IL-1 inhibitors linked to ‘significant reduction’ in COVID-19 mortality
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Interleukin-1 inhibitors are associated with a “significant reduction” in mortality among patients hospitalized with COVID-19, respiratory insufficiency and hyperinflammation, according to data published in The Lancet Rheumatology.
However, this association was not found with IL-6 inhibition, which was only effective in patients with “markedly high” C-reactive protein concentrations, the researchers noted.
“A subset of patients with severe COVID-19 develop a life-threatening hyperinflammatory response to the virus, which resembles the cytokine storm that develops after chimeric antigen receptor T-cell treatment or in macrophage activation syndrome, with release of interleukin (IL)-1, IL-6, IL-18, and interferon-,” Giulio Cavalli, MD, of Vita-Salute San Raffaele University, in Milan, Italy, and colleagues wrote. “To reduce deaths among patients with COVID-19 and hyperinflammation, treatment with cytokine-blocking biological agents has been proposed, with IL-6 and IL-1 as the most promising targets.”
“Currently, available evidence overall argues against the use of IL-6 inhibitors to treat COVID-19,” they added. “However, crucial questions remain unanswered pertaining to the role and therapeutic potential of IL-1 inhibition in COVID-19 — specifically, whether IL-1 inhibition confers an advantage over standard management, whether IL-1 inhibition is more effective than IL-6 inhibition, and how to identify those individuals who are most likely to benefit (or to deteriorate) upon treatment.”
To compare the impacts of IL-1 and IL-6 inhibitors among patients hospitalized with COVID-19, respiratory insufficiency and hyperinflammation, Cavalli and colleagues conducted a cohort study of individuals admitted to San Raffaele Hospital. For this study, respiratory insufficiency was defined as a ratio of the partial pressure of oxygen to the fraction of inspired oxygen of 300 mm Hg or less. Meanwhile, hyperinflammation was identified based on a serum C-reactive protein concentration of 100 mg/L or more, or a ferritin concentration of at least 900 ng/mL.
In all, the study included 392 patients, enrolled between Feb. 25, 2020, and May 20, 2020. Among these participants, 62 received the IL-1 inhibitor anakinra (Kineret, SOBI), while 55 received an IL-6 inhibitor — 29 received tocilizumab (Actemra, Genentech) and 26 were treated with sarilumab (Kevzara; Regeneron, Sanofi). A total of 275 received no interleukin inhibitors. The primary endpoint was survival, with a composite secondary endpoint of death or mechanical ventilation as an adverse clinical outcome.
All participants received standard of care. The researchers used multivariable Cox regression analysis to compared clinical outcomes between the interleukin treatment groups, accounting for baseline differences. They also used interaction tests to examine the probability of survival based on C-reactive protein or lactate dehydrogenase concentrations.
According to the researchers, the multivariable analysis found that patients who received IL-1 inhibitors demonstrated a significantly reduced mortality risk (HR = 0.45; 95% CI, 0.204-0.99), compared with those who went without any interleukin inhibitors. However, patients in the IL-6 inhibition group did not (HR = 0.9; 95% CI, 0.412-1.966. The multivariable analysis also showed that there was no difference in adverse clinical outcome risk among patients treated with IL-1 (HR = 0.866; 95% CI, 0.482-1.553) or IL-6 (HR = 0.882; 95% CI, 0.452-1.722) inhibitors relative to patients who did not receive any interleukin therapy.
However, for increasing C-reactive protein concentrations, participants treated with IL-6 inhibitors did demonstrated a significantly reduced risk of mortality (HR = 0.99; 95% CI, 0.981-0·999) and adverse clinical outcomes (HR = 0.987; 95% CI, 0.979-0·995), compared with those without interleukin inhibitors.
For decreasing concentrations of serum lactate dehydrogenase, patients in both the IL-1 and IL-6 inhibition groups had a reduced risk of mortality. However, for increasing concentrations, participants in both groups were associated with an increased risk of mortality (IL-1 HR = 1.009; 95% CI, 1.003-1.014 and IL-6 HR = 1.006; 95% CI, 1.001-1.011) and adverse clinical outcomes (IL-1 HR = 1.006; 95% CI, 1.002-1.010 and IL-6 HR = 1.005; 95% CI, 1.001-1.010), compared with those who did not receive interleukin inhibitors.
“IL-1 inhibition, but not IL-6 inhibition, was associated with a significant reduction of mortality in a large cohort of patients admitted to hospital with COVID-19 and hyperinflammation,” Cavalli and colleagues wrote. “IL-6 inhibition was only effective in a subgroup of patients with markedly high C-reactive protein concentrations, whereas both IL-1 inhibition and IL-6 inhibition were more effective in patients with low lactate dehydrogenase concentrations. Validation of these study findings, particularly concerning the efficacy of IL-1 inhibition in COVID-19, requires controlled investigations.”
Perspective
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Rheumatologists, as well as a number of our medications, have been tapped to treat some of the more serious complications of COVID-19 during the pandemic. Some, like hydroxychloroquine, have been shown to be ineffective and eventually passed on, while others show much more promise.
The study by Cavalli and colleagues provides several key insights into the hyperinflammatory state seen in COVID-19 infections and its optimal management. First, it demonstrates the superiority of IL-1 inhibition in addressing COVID-19 hyperinflammation. This is likely attributable to the upstream position of IL-1 in the inflammatory cascade (i.e., inhibition of IL-1 will also directly lead to a reduction in IL-6). Second, it identifies specific subgroups of patients who will benefit more from specific cytokine inhibition. Specifically, patients with lower LDH levels appear to benefit more from either form of cytokine inhibition.
This finding highlights the importance of employing this therapeutic approach earlier in the course of the disease before patients have experienced extensive tissue damage and become more refractory to treatment. Finally, while it bolsters the findings from previous large RCTs that have demonstrated the relative inefficacy of IL-6 inhibition, it does reveal a select group of patients with markedly elevated CRP levels for whom IL-6 inhibition may still be a viable treatment option.
Given the urgent nature of managing critically ill COVID-19 patients, there are some inherent real-world limitations in executing carefully controlled studies when evaluating different therapeutic approaches. As such, cohort studies such as this one are a primary source of data when evaluating various treatment strategies. As acknowledged by the authors, there are several confounding factors which bear noting, including significant baseline clinical and demographic differences in the disparate treatment arms, unavailability of two potentially important prognostic data points (i.e., ineligibility to respiratory support and D-dimer levels), inclusion of two different IL-6 inhibitors that were analyzed as a single treatment option and the limited sample size.
As we have seen over the last year, our understanding of COVID-19 is continually evolving and we course-correct as more real-world data is collected. This study adds significantly to this knowledge base, warrants controlled trials of IL-1 inhibition, and provides potentially actionable strategies to help mitigate the catastrophic outcomes seen in some individuals with COVID-19 infections.
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