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People randomized to the Janus kinase (JAK) inhibitor baricitinib (Olumiant) to treat COVID-19 pneumonia in a clinical trial only saw a survival benefit if they had obesity, a post-hoc analysis found.

Death within 28 days of starting treatment occurred in 5.6% of patients with body mass index (BMI) values >30, compared with 9.2% of those assigned to placebo, according to Dennis G. McGonagle, MBBCh, PhD, of the University of Leeds in England, and colleagues.

That translated to an age-adjusted rate ratio of 0.6 (P<0.05), the group . A similar gap was seen in overweight patients (BMI ≥25 and ≤30).

In contrast, the same comparison made in patients with BMI <25 yielded survival rates of 6.6% with baricitinib versus 8.1% in the placebo group, which missed the P<0.05 threshold. The nonsignificance was not easily attributable to small sample size, as there were 120 and 132 patients with normal-range BMI assigned to baricitinib and placebo, respectively, and a total of 26 deaths among them.

The new findings come from an age- and BMI-stratified analysis of data from the multinational , conducted early in the pandemic, in which a total of 1,525 patients with COVID-19 pneumonia needing oxygen support were randomized to baricitinib or placebo on top of standard treatments including antivirals and/or corticosteroids. (Primary results were in 2021.) Approximately 17% of each arm were in the normal BMI range; roughly 40% were overweight and the remainder had obesity.

Overall, 162 patients died within 28 days, although seven of these were excluded from the analysis because data on BMI and age were missing. Most of the deaths occurred in patients 65 and older, who represented 30% of the total sample.

The investigators had no solid explanation for how excess body fat could make baricitinib more effective in COVID-19 pneumonia. In previous studies, COVID-19, obesity, and JAK inhibition all appeared to promote thrombosis, such that baricitinib ought to worsen, not improve, survival in COVID patients with overweight/obesity. Responses to JAK inhibitors in rheumatologic diseases have, indeed, among individuals with obesity.

"[O]ur findings are remarkable and suggest a hitherto unappreciated mechanism for this 'JAK thrombosis-related paradox,'" McGonagle and colleagues wrote. The group suggested that coagulability and thrombosis associated with obesity are key factors: "[T]his population has poorer tissue oxygenation and suffers more from COVID-19 immunothrombosis that is controlled when treated with baricitinib and standard COVID-19 therapy," they noted. In particular, the researchers argued that the use of corticosteroids alongside baricitinib may account for the "counterintuitive" results.

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