Could anakinra outmatch dexamethasone/tocilizumab in COVID-19?
Bulletin of the National Research Centre volume 46, Article number: 100 (2022)
The hyperinflammatory state leading to an aberrant cytokine production, culminating in acute respiratory distress syndrome, sepsis and multi-organ dysfunction contribute much to the pathophysiologies of severe COVID-19. These severe patients have similar clinical manifestations with patients suffering from certain auto-inflammatory disorders and cytokine storm syndromes. Interestingly, anakinra (blocking both IL-1α and IL-1β) has shown promises in treating these patients with hyperinflammatory disorders, sepsis with multiorgan failures. Another inflammasome, AIM2, involved in production of IL-1 has also been found to be implicated in COVID-19. IL-1β, a known procoagulant, causes induction of tissue factor with increasing vascular endothelial permeability loss ensuing in hypercoagulability-one of the cardinal features of the disease. Hence, anakinra a 17kD recombinant human IL-1 receptor antagonist, used widely in Rheumatoid Arthritis treatments might prove efficacious in attenuating the hyperinflammatory state of the disease. Indeed, some of the controlled clinical trials have shown anakinra to effectively decrease mortality and hospital stay. Targeted cytokine blocking are always preferable in comparison with non-specific blocking (steroids) as it is more restrained with the chances of dampening of systemic immune system being much less. Early cell death and neutrophil migration have been one of the pivotal events in COVID-19 pathogenesis. Hence, suPAR levels which measures IL-1α (necroptosis) and S100A8/A9 (neutrophil migration) can perhaps be a good early biomarker predicting the disease progression. Lastly and importantly, as the vaccines are raised against spike protein and the different variants of concern are known to evade the neutralizing antibodies by varying degrees, it will be deserving to assess anakinra, against the variants of concern as an immunomodulatory drug.
To the Editor:
The attenuation of the hyperinflammated state has been thought as a measure to contain the pathophysiologies of severe COVID-19.These severe patients share similar phenotypes with patients suffering from autoinflammatory disorders like- adult onset still’s disease and familial mediterranean fever (Cavalli et al. 2020; Huet et al. 2020). Also, patients suffering from cytokine storm syndromes with hyperinflammations like- macrophage activation syndrome, haemophagocytic lymphohistiocytosis and chimeric antigen receptor T-cell (CART) mediated cytokine release syndrome share clinical manifestations with severe COVID-19 patients (Cavalli et al. 2020; Huet et al. 2020). As a result, various clinical trials with non-selective cytokine inhibition by glucocorticoids (dexamethasone) and selective targeted cytokine inhibition (blocking IL-1, IL-6, GM-CSF, etc.) are being pursued for managing COVID-19(https://www.covid-trials.org). Initially, the concept of involvement of IL-1 in the pathophysiology of COVID-19 was little sceptical and underappreciated, as IL-1 was not found to be highly activated in patients. IL-1 is a notoriously known cytokine, for its propensity toward degradation, makes it difficult to analyze from patient’s sample. But now, compelling evidences from different laboratories have shown IL-1 activation and NLRP3/AIM2 inflammasome involvement in the pathogenesis of the disease (Junqueira et al. 2021; Vora et al. 2021) with anakinra having a benefiting effect (Cavalli et al. 2020; Huet et al. 2020; Kyriazopoulou et al. 2021a, b; Vora et al. 2021).
Both dexamethasone and tocilizumab (anti-IL-6R), are powerful immunosuppressants known for excessive dampening of immune system leading to downscaling of Procalcitonin (PCT) and CRP levels – ensuing in probable downside of faulty diagnostic capacity detection of secondary bacterial infections (Kooistra et al. 2021). Hence, antibiotic usage and stewardship becomes skewed.
Targeted inhibitions are always preferred in comparison with non-selective inhibitions as it leads to lesser degree of immunosuppression with ensuing secondary infections (Hooftman and O’Neill 2021). Dexamethasone, being a NF-κB inhibitor, by IκBα activation (Auphan et al. 1995), broadly inhibits a wide array of NF-κB dependent pro-inflammatory cytokines like- IL-1, IL-2, IL-6, 1L-8, IL-18, TNF-α, CXCL1, CXCL10, Rantes, etc. (Adcock 2001; Hooftman and O’Neill 2021). The rise of mucormycosis events in India further substantiates the immunosuppression effects of corticosteroids, especially in diabetic patients (Hooftman and O’Neill 2021). More over, glucocorticoids being known to induce hyperglycemia by provoking insulin resistance and beta cell dysfunctioning could lead to exacerbating the comorbid diabetic condition (Suh and Park 2017).
