Continuing Education Activity

Baricitinib is a medication traditionally used in the management and treatment of Rheumatoid Arthritis. However, with the recent advent of the COVID-19 global pandemic, several agents have been evaluated for the management of this disease. Baricitinib is in the JAK inhibitor class of medications. This activity reviews the indications, action, and contraindications for the concurrent use of Remdesivir and Baricitinib as valuable agents in the management of COVID-19. This activity will highlight the mechanism of action, adverse event profile, and other key factors like indications and contraindications, dosing, pharmacodynamics, pharmacokinetics, pertinent for members of the interprofessional team in the management of patients with COVID-19 and related conditions

Objectives:

• Describe the pathophysiology of COVID-19 and the role of Baricitinb in the management of the disease. Summarize the epidemiology of Addison disease.

• Identify the indications for using Baricitinib in combination with Remdesivir in hospitalized patients.

• Review the contraindications and adverse events associated with the use of Baricitinib and Remdesivir.

• Describe the importance of a multidisciplinary team in the management of COVID-19 leading to safe and effective use of Baricitinib and Remdesivir in hospitalized COVID-19 patients.

Introduction

The World Health Organization (WHO) declared COVID-19 a global pandemic on March 11, 2020. Since the isolation and recognition of SARS-CoV-2 as the causative agent behind COVID-19, as of 9th May 2021, there have been 157,289,118 confirmed cases of COVID-19, including 3,277,272 deaths, reported to WHO. SARS-CoV-2 is an enveloped virus with ribonucleic acid as its genetic material. Due to its high virulence, it has wreaked havoc on countries worldwide, with an overwhelming number of infections following outbreaks. This has led to a near-collapse of the healthcare infrastructure in some countries. With the advent of a better understanding of the disease process and the pathophysiology of severe disease, it has become clear that there is a need for therapeutic agents that can hamper the course of the disease.

The pathogenesis of COVID-19 is a complex interplay between direct tissue injury from viral invasion and a heightened immune response from the host. The early phase of the disease is characterized by viral entry into the host cells. The SARS-CoV-2 virus enters the host cells by attaching to the ACE-2 receptors that are present in abundance in the respiratory epithelium, the nasal mucosa, esophagus, etc. [1]. This attachment is specifically between the spike protein S1 and the ACE-2 receptors. After the initial attachment, the viral spike protein subunit S2 primes the host transmembrane serine protease 2 (TMPRSS2) and facilitates the process of endocytosis, or cell entry. Once the virus has gained entry into the cell, it replicates and assembles virions[2]. See Figure. Endocytosis of SARS-CoV-2.

Following the entry of the virus into the cells and direct virus-mediated tissue damage, the late phase of the disease commences. The host cells trigger an immune response by activating T-lymphocytes, neutrophils, and monocytes. Neutrophil recruitment is followed by the release of cytokines such as Interleukin-1 (IL-1), Interleukin-6 (IL-6), IL-1β, IL-8, IL-12, Interferon Gamma (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-α (TNF α). In cases of severe COVID -19, there is evidence of a heightened immune response categorized as “Cytokine Storm” which leads to several deleterious effects on the body. The Cytokine storm is caused by the release of high levels of cytokines, especially IL-6 and TNF-α causing an intense inflammatory response[3]. Apart from the IL-6 and TNF-α, the binding of SARS-CoV-2 to the Toll-Like Receptor (TLR) induces the release of pro-IL-1β, which is cleaved into the active mature IL-1β that mediates lung inflammation and fibrosis[4].

Over the course of the past year, our understanding of the pathophysiology of COVID-19 has improved. With ongoing randomized controlled trials evaluating therapies for COVID -19, like the RECOVERY Trial recruiting over 39,000 individuals, the guidelines for therapy for COVID-19 remain fluid. Despite a better understanding of the disease, the mortality and morbidity associated with COVID-19 remains unacceptably high.  The recent wave of overwhelming cases in the Republic of India is a grave example of the potential for disaster with COVID-19. There is a need for agents that can be added to the existing arsenal of approved medications. An ideal therapeutic agent should be reliable with robust clinical benefits. The recommendation for its use should be backed by evidence, and it should have a favorable and benign side effect profile. Apart from this, the agent should be readily available to the masses, should be inexpensive, and should be able to meet an exorbitant demand with an efficient supply chain. In an attempt to apply these criteria through this review; we evaluate the evidence for and against the concurrent use of Remdesivir and Baricitinib, indications and contraindications, mechanism of action, and the side effect profile of these drugs.

