Deficiency of IL-1 Receptor AntagonistM86.0-

Interleukin-1 receptor antagonist deficiency syndrome (DIRA; MIM: 612852) was first described in 2009 by Aksentijevich et al. as a rare autoinflammatory disease with very early onset, systemic inflammation (high concentration of acute phase reactants) and pronounced skin and bone involvement.

Interleukin-1 receptor antagonist deficiency syndrome -DIRA- is a life-threatening, rare, autosomal recessive, autoinflammatory syndrome caused by loss-of-function (LOF) mutations in the interleukin-1 receptor antagonist gene(IL1RN gene). The interleukin-1 receptor antagonist (IL1RA) encoded by this gene is secreted by a variety of immune and non-immune cells. It binds non-productively to the interleukin-1 receptors (IL1R) on the cell surface and thus prevents the pro-inflammatory effect of interleukin-1beta and other interleukins.

The receptor antagonist thus contributes to the control of the inflammatory process. Its loss of function leads to continuous pro-inflammatory signaling and to the systemic signs of inflammation.

<100 patients have been identified worldwide.

Interleukin-1 receptor antagonist deficiency syndrome/DIRA is a genetic disease caused by a mutation in the IL1RN gene. The gene codes for a protein, the IL1 receptor antagonist (IL1-RA), which plays an important role in controlling inflammatory processes in the body. It binds non-productively to the interleukin-1 receptor (IL1R) on the cell surface and thus prevents the pro-inflammatory effect of interleukin-1beta and other interleukins. The receptor antagonist thus contributes to the control of the inflammatory process. The mutations lead to the absence or to a non-functional IL1 receptor antagonist. Since 2009, at least 18 different mutations localized along the entire IL1RN gene have been described in patients from different countries.

DIRA is inherited in an autosomal recessive manner. This means that it is not sex-specific and that neither parent has to be symptomatic. In order to develop DIRA, two mutated genes must be transmitted, one from the mother and the other from the father (parents = carriers/ only carry a mutated copy of the gene, but are not affected themselves). Parents of a child with DIRA have a 25% risk that the next child will also have DIRA. Prenatal diagnosis is possible.

Clinically, from birth or shortly after birth, accompanied by fever attacks, leukocytosis and possibly thrombocytosis, generalized cutaneous pustulosis (subcorneal pustular dermatitis) and signs of infantile cortical hyperostosis are seen. There is a risk of sepsis.

Initially, systemic corticosteroids can reduce the symptoms of the disease, but they usually also cause undesirable side effects. Painkillers are usually needed to bridge the time until Anakinra starts to take effect.

Anakinra (^Kineret®), an artificial IL-1RA, has proven to be the only effective therapy. In this way, the lack of IL-1-RA can be eliminated.

Rilonacept (weekly injections (2.2 mg/kg), a long-acting interleukin-1 inhibitor, is suitable for long-term therapy.

1. Aksentijevich I et al. (2009) An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. New Eng J Med 360: 2426-2437.
2. Garg M et al. (2017) Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonist. JCI Insight 2:e94838.
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