Even, inhibitory effect of dexamethasone can partially be attributed to NLRP3 inflammasome inhibition (Hooftman and O’Neill 2021). More so, with IL-1 working upstream of IL-6 (Kyriazopoulou et al. 2021a), it perhaps makes a worthy approach to target IL-1 blocking for the diseased state by usage of anakinra (which is dual blocker of IL-1α and IL-1β). The recent SAVE-MORE trial guided by soluble urokinase plasminogen activator receptor ( suPAR levels ≥ 6 ng/ml), showed anakinra to have mortality benefits and less secondary infections- by inhibiting IL-6, CRP and lymphocyte counts, even with dexamethasone co-administration (Kyriazopoulou et al. 2021b). suPAR, a biomarker indicative of presence of alarmins like- neutrophil migration promoting calprotectin (S100A8/A9) and IL-1α, is activated earlier than CRP and IL-6 (Kyriazopoulou et al. 2021b). Interestingly, in the CAN-COVID trial, canakinumab (specific monoclonal antibody against IL-1β) failed to show survival benefits (Kyriazopoulou et al. 2021b). This can perhaps be explained by the necessity of IL-1α in the pathogenesis phenomena. IL-1α is known as one of the crucial cytokines liberated initially from lung necrotic cells, which further helps in amplifying the inflammatory loop (Gupta 2020a). With amplification, extended IL-1 family members like IL-36γ and IL-33 cytokines can be produced from the necrotic cells (Martin 2016). IL-36γ is known to inhibit immunoregulatory Treg cell development (Harusato et al. 2017), which could lead to exacerbation of the diseased state. Furthermore, IL-33 induces IL-10 production (Sattler et al. 2014) and enhanced IL-10 has been correlated with increasing IFN-γ producing CD4+/CD8+T cells and PD1+/Tim3+ population – ensuing in T cell exhaustion in severe COVID-19 patients (Lu et al. 2021). Hence, IL-1 can play a central role in upheavaling the immune system in severe patients.
With COVID-19 being characterized by hypercoagulability, IL-1α can play a contributory role to coagulation phenomena too- by itself getting thrombin activated and inducing platelet productions (Burzynski et al. 2019). Simultaneously, with complement factors known to be activated in COVID-19 (Ma et al. 2021) and also a priming agent for NLRP3 signaling (Niyonzima et al. 2020), the diseased state can be thought as an interplay between IL-1 and complement system. Interestingly, aberrent cytokine release with concurrent neurological defects are known bystander effects of CART therapy with IL-1/IL-6 production from monocytes contributing to it (Norelli et al. 2018). Intriguingly, tocilizumab failed to protect mice from neurological damages (meningeal inflammation), while anakinra protected mice both from cytokine release and neurotoxicity (Norelli et al. 2018). With COVID-19 patients known to manifest neurological symptoms and NLRP3 known to be implicated in neurological diseases like Alzheimer’s (Heneka et al. 2013)—blocking IL-1 can conceivably be more efficacious than IL-6 in managing COVID-19. Lastly, the cytokine release induced neurological defects can also shed some light in understanding the long COVID-19 pathology.
Hence, anakinra will perhaps have an edge over IL-6 and dexamethasone with more restrained and specific immunosuppressing capacity by taming the hyperinflammated and hypercoagulable states. The staggering 10 days half-life of tocilizumab in comparison with 4–6 h for anakinra, further substantiates it. More so, with neutrophil migration and cell death (IL-1α) contributing much to COVID-19 pathology (Gupta 2020a, b), suPAR can be a better early biomarker than non-specific markers (PCT/CRP) for COVID-19 progression.
Availability of data and materials
- IL-1 α/β/2/6/8/18/33/36:
Interleukin 1 alpha/beta /2/6/8/33/36.
Chimeric Antigen Receptor T-cell
Soluble urokinase plasminogen activator receptor.
