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

Cirino Botta,Flavia Biamonte,Andrea Bruni,Pino Pasqua,Francesco Saverio Costanzo,Francesco Cesario,Alessia Indrieri,Eugenio Garofalo,Francesco Mendicino,Federico Longhini

doi:10.3389/fonc.2020.599502

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.

Highlights

Since late December 2019, severe atypical pneumonia cases requiring prompt hospitalization and frequent access to Intensive care Units (ICUs) have been reported in China
We review the current knowledge on the immune and inflammatory response to SARS-CoV-2 from a hematological and molecular point of view (Figure 1) and we report the results of one of the first COVID-19 patients admitted to ICU treated with the JAK2-inhibitor ruxolitinib, belonging to a group of patients who started this treatment under off-label use on March 27th 2020
In addition to significantly reducing the serum levels of IL-6 and C-reactive protein (CRP) [77, 112], ruxolitinib could influence the regulation of several inflammatory cytokines [36, 113], and reduce hyperferritinemia

Summary

INTRODUCTION

Since late December 2019, severe atypical pneumonia cases requiring prompt hospitalization and frequent access to Intensive care Units (ICUs) have been reported in China. JAK signaling inhibitors (baricitinib, fedratinib, and ruxolitinib), already approved for the treatment of several diseases including rheumatoid arthritis, myelofibrosis and acute graft-versus-host disease (a-GVHD), have been reported to counteract the host inflammatory response dependent on excessive pro-inflammatory cytokines and chemokines release, representing an interesting drug repurposing therapeutic strategy (see below) On these premises, a number of clinical trials are investigating the efficacy and safety of JAK inhibitors in COVID-19 patients, especially taking into account the balance between benefits and potential side effects connected to these treatments (Supplementary Table 1). The patient began the standard medical therapy used at that time in our institution, which included a combination of hydroxychloroquine, azithromycin, lopinavir/ritonavir, corticosteroids and LMWH, without significant clinical benefit after 10 days of continuous administration Inflammatory markers such as LDH, ferritin, CRP, and IL-6 constantly increased, and the worsening of respiratory function (PaO2 FiO2 ratio < 200) required ICU admission and orotracheal intubation with passive mechanical ventilation. The patient is currently (after 6 months from discharging) in perfect conditions with all laboratory exams within the range of normality (data not shown)

DISCUSSION

Findings

ETHICS STATEMENT