COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm

Abstract

Since SARS-CoV-2 outbreak in December 2019, world health-system has been severely impacted with increased hospitalization, Intensive-Care-Unit (ICU) access and high mortality rates, mostly due to severe acute respiratory failure and multi-organ failure. Excessive and uncontrolled release of proinflammatory cytokines (cytokine release/storm syndrome, CRS) have been linked to the development of these events. The recent advancements of immunotherapy for the treatment of hematologic and solid tumors shed light on many of the molecular mechanisms underlying this phenomenon, thus rendering desirable a multidisciplinary approach to improve COVID-19 patients’ outcome. Indeed, currently available therapeutic-strategies to overcome CRS, should be urgently evaluated for their capability of reducing COVID-19 mortality. Notably, COVID-19 shares different pathogenic aspects with acute graft-versus-host-disease (aGVHD), hemophagocytic-lymphohistiocytosis (HLH), myelofibrosis, and CAR-T-associated CRS. Specifically, similarly to aGVHD, an induced tissue damage (caused by the virus) leads to increased cytokine release (TNFα and IL-6) which in turn leads to exaggerated dendritic cells, macrophages (like in HLH) and lymphocytes (as in CAR-T) activation, immune-cells migration, and tissue-damage (including late-stage fibrosis, similar to myelofibrosis). Janus Kinase (JAK) signaling represents a molecular hub linking all these events, rendering JAK-inhibitors suitable to limit deleterious effects of an overwhelming inflammatory-response. Accordingly, ruxolitinib is the only selective JAK1 and JAK2-inhibitor approved for the treatment of myelofibrosis and aGVHD. Here, we discuss, from a molecular and hematological point of view, the rationale for targeting JAK signaling in the management of COVID-19 patients and report the clinical results of a patient admitted to ICU among the firsts to be treated with ruxolitinib in Italy.

Scars of COVID-19: A bibliometric analysis of post-COVID-19 fibrosis

“…In COVID-19 patients, excessive release of cytokine, including IL1-β, IL-2, IL-6, IL-7, IL-8, IP10, MCP1, MIP1A, and tumor necrosis factor-α (TNF-α), exacerbated COVID-19 manifestation ( 2 , 52 , 53 ). Proinflammatory cytokine accumulation promoted dendritic cells exaggeration, lymphocyte stimulation, macrophage activation, neutrophil recruitment, immune-cells migration, exosome-mediated crosstalk induction, and ultimate tissue damage including fibrosis ( 18 , 19 ). In addition, another cytokine transforming growth factor beta (TGF-β) was paramount in the fibrosis initiation and remodeling process ( 20 ).…”

“…Prolonged mechanical ventilation (MV) ( 14 , 15 ), epithelial injury ( 16 ), and endothelial injury ( 17 ) may activate pro-fibrotic responses. Cytokine storm is considered an essential element in the PCF process ( 18 , 19 ). Excessive release of cytokine tumor necrosis factor-α (TNF-α) initiates fibrosis and lung remodeling ( 20 ).…”

Janus Kinase Inhibitors and Coronavirus Disease (COVID)-19: Rationale, Clinical Evidence and Safety Issues

“…By means of cytokines release in response to the SARS-CoV-2, JAK inhibitors are also suggested as a promising approach in patients with COVID-19 for their anti-inflammatory and immunomodulatory activity ( Figure 1 ). Indeed, the inhibition of JAK enzymes, which mediate signaling of pro-inflammatory cytokines including IL6, may mitigate the effects of cytokines released in response to the virus, and limit the damage in patients with severe disease [ 16 ]. Among JAK inhibitors, baricitinib 4 mg/day exerted a dual action characterized by the inhibition both of viral endocytosis into the cells and the cytokine outbreak, showing promising effects for the favorable clinical outcome of COVID-19 patients [ 17 ].…”

Characteristics of unvaccinated and vaccinated critically ill COVID-19 patients in calabria region (Italy): A retrospective study

“…The rapid surge of a novel coronavirus (SARS-CoV-2) in 2020 exceeded the capacity of Intensive Care Units (ICU) to care patients with acute respiratory failure and SARS-CoV-2 related disease (COVID-19) ( 1 – 3 ). Behind the attempt to test several pharmacological therapies to treat patients with COVID-19 ( 4 – 7 ), anti-SARS-CoV-2 vaccines have been developed to prevent the development of critical forms of COVID-19 leading to ICU admission ( 8 ). The first cycle of vaccination with BNT162b2 vaccine consists in two consecutives mRNA doses administered 21 days apart ( 9 ),and it induces an efficient immune response in 95% of naïve individuals ( 10 ).…”