Nod Like Receptor family pyrin domain containing 3
Absent in melanoma 2
Anti-Interleukin 6 receptor
Nuclear factor kappa-light-chain-enhancer of activated B cells
Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha
Tumor necrosis factor-α
C-X-C motif chemokine ligand 1/10
suPAR-guided Anakinra treatment for Validation of the risk and Early Management Of severe respiratory failure by COVID-19
Efficacy testing of canakinumab in patients hospitalized with severe COVID-1
Programmed Cell Death Protein 1
T cell immunoglobulin and mucin domain-containing protein 3
Adcock M (2001) Glucocorticoid-regulated transcription factors. Pulm Pharmacol Ther 14:211–219. https://doi.org/10.1006/pupt.2001.0283
Auphan N, DiDonata JA, Rosette C et al (1995) Immunosuppression by glucocorticoids: Inhibition of NF-kB Activity through Induction of IkB synthesis. Science 270:286–290. https://doi.org/10.1126/science.270.5234.286
Burzynski LC, Humphry M, Pyrillou K et al (2019) The coagulation and immune systems are directly linked through the activation of interleukin-1α by thrombin. Immunity 50:1033–1042. https://doi.org/10.1016/j.immuni.2019.03.003
Cavalli G, Luca GD, Campochiaro C et al (2020) Interleukin-1 blockade with high dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation : a retrospective cohort study. Lancet Rhematol 2:E325-331. https://doi.org/10.1016/S2665-9913(20)30127-2
Gupta R (2020a) Anakinra: a silver lining in COVID-19? Crit Care 24:598. https://doi.org/10.1186/s13054-020-03312-8
Gupta R (2020b) The double edged interferon riddle in COVID-19 pathogenesis. Crit Care 24:631. https://doi.org/10.1186/s13054-020-03337-z
Harusato A, Abo H, Ngo VL et al (2017) IL-36γ signaling controls the induced regulatory T cell-Th9 cell balance via NFκB activation and STAT transcription factors. Mucosal Immunol 10:1455–1467. https://doi.org/10.1038/mi.2017.21
Heneka MT, Kummer MP, Stutz A et al (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493:674–678. https://doi.org/10.1038/nature11729
Hooftman A, O’Neill LAJ (2021) Can NLRP3 inhibitors improve on dexamethasone for the treatment of COVID-19? Curr Res Pharmacol Drug Discov 2:100048. https://doi.org/10.1016/j.crphar.2021.100048
Huet T, Beaussier H, Voisin O et al (2020) Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheumatol 2:E393-400. https://doi.org/10.1016/S2665-9913(20)30164-8
Junqueira C, Crespo A, Ranjbar S et al (2021) SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release. Res Square. https://doi.org/10.21203/rs.3.rs-153628/v1
Kooistra EJ, van Berkel M, van Kempen NF et al (2021) Dexamethasone and tocilizumab treatment considerably reduces the value of C-reactive protein and procalcitonin to detect secondary bacterial infections in COVID-19 patients. Crit Care 25:281. https://doi.org/10.1186/s13054-021-03717-z
Kyriazopoulou E, Huet T, Cavalli G et al (2021a) Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis. Lancet Rheumatol 3:e690-697. https://doi.org/10.1016/S2665-9913(21)00216-2
Kyriazopoulou E, Poulakou G, Milionis H et al (2021b) Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial. Nat Med 27:1752–1760. https://doi.org/10.1038/s41591-021-01499-z
Lu L, Zhang H, Dauphars DJ et al (2021) A Potential Role of Interleukin 10 in COVID-19 Pathogenesis. Trends Immunol 42:3–5. https://doi.org/10.1016/j.it.2020.10.012
Ma L, Sahoo SK, Cano M et al (2021) Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection. Sci Immunol 6(59):eabh2259. https://doi.org/10.1126/sciimmunol.abh2259
Martin SJ (2016) Cell death and inflammation: the case for IL-1 family cytokines as the canonical DAMPs of the immune system. FEBS J 283:2599–2615. https://doi.org/10.1111/febs.13775
Niyonzima N, Bakke SS, Ida G et al (2020) Cholesterol crystals use complement to increase NLRP3 signaling pathways in coronary and carotid atherosclerosis. EBioMedicine 60:102985. https://doi.org/10.1016/j.ebiom.2020.102985
Norelli M, Camisa B, Barbiera G et al (2018) Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med 24:739–748. https://doi.org/10.1038/s41591-018-0036-4
Sattler S, Ling G-S, Xu D et al (2014) IL-10-producing regulatory B cells induced by IL-33 (BregIL-33) effectively attenuate mucosal inflammatory responses in the gut. J Autoimmun 50:107–122. https://doi.org/10.1016/j.jaut.2014.01.032
Suh S, Park MK (2017) Glucocorticoid-induced diabetes mellitus: an important but overlooked problem. Endocrinol Metab 32:180–189. https://doi.org/10.3803/EnM.2017.32.2.180
Vora SM, Lieberman J, Wu H (2021) Inflammasome activation at the crux of severe COVID-19. Nat Rev Immunol 21:694–703. https://doi.org/10.1038/s41577-021-00588-x
RG is very grateful to Dr Katherine Fitzgerald and Dr Douglas Golenbock (UMass Chan Medical School) for the initial insightful discussions. RG is also very thankful to Dr Rosane de Oliveira (University of Massachusetts Medical School), Dr Anubhab Nandy (Boston Children’s Hospital) and Dr Vijay Rathinam (University of Connecticut Health Centre) for supporting him with many literatures, which were not accessible to him, which eventually helped him writing the manuscript.
The study hasn’t received any funding as yet.
Ethics approval and consent to participate
Consent for publication
Yes, the clinical details of patients included in the study are all from published literatures. Hence, consents of participants are not included and applicable.
The author don’t have any competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Gupta, R. Could anakinra outmatch dexamethasone/tocilizumab in COVID-19?. Bull Natl Res Cent 46, 100 (2022). https://doi.org/10.1186/s42269-022-00781-5