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Objective: We researched the findings of musculoskeletal ultrasound sonography (MSUS) on primary Sjogren’s syndrome in childhood (pSS-C) with articular manifestations. The correlation of rheumatoid...

Primary systemic vasculitis (PSV) is a rare disorder in children and difficult to distinguish from other diseases. However, appropriate diagnosis and prompt treatment will affect on the morbidity and mortality of intractable PSV. In this study, we conducted a nationwide survey in Japan, to clarify epidemiology and clinical outcome of PSV.We had sent survey questionnaires to most of the Japanese institutions that employed pediatricians, requesting the number of patients with refractory PSV who were diagnosed and treated between 2007 and 2011. Respondents were asked to provide detailed information on the clinical and laboratory features of each case they had managed. Those with Kawasaki disease or Henoch-Shönlein purpura vasculitis (IgA vasculitis) were excluded.Of all the institutions surveyed, 1123 (37.3%) patients responded, finally, total of 49 patients with intractable PSV, defined by those with resistant to treatment and steroid-dependent, or with any complication associated with prognosis, were selected. The diagnosis was Takayasu arteritis in 31, polyarteritis nodosa in 11, granulomatosis with polyangitis in 2, microscopic polyangitis in 1, and ANCA negative microscopic polyangitis in 1. In those with Takayasu arteritis, 67% were treated with an immunosuppressive agent, 22% with biological modifiers, and 16% with surgical procedures. In other types of disease, 88% of the patients were treated with an immunosuppressive agent, and 12% with biological modifiers. Two with Takayasu arteritis died being terminally ill.This nationwide survey establishes the heterogeneous characteristics of PSV in children. Although questionnaire-based, the results of our analysis should be useful in planning prospective studies to identify the most effective therapy for each subtype of multifaceted disease.

Granulomatosis with polyangiitis (GPA) is characterised by necrotizing angiitis of the arterioles, capillary and venules in the respiratory tract and kidney. GPA patients show other various symptoms and emergent progression, though skin lesions caused by obstruction of the middle arteries is not frequent. GPA is rare in children and little is known about the incidence of GPA in children and adolescents. Cryofibrinogen is cryoprecipitate in the plasma and cryofibrinogenaemia is a rare disorder that may develop skin manifestation after cold exposure. The symptom of cryofibrinogenaemia is usually mild, though it sometimes presents severe manifestations. We will report a first paediatric case who overlapped GPA and cryofibrinogenaemia, also accompanying skin gangrene.

The objective of this study was to evaluate the efficacy, pharmacokinetics, and safety of adalimumab in patients with polyarticular juvenile idiopathic arthritis (JIA) in Japan. Patients aged 4 to 17 years were enrolled in a single-arm, open-label, multicentre study of adalimumab. Patients weighing

Adalimumab is a monoclonal antibody produced by DNA recombination technology, and is the first human monoclonal antibody against human tumor necrosis factor (TNF)-α in the world. Adalimumab binds with high affinity and specificity to soluble TNF-α and normalizes its biological action. The clinical development of adalimumab started in Europe. Adalimumab was approved for the treatment of rheumatoid arthritis (RA) in December 2002 in the United States and in September 2003 in the European Union. Since then, adalimumab has been approved for the expanded indications of psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD), psoriasis (Ps), and juvenile idiopathic arthritis (JIA) in the United States and the European Union, and it is now used widely for the treatment of these diseases. In Japan, adalimumab was approved for the treatment of RA in April 2008, and its use was approved for the indications of Ps and PsA in January 2010, and for CD and AS in October 2010. In Japan, children who have been diagnosed and treated according to the "Proposal for juvenile idiopathic arthritis guidance on diagnosis and treatment for primary care pediatricians and nonpediatric rheumatologists (2007)" (published in this journal in 2007; see reference 1 in the main text), but who have responded poorly to treatment must move onto the next stage of treatment. Such treatments include biological drugs, which, however, should be used with strict adherence to the indications and exclusion criteria and should be used, for the time being, only by physicians trained in how to use them. In Japan, adalimumab was approved for the treatment of JIA in July 2011. Although this drug has brought about a revolutionary advance in the treatment of JIA, it is our task to maximize its therapeutic effects and minimize its toxic effects. The guidance presented here define the indications, exclusion criteria, usage, and evaluation criteria of adalimumab for the treatment of polyarticular JIA.

