The dynamics of laboratory markers reflecting cytokine overproduction in macrophage activation syndrome complicated with systemic juvenile idiopathic arthritis.

OBJECTIVES: To validate the correlation between laboratory markers reflecting disease activity of macrophage activation syndrome (MAS) and serum cytokine levels and identify the valuable laboratory markers that change over time for a prompt MAS diagnosis. METHODS: Serum cytokine levels were determined by enzyme-linked immunosorbent assay and compared with laboratory markers reflecting MAS disease activity.The changes in values were evaluated from the acute phase of systemic juvenile idiopathic arthritis (s-JIA) to MAS diagnosis. RESULTS: CXCL9 was significantly correlated with aspartate aminotransferase (AST), lactate dehydrogenase (LDH), D dimer, and urine ß2 microglobulin levels. sTNF-RII was significantly correlated with platelet counts, AST, LDH, D dimer, and ferritin levels. Significant changes in platelet count, LDH, and D dimer levels were observed. Decreased platelet counts were the most valuable indicator for MAS diagnosis. CONCLUSION: Monitoring the laboratory markers that change over time, particularly decreased platelet counts, was valuable for the prompt MAS diagnosis in s-JIA.

Clinical significance of serum cytokine profiles for differentiating between Kawasaki disease and its mimickers.

OBJECTIVES: To investigate the clinical significance of serum cytokine profiles for differentiating between Kawasaki disease (KD) and its mimickers. METHODS: Patients with KD, including complete KD, KD shock syndrome (KDSS), and KD with macrophage activation syndrome (KD-MAS), and its mimickers, including multisystem inflammatory syndrome in children, toxic shock syndrome, and Yersinia pseudotuberculosis infection, were enrolled. Serum levels of interleukin (IL)-6, soluble tumor necrosis factor receptor type II (sTNF-RII), IL-10, IL-18, and chemokine (C-X-C motif) ligand 9 (CXCL9) were measured using enzyme-linked immunosorbent assay and compared them with clinical manifestations. RESULTS: Serum IL-6, sTNF-RII, and IL-10 levels were significantly elevated in patients with KDSS. Serum IL-18 levels were substantially elevated in patients with KD-MAS. Patients with KD-MAS and KD mimickers had significantly elevated serum CXCL9 levels compared with those with complete KD. Area under the receiver operating characteristic curve analysis showed that serum IL-6 was the most useful for differentiating KDSS from the others, IL-18 and CXCL9 for KD-MAS from complete KD, and CXCL9 for KD mimickers from complete KD and KD-MAS. CONCLUSION: Serum cytokine profiles may be useful for differentiating between KD and its mimickers.

One-year-old boy with refractory Listeria monocytogenes meningitis due to persistent hypercytokinemia.

We had a case of Listeria monocytogenes (LM) meningitis complicated with hypercytokinemia and hemophagocytic lymphohistiocytosis in a healthy 22-month-old boy. He was admitted to our hospital with a fever, vomiting, mild consciousness disturbances, and extraocular muscle paralysis. Magnetic resonance imaging (MRI) revealed bilateral deep white matter lesions. After receiving ampicillin, meropenem, and gentamicin, his cerebrospinal fluid (CSF) culture results turned negative on the third day of hospitalization. However, the fever intermittently persisted, and it took approximately 40 days to completely resolve. During this period, various inflammatory cytokine levels, particularly neopterin, in the blood and CSF remained elevated. Therefore, long-term administration of corticosteroids in addition to antibiotics was required. The use of dexamethasone appeared to be effective for neurological disorders such as consciousness disturbance and extraocular muscle paralysis associated with abnormal brain MRI findings. LM meningitis may present with encephalopathy and persistent fever due to hypercytokinemia. In such cases, corticosteroid therapy should be considered.

Apoptosis inhibitor of macrophage as a biomarker for disease activity in Japanese children with IgA nephropathy and Henoch-Schönlein purpura nephritis.

