Mao Mizuta

Interleukin-18 for predicting the development of macrophage activation syndrome in systemic juvenile idiopathic arthritis.

To assess the role of IL-6/IL-18 in the pathogenesis of systemic juvenile idiopathic arthritis (s-JIA) and to investigate the clinical significance of serum IL-18 levels for predicting macrophage activation syndrome (MAS) development, we measured the serum IL-6/IL-18 levels in 76s-JIA patients, including 15 with MAS, and compared them with the clinical features. We identified 2 distinct subsets on the basis of serum IL-6/IL-18 levels. The IL-18-dominant subset had more patients who developed MAS. Serum IL-18 levels during active phase in patients with MAS were significantly higher than those without MAS. The cutoff value of serum IL-18 levels for predicting MAS development was 47750 pg/ml. The patients with IL-18 dominant subset at their disease onset were significantly more likely to develop MAS after TCZ therapy started. IL-18 might have a key role in the pathogenesis of MAS. Serum IL-18 levels >47750 pg/ml might be useful to predict MAS development.

Serum ferritin levels as a useful diagnostic marker for the distinction of systemic juvenile idiopathic arthritis and Kawasaki disease

Abstract Objectives: The clinical features and laboratory parameters of patients with Kawasaki disease (KD) and systemic juvenile idiopathic arthritis (s-JIA) tend to overlap. Furthermore, there have been no definitive biomarkers for these diseases, making clinical diagnosis difficult. The purpose of this study was to investigate the diagnostic value of serum ferritin levels for differentiating KD from s-JIA and predicting the disease severity of KD. Methods: We analyzed 228 patients with KD and 81 patients with s-JIA. Serum ferritin levels were compared between patients with s-JIA and KD. Furthermore, serum ferritin levels in patients with KD were compared with respect to clinical features such as responsiveness to intravenous immunoglobulin (IVIG) therapy. Results: Serum ferritin levels in KD patients with no response to IVIG therapy were significantly higher than those in KD patients with a good response to IVIG therapy. Serum ferritin levels in patients with KD needing plasma exchange (PE) were significantly higher than those in patients not needing PE. However, serum ferritin levels overlapped between severe KD patients with nonresponsiveness to IVIG therapy or needing PE and other patients with mild KD. Furthermore, patients with s-JIA showed a distinct elevation of serum ferritin levels compared with KD patients. The cutoff value of serum ferritin levels for differentiating KD from s-JIA was 369.6 ng/ml. Conclusions: Serum ferritin levels were significantly elevated in s-JIA patients compared with KD patients. Measurement of serum ferritin levels can be useful for differentiating s-JIA from KD.

Leopard skin appearance of cutaneous polyarteritis nodosa on 18Ffluorodeoxyglucose positron emission tomography

An 8-year-old girl was referred to us with fever, erythematous papules and painful subcutaneous nodules located over her extremities and bilateral arthritis of the ankles and knees. Laboratory findings revealed leucocytosis (13 410/mm) and elevated CRP concentration (1.4 mg/dl) and ESR (61 mm/h). MRI of the thighs revealed multiple high-signal nodular lesions throughout the subcutaneous tissue and subfascial muscle tissue of the thighs. F-Fluorodeoxyglucose PET (F-FDG-PET) revealed a unique, leopard skin appearance with multiple, disseminated hot spots throughout the muscle and subcutaneous tissue in upper and lower extremities (Fig. 1). A skin biopsy of a subcutaneous nodule revealed necrotizing vasculitis. The diagnosis of cutaneous PAN was made. She was treated with prednisolone and maintained on ciclosporin and monthly infusions of CYC. F-FDG-PET is a promising new technique to evaluate metabolic activity, with F-FDG accumulations in cells that have a high rate of glycolysis [1]. Increased uptake of F-FDG is observed in vasculitis lesions with infiltrations of inflammatory cells [2]. In this patient, F-FDG-PET revealed a unique, leopard skin appearance with multiple, disseminated hot spots throughout the muscle and subcutaneous tissue. These findings indicate that F-FDG-PET is useful for the evaluation of the extent and location of inflammation in patients with cutaneous PAN.

Characteristic elevation of soluble TNF receptor II : I ratio in macrophage activation syndrome with systemic juvenile idiopathic arthritis

To investigate the clinical significance of soluble tumour necrosis factor receptor (sTNF‐R) II/I ratio as an indicator of the diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s‐JIA), we measured the serum sTNF‐RI and II levels in 117 patients with s‐JIA, including 29 patients with MAS, 15 with Epstein–Barr virus‐induced haemophagocytic lymphohistiocytosis (EBV‐HLH), 15 with Kawasaki disease (KD) and 28 healthy controls (HCs). We determined their correlation with measurements of disease activity and severity. Furthermore, we measured serum interleukin (IL)‐18 levels in patients with EBV‐HLH and compared these in levels in patients with MAS. The sTNF‐RII/I ratio was elevated significantly in MAS and EBV‐HLH patients compared with those in the acute phase of s‐JIA and KD patients, whereas there were no significant differences between HCs and those in the acute phase of s‐JIA. The sTNF‐RII/I ratio increased profoundly as MAS developed and correlated positively with disease activity. Serum IL‐18 levels were elevated significantly in MAS patients compared with EBV‐HLH patients. The monitoring of serum IL‐18 and sTNF‐RII/I might be useful for the diagnosis of MAS and the differentiation between MAS and EBV‐HLH.

