Table 1.

Genetic biomarkers proposed for the diagnosis, activity, and prognosis of sJIA and MAS.

Reference/Year	Predictive Effects in sJIA and MAS
[20]. De Benedetti, F.; Meazza, C.; Vivarelli, M.; Rossi, F.; Pistorio, A.; Lamb, R.; Lunt, M.; Thomson, W.; Ravelli, A.; Donn, R.; et al. Functional and prognostic relevance of the −173 polymorphism of the macrophage migration inhibitory factor gene in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2003, 48, 1398–407. https://doi.org/10.1002/art.10882	Patients with sJIA onset with MIF-173*C-allele-associated persistent active disease have higher concentrations of MIF in serum and synovial fluid, as well as a weaker response to glucocorticoid therapy. The MIF-173*C-positive allele in patients with sJIA is a predictor of poor steroid therapy outcomes.
[21]. Yanagimachi, M.; Naruto, T.; Miyamae, T.; Hara, T.; Kikuchi, M.; Hara, R.; Imagawa, T.; Mori, M.; Sato, H.; Goto, H.; Yokota, S. Association of IRF5 polymorphisms with susceptibility to macrophage activation syndrome in patients with juvenile idiopathic arthritis. J. Rheumatol. 2011, 38, 769–774. https://doi.org/10.3899/jrheum.100655	IRF5 gene polymorphism influences the susceptibility to MAS in sJIA, so IRF5 could trigger MAS in sJIA.
[22]. Canna, S.W.; de Jesus, A.A.; Gouni, S.; Brooks, S.R.; Marrero, B.; Liu, Y.; DiMattia, M.A.; Zaal, K.J.; Sanchez, G.A.; Kim, H.; et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat. Genet. 2014, 46, 1140–1146. https://doi.org/10.1038/ng.3089	An activating de novo mutation (c.1009A > T, p.Thr337Ser) in the nucleotide-binding domain of inflammasome component NLRC4 generates early-onset repeated episodes of fever, as well as MAS.
[23]. Ombrello, M.J.; Remmers, E.F.; Tachmazidou, I.; Grom, A.; Foell, D.; Haas, J.P.; Martini, A.; Gattorno, M.; Özen, S.; Prahalad, S. et al. International Childhood Arthritis Genetics (INCHARGE) Consortium. HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis. Proc. Natl. Acad. Sci. USA 2015, 112, 15970–15975. https://doi.org/10.1073/pnas.1520779112	HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA, as well as the HLA-DRB1*11 haplotypes HLA-DQA1*05–HLA-DQB1*03.
[24]. De Silvestri, A.; Capittini, C.; Poddighe, D.; Marseglia, G.L.; Mascaretti, L.; Bevilacqua, E.; Scotti, V.; Rebuffi, C.; Pasi, A.; Martinetti, M.; et al. HLA-DRB1 alleles and juvenile idiopathic arthritis: Diagnostic clues emerging from a meta-analysis. Autoimmun. Rev. 2017, 16, 1230–1236. https://doi.org/10.1016/j.autrev.2017.10.007	HLA-DRB1*04 was confirmed to play a predisposing role in sJIA.
[25]. Arthur, V.L.; Shuldiner, E.; Remmers, E.F.; Hinks, A.; Grom, A.A.; Foell, D.; Martini, A.; Gattorno, M.; Özen, S.; Prahalad, S.; et al. IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis. Arthritis Rheumatol. 2018, 70, 1319–1330. https://doi.org/10.1002/art.40498	sJIA-associated SNPs were interdependent with IL1RN expression in LCLs, with an inverse correlation between sJIA risk and IL1RN expression. Homozygous high-expression alleles predicted the failure of anakinra therapy, making them ideal candidate biomarkers to manage the treatment of sJIA.
[26]. Hou, X.; Qu, H.; Zhang, S.; Qi, X.; Hakonarson, H.; Xia, Q.; Li, J. The Multi-Omics Architecture of Juvenile Idiopathic Arthritis. Cells 2020, 9, 2301. https://doi.org/10.3390/cells9102301	Several HLA alleles (both HLA class I and class II genes) and 23 non-HLA genetic loci were associated with different JIA subtypes. HLA class II alleles were significantly associated with sJIA. HLA-DRB1*11 had a strong association and SNP rs151043342 had the strongest association with sJIA. Nuclear factor interleukin-3-regulated gene (NFIL3) mutations drove elevated IL-1β, sensitizing patients to arthritis and rewiring the innate immune system for overproduction of IL-1. The laccase (multicopper oxidoreductase) domain-containing 1 (LACC1) gene regulated inflammation (i.e., macrophages, dendritic cells, and TNF-α levels). The Unc-13 homolog D (UNC13D) gene disrupted transcription factor binding.
[27]. Zhou, M.; Guo, R.; Wang, Y.F.; Yang, W.; Li, R.; Lu, L. Application of Weighted Gene Coexpression Network Analysis to Identify Key Modules and Hub Genes in Systemic Juvenile Idiopathic Arthritis. BioMed Res. Int. 2021, 2021, 957569. https://doi.org/10.1155/2021/9957569	The ALAS2, AHSP, TRIM10, TRIM58, and KLF1 genes were associated with sJIA, but also with the differentiation of red blood cells, which may be related to anemia or MAS. The KLRB1, KLRF1, CD160 and KIR genes might have a relationship with the dysregulation of NK cell function in sJIA. These results may deepen the comprehension of the pathophysiology of sJIA, and the hub genes may play the part of future biomarkers and treatment targets for sJIA.
[28]. Zhang, M.; Dai, R.; Zhao, Q.; Zhou, L.; An, Y.; Tang, X.; Zhao, X. Identification of Key Biomarkers and Immune Infiltration in Systemic Juvenile Idiopathic Arthritis by Integrated Bioinformatic Analysis. Front. Mol. Biosci. 2021, 8, 681526. https://doi.org/10.3389/fmolb.2021.681526	The hub genes ARG1 and PGLYRP1 are potential biomarkers for the early diagnosis of sJIA.
[29]. Ren, Y.; Labinsky, H.; Palmowski, A.; Bäcker, H.; Müller, M.; Kienzle, A. Altered molecular pathways and prognostic markers in active systemic juvenile idiopathic arthritis: integrated bioinformatic analysis. Bosn. J. Basic Med. Sci. 2022, 22, 247–260. https://doi.org/10.17305/bjbms.2021.6016	A total of 118 DEGs were identified, of which 94 were upregulated (most: CD177, OLFM4, ARHGEF12, MMP8, PLOD2, CEACAM6, and CEACAM8) and 24 were downregulated (most: TCL1A, ALOX15, and HLA-DQB) in active sJIA. A hub gene set of eight upregulated genes (ARG1, DEFA4, HP, MMP8, MMP9, MPO, OLFM4, and PGLYRP1) and none downregulated was also identified. TPM2 and GZMB were identified as possible markers of positive short-term responses to canakinumab.