Background/Purpose: Multisystem inflammatory syndrome in children (MIS-C) is a novel clinical entity presenting following SARS CoV2 infection. This study describes a subgroup of MIS-C patients that develop a systemic juvenile idiopathic arthritis (sJIA)-like illness. Their clinical characteristics, treatment response, patient outcomes, and biologic data are compared to a large cohort of MIS-C patients. No specific diagnostic tests are available to differentiate between MIS-C and sJIA. Polygenic risk score (PRS) analysis will assess whether the genetic burden in sJIA is also seen in MIS-C.

Methods: Clinical data and biospecimens from treatment naïve MIS-C patients were collected prospectively within a single tertiary care center. All MIS-C patients fulfilled the Royal College of Paediatrics and Child Health case definition. 70% of the co-diagnosis patients satisfied CDC MIS-C criteria. Whole genome sequencing was performed on a subset of 249 samples (68 MIS-C, 181 acute COVID controls) using Illumina Nextera Custom Capture Assays and Illumina sequencers. Called variants were identified using Dragen. Publicly available genome-wide association study summary statistics for COVID-19 severity and sJIA were utilized for calculating PRS for each individual via the Pruning+Thresholding method. The top four principal components adjusted the PRS to avoid confounding due to population stratification, followed by logistic regressions to test the association between the constructed scores and MIS-C. Best models were selected based on the highest variability explained using Nagelkerke R-squared as a metric.

Results: Ten MIS-C patients of the 298 studied, were diagnosed and treated with an sJIA-like illness. The evolution of the sJIA-like illness was insidious with a co-diagnosis made a median of 40 days following the initial MIS-C diagnosis. In comparison to the MIS-C patients, the co-diagnosis subgroup had a longer duration of fever, with a greater incidence of arthritis, macrophage activation syndrome and also development of coronary artery lesions. Biochemically, the two groups had notable differences. The sJIA-MISC patients had greater leukocytosis, neutrophilia, more substantial anemia, hyperferritinemia and elevations in ESR. In terms of disease severity, co-diagnosis patients had a longer length of stay and requirement for respiratory support. All 10 co-diagnosis patients required biologic therapy. All received IL-1 inhibition, however, disease was refractory in 30% and subsequently required IL-6 inhibition.

We calculated two PRSs (COVID-19 severity and sJIA), representing distinct biologic pathways to investigate shared genetic contributions with MIS-C. No significant association between MIS-C and acute COVID-19 severity PRS (p=0.451, OR = 1.023, 95% CI [0.9645,1.0845]) was observed. However, SJIA PRS was found to be significantly associated with the MIS-C status (p=0.014, OR = 1.063, 95% CI [1.0136,1.1182]) after Bonferroni correction.

Conclusion: MIS-C and sJIA have overlapping clinical features and treatments, as well as shared genetic contributions suggesting shared immunobiology.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/multisystem-inflammatory-syndrome-in-children-and-systemic-juvenile-idiopathic-arthritis-share-clinical-phenotypes-and-genetic-contributions/