Patients carrying two loss-of-function (or hypomorphic) alleles of STAT1 are vulnerable to intracellular bacterial and viral diseases. Heterozygosity for loss-of-function dominant-negative mutations in STAT1 is responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD), whereas heterozygosity for gain-of-function loss-of-dephosphorylation mutations causes AD chronic mucocutaneous candidiasis (CMC). The two previously reported types of AD MSMD-causing STAT1 mutations are located in the tail segment domain (p.L706S) or in the DNA-binding domain (p.E320Q and p.Q463H), whereas the AD CMC-causing mutations are located in the coiled-coil domain. We identified two cases with AD-STAT1 deficiency in two unrelated patients from Japan and Saudi Arabia carrying heterozygous missense mutations affecting the SH2 domain (p.K637E and p.K673R). p.K673R is a hypomorphic mutation that impairs STAT1 tyrosine phosphorylation, whereas the p.K637E mutation is null and affects both STAT1 phosphorylation and DNA-binding activity. Both alleles are dominant negative and result in impaired STAT1-mediated cellular responses to interferon (IFN)-γ and IL-27. In contrast, STAT1-mediated cellular responses against IFN-α and IFN-λ1 were preserved at normal levels in patients' cells. We describe here the first dominant mutations in the SH2 domain of STAT1, revealing the importance of this domain for tyrosine phosphorylation and DNA binding, as well as for antimycobacterial immunity.

Somatic mosaicism has been described in several primary immunodeficiency diseases and causes modified phenotypes in affected patients. X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by hypomorphic mutations in the NF-κB essential modulator (NEMO) gene and manifests clinically in various ways. We have previously reported a case of XL-EDA-ID with somatic mosaicism caused by a duplication mutation of the NEMO gene, but the frequency of somatic mosaicism of NEMO and its clinical impact on XL-EDA-ID is not fully understood. In this study, somatic mosaicism of NEMO was evaluated in XL-EDA-ID patients in Japan. Cells expressing wild-type NEMO, most of which were derived from the T-cell lineage, were detected in 9 of 10 XL-EDA-ID patients. These data indicate that the frequency of somatic mosaicism of NEMO is high in XL-ED-ID patients and that the presence of somatic mosaicism of NEMO could have an impact on the diagnosis and treatment of XL-ED-ID patients.

We created the final bill of "Intravenous cyclophosphamide (IVCY) for the treatment of rheumatic disease of children in general" in order to get approval for the off-label use of IVCY from the Study Group on Pediatric Drug Therapy. As a result, this study group approved IVCY's off-label use in children via public applications. We could create IVCY regimen specific for Japanese children independently of the efficacy, dosage, and administration applied in Germany, which at the time of application was the only country in Europe and the USA where IVCY was approved. Later, its use in adults was given approval through public applications after being fully reviewed by the Study Group on Unapproved and Off-label Drugs of High Medical Need. Consequently, IVCY is now available for the treatment of both childhood and adult rheumatic diseases in general.

An infantile case of hemophagocytic syndrome (HPS) with systemic juvenile idiopathic arthritis (s-JIA), refractory to methylprednisolone pulse therapy and cyclosporine A administration, was successfully treated by plasma exchange. The patient was a one-year-old Japanese girl who had developed recurrent steroid-dependent signs, including fever, skin eruption, and hepatopathy, while in France, where she had been diagnosed as having s-JIA at eight months of age. As a high fever and rheumatoid rash were evident on arrival at our hospital, she was admitted and given intravenous methylprednisolone pulse therapy and cyclosporine A. She developed pancytopenia with a generalized clonic seizure, high fever, and liver dysfunction after her cytomegalovirus (CMV) titer became positive during the course of treatment; therefore, she was treated with ganciclovir. She was subsequently diagnosed as having HPS complicating s-JIA from the findings of a bone marrow aspirate. At this time, her blood examination data including a high level of C-reactive protein and hyperferritinemia, suggested that her s-JIA was very active, and the pancytopenia continued after her CMV titer became negative. Therefore, CMV infection against a background of active s-JIA could have triggered the HPS in this case. Because the HPS was resistant to an immunosuppressive regime of methylprednisolone pulse therapy and cyclosporine A, plasma exchange therapy was started. After three sessions of this therapy, the patient's symptoms and laboratory data were markedly improved. Our experience suggests that plasma exchange should be considered as a therapeutic tool for HPS refractory to conventional therapy.

Objectives:Systemic juvenile idiopathic arthritis (sJIA) is a rheumatic disease in childhood characterised by systemic symptoms and a relatively poor prognosis. Peripheral leukocytes are thought to play a pathological role in sJIA although the exact cause of the disease is still obscure. In this study, we aimed to clarify cellular functional abnormalities in sJIA.Methods:We analysed the gene expression profile in peripheral leukocytes from 51 patients with sJIA, 6 patients with polyarticular type JIA (polyJIA) and 8 healthy children utilising DNA microarrays. Gene ontology analysis and network analysis were performed on the genes differentially expressed in sJIA to clarify the cellular functional abnormalities.Result:A total of 3491 genes were differentially expressed in patients with sJIA compared to healthy individuals. They were functionally categorised mainly into a defence response group and a metabolism group according to gene ontology, suggesting the possible abnormalities in these functions. In the defence response group, molecules predominantly constituting interferon (IFN)γ and tumour necrosis factor (TNF) network cascades were upregulated. In the metabolism group, oxidative phosphorylation-related genes were downregulated, suggesting a mitochondrial disorder. Expression of mitochondrial DNA-encoded genes including cytochrome c oxidase subunit 1(MT-CO1) and MT-CO2 were suppressed in patients with sJIA but not in patients with polyJIA or healthy children. However, nuclear DNA-encoded cytochrome c oxidases were intact.Conclusion:Our findings suggest that sJIA is not only an immunological disease but also a metabolic disease involving mitochondria disorder.

