Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contributing to coronavirus disease 2019 (COVID-19), continues to plague the United States (U.S.) and the world. With a reported 30 million confirmed cases and over 500,000 deaths in the U.S. alone, the need for lifesaving therapies is crucial.¹ Despite much headway, there is a mounting and continually evolving body of knowledge about this virus and its sequelae. While most symptomatic patients have a mild clinical course, approximately 20% require hospitalization, with upwards of 20% requiring an intensive care unit (ICU) transfer.^2,3 Severe COVID-19 is characterized by clinical criteria and lung damage often seen concomitantly with high concentrations of circulating cytokines, including interleukin-6 (IL-6). This overproduction of cytokines and unregulated host response promote inflammation leading to cell damage otherwise known as cytokine storm. For patients with COVID-19, the number of immune cells and other inflammatory indices, particularly IL-6, are significantly higher among severely and critically ill patients. A high level of cytokines may also be associated with a worse prognosis.⁴

Baricitinib, a Janus kinase (JAK) inhibitor which modulates the production of cytokines to reduce inflammation, is gaining immense interest as a potential treatment option for hospitalized patients diagnosed with severe COVID-19. Historically this agent has been used for the treatment of rheumatoid arthritis (RA), with a U.S. Food and Drug Administration (FDA)-approved dose of 2 mg daily.⁵ Baricitinib inhibits JAK 1 and 2, which are involved in stimulating hematopoiesis and immune cell function through the signaling pathway.⁵ Inhibition of JAK prevents the activation of signal transducer and activator of transcription (STAT) proteins and reduces serum immunoglobulin (Ig) G, IgM, IgA, and C-reactive protein (CRP).^6,7,8 Therefore, it prevents hyperinflammation (by reducing select inflammatory markers), improves lymphocyte counts, and improves oxygenation. 

Additionally, JAK inhibitors prevent phosphorylation of key proteins involved in the signal transduction that leads to immune activation and inflammation (e.g., the cellular response to proinflammatory cytokines such as IL-6), as shown in Figure 1.^9,10 With the ability to decrease inflammation by inducing immunosuppression, baricitinib possesses theoretical antiviral activity through interference with viral endocytosis, potentially preventing entry into and infection of susceptible cells.¹¹ This mechanistic advantage led to clinical investigation of baricitinib as a potential therapy against SARS-CoV-2. Early evaluation was limited to retrospective cohort designs and non-controlled pilot studies as noted in Table 1. Initial interest prompted the inclusion of baricitinib as an investigational agent in the ACTT-2 trial. In this study, Kalil et al conducted a double-blind, randomized, placebo-controlled trial and demonstrated that baricitinib in combination with remdesivir (RDV) resulted in a reduced time to recovery (7 days vs. 8 days with placebo) and a 30% higher odds of clinical improvement by day 15 (OR 1.3, 95% CI 1.0-1.6). Those patients receiving supplemental high-flow oxygen or noninvasive mechanical ventilation demonstrated the greatest benefit with an even shorter time to clinical improvement (10 days vs. 18 days with placebo).8 In light of this evidence, the FDA issued an Emergency Use Authorization (EUA) in November 2020 for the use of baricitinib in combination with remdesivir in hospitalized patients with suspected or confirmed COVID-19 requiring supplemental oxygen. The role of baricitinib will be further investigated in combination with remdesivir compared to standard of care, dexamethasone plus remdesivir, in the currently enrolling ACTT-4 trial. One potential benefit of baricitinib is the reduction of profound immunosuppression that may be solicited compared to dexamethasone use.

Table 2 provides additional information regarding baricitinib therapy and a specific institution’s protocol for the treatment for COVID-19.

Despite concerns about immunosuppression, secondary infections, and thrombosis with the use of JAK inhibitors, baricitinib was not associated with a significantly higher incidence of adverse events or thromboembolic events in the treatment of COVID-19.¹⁰ This may in part be due to its short half-life (~9-12 hours) and short duration of treatment, as more of the serious adverse effects have been reported after prolonged therapy. According to the ACTT-2 trial, the most common side effects seen with the acute use of combination baricitinib and RDV were hyperglycemia, anemia, decreased lymphocyte count, and acute kidney injury.8 Event rates were similar between baricitinib and placebo.

The combination of baricitinib, an anti-inflammatory medication, and RDV, an antiviral, reduced time to recovery of patients hospitalized with COVID-19, especially those requiring high-flow oxygen or non-invasive mechanical ventilation therapy. Future studies will evaluate the potential benefits of baricitinib compared to the current standard of care for the treatment of COVID-19. However, the combination of baricitinib plus RDV may benefit hospitalized patients requiring high-flow oxygen or non-invasive mechanical ventilation therapy who cannot otherwise tolerate corticosteroids.