reports have suggested that anakinra might be effective in treating the rash and other symptoms of NOMID. Anakinra is a biologic agent, a medicine based on compounds that are made by living cells and used to stimulate or restore the ability of the immune system to fight disease and/or infection. It works by blocking the effects of IL-1beta (IL-1ß), and is approved for treating rheumatoid arthritis. Until the new NIAMS study, however, the agent had not been systematically assessed in a larger group of patients with NOMID, and its effect on the most devastating organ manifestations -- including the central nervous system, the eyes and the ears -- had not been investigated, says Raphaela Goldbach-Mansky, M.D., a rheumatologist and the study's lead author.

To determine the possible role of anakinra in treating NOMID, the researchers treated 18 NOMID patients (12 with identifiable "CIAS1" mutations) ages 4 to 32 with daily doses of anakinra based on body weight. At one, three and six months they assessed the treatment's effectiveness.

All 18 of the patients, they found, had an immediate clinical response to anakinra. Rash and conjunctivitis (inflammation of the membrane lining the eyelids), both common in NOMID, disappeared within three days. By three months, laboratory measures of inflammation, including erythrocyte sedimentation rate, c-reactive protein and serum amyloid A protein (SAA), had improved, and by six months, 33 per cent of the patients showed improved hearing and another half of the patients had no further hearing loss from baseline. Other confirmed benefits of treatment included disappearance or lessening of headaches, reduction of central nervous system lesions, ability to lower corticosteroid doses, and remission of inflammation in more than half of patients by month six. At month three, disease flared in 11 patients when they were withdrawn from anakinra as part of the study, but when anakinra was restarted, the disease quickly responded again. Daily injections would be required for any long-term treatment.

"This study demonstrates the efficacy of anakinra in improving major organ manifestations and helps confirm the role of IL-1beta (IL-1ß) in many features of the disease; most importantly, the central nervous system," says Dr. Goldbach-Mansky.

Because NOMID is a rare disease (400 to 600 children in the United States), the study was necessarily small and lacked a control group, but the study was strengthened by the magnitude of the clinical response to the agent and the fact that the disease flared when anakinra was temporarily stopped, she says.

"NOMID is a devastating disease for which previously there was little understanding or effective treatment," says NIAMS Director Stephen I. Katz, M.D., Ph.D. "This study not only provides hope -- in the way of an already-available agent -- but it also provides a better understanding of the mechanism of the disease's damaging effects."

Furthermore, notes Goldbach-Mansky, anakinra was safe in this clinical investigation. Unlike some other treatments used for NOMID, it caused no serious side effects in any of the patients during the study.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases.