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.