Interleukin-6 receptor blockade in patients with COVID-19: placing clinical trials into context

Abstract

The pleiotropic cytokine interleukin-6 (IL-6) has been implicated in the pathogenesis of COVID-19, but uncertainty remains about the potential benefits and harms of targeting IL-6 signalling in patients with the disease. The efficacy and safety of tocilizumab and sarilumab, which block the binding of IL-6 to its receptor, have been tested in adults with COVID-19-related acute respiratory illness in randomised trials, with important differences in trial design, characteristics of included patients, use of co-interventions, and outcome measurement scales. In this Series paper, we review the clinical and methodological heterogeneity of studies of IL-6 receptor antagonists, and consider how this heterogeneity might have influenced reported treatment effects. Timing from clinical presentation to treatment, severity of illness, and concomitant use of corticosteroids are among the factors that might have contributed to apparently inconsistent results. With an understanding of the sources of variability in these trials, available evidence could be applied to guide clinical decision making and to inform the enrichment of future studies.

Figure

Proposed use of IL-6R blockade in patients with COVID-19-associated hypoxaemic respiratory failure A conceptual model of the time-course of infection from the asymptomatic phase to more severe phases in patients who develop critical illness. The model includes completed RCTs and the main physiological features of disease in each phase. We propose a potential time window in which IL-6R blockade might be more effective. The length of each RCT box is proportional to the time from symptom onset or hospitalisation to randomisation in each trial population, and the location corresponds to the severity, on average, of enrolled patients. For many patients, the progression from the asymptomatic phase to critical illness occurs in a short period of time, and the current representation might not be applicable in the case of rapid progression. Trials that appear in light orange are those that were positive for the primary outcome. ICU=intensive care unit. IL-6R=interleukin-6 receptor. RCT=randomised controlled trial. Figure originally created using BioRender.