INTRODUCTION
The pathogenesis of severe Coronavirus Disease 2019 (COVID-19) involves
an excessive host inflammatory response to severe acute respiratory
syndrome (SARS)-CoV-2 virus that is characterised by a marked increase
in systemic cytokines and inflammatory biomarkers. These changes
resemble cytokine storm that is observed during macrophage activation
syndrome or after chimeric antigen receptor T (CAR-T)-cell therapy [1,
2]. Given the lack of antiviral substances with efficacy against
SARS-CoV-2 infection, which are capable of preventing the associated
hyper-inflammatory immune response, glucocorticoids and various
anti-cytokine agents (interleukin-6 inhibitors in particular) were
widely used for the treatment of moderate to severe COVID-19 in real
life practice and were investigated in multiple observational and
randomised clinical trials [3]. In the RECOVERY study, the
administration of dexamethasone, a glucocorticoid with broad
anti-inflammatory activity, resulted in lower 28-day mortality among
hospitalised patients with COVID-19 who were receiving either invasive
mechanical ventilation or supplemental oxygen therapy alone [4].
Conflicting evidence exists about the role of tocilizumab, an
interleukin (IL)-6 receptor inhibitor, on mortality rates in severe
COVID-19 [5-7]. Nevertheless, the U.S. Food and Drug Administration
(FDA) issued an emergency use authorisation for the use of tocilizumab
in patients receiving glucocorticoids and requiring supplemental oxygen,
non-invasive or invasive mechanical ventilation or extracorporeal
membrane oxygenation.
Inhibition of Janus kinases (JAK), a family of cytoplasmic tyrosine
kinases that participate in the intracellular signalling downstream the
receptors of multiple cytokines, including IL-2, IL-6, IL-10,
interferon-γ, and granulocyte–macrophage colony-stimulating factor, has
been proposed as a potential therapeutic strategy for severe SARS-CoV-2
infection [8]. Moreover, the JAK 1/2 inhibitor baricitinib was
postulated to exert direct anti-viral effects preventing SARS-CoV-2
cellular entry [9]. In a double blind, randomised,
placebo-controlled trial, baricitinib plus remdesivir was superior to
remdesivir alone in reducing recovery time and accelerating improvement
in clinical status among hospitalised adults with COVID-19 [10]. The
survival rate and the time-to-death analyses favoured this combination,
particularly among those requiring high-flow nasal oxygen or
non-invasive ventilation. The differences between the two groups,
however, did not reach statistical significance, although the odds of
progression to death or invasive ventilation were 31% lower in the
combination than in the control group.
Tofacitinib is an orally administered, non-selective JAK-inhibitor that
is approved for treatment of various inflammatory diseases. The recently
published, randomised placebo-controlled trial from Brazil, treatment
with tofacitinib led to a lower risk of death or respiratory failure
through day 28 than placebo among patients hospitalised with COVID-19
pneumonia [11].
The objective of this study (TOFA-COV-2) was to assess the efficacy of
tofacitinib in reducing the risk of invasive mechanical ventilation or
death in patients with moderately severe COVID-19.