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Objective To investigate the long-term efficacy and safety of the IL-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK). Methods Patients completing the randomized, double-blind, placebo-controlled period of the TAKT (Takayasu arteritis Treated with Tocilizumab) trial were followed up during open-label extended treatment with weekly s.c. tocilizumab 162 mg for up to 96 weeks or longer, with oral glucocorticoid tapering performed at the investigators’ discretion. Endpoints of the extension analysis included steroid-sparing effects of tocilizumab, imaging data, patient-reported outcomes (36-Item Short Form Health Survey) and safety. Results All 36 patients enrolled in the double-blind period entered the open-label extension; 28 patients received tocilizumab for 96 weeks. The median glucocorticoid dose was 0.223 mg/kg/day at the time of relapse before study entry, 0.131 mg/kg/day (interquartile range 0.099, 0.207) after 48 weeks and 0.105 mg/kg/day (interquartile range 0.039, 0.153) after 96 weeks. Overall, 46.4% of patients reduced their dose to Conclusion These results in patients with Takayasu arteritis provide evidence of a steroid-sparing effect and improvements in well-being during long-term treatment with once-weekly tocilizumab 162 mg, with no new safety concerns. Trial registration JAPIC Clinical Trials Information, http://www.clinicaltrials.jp/user/cteSearch_e.jsp, JapicCTI-142616.

Novel Coronavirus Disease (COVID-19) swept the world and Led to a global pandemic SARS-CoV-2, which is thought to have derived from bats as their reservoir hosts, has over time and similarly as with SARS-CoV, combined with human angiotensin converting enzyme 2 (ACE2) Thus, this caused infections in cells and established them into a human 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-1SS, IL-8, TNF-a, and other chemokines such as G-CSF, IP10, MCPl, to develop an increase the inflammatory responses In the case of COVID-19, it revealed that excessive inflammatory responses occur, and that the exaggerated proinflammatory cytokines and chemokines are detected in COVID-19 patients' sera resulting in cytokine release syndrome (CRS) or cytokine storm (CS) This causes coagulation abnormalities, excessive oxidation development, vital organ damages, immune system failure, and finally, progresses to disseminated intravascular coagulation (DIC) and multiple organ failure (MOF) Additionally, excessive inflammatory responses lead to mitochondrial dysfunction due to progressive and persistent stress which leads to cells and mitochondrial fracturing products containing mitochondrial DNA and damaged cell debris which in turn are involved in the chronic excessive inflammation as damage-associated molecular patterns (DAMPs) Thus, respiratory infection progressively leads to DIC from acute respiratory distress syndrome (ARDS) including vascular endothelial cell damages and coagulation-fibrinolysis system disorders Then, this worsens to central nervous system disorders, renal failure, liver failure, and finally to MOF With regards to treatments for COVID-19, the followings are progressive and multiple steps for mitigating the excessive inflammatory response and subsequent cytokine storm in patients Firstly, the administering of Favipiravir for the suppression of SARS-CoV-2, and Nafamostat for the inhibition of ACE2 function should be considered Then, the administration of anti-rheumatic drugs (monoclonal antibodies which combine with the leading cytokines (IL-1SS, IL-6) and/or cytokine receptors such as Tocilizumab) Finally, melatonin may be effective under recognition of the pathology of CRS/CS for the improvement of mitochondrial function The paper will further explore these subjects with reports mostly from China and Europe Новая коронавирусная болезнь (COVID-19) охватила весь мир и привела к глобальной пандемии Предполагается, что возбудитель заболевания - вирус SARS-CoV-2 использует летучих мышей в качестве промежуточных хозяев Попадая в организм человека, так же как и SARS-CoV, SARS-CoV-2 начинает взаимодействовать с ангиотензин-превращающим ферментом 2 (ACE2), рецептором на поверхности клетки В результате такого взаимодействия вирус проникает в клетки и запускает инфекционный процесс в организме человека, а заболевание получило название COVID-19 В ответ на вирусную инфекцию активируется система врожденного иммунитета, что приводит к усилению производства и высвобождению провоспалительных цитокинов, таких как IL-6, IL-1SS, IL-8, TNF-a, а также хемокинов, таких как G-CSF, IP10, MCP1, и развитию воспалительной реакции COVID-19 сопровождается чрезмерным воспалением и повышенным содержанием провоспалительных цитокинов и хемокинов в сыворотке крови, что свидетельствует о развитии синдрома высвобождения цитокинов, или «цитокинового шторма» В ходе развивающегося синдрома высвобождения цитокинов происходят нарушения коагуляции, чрезмерный оксидативный стресс, повреждение жизненно важных органов и нарушение функций иммунной системы Эти проявления прогрессируют и в конце концов приводят к развитию синдрома диссеминированного внутрисосудистого свертывания и полиорганной недостаточности Чрезмерные воспалительные реакции и прогрессирующий оксидативный стресс вызывают дисфункцию и повреждение митохондрий В результате в зоне воспаления накапливаются фрагменты разрушенных клеток и остатки разрушенных митохондрий, содержащие митохондриальную ДНК Эти продукты разрушения клеток, в свою очередь, действуя как молекулярные паттерны, связанные с повреждением, пролонгируют острое воспаление до развития хронического чрезмерного воспаления Таким образом, вирус, первоначально попадая в легкие, инициирует острый респираторный дистресс-синдром с последующим развитием синдрома диссеминированного внутрисосудистого свертывания Этот синдром сопровождается повреждением эндотелиальных клеток сосудов и нарушением системы свертывания крови Прогрессирование этих нарушений приводит к расстройствам центральной нервной системы, почечной и печеночной недостаточности и, наконец, к полиорганной недостаточности Лечение пациентов с COVID-19 должно быть основано на подавлении чрезмерного воспалительного ответа и «цитокинового шторма» Для этого есть несколько возможностей Целесообразно рассмотреть, во-первых, назначение фавипиравира для снижения активности SARS-CoV-2 и нафамостата для подавления функции ACE2, а во-вторых, назначение противоревматических препаратов (таких как моноклональные антитела, которые нейтрализуют или цитокины IL-1SS и IL-6, или рецепторы этих цитокинов, например тоцилизумаб) Наконец, для улучшения нарушенных функции митохондрий при синдроме высвобождения цитокинов/«цитокиновом шторме» может оказаться эффективным мелатонин В обзоре все эти вопросы рассмотрены в основном на материалах отчетов из Китая и стран Европы

