Fever of unknown origin is a diagnostic challenge in children, especially for differentiation of systemic‐onset juvenile idiopathic arthritis (systemic‐onset JIA) and infectious diseases. We undertook this study to analyze the relevance of myeloid‐related proteins (MRPs) 8 and 14, endogenous activators of Toll‐like receptor 4, in diagnosis and pathogenesis of systemic‐onset JIA.

Serum concentrations of MRP‐8/MRP‐14 were analyzed in 60 patients with systemic‐onset JIA, 85 patients with systemic infections, 40 patients with acute lymphoblastic leukemia, 5 patients with acute myeloblastic leukemia, 18 patients with neonatal‐onset multisystem inflammatory disease (NOMID), and 50 healthy controls. In addition, we investigated the link between interleukin‐1β (IL‐1β) and MRP‐8/MRP‐14 in systemic‐onset JIA.

Serum MRP‐8/MRP‐14 concentrations were significantly (P < 0.001) elevated in patients with active systemic‐onset JIA (mean ± 95% confidence interval 14,920 ± 4,030 ng/ml) compared with those in healthy controls (340 ± 70 ng/ml), patients with systemic infections (2,640 ± 720 ng/ml), patients with acute lymphoblastic leukemia (650 ± 280 ng/ml), patients with acute myeloblastic leukemia (840 ± 940 ng/ml), and patients with NOMID (2,830 ± 580 ng/ml). In contrast to C‐reactive protein levels, MRP‐8/MRP‐14 concentrations distinguished systemic‐onset JIA from infections, with a specificity of 95%. MRP‐14 in serum of patients with systemic‐onset JIA was a strong inducer of IL‐1β expression in phagocytes.

The analysis of MRP‐8/MRP‐14 in serum is an excellent tool for the diagnosis of systemic‐onset JIA, allowing early differentiation between patients with systemic‐onset JIA and those with other inflammatory diseases. MRP‐8/MRP‐14 and IL‐1β represent a novel positive feedback mechanism activating phagocytes via 2 major signaling pathways of innate immunity during the pathogenesis of systemic‐onset JIA.