Variation in Early Anakinra Use and Short-Term Outcomes in Multisystem Inflammatory Syndrome in Children

Abstract

Objective: Evidence regarding effectiveness of interleukin-1 receptor antagonism in multisystem inflammatory syndrome in children (MIS-C) is lacking. We characterized variation in initial treatment with anakinra and evaluated cardiovascular outcomes associated with adding anakinra to standard initial therapy.

Methods: We conducted a retrospective cohort study of MIS-C cases in a US surveillance registry from November 2020 to December 2021. Day 0 was the first calendar day of immunomodulatory treatment. Factors associated with initial anakinra use (days 0-1) were identified. We compared cases in patients ages 2-20 years receiving intravenous immunoglobulin (IVIG) and glucocorticoids versus anakinra plus IVIG and/or glucocorticoids on days 0-1, using inverse probability weighting to balance disease severity. Primary outcomes were vasopressor requirement on day 3 and impaired left ventricular ejection fraction on days 3-4. The secondary outcome was 50% reduction in C-reactive protein on day 3.

Results: Among 1,516 MIS-C cases at 44 sites, 193 (13%) patients received anakinra alone or with other immunomodulators as initial treatment (range 0-74% by site). Site accounted for 59% of residual variance in anakinra use. After balancing disease severity, initial treatment with anakinra plus IVIG and/or glucocorticoids (n = 121) versus IVIG plus glucocorticoids (n = 389) was not associated with significant differences in vasopressor requirement (25.6% versus 20.1%, respectively; risk ratio [RR] 1.27 [95% confidence interval (95% CI) 0.88-1.84]), ventricular dysfunction (33.7% versus 25.7%, respectively; RR 1.31 [95% CI 0.98-1.75]), or C-reactive protein reduction.

Conclusion: We identified substantial variation in initial anakinra use in a real-world population of children with MIS-C, but no average short-term improvement in cardiovascular outcomes associated with early addition of anakinra to IVIG and/or glucocorticoids compared to IVIG and glucocorticoids alone.

Figure 1.

Bar graph representing the proportion of MIS-C cases contributed by each site that received anakinra alone or in combination with other immunomodulators as initial treatment on days 0–1, in ascending order. Each bar is labeled on the x-axis with the total number of MIS-C cases contributed by that site.

Figure 2.

Flow diagram of selection criteria and sample sizes at each stage of the propensity weighted analysis. Boxes with thick borders indicate the final sample sizes in the inverse probability of treatment weighted estimates of the average treatment effect (ATE) of anakinra plus intravenous immunoglobulin (IVIG) and/or glucocorticoids (GC) compared to IVIG and GC alone. *Cases with a <10% predicted probability of receiving either treatment were removed to preserve clinical equipoise; in this cohort, only those with <10% probability of receiving anakinra needed to be removed, as no cases had <10% probability of receiving only IVIG and GC.

Figure 3.

Standardized mean differences in individual covariates between the anakinra plus IVIG and/or glucocorticoid initial treatment group (N=121) and the IVIG and glucocorticoid initial treatment group (N=389), before and after inverse probability of treatment weighting. By convention, standardized differences less than 0.1 indicate adequate balance. eGFR = estimated glomerular filtration rate; LVEF = left ventricular ejection fraction; CRP = C-reactive protein; N/L ratio = neutrophil:lymphocyte ratio; SVI = social vulnerability index

Figure 4.

Relative risks (RR) of clinical outcomes in children with MIS-C receiving anakinra as initial therapy (with intravenous immunoglobulin [IVIG] and/or glucocorticoids [GC]) compared to IVIG and GC alone, estimated using inverse probability weighted models with site-level random effects. Clinical outcomes were assessed on day 3 of treatment, except for left ventricular ejection fraction (LVEF), which was assessed on day 3–4, using either complete case analysis (N=327 LVEF recorded on day 3–4) or last observation carried forward (N=497). The direction of the average treatment effect for C-reactive protein (CRP) is represented as failure to achieve 50% reduction in CRP from admission.