Function

Anti-inflammatory properties of Baricitinib

Baricitinib is a selective and reversible inhibitor of Janus Kinases (JAK) JAK1 and JAK2 originally approved for use in individuals with rheumatoid arthritis (RA). Its use has been justified by proven dampening of the inflammatory response[5]. The JAK/STAT pathway has been identified as one of the subcellular pathways that mediate signal transduction of external stimuli to the nuclei of the cell, thereby mediating normal as well as aberrant immune responses. When cytokines attach to their receptors on the surface of the cell, a conformational change in the receptor leads to activation of the associated JAK complex. Once activated, the JAK complex autophosphorylates, creating a docking site for signaling molecules of the STAT family. The activated JAK complex also shows increased Janus Kinase activity leading to further phosphorylation of the STAT signaling pathway. The phosphorylated STAT molecules are then released from the receptor, translocate to the nucleus and lead to DNA sequence activation. This ultimately leads to target gene transcription[6]. The JAK signaling pathway family includes 4 proteins, the JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2)[7]. Disruption of one or more of the JAK proteins is associated with an interruption in the signal transduction pathway and can lead to the beneficial effects of dampening a heightened immune response[8]. Cytokines implicated in causing the cytokine storm like the IFN-γ, IL-6, etc. have a JAK-mediated mechanism of action. IL6 is associated with JAK1, JAK2, and TYK2[9], whereas IFN-γ activity is mediated by JAK1/JAK2[10]. Stebbing and colleagues validated the above-mentioned mechanism in their study. On evaluating the in-vitro pharmacology in relevant leucocytes as well as in-vivo pharmacokinetics of Baricitinib, they were able to demonstrate inhibition of IL-2, IL-6, IL-10, IFN-γ, and GM-CSF[11]. See Figure. Baricitinib Mechanism of Action

Antiviral Activity of Baricitinib

The potential antiviral activity of Baricitinib is embedded in the mechanism of viral cell entry of several viruses including SARS-CoV-2. The virus gains entry into the cells by a process known as clathrin-mediated endocytosis[12]. Clathrin is a protein that is found in abundance on the inner surface of the cell membrane, this protein is involved in making the vesicle-like covering around the viral particle leading to endocytosis/entry into the cell. The first step in the process involves the binding of SARS-CoV-2 to the host cell surface receptor / ACE 2. This leads to the activation of 2 kinases, the AP2-associated protein kinase 1 (AAK-1) as well as the cyclin D-associated kinase (GAK). These two kinases namely the AAK-1 and the GAK lead to the activation of host proteins called the adaptor protein complexes (APs). These APs recruit clathrin to form the cage-like structure around the virus leading to endocytosis. Baricitinib has been shown to inhibit AAK-1, and this has been the basis of the proposed antiviral action[13]. This mechanism of action was suggested by a London-based machine learning study (Benevolent) that evaluated a large repository of approved medications and found potential inhibitory activity at clinically achievable serum concentrations. Baricitinib uniquely showed a high affinity for AAK-1 in comparison to other JAK inhibitors like Tofacitinib and Upadacitinib[14]. It should be noted that SARS-CoV-2 utilizes several endocytotic pathways for viral entry and this benefit could easily be circumvented with viral utilization of an alternate endocytotic pathway[15]. Image 2 depicts the proposed antiviral action of Baricitinib.

Evidence

To categorize and interpret the current evidence in the context of COVID-19 therapy, it is important to discuss the 8-point ordinal scale which categorizes COVID-19 based on disease severity (see Figure. NIAID Ordinal Scale for COVID-19 Severity). The image depicts the widely accepted 8-point ordinal scale for COVID 19 severity and clinical improvement. The scores ranging from 4 to 7 include hospitalized individuals requiring some form of oxygen supplementation, with incremental severity based on oxygen requirements, and supportive care. Goletti and Cantini[16] aptly summarize the current evidence for COVID-19 therapy in their editorial. In the Adaptive COVID-19 treatment trial (ACTT-1)[17] the investigators found a shorter time to recovery in patients treated with Remdesivir in comparison to placebo (10 days vs 15 days; rate ratio for recovery, 1.29; 95% confidence interval {CI}, 1.12 t0 1.49, P<0.001). Their study involved 1062 hospitalized patients with an ordinal scale of 4 to 7. The maximal benefit from the drug was noticed in patients with an ordinal scale of 4 (not on supplemental oxygen) and 5 (on low flow oxygen). Thus Remdesivir was accepted as a therapy benefiting patients with mild disease to moderate disease, with a maximal benefit when started early, and in patients with milder disease[17].