Summary Background Systemic-onset juvenile idiopathic arthritis does not always respond to available treatments, including antitumour necrosis factor agents. We investigated the efficacy and safety of tocilizumab, an anti-interleukin-6-receptor monoclonal antibody, in children with this disorder. Methods 56 children (aged 2–19 years) with disease refractory to conventional treatment were given three doses of tocilizumab 8 mg/kg every 2 weeks during a 6-week open-label lead-in phase. Patients achieving an American College of Rheumatology Pediatric (ACR Pedi) 30 response and a C-reactive protein concentration (CRP) of less than 5 mg/L were randomly assigned to receive placebo or to continue tocilizumab treatment for 12 weeks or until withdrawal for rescue medication in a double-blind phase. The primary endpoint of the double-blind phase was an ACR Pedi 30 response and CRP concentration of less than 15 mg/L. Patients responding to tocilizumab and needing further treatment were enrolled in an open-label extension phase for at least 48 weeks. The analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, numbers NCT00144599 (for the open-label lead-in and double-blind phases) and NCT00144612 (for the open-label extension phase). Findings At the end of the open-label lead-in phase, ACR Pedi 30, 50, and 70 responses were achieved by 51 (91%), 48 (86%), and 38 (68%) patients, respectively. 43 patients continued to the double-blind phase and were included in the efficacy analysis. Four (17%) of 23 patients in the placebo group maintained an ACR Pedi 30 response and a CRP concentration of less than 15 mg/L compared with 16 (80%) of 20 in the tocilizumab group (p Interpretation Tocilizumab is effective in children with systemic-onset juvenile idiopathic arthritis. It might therefore be a suitable treatment in the control of this disorder, which has so far been difficult to manage. Funding Chugai Pharmaceuticals.

The Pediatric Standing Committee of the Japan College of Rheumatology, in collaboration with the Pediatric Rheumatology Association of Japan, produced guidance on the diagnosis and treatment for juvenile idiopathic arthritis (JIA) for primary care pediatricians and nonpediatric rheumatologists in Japan. This guidance aims to achieve early diagnosis and treatment for JIA, which is similar to adult rheumatoid arthritis (RA), based on recent progress in rheumatology, and to resolve arthritis at an early stage and improve the prognosis of the affected inflammatory joints. It describes clinical symptoms and laboratory findings characteristic to JIA in order to make early diagnosis and treatment possible, and also serves as a triage of patients who are refractory to the treatment protocol described here and need more aggressive interventions. However, because JIA is a complicated and heterogeneous disease and the optimal treatment approach can be diverse and different patient by patient, these guidelines should be viewed as recommendations and be individualized according to the condition of the patient. Finally, we hope that this guidance will trigger exploration for further information by referring to the textbooks and literature listed at the end of these guidelines.

PFAPA is non-hereditary syndrome characterized by periodic episodes of high fever, aphthous stomatitis, pharyngitis and cervical adenitis. It manifests usually in early childhood, especially before 5 years of age, and last for several years. Its etiology is unknown, but some recent reports suggest a dysregulation of the immune response with continuous pro-inflammatory cytokine activation and a reduced anti-inflammatory response both during and between febrile attacks. The diagnosis is clinical and it is important to exclude other entities of similar presentation with periodic fever and orofacial manifestations. The findings of laboratory are unspecified and show only nonspecific acute inflammatory response. Several treatments have been performed but with various results. Most effective therapy for a fast resolution of the symptoms is one or two doses of oral prednisone, but its efficacy is not permanent. Effectiveness of cimetidine and tonsillectomy in PFAPA is not clear as yet. PFAPA is a benign syndrome and the prognosis is better than other autoinflammatory syndromes, because PFAPA patients grow normally and symptoms diminish within a few years.

