What biologics can inhibit IL 6

What biologics can inhibit IL 6? What are its uses and toxicities?

Tocilizumab (Actemra) is a humanized IgG1κ monoclonal antibody that binds to the soluble and membrane-bound forms of the IL-6 receptor (IL-6R). This antibody inhibits IL-6 signaling of cells that constitutively express IL-6R as well as cells that bind the soluble form of IL-6R that interacts with gp130 on a wide variety of cells. Half-life is 8 to 14 days depending on dose. MTX does not help to increase the exposure to tocilizumab. It is controversial whether or not tocilizumab is more effective when used in combination with MTX.

  • • Available formulation: 80-mg, 200-mg, 400-mg single-use vials for IV administration; 162-mg prefilled (1 mL) ready-to-use, single-use syringe for SC administration.
  • • Adult RA IV dose: 4 mg/kg IV once every 4 weeks as a 60-minute infusion. Can increase to 8 mg/kg IV (not to exceed 800 mg) monthly if needed.
  • • Adult RA SC dose: if ≥100 kg body weight 162 mg SC weekly; if <100 kg body weight, 162 mg SC every other week. If not effective, the dose can be increased to weekly.
  • • Adult GCA SC dose: 162 mg SC weekly. IV dose not FDA-approved.
  • • Systemic JIA (Still’s disease; aged >2 years) and cytokine release syndrome from chimeric antigen receptor T-cell therapy: patient weight <30 kg: use 12 mg/kg IV every 2 weeks; ≥30 kg: use 8 mg/kg IV every 2 weeks.
  • • Polyarticular JIA (age >2 years) IV dose: patient weight <30 kg: use 10 mg/kg IV every 4 weeks; ≥30 kg: use 8 mg/kg IV every 4 weeks.
  • • Polyarticular JIA (age >2 years) SC dose: patient weight <30 kg: use 162 mg every 3 weeks; ≥30 kg: use 162 mg every 2 weeks.
  • • Tocilizumab can be used with or without MTX or another csDMARD.
  • • Monitoring: CBC (with differential) and hepatic enzymes monthly until stable dose, then every 1 to 2 months. Lipid panel every 1 to 2 months until stable dose, then every 3 to 6 months.
  • • Adverse reactions: all adverse events more common on 8 mg/kg than on 4 mg/kg dose.
  • • Infusion reactions (8%): headaches, hypertension. Premedication usually not necessary. Serious reactions rare.
  • • Infections: upper respiratory (8%), serious infections (3–5 events/100 patient years), Herpes zoster, opportunistic (rare).
  • • Elevated hepatic enzymes: attributable to binding IL-6R on liver cells, which blocks antiapoptotic effects of IL-6 on liver cells.
    • Enzymes between 1 and 3 times upper limit of normal (ULN; 35%–50% of patients): reduce tocilizumab dose and/or modify DMARD (MTX) dose.
    • Enzymes more than three to five times ULN (5%): stop tocilizumab until enzymes less than three times ULN, then restart at lower dose and/or modify DMARD dose.
    • Enzymes more than five times ULN (0.5%–1.5%): discontinue tocilizumab.
  • • Neutropenia (29%): as a result of binding IL-6R on neutrophils.
    • Absolute neutrophil count (ANC) >1000/mm : continue tocilizumab.
    • ANC 500 to 1000/mm (2%–4% of patients): stop tocilizumab until ANC >1000/mm , then restart at lower dose.
    • ANC <500/mm (0.4%): discontinue tocilizumab.
  • • Thrombocytopenia (8%): discontinue if <50,000/mm (0.8%).
  • • Lipid elevations: mean increase low-density lipoprotein was 10 to 20 mg/dL and mean high-density lipoprotein increase was 3 to 5 mg/dL.
  • • Gastrointestinal perforations (0.26 events/100 patient years): IL-6 important for fibrotic healing and repair of gastrointestinal inflammation. More common in patients on nonsteroidal antiinflammatory drugs, corticosteroids, and who have previous history of diverticulitis.
  • • Macrophage activation syndrome: seen in 3% of systemic JIA patients treated with tocilizumab.
  • • No increase in malignancy, CHF, or demyelinating disease noted. Patients with hepatitis B were excluded from trials, and thus reactivation risk is unknown.
  • • Precautions: do not use in patients with active infection, hepatic enzymes >1.5× upper limit, platelet count <100,000/mm , history of diverticulitis or other IBD. Drug interactions include affecting blood levels of warfarin, cyclosporine, and theophylline. Lowers blood levels of omeprazole, atorvastatin, simvastatin, and birth control pills. Advise patients about birth control.
  • • Other diseases that it has been used with success: Castleman disease, Takayasu’s arteritis, Behćet’s disease, relapsing polychondritis, adult-onset Still’s disease, systemic sclerosis, and SLE. Does not work for spondyloarthropathies.

Sarilumab (Kevzara) is a fully human anti-IL-6Rα monoclonal antibody that binds the soluble and membrane-bound human IL-6Rα.

  • • Available formulation: 150-mg and 200-mg solution in a single-dose prefilled syringe and pen.
  • • Adult RA dose: 200 mg SC every 2 weeks. If develop toxicity, can decrease to 150-mg dose. Can be combined with other csDMARDs (e.g., MTX).
  • • Toxicity profile and monitoring schedule similar to tocilizumab

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