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Background. Immunoglobulin A vasculitis (IgAV) is the most common vasculitis of childhood. However, its etiology remains unknown. In the Mediterranean region, 10% of patients with IgAV harbor homozygous and compound heterozygous mutations in the Mediterranean fever (MEFV) gene. Thus, such mutations may be involved in the development of IgAV. Objective. We present a Japanese patient with IgAV harboring MEFV gene mutation. Further, a comprehensive literature analysis was performed to validate the clinical characteristics of Japanese patients with IgAV harboring MEFV mutation. Methods. A 5-year-old girl presented with IgAV. She experienced prolonged abdominal pain, which was steroid-resistant. When treatment with colchicine was started, her abdominal pain disappeared immediately. The serum interleukin-18 levels of the patient and other patients with IgAV and FMF were evaluated using enzyme-linked immunosorbent assay. Moreover, all exons of the MEFV gene were analyzed using the direct sequence method. A comprehensive search of Japanese patients with IgAV harboring MEFV gene mutations in PubMed, Ichushi-Web, and Medical Online was conducted. Results. The serum interleukin-18 level of the patient was higher than that of other patients with IgAV and was similar to that of patients with FMF harboring M694I mutation. In addition, the patient presented with E148Q/M694I mutation. In previous studies, only four patients presented with IgAV harboring MEFV gene mutation in Japan. Conclusion. MEFV gene mutations can be masked if the symptoms of IgAV are prolonged or if patients are refractory to treatment. Moreover, the prevalence of IgAV associated with MEFV gene mutation is low in Japan.

We aimed to assess the kinetics of the release of proinflammatory cytokines and to clarify clinical usefulness as an indicator of the disease activity in human parechovirus type 3 virus (HPeV3)-induced sepsis-like syndrome. We measured serum levels of neopterin, interleukin (IL)-6 and the soluble forms of tumor necrosis factor (TNF) receptor types I (sTNF-RI) and II (sTNF-RII). Serum samples were obtained from 12 patients with HPeV3-induced sepsis-like syndrome and 28 healthy children. Disease course after onset was divided into 3 phases: early (day 1-2), peak (day 3-6) and recovery (day 9-16) phases. Serum IL-6 levels rapidly and markedly elevated in early phase and gradually decreased to those in healthy children in recovery phase. Furthermore, serum neopterin, sTNFR-I and sTNFR-II levels increased rapidly and markedly in onset phase and remained elevated in peak phase. These levels gradually decreased in recovery phase. Serum IL-18 levels increased from onset phase to peak phase and decreased in recovery phase. These results indicate that proinflammatory cytokines, in particular, interferon gamma, TNF-α and IL-18 are closely related to the development of HPeV3-induced sepsis-like syndrome. Serum levels of these cytokines might be a useful indicator of the disease activity.

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.

The present study employed an antibody array that simultaneously detects 174 cytokines to identify cytokines involved in the development of macrophage activation syndrome (MAS) associated with systemic lupus erythematosus (SLE) with a view to elucidating potential predictive markers. Eight SLE patients, including four with MAS, were analyzed. Levels of 31 cytokines were significantly elevated in the MAS phase compared with those in the active phase of SLE. Among these cytokines, the MAS/active phase ratios of CXCL9 and soluble tumor necrosis factor receptor II (sTNFR-II) were highest. Elevated serum CXCL9 and sTNFR-II levels during the MAS phase were confirmed by ELISA and were strongly correlated with other inflammatory markers, reflecting the disease activity of MAS associated with SLE. These results highlight the clinical significance of serum CXCL-9 and sTNFR-II levels, and indicate they may be useful biomarkers for the diagnosis of MAS associated with SLE.

