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Deficiency of the interleukin-1 receptor antagonist

Author: Delwyn Dyall-Smith FACD, Dermatologist, 2011.

Table of contents

What is deficiency of the interleukin-1 receptor antagonist (DIRA)?

Deficiency of the interleukin-1 receptor antagonist (DIRA) (MIM 612852) is a very rare genetic autoinflammatory syndrome that presents in the first days of life. The severe inflammatory reaction resembles an acute severe systemic infection or infection of the bone. If recognised early, treatment with anakinra, a biologic agent, can prevent death from multiorgan failure.

Who gets DIRA and why?

DIRA has been diagnosed in only a very small number of children. It presents at birth or in the first days of life. Cases have been identified from families originating in Puerto Rico, Newfoundland (Canada), The Netherlands and Lebanon.

DIRA is an autosomal recessive genetic disorder, meaning each child of two carrier parents has a 25% chance of suffering from DIRA.

Molecular biology and genetics

DIRA is due to homozygous point mutations in the gene IL1RN (2q14.2) or a large genomic deletion that affects this gene and others in the IL family on chromosome 2. The same mutation is detected in all patients originating from a given area, suggesting a distinct founder effect in each region. Studies of normal controls from the same areas found carrier rates for the mutation of 0.2% in Newfoundland and 1.3% in Puerto Rica. These mutations, when homozygous, result in the complete absence of functional interleukin-1 receptor antagonist protein. Therefore interleukin-1 has unopposed effects on the receptor. Stimulation of the interleukin-1 receptor is a powerful activator of inflammatory pathways.

Clinical features of DIRA

The distinctive features of this syndrome are present at birth, or within days of birth, and are due to inflammatory changes in the skin and bone in the absence of fever.

In the first days of life, the common presenting features include:

  • Fetal distress
  • Pustular rash
  • Mouth lesions
  • Joint swelling
  • Painful movement
  • Enlargement of liver and spleen (hepatosplenomegaly)

All affected children develop the pustular rash, in which there may be discrete crops of pustules or a severe generalised pustular eruption that may resemble generalised pustular psoriasis.

Other skin/mucosal changes reported included:

All children develop inflammation in the bones, which cause painful movement and joint swelling. Changes on x-rays are characteristic.

Other features noted in single cases have included:

  • Inflammation of blood vessels in the brain (cerebral vasculitis)
  • Pulmonary haemosiderosis (iron deposition in the lungs) with progressive interstitial fibrosis (scarring)
  • Hypotonia (weak muscle tone)
  • Failure to thrive

High fever is not a typical feature.

If untreated, DIRA results in multiorgan failure and death in childhood.

How is DIRA diagnosed?

The presenting features of DIRA suggest a severe acute systemic infection (neonatal sepsis) and/or infection of bone (osteomyelitis); however all investigations for infection are negative.

The table below describes the results of investigations.

Useful tests in diagnosis of DIRA?
Blood tests
  • increased erythrocyte sedimentation rate (ESR)
  • increased C-reactive protein (CRP)
Skin biopsy
  • epidermal neutrophilic pustules
  • pustule formation along hair follicles
  • epidermal acanthosis (skin thickening)
  • hyperkeratosis (scaling)
  • heavy neutrophil infiltrate of dermis
  • clot formation (thrombosis) in blood vessels (one child)
  • balloon-like swelling of the ends of the ribs (all children)
  • periosteal elevation along multiple long bones
  • heterotopic ossification around the hip
  • multifocal osteolytic lesions (may result in vertebral crush fracture)
Bone biopsy
  • purulent osteomyelitis, but no infective organisms
  • fibrosis
  • sclerosis
  • vasculitis in adjacent fat and connective tissue
Cerebral MRI
  • evidence of vasculitis/vasculopathy (one child)
DNA analysis
  • point mutations or large genomic deletion involving the IL1RN gene resulting in the absence of functional interleukin-1 receptor antagonist

Treatment of DIRA

Children with DIRA can be effectively treated with anakinra, a biologic agent that is a recombinant form of interleukin-1 receptor antagonist, the protein these children lack. It had been recently made available to treat rheumatoid arthritis when DIRA was first described and characterised in detail.

Daily subcutaneous administration of anakinra replaces the missing protein with an excellent response, particularly in those children with point mutations. In the initial case series reported, complete and rapid resolution of the symptoms and signs occurred. The skin changes responded within days and the bone x-rays normalised in months. Blood markers of inflammation also returned to normal levels. The response in children with the large genomic deletion was less dramatic as blood markers did not normalise. The dose of anakinra was started at 1 mg/kg/day, and increased by 0.5 mg/kg/day until response achieved. Resolution of symptoms and signs has been reported as longlasting, with rapid deterioration within 36 hours of ceasing the anakinra treatment. Treatment will therefore be lifelong. Local injection site reactions (redness, itch, swelling) are a common adverse effect, but the treatment is otherwise well tolerated. Longterm follow-up is not yet available.

Note: anakinra is not registered or subsidised in New Zealand. In other countries such as the USA and Europe, its registered indication is rheumatoid arthritis.



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