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.

To assess the efficacy and safety of canakinumab in Japanese patients with systemic juvenile idiopathic arthritis (sJIA). This was an open-label, single-arm active treatment study. sJIA patients, aged ≥2 to

This study was conducted to assess the real-world safety and effectiveness of adalimumab in patients with juvenile idiopathic arthritis (JIA). In this all-case, postmarketing surveillance study (NCT01412021) conducted in Japan, patients receiving adalimumab for JIA affecting multiple joints were observed for 24 weeks. The safety (adverse drug reactions [ADRs]/serious ADRs) and effectiveness (4-variable Disease Activity Score in 28 joints using erythrocyte sedimentation rate [DAS28-4/ESR] remission rate) were assessed. In the safety population (n = 356), 90.3% (65/72; weight, ≥15–p = .0072), those with comorbidities vs. without (38.3% vs. 25.7%, p = .0155), and those receiving dose p = .0418). DAS28-4/ESR remission rate improved from 21.7% (36/166) at baseline to 74.7% (112/150) at week 24. Adalimumab was well tolerated and had acceptable safety and effectiveness in patients with JIA in the real-world setting.

Juvenile idiopathic arthritis (JIA) is the most common disease in pediatric rheumatism. There is no specific symptom or examination finding for JIA, and the diagnosis is made by exclusion and differentiation. Because non-pediatric rheumatologists are sometimes involved in medical care, 'proposal for JIA guidance on diagnosis and treatment for primary care pediatricians and non-pediatric rheumatologists' was first published in 2007. In these 10 years, a number of new findings on pathophysiology and treatment of JIA have been published; therefore, we propose this guidance of 2018th edition aiming at updating and standardization of JIA medical care in Japan. This edition included the management of uveitis, macrophage activation syndrome, infectious diseases before and during treatment. Moreover, details of biologics are also described. Although this guidance is tailored to adaptation of examinations and drugs, we do not purpose to limit the physicians' discretion in clinical practice. This guidance should be viewed as recommendations and be individualized according to the condition of the patient. We hope that medical care for JIA will advance and more patients will get benefit based on this guidance. Then, further revisions are needed due to changes in future conditions.

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.

Key Clinical Message We report two male siblings with SDS. They have the same compound heterozygous mutations. Only one of the siblings acquired cytogenetic abnormality of i(7q) 2 years after diagnosis, became transfusion‐dependent, and underwent allogeneic hematopoietic stem cell transplantation. These cases indicate that i(7q) is associated with significant cytopenia in SDS patients.

The objectives of this surveillance were to determine safety and effectiveness of etanercept in patients with juvenile idiopathic arthritis (JIA).In this postmarketing surveillance, patients aged 5-16 years with active polyarthritis JIA were treated with etanercept at the doses approved in the Japanese package insert. The occurrence and seriousness of adverse events (AEs) were assessed using the Japanese Medical Dictionary for Regulatory Activities version 15.1. Effectiveness was determined as the improvement from baseline in disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR), remission, and physician's assessment of overall improvement. The number of responders was expressed as a percentage. The last observation carried forward method was used to impute missing data.Safety analysis included 102 patients; 22 patients experienced 36 treatment-related AEs, three of which were unexpected. None of the AEs were deemed to need special safety warnings. Effectiveness analysis included 87 patients. At 24 weeks, 29/46 (63.0%) patients demonstrated either good or moderate response in DAS28-4/ESR and treatment was assessed to be markedly effective or effective by physicians in 79/83 (95.2%) patients.These data are consistent with earlier reports showing that etanercept was effective and demonstrated no safety signals in patients with JIA.

