Deficiency of the interleukin-1–receptor antagonist

Overview

Deficiency of the interleukin-1–receptor antagonist (DIRA) is a rare genetic autoinflammatory disorder characterized by severe systemic inflammation affecting skin, bones, and multiple organs. It typically presents in newborns or early infancy and arises from mutations leading to a deficiency or complete absence of interleukin-1 receptor antagonist (IL-1Ra), a protein crucial for regulating inflammation in the body. Without this antagonist, uncontrolled interleukin-1 signaling triggers excessive inflammatory responses.

Causes

DIRA results from mutations in the IL1RN gene, which encodes the interleukin-1 receptor antagonist protein. These genetic alterations lead to absent or severely reduced production of IL-1Ra. The condition follows an autosomal recessive inheritance pattern, meaning both parents must carry and pass on a mutated gene for the disorder to manifest in their child.

Symptoms

The symptoms of DIRA usually appear within days or weeks after birth, involving intense systemic inflammation. Typical manifestations include:

• Skin inflammation: Painful pustular rash, severe generalized redness, and skin lesions resembling pustular psoriasis.

• Bone inflammation (osteomyelitis): Painful swelling, tenderness, and inflammation of bones, particularly long bones, ribs, and clavicles.

• Joint inflammation and swelling: Arthritis-like symptoms, joint stiffness, swelling, and limited mobility.

• Systemic inflammation: Fever, fatigue, irritability, and poor weight gain or failure to thrive.

• Oral lesions: Painful sores or ulcers in the mouth, causing feeding difficulties.

• Respiratory involvement: Rarely, inflammation can affect the respiratory tract, leading to breathing difficulties.

Diagnosis

Diagnosing DIRA involves recognizing clinical signs combined with genetic testing. Diagnostic steps include:

• Clinical evaluation: Identifying characteristic skin and bone symptoms along with systemic inflammatory signs.

• Laboratory tests: Blood tests typically reveal elevated inflammatory markers (C-reactive protein, erythrocyte sedimentation rate), high white blood cell count, and absence or extremely low levels of IL-1Ra protein.

• Radiographic imaging: X-rays or MRI scans identify characteristic bone lesions indicative of sterile osteomyelitis or bone inflammation.

• Genetic testing: Confirmatory genetic sequencing to identify mutations in the IL1RN gene.

Treatment

The primary treatment for DIRA is targeted therapy aimed at reducing inflammation through the inhibition of interleukin-1 signaling. Key treatment strategies include:

• Anakinra: Recombinant IL-1 receptor antagonist, administered daily by subcutaneous injection, rapidly reducing symptoms and inflammation.

• Supportive treatments: Pain management, wound care, and nutritional support to address complications and improve overall quality of life.

• Monitoring and regular follow-up: Continuous monitoring for disease activity and potential side effects of therapy.

• Bone and joint management: Physical therapy, orthopedic interventions, or surgical interventions in severe cases to address bone deformities or joint damage.

Prognosis

The prognosis for individuals with DIRA has significantly improved with the advent of targeted IL-1 blockade therapies, notably Anakinra. Early diagnosis and initiation of treatment typically result in rapid symptom improvement, reduction of systemic inflammation, and prevention of irreversible bone and joint damage. If untreated, however, the condition can rapidly progress, leading to severe complications, disability, and potentially fatal outcomes. Early and sustained treatment ensures a better quality of life and generally favorable long-term outcomes.