4.2 IL-1 Receptor Inhibitors
Anakinra is a 17 kD, recombinant human IL-1 receptor antagonist that blocks the activity of pro-inflammatory cytokines IL-1α and IL-1β (Cawthorne et al., 2011; Dinarello, Simon, & van der Meer, 2012). Anakinra is primarily used in combination with methotrexate for reducing the symptoms and slowing the progression of joint damage in rheumatoid arthritis (National Institute for Health and Care Excellence, 2020a). It is also used for rare inflammatory conditions such as Cryopyrin-associated periodic syndromes and Still’s disease (National Institute for Health and Care Excellence, 2020a). It is administered via subcutaneous injection and is supplied as a single-use, pre-filled syringe containing 100 mg/0.67 mL (Swedish Orphan Biovitrum Ltd, 2007). Rheumatoid arthritis patients and those with Still’s disease and a body weight > 50 kg must be administered 100 mg anakinra, while patients with Still’s disease with a body weight < 50 kg should have weight-based dosing starting at 1-2 mg/kg (Swedish Orphan Biovitrum Ltd, 2007). The recommended starting dose for patients with Cryopyrin-associated periodic syndromes is 1-2 mg/kg. If tolerated, the dose can be increased to 3-4 mg/kg to a maximum of 8 mg/kg (Swedish Orphan Biovitrum Ltd, 2007). Anakinra has a short terminal half-life of approximately 4 -6 hours and so must be administered daily, preferably at the same time each day (Amgen Inc., 2001). Anakinra is currently not licensed for intravenous administration or treatment of sHLH but its use is endorsed by clinicians, where intravenous infusion, as opposed to subcutaneous injection, can achieve quicker and greater maximal plasma concentrations (Carter, Tattersall, & Ramanan, 2018; La Rosée et al., 2019; Mehta, Cron, Hartwell, Manson, & Tattersall, 2020).
Thus far, 16 clinical trials have been registered to assess the use of anakinra in patients with severe COVID-19. Additionally, 2 recent studies have reported positive outcomes with anakinra in COVID-19 induced acute respiratory distress syndrome (Cavalli et al., 2020; Clinical Trials.gov, 2020c; Huet et al., 2020). Participants were dosed 100 mg twice daily subcutaneously for 72 hours followed by 100 mg daily for 7 days in addition to standard of care (Huet et al., 2020). This retrospective study found that anakinra reduced rates of mortality and the need for mechanical ventilation in ICU patients (Huet et al., 2020). Anakinra was administered either subcutaneously or intravenously in the COVID-19 Biobank Study (Huet et al., 2020). Participants received subcutaneous injections at a dose of 100 mg twice daily or via slow intravenous infusion at 10 mg/kg per day until there was a 75 % reduction in serum C-reactive protein levels and sustained respiratory improvements (Cavalli et al., 2020). Whilst no safety concerns emerged with anakinra administered subcutaneously, it was discontinued due to a lack of clinical improvement and limited reduction in C-reactive protein (Cavalli et al., 2020). By contrast, intravenous anakinra was well-tolerated and improved clinical outcomes. Notably, 72 % of patients had improved respiratory function in comparison to 50 % within the standard treatment group (Cavalli et al., 2020). In both studies, cases of ALT ≥3 x ULN were observed in both the anakinra and the standard treatment arms. Four cases of bacteraemia following intravenous anakinra were reported in the COVID-19 Biobank Study, but there were no cases of bacterial infection in the Ana-COVID Study (Cavalli et al., 2020; Huet et al., 2020). Whilst both studies are encouraging, they should be considered proof-of-concept trials and larger randomised trials are still needed (Cavalli et al., 2020; Huet et al., 2020).
Subcutaneous administration of anakinra is associated with injection site reactions (Kaiser et al., 2012). In a review of 5 rheumatoid arthritis clinical trials, 71 % of participants receiving anakinra therapy reported injection site reactions in comparison to 28 % of participants on placebo (Mertens & Singh, 2009). Injection site reactions can range from immediate to delayed. In immediate cases, the reaction manifests as a burning sensation whereas delayed reactions present as a rash, pruritus or swelling (Kaiser et al., 2012). Anakinra has also been reported to lead to infection, neutropenia, thrombocytopenia, headache, and blood cholesterol increase when administered subcutaneously (Swedish Orphan Biovitrum Ltd, 2007).
Injection site reactions that arise immediately can be eased by placing an ice pack on the injection site before and after anakinra administration and delayed reactions can be treated with topical corticosteroids or anti-histamines (Kaiser et al., 2012). Increases in serious infection rate are common following anakinra use and frequently include upper respiratory infections, sinusitis, urinary tract infection and bronchitis (Bresnihan et al., 1998; Cohen et al., 2002; R. M. Fleischmann et al., 2003). Whilst rare, cases of opportunistic infection have been reported in anakinra monotherapy or in those receiving anakinra in combination with immunosuppressive agents (Salvana & Salata, 2009; Swedish Orphan Biovitrum Ltd, 2007). Neutrophil counts must be monitored during the first 6 months of anakinra treatment and quarterly henceforth (Swedish Orphan Biovitrum Ltd, 2007). In patients where the ANC is < 1.5 x 109/L, treatment must be discontinued immediately (Swedish Orphan Biovitrum Ltd, 2007). The higher doses being used in COVID-19 trials and the potential for a greater Cmax due to intravenous administration potentially raise additional safety concerns. However, since the duration of treatment will be shorter than that used in rheumatoid arthritis, coupled with the fact that patients will be hospitalised, should enable earlier detection of any untoward events.
Anakinra is catabolised and eliminated via glomerular filtration (Swedish Orphan Biovitrum Ltd, 2007; B.-B. Yang, Baughman, & Sullivan, 2003). Caution should be exercised and dose-adjustments may be required in moderate to severe renal impairment (Swedish Orphan Biovitrum Ltd, 2007; B.-B. Yang et al., 2003). During general infections and inflammatory diseases, CYP enzymes are primarily down-regulated (Mallick, Taneja, Moorthy, & Ghose, 2017). Similar to IL-6 inhibitors, it may be possible that anakinra treatment restores CYP levels in infected patients (Swedish Orphan Biovitrum Ltd, 2007). Therefore, caution should be exerted in COVID-19 patients receiving concomitant medications with a narrow therapeutic window drug. Mild interactions can occur between anakinra and warfarin, clopidogrel, clozapine and phenytoin (Group, 2020).