Background Macrophage activation syndrome (MAS) is a severe life-threatening condition that complicates systemic juvenile idiopathic arthritis (s-JIA). Differentiating MAS from these conditions is essential for selecting appropriate therapeutic interventions in a timely manner. However, there is no definite biomarkers that can effectively diagnose MAS. Objectives Our study aimed to compare the accuracy of serum biomarkers for the diagnosis of MAS complicating s-JIA and to investigate the clinical significance of serum neopterin levels as an indicator of disease activity and diagnosis of MAS complicating s-JIA. Methods Serum cytokine levels (neopterin, IL-18, and CXCL9 and soluble tumor necrosis factor receptor type I (sTNFR-I) and II were determined by enzyme-linked immunosorbent assay in 78 patients with s-JIA, including 21 with MAS. The accuracy of these levels for the diagnosis of MAS were compared. Next, serum neopterin levels, in total 125 patients with s-JIA, including 30 with MAS, 15 with Epstein–Barr virus-induced hemophagocytic lymphohistiocytosis (EBV-HLH), and 15 with Kawasaki disease (KD), as well as 28 healthy controls (HCs) were analysed. Results were compared with the clinical features of MAS. Results Receiver operating characteristic curve analysis revealed area under the curve values and cut off values of neopterin, IL-18, CXCL9, sTNFR-II/I ratio and ferritin were 0.9465/19.5nmol/l, 0.8895/69250ng/ml, 0.9333/3130pg/ml, 0.9395/3.796 and 0.8671/2560ng/ml, respectively. Serum neopterin levels were significantly elevated in patients with MAS and EBV-HLH compared with those in patients with acute-phase s-JIA and KD. Serum neopterin levels profoundly and rapidly increased as MAS developed and correlated positively with disease activity. Conclusion Serum neopterin levels may be used as a promising indicator of disease activity in s-JIA and MAS and for evaluating it. It may also be a useful marker to diagnose the transition to MAS from active-phase s-JIA. References [1] Huber C, et al. J Exp Med1984;160:310-6. [2] Bracaglia C, et al. Ann Rheum Dis2017;76:166-72. [3] Shimizu M, et al. Clin Exp Immunol2018;191:349-355. Disclosure of Interests None declared

Background Macrophage activation syndrome (MAS) is a severe, potentially life-threatening complication of childhood systemic inflammatory disorders. MAS occurs most often in children with systemic juvenile idiopathic arthritis and less commonly in children with Kawasaki disease (KD). Objectives Our study aimed to assess the kinetics of cytokine release and compare the accuracy of serum biomarkers for diagnosis of MAS, including neopterin, IL-18, IL-6 and soluble TNF receptor type I (sTNFR-I) and sTNFR-II levels, we analysed these levels in patients with KD, including those with MAS, and compared them to the clinical features of KD and MAS. Methods Serum neopterin, interleukin (IL)-18, IL-6 and soluble tumour necrosis factor receptor type I (sTNFR-I) and sTNFR-II levels were determined using enzyme-linked immunosorbent assay in 78 patients with KD, including five with MAS. Results were compared to the clinical features of MAS. Results Serum neopterin, IL-18, sTNFR-II levels and sTNFR-II/I ratio were significantly elevated in KD patients with MAS compared to those in the acute phase. Receiver operating characteristic curve analysis revealed areas under the curve and cutoff values of neopterin, IL-18, sTNFR-II levels and sTNFR-II/I ratio were 0.9750/30.0 nmol/L, 0.9813/1165 ng/mL, 0.9969/16,600 pg/mL and 0.9875/4.475, respectively. Serum sTNFR-II levels correlated positively with disease activity. Conclusion These findings indicate that interferon (IFN)–γ and tumour necrosis factor-α (TNF-α) are closely associated with the pathogenesis of MAS associated with KD. Serum sTNFR-II levels might be a useful marker to diagnose the transition to MAS. References [1] Garcia-Pavon S, et al. J Pediatr Hematol Oncol 2017;39:445-451. [2] Shimizu M, et al. Cytokine 2018;108:168-172. Disclosure of Interests None declared

