Baricitinib combination therapy: a narrative review of repurposed Janus kinase inhibitor against severe SARS-CoV-2 infection

Abstract

Purpose: The Coronavirus disease 2019 (COVID-19) pandemic is one of the most devastating global problems. Regarding the lack of disease-specific treatments, repurposing drug therapy is currently considered a promising therapeutic approach in pandemic situations. Recently, the combination therapy of Janus kinase (JAK) inhibitor baricitinib has been authorized for emergency COVID-19 hospitalized patients; however, this strategy's safety, drug-drug interactions, and cellular signaling pathways remain a tremendous challenge.

Methods: In this study, we aimed to provide a deep insight into the baricitinib combination therapies in severe COVID-19 patients through reviewing the published literature on PubMed, Scopus, and Google scholar databases. We also focused on cellular and subcellular pathways related to the synergistic effects of baricitinib plus antiviral agents, virus entry, and cytokine storm (CS) induction. The safety and effectiveness of this strategy have also been discussed in moderate to severe forms of COVID-19 infection.

Results: The severity of COVID-19 is commonly associated with a dysregulated immune response and excessive release of pro-inflammatory agents, resulting in CS. It has been shown that baricitinib combined with antiviral agents could modulate the inflammatory response and provide a series of positive therapeutic outcomes in hospitalized adults and pediatric patients (age ≥ two years old).

Conclusion: Baricitinib plus the standard of care treatment might be a potential strategy in hospitalized patients with severe COVID-19.

Keywords: Baricitinib; Cytokine storm; Janus kinase pathway; Repurposing drug therapy; Severe COVID-19.

Fig. 1

Schematic representation of SARS-CoV-2 structure, virus entry, and replication in host cells. Virus cell entry by endocytosis is a clathrin-dependent route. Baricitinib effect is usually related to the irregularity in AP2-associated protein kinase 1 and inhibiting SARS-CoV-2 cellular entry through the clathrin-dependent pathway. Antiviral function of remdesivir is related to inhibiting the RNA-dependent RNA polymerase (RdRp)

Fig. 2

Schematic depicting the cytokine storm (CS) mechanisms in severe COVID-19 patients. The pattern recognition receptors (PRRs) detect and respond to the pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs) are expressed by immune and non-immune cells. Retinoid acid-inducible gene I (RIG-I), cyclic GMP-AMP synthase (cGAS), and melanoma differentiation-associated gene 5 (MDA-5) are receptors for detecting the viral genome in the cytoplasm. The activation of these sensors leads to an increase of TIR-domain-containing adaptor inducing interferon β (TRIF), stimulation of interferon genes (STINGs), and mitochondrial antiviral-signaling protein (MAVS). The activation of interferon regulatory factor-3, 7 (IRF-3, IRF-7), and nuclear factor-kappa (NF-κB) initiate a subcellular signaling cascade, induce interferons (INFs) and pro-inflammatory cytokines, subsequently leading to CS phenomena

Fig. 3

Schematic representation of the JAK/STAT signaling pathway and inhibition effects of baricitinib. Various cytokines and growth factors can participate in signal transmission through the JAK pathway, including different interleukins (ILs), interferons (INFs α, β, and γ), granulocyte–macrophage colony-stimulating factor (GM-CSF), growth hormone (GH), epidermal growth factor (EGF), and leptin hormone. Interaction between the receptors and ligands leads to phosphorylation of the tyrosine residues of many target proteins by JAK enzymes and affects signal translocation from the extracellular to the intracellular. Then, phosphorylated STATs form dimers (STAT-STAT) can translocate into the nucleus, bind to specific DNA sequences, and transmit extracellular cytokine signals into transcriptional responses