Last Updated: October 19, 2021
Interleukin (IL)-6 is a pleiotropic, proinflammatory cytokine produced by a variety of cell types, including lymphocytes, monocytes, and fibroblasts. Infection by SARS-CoV induces a dose-dependent production of IL-6 from bronchial epithelial cells.1 COVID-19-associated systemic inflammation and hypoxemic 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 IL-6 levels or the effects of IL-6 may reduce the duration and/or severity of COVID-19.
There are two classes of Food and Drug Administration (FDA)-approved IL-6 inhibitors: anti-IL-6 receptor monoclonal antibodies (mAbs) (e.g., sarilumab, tocilizumab) and anti-IL-6 mAbs (i.e., siltuximab). These drugs have been evaluated in patients with COVID-19 who have systemic inflammation.
- See Therapeutic Management of Hospitalized Adults With COVID-19 for the COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations on the use of IL-6 inhibitors (e.g., sarilumab, tocilizumab) in hospitalized patients who require supplemental oxygen, high-flow oxygen, noninvasive ventilation, or invasive mechanical ventilation.
- The Panel recommends against the use of anti-IL-6 mAb therapy (i.e., siltuximab) for the treatment of COVID-19, except in a clinical trial (BI).
- Tocilizumab and sarilumab should be used with caution in groups of patients with COVID-19 that have not been adequately studied in clinical trials. This includes patients who are significantly immunosuppressed, particularly those who have recently received other biologic immunomodulating drugs, and those with:
- Alanine transaminase levels >5 times the upper limit of normal
- A high risk for gastrointestinal perforation
- An uncontrolled serious bacterial, fungal, or non-SARS-CoV-2 viral infection
- Absolute neutrophil counts <500 cells/µL
- Platelet counts <50,000 cells/µL
- Known hypersensitivity to the drug
- Tocilizumab and sarilumab should only be given in combination with a course of dexamethasone (or an alternative corticosteroid at a dose that is equivalent to dexamethasone 6 mg). See the Corticosteroids section for more information.
- Some clinicians may decide to assess the patient’s clinical response to dexamethasone before deciding whether tocilizumab or sarilumab is needed.
- In both the REMAP-CAP trial and the RECOVERY trial, 29% of patients received a second dose of tocilizumab at the discretion of the treating physicians. However, the available data are currently insufficient to recommend either for or against a second dose.5,6
- Cases of severe and disseminated strongyloidiasis have been reported in patients with COVID-19 during treatment with tocilizumab and corticosteroids.7,8 Many clinicians would initiate empiric treatment (e.g., with ivermectin) with or without serologic testing in patients who are from areas where Strongyloides is endemic (i.e., tropical, subtropical, or warm temperate areas).9
The results of the RECOVERY and REMAP-CAP trials provide consistent evidence that tocilizumab, when administered with corticosteroids, offers a modest mortality benefit in certain patients with COVID-19 who are severely ill, who are rapidly deteriorating and have increasing oxygen needs, and who have a significant inflammatory response.5,6 However, the Panel found it challenging to define the specific patient populations that would benefit from this intervention. If tocilizumab is not available, sarilumab may be used as an alternative because it has demonstrated a similar clinical benefit in improving survival and reducing the duration of organ support in the REMAP-CAP trial.10 However, the Panel recommends sarilumab only when tocilizumab is not available or is not feasible to use (BIIa) because the evidence for the efficacy of tocilizumab is more extensive than that for sarilumab; in addition, sarilumab is currently only approved for use as a subcutaneous (SQ) injection in the United States.
The data on the efficacy of siltuximab in patients with COVID-19 are currently limited.11
Anti-Interleukin-6 Receptor Monoclonal Antibodies
Tocilizumab is a recombinant humanized anti-IL-6 receptor mAb that is approved by the FDA for use in patients with rheumatologic disorders and cytokine release syndrome induced by chimeric antigen receptor T cell (CAR T-cell) therapy. Tocilizumab can be dosed as an intravenous (IV) infusion or a SQ injection. The IV formulation should be used to treat cytokine release syndrome.11
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 4d.
The 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).12-14 For example, trials that reported a treatment benefit of tocilizumab enrolled patients who were receiving higher levels of oxygen support (e.g., high-flow nasal cannula oxygen, noninvasive ventilation, invasive mechanical ventilation) and/or included more patients who used corticosteroids.15,16 Subsequently, the REMAP-CAP and RECOVERY trials—the two largest randomized controlled tocilizumab trials—both 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 intensive care unit and who were randomized to receive open-label tocilizumab or usual care.5 The RECOVERY trial enrolled hospitalized patients with COVID-19 into an open-label platform trial that included several treatment options;6 a subset of all trial participants who also had hypoxemia and CRP levels ≥75 mg/L were offered enrollment into a second randomization that evaluated tocilizumab versus usual care. Additional findings from the REMAP-CAP and RECOVERY trials 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 Hospitalized Adults With COVID-19.
The Panel’s recommendations for using tocilizumab are based on the collective evidence from the clinical trials reported to date (see Table 4d).
See ClinicalTrials.gov for a list of clinical trials that are evaluating the use of tocilizumab for the treatment of COVID-19.
