Table 4.

Chemokines and other biomarkers for the diagnosis, activity, and prognosis of sJIA and MAS.

Reference/Year	Chemokines and Other Biomarkers	Predictive Effects in sJIA and MAS
[146]. Mizuta, M.; Shimizu, M.; Inoue, N.; Nakagishi, Y.; Yachie. A. Clinical Significance of Serum CXCL9 Levels as a Biomarker for Systemic Juvenile Idiopathic Arthritis Associated Macrophage Activation Syndrome. Cytokine 2019, 119, 182–187. https://doi.org/10.1016/j.cyto.2019.03.018	CXCL9	CXCL9 showed the most significant increase following the onset of sJIA-MAS and was positively correlated with disease activity. Monitoring the serum levels of this chemokine would enable surveillance of sJIA-MAS.
[147]. Hinze, T.; Kessel, C.; Hinze, C.H.; Seibert, J.; Gram, H.; Foell, D. A dysregulated interleukin-18-interferon-γ-CXCL9 axis impacts treatment response to canakinumab in systemic juvenile idiopathic arthritis. Rheumatology 2021, 60, 5165–5174. https://doi.org/10.1093/rheumatology/keab113		There was a differential regulation of the IL-18–IFN-γ–CXCL9 axis in patients with sJIA, and the higher the IL-18/CXCL9 and IFN-γ/CXCL9 ratios, the better the clinical outcome in response to canakinumab in sJIA.
[148]. Bleesing, J.; Prada, A.; Siegel, D.M.; Villanueva, J.; Olson, J.; Ilowite, N.T.; Brunner, H.I.; Griffin, T.; Graham, T.B.; Sherry, D.D.; et al. The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. Arthritis Rheum. 2007, 56, 965–971. https://doi.org/10.1002/art.22416	sCD163 and soluble IL-2Rα (sCD25)	Elevated serum concentrations of sCD25 and sCD163 may be predictive biomarkers of MAS and help detect patients with subclinical MAS.
[149]. Reddy, V.V.; Myles, A.; Cheekatla, S.S.; Singh, S.; Aggarwal, A. Soluble CD25 in serum: a potential marker for subclinical macrophage activation syndrome in patients with active systemic onset juvenile idiopathic arthritis. Int. J. Rheum. Dis. 2014, 17, 261–267. https://doi.org/10.1111/1756-185X.12196		The presence of sCD25 levels > 7500 pg/mL can be considered a useful biomarker in the detection of patients with subclinical MAS.
[150]. Sakumura, N.; Shimizu, M.; Mizuta, M.; Inoue, N.; Nakagishi, Y.; Yachie, A. Soluble CD163, a unique biomarker to evaluate the disease activity, exhibits macrophage activation in systemic juvenile idiopathic arthritis. Cytokine 2018, 110, 459–465. https://doi.org/10.1016/j.cyto.2018.05.017		sCD163 might be a potential indicator of the disease activity and remission in sJIA and sJIA-MAS, as well as for patients receiving TCZ.
[151]. Verweyen, E.L.; Pickering, A.; Grom, A.A.; Schulert, G.S. Distinct Gene Expression Signatures Characterize Strong Clinical Responders Versus Nonresponders to Canakinumab in Children With Systemic Juvenile Idiopathic Arthritis. Arthritis Rheumatol. 2021, 73, 1334–1340. https://doi.org/10.1002/art.41640		A signature including upregulated CD163 expression was associated with non-response to canakinumab.
[143]. Takakura, M.; Shimizu, M.; Irabu, H.; Sakumura, N.; Inoue, N.; Mizuta, M.; Nakagishi, Y.; Yachie, A. Comparison of serum biomarkers for the diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Clin. Immunol. 2019, 208, 108252. https://doi.org/10.1016/j.clim.2019.108252	Neopterin	Serum neopterin levels may be used as an indicator of disease activity in sJIA and MAS, as well as for evaluating it. It may also be a useful marker to diagnose the transition to MAS from active sJIA.
