|Arthritis Drug Helps Debilitating Inflammatory Disease
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 Program 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
autoinflammatory 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 percent 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 program,” 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 percent
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
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. For more information
about NIAMS, call the information clearinghouse at (301) 495-4484 or (877)
22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit www.nih.gov.