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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 11  |  Issue : 6  |  Page : 280-283

Tolerability of Sarilumab – An anti-interleukin-6 receptor monoclonal antibody is controversial for the management of COVID-19


1 Department of Pharmacy Practice, SRM College of Pharmacy, SRM Institute of Science and Technology, Chengalpattu, Tamil Nadu, India
2 Department of Pharmacy Practice, Sri Ramachandra Faculty of Pharmacy, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India

Date of Submission21-Jul-2021
Date of Decision10-Oct-2021
Date of Acceptance15-Nov-2021
Date of Web Publication31-Dec-2021

Correspondence Address:
Dr. Kiran Kumar Rathinam
Department of Pharmacy Practice, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu - 603 203, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmrp.cmrp_71_21

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  Abstract 


The emerging upsurge of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) has resulted in a global pandemic which originated in Wuhan city, China. The complicated virology of SARS CoV-2 makes it difficult to evaluate the therapeutic management for this infection. Drug repurposing is been considered in the management of novel coronavirus. Sarilumab, a monoclonal antibody, is being considered in the management of SARS CoV-2 infection, because it binds to both membrane-bound and soluble human interleukin 6 (IL-6) Ra, thereby blocking both IL-6 canonical and trans-signalling pathways. In this study, we tried to evaluate the reasons why Sarilumab is a not suitable option for treating novel coronavirus.

Keywords: COVID-19, cytokine release syndrome, interleukin 6, monoclonal antibody, sarilumab


How to cite this article:
Abraham JJ, Michelle I J, Shevaani S A, Rathinam KK, Rajanandh MG, Mahalingam VT. Tolerability of Sarilumab – An anti-interleukin-6 receptor monoclonal antibody is controversial for the management of COVID-19. Curr Med Res Pract 2021;11:280-3

How to cite this URL:
Abraham JJ, Michelle I J, Shevaani S A, Rathinam KK, Rajanandh MG, Mahalingam VT. Tolerability of Sarilumab – An anti-interleukin-6 receptor monoclonal antibody is controversial for the management of COVID-19. Curr Med Res Pract [serial online] 2021 [cited 2022 Jan 16];11:280-3. Available from: http://www.cmrpjournal.org/text.asp?2021/11/6/280/334581



In early December 2019, the first case of pneumonia of unknown origin was reported in Wuhan, China. The pathogen was recognised as a novel-enveloped RNA beta coronavirus, which has been then named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is an enveloped, single-stranded RNA beta coronavirus, similar to SARS-CoV-1 and Middle East Respiratory Syndrome coronavirus (MERS).[1] Considering the past treatment experience with SARS and MERS, many efforts in developing vaccines and treatment are being undertaken. Develop a new drug takes a long time and may not be of immediate help in the current situation. The drugs (already tested in humans) which are in use for other indications may be tried as an immediate treatment for COVID-19. The potentially repurposing drugs include (a) Lopinavir/ritonavir, an antiretroviral protease inhibitor (b) remdesivir, which is an adenosine nucleotide analogue with broad-spectrum antiviral activity (c) chloroquine and hydroxychloroquine and aminoquinolones (d) ribavirin and guanosine analogue (e) favipiravir, an RNA-dependent RNA polymerase inhibitor, (f) monoclonal antibodies such as tocilizumab, sarilumab and IL-6 inhibitor.[2] All these drugs have shown promising results in their in vitro study and there are ongoing clinical trials, to find their safety and efficacy in treating against SARS-CoV-2.

Sarilumab is a subcutaneously administered human monoclonal antibody directed against IL-6R. IL-6 is a pleiotropic proinflammatory cytokine produced by innate immune cells such as monocytes, macrophages, mesenchymal, endothelial cells and fibroblasts, after the recognition of pathogen-associated molecular patterns and damage-associated molecular patterns.[3] It is widely involved in the regulation of immune and inflammatory responses, such as migration and activation of T-cells, stimulation of haematopoietic precursor cell proliferation and differentiation and induction of immunoglobulin secretion.[4]

IL-6 is an important member of the cytokine network and plays a central role in cytokine release syndrome (CRS). SARS-CoV-2 initiates the CRS by binding to the alveolar epithelial cells, where the virus activates the innate immune system and adaptive immune system, resulting in the release of a large number of cytokines, including IL-6 and IL-1b through the toll-like receptors which is a mediator of lung inflammation, fever and fibrosis.[5] CRS is the most severe adverse effect induced by SARS COV 2 which induces the activation of bystander cells to release massive amounts of interferon γ (IFN-γ) and tumour necrosis factor-α (TNF-α), which facilitate the activation of innate immune cells, including macrophages and endothelial cells, to secrete IL-6 and other inflammatory mediators.[6] Hence, IL-6 inhibition would potentially diminish the detrimental immune response caused by SARS-CoV-2.