[166]. Wittkowski, H.; Frosch, M.; Wulffraat, N.; Goldbach-Mansky, R.; Kallinich, T.; Kuemmerle-Deschner, J.; Frühwald, M.C.; Dassmann, S.; Pham, T.H.; Roth, J.; et al. S100A12 is a novel molecular marker differentiating systemic-onset juvenile idiopathic arthritis from other causes of fever of unknown origin. Arthritis Rheum. 2008, 58, 3924–3931. https://doi.org/10.1002/art.24137	S100 proteins as follows: calgranulin A (S100A8) or MRP 8 calgranulin B (S100A9/MRP14) calgranulin C (S100A12/MRP 6) calprotectin (CP) or MRP-8/MRP-14, or S100A8/A9 heterocomplex	S100A12 is a useful biomarker in confirming the positive diagnosis of sJIA and excludes early severe systemic infections and several inflammatory or neoplastic disorders.
[167]. Holzinger, D.; Frosch, M.; Kastrup, A.; Prince, F.H.; Otten, M.H.; Van Suijlekom-Smit, L.W.; ten Cate, R.; Hoppenreijs, E.P.; Hansmann, S.; Moncrieffe, H.; et al. The Toll-like receptor 4 agonist MRP8/14 protein complex is a sensitive indicator for disease activity and predicts relapses in systemic-onset juvenile idiopathic arthritis. Ann. Rheum. Dis. 2012, 71, 974–980. https://doi.org/10.1136/annrheumdis-2011-200598		MRP8/14 (calprotectin) serum concentration was the first predictive biomarker indicating subclinical disease activity and stratifying patients at risk of relapse during clinically inactive sJIA.
[168]. Shenoi, S.; Ou, J.N.; Ni, C.; Macaubas, C.; Gersuk, V.H.; Wallace, C.A.; Mellins, E.D.; Stevens. A.M. Comparison of biomarkers for systemic juvenile idiopathic arthritis. Pediatr. Res. 2015, 78, 554–559. https://doi.org/10.1038/pr.2015.144		In a small cohort, S100 proteins were identified as specific diagnostic biomarkers for febrile patients with sJIA. Decreased PD-L1 surface expression on circulating myeloid cells in sJIA indicated a possible mechanism for the loss of peripheral immune regulation.
[169]. Aljaberi, N.; Tronconi, E.; Schulert, G.; Grom, A.A.; Lovell, D.J.; Huggins, J.L.; Henrickson, M.; Brunner, H. The use of S100 proteins testing in juvenile idiopathic arthritis and autoinflammatory diseases in a pediatric clinical setting: a retrospective analysis. Pediatr. Rheumatol. Online J. 2020, 18, 7. https://doi.org/10.1186/s12969-020-0398-2		S100A8/9 and S100A12 proteins were highly elevated in sJIA compared to nsJIA and other autoinflammatory diseases. Therefore, the authors concluded that S100 proteins (i.e., S100A8/9 and S100A12) are valuable biomarkers of disease activity in sJIA, but not in other autoinflammatory syndromes or nsJIA.
[18]. Park, C.; Miranda-Garcia, M.; Berendes, R.; Horneff, G.; Kuemmerle-Deschner, J.; Ganser, G.; Huppertz, H.I.; Minden, K.; Haas, J.P.; Jansson, A.F.; et al. MRP8/14 serum levels as diagnostic markers for systemic juvenile idiopathic arthritis in children with prolonged fever. Rheumatology 2021, keab729. https://doi.org/10.1093/rheumatology/keab729		Compared with ferritin, IL-18, ESR, soluble IL-2 receptor, and procalcitonin, MRP8/14 showed the best accuracy in the diagnosis of sJIA.
[170]. La, C.; Lê, P.Q.; Ferster, A.; Goffin, L.; Spruyt, D.; Lauwerys, B.; Durez, P.; Boulanger, C.; Sokolova, T.; Rasschaert, J.; Badot, V. Serum calprotectin (S100A8/A9): a promising biomarker in diagnosis and follow-up in different subgroups of juvenile idiopathic arthritis. RMD Open 2021, 7, e001646. https://doi.org/10.1136/rmdopen-2021-001646		The study confirmed the potential uses of sCP as a biomarker in the diagnosis and follow-up of sJIA.
