Biologic disease-modifying antirheumatic drugs to treat multisystem inflammatory syndrome in children

Abstract

Purpose of reviewMultisystem inflammatory syndrome in children (MIS-C) is a postinfectious complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection primarily affecting children. MIS-C shares features with Kawasaki disease (KD) and cytokine storm syndrome (CSS) frequently requiring intensive care support. Although intravenous immunoglobulin (IVIg) and glucocorticoids (GCs) are effective therapeutics for most, refractory MIS-C is treated with various biologic disease-modifying antirheumatic drugs (bDMARDs). Understanding the clinical features, inflammatory cytokines, and genetic associations provides rationale for bDMARD in treating severe MIS-C. Recent findingsChildren with MIS-C have clinical KD features and often present in hypovolemic and cardiogenic shock requiring volume repletion (gastrointestinaI losses) and cardiac pressor support (epinephrine). Investigation of MIS-C serum reveals elevated pro-inflammatory cytokines [interleukin (IL)-1, IL-6, IL-18, interferon gamma (IFNg), tumor necrosis factor (TNF)], but to a lesser extent than other established CSS. Gene sequencing of MIS-C children identifies heterozygous mutations in CSS associated genes. Treatment of refractory (IVIg and GC) MIS-C with bDMARDs to IL-1, IL-6, and TNF is efficacious for survival as well as resolving cardiac and coronary artery inflammation. Summary MIS-C is a postinfectious complication of SARS-CoV-2 resembling KD and CSS, both genetically and by pro-inflammatory cytokines. MIS-C that is refractory to IVIg and GC is routinely responsive to bDMARDs targeting IL-1, IL-6, and TNF.

Prediction of intravenous immunoglobulin retreatment in children with Kawasaki disease using models combining lymphocyte subset and cytokine profile in an East Asian cohort

“…As a component of the acute‐phase immune response, TNF‐α is trace or undetectable in healthy individuals, but its levels increase during the inflammatory state 38 . Serum TNF‐α levels have been reported to be notably elevated in children with KD 12 . However, the efficacy of the anti‐TNF‐α antibody infliximab in preventing the development of CAA in the pathogenesis of KD is controversial 4,14,39 .…”

“…However, there is significant variation in the identified independent risk factors for KD among children from different cities within the same region 7–11 . In addition, these prediction models tended to focus more on clinical features and indicators rather than on items associated with specific aspects of inflammation 11–15 . The diverse clinical perspectives on KD among researchers result in different factors being included in predictive models, and the varying number of cases can also lead to the development of distinct models.…”

“… 7 , 8 , 9 , 10 , 11 In addition, these prediction models tended to focus more on clinical features and indicators rather than on items associated with specific aspects of inflammation. 11 , 12 , 13 , 14 , 15 The diverse clinical perspectives on KD among researchers result in different factors being included in predictive models, and the varying number of cases can also lead to the development of distinct models. In fact, increasing evidence shows the pathogenesis of KD is mainly promoted by abnormal and unbalanced innate and adaptive immune responses.…”

Clinical Features of COVID-19 in Pediatric Rheumatic Diseases: 2020–2022 Survey of the Pediatric Rheumatology Association of Japan

“…Pediatric COVID-19 infections are associated with specific sequela. Multisystem inflammatory syndrome in children (MIS-C) is a postinfectious complication of SARS-CoV-2 infection primarily affecting children [ 16 ]. Many patients with MIS-C had a documented history of COVID-19 within the two months before developing MIS-C during the Omicron variant epidemic [ 17 ].…”

“…Although intravenous immunoglobulin and glucocorticoids are effective therapeutics for most patients with MIS-C, patients with refractory MIS-C are treated with various biologics. Understanding the clinical features and the role of inflammatory cytokines provides a rationale for using biologics in treating severe MIS-C [ 16 ].…”