Soluble CD163, a unique biomarker to evaluate the disease activity, exhibits macrophage activation in systemic juvenile idiopathic arthritis

HighlightsSerum sCD163 levels correlated positively with the disease activity of s‐JIA, even in patients receiving tocilizumab.Serum sCD163 level is a potential diagnostic laboratory criterion for clinical remission in patients with s‐JIA.Serum sCD163 levels profoundly increased with the progress of MAS in s‐JIA.Soluble CD163 is a unique biomarker to evaluate the disease activity, exhibits macrophage activation in s‐JIA. &NA; This study aims to investigate the clinical significance of serum soluble CD163 (sCD163) levels as a predictor of the disease activity of systemic juvenile idiopathic arthritis (s‐JIA). In this study, we examined 63 patients with s‐JIA, four with Epstein‐Barr virus‐induced hemophagocytic lymphohistiocytosis (EBV‐HLH), and seven with Kawasaki disease (KD), along with 14 healthy controls. We quantified serum cytokine levels (sCD163, neopterin, IL‐18, IL‐6) by enzyme‐linked immunosorbent assay and compared the results with the clinical features of s‐JIA. Serum sCD163 levels were significantly elevated in patients with s‐JIA associated macrophage activation syndrome (MAS) and EBV‐HLH compared to those in patients with acute‐phase s‐JIA and KD. In addition, serum sCD163 levels profoundly increased with the progress of MAS and correlated positively with the disease activity of s‐JIA, even in patients receiving tocilizumab. Furthermore, serum sCD163 levels significantly decreased in the inactive phase compared to those in the active phase and normalized in remission. The correlation between macrophage activation and serum sCD163 levels might be a unique indicator of the disease activity and a potential diagnostic laboratory criterion for clinical remission in patients with s‐JIA, including those receiving tocilizumab.

Disruption of vascular endothelial homeostasis in systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: The dynamic roles of angiopoietin-1 and -2

To assess the role of angiopoietin (Ang)-1 and Ang-2 and to investigate the clinical significance of serum levels of them in systemic juvenile idiopathic arthritis (s-JIA)-associated macrophage activation syndrome (MAS), we determined these levels in 51 patients with s-JIA, 11 patients with polyarticular JIA (poly-JIA), 12 patients with virus associated hemophagocytic syndrome (VAHS), 12 patients with Kawasaki disease (KD), and 15 age-matched healthy controls (HC). The results were compared with clinical features of MAS. During the MAS phase, serum Ang-1 levels were significantly decreased compared with those during the active and inactive phases. Serum Ang-2/1 ratio were significantly elevated during the MAS phase, compared with those during the active and inactive phases. There was a rapid increase in the Ang-2/1 ratio at the onset of MAS. Serum Ang-1 and the Ang-2/1 ratio significantly correlated with measures of disease activity, including AST and LDH. Ang-2/1 dysregulation was also observed in patients with VAHS, whereas not observed in most cases of KD. The homeostasis of vascular endothelial function by Ang-1 and Ang-2 is disrupted in MAS. Serum Ang-1 levels and the Ang-2/1 ratio might represent promising indicators of disease activity for MAS.

Transient natural killer cell dysfunction associated with interleukin-18 overproduction in systemic juvenile idiopathic arthritis

