Natsumi Inoue

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.

Cytokine profile in adult-onset Still's disease: Comparison with systemic juvenile idiopathic arthritis

To compare pro-inflammatory cytokine profiles and kinetics in patients with adult-onset Stills disease (AOSD) to those in patients with systemic juvenile idiopathic arthritis (s-JIA), we analyzed serum cytokine concentrations in 33 patients with AOSD and 77 patients with s-JIA and compared them with clinical features. Patients with AOSD and s-JIA shared a common cytokine profile pattern of a significant increase in IL-18. Patients with AOSD were classified into two subgroups based on serum IL-6 and IL-18 levels. The number of patients with arthritis was significantly higher in the IL-6-dominant subgroup. The cytokine patterns associated with s-JIA and AOSD share common features, such as a significant and predominant increase in IL-18. Distinct IL-6- and IL-18-based cytokine profiles might be responsible for distinct clinical manifestations. The presence of two distinct subgroups in patients with both diseases further supports the view that s-JIA and AOSD share a disease category.

Extensive serum biomarker analysis in patients with enterohemorrhagic Escherichia coli O111-induced hemolytic-uremic syndrome

Proinflammatory cytokines are related to the pathogenesis of enterohemorrhagic Escherichia coli infection and hemolytic-uremic syndrome (HUS). We employed an antibody array that simultaneously detects 174 serum cytokines. We identified five serum biomarkers, namely insulin growth factor-binding protein-2, angiopoietin-2, soluble interleukin-6 receptor, soluble tumor necrosis factor receptor type II, and matrix metalloprotease protein-3 whose levels increased with the development of HUS. Furthermore, the levels of these cytokines were significantly increased in severe HUS compared with mild HUS. These cytokines might play an important role in the pathogenesis of HUS and may also be used to predict the severity of HUS.

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.

Serum tau protein as a marker of disease activity in enterohemorrhagic Escherichia coli O111-induced hemolytic uremic syndrome

Tau protein levels in cerebrospinal fluid (CSF) and serum are elevated in patients with various central nervous system diseases. We investigated whether serum tau protein levels are useful for predicting and assessing disease activity of acute encephalopathy (AE) in enterohemorrhagic Escherichia coli (EHEC) O111-induced hemolytic uremic syndrome (HUS; EHEC encephalopathy). Serum samples were obtained from 14 patients with EHEC O111/HUS, 20 patients with non-EHEC-related AE, and 20 age- and sex-matched healthy controls. CSF samples were obtained from 2 patients with EHEC encephalopathy and 20 patients with non-EHEC-related AE. Tau protein levels and levels of several proinflammatory cytokines were quantified by enzyme-linked immunosorbent assays. Results were compared with the clinical features of EHEC encephalopathy, including magnetic resonance image (MRI) findings. Serum tau levels in patients with EHEC encephalopathy were significantly elevated compared with those in patients with EHEC O111/HUS without encephalopathy, patients with non-EHEC-related AE, and healthy controls. The ratio of CSF tau levels to serum tau levels was >1.0 in all patients with non-EHEC-related AE but <1.0 in 2 patients with EHEC encephalopathy. Serum tau protein levels increased rapidly and markedly in patients with severe EHEC 0111/HUS and encephalopathy when HUS occurred, but were not elevated in mild patients, even in the HUS phase. Furthermore, changes in serum tau protein levels in patients with EHEC encephalopathy were consistent with abnormalities on brain MRI and were positively correlated with proinflammatory cytokine levels. Our results indicate that serum tau protein might be useful to predict and assess disease activity of EHEC encephalopathy.

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.

Immunostaining of Sulfatide-Storing Macrophages in Gallbladder of a Patient With Metachromatic Leukodystrophy

To the Editor: Metachromatic leukodystrophy (MLD) is a lysosomal storage disease resulting from a deficiency in arylsulfatase A, leading to accumulation of sulfatide, mainly in neural tissues.1 Lysosomal storage of sulfatide also occurs in visceral organs such as the gallbladder, which is known to the lethal complication as hemobilia.2 The pathological findings of hemobilia have previously been reported as hyperplastic epithelium, thickened mucosa, and infiltration of macrophages bearing metachromatic material in submucosal tissue. Several reports have demonstrated accumulation of sulfatide as a metachromatic appearance on toluidine blue staining or cytoplasmic lamellated material under electron microscopy.2,3 However, metachromasia on toluidine blue staining suggests the presence of either sulfatide or mucin. Despite the biological importance in MLD, attempts to visualize sulfatide specifically in tissue sections have not been reported so far. Here, we describe the pathologic findings of gallbladder alteration in a six-year-old boy with MLD using immunostaining with antigalactocerebrosidesulfatide (anti-GalC-SUL) antibody. A six-year-old boy, who had been diagnosed with MLD at age two years after deterioration of motor and mental performance, presented to our hospital after developing a black stool. He was pale and tachycardic (heart rate, 164 beats per minute). Blood pressure was within the normal range (88 50 mm Hg). Blood testing revealed severe anemia (hemoglobin, 4.0 g dL) and hypoproteinemia (total protein, 5.1 g dL). Abdominal ultrasonography demonstrated dilatation of intrahepatic bile ducts and diffuse thickening wall of the gallbladder. Gastrointestinal fiber revealed active bleeding through the ampulla of Vater (Figure A). The patient underwent emergency cholecystectomy to resolve active hemobilia. The gallbladder was enlarged and bleeding from the thickened gallbladder wall. Postoperatively, anemia was improved and no episodes of rebleeding were seen. On gross examination the gallbladder wall was markedly thickened, but the mucosal surface was smooth. Clear and

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.