What are Interleukin-1 (IL-1) inhibitors?

What are IL-1 Inhibitors?

IL-1 inhibitors are a class of biologic medications that block the activity of interleukin-1 (IL-1), a key pro-inflammatory cytokine that drives inflammation in autoinflammatory diseases, crystal-induced arthritis, and other inflammatory conditions. 1

Mechanism of Action

IL-1 inhibitors work by preventing IL-1α and IL-1β from binding to their cell surface receptors, thereby blocking the inflammatory cascade that these cytokines trigger. 2, 3 Unlike cytokines such as TNF, IL-2, IL-6, IL-12, IL-15, and IL-23 that use the JAK-STAT signaling pathway, IL-1 operates through a distinct receptor-mediated mechanism. 1

The three FDA-approved IL-1 inhibitors employ different blocking strategies:

• Anakinra (Kineret): A recombinant IL-1 receptor antagonist that competitively inhibits both IL-1α and IL-1β from binding to the IL-1 type I receptor (IL-1RI). 2 It consists of 153 amino acids with a molecular weight of 17.3 kilodaltons and differs from native human IL-1Ra by having an additional methionine residue at its amino terminus. 2

• Canakinumab: A monoclonal antibody that specifically neutralizes IL-1β only. 1

• Rilonacept (Arcalyst): A dimeric fusion protein (IL-1 Trap) consisting of the ligand-binding domains of IL-1R1 and IL-1RAcP linked to the Fc portion of human IgG1, functioning as a soluble decoy receptor that binds both IL-1α and IL-1β with extremely high affinity (equilibrium dissociation constants of 1.4 pM for IL-1α and 0.5 pM for IL-1β). 3, 4

Primary Clinical Indications

IL-1 inhibitors are first-line therapy for IL-1-mediated autoinflammatory diseases, where they control inflammation without requiring glucocorticoids. 1

Autoinflammatory Diseases (FDA/EMA Approved)

• Cryopyrin-Associated Periodic Syndromes (CAPS): Including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID/CINCA). Canakinumab is approved at 2-8 mg/kg every 4-8 weeks depending on severity; rilonacept at loading dose 4.4 mg/kg weekly then maintenance 2.2 mg/kg weekly; anakinra at 1-8 mg/kg/day. 1

• TNF Receptor-Associated Periodic Syndrome (TRAPS): Canakinumab approved at 2-4 mg/kg every 4 weeks. 1

• Mevalonate Kinase Deficiency (MKD): Canakinumab approved at 2-4 mg/kg every 4 weeks. 1

• Deficiency of IL-1 Receptor Antagonist (DIRA): Anakinra approved at 1-8 mg/kg/day; rilonacept at 4.4 mg/kg weekly. 1

Still's Disease

For systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD), IL-1 and IL-6 inhibitors should be prioritized over prolonged glucocorticoid use due to high efficacy evidence, and should be initiated as early as possible when diagnosis is established. 1 Among IL-1 inhibitors, anakinra appears to have the most reassuring safety profile. 1

Crystal-Induced Arthritis

• Acute Gout Flares: IL-1 inhibitors (particularly canakinumab 150 mg subcutaneously as a single dose) are conditionally recommended for patients with frequent flares who have contraindications to colchicine, NSAIDs, and corticosteroids. 1, 5 Current infection is an absolute contraindication. 1, 5

• Pseudogout (CPPD): IL-1 inhibitors are considered third-line therapy when conventional therapies are contraindicated, ineffective, or poorly tolerated, with anakinra dosed at 100 mg subcutaneously daily for 3 consecutive days for acute treatment. 6

Special Circumstances

IL-1 and IL-6 inhibitors may be continued in pediatric rheumatic disease patients with symptomatic COVID-19 infection, unlike other biologics which should be temporarily withheld. 1 This reflects their potential benefit in managing hyperinflammation while maintaining disease control in conditions like systemic-onset JIA that are particularly sensitive to medication disruptions. 1

Pharmacokinetics and Dosing Considerations

• Anakinra: Bioavailability 95% after subcutaneous injection, peak plasma concentrations at 3-7 hours, terminal half-life 4-6 hours, requiring daily dosing. 2 Clearance is substantially reduced in renal impairment (70% reduction in severe renal insufficiency), necessitating dose adjustment to every other day in patients with creatinine clearance <30 mL/min. 2

• Rilonacept: Steady state reached by 6 weeks in CAPS and 2 weeks in recurrent pericarditis, with average trough levels approximately 24 mcg/mL and in vivo half-life of approximately 7 days, allowing weekly dosing. 3

• Canakinumab: Provides sustained IL-1β blockade allowing dosing intervals of 4-8 weeks depending on indication and disease severity. 1

Safety Profile and Monitoring

The safety profile for IL-1 blocking treatment has generally been favorable, but vigilant monitoring for infections is essential. 1

Infection Risk

• Respiratory tract infections with Streptococcus pneumoniae and skin infections due to Staphylococcus require particular attention. 1
• Patients receiving or planning to initiate anti-IL-1 therapy should receive pneumococcal vaccinations, preferably before starting treatment but acceptable during treatment. 1
• Current infection is an absolute contraindication to IL-1 blocker use. 1, 5
• IL-1 inhibitors may increase the risk of serious infections including sepsis. 6

Comparative Safety

Among IL-1 inhibitors, serious adverse events and infectious complications appear less frequent with anakinra compared to IL-6 inhibitors. 1 Notably, anakinra has been used safely in critically ill patients with sepsis in intensive care units. 1

Pregnancy Considerations

In women with IL-1-mediated autoinflammatory diseases requiring biologic treatment who are considering pregnancy, regulatory advice and clinical case series support the use of anakinra rather than other anti-IL-1 agents. 1 A benefit-risk discussion should occur before conception, weighing untreated disease risks to mother and fetus against continuing biologic agents. 1

Treatment Monitoring and Goals

The ultimate goal is complete remission, defined as absence of clinical symptoms and normal inflammatory markers (CRP <5-10 mg/L). 1

• Disease activity should be monitored using daily symptom diaries or Autoinflammatory Diseases Activity Index (AIDAI), physician global assessment (PGA), and patient/parent global assessment (PPGA). 1
• IL-1 targeted therapies need continuous administration in most patients, with dose and frequency adjusted to control disease activity and normalize inflammatory markers. 1
• Proteinuria should be evaluated every 6 months in all patients with IL-1-mediated autoinflammatory diseases, particularly those with family history of amyloidosis. 1

Critical Pitfalls to Avoid

• Never use IL-1 inhibitors in patients with active infection - this is an absolute contraindication. 1, 5
• Do not assume all IL-1 inhibitors have identical safety profiles - anakinra has the most favorable safety data. 1
• Avoid stopping IL-1 therapy abruptly in patients with autoinflammatory conditions, as disease flares can be severe and lead to organ damage. 1
• Do not overlook renal function when prescribing anakinra - dose adjustment is mandatory in severe renal impairment. 2
• The cost of IL-1 inhibitors is substantially higher than conventional therapies, which may limit access and requires consideration in treatment planning. 6