[174]. Trachtman, R.; Murray, E.; Wang, C.M.; Szymonifka, J.; Toussi, S.S.; Walters, H.; Nellis, M.E.; Onel, K.B.; Mandl, L.A. Procalcitonin Differs in Children With Infection and Children With Disease Flares in Juvenile Idiopathic Arthritis. J. Clin. Rheumatol. 2021, 27, 87–91. https://doi.org/10.1097/RHU.0000000000001170	Procalcitonin	The study found that CRP, ESR, and serum PCT levels are biomarkers that can be used to distinguish severe bacterial infection from active JIA at onset, but PCT was the most accurate. PCT can be used as a biomarker to help clinicians guide therapy.
[194]. Bobek, D.; Grčević, D.; Kovačić, N.; Lukić, I.K., Jelušić, M. The presence of high mobility group box-1 and soluble receptor for advanced glycation end-products in juvenile idiopathic arthritis and juvenile systemic lupus erythematosus. Pediatr. Rheumatol. Online J. 2014, 12, 50. https://doi.org/10.1186/1546-0096-12-50	HMGB1/sRAGE AGEs and sRAGEs	The study found positive correlations between serum HMGB1 and ESR, CRP, and α2 globulin—and vice versa for sRAGE—as inflammatory markers in children with sJIA. Elevated serum HMGB1 levels have been associated with hepatosplenomegaly and/or serosis in sJIA.
[195]. Xu, D.; Zhang, Y.; Zhang, Z.Y.; Tang, X.M. Association between high mobility group box 1 protein and juvenile idiopathic arthritis: a prospective longitudinal study. Pediatr. Rheumatol. 2021, 19, 112. https://doi.org/10.1186/s12969-021-00587-1		Serum HMGB1 could be considered to be a sensitive inflammatory biomarker for the assessment of clinical activity in JIA; it was found to be specifically elevated at first presentation in children with sJIA.
[196]. Wu, J.F.; Yang, Y.H.; Wang, L.C.; Lee, J.H.; Shen, E.Y.; Chiang, B.L. Comparative usefulness of C-reactive protein and erythrocyte sedimentation rate in juvenile rheumatoid arthritis. Clin. Exp. Rheumatol. 2007, 25, 782–785. PMID: 18078633	Routine laboratory data in sJIA-MAS (CRP, ESR, Fg, D-dimer, serum ferritin, ferritin/ESR ratio, LDH, AST)	ESR is a useful biomarker in the diagnosis of sJIA—much more valuable than CRP—whereas a high initial CRP value may strongly predict treatment failure.
[197]. Bloom, B.J.; Alario, A.J.; Miller, L.C. Persistent elevation of fibrin d-dimer predicts long term outcome in systemic juvenile idiopathic arthritis. J. Rheumatol. 2009, 36, 422–426. https://doi.org/10.3899/jrheum.070600		D-dimer could more accurately reflect the disease activity and prognosis as compared to clinical features in patients with sJIA.
[198]. Gorelik, M.; Fall, N.; Altaye, M.; Barnes, M.G.; Thompson, S.D.; Grom, A.A.; Hirsch, R. Follistatin-like protein 1 and the ferritin/erythrocyte sedimentation rate ratio are potential biomarkers for dysregulated gene expression and macrophage activation syndrome in systemic juvenile idiopathic arthritis. J. Rheumatol. 2013, 40, 1191–1199. https://doi.org/10.3899/jrheum.121131		In sJIA, elevated serum levels of FSTL-1 prior to treatment were related to a disorder of gene expression that predicts hidden MAS and progression to true MAS. Serum ferritin/ESR ratio may be superior to ferritin alone in discerning the obvious MAS from sJIA at onset.
[199]. Minoia, F.; Bovis, F.; Davì, S.; Horne, A.; Fischbach, M.; Frosch, M.; Huber, A.; Jelusic, M.; Sawhney, S.; McCurdy, D.K.; et al. Pediatric Rheumatology International Trials Organization, the Childhood Arthritis & Rheumatology Research Alliance, the Pediatric Rheumatology Collaborative Study Group and the Histiocyte Society. Development and initial validation of the MS score for diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Ann. Rheum. Dis. 2019, 78, 1357–1362. https://doi.org/10.1136/annrheumdis-2019-215211		MS score, which comprises seven variables (CNS dysfunction, hemorrhagic manifestations, active arthritis, platelet count, Fg, LDH, and ferritin), could be a valuable practical instrument that can be used by clinicians in the early diagnosis of sJIA-MAS.
