Biologic Disease-Modifying Antirheumatic Drugs to Treat Multisystem Inflammatory Syndrome in Children

Randy Q. Cron


Curr Opin Rheumatol. 2022;34(5):274-279. 

In This Article

Pathophysiology of Multisystem Inflammatory Syndrome in Children

Although MIS-C was a surprise to the world during the early phase of the SARS-CoV-2 pandemic, there had been previous coronavirus outbreaks associated with KD-like illness.[13] This led some to suggest that KD should be considered a syndrome, rather than a disease, that can potentially result from several infectious or environmental triggers.[14] The fact that the peak of MIS-C cases occurred approximately one month following the peak of COVID-19 in various geographic outbreaks, combined with the presence of SARS-CoV-2 antibodies and frequently negative RT-PCR evidence of ongoing infection, suggested that MIS-C was a postinfectious process. Even when PCR evidence of the virus was detected in children with MIS-C, the viral burden (perhaps residual viral nucleic acid) was exceeding low (e.g. required high PCR cycle numbers for detection).[15] Thus, therapy focused quickly on dampening the hyper-inflammatory immune response rather than antiviral approaches. A recent report suggested that the combination of IVIg, a traditional biologic agent, with GCs is associated with a lower risk of new or persistent cardiovascular involvement than IVIg alone.[16] This likely bespeaks to the severe inflammatory state associated with MIS-C and its inclusion under the broad cytokine storm syndrome (CSS) umbrella.[17]

The prototypic CSS is familial hemophagocytic lymphohistiocytosis (fHLH) which typically presents in infancy as a result of largely homozygous (autosomal recessive) genetic defects in genes critical to the perforin-mediated cytolytic pathway employed by cytotoxic lymphocytes (CD8+ T cells and natural killer (NK) cells).[18] Absent or delayed killing of virally-infected antigen presenting cells (APC) not only results in viral persistence (the trigger in genetically susceptible hosts) but in prolonged interaction between the cytolytic lymphocyte and the APC. This prolonged engagement resulting from defective cytolysis yields increased pro-inflammatory cytokine production (e.g. TNF, IFNγ) believed to contribute to the multiorgan system failure of CSS.[19–21] As fHLH is rare (1 in 5000 live births), heterozygous hypomorphic[22] or dominant-negative defects in fHLH genes[21,23] are believed to contribute to the much more common secondary forms of HLH[24] through a threshold model of disease.[25] There has even been evidence for fHLH heterozygous gene defects serving as a risk factor for developing severe COVID-19[26,27] similar to what has been reported for H1N1 influenza.[28]

Few studies have explored genetic contributions as to why some children go on to develop MIS-C while most infected with SARS-CoV-2 do not. Recently, heterozygous defects in immune related genes (e.g. TLR3, IFNB1) were identified among a cohort of MIS-C children from the Middle East.[29] Previously, haploinsufficiency in SOCS1 (suppressor of cytokine signaling 1) was reported in children with MIS-C.[30] The same group of investigators also identified a boy with MIS-C possessing a missense mutation in the X-linked gene XIAP.[31] Intriguingly, mutations in XIAP are established risk factors for HLH development.[32] Similarly, a toddler with MIS-C was found to have homozygous defects in the fHLH gene STX11.[33] Along these lines of reason, a recent cohort of 39 children with MIS-C was explored for fHLH gene mutations, and 25% possessed heterozygous mutations in traditional HLH genes (LYST, STXBP2, PRF1, UNC13D, AP3B1) and DOCK8,[34] a newly proposed HLH gene.[18,34,35] Thus, genetic defects in HLH genes may serves as risk alleles for developing the CSS associated with MIS-C (Table 2).

The clinical and laboratory features of CSS were present in studied cohorts of children with MIS-C; however, the severity of many of the laboratory features detected in the blood did not reach the extent of elevation as seen in more traditional CSS, like macrophage activation syndrome (MAS).[7,36] While markers of CSS/MAS, including sCD25, ferritin, IL-18, and CXCL9 (indirect correlate with interferon-gamma (IFNγ)), were elevated in children with MIS-C, the degree of elevation was typically a log or more less than detected in children with other causes of CSS/MAS.[9] The initial reports evaluating the cytokine milieu in children with MIS-C identified IL-1β, IL-6, IL-10, TNF, and IFNγ as cytokines elevated in the serum of children with MIS-C.[9,15] Whereas IL-10 is a regulatory cytokine likely representing the body's attempt to dampen the ongoing hyper-inflammatory state, the other elevated cytokines are all targetable with currently available bDMARDs.[32] Recently, it was reported that patients with MIS-C and HLH both show robust T cell activation with elevated T-helper-1 (Th1) and pro-inflammatory cytokines, including IFNγ.[37] Again, the amplitude of cytokinemia was higher in HLH than MIS-C, and MIS-C patients also had a distinguishing feature of elevated Th2 cytokines such as IL-4 and IL-13.[37] Fortunately, these immune parameters were resolved at MIS-C follow-up visits.[37] Thus, although not identical to HLH, MIS-C patients share a hyper-inflammatory phenotype providing rationale for biologic therapeutics targeting pro-inflammatory cytokines.