Last Updated: April 21, 2021
Interleukin (IL)-6 is a pleiotropic, proinflammatory cytokine produced by a variety of cell types, including lymphocytes, monocytes, and fibroblasts. Infection by the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) induces a dose-dependent production of IL-6 from bronchial epithelial cells.1 COVID-19-associated systemic inflammation and hypoxic respiratory failure can be associated with heightened cytokine release, as indicated by elevated blood levels of IL-6, C-reactive protein (CRP), D-dimer, and ferritin.2-4 It is hypothesized that modulating the levels of IL-6 or its effects may reduce the duration and/or severity of COVID-19 illness.
There are two classes of Food and Drug Administration (FDA)-approved IL-6 inhibitors: anti-IL-6 receptor monoclonal antibodies (e.g., sarilumab, tocilizumab) and anti-IL-6 monoclonal antibodies (i.e., siltuximab). These drugs have been evaluated for the management of patients with COVID-19 who have systemic inflammation. The COVID-19 Treatment Guidelines Panel’s (the Panel’s) recommendations on the use IL-6 inhibitors in patients with COVID-19 and related clinical data to date are described below.
- The Panel recommends using tocilizumab (single intravenous [IV] dose of tocilizumab 8 mg/kg actual body weight up to 800 mg) in combination with dexamethasone (6 mg daily for up to 10 days) in certain hospitalized patients who are exhibiting rapid respiratory decompensation due to COVID-19. These patients are:
- Recently hospitalized patients (i.e., within first 3 days of admission) who have been admitted to the intensive care unit (ICU) within the prior 24 hours and who require invasive mechanical ventilation, noninvasive ventilation, or high-flow nasal canula (HFNC) oxygen (>0.4 FiO2/30 L/min of oxygen flow) (BIIa); or
- Recently hospitalized patients (i.e., within first 3 days of admission) not admitted to the ICU who have rapidly increasing oxygen needs and require noninvasive ventilation or HFNC oxygen and who have significantly increased markers of inflammation (CRP ≥75 mg/L) (BIIa).
- For hospitalized patients with hypoxemia who require conventional oxygen therapy, there is insufficient evidence to specify which of these patients would benefit from the addition of tocilizumab. Some Panel members would also give tocilizumab to patients who are exhibiting rapidly increasing oxygen needs while on dexamethasone and have a CRP ≥75 mg/L, but who do not yet require noninvasive ventilation or HFNC oxygen as described above.
- There are insufficient data for the Panel to recommend either for or against the use of sarilumab for hospitalized patients with COVID-19 who are within 24 hours of admission to the ICU and who require invasive mechanical ventilation, noninvasive ventilation, or high-flow oxygen (>0.4 FiO2/30 L/min of oxygen flow).
- The Panel recommends against the use of anti-IL-6 monoclonal antibody therapy (i.e., siltuximab) for the treatment of COVID-19, except in a clinical trial (BI).
- Tocilizumab should be avoided in patients who are significantly immunosuppressed, particularly in those with recent use of other biologic immunomodulating drugs, and in patients who have alanine aminotransferase >5 times the upper limit of normal; high risk for gastrointestinal perforation; an uncontrolled serious bacterial, fungal, or non-SARS-CoV-2 viral infection; absolute neutrophil count <500 cells/µL; platelet count <50,000 cells/µL; or known hypersensitivity to tocilizumab.
- Tocilizumab should only be given in combination with a course of dexamethasone (or an alternative corticosteroid at a dose equivalency to dexamethasone 6 mg) therapy.
- Some clinicians may assess the patient’s clinical response to dexamethasone before deciding whether tocilizumab is needed.
- Although some patients in the Randomised, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) and the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial received a second dose of tocilizumab at the discretion of treating physicians, there are insufficient data to indicate which patients, if any, would benefit from an additional dose of tocilizumab.
- Cases of severe and disseminated strongyloidiasis have been reported with use of tocilizumab and corticosteroids in patients with COVID-19.5,6 Prophylactic treatment with ivermectin should be considered for patients who are from strongyloidiasis endemic areas.7
The results of the RECOVERY trial and REMAP-CAP provide consistent evidence that tocilizumab, when administered with corticosteroids, offers a modest mortality benefit in certain patients with COVID-19 who are severely ill, rapidly deteriorating with increasing oxygen needs, and have a significant inflammatory response. However, the Panel found it challenging to define the specific patient population(s) that would benefit from this intervention. See an overview of the clinical trial data on the use of tocilizumab in patients with COVID-19 below.
Sarilumab and tocilizumab have a similar mechanism of action. However, in REMAP-CAP, the number of participants who received sarilumab was relatively small. Moreover, the trial evaluated sarilumab for IV administration, which is not the approved formulation in the United States. The results of randomized controlled trials of sarilumab that are underway will further define the role sarilumab plays in the treatment of COVID-19.
