4.1 IL-6 Receptor Inhibitors
Both tocilizumab and sarilumab are humanised anti-IL-6 receptor monoclonal antibodies used for the treatment of moderate – severe rheumatoid arthritis, whereas siltuximab is a chimeric, human-mouse anti-IL-6 receptor monoclonal antibody used for treatment of Multicentric Castleman’s disease (MCD) (Deisseroth et al., 2015; National Institute for Health and Care Excellence, 2020c). Due to their long half-life, IL-6 inhibitors do not need to be taken daily; however, given that they are currently indicated for chronic diseases, patients receive IL-6 inhibitor treatments for life or until treatment failure (Janssen Biotech Inc; Roche Pharma; Sanofi-Aventis).
Clinical trials to assess the efficacy and safety of tocilizumab, sarilumab and siltuximab for the treatment of the inflammatory phase of COVID-19 are ongoing. Whilst the exact dosing regimens vary between trials, COVID-19 patients will be receiving a single or short course intravenous infusion or subcutaneous injection of the IL-6 inhibitor (clinical trial identifiers NCT04317092, NCT04315298, NCT04327388, NCT04330638, NCT04322188).
Due to their similarity, it is not surprising that tocilizumab, sarilumab and siltuximab have comparable safety profiles. Thus far, evidence from clinical trials in patients with rheumatoid arthritis and MCD or post-marketing have revealed that IL-6 inhibitors are generally well-tolerated. Participants were enrolled on these trials for a minimum of 6 months and in some cases up to 24 months. Individuals with diabetes, a history of recurrent infection, age ≥ 65 and corticosteroid use have been shown to be at an increased risk of developing a more serious infection following IL-6 inhibitor use (Jones et al., 2010). Whilst adverse reactions were typically seen following chronic IL-6 inhibitor treatment, the potential for COVID-19 patients to develop an adverse drug reaction (ADR) following a single or small number of doses should not be ignored.
The most common infections reported in patients receiving anti-IL6 therapy include skin infections, respiratory infections, urinary tract infections and in some cases, opportunistic infections ranging from tuberculosis to herpes (Emery et al., 2008; Emery et al., 2019; R. Fleischmann et al., 2017; R. M. Fleischmann et al., 2013; M. C. Genovese et al., 2015; Mark C Genovese et al., 2008; M. C. Genovese et al., 2019; Hoshi et al., 2012; Huizinga et al., 2014; Janssen Biotech Inc, 2019; Jones et al., 2010; Kameda et al., 2020; McCarty & Robinson, 2018; Pawar et al., 2019; J. S. Smolen et al., 2008; Tanaka et al., 2019; Weinblatt et al., 2013). Neutropenia has also been reported with all 3 drugs when tested for their intended therapeutic use, and in some trials, this led to patient discontinuation (Emery et al., 2008; R. Fleischmann et al., 2017; R. M. Fleischmann et al., 2013; M. C. Genovese et al., 2015; Mark C Genovese et al., 2008; Huizinga et al., 2014; Janssen Biotech Inc, 2019; Jones et al., 2010; J. S. Smolen et al., 2008). Absolute neutrophil count (ANC) must be monitored every 4 – 8 weeks and in those who develop an ANC < 0.5 x 109/L, treatment must be discontinued (National Institute for Health and Care Excellence; Roche Pharma; Sanofi-Aventis). Gastrointestinal manifestations (upper abdominal pain, mouth ulceration and nausea) have also been reported with IL-6 inhibitors. A systematic review and meta-analysis of 35 COVID-19 studies found that 15 % of patients experienced gastrointestinal disturbance manifested as vomiting, diarrhoea and loss of appetite. This has been postulated to be due to the expression of ACE2 on gastrointestinal epithelial cells (Mao et al., 2020; Qi, Qian, Zhang, & Zhang, 2020). Therefore, differentiating between COVID-19-induced gastrointestinal disorders and those evoked by IL-6 therapy may present a challenge in terms of causality and the need to modify or stop therapy. Increases in lipid profiles (total cholesterol, low-density lipoprotein, high-density lipoprotein and triglycerides) have also been reported in patients receiving IL-6 inhibitors as either monotherapy or combination therapy (Emery et al., 2008; R. M. Fleischmann et al., 2013; M. C. Genovese et al., 2015; Mark C Genovese et al., 2008; M. C. Genovese et al., 2019; Huizinga et al., 2014; Janssen Biotech Inc, 2019; Jones et al., 2010; Kameda et al., 2020; J. S. Smolen et al., 2008; Tanaka et al., 2019). However, the incidence of major cardiovascular events was infrequent, and lipid elevation resolved with statin therapy (M. C. Genovese et al., 2015; M. C. Genovese et al., 2019).
Tocilizumab is associated with an increased risk of hepatotoxicity, usually manifested as an asymptomatic rise in ALT (Anger et al., 2017; Drepper, Rubbia-Brandt, & Spahr, 2013; R. M. Fleischmann et al., 2013; Jones et al., 2010; Mahamid, Mader, & Safadi, 2011; Maini et al., 2006; Nishimoto et al., 2009; Pawar et al., 2019; J. S. Smolen et al., 2008). Liver injury has also been reported with a liver biopsy from a female patient who had taken tocilizumab for a month revealing focal necrosis of hepatocytes with steatosis and early fibrosis (Mahamid et al., 2011). COVID-19 also has effects on the liver, and again causality assessment may be difficult (Guan et al., 2020). The prescribing instructions for tocilizumab and sarilumab indicate that liver function tests are required every 4 – 8 weeks following treatment commencement and then every 3 months thereafter (Roche Pharma; Sanofi-Aventis). If liver enzymes are 1 -3 x ULN, the dose of tocilizumab and sarilumab can be reduced until ALT or AST have normalised and then treatment resumed at the therapeutic dose. Where laboratory findings are > 3 – 5 x ULN, treatment with IL-6 inhibitors must be paused and then recommendations for 1 – 3 x ULN followed. If elevations persist or are > 5 x ULN, tocilizumab and sarilumab treatment must be discontinued immediately (Roche Pharma; Sanofi-Aventis). Whilst sarilumab and siltuximab are associated with abnormalities in liver function tests, they are typically short-lived and asymptomatic (LiverTox, 2016, 2017b). Pre-existing liver disease can worsen symptoms of DILI, and in some cases increase susceptibility (David & Hamilton, 2010).
Tocilizumab, sarilumab and siltuximab are expected to undergo metabolism via catabolic pathways and not CYP450 processes (McCarty & Robinson, 2018). Therefore, due to the lack of hepatic metabolism, it is assumed that the PK of the IL-6 inhibitors will not be altered in patients with pre-existing liver disease (Abou-Auda & Sakr, 2010). However, tocilizumab, sarilumab and siltuximab have been shown to restore and improve CYP levels (Janssen Biotech Inc, 2019; Roche Pharma, 2013; Sanofi-Aventis, 2017). This is of particular importance as CYP levels may remain elevated following treatment discontinuation due to the long half-life of the compounds. Therefore, this may be a consideration for further evaluation for any dosing adjustment requirements if patients are taking medication that are metabolised by CYP enzymes.