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Rostamian A, et al. The application of anti-IL-6 agents can up-regulate the drug-metabolizing enzymes and transporters and reduce cytochrome P450 3A4 (CYP3A4) level [70], therefore drugs that are metabolized through CYP3A4 should not be administered by sarilumab. McGonagle D, et al. Noteworthy, IL-I receptor antagonist (IL-1 Ra) can modulate and prevent excessive IL-1-mediated inflammatory responses via binding to IL-1 receptors. Two main types of IL-6 inhibitors as monoclonal antibodies are available, targeting IL-6 (siltuximab) or the corresponding receptor (tocilizumab and sarilumab). IL-1 and IL-1 are synthesized as precursor proteins; hence specific cellular proteases are needed to cleave and form mature cytokines for interacting with cell surface receptors. Chinese clinical guidance for COVID-19 pneumonia diagnosis and treatment. 2008;181(8):5490500. With this evidence, a great deal of attention has been paid to dampening signaling pathways of inflammatory cytokines aiming to reduce inflammatory responses and mortality in patients suffering from COVID-19. Rondeau J-M, et al. Along with this, several inflammatory-associated transcription factors are activated, for instance, NF-kB, activator protein-1, JNK, p38, mitogen-associated protein kinases (MAPKs), extracellular signal-regulated kinases (ERKs), and interferon-regulating genes [88]. Anakinra in hospitalized patients with severe COVID-19 pneumonia requiring oxygen therapy: results of a prospective, open-label, interventional study. California Privacy Statement, In addition, B-cells, T-cells, and fibroblasts can synthesize TNF-. Google Scholar. Identifying the underlying mechanisms can aid in developing therapeutic strategies and speed up recovery.
Li CK, et al. This disease leads to pneumonia infection named coronavirus disease 2019 (COVID-19), posing an enormous threat to global health [1]. Ann Rheum Dis. Read Online Crit Care Med Soc Crit Care Med. The mechanism of actions of these antagonists is based on binding to their cognate ligands such as sTNF or tmTNF, and for etanercept, by binding to LT3 and LT2 and blocking downstream cascades. Since then, it has been rapidly spreading worldwide and becoming a public health concern worldwide. Virology Journal 2020;395(10229):10334. 2020;2(6):e32531. All patients were administered tocilizumab. efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. 
Wu D, Yang XO. Google Scholar. MedRxiv; 2020. Elevated plasma levels of selective cytokines in COVID-19 patients reflect viral load and lung injury. Covid-19 autopsies, Oklahoma, USA. Autoimmun Rev. 2021;3(4):e25361. Numerous studies have assessed the tolerability and efficacy of sarilumab in patients suffering from RA. Infect Dis Poverty. Besides, affected patients on anti-TNF treatment face a better outcome [125]. 2021;181(1):2431. PubMed In other words, upon binding IL-6 to its receptor, the complex interacts with gp130, resulting in dimerization and activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Based on recent studies, it was strikingly shown that the level of inflammatory cytokines is increased in COVID-19. PubMed
In addition, there was a strong linear association between severe lung injury and the level of 15 cytokines including, IFN-, IFN-2, IL-1ra, IL-2, 4, 7, 10, 12, and 17, as well as chemokines such as IP-10, macrophage colony-stimulating factor (M-CSF) and G-CSF. In addition, it has been shown that using IL-6 inhibitors in autoimmune conditions increases the risk of severe infections and enhances the level of blood transaminase. Interleukin-6 as a Potential Predictor of COVID-19 disease severity in hospitalized patients and its association with clinical laboratory routine tests. Fleischmann RM, et al. Expert Opin Biol Ther. PubMed Central Yang X, et al. Growing evidence has demonstrated the efficacy of tocilizumab therapy in COVID patients [62]. F1000Research. Katia et al. TNF biology, pathogenic mechanisms and emerging therapeutic strategies.
TNF is initially synthesized as a bioactive transmembrane precursor protein with a molecular weight of 26kDa. Five specific inhibitors against TNF were initially approved for clinical applications, including infliximab, adalimumab, golimumab, certolizumab, and etanercept. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Patients received a high dose of anakinra at a dose of 5mg/kg twice daily. 2020;52(5):7313. Cytokine. Interleukin-6 and its receptors: a highly regulated and dynamic system. In the case of ACE2 receptors, it is hypothesized that the COVID-19 first attacks several organs expressing ACE2 receptors, such as the heart, brain, vessels, liver, kidney, and, more importantly, lung [25]. Int J Infect Dis. Nature. Despite the remarkable properties of canakinumab, some reports have stated hematological alterations such as leukopenia, thrombocytopenia, and neutropenia in treated patients. This is an FDA-approved drug used to treat patients suffering from multicentric castleman disease (MCD) [75].
reported that overproduction of IL-6 levels could enhance IL-17-producing Th17 cells.