[200]. Eloseily, E.M.; Minoia, F.; Crayne, C.B.; Beukelman, T.; Ravelli, A.; Cron, R.Q. Ferritin to erythrocyte sedimentation rate ratio: simple measure to identify macrophage activation syndrome in systemic juvenile idiopathic arthritis. ACR Open Rheumatol. 2019, 1, 345–349. https://doi.org/10.1002/acr2.11048		Serum ferritin/ESR ratio is a valuable parameter for the diagnosis of sJIA-MAS, and the serum ferritin level alone can be used in screening to detect MAS among febrile patients.
[201]. Zou, L.X.; Zhu, Y.; Sun, L.; Ma, H.H.; Yang, S.R.; Zeng, H.S.; Xiao, J.H.; Yu, H.G.; Guo, L.; Xu, Y.P.; Lu, M.P. Clinical and laboratory features, treatment, and outcomes of macrophage activation syndrome in 80 children: a multi-center study in China. World J. Pediatr. 2020, 16, 89–98. https://doi.org/10.1007/s12519-019-00256-0		Increased serum ferritin, ferritin/ESR ratio, AST, and LDH, along with decreased serum albumin, could be predictive parameters of the emergence of sJIA-MAS.
[202]. Ganeva, M.; Fuehner, S.; Kessel, C.; Klotsche, J.; Niewerth, M.; Minden, K.; Foell, D.; Hinze, C.H.; Wittkowski, H. Trajectories of disease courses in the inception cohort of newly diagnosed patients with JIA (ICON-JIA): the potential of serum biomarkers at baseline. Pediatr. Rheumatol. Online J. 2021, 19, 64. https://doi.org/10.1186/s12969-021-00553-x		Elevated baseline levels of CRP, S100A8/A9, and S100A12, as well as increased ESR, were associated with the necessity to escalate therapy during the first 12 months.
[209]. Dev, S.; Singh, A. Study of role of serum amyloid A (SAA) as a marker of disease activity in juvenile idiopathic arthritis. J. Fam. Med. Prim. Care 2019, 8, 2129–2133. https://doi.org/10.4103/jfmpc.jfmpc_339_19	SAA	SAA is a more sensitive laboratory marker than ESR and CRP for assessing the presence of active joints in JIA.
[218]. Shimizu, M.; Nakagishi, Y.; Inoue, N.; Mizuta, M.; Yachie, A. Leucine-rich α2-glycoprotein as the acute-phase reactant to detect systemic juvenile idiopathic arthritis disease activity during anti-interleukin-6 blockade therapy: A case series. Mod. Rheumatol. 2017, 27, 833–837. https://doi.org/10.1080/14397595.2016.1270795	LRG	Serum LRG levels might be a potential biomarker of sJIA disease activity during IL-6 blockade treatment.
[219]. Shimizu, M.; Inoue, N.; Mizuta, M.; Nakagishi, Y; Yachie, A. Serum Leucine-Rich α2-Glycoprotein as a Biomarker for Monitoring Disease Activity in Patients with Systemic Juvenile Idiopathic Arthritis. J. Immunol. Res. 2019, 2019, 3140204. https://doi.org/10.1155/2019/3140204		Serum LRG levels were positively correlated with serum CRP and ferritin levels in sJIA and reflected disease activity; thus, they may be useful for monitoring sJIA disease activity.
[220]. Lee, P.Y.; Schulert, G.S.; Canna, S.W.; Huang, Y.; Sundel, J.; Li, Y.; Hoyt, K.J.; Blaustein, R.B.; Wactor, A.; Do, T.; et al. Adenosine deaminase 2 as a biomarker of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Ann. Rheum. Dis. 2020, 79, 225–231. https://doi.org/10.1136/annrheumdis-2019-216030	ADA2	The utility of research on plasma ADA2 activity as a future diagnostic biomarker of sJIA-MAS was demonstrated. The monocyte/macrophage origin of ADA2 and induction by IL-18 and IFN-γ provide further support for the key role of MAS in this life-threatening complication of sJIA.