S100A12 Is a Novel Molecular Marker Differentiating Systemic-Onset Juvenile Idiopathic Arthritis From Other Causes of Fever of Unknown Origin

Objective. Fever of unknown origin (FUO) in children presents a diagnostic challenge. The differential diagnosis includes systemic-onset juvenile idiopathic arthritis (JIA), an autoinflammatory syndrome associated with activation of phagocytic cells that, at presentation, is difficult to differentiate from severe systemic infections. The aim of this study was to investigate whether serum concentrations of the phagocytic proinflammatory protein S100A12 may help in deciding whether to treat patients with FUO with antibiotics or immunosuppressive agents. Methods. Serum samples were obtained from 45 healthy control subjects and from 240 patients (60 with systemic-onset JIA, 17 with familial Mediterranean fever [FMF], 18 with neonatal-onset multisystem inflammatory disease [NOMID], 17 with Muckle-Wells syndrome [MWS], 40 with acute lymphoblastic leuke-mia [ALL], 5 with acute myeloblastic leukemia [AML], and 83 with systemic infections). All samples were collected at the time of presentation, before the initiation of any treatment, and concentrations of S100A12 were determined by enzyme-linked immunosorbent assay. Results. The mean +/- 95% confidence interval serum levels of S100A12 were as follows: in patients with JIA, 7,190 +/- 2,690 ng/ml; in patients with FMF, 6,720 +/- 4,960 ng/ml; in patients with NOMID, 720 +/- 450 ng/ml; in patients with MWS, 150 +/- 60 ng/ml; in patients with infections, 470 +/- 160 ng/ml; in patients with ALL, 130 80 ng/ml; in patients with AML, 45 +/- 60 ng/ml; in healthy control subjects, 50 +/- 10 ng/ml. The sensitivity and specificity of S100A12 to distinguish between systemic-onset JIA and infections were 66% and 94%, respectively. Conclusion. S100A12, a marker of granulocyte activation, is highly overexpressed in patients with systemic-onset JIA or FMF, which may point to as-yet unknown common inflammatory mechanisms in these diseases. The measurement of S100A12 serum levels may provide a valuable diagnostic tool in the evaluation of FUO.