There is accumulating evidence for a key role of interleukin (IL)-18 as a driver of systemic juvenile idiopathic arthritis (s-JIA) and its life-threating complication, macrophage activation syndrome (MAS). IL-18 is the most effective factor for regulating natural killer (NK) cell activity. Although it augments the cytolytic activity of NK cells, exposure to high IL-18 concentration induces NK cell death. NK cell dysfunction is a characteristic feature of MAS. Although a defect in the IL-18 receptor b phosphorylation has been proposed, the exact mechanism remains unclear. To test the hypothesis that exposure to high IL-18 concentration, as a consequence of its overproduction in s-JIA, induces NK cell exhaustion and secondary transient NK cell dysfunction, we monitored changes in serum IL18 from the active phase to remission in s-JIA patients and assessed NK cell activation in response to recombinant IL-18. Four s-JIA patients and 10 healthy controls (HC) were enrolled. The clinical characteristics of the s-JIA patients are listed in Table S1. This study was approved by the institutional review board of Kanazawa University, and informed consent was obtained from all the participants. Whole blood was cultured for 2 h at 37°C with or without IL-18. Recombinant human IL-18 (MBL, Nagoya, Japan) was used at indicated concentrations in all in vitro cell culture experiments. Monoclonal antibodies to CD56 and CD69 were purchased from BD Biosciences (Franklin Lakes, NJ, USA) and Beckman Coulter (Brea, CA, USA), respectively. Cells were analyzed using FACSCalibur and CellQuest Pro (both from BD Biosciences). NK cell activation was assessed according to mean fluorescence intensity (MFI) of surface CD69 expression on CD56 NK cells. Serum IL-18 was measured using a commercial enzyme-linked immunosorbent assay (MBL, Nagoya, Japan). Correlations were expressed using Spearman’s rank order correlation coefficient. P < 0.05 was considered to be statistically significant. As shown in Figures S1 and S2, NK cells from HC were activated by IL-18 in a dose-dependent manner, whereas NK cell activation by IL-18 was impaired in active s-JIA patients. NK cell activation by IL-18 was impaired in all four active sJIA patients. Next, we assessed the change in MFI of CD69 expression on CD56 NK cells, after stimulation with 10 ng/ mL IL-18, defined as DMFI10. DMFI10 recovered in all four s-JIA patients as serum IL-18 decreased in the inactive phase (Fig. 1). There was a significant negative correlation between DMFI10 and serum IL-18 (r = 0.9098, P < 0001; Fig. S3), although the extent of recovery of NK cell response to IL-18 varied between the four s-JIA patients. Decreased NK cytotoxic activity is associated with decreased perforin expression on NK cells in some s-JIA patients, but most s-JIA patients have a defect in NK cytotoxic activity, indicating the involvement of secondary effectors. IL-18 has been shown to play a key role in the pathogenesis of both s-JIA and MAS. Recently, this was illustrated by the persistently elevated IL-18 and recurrent MAS in patients with gain-of-function mutations in the NLRC4 inflammasome. In the present study, NK cell activation by IL-18 was impaired in patients with active s-JIA. Furthermore, NK cell activation was restored by exogenous IL-18 stimulation in patients with s-JIA in whom serum IL-18 was decreased after starting treatment. Furthermore, NK cell activation by IL-18 stimulation

Successful treatment of rituximab- and steroid-resistant nephrotic syndrome with leukocytapheresis

Although rituximab (RTX) is a promising therapeutic agent for treating steroid‐resistant nephrotic syndrome (SRNS) resistant to various immunosuppressive agents, some patients have shown resistance to RTX. We report the case of a patient with RTX‐resistant nephrotic syndrome and SRNS who was successfully treated with leukocytapheresis (LCAP). After LCAP, there was a significant reduction in proteinuria and in the total number of lymphocytes, T cells, and HLA‐DR+‐activated T cells. Moreover, the patient became sensitive to steroids and RTX. LCAP reduced circulating immune cells including activated T cells and could be effective in treating rituximab‐resistant nephrotic syndrome and SRNS and in achieving remission of proteinuria.

Clinical significance of serum soluble TNF receptor II level and soluble TNF receptor II/I ratio as indicators of coronary artery lesion development in Kawasaki disease

HighlightsSerum sTNFRI, sTNFRII and IL‐6 levels may indicate IVIG response in KD.Sustained elevation of serum sTNFR II level was linked to the CALs development.Sustained elevation of sTNFR II ratio was also linked to the CALs development.Serum sTNFRII level and sTNFRII/I may indicate the development of CALs in KD. Abstract To investigate the clinical significance of serum soluble tumor necrosis factor receptor (sTNFR) II level and sTNFR II/I ratio as indicators of the development of coronary artery lesions (CALs) in Kawasaki disease (KD), we measured levels of serum sTNFR I and II, interleukin (IL)‐6, IL‐18, and neopterin in 63 patients with KD, including nine patients with CALs and 20 healthy controls. At the time of diagnosis of KD before intravenous immunoglobulin (IVIG) treatment, serum sTNFR I and II levels were found to be significantly higher in non‐responders to IVIG treatment than in responders. On the contrary, serum sTNFR II levels and sTNFR II/I ratio were significantly higher in patients with KD having CALs than in those without CALs. Longitudinal observation in a patient with KD who is unresponsive to IVIG revealed sustained elevation of serum sTNFR II level, and elevated sTNFR II/I ratio was linked to the CALs development. Increase in serum sTNFR II level and elevated sTNFR II/I ratio may be promising indicators of the development of CALs in KD.

Validation of Classification Criteria of Macrophage Activation Syndrome in Japanese Patients With Systemic Juvenile Idiopathic Arthritis

To validate whether the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA) is practical in the real world.