Acute megakaryoblastic leukemia (AMKL) in children without Down syndrome (DS) has an extremely poor outcome with 3-year survival of less than 40%, whereas AMKL in children with DS has an excellent survival rate. Recently, a novel recurrent translocation involving CBFA2T3 and GLIS2 was identified in about 30% of children with non-DS AMKL, and the fusion gene was reported as a strong poor prognostic factor in pediatric AMKL. We report the difficult clinical courses of pediatric patients with AMKL harboring the CBFA2T3-GLIS2 fusion gene.Down sendromu (DS) olmayan çocuklarda akut megakaryoblastik löseminin (AMKL) prognozu çok kötü ve 3 yıllık sağkalım %40’ın altında iken, DS’li çocuklarda AMKL’nin sağkalım oranı mükemmeldir. Yakın zamanda, DS olmayan AMKL’li çocukların yaklaşık %30’unda CBFA2T3 ve GLIS2’yi içeren yeni bir tekrarlayan translokasyon tanımlandı ve füzyon geninin pediatrik AMKL olgularında kötü prognoz ile ilişkili güçlü bir prognostik belirteç olduğu bildirildi. CBFA2T3-GLIS2 füzyon genini taşıyan AMKL tanılı pediatrik hastalarda sorunlu klinik seyri bildiriyoruz.

Background: To investigate efficacy and safety of intravenous abatacept in Japanese patients with active polyarticular-course juvenile idiopathic arthritis (pJIA). Methods: In this phase III, open-label, multicenter, single-arm study, patients with pJIA aged 4–17 years who failed ≥1 biologic or methotrexate received weight-tiered (< 75 kg: 10 mg/kg; 75–100 kg: 750 mg; > 100 kg: 1000 mg) intravenous abatacept at Weeks 0, 2, 4, and every 4 weeks thereafter. The study comprised a short-term period (16 weeks) and ongoing long-term period. Primary endpoint: Week 16 JIA-American College of Rheumatology criteria 30 (JIA-ACR30) response rate. Secondary endpoints/outcomes included Week 16 JIA-ACR50/70/90 response and inactive disease rates, Childhood Health Assessment Questionnaire-Disability Index (CHAQ-DI), pharmacokinetics, safety, and immunogenicity. Proportions of patients achieving Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein (JADAS27-CRP) remission (score < 1) and minimal disease activity (MDA; score < 3.8), were among exploratory endpoints. Results: All 20 patients who received study medication completed the short-term period. During the long-term period, two patients discontinued due to insufficient efficacy or patient decision. Median age and disease duration at baseline were 10.5 and 0.75 years, respectively. Week 16 JIA-ACR30 response rate (primary endpoint) was 90.0% (18/20). JIA-ACR50/70/90 response and inactive disease rates at Week 16 were 75.0% (15/20), 70.0% (14/20), 35.0% (7/20), and 25.0% (5/20), respectively. At Week 52, JIA-ACR30/50/70/90 response and inactive disease rates were observed by 88.9% (16/18), 88.9% (16/18), 83.3% (15/18), 66.7% (12/18) and 44.4% (8/18), respectively. CHAQ-DI improved after Week 12. JADAS27-CRP remission and MDA were achieved by 15.0% (3/20) and 45.0% (9/20) of patients at Week 16, and by 50.0% (9/18) and 78.0% (14/18) of patients at Week 52, respectively. The mean abatacept pre-dose serum concentration was above the target therapeutic exposure (10 μg/ml) from Week 8 through Week 16. All adverse events were of mild/moderate intensity, except for one case of severe gastroenteritis. No deaths, malignancies, or autoimmune disorders were observed. No antidrug antibodies were detected through Week 16; one patient had a positive immunogenic response during the cumulative period. Conclusion: Intravenous abatacept was efficacious and well tolerated in Japanese patients with active pJIA., 論文

Background The aim of this study was to evaluate the performance of two interferon-γ release assays (IGRA), QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB, for pediatric patients with rheumatic disease in Japan and to analyze the frequencies of indeterminate test results with these kits. Methods An IGRA was performed in 108 patients 0.5 mg/kg and in patients with active underlying disease. Use of biologicals and other immunosuppressants had no effect on these measurements. Conclusions IGRA are very useful for excluding tuberculosis infection in patients with rheumatic disease before starting new immunosuppressant therapy. Furthermore, the T-SPOT.TB test was suitable for evaluating latent tuberculosis infection even under immunosuppression, when TB tests are generally hard to perform.

