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28th June 2021
It has become increasing clear that severe manifestations of COVID-19 are largely driven by an exaggerated immune response by interleukin-6, tumour necrosis factor and other cytokines and which has been described as a cytokine storm. Tofacitinib is an oral Janus kinase inhibitor which blocks signal transduction once a cytokine has attached to its cell surface receptor, hence attenuating the cellular response. Furthermore, tofacitinib suppresses the production of both interleukin-17 and interferon-gamma which are implicated in the pathogenesis of acute respiratory distress syndrome, a common complication from infection with COVID-19. Thus, tofacitinib has the potential to act on more than one pathway to help ameliorate the damage that occurs in those infected with COVID-19. Based on these likely benefits, a team from the Hospital Israelita, Albert Einstein, Sao Paulo, Brazil, undertook a randomised, double-blind, placebo, controlled trial, to investigate the safety and efficacy of tofacitinib in patients hospitalised with COVID-19 pneumonia and who were not in receipt of either non-invasive or invasive ventilation. Patients were 18 years and over and a positive PCR test for COVID-19 and who had radiographic evidence of pneumonia and randomised (1:1) to tofacitinib or placebo. Tofacitinib was given as an oral dose of 10mg twice daily for up to 14 days or until hospital discharge. All participants received standard care and which included the use of glucocorticosteroids, antibiotics, anticoagulants and antiviral agents although concomitant use of other JAK inhibitors or interleukin-6 inhibitors were not permitted. All patients were assessed daily up to day 28 while in hospital. The primary outcome was death or respiratory failure during the 28-day follow-up period and a secondary outcome was the cumulative incidence of death through any cause up to day 28.
A total of 289 patients with a mean age of 56 years (34.9% female) were included and randomised to tofacitinib (144) or matching placebo (145). Furthermore, a third (34.9%) of patients were aged 65 years and over and the majority (83.4%) of White ethnicity. The most common co-morbidity was hypertension (50.2%) followed by diabetes (23.5%) and dyslipidaemia (17.3%) and the median body mass index was 29.7. Death or respiratory failure (the primary outcome) occurred in 18.1% of those receiving tofacitinib and in 29% of those assigned to placebo (risk ratio, RR = 0.63, 95% CI 0.41–0.97, P = 0.04). In addition, death due to any cause (a secondary outcome) occurred in 2.8% of the tofacitinib group and 5.5% of the placebo group although this difference was not statistically significant.
Discussing their findings, the authors commented how the beneficial effects of tofacitinib appeared to be independent of age, gender or use of standard care therapy such as corticosteroids. They proposed that the data in the current study suggested an added benefit from the use of JAK inhibitors in patients with COVID-19-related pneumonia.
Guimaraes PO et al. Tofacitinib in Patients Hospitalised with Covid-19 Pneumonia. N Eng J Med 2021