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.

Keywords: COVID-19; JAK2; ferritin; hyperinflammation; ruxolitinib.

Figure 1

Cartoon representing the overview of the pathogenesis of COVID-19 and the potential activity of ruxolitinib. The left part of the picture reports the most common pathogenetic events happening along SARS-Cov2 infection in 85/90% of patients: after virus invasion, antigen presentation, and establishment of an adaptive immune response, lungs reach the viral clearance with low or no symptoms. The right part of the figure reports instead the worse scenario where an exacerbation of the inflammatory response characterized by increased neutrophils and Th17 activation lead to ferritin overload, alveolar damage with fibrosis, and disseminated intravascular coagulation (DIC) which could potentially kill the patient. These events mainly depend on an uncontrolled activation of the JAK-STAT pathway (trough canonical and non-canonical signaling) which finally leads to uncoordinated production and release of inflammatory cytokines (CRS) within the alveolar microenvironment. By targeting the JAK-STAT pathway, ruxolitinib could disrupt this “vicious circle” and restore the correct alveolar functionality.

Figure 2

(A) CT-scan at baseline and after ruxolitinib treatment demonstrating the resolution of the ground-glasses areas at two different levels. (B) Timeline reporting ferritin modulation according to patient treatment; ruxo, ruxolitinib. (C) Patient laboratory values at baseline, 5 and 7 days, and at the time of discharge. n.a., not available.