The purpose of targeting the IL-6 receptor can further be justified by the fact that COVID-19 has some similarities in the clinical progression of cases in acute respiratory distress syndrome, acute cardiac injury and acute kidney disease where IL-6 seems to play a key role as it is markedly elevated along with granulocyte-macrophage colony-stimulating factor, IFN-γ, IL-8, IL-10, IL-2 and TNF-α.[7],[8] These pro-inflammatory mediators also mediate extensive pulmonary pathology, which lead to massive infiltration of neutrophils and macrophages, diffuse alveolar damage with the formation of hyaline membranes and diffuse thickening of the alveolar wall. In deceased patients, spleen atrophy and lymph node necrosis were also observed, indicative of immune-mediated damage.[2]

Sarilumab binds with both membrane-bound and soluble human IL-6Ra, thereby blocking both IL-6 canonical and trans-signalling pathways.[9] Consequently, it interrupts the cytokine-mediated inflammatory signalling cascade, inhibits CRS and also blocks IL-6-induced cellular responses such as cell proliferation[1] [Figure 1]. Moreover, many studies suggest that treatment with Sarilumab showed effective clinical results in suppressing the inflammatory processes by the blockade of IL-6 receptors. Therefore, Sarilumab was proposed to be an effective treatment in severe patients of COVID-19 to abate the inflammatory cytokine storm and reduce mortality.
Figure 1: Mechanism of Sarilumab targeting soluble forms of the interleukin-6 receptor

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Although Sarilumab has established promising results in clinical trials and the role of inhibition of IL-6R in the treatment of COVID-19 is evident, the use of Sarilumab is still a debatable choice. Several studies have reported serious adverse events associated with the use of Sarilumab. In MONARCH and KAKEHASI trials, a higher incidence of infections was observed in the Sarilumab-treated group.[10],[11] Similar conclusions were also reported from various clinical studies which indicated serious infections as the most common treatment-emergent adverse event.[12] The common infections and infestations reported as treatment emergent adverse event in the patients included upper respiratory infections, urinary tract infections, nasopharyngitis and oral herpes. An immunosuppressant like Sarilumab was also found to increase the risk of reactivation of latent infections in the patients. Moreover, researchers have concluded that Sarilumab should not be administered to patients if they have Chronic infection, history of serious opportunistic infections, human immunodeficiency virus infection, tuberculosis or underlying conditions that may predispose them to infections. Zhou et al. have highlighted that 50% of the study population affected with COVID have experienced secondary infections.[13] The use of Sarilumab in COVID-19 may further exacerbate the conditions of the patients, considering the possibility of secondary infections and the risk of reactivation of latent infections associated with Sarilumab treatment.

Sarilumab is also known to induce neutropenia in the patients by the decline in the levels of neutrophils observed after the treatment initiation as reported in several clinical studies [Table 1].[10],[12],[14],[15],[16],[17],[18] Furthermore, Sarilumab treatment had to be discontinued in some patients due to severe neutropenia. In addition to this, thrombocytopenia is also associated with the initiation of Sarilumab therapy.[10],[11] Consequently, various studies suggest restricting the use of Sarilumab in patients with an absolute neutrophil count <1 × 10^9 cells/L or those with a platelet count <50 × 10^9 cells/L.[19] Many epidemiological studies indicate that the values of these parameters in COVID-19 patients are closer to the threshold range [Table 2].[20],[21],[22],[23] Hence, Sarilumab therapy may further deteriorate the health condition of COVID patients and may also render them vulnerable to secondary infections.
Table 1: Evidence of clinical trial data showing neutropenia with initiation of sarilumab

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Table 2: Evidence of laboratory findings of patients infected with COVID-19

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A higher incidence of transaminase elevations was associated with Sarilumab therapy. Several studies have recommended not to initiate Sarilumab treatment in patients with elevated transaminases, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <1.5 × ULN. Although epidemiological studies show normal levels of ALT in COVID patients, some percentage of the population was reported to have elevated ALT levels which pose a potential risk for the treatment initiation.

Sarilumab was proposed to have therapeutic potential in the management of SARS CoV-2 infection to reduce mortality; however, it lacked significant clinical improvement in hospitalised COVID-19 patients. Despite having a good safety profile, considering the higher incidences of infection, neutropenia and ALT elevation associated with the therapy, Sarilumab may not be an ideal choice for the treatment of COVID-19 as the risks outweigh the benefits.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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