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Interleukin-1 Inhibitors

Last Updated: July 17, 2020

Recommendation

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

Rationale

There are case series data but no clinical trial data on the use of IL-1 inhibitors in patients with COVID-19.

Anakinra is a recombinant human IL-1 receptor antagonist. It is approved by the Food and Drug Administration (FDA) 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. Case reports and case series have described favorable responses to anakinra in patients with these syndromes, including a survival benefit in patients with sepsis and reversal of cytokine storm after tocilizumab failure in adults with MAS.2,3

Clinical Data for COVID-19

  • A case-control study compared outcomes in 52 consecutive patients with COVID-19 treated with anakinra and 44 historical controls. The patients in both groups were all admitted to the same hospital in Paris, France. Case patients were consecutive admissions from March 24 to April 6, 2020, with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or lung infiltrates on chest imaging typical of COVID-19, and either significant hypoxia (SpO2 ≤93% with ≥6L/min O2) or worsening hypoxia (SpO2 ≤93% with >3L/min O2 and a loss of ≥3% of O2 saturation on room air in the previous 24 hours). The historic controls were patients who fulfilled the same eligibility criteria and admitted to the hospital during the same period. As standard of care for both groups, some patients received hydroxychloroquine, azithromycin, or parenteral beta-lactam antibiotics. Anakinra was dosed as 100 mg subcutaneous (SQ) twice daily for 72 hours, followed by anakinra 100 mg SQ daily for 7 days. Clinical characteristics were similar between the groups, except that the cases had a lower mean body mass index than the controls (25.5 kg/m2 vs. 29.0 kg/m2, respectively), longer duration of symptoms (mean of 8.4 days for cases vs. 6.2 days for controls), and a higher frequency of hydroxychloroquine use (90% for cases vs. 61% for controls) and azithromycin use (49% for cases vs. 34% for controls). The primary outcome of admission to the intensive care unit for mechanical ventilation or death occurred among 13 case patients (25%) and 32 control patients (73%) (hazard ratio 0.22; 95% confidence interval, 0.11 to 0.41). However, within the first 2 days of follow up, in the control group, six patients (14%) had died and 19 patients (43%) had reached the composite primary outcome, which further limited intragroup comparisons and specifically analyses of time to event. C-reactive protein (CRP) levels decreased by Day 4 among those receiving anakinra. Thromboembolic events occurred in 10 patients (19%) who received anakinra and in five control patients (11%). The clinical implications of these findings are uncertain due to limitations in the study design related to unmeasured confounding combined with the very high early event rate among the retrospective controls.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 medical center in Italy. All patients had COVID-19 with 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 anakinra 5 mg/kg twice daily 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. Patients in both the anakinra and control 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 than in the control group (90% vs. 56%, respectively; P = 0.009). However, the patients in the anakinra group were younger than those in the control group (median age 62 years vs. 70 years, respectively), and fewer 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
  • Other small case series have reported anakinra use for the treatment of COVID-19 and anecdotal evidence of improvement in outcomes.6

Clinical Trials

See ClinicalTrials.gov for a list of clinical trials evaluating anakinra for the treatment of COVID-19.

Adverse Effects

Anakinra was not associated with any significant safety concerns when used in clinical trials for the treatment of sepsis.7-9 Increased rates of infection were reported with prolonged anakinra use in combination with tumor necrosis factor-alpha blockade, but not with short-term use.10

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.11

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 FDA-approved only for SQ injection.

References

  1. Anakinra (Kineret) Prescribing Information. Food and Drug Administration. 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103950s5136lbl.pdf. Accessed April 8, 2020.
  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. Huet T, Beaussier H, Voisin O, et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheumatology. 2020;2(7):e393-e400. Available at: https://www.thelancet.com/pdfs/journals/lanrhe/PIIS2665-9913(20)30164-8.pdf.
  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;2(6): e325-e331. Available at: https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30127-2/fulltext.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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