There are only limited data describing the potential for efficacy of siltuximab in patients with COVID-19.11
Anti-Interleukin-6 Receptor Monoclonal Antibodies
Tocilizumab is a recombinant humanized anti-IL-6 receptor monoclonal antibody that is approved by the FDA for use in patients with rheumatologic disorders and cytokine release syndrome (CRS) induced by chimeric antigen receptor T cell (CAR T-cell) therapy. Tocilizumab can be dosed for IV or subcutaneous (SQ) injection. The IV formulation should be used to treat CRS.8
Clinical Data for COVID-19
Clinical data on the use of tocilizumab (and other IL-6 inhibitors) for the treatment of COVID-19, including data from several randomized trials and large observational studies, are summarized in Table 4b.
Initial studies that evaluated the use of tocilizumab for the treatment of COVID-19 produced conflicting results. Many of these trials were limited by low power, heterogenous populations, and/or a low frequency of concomitant use of corticosteroids (now the standard of care for patients with severe COVID-19).9-11 For example, trials that reported a treatment benefit of tocilizumab enrolled patients who were receiving higher levels of oxygen support (e.g., HFNC oxygen, noninvasive ventilation, invasive mechanical ventilation) and/or included more patients who used corticosteroids.12,13 Subsequently, REMAP-CAP and the RECOVERY trial—the two largest randomized controlled tocilizumab trials—reported a mortality benefit of tocilizumab in certain patients, including patients exhibiting rapid respiratory decompensation associated with an inflammatory response. REMAP-CAP enrolled a narrowly defined population of critically ill patients who were enrolled within 24 hours of starting respiratory support in an ICU and randomized to receive open-label tocilizumab or usual care.14 The RECOVERY trial enrolled hospitalized patients with COVID-19 into an open label, platform trial of several treatment options;15 a subset of participants with hypoxemia and CRP ≥75 mg/L were offered enrollment into a second randomization to tocilizumab versus usual care. Additional findings from REMAP-CAP and the RECOVERY trial and the rationale for using tocilizumab in certain hospitalized patients who are exhibiting rapid respiratory decompensations due to COVID-19 can be found in Therapeutic Management of Adults With COVID-19.
The Panel’s recommendations for using tocilizumab are based on the collective evidence from clinical trials reported to date (see Table 4b).
Ongoing trials are evaluating the use of tocilizumab for the treatment of COVID-19. See ClinicalTrials.gov for the latest information.
The primary laboratory abnormalities reported with tocilizumab treatment are elevated liver enzyme levels that appear to be dose dependent. Neutropenia or thrombocytopenia are uncommon. Additional adverse effects, such as risk for serious infections (e.g., tuberculosis [TB], bacterial or fungal infections) and bowel perforation, have been reported only in the context of tocilizumab use for the treatment of chronic disease.
Considerations in Pregnancy
There are insufficient data to determine whether there is a tocilizumab-associated risk for major birth defects or miscarriage. Monoclonal antibodies are actively transported across the placenta as pregnancy progresses (with greatest transfer during the third trimester) and may affect immune responses in utero in the exposed fetus. Given the paucity of data, current recommendations advise against the use of tocilizumab during pregnancy.16 Decisions about tocilizumab administration during pregnancy must include shared decision-making between the pregnant individual and their health care provider, considering potential maternal benefit and fetal risks.
Considerations in Children
There are no systematic observational or randomized controlled trial data available on the effectiveness of tocilizumab for the treatment of COVID-19 or multisystem inflammatory syndrome in children (MIS-C) in children. Tocilizumab has been used for children with CRS associated with CAR T-cell therapy and systemic and polyarticular juvenile idiopathic arthritis.17 There are insufficient data for the Panel to recommend either for or against the use of tocilizumab in hospitalized children with COVID-19 or MIS-C.
Sarilumab is a recombinant humanized anti-IL-6 receptor monoclonal antibody that is approved by the FDA for use in patients with rheumatoid arthritis. It is available as an SQ formulation and is not approved for the treatment of CRS.
Clinical Data for COVID-19
Clinical data for sarilumab (and other IL-6 inhibitors) as treatment for COVID-19, including data from several randomized trials and large observational studies, are summarized in Table 4b.
An adaptive Phase 2 and 3 double-blind, placebo-controlled randomized (2:2:1) trial compared the efficacy and safety of sarilumab 400 mg IV and sarilumab 200 mg IV versus placebo in patients hospitalized with COVID-19 (ClinicalTrials.gov Identifier NCT04315298). Results from this trial did not support a clinical benefit of sarilumab in hospitalized patients receiving supplemental oxygen.18 Preliminary efficacy results from REMAP-CAP for sarilumab were similar to those for tocilizumab. Compared to placebo, sarilumab reduced both mortality and time to ICU discharge, and increased the number of organ support-free days; however, the number of participants who received sarilumab in this trial was relatively small, limiting the conclusions and implications of these findings.19
Ongoing trials are evaluating the use of sarilumab for the treatment of COVID-19. See ClinicalTrials.gov for the latest information.
