Introduction to Canakinumab

Canakinumab (trade name: Ilaris) is a human monoclonal antibody targeted against interleukin-1β (IL-1β). It was first approved by the FDA in 2009 and has since become an important treatment option for several autoinflammatory disorders, particularly in pediatric patients.

• Class: Interleukin-1 inhibitor
• Type: Fully human IgG1/κ monoclonal antibody
• Half-life: 26 days
• Route of administration: Subcutaneous injection

Canakinumab's ability to effectively inhibit IL-1β has made it a valuable tool in managing various inflammatory conditions, especially those characterized by overproduction of IL-1β.

Mechanism of Action

Canakinumab works through the following mechanisms:

1. Selective binding to human IL-1β with high affinity
2. Neutralization of IL-1β bioactivity
3. Inhibition of IL-1β interaction with IL-1 receptors
4. Suppression of IL-1β-induced gene activation and inflammatory mediator production

The IL-1 pathway in inflammation:

• IL-1β is a key mediator of inflammatory response
• It's produced by activated macrophages as a proprotein
• Caspase-1 cleaves the proprotein to its active form
• Canakinumab prevents the interaction of active IL-1β with its receptors

By inhibiting IL-1β, canakinumab effectively reduces inflammation in various autoinflammatory conditions, particularly those characterized by overproduction or inappropriate activation of IL-1β.

Indications

FDA-approved indications:

• Cryopyrin-Associated Periodic Syndromes (CAPS), including:
  • Familial Cold Autoinflammatory Syndrome (FCAS)
  • Muckle-Wells Syndrome (MWS)
• Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS)
• Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD)
• Familial Mediterranean Fever (FMF)
• Still's disease, including Adult-Onset Still's Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA)

Off-label uses in pediatrics:

• Refractory Kawasaki disease
• Behçet's disease
• Schnitzler syndrome
• Chronic recurrent multifocal osteomyelitis (CRMO)

Canakinumab has shown particular efficacy in managing these rare autoinflammatory disorders, many of which predominantly affect pediatric populations.

Dosage and Administration

Dosing of canakinumab varies based on the condition being treated and the patient's body weight. Here are the general guidelines:

Condition	Age/Weight	Dosage	Frequency
CAPS (FCAS, MWS)	≥ 4 years, > 40 kg	150 mg	Every 8 weeks
	≥ 4 years, ≤ 40 kg	2 mg/kg	Every 8 weeks
TRAPS, HIDS/MKD, FMF	> 40 kg	150 mg	Every 4 weeks
	≤ 40 kg	2 mg/kg	Every 4 weeks
SJIA	≥ 2 years	4 mg/kg (max 300 mg)	Every 4 weeks

Administration:

• Given as a subcutaneous injection
• Common injection sites: upper arm, thigh, or abdomen
• Rotate injection sites to prevent reactions
• Solution should be clear to opalescent, colorless to slightly brownish-yellow
• Bring to room temperature before injection

Adverse Effects

Common adverse effects (incidence ≥ 10%):

• Nasopharyngitis
• Diarrhea
• Influenza
• Headache
• Nausea
• Injection site reactions

Serious adverse effects:

• Serious infections: Increased risk due to immunosuppression
• Macrophage activation syndrome (MAS): Particularly in patients with SJIA
• Hypersensitivity reactions: Including anaphylaxis
• Immunogenicity: Development of anti-canakinumab antibodies
• Hepatotoxicity: Elevated liver enzymes reported

Pediatric-specific concerns:

• Growth and development: Regular monitoring recommended
• Immunizations: Live vaccines should be avoided
• Long-term effects: Limited data on long-term use in pediatric populations

Precautions and Contraindications

Contraindications:

• Confirmed hypersensitivity to canakinumab or any of its components
• Active, severe infections

Precautions:

• Infections: Increased risk of serious infections. Screen for latent tuberculosis before initiation
• Immunosuppression: May increase susceptibility to infections
• Vaccinations: Avoid live vaccines during treatment
• Macrophage Activation Syndrome (MAS): Monitor for signs and symptoms, particularly in SJIA patients
• Malignancies: Potential increased risk, though not definitively established
• Hyperlipidemia: Monitor lipid levels periodically
• Pregnancy: Limited human data; animal studies show no harm to fetus
• Lactation: No data on presence in human milk; consider developmental and health benefits of breastfeeding

Clinical Pearls

• Canakinumab's long half-life allows for less frequent dosing compared to other IL-1 inhibitors, improving adherence in pediatric patients
• Response to canakinumab can be rapid, with some patients experiencing symptom relief within 24 hours of the first dose
• In CAPS, canakinumab has shown efficacy in improving hearing and vision outcomes, which are often affected by the disease
• For patients transitioning from anakinra to canakinumab, there should be no washout period; canakinumab can be administered immediately after the last anakinra dose
• Monitoring of acute phase reactants (e.g., CRP, SAA) can be helpful in assessing disease activity and response to therapy
• In SJIA, canakinumab has demonstrated steroid-sparing effects, allowing for reduction or discontinuation of corticosteroids in many patients
• Patients should be educated about the signs and symptoms of infection and the importance of seeking prompt medical attention if these occur
• Canakinumab may affect the way the body fights infections, so routine health screening and vaccinations should be up to date before starting therapy