Ruxolitinib as a treatment strategy for SARS-CoV-2 pneumonia: clinical experience in a real-world setting.

INTRODUCTION: Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) infection is characterised by a viral phase and a severe pro-inflammatory phase. The inhibition of the JAK/STAT pathway limits the pro-inflammatory state in moderate to severe COVID-19. METHODOLOGY: We analysed the data obtained by an observational cohort of patients with SARS-CoV-2 pneumonia treated with ruxolitinib in 22 hospitals of Mexico. The applied dose was determined based on physician's criteria. The benefit of ruxolitinib was evaluated using the 8-points ordinal scale developed by the NIH in the ACTT1 trial. Duration of hospital stay, changes in pro-inflammatory laboratory values, mortality, and toxicity were also measured. RESULTS: A total of 287 patients were reported at 22 sites in Mexico from March to June 2020; 80.8% received ruxolitinib 5 mg BID and 19.16% received ruxolitinib 10 mg BID plus standard of care. At beginning of treatment, 223 patients were on oxygen support and 59 on invasive ventilation. The percentage of patients on invasive ventilation was 53% in the 10 mg and 13% in the 5 mg cohort. A statistically significant improvement measured as a reduction by 2 points on the 8-point ordinal scale was described (baseline 5.39 ± 0.93, final 3.67± 2.98, p = 0.0001). There were 74 deaths. Serious adverse events were presented in 6.9% of the patients. CONCLUSIONS: Ruxolitinib appears to be safe in COVID-19 patients, with clinical benefits observed in terms of decrease in the 8-point ordinal scale and pro-inflammatory state. Further studies must be done to ensure efficacy against mortality.

Approaches to the Potential Therapy of COVID-19: A General Overview from the Medicinal Chemistry Perspective.

In spite of advances in vaccination, control of the COVID-19 pandemic will require the use of pharmacological treatments against SARS-CoV2. Their development needs to consider the existence of two phases in the disease, namely the viral infection and the inflammatory stages. The main targets for antiviral therapeutic intervention are: (a) viral proteins, including the spike (S) protein characteristic of the viral cover and the viral proteases in charge of processing the polyprotein arising from viral genome translation; (b) host proteins, such as those involved in the processes related to viral entry into the host cell and the release of the viral genome inside the cell, the elongation factor eEF1A and importins. The use of antivirals targeted at host proteins is less developed but it has the potential advantage of not being affected by mutations in the genome of the virus and therefore being active against all its variants. Regarding drugs that address the hyperinflammatory phase of the disease triggered by the so-called cytokine storm, the following strategies are particularly relevant: (a) drugs targeting JAK kinases; (b) sphingosine kinase 2 inhibitors; (c) antibodies against interleukin 6 or its receptor; (d) use of the traditional anti-inflammatory corticosteroids.

Calming the inflammatory storm in severe COVID-19 infections: Role of biologics- A narrative review.

The risk of Coronavirus infection continues, and the fear of resurgence indicates the lack of a successful therapeutic strategy. In severe COVID-19 infection, many immune cells and their products are involved, making management difficult. The abundant release of cytokines and chemokines in severe COVID-19 patients leads to profound hyper inflammation and the mobilization of immune cells, triggering the cytokine storm. The complications associated with the cytokine storm include severe respiratory distress, intravascular coagulation, multi-organ failure, and death. The enormous formation of interleukin (IL)-6 and hemopoietic factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) are implicated in the severity of the infection. Moreover, these inflammatory cytokines and factors signal through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway causing the activation of cytokine-related genes. The neutralization of these proteins could be of therapeutic help in COVID-19 patients and could mitigate the risk of mortality. IL-6 antagonist, IL-6 receptor antagonists, GM-CSF receptor inhibitors, and JAK-STAT inhibitors are being investigated to prevent intense lung injury in COVID-19 patients and increase the chances of survival. The review focuses the role of IL-6, GM-CSF, and JAK-STAT inhibitors in regulating the immune response in severely affected COVID-19 patients.

Interleukin-6 Blocking vs. JAK-STAT Inhibition for Prevention of Lung Injury in Patients with COVID-19.

The severe respiratory insufficiency observed during COVID-19 infection may not be directly related to a cytopathogenic effect induced by the virus itself, but to an exaggerated and inappropriate immune response. In an effort to reduce the severity of organ dysfunction, including respiratory insufficiency, monoclonal antibodies (Mabs) that block the interleukin-6 receptor, such as tocilizumab, sarilumab, and siltuximab, are under investigation for the treatment of COVID-19. However, blocking of just one of the many cytokines involved in the inflammatory reaction may not slow down the magnitude of the process. Since timing is important, the immune deficiency induced by IL6 blockade at the late immunodeficiency phase of sepsis that follows the initial inflammatory response may be detrimental. Finally, monitoring the degree and duration of IL6 blockade may be challenging because of the long half-life of Mabs (2-3 weeks). Pro- and anti-inflammatory cytokines act through a common JAK-STAT signaling pathway, which can be inhibited by JAK-STAT inhibitors. Ruxolitinib, a tyrosine kinase inhibitor selective for JAK1, 2, blocks many pro- and anti-inflammatory cytokines including IL6. Ruxolitinib has favorable pharmacodynamics and an acceptable safety profile. The short half-life (4-6 h) of the drug offers the opportunity for ideal monitoring of the degree and duration of cytokine blocking, simply by the adjusting dose and duration of therapy. From a theoretical point of view, the balanced control of cytokine blockade throughout the course of the septic process should be the cornerstone of modern management. According to this hypothesis, maximization of blocking should be attempted at the phase of hyper-inflammation for preventing severe organ damage, while pro-inflammatory blockade should be minimized at the late phase of immunoparalysis for prevention of secondary infections. Based on the above considerations, we consider that the efficacy and safety of this drug deserves testing in the context of a controlled randomized trial.