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).