4.3 JAK Inhibitors
Baricitinib is an oral disease-modifying anti-rheumatic drug (DMARD),
traditionally used in the treatment of moderate to severe active
rheumatoid arthritis (Al-Salama & Scott, 2018). By acting as an
ATP-competitive kinase inhibitor, baricitinib can selectively and
potently inhibit janus kinases (JAKs) 1 and 2 in a reversible manner.
JAKs are essential in the transduction of intracellular signals for
various cytokines involved in the inflammatory and immune responses, and
so by inhibiting these kinases, baricitinib is able to relieve symptoms
of rheumatoid arthritis for many patients (Fridman et al., 2010).
As described previously, a common characteristic of COVID-19, much like
another beta-coronavirus disease SARS, is a profuse inflammatory
response (Huang et al., 2020; Stebbing et al., 2020). Increased levels
of pro-inflammatory cytokines, such as interferon (IFN) -γ and IL-1β,
have been observed in confirmed COVID-19 cases (Huang et al., 2020;
Mehta, McAuley, et al., 2020; Russell et al., 2020). Furthermore, the
levels of some specific cytokines appear to be related to disease
severity; patients requiring admission to intensive care units show
increased levels of TNFα and monocyte chemoattractant protein 1 (MCP1).
The rationale behind repurposing baricitinib as a treatment for COVID-19
is centred on this potential for severely ill patients to present with a
cytokine storm (Mehta, McAuley, et al., 2020; Russell et al., 2020). By
dampening the inflammatory response, it is postulated that baricitinib
will be able to relieve COVID-19 symptoms. Data modelled using
artificial intelligence techniques suggests baricitinib may work by
inhibiting virus entry into cells via an endocytic regulator known to be
involved in coronavirus internalisation, AP2-associated protein kinase 1
(AAK1) (Burkard et al., 2014; Richardson et al., 2020). Baricitinib, as
well as being capable of JAK1 and JAK2 inhibition, is a high-affinity
inhibitor of AAK1 (Richardson et al., 2020).
Patients tend to tolerate baricitinib well, and it has a relatively good
safety profile (Keystone et al., 2015). However, as with tocilizumab and
sarilumab treatment, a very common (≥ 1/10) AE observed in patients
taking baricitinib, but not in the placebo arm, is upper respiratory
tract infection, which may be related to its ability to suppress the
immune system (Eli Lilly, 2017). Patients taking baricitinib have the
potential to develop respiratory tract infections which may make it
difficult to distinguish whether any deterioration is due to COVID-19 or
a secondary infection. Other opportunistic infections including herpes
zoster and urinary tract infections were also more common in the treated
arm compared to placebo, and dose reduction is recommended for patients
with a history of chronic infections (Eli Lilly, 2017; Josef S. Smolen
et al., 2018). Secondary infections are not uncommon in severe COVID-19
patients and so the use of a drug that may make patients increasingly
prone to infections will depend on the harm-benefit ratio for severe
cases of COVID-19 (World Health Organisation, 2020a).
Baricitinib is currently still being trialled in patients with COVID-19
with a therapeutic dose of 2-4 mg once daily which is the same as the
recommended dosage for the treatment of rheumatoid arthritis (Cantini et
al., 2020; Richardson et al., 2020). There have been a small number of
reports from patients taking this recommended dosage for the treatment
of rheumatoid arthritis presenting with deep vein thrombosis (DVT),
which was severe in some of these cases (Taylor et al., 2019). This is a
cause for concern as there are increasing reports of COVID-19 patients,
especially those who are critically ill and in the ICU, with thrombotic
complications including pulmonary embolism and other venous and arterial
thrombotic events (Klok et al., 2020; Middeldorp et al.). As baricitinib
has been reported to cause DVT, there is the potential for disease-drug
interactions with COVID-19 patients taking baricitinib potentially more
likely to develop thrombotic complications. In order to mitigate this
risk, alternative JAK inhibitors, which have a lower risk of thrombotic
events, such as ruxolitinib, may be considered in the context of
COVID-19 (Alvarez-Larran et al., 2018). However, unlike baricitinib,
ruxolitinib is primarily metabolised by CYP3A4 (L. P. H. Yang &
Keating, 2012). This means that prescribing ruxolitinib instead of
baricitinib may increase the risk of CYP3A4-related DDIs (Ogu & Maxa,
2000). Baricitinib is not predicted to be involved in any problematic
DDIs. Coadministration with both CYP3A inhibitors (fluconazole) and
inducers (rifampicin) failed to result in any clinically relevant
changes to baricitinib exposure (Eli Lilly, 2017).
Emerging reports have revealed that patients with COVID-19 experience
renal impairment, which could be attributed ACE2 receptor expression on
kidney endothelial cells (Varga et al., 2020). Baricitinib should not be
given to patients with renal impairment as the majority of the drug is
cleared through the kidneys, and monitoring of renal function will be
important to prevent AEs related to over-exposure to baricitinib in
those with deteriorating renal function (Eli Lilly, 2017).