Objective: We investigated the role of antioxidants in airway hyperresponsiveness to acetylcholine using young asthma model mice, which were sensitized and stimulated with ovalbumin. Methods: The mice had been fed either a normal diet, an α-tocopherol-supplemented diet or a probucol-supplemented diet 14 days before the first sensitization. They were immunized with antigen at intervals of 12 days and, starting from 10 days after the second immunization, they were exposed to antigen 3 times every 4th day using an ultrasonic nebulizer. Twenty-four hours after the last antigen inhalation, airway responsiveness to acetylcholine was measured and bronchoalveolar lavage fluid (BALF) was collected. A blood and lung tissue study was also carried out. Results: Twenty-four hours after the last antigen challenge, both IL-4 and IL-5 in the BALF of α-tocopherol-supplemented mice were significantly decreased. The IL-5 level in probucol-supplemented mice was also decreased, but there was no difference in IL-4 levels. The serum IgE level was decreased in probucol-supplemented mice. Differential cell rates of the fluid revealed a significant decrease in eosinophils due to antioxidant supplementation. Airway hyperresponsiveness to acetylcholine was also repressed in antioxidant-supplemented mice. In histological sections of lung tissue, inflammatory cells and mucus secretion were markedly reduced in antioxidant-supplemented mice. We investigated the antioxidant effect on our model mice by examining 8-isoprostane in BALF and lung tissue, and acrolein in BALF; however, our experiment gave us no evidence of the antioxidant properties of either α-tocopherol or probucol contributing to the reduction of airway inflammation. Conclusion: These findings indicate that α-tocopherol and probucol suppress allergic responses in asthma model mice, although these two drugs cause suppression in different ways that are unrelated to antioxidation.

We administered high-dose vitamin E to healthy adult male volunteers and assessed the safety of such supplementation. Fourteen volunteers received daily 1,200 IU of vitamin E (800 mg of D-alpha-tocopherol) for 28 d and eight controls were also enrolled. The volunteers treated with vitamin E showed no abnormalities during the study period. The alpha-tocopherol concentrations of plasma and platelets were markedly elevated by vitamin E treatment, but there were no significant differences in platelet aggregation, coagulation, and the clinical parameters between the two groups. In conclusion, a high dose of vitamin E for 28 d had no adverse effects in healthy men.

Articular manifestations (joint swelling, joint tenderness) are common extra-glandular manifestations of primary Sjogren’s syndrome (SjS). In past studies those have been reported that anti-cyclic citrullinated peptide antibody (ACPA) is associated with arthritis in adult SjS and that there is no clear method to distinguish arthritis of primary SjS from early rheumatoid arthritis, but there is no report on children. Musculoskeletal ultrasound (MSUS) can clearly evaluate arthritis or enthesitis which are difficult to assess in detail by only physical examination.

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)

Objective Rapidly progressive interstitial lung disease (RP-ILD) is a rare but potentially fatal complication of JDM. The aim of this study was to establish markers for the prediction and early diagnosis of RP-ILD associated with JDM. Methods The clinical records of 54 patients with JDM were retrospectively reviewed: 10 had RP-ILD (7 died, 3 survived), 19 had chronic ILD and 24 were without ILD. Routine tests included a high-resolution CT (HRCT) scan of the chest and measurement of serum levels of creatine phosphokinase, ferritin and Krebs von den Lungen-6 (KL-6). Anti-melanoma differentiation-associated gene 5 (MDA5) antibodies and IL-18 levels were measured by ELISA. Results No differences were found in the ratio of juvenile clinically amyopathic DM between the three groups. Initial chest HRCT scan findings were variable and could not distinguish between RP-ILD and chronic ILD. Anti-MDA5 antibodies were positive in all 8 patients with RP-ILD and 10 of 14 with chronic ILD, but none of the patients without ILD. Serum levels of anti-MDA5 antibody, ferritin, KL-6 and IL-18 were significantly higher in the RP-ILD group than in the chronic ILD and non-ILD groups. Serum levels of IL-18 positively correlated with serum KL-6 (R = 0.66, P Conclusion High serum levels of IL-18, KL-6, ferritin and anti-MDA5 antibodies (e.g. >200 units by ELISA) are associated with RP-ILD. These can be used as an indication for early intensive treatment. Both alveolar macrophages and autoimmunity to MDA5 are possibly involved in the development of RP-ILD associated with JDM.

卵殻カルシウムを添加したチョコレートおよび卵殻カルシウムを含まないチョコレートをヒトに投与し, 糞便中総脂質, 脂肪酸, カルシウムを測定するとともに, その安全性について検討を行った。1) 卵殻カルシウムを添加したチョコレート摂取群(Ca添加群) は, 卵殻カルシウムを含まないチョコレート摂取群 (コントロール群) に比して糞便中総脂質が有意に高値であった。2) 糞便中カルシウム濃度と糞便中総脂質濃度は, 有意な正の相関関係にあった。3) 脂肪酸分析の結果, Ca添加群は, コントロール群に比してパルミチン酸およびステアリン酸の吸収率が有意に低値であった。4) 試験期間中, 2群間で血清中各種脂質, カルシウム, リン, 脂溶性ビタミンに有意な変動はなかった。5) いずれのチョコレートの摂取期間中も重篤な副作用は認めなかった。以上より, ヒトにおいて卵殻カルシウムはチョコレート中に含まれる脂質の吸収抑制効果を示すことが示唆された。

To investigate the antioxidant status of obese children, we analyzed beta-carotene and alpha-tocopherol levels in plasma and low density lipoprotein (LDL). We also analyzed the fatty acid composition of LDL as a substrate for oxidative stress. The plasma beta-carotene and alpha-tocopherol levels were relatively lower in obese girls than in normal controls. However, the plasma alpha-tocopherol/lipids ratio was significantly lower in obese girls than in normal controls. Both LDL beta-carotene and LDL alpha-tocopherol levels were significantly lower in obese girls than in normal controls, although no obvious differences were observed in plasma levels. In obese girls LDL contained more polyunsaturated fatty acid (PUFA) compared with normal controls. When the peroxidizability index (PI) was calculated to estimate the susceptibility of lipids to oxidative stress, obese girls had significantly higher PI values than normal controls. Both the LDL beta-carotene/PI ratio and the LDL alpha-tocopherol/PI ratio were significantly lower in obese girls than in normal controls. These results indicate the increased susceptibility of LDL to oxidative stress in obese girls which may promote atherosclerosis later in life.