Background Macrophage activation syndrome (MAS) is a severe, potentially life-threatening complication of pediatric rheumatic diseases. MAS occurs most often in children with systemic juvenile idiopathic arthritis (s-JIA) and less commonly in children with systemic lupus erythematosus (SLE), Kawasaki disease (KD) and juvenile dermatomyositis (JDM). The hallmark of MAS includes uncontrolled and dysfunctional immune responses involving continual activation and expansion of T lymphocytes and macrophages, which in turn lead to marked hypercytokinemia. However, it is still unknown which cytokines play a key role in the pathogenesis of MAS among different backgrounds. Objectives This study was aimed to clarify cytokines involved in the development of MAS among different background rheumatic diseases and to identify the serum biomarkers for the diagnosis of MAS. Methods Serum neopterin, interleukin (IL)-18, IL-6, tumor necrosis factor (TNF)-α and soluble TNF receptor type I (sTNFR-I) and sTNFR-II levels were determined using enzyme-linked immunosorbent assay in 112 s-JIA patients including 30 with MAS, 8 SLE patients including 3 with MAS, 67 KD patients including 4 with MAS, and 7 JDM patients including 3 with MAS. Cytokine profiles in MAS phase of each disease were compared to those in active phase. Results Serum neopterin levels in patients with s-JIA, SLE and KD were significantly elevated in MAS phase compared to those in active phase. Serum neopterin levels in patients with JDM were also elevated in MAS phase compared to those in active phase, although statistically significant. Serum sTNFR-I levels in patients with s-JIA and SLE were significantly elevated in MAS phase compared to those in active phase. Serum sTNFR-I levels in patients with KD and JDM were also elevated in MAS phase compared to those in active phase, although statistically significant. Serum sTNFR-II levels in patients with s-JIA and KD were significantly elevated in MAS phase compared to those in active phase. Serum sTNFR-II levels in patients with JDM were also elevated in MAS phase compared to those in active phase, although statistically significant. Serum IL-18 levels in patients with s-JIA were significantly elevated in both active and MAS phase compared to those in patients with other diseases. There were no significant differences of serum IL-6 and TNF-α levels among different backgrounds. Conclusion The elevation of serum neopterin levels was the common finding in patients with MAS even in different backgrounds. These findings indicate that overproduction of interferon (IFN)-γ might be closely related to the development of MAS. Serum neopterin levels which reflect IFN-γ production might be a promising biomarker for the disease activity of MAS. References [1] Huber C, et al. J Exp Med 1984;160:310-6. [2] Bracaglia C, et al. Ann Rheum Dis 2017;76:166-72. Disclosure of Interests None declared

The present study aimed to assess the kinetics of cytokine release and compare the accuracy of serum biomarkers for the diagnosis of macrophage activation syndrome (MAS) associated with Kawasaki disease (KD). Serum neopterin, interleukin (IL)-18, IL-6 and soluble tumour necrosis factor receptor type I (sTNFR-I) and sTNFR-II levels were determined using enzyme-linked immunosorbent assay in 78 patients with KD, including five with MAS. Results were compared to the clinical features of MAS. Serum neopterin, IL-18, sTNFR-II levels and sTNFR-II/I ratio were significantly elevated in KD patients with MAS compared to those in the acute phase. Receiver operating characteristic curve analysis revealed areas under the curve and cutoff values of neopterin, IL-18, sTNFR-II levels and sTNFR-II/I ratio were 0.9750/30.0 nmol/L, 0.9813/1165 ng/mL, 0.9969/16,600 pg/mL and 0.9875/4.475, respectively. Serum sTNFR-II levels correlated positively with disease activity. These findings indicate that overproduction of interferon (IFN)–γ and TNF-α reflected by increased serum levels of neopterin and sTNFR-II are closely associated with the pathogenesis of MAS associated with KD. Serum sTNFR-II levels might be a useful marker to diagnose the transition to MAS.

Our study aimed to compare the accuracy of serum biomarkers for the diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s-JIA). Serum cytokine levels (neopterin, IL-18, and CXCL9 and soluble tumor necrosis factor receptor type I (sTNFR-I) and II) were determined by enzyme-linked immunosorbent assay in 78 patients with s-JIA, including 21 with MAS. Receiver operating characteristic curve analysis revealed area under the curve values and cut off values of neopterin, IL-18, CXCL9, sTNFR-II/I ratio and ferritin were 0.9465/19.5 nmol/l, 0.8895/69250 ng/ml, 0.9333/3130 pg/ml, 0.9395/3.796 and 0.8671/2560 ng/ml, respectively. Serum neopterin levels were significantly elevated in patients with MAS and those were correlated positively with disease activity. In conclusion, serum neopterin levels may be used as a promising indicator of disease activity in s-JIA and MAS and for evaluating it. It may also be a useful marker to diagnose the transition to MAS from active-phase s-JIA.