Deficiency of the interleukin-1–receptor antagonist

Deficiency of the interleukin-1–receptor antagonist (DIRA) is a rare, autosomal recessive, genetic autoinflammatory syndrome resulting from mutations in IL1RN, the gene encoding the interleukin 1 receptor antagonist.

The mutations result in an abnormal protein that is not secreted, exposing the cells to unopposed interleukin 1 activity. This results in sterile multifocal osteomyelitis (bone inflammation in multiple places), periostitis (inflammation of the membrane surrounding the bones), and pustulosis (due to skin inflammation) from birth.

DIRA is a newly discovered autoinflammatory disease. Children with the disorder display a constellation of serious and potentially fatal symptoms that include swelling of bone tissue; bone pain and deformity; inflammation of the periosteum (a layer of connective tissue around bone); and a rash that can span from small individual pustules to extensive pustulosis that covers most of the patient’s body. Most of the children begin to have symptoms from birth to 2 weeks of age.

Children with DIRA have inherited mutations in IL1RN, a gene that encodes a protein known as IL-1 receptor antagonist (IL-1Ra). IL-1Ra binds to the same cell receptors as the inflammatory protein IL-1, and blocks its inflammatory actions. Without IL-1Ra, the children’s bodies cannot control systemic inflammation that can be caused by IL-1. Although mutations that cause DIRA are rare, as many as 2.5 percent of the population of northwest Puerto Rico are carriers. Since DIRA is recessively inherited, these data suggest that it may be present in about 1 in 6,300 births in this population. Mutations may also be more common in individuals of Dutch descent.

Most patients with DIRA respond well to anakinra, the same drug previously mentioned for NOMID treatment, a synthetic form of human IL-1Ra.

See also

• Neonatal onset multisystem inflammatory disease (NOMID)

References

• Aksentijevich I, Masters SL, Ferguson PJ et al.. An Autoinflammatory Disease with Deficiency of the Interleukin-1–Receptor Antagonist. N Engl J Med. 2009; 360: 2426-2437.
• Understanding Autoinflammatory Diseases: Deficiency of the Interleukin-1 Receptor Antagonist (DIRA) - US National Institute of Arthritis and Musculoskeletal and Skin Diseases. NIH Publication No. 10–7576