Objective Systemic juvenile idiopathic arthritis (sJIA) is characterized by fever, arthritis, rash, hepatosplenomegaly, and macrophage activation syndrome; however, its pathogenesis is still unclear. Elevated serum interleukin (IL)‐18 concentrations and decreased natural killer (NK) cell activity are characteristic of active disease; thus, we examined IL‐18 signaling in NK cells from sJIA. Methods We analyzed mitogen‐activated protein kinase (MAPK) p38 and nuclear factor κ light chain enhancer of activated B cells (NFκB) p65 phosphorylation in NK cells after in vitro recombinant IL‐18 (rIL‐18) stimulation in 31 patients with sJIA. Associations between clinical features, serum IL‐18, and phosphorylation intensity were analyzed. Furthermore, we investigated the effects of high IL‐18 concentrations on phosphorylation in NK cells. Results Patients were divided according to their disease activity: systemic features (n = 8), chronic arthritis (n = 7), remission on medication (n = 10), and remission off medication (n = 6). MAPK p38 and NFκB p65 phosphorylation intensity were the highest in healthy controls, followed by remission off medication, remission on medication (vs. control; MAPK p38, P < 0.01; NFκB p65, P < 0.05), chronic arthritis (P < 0.001, P < 0.001), and systemic features (P < 0.001, P < 0.001). The systemic features group showed a complete defect in phosphorylation. Serum IL‐18 was the highest in the systemic features group followed by chronic arthritis, remission on medication (P < 0.01), remission off medication (P < 0.01), and healthy controls (P < 0.01). Phosphorylation intensity was negatively correlated with serum IL‐18 (MAPK p38, r2 = 0.42; NFκB p65, r2 = 0.54). Furthermore, healthy control NK cells were cultured with rIL‐18; impaired phosphorylation was reproduced in vitro. Conclusion Impaired IL‐18 signaling in NK cells correlated with disease activity in sJIA. High serum IL‐18 exposure induces impaired MAPK and NFκB phosphorylation in NK cells.

Adult patients with ANCA-associated vasculitis (AAV) could be often complicated by other rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus but which is rare in children. We report two children with microscopic polyangiitis (MPA) complicated by Polyarticular RF-positive juvenile idiopathic arthritis. Case 1 was a 23year-old female. She developed MPA at the age of 10. She had achieved remission by methylprednisolone pulse therapy (MPT) and intravenous cyclophosphamide. However, arthritis occurred 16 months later and she was diagnosed with pJIA. Methotrexate (MTX) was added and arthritis was resolved. Case 2 was a 14-year-old female. She developed arthritis at the age of 11. She was diagnosed as having pJIA two years later. She was initially treated with prednisolone, MTX and etanercept. However, she presented hematuria and proteinuria at the age of 14 and was diagnosed with MPA. MPT combined with rituximab significantly ameliorated her symptom. Although concomitance of pJIA and AAV is quite rare, considering its possibility is important when patients developed unexpected clinical symptoms. Furthermore, it is important to choose of therapy which can simultaneously cover bothdiseases, especially therapy for MPA is associate with the prognosis.

Example of the purple eyelid sign in multisystem inflammatory syndrome in children. (a) and (b), Case 3; (c), Case 4; (d), Case 5; (e), Case 6. We obtained the consent of the patients' families to use their photographs.