The primary lab abnormalities that have been reported with sarilumab treatment are transient and/or reversible elevations in liver enzymes that appear to be dose dependent and rare occurrences of neutropenia and thrombocytopenia. Risk for serious infections (e.g., TB, bacterial or fungal infections) and bowel perforation have been reported only with long-term use of sarilumab.
Considerations in Pregnancy
There are insufficient data to determine whether there is a sarilumab-associated risk for major birth defects or miscarriage. Monoclonal antibodies are actively transported across the placenta as pregnancy progresses (with greatest transfer during the third trimester) and may affect immune responses in utero in the exposed fetus.
Considerations in Children
There are no data on the use of sarilumab in children other than data from ongoing trials assessing the drug’s safety in children with juvenile idiopathic arthritis. There are no systematic observational or randomized controlled trial data available on the efficacy of sarilumab for the treatment of COVID-19 or MIS-C in children.
The SQ formulation of sarilumab is not approved for the treatment of CRS. The IV formulation is not approved by the FDA, but it is being studied in a clinical trial of hospitalized patients with COVID-19.
Anti-Interleukin-6 Monoclonal Antibody
Siltuximab is a recombinant human-mouse chimeric monoclonal antibody that binds IL-6 and is approved by the FDA for use in patients with multicentric Castleman disease. Siltuximab prevents the binding of IL-6 to both soluble and membrane-bound IL-6 receptors, inhibiting IL-6 signaling. Siltuximab is dosed as an IV infusion.
Clinical Data for COVID-19
There are limited data describing the efficacy of siltuximab in patients with COVID-19.20 There are no data describing clinical experiences using siltuximab for patients with other novel coronavirus infections (i.e., severe acute respiratory syndrome [SARS], Middle East respiratory syndrome [MERS]).
See ClinicalTrials.gov for a list of current clinical trials for siltuximab and COVID-19.
The primary adverse effects reported for siltuximab have been related to rash. Additional adverse effects (e.g., serious bacterial infections) have been reported only with long-term dosing of siltuximab once every 3 weeks.
Considerations in Pregnancy
There are insufficient data to determine whether there is a siltuximab-associated risk for major birth defects or miscarriage. Monoclonal antibodies are transported across the placenta as pregnancy progresses (with greatest transfer during the third trimester) and may affect immune responses in the exposed fetus.
Considerations in Children
The safety and efficacy of siltuximab have not been established in pediatric patients.
- Yoshikawa T, Hill T, Li K, Peters CJ,Tseng CT. Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells. J Virol. 2009;83(7):3039-3048. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19004938.
- Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32171076.
- Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31986264.
- Wang Z, Yang B, Li Q, Wen L,Zhang R. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32176772.
- Lier AJ, Tuan JL, Davis MW, et al. Case report: disseminated strongyloidiasis in a patient with COVID-19. Am J Trop Med Hyg. 2020. Available at: https://pubmed.ncbi.nlm.nih.gov/32830642/
- Marchese V, Crosato V, Gulletta M, et al. Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. Infection. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32910321.
- Stauffer WM, Alpern JD,Walker PF. COVID-19 and dexamethasone: a potential strategy to avoid steroid-related strongyloides hyperinfection. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32761166.
- Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23(8):943-947. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29622697.
- Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with COVID-19. N Engl J Med. 2020;383(24):2333-2344. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33085857.
- Gupta S, Wang W, Hayek SS, et al. Association between early treatment with tocilizumab and mortality among critically ill patients with COVID-19. JAMA Intern Med. 2021;181(1):41-51. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33080002.
- Hermine O, Mariette X, Tharaux PL, et al. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181(1):32-40. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33080017.
- Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with COVID-19 pneumonia. N Engl J Med. 2021;384(1):20-30. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33332779.
- Rosas IO, Brau N, Waters M, et al. Tocilizumab in hospitalized patients with severe COVID-19 pneumonia. N Engl J Med. 2021. Available at: https://pubmed.ncbi.nlm.nih.gov/33676590/.
- REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33631065.
- RECOVERY Collaborative Group, Horby PW, Pessoa-Amorim G, et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv. 2021;preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.02.11.21249258v1.
- Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol. 2020;72(4):529-556. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32090480.
- Tocilizumab (Actemra) [package insert]. Food and Drug Administration. 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125276s131lbl.pdf.
- Lescure FX, Honda H, Fowler RA, et al. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33676590.
- The REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19–Preliminary report. medRxiv. 2021. Available at: https://www.medrxiv.org/content/10.1101/2021.01.07.21249390v1.
- Gritti G, Raimondi F, Ripamonti D, et al. Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support. medRxiv. 2020. Available at: https://www.medrxiv.org/content/10.1101/2020.04.01.20048561v1.