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).