What is the treatment for conditions associated with elevated Interleukin-6 (IL-6) levels, such as rheumatoid arthritis or severe Coronavirus Disease 2019 (COVID-19)?

Treatment of Elevated IL-6 Conditions

For rheumatoid arthritis, tocilizumab (an IL-6 receptor inhibitor) is FDA-approved and effective, while for severe COVID-19, tocilizumab should be used in hospitalized patients receiving systemic corticosteroids with progressive disease (oxygen saturation <92% or requiring oxygen therapy, and CRP ≥75 mg/L). 1, 2

Rheumatoid Arthritis Management

IL-6 Inhibitor Therapy

• Tocilizumab is FDA-licensed for rheumatoid arthritis and blocks the IL-6 receptor, providing effective disease control. 1, 3
• Continue biologics and JAK inhibitors in patients with stable rheumatic disease without COVID-19 exposure, as discontinuation leads to disease flare in a large proportion of patients. 2
• The risk of serious infection with biologics must be balanced against the risk of disease flare and subsequent need for rescue glucocorticoids, which may further increase infection risk. 2

Important Safety Monitoring

• Tocilizumab carries an FDA black box warning for serious infections including tuberculosis, bacterial, invasive fungal, and viral infections. 2, 1
• Screen for latent tuberculosis before initiating therapy and treat with standard antimycobacterial therapy if positive. 1
• Monitor liver enzymes (ALT, AST, alkaline phosphatase, total bilirubin) every 4-8 weeks for the first 6 months, then every 3 months thereafter. 1
• Do not initiate treatment if ALT or AST >1.5× ULN; discontinue if levels exceed 5× ULN. 1
• Monitor neutrophils every 4-8 weeks initially, then every 3 months; do not initiate if ANC <2000/mm³ and discontinue if ANC <500/mm³. 1
• Monitor platelets on the same schedule; do not initiate if platelets <100,000/mm³ and discontinue if <50,000/mm³. 1

Severe COVID-19 Management

Patient Selection Criteria

• Tocilizumab is indicated for hospitalized patients with progressive COVID-19 defined as oxygen saturation <92% on room air or requiring oxygen therapy, AND CRP ≥75 mg/L. 2, 1
• The patient should already be receiving systemic corticosteroids, as the mortality benefit of tocilizumab was demonstrated primarily in this population (5.9% absolute risk reduction in 28-day mortality). 1
• Do not use tocilizumab in patients not receiving corticosteroids, as this subgroup showed no mortality benefit (hazard ratio 1.16). 1

Dosing and Administration

• Administer intravenous tocilizumab at weight-tiered dosing: 8 mg/kg (up to 800 mg maximum) as a single infusion. 1
• Do not initiate if ALT or AST >10× ULN in COVID-19 patients, as multi-organ failure with liver involvement is a recognized complication. 1
• Do not initiate if ANC <1000/mm³ or platelets <50,000/mm³. 1

Pediatric COVID-19 Considerations

• Tocilizumab is NOT recommended for most pediatric patients with COVID-19 and hyperinflammation, given lack of benefit in randomized controlled trials in adults and long-lasting immunosuppressive effects. 2
• Glucocorticoids should be first-tier immunomodulatory treatment in children with COVID-19 and hyperinflammation. 2
• Anakinra (IL-1 inhibitor) at >4 mg/kg/day IV or SC should be considered for refractory disease despite glucocorticoids or when steroids are contraindicated, particularly before invasive mechanical ventilation. 2

Critical Clinical Caveats

Infection Risk in Immunosuppressed Patients

• In rheumatic patients on long-term immunosuppressive therapy, tocilizumab may weaken anti-infectious immunity and increase risk of opportunistic infections including Pneumocystis jirovecii and Aspergillus fumigatus. 4
• Close monitoring is essential, and antimicrobial prophylaxis should be considered in high-risk patients. 4
• The dual role of IL-6 as both pro-inflammatory (driving cytokine storm) and protective (supporting anti-infectious immunity) creates a therapeutic dilemma requiring careful patient selection. 4

Timing and Clinical Context

• Early intervention before mechanical ventilation appears more beneficial than late administration in critically ill patients. 2
• The decision to use tocilizumab must balance potential benefit against risks, particularly in patients with baseline hepatic dysfunction, cytopenias, or active infection. 1
• Evidence from early 2020 studies was insufficient to support tocilizumab use outside clinical trials, but subsequent large randomized trials (RECOVERY, EMPACTA) established efficacy in specific patient populations. 2, 1

Alternative IL-6 Pathway Inhibitors

• Sarilumab (another IL-6R inhibitor) and siltuximab (direct IL-6 inhibitor) are under investigation for COVID-19 but lack the robust evidence base of tocilizumab. 5, 6
• JAK inhibitors (baricitinib, tofacitinib) that block IL-6 downstream signaling may be considered in refractory cases but have broad immunosuppressive effects. 2