key: cord-0853710-2fqicelj
authors: Bulat, Vedrana; Situm, Mirna; Azdajic, Marija Delas; Likic, Robert
title: Potential role of IL‐17 blocking agents in the treatment of severe COVID‐19?
date: 2020-07-05
journal: Br J Clin Pharmacol
DOI: 10.1111/bcp.14437
sha: 4ec98dacbf9ce8e4f02439279800fba06a69844d
doc_id: 853710
cord_uid: 2fqicelj

nan

Earlier this year, Zhe Xu and colleagues provided a detailed case report of a 50-year-old man with COVID-19 in the Lancet Respiratory Medicine journal. 1 This case is particularly interesting since it provides a detailed day-to-day account of the hospitalisation, laboratory parameters and histological findings in a patient who neither belonged to a very high-risk age group, nor did he have any other comorbidity. 2 The patient's assessment revealed an overactivation of T cells manifested by an increase in the Th17 subset of CD4+ T cells leading to increased production of IL-17 and IL-22 cytokines which in turn caused the cytokine release storm (CRS) with a rapid and severe deterioration of the patient's condition. 1 Pathologic postmortem lung analysis revealed a high number of Th17 lymphocytes in alveolar spaces.

Besides the referenced case report, there is emerging body of evidence supporting the role of IL-17 in the pathogenesis of severe COVID-19 disease, including two recent publications reviewing the immune response in patients with COVID-19, that further emphasise the Th17-type cytokine storm in pathogenesis of the disease. 3, 4 Wu and Yang highlighted the Th17 response in CRS of COVID-19 and proposed using fedratinib, a Janus kinase 2 (JAK2) inhibitor which blocks downstream cellular Th17 signalling pathway, in the treatment of CRS of COVID-19 patients. 3 However, in our view, JAK inhibition of intracellular enzymes would also be associated with significant disadvantages entailing unintended and/or off-target effects leading to difficulty in predicting JAK2 inhibitors' biological effects. 5 Since the increase in Th17 CD4+ T cells is also found in several inflammatory diseases, such as in severe plaque psoriasis, 6 To date, there have been three IL-17 blocking agents available: secukinumab, ixekizumab and brodalumab. 5 Secukinumab and ixekizumab are monoclonal IgG1 antibodies that bind specifically to IL-17A and that have been demonstrated to be very effective in the treatment of severe plaque psoriasis. 12 Both drugs have a quick onset of action, high efficacy, tolerability and a well-established safety profile which does not include a decrease in the lymphocyte count. 5 The substantial decrease in the total number of lymphocytes was found in patients with severe COVID-19, and this seems to facilitate viral replication. 13 In contrast to TNF-α inhibitors, IL-17 blocking agents are not associated with a decrease in lymphocyte count. 14 Brodalumab, a human monoclonal IgG2κ antibody against IL-17 receptor A (IL-17RA), was shown to be superior to placebo and ustekinumab for psoriasis treatment, due to complete blockade of key mediators of the T helper 17 pathway. 5 Brodalumab as an IL-17 receptor blocker could potentially offer improved efficacy; however, patient suicides reported during the AMAGINE trial involving brodalumab raised some concerns regarding the safety of this agent, even though causal relationship was not unequivocally demonstrated. 5 We believe that secukinumab, a fully human monoclonal antibody which exhibits significantly lower immunogenicity potential in patients with moderate-to-severe plaque psoriasis compared to ixekizumab (a humanised monoclonal antibody), would be best suitable for the treatment of severe COVID-19 patients. 15 infections. 17 Li et al. demonstrated that pandemic H1N1 influenza virus caused acute lung injury in an IL-17-dependent manner in mice. 18 They also reported that the response to pandemic H1N1 influenza virus in mice was improved by IL-17-blocking agents, which reduced disease duration, as well as cellular and fluid infiltrates. IL-17 blocking agents decreased pulmonary recruitment of inflammatory cells, cytokine production by T cells and the formation of lung oedema without preventing virus clearance in mice. 18 These broad beneficial effects support further the idea that IL-17 blocking agents might be tested as potential treatment in severe COVID-19 patients.

