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Deficiency of Interleukin-1-receptor antagonist
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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.

Signs and symptoms

The presence of neutrophilic dermatosis characterized by intraepidermal pustules, marked edema of the papillary dermis, and dense dermal and subcutaneous neutrophilic infiltrates should raise the suspicion of the presence of this disorder. Other manifestations of DIRA include vesicular stomatitis, mouth ulcers, widening of ribs, periosteal reaction, joint swelling, cervical vertebral fusion, hepatosplenomegaly, and vasculopathy. Mutations in IL1RN result in deficiency of the IL-1Ra, which leads to unopposed signaling of IL-1, leading to an inflammatory increase in response to various triggers, including mechanical skin stimulation, cather placement and intubation. Approximately one third of children with DIRA are symptomatic at birth, presenting with intrauterine growth reatrdation, but approximately two-thirds of individuals with DIRA develop pustular skin rashes, gastrointestinal reflux, and multifocal osteomylelitis within the newborn period. In some cases, it can lead to the development of systemic inflammatory response syndrome resulting in death.

Signaling pathway

Children with DIRA have inherited mutations in IL1RN, a gene that encodes a protein known as interleukin-1 receptor antagonist (IL-1Ra). IL-1Ra binds to the same cell receptors as the inflammatory protein interleukin-1, and blocks its inflammatory actions. Without IL-1Ra, the children's bodies cannot control systemic inflammation that can be caused by interleukin-1.

Epidemiology

A growing number of monogenic autoinflammatory diseases involving IL-1 dysregulation are being described. Approximately one third of children with DIRA are symptomatic at birth, presenting with intrauterine growth retardation, but approximately two-thirds of individuals with DIRA develop pustular skin rashes, gastrointestinal reflux, and multifocal osteomylelitis within the newborn period. In some cases, it can lead to the development of systemic inflammatory response syndrome resulting in death. 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.

Treatment

Antibiotics and conventional disease-modifying antirheumatic drugs including steroids are of limited benefit, but blocking IL-1 signlaing with anakinra dramatically improves clinical symptoms within days, normalizes acute-phase reactants, and permits appropriate growth. Patients with DIRA need to remain in life long IL-1 inhibitory therapy; previous attempts at stopping or weaning anakinra have led to disease flares. Long term efficacy and safety of anakinra treatment are currently under investigation, and it is not established whether longer acting IL-1 inhibitors, such as canakinumb, are as effective as anakinra in the treatment of individuals with DIRA.