The Randomized Evaluation of COVID-19 therapy (RECOVERY) trial investigators on the other hand evaluated the utility of using dexamethasone in hospitalized individuals[18]. They used the dose of 6mg of dexamethasone per day for 10 days and compared 2104 cases to 4321 controls. They found that the incidence of death was lower in the dexamethasone group in mechanically ventilated patients in comparison to the usual care group or controls (29.3% vs 41.4%; rate ratio 0.64; 95% CI, 0.51 to 0.81). Since the investigators did not use an ordinal scale, the likely ordinal scale for this subgroup of mechanically ventilated patients was 7. The benefit of using dexamethasone, however, was less clear in individuals receiving supplemental oxygen in lesser degrees.

Based on the findings of the abovementioned trials, Goletti and Cantini extrapolate that Remdesivir is most effective in early disease with an ordinal scale of 4-5 and dexamethasone is more effective in the later course of the disease with an ordinal scale of 6-7. They point out a need to evaluate therapy for the so-called “Grey Zone” or individuals with an ordinal scale severity of 5-6.

Kalil et al in their recent study the Adaptive COVID-19 Treatment Trial -2 (ACTT-2)[19] shed light on the utility of combination therapy with Remdesivir and Baricitinib for hospitalized individuals with COVID-19. This was a double-blinded, randomized, placebo-controlled trial. All their study participants received Remdesivir with either Baricitinib or placebo. Based on the inclusion criterion, 1033 patients underwent randomization with an equitable distribution between the combination therapy group and controls (515 vs 518). While the study showed a mediocre change in time to recover in the overall study (median, 7 days vs. 8 days; rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P=0.03) the efficacy of the combination treatment was most pronounced in patients with an ordinal score of 6 (On high flow nasal cannula); in this group, the time to recovery was 10 days in the combination group and 18 days in the control group (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). Overall, the combination group also had 30% higher odds of improvement at day 15 than the control group (odds ratio, 1.3; 95% CI, 1.0 to 1.6). The incidence of serious adverse events was lower in the combination group than in the control group (16.0% vs. 21.0%; difference, −5.0 percentage points; 95% CI, −9.8 to −0.3) suggesting that the tolerability of baricitinib was similar to placebo, with a lower incidence of adverse events in the combination group in comparison to placebo. The study was not powered to detect a difference in mortality between the two groups, but there was a trend towards improved survival rate in the combination group. The investigators did not find any evidence of increased risk of superinfection or thromboembolic events[19].

A limitation to the interpretation of the ACTT-2 trial is the absence of data on concurrent use with corticosteroids, as this trial was conducted before the results of the RECOVERY trial. Rodriguez -Garcia et al performed an observational study comparing the use of a combination of Baricitinib with corticosteroids vs steroids alone[20]. They found that oxygen requirements were lower in the combination group, with a lower need for supplemental oxygen at discharge as well as at 1 month from disease onset. However, there are several flaws in this study that are inherent to all observational studies. 

Issues of Concern

Baricitinib is a relatively new drug, and our knowledge about its safety and efficacy profile will build over time. Baricitinib is orally administered and gets rapidly absorbed leading to a peak concentration within 60 minutes, food appears to have no effect on the pharmacokinetics of the medication. The pharmacokinetics of Baricitinib follows a linear curve and there is no accumulation of clinical significance. It is moderately distributed into tissues with 50% binding to plasma proteins and a volume of distribution of 1.1L[6]. Baricitinib is cleared by the kidneys by the process of active secretion and filtration. Naturally, its half-life is extended in patients with renal failure or ESRD. It is cleared efficiently with hemodialysis, however, the data on its clearance with continuous renal replacement and extracorporeal membrane oxygenation is slim. The manufacturers have advised against the use of Baricitinib in patients with end-stage renal disease. This may cause a problem in critically ill patients requiring these modalities of rescue therapy. It is also unclear if Baricitinib can be administered to pregnant or breastfeeding patients with lacking data on whether it crosses the placenta or if it causes any fetal toxicity. Uniquely, Baricitinib can cause a rapid rise in the platelet count that is not seen in any other JAK inhibitors[21]. Clinicians should be aware of this effect, as thrombocytosis can be mistaken as a sign of sepsis.

