medwireNews: Autoantibodies against interleukin-1 receptor antagonist (IL-1Ra) are present in a large proportion of patients with multisystem inflammatory syndrome in children (MIS-C), say researchers.
The study, which is published in The Lancet Rheumatology, involved 21 patients with MIS-C aged a median of 7 years who were treated in hospitals in Germany and Spain.
“Although the small number of patients with MIS-C enrolled in this study might pose a limitation, the high numbers of controls (both inflammatory and non-inflammatory) highlight our findings as unique rather than an epiphenomenon,” say Lorenz Thurner (Saarland University, Homburg, Germany) and study co-authors.
The team detected anti-IL-1Ra antibodies in 62% of the MIS-C patients, but in none of 33 children with a suspected growth disorder, 24 with Kawasaki disease, 10 with inactive systemic juvenile idiopathic arthritis (JIA), 146 with mild or asymptomatic COVID-19, or 462 healthy children.
The finding of anti-IL-1Ra antibodies in the MIS-C patients is “in accordance with those in our preprint paper on adults with critical COVID-19, in whom anti-IL-1Ra antibodies were detected in a high proportion of patients (about 50%),” say the researchers.
Antibody titers in the children ranged from 1 in 200 to 1 in 800 and all but one patient had exclusively immunoglobulin (Ig)G antibodies; the other also had IgM antibodies.
The team previously detected progranulin antibodies in a high proportion of adults with critical COVID-19, but these appeared in just one of the MIS-C patients.
In line with the presence of the autoantibodies, plasma levels of free IL-1Ra were significantly lower in patients with autoantibodies than in those without, at an average of 279.4 versus 1746.0 pg/mL. Their levels were also significantly lower than in two tested control groups (Kawasaki disease and JIA) and this remained the case after excluding two MIS-C patients who had received intravenous Ig prior to having blood samples taken.
Of note, the researchers identified a hyperphosphorylated version of IL-1Ra in all the MIS-C patients with autoantibodies but none in those without or in any of the tested controls.
And in two MIS-C patients with follow-up blood samples, “we observed the disappearance of hyperphosphorylated IL-1Ra, which preceded the disappearance of anti-IL-1Ra antibodies,” say Thurner and team.
They conclude: “Collectively, data from both COVID-19 and MIS-C suggest that atypical post-translational modifications are associated with SARS-CoV-2-infection itself or the resulting inflammatory environment, and that these modifications are likely to be immunogenic.”
Writing in a linked commentary, Hamid Bassiri and Scott Canna, both from The Children’s Hospital of Philadelphia in Pennsylvania, USA, say: “These observations are provocative, placing IL-1 signalling downstream of SARS-CoV-2 infection but upstream of hyperinflammation in patients with MIS-C.”
They highlight remaining questions, including what triggers IL-1Ra hyperphosphorylation, why adults with anti-IL-1Ra autoantibodies do not develop MIS-C, and what mechanisms account for MIS-C in patients without these autoantibodies.
The commentators caution that given the limitations of the study – including few longitudinal samples and incomplete mechanistic evaluation – the findings “should neither affect clinical decision making, nor favour an expanded front-line use of anakinra (recombinant IL-1Ra) in patients with MIS-C, particularly given the complete response of most patients to IVIG and glucocorticoids.”
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group
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Lancet Rheumatol 2022; doi:10.1016/S2665-9913(22)00064-9
Lancet Rheumatol 2022; doi:10.1016/S2665-9913(22)00090-X