Distinct roles of IL-18 and IL-1ß in murine model of macrophage activation syndrome.

BACKGROUND: IL-18 and IL-1ß play a central role in the pathogenesis of systemic juvenile idiopathic arthritis and its life-threatening complication, macrophage activation syndrome (MAS). OBJECTIVES: This study aimed to clarify the role of IL-18 and IL-1ß in the pathogenesis of MAS. METHODS: We developed a mouse model to evaluate the role of each cytokine with Toll-like receptor 9 stimulation after continuous infusion with IL-18, IL-1ß, and a combination of both for 7 days. The symptoms and laboratory findings were compared among the IL-18, IL-1ß, and combination (IL-18+IL-1ß) groups. RESULTS: Body weight was significantly decreased in the IL-1ß and combination groups. Splenomegaly was observed in all groups, whereas hepatomegaly was noted in the IL-18 group only. Decreased T-cell numbers, anemia, and thrombocytopenia were observed in the combination group. IFN-γ, CXCL9, and IL-12A mRNA levels were upregulated and IL-10 mRNA levels in the spleen were downregulated in the IL-18 group. Hepatomegaly and splenomegaly in the IL-18 group were observed in a dose-dependent manner. TNF-α, CXCL9, and IL-12A mRNA levels were upregulated only in those mice with extremely elevated plasma IL-18 levels. CONCLUSION: IL-18 and IL-1ß have distinct roles in the pathogenesis of MAS. Dual blockade of IL-18 and IL-1ß might be necessary to treat MAS.

CD169 expression on monocytes as a marker for assessing type I interferon status in pediatric inflammatory diseases.

BACKGROUND: Evaluation of type I interferons (IFNs) in inflammatory or autoimmune diseases is challenging because of their rapid clearance in peripheral blood. The IFN gene expression signature has recently been used to evaluate the IFN status; however, this is often a labor-intensive and time-consuming procedure. Therefore, we assessed the feasibility of measuring expression of an IFN-inducible protein, CD169 (Siglec-1), on monocytes and circulating levels of soluble CD169 as alternative markers for type I IFN status in various pediatric inflammatory diseases. METHODS: Data from flow cytometric analysis of surface CD169 on monocytes and an enzyme-linked immunosorbent assay of soluble CD169 in peripheral blood were compared with serum IFN-α levels in 8 patients with viral infections, 5 with bacterial infections, 10 with systemic lupus erythematosus (SLE), 5 with Kikuchi-Fujimoto disease (KFD), 7 with Kawasaki disease (KD), and 8 with inflammatory bowel disease (IBD), and in 8 healthy controls. RESULTS: Surface CD169 expression was detected mainly on CD14+ monocytes and was significantly increased in patients with viral infections, SLE, and KFD, but not in patients with bacterial infections, KD, and IBD. There were similar trends for circulating soluble CD169; however, there was a significant increase only in patients with viral infections. Surface CD169 levels were significantly correlated with serum levels of IFN-α and soluble CD169. CONCLUSION: Analysis of CD169 expression on CD14+ monocytes may be useful for rapid assessment of type I IFN status for differentiation of pediatric inflammatory diseases from type 1 IFN-mediated diseases.

Comparison of serum biomarkers for the diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.

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.

Extensive serum biomarker analysis in patients with macrophage activation syndrome associated with systemic lupus erythematosus.

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.

Cytokine profile of macrophage activation syndrome associated with Kawasaki disease.

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.

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

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.

An Adolescent Case of Anti-MDA5 Antibody-Positive Juvenile Dermatomyositis With Interstitial Lung Disease Successfully Treated by Multitarget Therapy Avoiding Cyclophosphamide: A Case Report and Literature Review.

Juvenile dermatomyositis (JDM) patients who test positive for the antimelanoma differentiation-associated gene 5 (MDA5) antibody have a poor prognosis because of rapidly progressing interstitial lung disease (ILD). However, agreement on the best treatment for this condition remains elusive. We encountered a 13-year-old girl with anti-MDA5 antibody-positive JDM who presented with arthritis and was already showing signs of ILD when she was admitted to the hospital. While cyclophosphamide (CY) is commonly used, it can cause gonadal disorders and other complications when administered to adolescent females. Consequently, we chose multitarget therapy, which includes tacrolimus and mycophenolate mofetil. Her ILD and skin symptoms gradually improved, and she was able to maintain remission and avoid CY administration for three years. We conducted a thorough literature review to determine the efficacy and safety of multitarget therapy for anti-MDA5 antibody-positive DM and JDM. Multitarget therapy shows promise as a potentially effective and relatively safe treatment. The ability to avoid CY, which is especially important for adolescent patients concerned about fertility preservation, highlights a significant benefit of this multitarget therapy for anti-MDA5 antibody-positive DM and JDM patients.

IgA Vasculitis in Japanese Patients Harboring MEFV Mutations: A Case Report and Review of the Literature.

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. Herein, we present a five-year-old girl presented with IgAV. She experienced prolonged abdominal pain, which was steroid-resistant. When treatment with colchicine was started, her abdominal pain resolved immediately. The serum interleukin (IL)-18 levels of the patient and other patients with IgAV and familial Mediterranean fever (FMF) were evaluated using enzyme-linked immunosorbent assay. The serum IL-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. Moreover, all exons of the MEFV gene were analyzed using the Sanger sequencing and the patient presented with E148Q/M694I mutation. Further, a comprehensive search of Japanese patients with IgAV harboring MEFV gene mutations in PubMed, Ichushi-Web, and Medical Online was conducted to validate the clinical characteristics of Japanese patients with IgAV harboring MEFV gene mutation. In previous studies, only five patients presented with IgAV harboring MEFV gene mutation in Japan.  The prevalence of IgAV associated with MEFV gene mutation may be low in Japan. However, MEFV gene mutations should be suspected if the symptoms of IgAV are prolonged or if patients are refractory to treatment. In such case, IL-18 monitoring and colchicine treatment may be useful for IgAV with MEFV gene mutation.

Oligomeganephronia with PAX2 gene deletion diagnosed at the third renal biopsy: a case report.

Oligomeganephronia is a congenital anomaly of the kidney and urinary tract. It is often categorized as one of the hypoplastic kidney conditions. The pathological diagnosis of oligomeganephronia is challenged by the absence of clear diagnostic criteria, which often leads to subjective interpretations by pathologists. This report presents the case of a 7-year-old girl who was diagnosed with oligomeganephronia through a third renal biopsy, which was confirmed by gene analysis revealing PAX2 deletion. Two previous renal biopsies, with the naked eye through a microscope, failed to identify glomerular hypertrophy and sparse glomerular distribution density. However, using digital images, the glomeruli were larger than those of age-matched controls, and the number of glomeruli within the renal cortex area revealed sparse glomerular distribution density. Image processing allows for objective evaluation of the glomerular size and glomerular distribution density, providing a quantitative assessment. For earlier diagnosis of oligomeganephronia, an appropriate objective standardized method for measuring glomerular size and glomerular distribution density should be established.

Cytokine Profiles in Human Parechovirus Type 3-induced Sepsis-like Syndrome.

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.