Jorgensen et al[6] review the safety profile of the medication and point that a majority of the data is associated with a 4 mg /day dose of Baricitinib. The data for a 2 mg /day dose continues to strengthen with wider use of Baricitinib. Based on our existing knowledge of the medication it is evident that the common side effects are upper airway infections and headaches[21]. However, rapid decrease in neutrophil counts, drop in hemoglobin, the elevation of creatinine phosphokinase, the elevation of liver enzymes, the elevation of serum creatinine has been reported in the literature[22]. Given the fact that Baricitinib is likely to be administered with Remdesivir as in the ACTT-2 study, the patients are likely to have frequent monitoring of renal and hepatic parameters during administration. Baricitinib has also been associated with reactivation of Herpes Zoster and clinicians should be aware of this risk.

Baricitinib has also been associated with a dose-dependent increased tendency to have venous as well as arterial thromboembolism, which is similar to other disease-modifying anti rheumatoid drugs (DMARD’s). It is for this reason that the FDA approved a 2 mg/day dose of Baricitinib for the treatment of rheumatoid arthritis, as the benefit of administering a 4 mg/day dose was unclear with an increased risk of thromboembolic events[23]. COVID-19 is associated with immune modulated hypercoagulability and whether the immunosuppressive effects of Baricitinib will act as a positive influence, or if its tendency to cause thromboembolic events will increase the risk of clots remains to be evaluated. The largest study to date with COVID-19 is ACTT-2 and the incidence of adverse events was noted to be less than the placebo arm which continues to be reassuring.  

Based on the guideline issued by the FDA for the administration of Baricitinib, dose adjustment should be made for renal impairment. For eGFR between 30-60, the recommended dose is 2 mg /day. For eGFR between 15-30 the recommended dose is 1 mg /day while evaluating risks and benefits and its use is not recommended for eGFR below 15. Its use is also not recommended in patients with severe hepatic impairment. As hematologic derangements have been noted with Baricitinib use, its administration is not recommended in patients with a hemoglobin of <8gm/dl, an absolute neutrophil count (ANC) of <1000 cells/mm, and an absolute lymphocyte count of <500 cells/mm.

Clinical Significance

Despite the advent of a better understanding of COVID-19, the mortality and morbidity in hospitalized individuals with mild to moderate disease remain unacceptably high. During phases of overwhelming crisis as seen in countries worldwide over the past year, it has become evident that healthcare infrastructure across the globe can get overwhelmed. While oxygen supplementation can be provided in regular ward settings, mechanical ventilation with endotracheal intubation requires a significant amount of resources. Specialized equipment, trained physicians, and nursing staff fluent in managing critically ill patients and ICU beds remain in shortage across the globe. Combination therapy with Remdesivir and Baricitinib holds the promise of potentially decreasing oxygen requirements, as well as avoiding worsening in patients with an ordinal score of 5 and 6. This group of patients is at a high risk of requiring escalation of care, as well as having clinical worsening requiring mechanical ventilation. Hence the combination therapy can avoid significant morbidity as well as conserve valuable resources. Further studies are underway for the evaluation of Baricitinib and Remdesivir in combination with corticosteroids.  

Other Issues

Limitations

The ACTT-2 study was well designed and provided valuable data, however, it was not powered to evaluate a mortality benefit associated with combination therapy of Remdesivir and Baricitinib. This proves to be a limitation in making this combination a standard of care. It will be interesting to see the results of the next phase of the Recovery trial, which will shed light on the concurrent use of steroids with Baricitinib. 

Enhancing Healthcare Team Outcomes

Over the course of the past year, the utility of a multidisciplinary approach has been proven in the care of patients with COVID-19. For hospitalized patients requiring oxygen, early involvement of infectious disease consultants as well as pulmonary physicians can help direct therapy. This leads to standardization of care for patients with respiratory failure due to COVID-19. Hospitals have formulated peer review and planning committees for early incorporation of evidence as soon as new trials are published. The involvement of physicians working at the grass-root level in such committees leads to efficient incorporation of new policies and guidelines. The involvement of pharmacists in the process of patient selection and drug approval has been a tried and tested patient safety mandate. Regular education and knowledge update are key to the efficient management of patients with COVID-19.