The primary laboratory abnormalities reported with tocilizumab treatment are elevated liver enzyme levels that appear to be dose dependent. Neutropenia or thrombocytopenia are uncommon. In randomized trials, no excess secondary infections were seen among patients who received combination therapy compared to study controls. Additional adverse effects, such as serious infections (e.g., tuberculosis [TB], bacterial or fungal infections) and bowel perforation, have been reported.17
Considerations in Pregnancy
There are insufficient data to determine whether there is a tocilizumab-associated risk for major birth defects or miscarriage. mAbs are actively transported across the placenta as pregnancy progresses (with the greatest transfer occurring during the third trimester), and this 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.18 The decision to use tocilizumab during pregnancy should be a collaborative effort between pregnant individuals and their health care providers, and the decision-making process should include a discussion of the potential risks and benefits.
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). Tocilizumab has been used for children with cytokine release syndrome associated with CAR T-cell therapy and systemic and polyarticular juvenile idiopathic arthritis.19 There is insufficient evidence for the Panel to recommend either for or against the use of tocilizumab in hospitalized children with COVID-19 or MIS-C.
On June 24, 2021, the FDA issued an Emergency Use Authorization (EUA) for the use of tocilizumab in combination with corticosteroids in hospitalized adults and children aged ≥2 years with COVID-19 who require supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation.20 Per this EUA, if a patient’s clinical signs or symptoms worsen or do not improve after the first dose of tocilizumab, one additional infusion of tocilizumab may be administered at least 8 hours after the initial IV infusion. If there is a local or regional shortage of tocilizumab, sarilumab can be used as an alternative (see Therapeutic Management of Hospitalized Adults With COVID-19).10
Sarilumab is a recombinant humanized anti-IL-6 receptor mAb 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 cytokine release syndrome.
Clinical Data for COVID-19
The clinical data on the use of sarilumab as a treatment for COVID-19 are summarized in Table 4d.
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 to placebo in hospitalized patients 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.21
A similar adaptive design study that was conducted in the United States in patients with severe and critical COVID-19 also failed to show a benefit of sarilumab. In this trial, there was a numerical decrease in mortality among participants with critical COVID-19 pneumonia who required mechanical ventilation and who received corticosteroids; however, because of the small sample size in this study, the result was not statistically significant.22 In the REMAP-CAP trial, the efficacy results for sarilumab were similar to those for tocilizumab. Compared to the patients in the standard of care arm (n = 418), those who were randomized to receive sarilumab (n = 485) had more organ support-free days (OR 1.50; 95% CrI, 1.13–2.00) and better survival rates while hospitalized (OR 1.51; 95% CrI, 1.06–2.20). A notable limitation to the sarilumab findings in the REMAP-CAP trial is that patients in the standard of care arm were enrolled earlier in the pandemic than patients who received sarilumab (i.e., randomization for the standard of care arm closed on November 19, 2020, and randomization for the sarilumab arm continued through April 10, 2021).10
See ClinicalTrials.gov for a list of clinical trials that are evaluating the use of sarilumab for the treatment of COVID-19.
The primary laboratory abnormalities that have been reported with sarilumab treatment are transient and/or reversible elevations in liver enzyme levels that appear to be dose dependent and rare occurrences of neutropenia and thrombocytopenia. Additional adverse effects, such as serious infections (e.g., TB, bacterial or fungal infections) and bowel perforation, have been reported, but 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. mAbs are actively transported across the placenta as pregnancy progresses (with the greatest transfer occurring during the third trimester), and this 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 that are 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 IV formulation of sarilumab is not approved by the FDA, but it is being studied in a clinical trial of hospitalized patients with COVID-19. In the REMAP-CAP trial, a single SQ dose of sarilumab 400 mg was reconstituted in 100 cc 0.9% NaCl and given as an IV infusion over a 1-hour period.10
Anti-Interleukin-6 Monoclonal Antibody
Siltuximab is a recombinant human-mouse chimeric mAb 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 on the efficacy of siltuximab in patients with COVID-19.23 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 clinical trials that are evaluating the use of siltuximab for the treatment of 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. mAbs are transported across the placenta as pregnancy progresses (with the greatest transfer occurring during the third trimester), and this may affect immune responses in utero 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;71(15):769-777. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32176772.
- 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;384(16):1491-1502. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33631065.
- RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637-1645. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33933206.
- Lier AJ, Tuan JL, Davis MW, et al. Case report: disseminated strongyloidiasis in a patient with COVID-19. Am J Trop Med Hyg. 2020;103(4):1590-1592. 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. 2021;49(3):539-542. 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.
- The REMAP-CAP Investigators, Derde LPG. Effectiveness of tocilizumab, sarilumab, and anakinra for critically ill patients with COVID-19: the REMAP-CAP COVID-19 immune modulation therapy domain randomized clinical trial. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.06.18.21259133v2.
- 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;384(16):1503-1516. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33631066.
- Charan J, Dutta S, Kaur R, et al. Tocilizumab in COVID-19: a study of adverse drug events reported in the WHO database. Expert Opin Drug Saf. 2021;20(9):1125-1136. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34162299.
- 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.
- Food and Drug Administration. Letter of authorization: EUA for tocilizumab (Actemra) for the treatment of coronavirus disease 2019 (COVID-19). 2021. Available at: https://www.fda.gov/media/150319/download.
- 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;9(5):522-532. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33676590.
- Sivapalasingam S, Lederer DJ, Bhore R, et al. A randomized placebo-controlled trial of sarilumab in hospitalized patients with COVID-19. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.05.13.21256973v3.
- Gritti G, Raimondi F, Ripamonti D, et al. IL-6 signalling pathway inactivation with siltuximab in patients with COVID-19 respiratory failure: an observational cohort study. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.04.01.20048561v4.