Raheleh Farahzadi and Tohid Ghasemnejad contributed equally to this work, Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614731, Iran, Soheila Montazersaheb,Mohammad Saeid Hejazi,Vahideh Tarhriz&Tohid Ghasemnejad, Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran, Food and Drug Safety Research Center, Tabriz University of Medical Science, Tabriz, Iran, Novin Medical Genetic Laboratory, Mazandaran University of Medical Science, Sari, Iran, Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614731, Iran, You can also search for this author in At an elevated level of IL-6, the buffering capacity of sgp130 is not enough to overcome this; thereby, IL-6 mediated inflammatory responses are initiated. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia, Italy. 2021;9:399405. Lancet Respir Med. Hirano T, Murakami M. COVID-19: a new virus, but a familiar receptor and cytokine release syndrome. Anakinra is a recombinant interleukin-1 receptor antagonist, which blocks the signaling pathways of both IL-1 and IL-1. have surveyed the effect of canakinumab in COVID-19 disease. CAS Part of 2019. https://doi.org/10.1172/jci.insight.123158. Altogether, it is hypothesized that IL-17 blockade is an immunologically plausible approach to improve the aberrant immune responses in COVID-19 and hinder ARDS-associated mortality [119]. However, Franois-Xavier Lescure et al. Proc Natl Acad Sci. Crit Care. J Immunol. Eur J Intern Med. Moreover, the hyperinflammatory status was improved by reducing CRP levels [98]. Collectively, the uncontrolled release of cytokines may cause multi-organ damage in COVID-19 patients. A substantial reduction in the count of white blood cells, platelets, and neutrophils was detected, accompanied by an increment in the lymphocyte count in canakinumab-treated patients. By using this website, you agree to our Neurocrit Care. CRS is one of the possible events for the progressive and severe forms of COVID-19 and its mortality. In a retrospective study, Xu et al. Privacy Lancet Rheumatol. Eur J Immunol. Katia F, et al. On day 29, this placebo-controlled trial revealed no significant differences in survival rate between sarilumab receiving patients and placebo one, implying the ineffectiveness of sarilumab in severe conditions [73]. Ye Q, Wang B, Mao J. Cytokine storm in COVID-19 and treatment. C Anakinra and Canakinumab antagonize the IL-1 mediated inflammation via binding to corresponding receptors. CAS These clinical effects are more common in patients with severe forms of COVID-19 disease [27]. Wang Y, et al. Gremese E, et al. Rev Med Virol. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. 2018;110:23742. Preliminary predictive criteria for COVID-19 cytokine storm.
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An overview of the literature indicates that IL-6, IL-2, IL-7, IL-10, granulocyte colony-stimulating factor (G-CSF), IFN- , inducible protein (IP)-10, TNF-, MCP-1, macrophage inflammatory protein (MIP)-1 play a crucial role in the pathogenesis of COVID-19 [40]. Hum Vaccines Immunotherap. 2020;38(1):19. 2020;13:673. Immunotherapy. In other words, ARDS is a consequence of CRS and leads to respiratory epithelium damage [30]. The serum level of CRP was declined, too. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial. Lancet Respir Med. Open Biol. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. In a prospective, open-label, interventional trial, anakinra was evaluated in hospitalized patients with COVID-19 who required invasive mechanical ventilation. Caricchio R, et al. SM as well as RF as main colleagues had main contribution in design, and manuscript writing; RF as executive of the project involved in the approval of the project, and manuscript writing.
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Moreover, IL-6 showed the ability to down-regulate drug-metabolizing enzymes and corresponding transporters via binding to the cognate receptors. Immunity. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 2020;34:106271.
A potent and highly selective inhibitor such as the A17 prodomain can be used in the severe form of COVID-19 with CRS [81, 82]. Ucciferri C, et al. Patel S, Wadhwa M. Therapeutic use of specific tumour necrosis factor inhibitors in inflammatory diseases including COVID-19. COVID-19 infection: an overview on cytokine storm and related interventions, https://doi.org/10.1186/s12985-022-01814-1, https://doi.org/10.1172/jci.insight.123158, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/. Manage cookies/Do not sell my data we use in the preference centre. In this situation, no signaling has occurred even at a high level of IL-6 [72]. SSRN J. In addition to the mature form, the precursor of IL-1 is also active. BioRxiv; 2020. efficacy of tocilizumab in patients hospitalized with Covid-19. CRS is an acute and uncontrolled inflammatory response characterized by multi-organ dysfunction and diverse clinical manifestations such as fever [3]. Liu L, et al. All these events lead to irreversible alteration via pulmonary fibrosis [123]. 2004;72(8):44105.
Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH 17 cells. Am J Respir Crit Care Med. 2020;323(11):10619. IL-6 binds to the soluble or membrane-bound receptor, forming a complex with ubiquitously expressed gp130 protein. It is well established that TNF- has a fundamental role in almost acute inflammatory responses as an amplifier and even as a coordinator of inflammation. In addition to its effect on IL-17, fedratinib may also inhibit GM-CSF activity, as GM-CSF can interact with JAK2 to mediate signaling. Article Overview of the IL-1 family in innate inflammation and acquired immunity. sgp130Fc is an exclusive inhibitor of IL-6 trans-signaling. Besides, recent studies suggest that excessive production of some cytokines, such as IL-6 may be the leading cause of inflammatory response in COVID-19 [19]. Indeed, the CRS is closely associated with fatal outcomes in critically severe COVID-19 patients. 1D) [113]. Dinarello CA. Anakinra could prevent the requirement of mechanical ventilation and mortality in 25% of treated subjects compared to 37% of historical patients, conferring the effectiveness of this therapeutic intervention in the severe form of COVID-19 [100]. Anakinra for severe forms of COVID-19: a cohort study. Interleukin-17A (IL-17A), a key molecule of innate and adaptive immunity, and its potential involvement in COVID-19-related thrombotic and vascular mechanisms. 2021;18(6):1356. 2006;65(8):100612. ACE2, as a transmembrane receptor, is mainly found in type II alveolar cells, bronchial epithelial cells, myocardial cells, oesophagus epithelial cells, liver cholangiocytes, neurons and glia, stomach, cholangiocytes, adipose tissue, pancreatic exocrine glands and islets, renal tubules, stomach epithelial cells, ileum, rectum and many other sites [34]. 
Indeed, TCZ as a competitive antagonist for soluble and membrane IL-6R, inhibits both cis- and trans-signaling pathways, thus reducing inflammatory responses [59]. As explained in previous sections, there is a life-threatening-associated cytokine storm in the advanced stage of COVID-19 disease, leading to diffuse alveolar epithelial and endothelial injury in the lung of affected patients [93].
Nephrol Dial Transplant. As discussed above, the soluble form of IL-6R is generated by the enzymatic activity of ADAM17 (Fig. Given the profound role of excessive TNF in the development, pathogenesis, and poor outcome of COVID-19, blockade of TNF offers a clinically effective intervention in this regard.
Kim B, et al.
It can be produced by stromal, almost all immune cells, and other cells such as endothelial cells, fibroblasts, keratinocytes, and tumor cells. To release the soluble active TNF protein (17kDa), it can undergo proteolytic cleavage by the TNF--converting enzyme, ADAM17. Yang M. Cell pyroptosis, a potential pathogenic mechanism of 2019-nCoV infection. COVID-19 gone bad: a new character in the spectrum of the hyperferritinemic syndrome? Park MD. 2021;40:90519. Cytokines and COVID-19: friends or foes? Tocilizumab (TCZ) is a recombinant humanized anti-IL-6R monoclonal antibody that can inhibit cytokine storms through blockade of IL-6 signaling (Fig. Lancet Respir Med. It is well documented that the release of IL-1 mainly depends on the expression of the (NLR family pyrin domain containing 3) NLRP3 inflammasome, which controls the maturation of IL-1. Pearce L, Davidson SM, Yellon DM. JAMA Intern Med. 2021;9:52232. Villaescusa L, Zaragoz F, Gayo-Abeleira I, Zaragoz C. A New Approach to the Management of COVID-19. Cytokine storm is defined as acute overproduction and uncontrolled release of pro-inflammatory markers, both locally and systemically. In: Mackiewicz A, Kurpisz M, eromski J, editors. Based on this evidence, the efficacy of IL-1 blockade may be related to endotheliopathy of COVID-19 to secrete IL-1. Commission CNH. Growing evidence revealed the crucial role of IL-1 family members in inflammation. Dinarello CA. 2020;27:100553. J Med Virol. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. 2017;137:8292. Chen J-J, et al. Nat Immunol.