To examine whether or not beta-carotene alters immune indexes, we performed a single-blind trial in healthy male nonsmokers. Lymphocyte subsets were assessed by double labeling with monoclonal antibodies before and after 44 wk of administration of either beta-carotene (60 mg/d; n = 10) or placebo (n = 10). In addition, we measured the beta-carotene concentrations in plasma, mononuclear cells (MNC), platelets, and red blood cells (RBCs), as well as the plasma alpha-tocopherol concentration. An increase of plasma and MNC beta-carotene concentrations to four and three times the baseline value was noted after 2 and 4 wk, respectively. The CD4-CD8 ratio increased after 9 mo of beta-carotene administration whereas natural killer cells, virgin T cells, memory T cells, and cytotoxic T cells remained unaltered throughout the study. No side effects or toxicities were detected by a questionnaire survey and routine laboratory tests.

Twenty-two children with Donw's syndrome and 25 age-matched control children were examined to determine their levels of antioxidant enzymes and vitamins. Cu, Zn-superoxide dismutase (SOD), Mn-SOD, glutathione peroxidase (GSH-Px) and catalase were studied as antioxidant enzymes, while α-tocopherol, β-carotene, and retinol were studied as antioxidant vitamins. The Cu, Zn-SOD activity and immoreactive protein levels in plasma and red blood cells were higher in Down's syndrome children than in control children, while plasma Mn-SOD was lower in Down's syndrome children than in controls. Red cell GSH-Px and catalase activities were lower in Down's syndrome than in the controls, but the difference was not significant. There were also no significant differences in the α- and γ-tocopherol levels in plasma, platelets, mononuclear cells, polymorphonuclear cells, and buccal mucosal cells between the Down's syndrome children and the control children. Finally, no significant differences were observed in plasma β-carotene and retinol levels.

We evaluated the safety and efficacy of tocilizumab in polyarticular-course juvenile idiopathic arthritis (pJIA) with polyarticular or oligoarticular onset. Patients received 8 mg/kg tocilizumab every 4 weeks in the open-label studies: initial study (to week 12) and then an extension study (at least 48 weeks). Nineteen patients intractable to conventional methotrexate therapy were enrolled. Seventeen patients had polyarticular-onset pJIA; two had oligoarticular-onset pJIA. Mean age was 11.6 years; mean disease duration 5.3 years. American College of Rheumatology Pediatric (ACR Pedi) 30, 50, 70, and 90 response rates, respectively, were 94.7%, 94.7%, 57.9%, and 10.5% at week 12, and 100%, 94.1%, 88.2%, and 64.7% at week 48. Mean disease activity score (DAS28) remained below the remission level (2.6) from week 24. Administration was discontinued in two patients during the extension study because the ACR Pedi 50 response was judged insufficient (one patient) and antitocilizumab antibodies developed (one patient). Adverse events were generally mild, and the four serious adverse events resolved spontaneously or with treatment. In conclusion, tocilizumab showed early and sustained efficacy and tolerability for treating intractable pJIA, which suggests that it is a promising new treatment for this disease.

Etanercept is a dimeric fusion protein consisting of the extracellular domain of human tumor necrosis factor receptor II (TNFR II, molecular weight 75 kDa) coupled to the Fc region of human immunoglobulin (IgG1). It is produced by recombinant DNA technology by first introducing the gene into Chinese hamster ovarian cells and then purifying the protein from the culture supernatant. The mechanism of action of etanercept consists of binding to serum TNF-alpha and lymphotoxin (LT)-alpha (TNF-beta), which prevents TNF-alpha and LT-alpha from binding to the TNF-alpha receptor on the plasma membrane of the target cell. Etanercept is currently approved for treating adult rheumatoid arthritis (RA) in more than 70 countries worldwide. In Japan, it was approved for this target group in January 2005. The USA and Europe were the first to approve entanercept for use in treating juvenile idiopathic arthritis (JIA), initially for the treatment of active polyarticular JIA in patients not responding to disease-modifying antirheumatic drugs (USA in May 1999, followed by the EU in February 2000). Thereafter, the drug received approval for the treatment of JIA in many other countries. In Japan, children who have been diagnosed and treated according to Yokota et al. (Mod Rheumatol 17:353-363, 2007), but who have responded poorly to treatment must move onto the next stage of treatment. Such treatments include biological drugs, which, however, should be used with strict adhesion to the indications and exclusion criteria and should be used, for the time being, only by physicians trained on how to use them. In Japan, etanercept was approved in July 2009 for use in children. Although this drug has brought about a revolutionary advance in the treatment of JIA, it is our task to maximize its therapeutic effects and minimize its toxic effects. The guidelines presented here define the indications, exclusion criteria, usage, and evaluation criteria of etanercept for the treatment of polyarticular JIA.

Background: Mycoplasma pneumoniae infection is diagnosed commonly by marked elevation of serum antibodies, but this requires several days and consequently M. pneumoniae infection might be overlooked in some cases. Recently an ImmunoCard Mycoplasma rapid diagnosis test (IC) has been developed and used clinically. One of the advantages of this diagnosis test is that clinicians can recognize the infection by a single administration at the beginning of treatment. Methods: A total of 1033 children aged 1–15 years (average 2.0 years) were examined. The diagnosis of M. pneumoniae infection was made mainly on the basis of a positive reaction to the IC. Also where possible, particle agglutination (PA) was performed as a confirmatory test. Diagnosis was made on the basis of a fourfold or greater rise in the PA antibody titer by paired sera or an initial single PA titer >1:320. Arthritis was diagnosed mainly on clinical symptoms. Additionally, ultrasonography (US) was conducted to confirm arthritis. In using US, arthritis was defined as an enlargement of the low echoic section or fluid retention inside the articular capsule. Results: IC was used in 1033 patients and results were positive in 348 (33.6%). Of these 348, there were 70 cases of pneumonia (20.1%) and four cases of arthritis (1.1%). IC was positive in all of the cases of arthritis, and in two of the four arthritis patients the PA titers were also useful for diagnoses. In three of four cases, US was performed and lesions were observed in two of three cases. Three of the four arthritis patients were infants and only one of these three had pneumonia. Conclusions: Using IC as a screening test, occult M. pneumoniae infections were discovered that would otherwise have been overlooked. These included two patients with US-proved arthritis. Arthritis in the absence of pneumonia may not be an unusual manifestation in infants infected by this organism.

Methotrexate (MTX), the primary treatment for the articular-type juvenile idiopathic arthritis (JIA), is effective and brings about radiological improvement. Patient compliance is good, and it is recognized that its known side effects, namely, disruption of liver function and induction of pulmonary lesions, are unlikely to be severe at the low MTX doses that are administered. In Japan, MTX was granted approval in 1999 by the then Ministry of Health and Welfare specifically for treating rheumatoid arthritis in adult patients, allowing it be generally used in medical institutions for patients having National Health Insurance. However, in the pediatric field, its use outside the indications has so far been unavoidable, and has been left to the discretion of the physician. Finally, at the present conference, expansion of the indications of MTX for JIA was approved in Japan. It is noteworthy that this expansion of indications was achieved without requiring clinical trials on children sponsored by the pharmaceutical company: it was achieved rather by collecting necessary information through ongoing efforts (including collection and analysis of information about approval status in foreign countries, adequate evidence from the literature, implementation of a clinical use survey in Japan, etc.). It also merits attention that the maximum dose (10 mg/m2) was set on the basis of pharmacokinetic data from children, rather than relying on the dosing method and dose for adults.

To reveal the frequency and the clinical characteristics of dystrophic calcification that occurs in children with juvenile dermatomyositis, multi-center analysis was constructed.Fifty children with JDM were enrolled, and 14 of them (28.0%) were complicated with calcinosis. Clinical symptoms and laboratory tests at onset, initial therapy and disease course were compared in children with and without calcinosis.The mean age of the onset of calcinosis was 4.78 +/- 3.33 years, and it was younger than those of children without calcinosis (8.66 +/- 3.85 years) (P = 0.0017). No differences of clinical manifestation except Gower's sign were observed. The frequency of positive anti-nuclear antibody was 7.1% in children with calcinosis and 52.9% without calcinosis (P = 0.0112). The initial therapy of methylprednisolon pulses gave no effects on prognosis of calcium deposition. The calcinosis appeared in 1.56 +/- 1.91 year after the onset of the disease. The various types of calcium deposition including large tumorous clumps, subcutaneous plaques or nodules, sheet-type calcification were deserved. They appeared over knee joints (64.3%), elbow joint (64.3%), and hip processes (50.0%). Calcinosis affecting the subcutaneous tissues frequently resulted in painful superficial ulceration of the overlying skin (42.9%), local infection (50.0%), and limitation of joint movement (14.3%). Although aluminum phosphate was effective in 2 children among 7, no other effective treatment was recommended. In 5 cases, surgical removal of tumorous clumps was operated. Thus, juvenile dermatomyositis is frequently complicated with calcinosis. This type of calcinosis was found to be unlikely to resolve completely, and resulted in severe disability in children.

Systemic-onset juvenile idiopathic arthritis (sJIA) is a chronic childhood disease associated with many complications.1–5 Treatments comprise non-steroidal anti-inflammatory drugs, corticosteroids, disease-modifying antirheumatic drugs and biologics,6–9 including tocilizumab, an interleukin-6 receptor monoclonal antibody.10 Results of a randomised, placebo-controlled, phase III trial of tocilizumab in sJIA patients at eight Japanese hospitals, as well as the first 48 weeks of an open-label extension, have been published.3 Protocols and amendments for this extension phase were approved by the Japanese Ministry of Health, Labor and Welfare and the institutional review board at each centre. Of 56 patients initially enrolled, six withdrew during the open-label, lead-in phase (anti-tocilizumab antibodies, three; anaphylactoid reaction, one; gastrointestinal haemorrhage, one; non-efficacy, one). During the double-blind phase, one patient from each treatment arm withdrew because of adverse events (AEs) but re-entered the open-label extension after the resolution of AEs. In total, 50 patients responding to tocilizumab and needing further treatment entered the open-label extension; two patients subsequently withdrew within the first year because of AEs. Herein, the long-term efficacy and safety of treatment through 144 weeks are presented. …

We describe a 23-year-old female who developed SLE 9 years after asymptomatic idiopathic thrombocytopenic purpura (ITP) with positive antinuclear antibody (ANA). Although the platelet count was normal before the onset of SLE, the titer of ANA was gradually increased and also autoantibodies, including antibodies to SS-A/Ro, single-stranded DNA (ss-DNA) and nuclear ribonucleoprotein (RNP) changed to positive. At 23 years of age, the patient was admitted to our hospital because of fever, butterfly rash and polyarthritis. Anti double-strand DNA (ds-DNA) antibody and anti Smith antigen (Sm) antibody were positive and the platelet count and titer of complements were decreased. The patient was diagnosed as SLE and treated with 60 mg/day of prednisolone. Despite steroid therapy, psychiatric symptoms appeared. Additional treatments with steroid pulse therapy and double filtration plasmaphresis resulted in the improvement of SLE including the central nervous system manifestations. This case suggested that increased titer of ANA and the appearance of antibodies to SS-A, ss-DNA, RNP, ds-DNA and Sm in ITP patients predict the development of SLE. Routine checkup of autoantibodies is needed to manage ITP with positive ANA.

Spondyloarthritis (SpA) is thought to be very rare in Japan, because possession rate of HLA-B27 in healthy people is 0.4% and it is significantly lower than that of other countries (5%). This makes it difficult for Japanese physicians to diagnose SpA early. Since 10-20% of SpA patients experience symptoms in their childhood, it is very important to distinguish them from other chronic arthritis patients for pediatric rheumatologists.

Systemic juvenile idiopathic arthritis (sJIA) is characterised by systemic inflammatory symptoms such as spiking fever, skin rash, pericarditis and hepatosplenomegaly, along with arthritis.1 We reported the abnormal expression of genes involved in cytokine networks and mitochondrial function in patients with sJIA identified by DNA microarray.2 The current study was performed to extend these results. To identify genes that correlate with arthritis severity or systemic inflammation in patients with sJIA, we further analysed the 3491 genes identified by prior microarray analysis to be abnormally expressed in the peripheral blood of 51 patients with sJIA.2 They all fulfilled International League of Associations for Rheumatology (ILAR) criteria.3 Of these …

Plasma beta-carotene, alpha-tocopherol and retinol were measured in 15 female and 5 male children with insulin-dependent diabetes mellitus (IDDM), and the correlations with plasma hemoglobin A1c (HbA1c) and fructosamine were analyzed. Twelve female and 8 male children served as age-matched controls. The plasma beta-carotene and alpha-tocopherol levels of the IDDM children were significantly higher than those of the control children, but there were no differences in plasma retinol or total lipid levels. The plasma beta-carotene level, beta-carotene/retinol ratio and beta-carotene/total lipids ratio each showed significant correlations with serum HbA1c and fructosamine in all subjects studied. Similarly, the plasma alpha-tocopherol level and alpha-tocopherol/total lipids ratio were correlated with these indexes of glycemic control. These findings suggest certain mechanisms may exist to prevent lipid peroxidation and vascular complications in IDDM patients.

Naturally occurring carotenoids have attracted much attention owing to their potential usefulness in cancer prevention. However, little is known about the absorption and metabolism of β-carotene, especially 9-cis β-carotene. We investigated stereoisomers of β-carotene in plasma and blood cells of healthy male volunteers after ingesting daily either 60 mg of synthesized all-trans β-carotene preparation, a naturally occurring β-carotene derived from Dunaliella bardawil, or placebo for 44 weeks. Basal levels of 9-cis β-carotene in plasma, platelets, and mononuclear cells were 10%, 20%, and 25% of those of the all-trans form, respectively. The plasma levels reached a maximum after 2 weeks of administration and plateaued thereafter in the subjects who took the β-carotene preparations. The all-trans β-carotene level in the subjects given the synthesized all-trans form was almost twice that for the Dunaliella preparation. The plasma 9-cis level was found to be higher in the all-trans β-carotene group than in the Dunaliella group, despite no intake of the 9-cis form in the all-trans group and the higher intake of the 9-cis form in the Dunaliella group. This finding suggests that isomerization of the all-trans form to the 9-cis form may occur in the body either during or after absorption. The CD4/CD8 ratio increased after 9 months of all-trans β-carotene administration, whereas natural killer cells, virgin T cells, memory T cells, and cytotoxic T cells remained unaltered throughout the study.

For 44 wk, thirty male volunteers were given daily either 60 mg of synthesized all-trans beta-carotene, a naturally-occurring beta-carotene derived from Dunaliella bardawil, or a placebo. Basal levels of 9-cis beta-carotene in plasma, platelets, and mononuclear cells were 10, 20, and 25% of those of the all-trans form, respectively. The plasma levels reached a maximum after two weeks of administration and plateaued thereafter in the subjects who took the beta-carotene preparations. The all-trans beta-carotene level in the subjects given the synthesized all-trans form was almost twice that for the Dunaliella preparation. The plasma 9-cis level was found to be higher in the all-trans beta-carotene group than in the Dunaliella group, despite no intake of the 9-cis form in the all-trans group and the higher intake of the 9-cis form in the Dunaliella group. This finding suggests that isomerization of the all-trans form to the 9-cis form may occur in the body either during or after absorption.

Abstract 1734 Mendelian susceptibility to mycobacterial disease (MSMD) is a rare congenital disorder characterized by susceptibility to infection by poorly virulent intracellular pathogens such as BCG, non-tuberculosis mycobacterium and Salmonellae. MSMD is associated with genetic defects in the IL-12/IFN-γ pathway, and six responsible genes, IFNGR1, IFNGR2, IL12B, IL12RB1, STAT1, and NEMO have been identified so far. Singnal transducer and activation of transcription 1 (STAT1) is a DNA-binding factor which regulates specific gene transcription. IFN-γ stimulation results in phosphorylation of STAT1 at Tyr701 (Y701) to induce the homodimerization, so called a gamma-activated factor (GAF), through the conformational change and the nuclear import. The GAF binds to the gamma-activated sequence (GAS) to induce the transcriptional activities. Patients with STAT1 deficiency were known in both recessive and dominant forms and three mutations in STAT1, L706S, E320Q and Q463H, have previously been reported from three family with an autosomal-dominant form of STAT1 partial deficiency. L706S mutation in the tail segment domain of STAT1 is shown to impair the phosphorylation at Tyr701. Although the phosphorylation is normal in other two mutations, the E320Q or Q463H mutant, in which the DNA-binding ability was abolished. Here we identified a novel heterozygous STAT1 mutation, 2018A>G (K673R), in a Japanese patient with MSMD. This was thought to be first report whose mutation was identified in the SH2 domain of autosomal-dominant form of STAT1. He had a past history of BCGitis after vacctination and multifocal osteomyelitis at the age of 5. Bone biopsy revealed granulomatous change without detecting Mycobacterium. The same mutation was also identified in his father and older sister. Although his sister had a history of BCGitis, his father had no clinical manifestations. A peripheral blood mononuclear cells from the patient could not sufficiently produce TNF-α in response to IFN-γ. EB-transformed B cells from the patient showed that induction of STAT1 phosphorylation by IFN-γ was partially impaired. We generated Flag-tagged STAT1 expression constructs of wild-type (WT) and three mutants including our mutant and analyzed molecular functions along with STAT1 signaling. K673R STAT1 showed partial impairment in the phosphorylation in response to both IFN-α and IFN-γ. Further, the electrophoretic mobility shift assay revealed that the K673R mutant abolished the DNA-binding ability. The nuclear translocation was normally detected. Curiously, dose-dependent negative effect on WT STAT1 was observed in K673R mutant by the reporter assay. K673R mutant interacted with WT to abrogate the DNA-binding activity, thus, exerted a dominant-negative effect on the transcription activity of WT STAT1. Based on these results, a novel heterozygous mutation, K673R, in SH2 domain of the STAT1 gene impaired the STAT1 signal transduction in a dominant-negative manner. K673R mutation in STAT1 may play an important role in molecular pathogenesis of MSMD. Disclosures: No relevant conflicts of interest to declare.

The beta-carotene concentrations in plasma, blood cells and buccal mucosal cells were determined by high-performance liquid chromatography with electrochemical detection. This method was 1,000 times more sensitive than the conventional spectrophotometric method. Polymorphonuclear cells and red blood cells had lower beta-carotene levels than the other cells. After oral administration of 580 mg/day of all-trans beta-carotene to human male volunteers for a week, the beta-carotene concentrations in all cell types increased at least several times above the original levels.