Not much is known yet about how the polymorphism causes disease or about the mechanism, Dr. Siegel said. However, he noted, information about TRAPS has “opened up new understanding about TNF receptor 1.”
DIRA: Mutations in IL1RN
The recent discovery of DIRA, a deficiency of the interleukin-1 (IL-1) receptor antagonist, is helping researchers understand the potential role of IL-1 in other autoinflammatory diseases. Children diagnosed with DIRA have inherited mutations in IL1RN, a gene that encodes IL-1Ra.
Raphaela Goldbach-Mansky, MD, chief of the NIAMS Translational Autoinflammatory Disease Section, said that patients with DIRA present with bone tissue swelling, bone pain and deformity, inflammation of the periosteum, and rashes that can include extensive postulosis. A rare and potentially fatal disease, it has been successfully treated with anakinra, an IL-1 receptor antagonist, but the disease is unresponsive to steroids.
Other IL-1–related disorders include neonatal-onset multisystem inflammatory disease, also known as NOMID; chronic infantile neurologic, cutaneous, articular syndrome, which is also known as CINCA; familial cold autoinflammatory syndrome, also known as FCAS; and Muckle-Wells syndrome, or MWS. All belong to the disease spectrum called cryopyrin-associated periodic syndromes (CAPS).
Diseases classified as CAPS stem from overproduction of active IL-1b, and some have responded to treatment with anakinra, the IL-1 receptor antagonist. According to Dr. Goldbach-Mansky, patients with NOMID can have early hearing loss, joint contractures, headaches, and mental retardation. Early and aggressive treatment is vital for those patients, she said.
“NOMID and DIRA present the rare cases where a master cytokine pathway is known and clinically confirmed to play a pivotal role in human disease,” Dr. Goldbach-Mansky said. Identification of the IL-1–related disorders may also indicate a role for IL-1 in more common diseases, such as gout, type 2 diabetes, fibrosing lung disease, and Alzheimer’s disease, she said.
DIRA is also one of the inflammatory bone disorders that may be difficult to diagnose. Chronic recurrent multifocal osteomyelitis, or CRMO, is another that generally occurs in childhood, primarily among girls.
CRMO: Recurrent Fever and Bone Pain
Peggy Ferguson, MD, assistant professor of pediatrics at the University of Iowa in Iowa City, said that young patients diagnosed with CRMO present with recurrent fever and bone pain, and they develop multiple inflammatory bone lesions, sometimes with mandibular involvement. On X-ray, the osteolytic lesions are surrounded by sclerosis. CRMO can occur in association with palmoplantar pustulosis, pyoderma gangrenosum, and spondylarthropathy.
“Lab studies don’t help at all,” Dr. Ferguson said, adding that many children who present with CRMO have negative cultures. They do not respond to antibiotics. The trigger for CRMO remains unclear, Dr. Ferguson said. Infections have been suggested as a possible trigger, but no microorganism has been determined. For some children, a history of trauma may trigger the disease.