Th1 cells primarily regulate the adaptive immune response through cytokine production, and cytotoxic T-lymphocytes (CTLs), known as CD8+ T cells, kill virus-infected cells [112]. Aghagoli G, et al. Activation of Th17 cells can lead to the secretion of multiple inflammatory cytokines. 2014;15(12):112633. Cytokine. IL-17 is a member of pro-inflammatory cytokines secreted by Th17 cells, which has a crucial role in the recruitment of monocytes and neutrophils to the site of infection. Relying on this, cis-activation of IL-6 causes several effects on immune systems in terms of the acquired (B and T cells) and innate (macrophages, neutrophils, and natural killer cells) systems, developing CRS [51]. Cavalli G, et al. With these backgrounds, a vast range of anti-inflammatory approaches is being developed to dampen CRS and save the life of affected patients.
2006;8(2):16. A recent study showed the effectiveness of sarilumab in improving the symptoms of respiratory functions by decreasing oxygen demand by up to 30% [45].
This virus affects the respiratory tract and usually leads to pneumonia in most patients and acute respiratory distress syndrome (ARDS) in 15% of cases. Infect Immun. Growing evidence is being documented on the possible role of the pro-inflammatory cytokines in COVID-19 pathogenesis and related complications [5]. Importantly, ARDS seems to be the most serious complication of COVID-19, with a high mortality rate. Ramrez J, Caete JD. 1B).
However, a crucial question arises regarding the therapeutic efficacy of IL-1 blockade, and whether IL-1 inhibition may confer a benefit over standard care management. J Clin Transl Hepatol. Springer; 2017.
Anakinra for the treatment of rheumatoid arthritis: a safety evaluation. 2021;80(1):8895. Davis CC, Shah KS, Lechowicz MJ.
In addition to standard care, anakinra is administered at a dose of 100mg twice daily for 3days which is followed by 100mg once daily for 7days. Diao B, et al. Furthermore, inhibition of ADAM-17-mediated cleavage may potentially suppress IL-6-trans-induced inflammation. et al. Terms and Conditions, Pathophysiology of COVID-19-associated acute respiratory distress syndromeauthors reply. Given the swift outbreak of this disease, China National Health Commission has quickly approved tocilizumab for the treatment of critical patients affected by COVID-19 [61]. This article will address the current understanding of cytokines-induced alterations in COVID-19, focusing on interleukin (IL)-6, IL-1, IL-17, and tumor necrosis factor (TNF). Furthermore, the superior safety of anakinra is attributed to lower opportunistic infections and short half-life through the rapid clearance compared to the prolonged half-life of IL-6 inhibitors (23weeks) [109]. 2021;103:28896. Antivir Res.
According to their findings, canakinumab therapy considerably improved respiratory dysfunction and blood parameters compared to standard treatment. 2020;92(11):236870. Natl Sci Rev. Following this process, phosphorylation and activation of the JAK/STAT3 pathway occurred [55]. IL-6: regulator of Treg/Th17 balance. (2015) evaluated 48 cytokines in the blood plasma of COVID-19 patients.
Growing studies have indicated that elevated levels of IL-6 are associated with CRS [45]. ADAM17 inhibition may exert a protective effect on COVID-19. Moreover, IL-17 can induce secretion of G-CSF, GM-CSF, and various chemokine ligands, for instance, CXCL1, CXCL2, and CXCL8. IL-6 trans-signaling pathway is positively correlated with disease-induced inflammation. Colafrancesco S, et al. Addressing the detrimental activities of the trans-mediated pathway of IL-6, selective blockage of this pathway can prevent inflammatory responses. Immunol Rev. J Med Virol. JCI Insight. Verdecchia P, et al. CAS Both have high efficacy, tolerability, and a good safety profile, without decreasing the lymphocyte count. Google Scholar. Acute kidney injury is also prevalent in ICU admitted COVID-19 patients due to the activation of the innate and adaptive immune systems and inflammation caused by virus infiltration and cytopathic effects [29]. On the other hand, an IL-1 receptor antagonist (IL-1Ra) can limit inflammatory reactions and tissue damage during ARDS. 2013;2(1):15.
Raheleh Farahzadi or Tohid Ghasemnejad. Bradley J. TNF-mediated inflammatory disease. Provided by the Springer Nature SharedIt content-sharing initiative. In a prospective study in Italy on 100 patients with severe COVID-19, two-dose administration of TCZ every 12h could improve the respiratory condition in a significant manner in 77 patients within 10days. Given the broad expression of gp130 in most cells and subsequent activation by the IL-6/sIL-6R complex, a control mechanism is needed to avert IL-6- mediated inflammatory response under steady-state conditions. J Tianjin Univ Tradit Chin Med. It is crucial to note that the reduction of T cells is correlated with the severity of COVID-19 in affected patients. In this case, creating a hypercoagulable state leads to the occlusion of cerebral vessels and brain damage.