Tocilizumab, a recombinant human monoclonal IgG1 antibody that specifically binds to soluble and membrane-bound IL-6 receptors, has been shown to be effective in the treatment of severe COVID-19 by blocking IL-6 signalling and its proinflammatory response. 19, 20 Until now, several clinical trials have been registered in order to assess safety and efficacy of tocilizumab in the treatment of severe COVID-19 pneumonia in adult patients. 19, 20 Since IL-17 inhibitors and tocilizumab share the common Th17 signalling pathway, IL-17 blocking agents could also prove as safe and effective therapy for severe COVID-19. They might be even more effective than tocilizumab, since IL-17 precedes synthesis of potent proinflammatory cytokines IL-6 and TNF-α. Moreover, subcutaneous route of administration of IL-17 blocking agents could prove more convenient than intravenous administration of tocilizumab.

In the treatment of severe plaque psoriasis, secukinumab is administered subcutaneously in the dose of 300 mg once weekly during the first month of treatment, followed by a dose of 300 mg every 4 weeks. Ixekizumab is also administered subcutaneously 160 mg every 2 weeks during the first 3 months, followed by a dose of 160 mg every 4 weeks. The recommended brodalumab dose in the treatment of severe plaque psoriasis is 210 mg once weekly during the first 2 weeks of treatment, followed by a dose of 210 mg every 2 weeks administered subcutaneously.

F I G U R E 1 T helper 17 (Th17) cells are differentiated from naïve precursor T cells in response to coronavirus presentation, after costimulation by antigen presenting cells and transforming growth factor-β (TGF-β) secretion. Th17 cells produce interleukin-17A (IL-17A) causing wide spectrum cell activation (e.g., dendritic cells, endothelial cells and fibroblasts). IL-17 contributes to cytokine release storm by stimulating excessive and uncontrolled production of proinflammatory interleukins (e.g., IL-1β, IL-6 and IL-8), tumour necrosis factor-alpha, colony stimulating factors and chemokines. Secukinumab and ixekizumab are immunomodulators that block IL-17A and could be beneficial in therapy of severe COVID-19. Brodalumab is directed against interleukin-17 receptor A (IL-17RA), another potential target molecule in therapy of severe COVID-19. CCL20, chemokine CC motif ligand 20; CXCR2, CXC chemokine receptor 2; G-CSF, granulocyte colonystimulating factor; GM-CSF, granulocyte-macrophage CSF; IL, interleukin; R, receptor; Th17 cells, T helper 17 cells; Treg, regulatory T cells; TGF-β, transforming growth factor-β;TNF-α, tumour necrosis factor-alpha It is worth noting that IL-17 blocking agents have not yet been evaluated in clinical trials for severe COVID-19 and patients would not receive the same dosage as patients with severe plaque psoriasis.

Also, the timing of IL-17 blocking agent administration to severe COVID-19 patients would be crucial. It would perhaps be best to begin the treatment in the middle stage of CRS, when a significant increase in IL-6 levels is to be expected. 1, 21 While we currently do not have a vaccine or highly effective antiviral treatments for COVID-19, repurposing certain immunomodulators, such as IL-17 blocking agents, might help to prevent CRS in severe COVID-19 cases, thereby further improving patients' out- 

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TH17 responses in cytokine storm of COVID-19: an emerging target of JAK2 inhibitor Fedratinib

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Critical role of interleukin (IL)-17 in inflammatory and immune disorders: an updated review of the evidence focusing in controversies

Elevated plasma level of selective cytokines in COVID-19 patients reflect viral load and lung injury

Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed

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Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, exhibits minimal immunogenicity in patients with moderate-to-severe plaque psoriasis

Secukinumab demonstrates significantly lower immunogenicity potential compared to Ixekizumab

Critical role of IL-17RA in immunopathology of influenza infection

IL-17 response mediates acute lung injury induced by the 2009 pandemic influenza A (H1N1) virus

The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the perspectives of clinical immunologists from China

Tocilizumab treatment in COVID-19: a single center experience

The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality