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The Novel Coronavirus Disease 2019 (COVID-19) has swept the world and caused a global pandemic. SARS-CoV-2 seems to have originated from bats as their reservoir hosts over time. Similar to SARS-CoV, this new virus also exerts its action on the human angiotensin-converting enzyme 2. This action causes infections in cells and establishes an infectious disease, COVID-19. Against this viral invasion, the human body starts to activate the innate immune system in producing and releasing proinflammatory cytokines such as IL-6, IL-1β, IL-8, TNF-α, and other chemokines, such as G-CSF, IP10 and MCPl, which all develop and increase the inflammatory response. In cases of COVID-19, excessive inflammatory responses occur, and exaggerated proinflammatory cytokines and chemokines are detected in the serum, resulting in cytokine release syndrome or cytokine storm. This causes coagulation abnormalities, excessive oxidation developments, mitochondrial permeability transition, vital organ damage, immune system failure and eventually progresses to disseminated intravascular coagulation and multiple organ failure. Additionally, the excessive inflammatory responses also cause mitochondrial dysfunction due to progressive and persistent stress. This damages cells and mitochondria, leaving products containing mitochondrial DNA and cell debris involved in the excessive chronic inflammation as damage-associated molecular patterns. Thus, the respiratory infection progressively leads to disseminated intravascular coagulation from acute respiratory distress syndrome, including vascular endothelial cell damage and coagulation-fibrinolysis system disorders. This condition causes central nervous system disorders, renal failure, liver failure and, finally, multiple organ failure. Regarding treatment for COVID-19, the following are progressive and multiple steps for mitigating the excessive inflammatory response and subsequent cytokine storm in patients. First, administering of favipiravir to suppress SARS-CoV-2 and nafamostat to inhibit ACE2 function should be considered. Second, anti-rheumatic drugs (monoclonal antibodies), which act on the leading cytokines (IL-1β, IL-6) and/or cytokine receptors such as tocilizumab, should be administered as well. Finally, melatonin may also have supportive effects for cytokine release syndrome, resulting in mitochondrial function improvement. This paper will further explore these subjects with reports mostly from China and Europe.

The patient, a 13-year-old boy, was diagnosed with juvenile enthesitis-related arthritis at the age of 12. Adalimumab was administered after the arthritis became refractory to methotrexate (MTX) an...

We report a 13-year-old Japanese boy with RASopathy (Noonan syndrome and Noonan-related syndromes) complicated by systemic lupus erythematosus (SLE). The diagnosis of RASopathy was made on the basis of stature and mental retardation, characteristic facial dysmorphia and sparse, thin hair. A heterozygous mutation in SHOC2 had been identified at the age of 9. He was evaluated by our institution for a chief complaint of fever and abdominal pain. He was found to have an enlarged cardiac silhouette (cardiothoracic ratio 77.8%) and extensive pericardial fluid, suggesting the presence of cardiac tamponade due to pericarditis. The patient met the diagnostic criteria for pediatric systemic lupus erythematosus (pSLE) (Japan Ministry of Health, Labour and Welfare, 1986); pericarditis, positive antinuclear antibody, immunological disorder (anti-ds DNA, anti-Sm, anti-U1 RNP), and hypocomplementemia. Other SLE features, such as rash, arthritis, renal involvement, and hematological disorders, were not observed. ...

Objective: Both genetic and environmental factors are associated with susceptibility to juvenile idiopathic arthritis (JIA). Many studies have reported that both a 'shared epitope' (SE) encoded by several HLA-DRB1 alleles and the peptidyl arginine deiminase type 4 (PADI4) gene polymorphisms are associated with susceptibility to rheumatoid arthritis (RA). However, it is uncertain whether JIA and RA share the latter genetic risk factor. Therefore, here we investigated relationships between HLA-SE and PADI4 polymorphisms with clinical subtypes of JIA. Methods: JIA patients (39 oligoarthritis, 48 RF-positive polyarthritis, 19 RF-negative polyarthritis and 82 systemic) and 188 healthy controls were genotyped for HLA-DRB1 by PCR-sequence-specific oligonucleotide probe methodology. Three PADI4 gene single nucleotide polymorphisms (SNPs), rs2240340, rs2240337 and rs1748033, were genotyped using TaqMan SNP Genotyping Assays. Results: Frequencies of the HLA-SE were higher in RF-positive polyarticular JIA than in healthy controls. RF-positive polyarticular JIA was associated with HLA-SE (OR = 5.3, 95% CI = 2.5-11.9, pc < 0.001). No associations were found between clinical subtypes of JIA and PADI4 allele frequency. Nonetheless, rs2240337 in the PADI4 gene was significantly associated with anti-cyclic citrullinated peptide antibody (ACPA)-positivity in JIA. The A allele at rs2240337 was a significant risk factor for ACPA positivity in JIA (OR = 5.6, 95% CI = 1.71-23.7 pc = 0.03). Conclusion: PADI4 gene polymorphism is associated with ACPA-positivity in JIA. The association of HLA-SE with RF-positive polyarticular JIA as well as RA is confirmed in Japanese. Thus, HLA-SE and PADI4 status both influence JIA clinical manifestations.

Mycoplasma pneumoniae (Mp) is one of the main pathogens causing community-acquired pneumonia, particularly in young individuals. Host immune response appears to play an important role in prolonged symptoms, as well as in the recent increasing prevalence of drug-resistant Mp isolated from patients. Case 1 had a prolonged clinical course caused by drug-resistant Mp and received steroid therapy despite Mp susceptibility to some antimicrobial agents. Serum cytokine profiles revealed elevation of interleukin-6/-10 and interferon-γ in acute phase. Case 2 had mycoplasmal myocarditis without any respiratory symptoms, which resolved spontaneously without the administration of any antimicrobial agent. These observations suggest that host immune response probably contributes to the etiology of Mp-associated complications.

Chédiak-Higashi syndrome (CHS) is one of the primary immunodeficiency syndromes accompanied by oculocutaneous albinism. It is characterized by existence of giant granule of neutrophils, and development of symptoms of hemophagocytic lymphohistiocytosis. CHS is a rare disorder and recognition of the disease is indispensable for its diagnosis. In our case, a four-month-old boy, virus-associated hemophagocytic syndrome (VAHS) was suspected from generation of fever, hepatosplenomegaly, and existence of atypical lymphocytes on admission. However, elevation of serum AST, LDH and ferritin were quite slight as VAHS, and rapid exacerbation of the findings was not seen. Associated virus was undetected. He was finally diagnosed as CHS developing hemophagocyctic lymphohistiocytosis based on the existence of a giant granule of neutrophils in the peripheral blood smear and oculocutaneous albisum and laboratory findings. Clinical outcome was successful after receiving HLA-matched unrelated bone marrow transplantation.

We encountered two human metapneumovirus (HMPV)-infected children who developed respiratory distress due to bronchopneumonia during hospitalization. There was no evidence of abnormal findings in the gastrointestinal or genitourinary tracts or the nervous or mucocutaneous systems. Their respiratory conditions rapidly improved upon the initiation of steroid therapy. Increases and decreases in serum concentrations of various inflammatory cytokines, including interferon-γ, and interleukin-6/10, were evaluated before and after steroid administration. General practitioners should be aware of the possibility of high-inflammatory cytokinemia when examining and treating children with HMPV infection and respiratory distress due to bronchopneumonia.

Cryopyrin-associated periodic syndrome (CAPS) comprises a group of rare, but severe, autoinflammatory syndrome, and includes 3 distinct conditions, familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (MONID). These syndromes are characterized by urticarial-like rash, periodic fever, central nervous system inflammation, an arthropathy, and the risk of amyloidosis. About 20% die by age 20 years in the most severe cases. The disease is associated with mutations in the NLRP3 gene that encodes for the protein cryopyrin, a component of the inflammasome complex that regulates the production and secretion of IL-1β. Canakinumab is a human IgG monoclonal antibody targeting IL-1β. The clinical trials of canakinumab for patients with CAPS in both western countries and Japan were well-tolerated in most patients, and provided significant advantages over existing competitive therapies. Although no serious adverse effects have been reported, the frequencies of common infectious diseases including nasopharyngitis, upper respiratory tract infections, and gastroenteritis were reported presumably due to the blockade of proinflammatory cytokine, IL-1β. For us pediatrician, it will be important to be more careful for infectious diseases to provide the maximum safety of canakinumab for these patients.

Fever is one of the critical symptoms of patients in pediatrics field. It indicates inflammatory focus somewhere in the body, and the major causes of fever are infectious diseases. Recent progresses of our knowledge about autoinflammatory syndrome promoted the investigation of the mechanism of fever, and suggested that the pro-inflammatory cytokines are the direct causative agents of fever. The basic science revealed that cooperation of IL-6 and IL-1β induces febrile response. Fever of unknown origin (FUO) remains a challenging problem. Rheumatic diseases, rare infectious diseases, and benign tumors and malignancies are diagnoses to be differentiated. FDG-PET is recently proved a valuable tool for the identification of the etiology in patients with FUO. Since the introduction of biological response modifiers into the treatment of patients with pediatric rheumatic diseases has shifted the therapeutic paradigm, a new concept that the blockade of a unique pro-inflammatory cytokine brings cessation of whole inflammatory responses affected tremendously the clinical medicine. A more investigation of inflammation and its pathophisiology will be needed in pediatric rheumatology.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome and has a varied genetic background. The polymorphism of interferon regulatory factor 5 gene (IRF5) was reported to be associated with susceptibility to macrophage activation syndrome. IRF5 acts as a master transcription factor in the activation of pro-inflammatory cytokines. We assessed associations of IRF5 gene polymorphisms with susceptibility to secondary HLH.Three IRF5 single nucleotide polymorphisms (rs729302, rs2004640, and rs2280714) were genotyped using TaqMan assays in 82 secondary HLH patients and 188 control subjects.There was a significant association of the GT/TT genotype at rs2004640 with secondary HLH susceptibility (p 0.01). The IRF5 haplotype (rs729302 A, rs2004640 T, and rs2280714 T) was associated with secondary HLH susceptibility (p 0.01).These findings indicate that IRF5 is a genetic factor influencing the susceptibility to secondary HLH and that the IRF5-associated immune response contributes to the pathogenesis of HLH.

Systemic juvenile idiopathic arthritis (s-JIA) is a rare inflammatory disease classified as a subtype of chronic childhood arthritis, manifested by spiking fever, erythematous skin rash, pericarditis and hepatosplenomegaly. The genetic background underlying s-JIA remains poorly defined. To detect copy number variations, we performed single nucleotide polymorphism (SNP) array analysis in 50 patients with s-JIA. We found a 13-kb intragenic deletion of CASP10 in one patient. RT-PCR of the mRNA extracted from the patient's lymphoblastoid cells revealed that CASP10 mRNA was truncated. Sequencing the mRNA revealed that this deletion resulted in a frame shift with an early stop codon. CASP10 is known as a causative gene for autoimmune lymphoproliferative syndrome (ALPS) type IIa, another childhood syndrome of lymphadenopathy and splenomegaly associated with autoimmune haemolytic anaemia and thrombocytopenia. TCR αβ(+) CD4/CD8 double-negative T cells in the peripheral blood as a diagnostic marker of ALPS were not high in this patient and lymphocyte apoptosis induced by anti-Fas antibody was normal, denying ALPS in the patient. The father and a sister of the patient showing no symptoms of ALPS or s-JIA, also had the same deletion. Furthermore, we found no other mutations of CASP10 in the other 49 s-JIA patients. These data suggest that the pathogenic significance of CASP10 mutations should be carefully evaluated in s-JIA or even ALPS type IIa in further studies.

Systemic-onset juvenile idiopathic arthritis (s-JIA) is a rare inflammatory disease classified as a subtype of chronic childhood arthritis, manifested by spiking fever, erythematous skin rash, pericarditis and hepatosplenomegaly. The genetic background underlying s-JIA remains poorly understood. To detect disease-related copy number variations (CNVs), we performed single-nucleotide polymorphism array analysis in 50 patients with s-JIA. We detected many CNVs, but most of them were inherited from either of normal-phenotype parents. However, in one patient, we could identify two de novo microduplications at 19q13.42 with the size of 77 and 622 kb, separated by a 109-kb segment of normal copy number. The duplications encompass NLRP family (NLRP2, NLRP9 and NLRP11) as well as IL11 and HSPBP1, all of which have an important role in inflammatory pathways. These genes may significantly contribute to the pathogenesis of s-JIA.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Methotrexate (MTX), which causes adverse effects, such as liver and/or renal dysfunction, is the most common disease-modifying antirheumatic drug used for the treatment of rheumatoid arthritis and articular-type juvenile idiopathic arthritis (JIA). • Pharmacogenetic studies analysing the MTX pathway genes would aid in the development of more personalized therapy. • Results regarding the influence of gene polymorphisms on the toxicity and efficacy of MTX are conflicting, and there are marked differences between racial groups in pharmacogenetics. WHAT THIS STUDY ADDS • The non-TT genotype at γ-glutamyl hydrolase (GGH) T16C is associated with a high risk of liver dysfunction due to MTX, even after adjustment for duration of MTX treatment. • Longer time interval from disease onset to MTX treatment and rheumatoid factor positivity are associated with lower efficacy of MTX in Japanese patients, as reported previously in Caucasian patients with JIA. AIMS We investigated whether several polymorphisms within the methotrexate (MTX) pathway genes were related to the toxicity and efficacy of MTX in 92 Japanese patients with articular-type juvenile idiopathic arthritis (JIA). METHODS Eight gene polymorphisms within the MTX pathway genes, namely, RFC, BCRP, MTHFR (two), FPGS, γ-glutamyl hydrolase (GGH; two) and ATIC, were genotyped using TaqMan assays. Liver dysfunction was defined as an increase in alanine transaminase to five times the normal upper limit. Non-responders to MTX were defined as patients refractory to MTX and were therefore treated with biologics. RESULTS The non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction (P = 0.028, odds ratio = 6.90, 95% confidence interval 1.38–34.5), even after adjustment for the duration of MTX treatment. A longer interval from disease onset to treatment (8.5 and 21.3 months, P = 0.029) and rheumatoid factor positivity (P = 0.026, odds ratio = 2.87, 95% confidence interval 1.11–7.39) were associated with lower efficacy of MTX. CONCLUSIONS The non-TT genotype at GGH T16C was associated with a high risk of liver dysfunction, presumably because the C allele of GGH C16T may reduce the activity of GGH. The time interval before MTX treatment and rheumatoid factor positivity were associated with the efficacy of MTX treatment. The pharmacogenetics of the MTX pathway genes affects the toxicity and efficacy of MTX in Japanese JIA patients.

Takayasu's arteritis (TA) is a chronic idiopathic inflammatory disease affecting primarily aorta and its proximal branches. Pediatric patients with TA tend to have more severe clinical course and be refractory to conventional treatments compared with adults. Corticosteroids are major treatment of TA, however, high dose is required to get remission. Particularly, adolescent patients are usually suffering from side-effects of excessive dose of corticosteroids. Immunosuppressants are added expecting the corticosteroid sparing agents. However, some patients, such as HLA-B52 positive, tend to be registant to these conventional treatments. Recently, several reports showed the efficacy of Infliximab, anti-tumor necrosis factor (TNF) alpha monoclonal antibody, for adult patients with refractory TA. We described three cases of adolescents with TA treated with Infliximab. It was initially effective in all three patients. However, serious infusion reaction occurred in one of them during 11(th) times of Infliximab infusion and she discontinued the therapy. Other two patients showed good response in initial phase, but clinical manifestations and laboratory findings became worse after several months. In these patients with secondary failure to Infliximab, increased dosage and shortening the interval of infusions provided effectiveness again. Infliximab would be a good choice for adolescent patients with TA refractory to conventional treatments. However, we should carefully monitor safety and efficacy of this agent considering its peculiarity.

Interleukin (IL)-6 is a causative agent of systemic juvenile idiopathic arthritis (sJIA), a chronic inflammatory disease complicated with severe growth impairment. Recent trials of anti-IL-6 receptor monoclonal antibody, tocilizumab, indicated that tocilizumab blocks IL-6/IL-6 receptor-mediated inflammation, and induces catch-up growth in children with sJIA. This study evaluates the effects of IL-6 on chondrogenesis by ATDC5 cells, a clonal murine chondrogenic cell line that provides an excellent model for studying endochondral ossification at growth plate. ATDC5 cells were examined for the expression of IL-6 receptor and gp130 by fluorescence-activated cell sorting analysis. Recombinant murine IL-6 was added to ATDC5 cultures to observe cell differentiation, using a quantitative RT-PCR for the chondrogenic differentiation markers type II collagen, aggrecan, and type X collagen. To block IL-6, the anti-mouse IL-6 receptor monoclonal antibody MR16-1 was added. As a result, the cells expressed IL-6 receptor and gp130. The expression of chondrogenic differentiation marker gene was reduced by IL-6, but this was abrogated by MR16-1. We conclude that IL-6 inhibits early chondrogenesis of ATDC5 cells suggesting that IL-6 may affect committed stem cells at a cellular level during chondrogenic differentiation of growth plate chondrocytes, and that IL-6 may be a cellular-level factor in growth impairment in sJIA.

We have determined the serum levels of heme oxygenase-1 (HO-1) in 56 patients with systemic-onset juvenile idiopathic arthritis (s-JIA) and compared these with serum HO-1 levels in healthy controls and patients with other pediatric rheumatic diseases. Serum HO-1 levels were measured by the sandwich enzyme-linked immunosorbent assay. The mean serum HO-1 level in s-JIA patients during the active phase was 123.6 ± 13.83 ng/ml, which was significantly higher than that in patients with polyarticular juvenile idiopathic arthritis (p-JIA), Kawasaki disease, systemic lupus erythematosus or mixed connective tissue disease (P < 0.0005). The serum levels of HO-1, cytokines and cytokine receptors in patients with s-JIA were also assessed at both the active and inactive phases. The serum HO-1 level in patients with s-JIA in the active phase was found to be significantly greater than that in patients with the disease in the inactive phase (P < 0.0001). An assessment of the relationships between serum HO-1 levels and other laboratory parameters or cytokines in patients with s-JIA did not reveal any strong correlations. These results suggest that the serum level of HO-1 may be a useful marker for the differential diagnosis of s-JIA. Further study will be necessary to elucidate the mechanism of HO-1 production and to clarify the role of HO-1 in the disease process.

Background: Whole blood interferon-γ assay QuantiFERON-TB2G (QFT-2G), which is a new specific method for diagnosing tuberculosis (TB), has been developed and used in the clinical field. The aim of the present study was to assess the usefulness of QFT-2G as an indicator, both for diagnosing childhood TB and for assessing therapeutic effectiveness. Methods: The subjects were 61 children introduced to the TB outpatient department for the first time between June 2004 and March 2006. QFT-2G, the tuberculin test and chest computed tomography (CT) were performed for all patients. Results: Ten patients having typical characteristics of primary tuberculosis (PTB) on chest CT, and diagnosed as having tubercle bacillus infections, all had positive reaction on QFT-2G. Of seven patients who had no abnormalities on diagnostic imaging but who reacted positively on QFT-2G, one developed TB later, and no TB was detected over the period of observation in 44 patients with negative QFT-2G at their first consultation. Moreover, four patients with non-tuberculous acid-fast bacilli in which Mycobacterium avium or Mycobacterium gordonae was detected had negative reaction on QFT-2G. In addition, all 10 patients with positive reactions on QFT-2G in whom the subsequent course of the disease was observed had decrease on QFT after treatment. Conclusions: QFT-2G is a powerful tool with a wide application both in diagnosis and in assessment of treatment effectiveness in PTB.

We herein report two female siblings with childhood-onset Systemic Lupus Erythematosus (SLE) who developed membranous lupus nephritis. The children were diagnosed as having SLE in reverse birth order at ages 11 and 14 years. Younger sister's initial symptom was edema and laboratory findings indicated proteinuria, hypocomplementemia and positive ANA/anti-dsDNA antibody. She was diagnosed as being SLE with membranous lupus nephritis based on International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification. Elder sister manifested general fatigue and edema twelve months after her sister. Laboratory findings showed proteinuria, hypocomplementemia, and positive ANA/anti-dsDNA antibody. A renal biopsy revealed mixed form of mesangial proliferative glomerulonephritis and membranous nephritis. Moreover, both of them were complicated with secondary Sjögren's syndrome. HLA typing was performed and the siblings were noted to have the same haplotype; A(*)0207, A(*)2402, B(*)4601, B(*)5201, B(*)5201, Cw(*)0102, Cw(*)1202, DRB1(*)0101, DRB1(*)0803.

While analyzing gene expression in collagen-induced arthritis, we discovered that a poorly characterized gene, follistatin-like protein 1 (FSTL-1), is highly overexpressed in mouse paws during early arthritis, especially at the interface of synovial pannus and eroding bone. In this study, we show that FSTL-1 is a novel proinflammatory molecule with a previously unrecognized role in inflammation. Transfection of FSTL-1 into macrophages and fibroblasts leads to up-regulation of proinflammatory cytokines, including IL-1β, TNF-α, and IL-6. Overexpression of FSTL-1 in mouse paws by gene transfer results in severe paw swelling and arthritis.

Systemic-onset juvenile idiopathic arthritis (sJIA) is a severe and steroid-dependent disease of unknown etiology that sometimes progresses to a fatal disease known as the macrophage activation syndrome. The investigation of inflammatory cytokines and receptor levels revealed an increase in interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R) in serum of patients with active sJIA. The clinical symptoms and signs of the disease are presumably attributable to the continuous elevation of IL-6 and sIL-6R levels in serum. The characteristic fever spikes parallel IL-6 levels. In children, a long-term exposure to high levels of IL-6 causes severe growth impairment, as suggested by recently established studies of IL-6 transgenic mice. The biological functions of IL-6 are expressed through the binding of IL-6/IL-6R complex to gp130. The administration of tocilizumab (a recombinant humanized anti-IL-6R monoclonal antibody) exerts its action by preventing the binding of IL-6 to its receptor and, therefore, preventing the activation of gp130. After a few cases of compassionate use of tocilizumab, phase I and II studies of tocilizumab were conducted in children with sJIA, revealing that tocilizumab abruptly reduced the typical symptoms of inflammation and improved laboratory abnormalities. This article describes the experience in Japan regarding the treatment of sJIA with tocilizumab and supports the hypothesis that high levels of IL-6 may play an important role in the pathogenesis and maintenance of this disease. A confirmation of the role of tocilizumab in the treatment of sJIA will be provided by the results of the ongoing phase III study in Japan.

Proinflammatory cytokinemia and subsequent endothelial cell activation are the major pathological features of Kawasaki disease (KD), which progresses to systemic vasculitis and results in coronary artery lesions (CALs). We studied the serum levels of proinflammatory cytokines and of the soluble receptors before and after intravenous gamma-globulin (IVGG) treatment to investigate whether the anti-inflammatory effect of IVGG was due to the reduction of increased serum levels of their cytokines and soluble receptors. In the acute phase of KD, the serum levels of interleukin (IL)-2 and IL-5, as well as those of IL-6, IL-10, and interferon-γ, were markedly higher than those in controls. The level of tumor necrosis factor-α was higher than that in the control, but the difference was slight and not significant. The soluble IL-6 receptor levels were lower than those of the controls. After IVGG administration, the increased levels of these cytokines and soluble receptors were abruptly down-regulated to within their normal ranges. The patients enrolled in the present study were all effectively treated with IVGG, without a steroid, and improved without any residual CALs. Overall, IVGG administration to patients with KD was found to be effective in reducing inflammatory processes and in preventing CALs, and was followed by reduction of the serum levels of the proinflammatory cytokines and their receptors.

Systemic-onset juvenile idiopathic arthritis (JIA) is a severe and steroid-dependent disease, which sometimes progresses to the fatal disease macrophage activation syndrome. An investigation of inflammatory cytokine levels revealed increases in IL-6 in serum of systemic-onset disease patients. Continuously elevated levels of IL-6 in serum may play a important role in manifesting the clinical symptoms and signs of systemic-onset JIA, including spiking fever, rash, arthritis, and serositis. The characteristic fever spikes parallel IL-6 levels. Long-term exposure to high levels of IL-6 in children results in severe growth impairment, which was strongly suggested by the recent establishment of IL-6 transgenic mice. To avoid disease progression to macrophage activation syndrome and the adverse effects of high-dose corticosteroids, it might be reasonable to inhibit the formation of IL-6/IL-6R complex in order to block the binding to gp130 receptor, a biologically active receptor for IL-6. This review will provide evidence of the relationship between IL-6 homeostasis and systemic-onset JIA, and our recent trials of anti-IL-6R antibody (MRA) for children with acute systemic disease intractable to long-term and high-dose corticosteroid therapy. MRA could be a therapeutic modality for children with systemic-onset JIA intractable to high-dose corticosteroids.

Background: Systemic lupus erythematosus (SLE) is one of the major collagen diseases in childhood. However, the pathogenesis of this disease still remains unknown. The disease is known as a chronic inflammatory disease. Since oral and intravenous corticosteroid therapy has been introduced into the treatment of SLE, the prognosis of patients has improved significantly. However, it has now become clear that there are limitations in the effectiveness, as well as adverse reactions when corticosteroids therapy is administered for a long-term period. Therefore, we have been attempting to improve the maintenance therapy of child-onset SLE. Methods: We have proposed and tested a new type of combination therapy using prednisolone (PSL) and mizoribine (MZR) in pediatric patients with SLE for maintenance therapy after the induction of remission. Results: Our results showed that this combination therapy is more effective than the previous regimen. In addition, no significant side-effects were observed in our study. Conclusion: This combination therapy is still not perfect. Efforts should be continued to establish an optimal therapy regimen for child-onset SLE.

We experienced a girl with polyarteritis nodosa (PN) diagnosed by myocardial biopsy. The symptoms began with high fever and skin rash. These symptoms and laboratory findings temporarily improved by oral prednisolone, however, she flared up with chest pain about 40 days after onset of the disease. Electrocardiogram indicated the elevation of ST-T levels and low voltage, and blood examination showed remarkable elevation of creatine phosphokinase (CK), white blood cell count (WBC), aspartate aminotransferase (AST) and lactic dehydrogenase (LDH) levels. We suspected systemic vasculitis and damage of coronary artery or/and heart muscle. Finally, she was diagnosed with classical polyarteritis nodosa by myocardial biopsy. Coronary angiography revealed no abnormalities. The combination therapy of cyclophosphamide pulses and plasma-exchange was very effective to suppress the disease activity.

Very few studies have reported radiographic improvement of damaged joints in patients with juvenile idiopathic arthritis (JIA) following treatment with biological response modifiers.1 We previously reported the efficacy and safety of tocilizumab, an anti-interleukin 6 receptor monoclonal antibody, in patients with systemic-onset JIA.2,–,4 In the present study, we investigated remodelling characteristics of damaged large joints, especially weight-bearing joints, by radiographic examination following tocilizumab treatment for 5 years. Seven patients (two female and five male) with systemic-onset JIA, receiving 8 mg/kg of tocilizumab intravenously every 2 weeks, were …

Objectives We evaluated histological changes occurring in renal biopsy specimens, between the time before initial induction therapy and after 12 months' maintenance therapy, as well as changes in laboratory parameters, SLE disease activity (SLEDAI), and dosage of corticosteroid (CS) in childhood-onset systemic lupus erythematosus (SLE) patients treated with mycophenolate mofetil (MMF). Methods A retrospective analysis was performed on nine patients diagnosed with childhood-onset SLE and lupus nephritis. They were treated with pulsed mPSL and intravenous cyclophosphamide as induction therapy and MMF (500-1500 mg/day) plus CS as maintenance therapy. Renal biopsy was performed before the initial induction therapy and after 12 months' maintenance therapy. Results Pathological findings at second biopsy were improved in eight of nine patients (89%). The findings of SLEDAI, urinalysis, and blood tests also showed improvement. CS doses could be tapered satisfactorily. Adverse events were observed in two patients. No patients treated with MMF experienced any disease flares during maintenance therapy. Conclusions MMF as maintenance therapy might be useful in that not only the histological findings of lupus nephritis were improved, but also CS doses could be beneficially tapered. Nonetheless, this is a retrospective report of only nine cases and further prospective multicenter studies are necessary.

Objective.Tocilizumab (TCZ), an antiinterleukin-6 receptor monoclonal antibody, is clinically beneficial in patients with systemic-onset juvenile idiopathic arthritis (sJIA). We investigated the clinical and radiological outcomes of TCZ therapy in patients with sJIA.Methods.We retrospectively evaluated 2 clinical trials (NCT00144599 and NCT00144612) involving 40 patients with sJIA who received intravenous TCZ (8 mg/kg) every 2 weeks. Clinical data and radiographs of the hands and large joints were assessed before and during TCZ treatment. The Poznanski score, modified Larsen scores of the hands and large joints, and Childhood Arthritis Radiographic Score of the Hip (CARSH) were recorded.Results.After a mean duration of 4.5 years of TCZ treatment, clinical data had improved significantly, the mean Poznanski score improved from −1.5 to −1.1, the mean Larsen score of the hands deteriorated from 7.0 to 10.0, the mean Larsen score for the large joints deteriorated from 5.9 to 6.8, and the CARSH worsened from 3.9 to 6.2. The Larsen score for the large joints improved in 11 cases (28%), remained unchanged in 8 cases (20%), and worsened in 21 cases (52%). Matrix metalloproteinase 3 (MMP-3) levels remained significantly higher (278 mg/dl) in patients with worsened Larsen scores than in patients with improved or unchanged scores (65 mg/dl). Logistic regression analysis showed that older age at disease onset was a significant risk factor for radiographic progression.Conclusion.The modified Larsen score of the large joints deteriorated in half the patients who had high MMP-3 levels during TCZ treatment and who were significantly older at disease onset.

Objective.To assess the longterm safety and effectiveness of tocilizumab (TCZ) in systemic-onset juvenile idiopathic arthritis (sJIA).Methods.The longterm extension phase of 2 pivotal studies (phase II with 11 patients and phase III with 56 patients) in patients with active sJIA was analyzed. Patients received open-label TCZ (8 mg/kg, every 2 weeks) without concomitant use of disease-modifying antirheumatic drugs.Results.In total, 67 patients were enrolled. All patients received corticosteroid at baseline. Median duration of exposure to TCZ was 3.4 years. Nine patients withdrew from the study [4 because of adverse events (AE), 4 because of the development of anti-TCZ antibodies, and 1 because of inadequate response]. Rates of AE and serious AE were 803.7/100 patient-years (PY) and 34.7/100 PY, respectively. The most common serious AE were infections (13.2/100 PY). No cases of malignancy or death were reported. Two serious infusion reactions were reported in patients testing negative for anti-TCZ antibodies. One definite macrophage activation syndrome (MAS) case and 1 potential MAS case were identified. American College of Rheumatology (ACR) response rates attained early in the TCZ treatment period were maintained throughout the study: at Week 168, JIA ACR 30, 50, 70, 90, and 100 response rates were 80.3%, 80.3%, 75.4%, 60.7%, and 18.0%, respectively. In total, 22 of 67 patients (32.8%) completely discontinued corticosteroids without flare.Conclusion.TCZ has demonstrated durability of effectiveness in the longterm treatment of children with sJIA and has shown good tolerability and a low discontinuation rate associated with AE, development of anti-TCZ antibodies, or inadequate response. (ClinicalTrials.govNCT00144599 and NCT00144612).(First Release March 15 2014; J Rheumatol 2014;41:759-67; doi:10.3899/jrheum.130690)

One month after treatment with γ-globulin for Kawasaki disease, an 18-month-old girl developed Evans' syndrome in addition to drug-induced hypersensitivity syndrome (DIHS) after a second γ-globulin treatment. She suffered from hyperbilirubinemia, hemolytic anemia, and thrombocytopenia. The findings and her clinical course involved plasma exchange and treatment with prednisolone, with good results. Peripheral lymphocyte stimulation tests indicated that γ-globulin was the likeliest cause of the DIHS. A real-time polymerase chain reaction test showed the human herpes virus (HHV)-6 genome in peripheral blood. We demonstrated that a primary infection or infection reactivation by the HHV-6 virus was involved in the development of γ-globulin-induced hypersensitivity and Evans' syndrome.

Background: To establish a treatment strategy for acute encephalopathy and encephalitis associated with influenza virus infection, the pathophysiology of the disease was investigated through manifestations and laboratory findings of patients. Patients and Methods: A child with central nervous system (CNS) complications during the course of influenza virus infection was analyzed in view of immunologic abnormalities. In addition, four children with acute encephalopathy and encephalitis were enrolled in the hypothermia treatment for the purpose of stabilizing the cytokine storm in the CNS. Results: The CNS symptoms preceded the systemic progression to the failure of multiple organs (MOF) and disseminated intravascular coagulopathy (DIC). The mild hypothermia suppressed the brain edema on computed tomography (CT) scanning and protected the brain from the subsequent irreversible neural cell damage. Conclusion: The replicated viruses at the nasopharyngeal epithelium may disrupt the olfactory mucosa and gain access to the brain via the olfactory nerve system. The direct virus–glial cell interaction or viral stimulation of the glial cells induces the production and accumulation of the pro-inflammatory cytokines, especially tumor necrosis factor (TNF)-α, in the CNS. The cytokine storm results in neural cell damage as well as the apoptosis of astrocytes, due to the TNF-α–induced mitochondrial respiratory failure. The disruption of the blood–brain barrier progresses to the systemic cytokine storm, resulting in DIC and MOF. Mild hypothermia appears promising in stabilizing the immune activation and the brain edema to protect the brain from ongoing functional, apoptotic neural and glial damage and the systemic expansion of the cytokine storm.

We reported 2 children with suspected primary vasculitis of mesenteric vessels. Both children were admitted to our hospital with the complaints of abdominal pain, bloody stool or diarrhea. Laboratory examination simultaneously revealed leukocytosis with dominant neutrophils, positive CRP, and hypoalbuminemia. Although prothrombin time and activated partial thromboplastin time were within normal limits, the increased levels of FDP-E, D-dimer, and von Willebrand factor activity were observed, which suggested the endothelial cell activation and the coagulation/fibrinolysis system activation. Abdominal echography and CT scanning demonstrated the edematous thickening of intestinal or colon walls probably due to the vasculitic permeability changes of mesenteric artery. During the disease courses, skin rash, bleeding tendency, arthritis and proteinuria were not observed, and no autoantibodies including anti-nuclear antibody, anti-DNA antibody, and myeloperoxidase-antineutrophil cytoplasmic antibody, were detected. Taken together, we suspected these children as restricted vasculitis of mesenteric vessels. Intravenous prednisolone was administrated, and the clinical and laboratory abnormalities recovered completely within 2 weeks. Thus, we suggested that the leukocyte counts, CRP, and the determination of von Willebrand factor and coagulation/fibrinolysis study accompanied with X-ray, echography, and CT scanning will be useful for the early diagnosis of vasculitis before the pathologic and irreversible vascular damage are demonstrated.

Background Systemic lupus erythematosus (SLE) is a systemic multisystem autoimmune disorder influenced by genetic background and environmental factors. Our aim here was to replicate findings of associations between 7 of the implicated single nucleotide polymorphisms (SNPs) in IRF5, BLK, STAT4, TNFAIP3, SPP1, TNIP1 and ETS1 genes with susceptibility to childhood-onset SLE in the Japanese population. In particular, we focused on gender differences in allelic frequencies. Methodology/Principal Findings The 7 SNPs were genotyped using TaqMan assays in 75 patients with childhood-onset SLE and in 190 healthy controls. The relationship between the cumulative number of risk alleles and SLE manifestations was explored in childhood-onset SLE. Logistic regression was used to test the effect of each polymorphism on susceptibility to SLE, and Wilcoxon rank sum testing was used for comparison of total risk alleles. Data on rs7574865 in the STAT4 gene and rs9138 in SPP1 were replicated for associations with SLE when comparing cases and controls (corrected P values ranging from 0.0043 to 0.027). The rs2230926 allele of TNFAIP3 was associated with susceptibility to SLE in males, but after Bonferroni correction there were no significant associations with any of the other four SNPs in IRF5, BLK, TNIP1 and ETS1 genes. The cumulative number of risk alleles was significantly increased in childhood-onset SLE relative to healthy controls (P = 0.0000041). Male SLE patients had a slightly but significantly higher frequency of the TNFAIP3 (rs2230926G) risk allele than female patients (odds ratio [OR] = 4.05, 95% confidence interval [95%CI] = 1.46–11.2 P

Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory, non-infectious disorder of skeletal system mainly seen in children. We report a case of CRMO presenting with fever and leg pain. The patient was an 11-year-old boy complaining of a fever, swelling and pain on his right foot, and pain on both legs. Although serum levels of CK and aldolase were not increased, MRI imaging suggested polymyositis. Muscle biopsy showed interstitial infiltration of inflammatory cells without any evidences of dermatomyositis or polymyositis. One month later, he complained of a swelling, pain and redness of his left clavicle as recurrently experienced during the recent 6 months, and MRI investigation indicated the diagnosis of osteomyelitis. Bone biopsy was performed and showed chronic inflammatory changes with negative bacterial culture. Multiple bone lesions and muscle uptake of FDG in his legs were revealed by whole body FDG-PET/CT, and he was diagnosed as having CRMO with interstitial myositis. The combinatorial administration of non-steroidal anti-inflammatory drugs and bisphosphonate successfully improved his clinical symptoms and laboratory abnormalities. To our knowledge, there is no report of a patient of CRMO associated with interstitial myositis.

Inflammation has often been considered a non-specific response, and to play only a bridging role in the activation of adaptive immunity. However, it is now accepted that inflammation is the product of an independent innate immune system closely linked to the adaptive immune system. The key mediators of inflammation are inflammatory cytokines, as determined by multiple lines of evidence both in vitro and in vivo. Due to the crucial role of inflammatory cytokines in the pathogenesis of autoimmune disorders, anti-cytokine treatment has been developed as a therapy for rheumatoid arthritis, juvenile idiopathic arthritis (JIA), and inflammatory bowel disease. We recently completed several clinical trials of anti-cytokine treatment for children with systemic inflammatory diseases: anti-IL-6 receptor monoclonal antibody (tocilizumab) for children with 2 subtypes of JIA (poly-JIA and systemic JIA), anti-TNF-alpha monoclonal antibody (infliximab) for children with Kawasaki disease, and anti-IL-1-beta monoclonal antibody (canakinumab) for children with cryopyrin-associated periodic syndrome. This review summarizes the basis of inflammation in terms of innate immunity and adaptive immunity in these systemic inflammatory diseases, clinical efficacy and tolerability of these biologic agents, and attempts to determine the roles of individual inflammatory cytokines in disease pathogenesis.

Cryopyrin-associated periodic syndrome (CAPS) is an orphan disease with incidence of about one in 1,000,000 persons. This autoinflammatory disease develops in the neonatal period or early childhood, with various inflammatory symptoms occurring repeatedly throughout the patient’s lifetime. It is caused by abnormality of the NLRP3 protein which mediates the intracellular signal transduction mechanism of inflammatory processes, resulting in continuous overproduction of interleukin (IL)-1β, which induces chronic inflammation and progressive tissue damage. Definitive diagnosis of CAPS is difficult, and treatment has also been difficult because of a lack of effective medications in Japan. Clinical studies of human anti-human IL-1β monoclonal antibody (canakinumab) treatment were conducted in Japan, and approval was granted for therapeutic use of canakinumab for CAPS in September 2011. Similar to other biological drugs, canakinumab is clinically highly effective. However, sufficient attention to the method of use and adverse drug reactions is necessary. This guidance describes the use of canakinumab in Japan for CAPS in relation to exclusion criteria, method of use, evaluation criteria, and adverse drug reactions.

A 14-day-old neonate was transferred to our university hospital because of respiratory distress and mild disturbance of consciousness. He had no history of abnormal pregnancy or delivery, but had developed apnea at 6 days old. Thereafter, respiratory distress progressed and his condition deteriorated. On admission to our hospital, several vesicles were found on the left upper arm, and moderate hepatomegaly was also present. Herpes simplex virus (HSV) type II genome was detected from serum, spinal fluid, and bone marrow. Laboratory examinations revealed typical abnormalities of disseminated intravascular coagulation, increased levels of serum ferritin, aspartate aminotransferase, and lactate dehydrogenase. Bone marrow aspiration demonstrated activated macrophages and hemophagocytosis. Spinal tap revealed numerous mononuclear cells. Meningitis and virus-associated hemophagocytic syndrome (VAHS) due to systemic HSV type II infection were thus diagnosed. Acyclovir (60 mg/kg/day) and vidarabine were promptly administered. Dexamethasone palmitate and intravenous cyclosporine were also administered for systemic inflammation due to VAHS. Finally, these aggressive therapies rescued the patient without any sequelae. In general, neonatal systemic HSV infection is life-threatening and results in poor intact survival. Our case report suggests that not only antiviral treatment for HSV, but also anti-inflammatory treatment including steroid and cyclosporine should be considered from the early phase of neonatal systemic HSV infection.

Cryopyrin-associated periodic syndromes (CAPS) are a group of rare autoinflammatory disorders; many cases of CAPS are caused by mutations in the NLRP3 gene. In these conditions, interleukin (IL)-1 is overproduced, and this overproduction plays a major role in disease onset and progression. CAPS include three variants, ranging in order of increasing severity from familial cold autoinflammatory syndrome, previously termed familial cold urticaria, through Muckle-Wells syndrome, to chronic infantile neurologic cutaneous articular syndrome, also known as neonatal onset multisystemic inflammatory disease. Diagnosis of CAPS is initially based on clinical manifestations and medical history, and later confirmed genetically. CAPS should be suspected when characteristic skin lesions, typical periodic fever episodes, bone/joint manifestations, and CNS involvement are recognized. CAPS are life-long diseases, and early diagnosis and early treatment with IL-1-targeted therapies may improve prognosis.

Objective.Kawasaki disease (KD) is an acute febrile disease in infants and young children. Five percent to 8% of cases will be complicated with coronary dilatation or aneurysm, although introduction of high-dose intravenous immunoglobulin (IVIG) therapy has provided remarkable results for reducing the frequency of cardiac involvement. We describe the results of an open-label trial of infliximab, an anti-tumor necrosis factor-α monoclonal antibody, for suppressing the progression of coronary artery lesions in cases of KD refractory to extensive IVIG therapy. Plasma exchange (PE) was available as a rescue therapy for patients refractory to infliximab.Methods.Twenty eligible patients fulfilled the diagnostic criteria for KD, and were primarily treated with IVIG up to 4 g/kg. “Refractory to IVIG” was defined as persisting or reemerging fever > 38°C and positive fractional changes of C-reactive protein, white blood cell counts, or neutrophil counts 48 hours after IVIG infusion. These cases were treated with infliximab, 5 mg/kg, which should begin within 10 days of disease onset. PE for patients refractory to infliximab was performed with 5% albumin.Results.There was rapid improvement of inflammatory symptoms as well as normalization of the inflammatory markers. Sequential examination by echocardiography up to disease Day 30 revealed that the inflamed and mildly dilated coronary artery at the beginning of the study regressed to normal size in the convalescent phase. Two out of 20 patients showed incomplete improvement of inflammatory symptoms after infliximab treatment, and were provided with PE therapy, with no complications.Conclusion.Eighteen of 20 patients were effectively treated with infliximab, and 2 cases were effectively treated with PE to prevent progression to coronary artery lesions. No adverse event such as anaphylactoid reaction, heart failure, severe infectious diseases, or tuberculosis was observed in this trial.

Objective.Systemic-onset juvenile idiopathic arthritis (systemic JIA) and macrophage activation syndrome (MAS), the most devastating complication of systemic JIA, are characterized by abnormal levels of proinflammatory cytokines. Interferon regulatory factor 5 (IRF5) is a member of the IRF family of transcription factors, and acts as a master transcription factor in the activation of genes encoding proinflammatory cytokines. Polymorphisms in theIRF5gene have been associated with susceptibility to autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. Our aim was to assess associations ofIRF5gene polymorphisms with susceptibility to systemic JIA and MAS.Methods.ThreeIRF5single-nucleotide polymorphisms (rs729302, rs2004640, and rs2280714) were genotyped using TaqMan assays in 81 patients with systemic JIA (33 with MAS, 48 without) and 190 controls.Results.There were no associations of theIRF5gene polymorphisms or haplotypes under study with susceptibility to systemic JIA. There was a significant association of the rs2004640 T allele with MAS susceptibility (OR 4.11; 95% CI 1.84, 9.16; p = 0.001). TheIRF5haplotype (rs729302 A, rs2004640 T, and rs2280714 T), which was reported as conferring an increased risk of SLE, was significantly associated with MAS susceptibility in patients with systemic JIA (OR 4.61; 95% CI 1.73, 12.3; p < 0.001).Conclusion.IRF5gene polymorphism is a genetic factor influencing susceptibility to MAS in patients with systemic JIA, and IRF5 contributes to the pathogenesis of MAS in these patients.

Juvenile idiopathic arthritis (JIA) is one of the most common forms of pediatric chronic arthritis. JIA is a clinically heterogeneous disease. Therefore, the genetic background of JIA may also be heterogeneous. The aim of this study was to investigate associations between human leukocyte antigen (HLA) and susceptibility to JIA and/or uveitis, which is one of the most devastating complications of JIA. A total of 106 Japanese articular JIA patients (67 with polyarthritis and 39 with oligoarthritis) and 678 healthy controls were genotyped for HLA-A, -B and -DRB1 by PCR-sequence-specific oligonucleotide probe methodology. HLA-A(*)02:06 was the risk factor for JIA accompanied by uveitis after adjustment for clinical factors (corrected P-value0.001, odds ratio (OR) 11.7, 95% confidence interval (CI) 3.2-43.0). On the other hand, HLA-DRB1(*)04:05 was associated with polyarticular JIA (corrected P-value0.001, OR 2.9, 95% CI 1.7-4.8). We found an association of HLA-A(*)02:06 with susceptibility to JIA accompanied by uveitis, which might be considered a separate clinical JIA entity. We also found an association between HLA-DRB1(*)04:05 and polyarticular JIA. Thus, clinical subtypes of JIA can be classified by the presence of the specific HLA alleles, HLA-A(*)02:06 and DRB1(*)04:05.

Behcet's disease (BD) is a multisystem immune-mediated inflammatory disorder. The choice of treatments depends on organ involvements and its severity. The treatments for pediatric patients usually consist of corticosteroids and immunosuppressants, but some of them are refractory to these treatments. Recently, tumor necrosis factor alpha (TNF-alpha) appears to play an important role in the immunopathogenesis in BD. We describe two patients with childhood-onset BD, successfully treated by anti-TNF agents. One patient, a 18-year-old male, was diagnosed as having BD at 8 years of age. He developed abdominal pain and bloody diarrhea at 17 years of age. Gastrointestinal endoscopic examination revealed esophageal and ileocolic ulceration consistent with intestinal BD. Methylpredonisolone pulse therapy and immunosuppressants were administrated, but did not respond. Infliximab infusions (4 mg/kg) were given at weeks of 0, 2, 6, and then every 8 weeks. A dramatic improvement in gastrointestinal symptoms and extraintestinal manifestations were observed. Another patient, a 9-year-old girl, developed recurrent oral ulcers and folliculitis at 4 years of age. She was diagnosed as having BD at 6 years of age, and treated with colchicines, corticosteroids and immunosuppressive agents. She was suffering from fever, malaise, and arthralgia in addition to mucocutaneous manifestation. At 8 years of age, etanercept was started at a dosage of 25 mg subcutaneously twice a week. A resolution of the systemic and mucocutaneous symptoms was achieved. Furthermore, she was free from corticosteroids in three months. Anti-TNF therapy would be a good choice for juvenile BD refractory to conventional treatments.

The therapeutic efficacy of corticosteroids and immunosuppressants on secretary glands of children with Sjogren syndrome was investigated examining the lip-biopsy specimen on both lymphocyte infiltration and fibrosis. Six children with primary Sjogren syndrome and two children with lupus-associated secondary Sjogren syndrome were evaluated according to the intensity of therapy. The shorter the term of medications of corticosteroids and immunosuppressants were, the lesser the extents of lymphocyte infiltration and fibrosis were, and the lower the doses of medications were, the lesser the efficacy was. Thus, in childhood Sjogren syndrome, appropriate corticosteroids and immunosuppressants may provide the suppressive effects on the progressive inflammatory destruction of secretary glands. Further evaluation with more patients is needed to determine the inclusion criteria of these treatments for sicca syndrome, especially in cases with no other organ involvement.

Pyoderma gangrenosum is a rare chronic ulcerative noninfectious disease of the skin. Half of patients are complicated with other autoimmune diseases, most commonly inflammatory bowel disease, Takayasu disease, and rheumatoid arthritis. It has been reported that approximately 4% of them were childhood-onset. The conventional treatments of pyoderma gangrenosum were described as systemic corticosteroids and cyclosporine. The combination of corticosteroids with immunosuppressants such as tacrolimus, mycophenolate mofetil has been reported as steroid-sparing modalities. We herein reported a girl, 12 years of age, having pyoderma gangrenosum refractory to the conventional combination of systemic prednisolone with cyclosporine, but successfully treated with infliximab, the anti-TNFalpha monoclonal antibody. Rapid improvement of pyoderma gangrenosum was seen within three doses of infliximab infusion. All skin lesions eventually healed completely and new skin ulcers were never coming out again. The dramatical improvement suggested that infliximab should be considered for patients with refractory pyoderma gangrenosum though further experiences and investigations are required to determine the mechanism of infliximab.

Mixed connective tissue disease (MCTD) includes clinical features of systemic lupus erythematosus (SLE), dermatomyositis/polymyositis (DM/PM), and systemic sclerosis (SSc) occurring in conjunction with a high anti-U1-RNP antibody titer. Childhood MCTD rarely manifests the symptoms and signs of DM/PM and SSc, and mostly does those of SLE. Thus, the diagnosis of childhood MCTD is inevitably based on the two major findings, Raynaud's phenomenon and a high titer of anti-U1-RNP antibody. However, in clinical setting there exist patients who have both anti-dsDNA antibody, a SLE disease-marker, and anti-U1-RNP antibody, a MCTD disease-marker, and thus it is hard to differentiate MCTD patients from SLE. Eighty children were enrolled in this study, and divided into 3 groups ; group A, those who are positive for anti-dsDNA antibody/negative for anti-U1-RNP antibody (48 cases, 60.0%), group B : those who are positive for both anti-dsDNA and anti-U1-RNP antibody (22 cases, 27.5%), group C; those who are negative for anti-dsDNA antibody/positive for anti-U1-RNP antibody (10 cases, 12.5%), and each of the clinical characteristics among these 3 groups was mutually examined. The results indicated that the frequency of hypocomplementemia in group B was close to group A rather than group C, and the frequencies of both hyper-gamma-globulinemia and Raynaud's phenomenon were very close to group C, but not to group A. On the contrary, the findings which seemed to be specific to MCTD, high titers of speckled type anti-nuclear antibody and rheumatoid factor, located at the middle between group A and group C. Thus, children in group B essentially carried characteristic symptoms and signs of both SLE and MCTD, and it will be difficult to differentiate these two diseases at the onset of the disease. Taken together, children with high titers of both anti-dsDNA antibody and anti-U1-RNP antibody as well as clinical symptoms and signs such as hyper-gamma-globulinemia, Raynaud's phenomenon, membranous nephritis, positive speckled type anti-nuclear antibody and rheumatoid factor should be followed and treated as children with MCTD along with SLE.

We report a case of classic polyarteritis nodosa complicated with renal infarction. A 14-year-old boy manifested fever, abdominal pain, watery and bloody diarrhea, and weight loss. Laboratory findings indicated anemia, increased levels of C-reactive protein, and erythrocyte sedimentation rate. Lower gastrointestinal endoscopic examination revealed multiple colorectal ulcerations, and histopathological findings were non-specific, suggesting gastrointestinal involvement of Behcet disease. The patient was referred to our hospital, and suspected to have vasculitis syndrome since the abnormal laboratory findings included persistently increased levels of FDP-E/fibrin monomer as well as inflammatory markers, and the extraordinary high excretion of beta 2-microglobulin, which indicated abrupt and massive expression of HLA class I molecule on endothelial cells due to interferon-gammanemia. To examine the site of vasculitis, 3D-CT angiography was applied to demonstrate bilateral renal infarction and renal artery microaneurysms. Together with the clinical, laboratory, and 3D-CT angiographic findings, he was finally diagnosed as having classic polyarteritis nodosa. After 12 month-course of intravenous cyclophosphamide pulses and prednisolone/azatioprine therapy, complete disappearances of inflammatory manifestations, and renal infarction and microaneurysms were documented. The diagnosis of classic polyarteritis nodosa is frequently delayed because both clinical symptoms and signs, and laboratory findings are not disease-specific, but early diagnosis and treatment are necessary to prevent serious organ damage. In addition to the precise estimation of laboratory findings such as inflammatory markers, and FDP-E/D-dimer/fibrin monomer, the newly developed 3D-CT angiography, a less invasive imaging technique, will be helpful to diagnose patients with classic polyarteritis nodosa, and intervene the disease progression with early and active treatment.

Sjogren syndrome (SS) is a common autoimmune disease that exhibits broad organ-specific and systemic manifestations, the most prevalent being decreased lacrimal and salivary gland function, xerostomia, and keratoconjunctivitis sicca. Secondary SS occurs associated with autoimmune diseases, most commonly systemic lupus erythematosus (SLE). Thirty-four childhood-onset SLE patients (2 boys and 32 girls, mean onset age 11.5+/-2.6 years) were evaluated for the presence of secondary SS using the classification criteria for SS revised by Japanese Ministry of Welfare in 1999. Clinical manifestations, serological findings, and renal pathology in SLE patients complicated with SS (SLE+SS, n=14) were compared with those in SLE with no SS autoantibodies (Ro/SS-A or La/SS-B) (SLE-no SS antibodies, n=14). Of all 34 cases, 20 (58.8%) were with positive Ro/SS-A or La/SS-B antibody. Fourteen of the 20 (70.0%) were diagnosed as having secondary SS and all of them were subclinical SS with no sicca symptoms. However, findings of Schirmer test, salivary flow test and minor salivary gland biopsy were positive in 2 of 16 (13.3%), 5 of 16 (31.3%), and 14 of 17 (82.4%) patients, respectively. Compared with the SLE-no SS antibodies group, patients with SLE+SS showed higher level of serum IgG and had higher frequency of anti-U1 RNP antibody and significantly more severe renal involvement. The revised criteria is useful for diagnosis of SS in early stage before the development of exocrine gland damage and appears to be helpful for long term follow-up in childhood-onset SLE associated with SS.

Mouse milk fat globule epidermal growth factor 8 (MFG-E8), which is secreted by a subset of activated macrophages, binds to apoptotic cells by recognizing phosphatidylserine and promotes their engulfment. Many apoptotic cells are left unengulfed in the germinal centers of the spleen in MFG-E8−/− mice, and these mice develop an autoimmune disease resembling human systemic lupus erythematosus (hSLE). Here, we report that hMFG-E8 bound to phosphatidylserine and an integrin αvβ3 complex. Increasing concentrations of MFG-E8 generated a bell-shaped response curve for the efficiency of phagocytosis. That is, in NIH3T3 and MFG-E8−/− thioglycollate-elicited peritoneal macrophages that do not express MFG-E8, hMFG-E8 enhanced engulfment at low concentrations but inhibited it at high concentrations. On the other hand, hMFG-E8 dose-dependently inhibited the engulfment of apoptotic cells by MFG-E8+/+ thioglycollate-elicited peritoneal macrophages, indicating that an excess of MFG-E8 has an inverse effect on the engulfment of apoptotic cells. To investigate the role of MFG-E8 in human disease, we generated two mAb against MFG-E8 and screened human blood samples for MFG-E8 using an ELISA. We found that some childhood-onset and adult SLE patients carried a significant level of MFG-E8 in their blood samples. These results suggested that the aberrant expression of MFG-E8 is involved in the pathoetiology of some cases of hSLE.

POSTER PRESENTAION, 8th International Congress of Familial Mediterranean Fever and Systemic Autoinflammatory Diseases/30 September - 3 October 2015/Dresden, Germany