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Interleukin-1 Inhibitors

Last Updated: June 11, 2020

Recommendation

  • There are insufficient data to recommend either for or against the use of interleukin-1 (IL-1) inhibitors, such as anakinra, for the treatment of COVID-19.

Rationale

There are no data from clinical trials on the use of IL-1 inhibitors in patients with COVID-19.

Anakinra is a recombinant human IL-1 receptor antagonist. It is approved to treat rheumatoid arthritis and cryopyrin-associated periodic syndromes, specifically neonatal-onset multisystem inflammatory disease.1 It is also used off-label for severe chimeric antigen receptor T cell (CAR T-cell)-mediated cytokine release syndrome (CRS) and macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis.

Rationale for Use in Patients with COVID-19

Endogenous IL-1 is elevated in patients with COVID-19 and other conditions, such as severe CAR-T-cell mediated CRS. There are case reports and series that describe a favorable response with anakinra in these syndromes, including survival benefit in sepsis and reversing cytokine storm in adults with MAS after tocilizumab failure.2,3

Clinical Data for COVID-19

  • A single-center case series reported outcomes following the open-label use of anakinra in nine hospitalized patients with COVID-19 who presented with 4 to 12 days of symptoms, required oxygen ≤6 liters/minute, and had serum C-reactive protein (CRP) ≥50 mg/L. Anakinra 100 mg was administered subcutaneously (SQ) every 12 hours for 3 days followed by 100 mg daily for up to 7 more days. Two of the nine patients also received hydroxychloroquine plus azithromycin; the other seven patients received no specific treatments. Anakinra was discontinued in one patient who progressed to acute respiratory failure after receiving the first dose of the drug. Data regarding the other eight patients indicated good clinical outcomes as assessed by oxygen flow, decline in CRP levels, and serial computerized tomography (CT) scans that showed no progression in infiltrates. By Day 11, none of the patients had died. Three patients experienced liver transaminase levels ≥3 times the upper limit of normal. However, the study results are difficult to interpret because of the low number of patients included in the case series and the absence of a comparison group.4
  • A single-center retrospective cohort study compared outcomes in 29 patients following open-label use of anakinra to outcomes in 16 historical controls enrolled at the same center in Italy. All patients had COVID-19, moderate to severe acute respiratory distress syndrome (ARDS) that required non-invasive ventilation, and evidence of hyperinflammation (CRP ≥100 mg/L and/or ferritin ≥900 ng/mL). High-dose intravenous (IV) anakinra 5 mg/kg twice daily (the IV formulation is not approved in the United States) was administered for a median of 9 days, followed by SQ administration of anakinra 100 mg twice daily for 3 days to avoid inflammatory relapses. Both the anakinra and control (standard treatment) groups received hydroxychloroquine and lopinavir/ritonavir. In the anakinra group, reductions in CRP levels were noted over several days following anakinra initiation and the 21-day survival rate was higher in the anakinra group than in the control group (90% vs. 56%, P = 0.009). However, the median age in the anakinra group was younger than in the control group (median 62 years vs. 70 years), and a smaller percentage of patients in the anakinra group had chronic kidney disease. High-dose anakinra was discontinued in seven patients (24%) because of adverse events (four patients developed bacteremia and three patients had elevated liver enzymes); however, retrospective assessment showed that these events occurred with similar frequency in the control group. An additional group of seven patients received low-dose SQ anakinra 100 mg twice daily; however, treatment in this group was stopped after 7 days because of lack of clinical or anti-inflammatory effects.5

Clinical Trials

A number of clinical trials for the treatment of COVID-19 are currently underway (a list of clinical trials is available here: Anakinra.

Adverse Effects

Anakinra was not associated with any significant safety concerns in trials of sepsis.6-8 Increased rates of infection were reported with prolonged use in combination with tumor necrosis factor-alfa blockade, but not with short-term use.9

Considerations in Pregnancy

There is limited evidence on which to base a recommendation in pregnancy, but unintentional first trimester exposure is unlikely to be harmful.10

Considerations in Children

Anakinra has been used extensively in the treatment of severely ill children with complications of rheumatologic conditions, including MAS. Pediatric data on the use of anakinra in ARDS/sepsis are limited.

Drug Availability

Procuring anakinra may be a challenge at some hospitals in the United States. Anakinra is approved only in an SQ formulation.

References

  1. Anakinra (Kineret) Prescribing Information. Food and Drug Administration. 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103950s5136lbl.pdf.
  2. Shakoory B, Carcillo JA, Chatham WW, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior Phase III trial. Crit Care Med. 2016;44(2):275-281. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26584195.
  3. Monteagudo LA, Boothby A, Gertner E. Continuous intravenous anakinra infusion to calm the cytokine storm in macrophage activation syndrome. ACR Open Rheumatol. 2020;2(5):276-282. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32267081.
  4. Aouba A, Baldolli A, Geffray L, et al. Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: case series. Ann Rheum Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32376597.
  5. Cavalli G, De Luca G, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatology. 2020. Available at: https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30127-2/fulltext.
  6. Fisher CJ, Jr., Dhainaut JF, Opal SM, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA. 1994;271(23):1836-1843. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8196140.
  7. Fisher CJ, Jr., Slotman GJ, Opal SM, et al. Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. Crit Care Med. 1994;22(1):12-21. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8124953.
  8. Opal SM, Fisher CJ, Jr., Dhainaut JF, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med. 1997;25(7):1115-1124. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9233735.
  9. Winthrop KL, Mariette X, Silva JT, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors). Clin Microbiol Infect. 2018;24 Suppl 2:S21-S40. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29447987.
  10. Flint J, Panchal S, Hurrell A, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part II: analgesics and other drugs used in rheumatology practice. Rheumatology (Oxford). 2016;55(9):1698-1702. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26750125.