BACKGROUND: To evaluate the apoptosis inhibitor of macrophage (AIM) deposition patterns on the kidneys of children with IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis (HSPN) and to investigate the clinical usefulness of serum and/or urinary AIM levels as biomarkers for the disease activity. METHODS: Immunohistochemical study was performed in the kidneys of 37 patients with IgAN and 10 patients with HSPN. Serum and urinary AIM levels in the patients and 20 healthy controls (HCs) were quantified by enzyme-linked immunosorbent assay. The results were compared with clinical features. RESULTS: In patients with IgAN and HSPN, AIM expression was observed in various areas, including the glomerular mesangial and capillary areas, the proximal and distal tubular epithelial cells, and on infiltrating macrophages in the glomeruli and interstitial areas. Serum and urinary AIM levels were significantly elevated in these patients compared with the HCs. Urinary AIM levels were positively correlated with the histological severity and degree of proteinuria and hematuria as well as urinary ß2 microglobulin and urinary N-acetyl-ß-D-glucosaminidase levels. CONCLUSIONS: AIM plays an important role in the pathogenesis of IgAN and HSPN. Urinary AIM levels can potentially reflect active renal inflammation in these diseases and may represent a useful biomarker for disease activity. IMPACT: Urinary AIM levels may represent a useful biomarker for disease activity of IgAN and HSPN. AIM expression was observed in the glomeruli, tubular epithelial cells, and infiltrating macrophages in glomeruli and interstitial area. U-AIM/Cr were significantly correlated not only with proteinuria, hematuria, and u-ß2MG and u-NAG levels but also with the activity index of histological findings in kidney biopsy specimens. Our results can emphasize the important role of AIM in the pathogenesis of IgAN and HSPN.

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

BACKGROUND: To compare the accuracy of serum biomarkers for the diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s-JIA) during tocilizumab therapy. METHODS: Serum cytokine levels of neopterin, IL-18, C-X-C motif chemokine ligand 9, soluble tumor necrosis factor receptor (sTNFR)-I, and sTNFR-II were determined by enzyme-linked immunosorbent assay in 36 patients with MAS complicating s-JIA including 12 patients receiving tocilizumab. Furthermore, the serum sTNFR-II/I ratio was compared with the clinical features of MAS. RESULTS: The levels of all serum cytokines at MAS diagnosis were significantly lower in the tocilizumab-treated group than in the tocilizumab-untreated group. In contrast, the serum sTNFR-II/I ratio at MAS diagnosis was comparable between the tocilizumab-treated and the tocilizumab-untreated groups. The receiver operating characteristic curve analysis revealed that the area under the curve and cut-off values of sTNFR-II/I ratio were 0.9722 and 4.71, respectively. The serum sTNFR-II/I ratio, which was significantly elevated in patients with MAS complicating s-JIA, was correlated positively with disease activity. CONCLUSIONS: These findings suggest that the serum sTNFR-II/I ratio might be a useful indicator to evaluate disease activity in MAS complicating s-JIA and a useful diagnostic marker for the transition from active-phase s-JIA to MAS even in tocilizumab-treated patients. IMPACT: This is the first study to analyze the role of tocilizumab in modifying the serum levels of biomarkers used for the diagnosis of MAS complicating s-JIA. We found the biomarker for the diagnosis of MAS complicating s-JIA during tocilizumab therapy. We hope our results might be useful for the development of a new criteria for the diagnosis of MAS complicating s-JIA in patients treated with tocilizumab in future.

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.

Possible correlation between serum interleukin-8 levels and the activity of myositis in anti-NXP2 antibody-positive dermatomyositis.

Anti-nuclear matrix protein 2 (NXP2) antibody-positive dermatomyositis (DM) is characterized by extensive and severe myositis. In this study, we evaluated which cytokines/chemokines involved with the activity of the myositis. We performed quantitative immunoassays using the MILLIPLEX® Multiplex Assays Using Luminex to evaluate serum levels of interferon-γ, interleukin (IL)-1ß, IL-6, IL-8, IL-12p40, and tumor necrosis factor-α in samples collected over time from a 9-year-old female with anti-NXP2 antibody-positive DM. In our case, the serum level of IL-8 was elevated when the myositis worsened, and decreased in accordance with the improvement of myositis, suggesting that the serum IL-8 levels were correlated with the myositis activity. Serum levels of IL-8 in samples from five patients with anti-NXP2 antibody-positive DM and five patients with anti-transcriptional intermediary factor 1γ (TIF1γ) antibody-positive DM without both interstitial lung disease (ILD) and malignancy before starting treatments, along with five healthy controls, were also evaluate by an enzyme-linked immunosorbent assay. Serum IL-8 levels were significantly elevated in anti-NXP2 or anti-TIF1γ antibody-positive DM patients with myositis but not ILD, than healthy controls. It was suggested that serum levels of IL-8 correlate with the activity of myositis in DM including anti-NXP2 antibody-positive DM.

Successful treatment with tofacitinib for anti-melanoma differentiation-associated gene 5 antibody-positive juvenile dermatomyositis: case reports and review of the literature.

Although the clinical efficacy of tofacitinib has been reported in adult patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive (Ab+) dermatomyositis, data on its use in refractory juvenile dermatomyositis (JDM) are scarce. We describe two female Japanese patients with anti-MDA5 Ab + JDM and rapidly progressive interstitial lung disease who achieved remission by adding tofacitinib to existing immunosuppressive drugs and present a literature review. While both patients received various immunosuppressive or anti-inflammatory treatments for induction therapy, remission could not be achieved. Subsequently, tofacitinib was administered to reduce the Krebs von den Lungen-6 level 5 months after diagnosis in one patient; the other patient received tofacitinib 4 months after diagnosis to reduce ferritin levels and skin manifestations. Subsequently, both patients achieved remission, and prednisolone was withdrawn. Tofacitinib reduced the interferon signature associated with dermatomyositis/JDM disease progression and exerted a therapeutic effect on dermatomyositis/JDM. We found six published cases from five articles of tofacitinib for refractory anti-MDA5 Ab + JDM. Except for one case of herpes simplex meningitis, the other cases, including ours, had improved disease activity without severe adverse events, and steroids and immunosuppressive medicines could be tapered. Tofacitinib could be considered an available therapy for refractory anti-MDA5 Ab + JDM.

Clinical Usefulness of T-Cell Receptor Vß Repertoire Analysis for Differentiating Multisystem Inflammatory Syndrome in Japanese Children From Toxic Shock Syndrome and Kawasaki Disease.

The specific expansion of T-cell receptor ß chain variable region (TCR-Vß21.3 + ) CD4 + and CD8 + T cells was observed in Japanese patients with multisystem inflammatory syndrome in children. In contrast, these findings were not observed in patients with toxic shock syndrome and Kawasaki disease. T-cell receptor ß chain variable region repertoire analysis to detect specific expansion of Vß21.3 + T cells might be useful for differentiating multisystem inflammatory syndrome in children from toxic shock syndrome and Kawasaki disease.

Cranial ultrasonography in diagnosis of infantile cerebral cavernous malformation.

The case of an infantile cerebral cavernous malformation detected by transfontanelle cranial ultrasonography. Infantile cerebral cavernous malformations tend to cause more major bleeding compared to those in older groups, so early detection and treatment are crucial. Cranial ultrasonography can contribute to the early diagnosis of infantile cerebral cavernous malformations.

Anti-Ku antibody-positive systemic sclerosis and idiopathic inflammatory myopathies overlap syndrome in children: a report of two cases and a review of the literature.

The occurrence of anti-Ku antibody-positive idiopathic inflammatory myopathy (IIM) in pediatric patients is rare, and therefore, the clinical phenotypes of this disease in such patients remain obscure. We herein report two cases of Japanese female pediatric patients with anti-Ku antibody-positive IIM. One case was unique in that it was complicated by pericardial effusion. Another patient had severe and refractory myositis with immune-mediated necrotizing myopathy. In addition, we reviewed literatures involving a total of 11 pediatric patients with anti-Ku antibody-positive IIM. The median age of the patients was 11 years, and most of them were girls. Skin rash, including erythematous nodules, malar rash, multiple brownish plaques, butterfly rash, heliotrope rash, periorbital edema, and Gottron's papules, was observed in 54.5% of the patients, scleroderma in 81.8%, and skin ulcer in 18.2%. Their serum creatine kinase level ranged from 504 to 10,840 IU/L. Furthermore, joint involvement was observed in 91% of the patients, interstitial lung disease in 18.2%, and esophageal involvement in 9.1%. All patients were treated with corticosteroids in combination with immunosuppressants. Pediatric patients with anti-Ku antibody-positive IIM had unique characteristics compared to adult patients. Skin manifestations, joint involvement and elevation of serum CK levels were more common in children than in adults. In contrast, ILD and esophageal involvement were less common in children than in adults. Although pediatric cases of anti-Ku antibody-positive IIM are rare, patients with IIM need to be tested for the presence of anti-Ku antibodies.

Serum interleukin-18 level as a possible early diagnostic marker of systemic juvenile idiopathic arthritis.

Early diagnosis of systemic juvenile idiopathic arthritis (s-JIA) is a prerequisite for therapeutic efficacy. However, it is often challenging because most patients with s-JIA do not show arthritis at disease onset and are simply diagnosed with fever of unknown origin. Serum ferritin levels have commonly been used to diagnose s-JIA because they increase in patients with this condition by more than 5 times their normal value. However, there are no definite biomarkers for s-JIA, which makes the clinical diagnosis of s-JIA difficult. We report a case of s-JIA in which interleukin (IL)-18 elevation was observed before ferritin elevation at the early phase of s-JIA. We propose serum IL-18 levels as a more useful biomarker for the early diagnosis of s-JIA compared to serum ferritin levels.