IL-6 Receptor Antagonists and Severe Post-COVID-19 Outcomes: An Emulated Target Trial

Mar 13, 2026medRxiv : the preprint server for health sciences

Blocking IL-6 Receptors and Severe Health Problems After COVID-19: A Simulated Trial

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Long Covid on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

In a cohort of 3,553 patients, IL-6 receptor antagonists were associated with a 40% lower risk of 12-month cumulative mortality compared to other biologic agents.

Prescription of IL-6 receptor antagonists was linked to a lower risk of diagnosed Long COVID, with an adjusted relative risk of 0.42.
Patients receiving IL-6 receptor antagonists had a reduced likelihood of probable Long COVID, indicated by an adjusted relative risk of 0.71.
The findings suggest that IL-6 receptor antagonists may help mitigate severe post-COVID-19 outcomes among patients with rheumatoid arthritis.

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BACKGROUND: Interleukin-6 (IL-6) is a cytokine that plays a key role in systemic hyperinflammation and may mediate the relationship between acute COVID-19 and severe long-term outcomes such as Long COVID or death. IL-6 modulating drugs may reduce patients' risk of severe post-COVID-19 outcomes.

METHODS: We conducted an emulated target trial in a retrospective cohort of patients with moderate-to-severe rheumatoid arthritis who were prescribed IL-6 receptor antagonists (sarilumab or tocilizumab, pooled treatment) or other biologic agents (anakinra or baricitinib, pooled comparator) in 2022. We compared the 12-month cumulative incidence of mortality and Long COVID (diagnosed and probable) between groups using Super Learner and targeted maximum likelihood estimation, adjusting for covariates of interest.

RESULTS: In our cohort of 3,553 patients, we found that prescription of IL-6 receptor antagonists was associated with a lower 12-month cumulative mortality (adjusted relative risk (aRR) 0.40, 95% CI 0.27, 0.59), diagnosed Long COVID aRR 0.42, 95% CI 0.23, 0.78), and probable Long COVID (aRR 0.71, 95% CI 0.61, 0.83), compared to prescription of other biologic agents, among rheumatoid arthritis patients.

CONCLUSIONS: IL-6 receptor antagonists may prevent the incidence of severe post-COVID-19 outcomes, such as Long COVID or mortality. This supports the hypothesis that IL-6 may be a mechanistic biomarker of COVID-19 sequelae and that acute COVID-19 severity may mediate this relationship.