BACKGROUND There have been no previous studies on the adequacy of combined evaluation of possible abusive head trauma cases by frontline medical personnel, hospital-based child protection teams, and child protective services in local districts of Japan. METHODS We conducted a questionnaire survey of hospitalized patients under 24 months old with a diagnosis of intracranial hemorrhage (ICH) from January 2011 to December 2013. Eleven large-scale general hospitals in Yokohama, Japan were surveyed, which provide centralized inpatient care to moderately-severely ill children. RESULTS A total of 51 ICH patients were listed from eight hospitals. Median patient age was 7 months, and 84% were younger than 12 months. The most common diagnosis on computed tomography was subdural hematoma (n = 26; 51%). Of a total of 51 cases, 31 (61%) occurred inside the home; the injury scene was unknown in six cases (12%). We reviewed these 37 cases from the viewpoint of evaluation with concern for suspected child abuse. Three out of 37 patients (8%) were not examined for inflicted skin lesions, and skeletal surveys and funduscopy were not conducted in 14 (38%) and 15 (41%), respectively. Thirteen out of 37 cases (35%) were not reported to hospital-based child protection teams and 22 (59%) were not reported to regional child protective services. CONCLUSION The sociomedical evaluation of possible child abuse appears to be systematically inadequate in Yokohama.

ObjectivesTo evaluate the safety and effectiveness of tocilizumab (TCZ) in patients with systemic juvenile idiopathic arthritis (sJIA) in real-world clinical settings in Japan.MethodsPaediatric patients with sJIA initiating TCZ between April 2008 and February 2012 and those previously enrolled in clinical trials who initiated TCZ before April 2008 were enrolled in a Japanese registry surveillance programme. Safety and effectiveness parameters were collected for 52 weeks.ResultsOf 417 patients enrolled, mean age was 11.2 years and 48.0% were female. TCZ exposure was 407.0 patient-years (PYs). Baseline corticosteroid use was higher than in clinical trials. Rates of total adverse events (AEs) and serious AEs (SAEs) were 224.3/100 PYs and 54.5/100 PYs, respectively, with SAEs higher than previously reported. The most frequent AEs and SAEs were infections and infestations (69.8/100 PYs and 18.2/100 PYs, respectively). 74 serious infections occurred in 55 patients (18.2/100 PYs); higher than previously reported. 26 macrophage activation syndrome events were reported in 24 patients (6.4/100 PYs). Fever and rash symptoms improved from baseline to week 52 (54.6% to 5.6% and 43.0% to 5.6%, respectively). At 4 weeks, 8 weeks and 52 weeks, 90.5%, 96.2% and 99.0% of patients achieved normal C reactive protein levels (ConclusionsThese first real-world data demonstrated that TCZ was well tolerated, with acceptable safety and effectiveness in patients with sJIA. Higher incidences of SAEs and serious infections may be due to differences, such as corticosteroid use and concomitant diseases, between patient populations enrolled in previously reported clinical trials and this study.

Vaccination is the most powerful way to prevent human beings from contracting infectious diseases including viruses. In the case of the human papillomavirus (HPV) vaccine, an unexpectedly novel disease entity, HPV vaccination associated neuro-immunopathetic syndrome (HANS), has been reported and remains to be carefully verified. To elucidate the mechanism of HANS, we applied a strategy similar to the active experimental autoimmune encephalitis (EAE) model - one of the most popular animal models used to induce maximum immunological change in the central nervous system. Surprisingly, mice vaccinated with pertussis toxin showed neurological phenotypes that include low responsiveness of the tail reflex and locomotive mobility. Pathological analyses revealed the damage to the hypothalamus and circumventricular regions around the third ventricle, and these regions contained apoptotic vascular endothelial cells. These data suggested that HPV-vaccinated donners that are susceptible to the HPV vaccine might develop HANS under certain environmental factors. These results will give us the new insight into the murine pathological model of HANS and help us to find a way to treat of patients suffering from HANS.

Objective.Rapidly progressive interstitial lung disease (RP-ILD) is an intractable and fatal complication of juvenile dermatomyositis (JDM). This study evaluated serum levels of B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) in JDM patients with complicating ILD, and their association with ILD phenotypes, clinical variables, and anti-melanoma differentiation-associated gene 5 (MDA5).Methods.We measured the levels of BAFF, APRIL, and anti-MDA5 in the sera of 23 JDM patients with ILD [8 in the RP-ILD group and 15 in the chronic ILD (C-ILD) group], 17 JDM patients without ILD (non-ILD group), and 10 age-matched controls, using the ELISA method. ILD was identified by high-resolution computed tomography.Results.Serum BAFF titers were significantly higher in the JDM patients with RP-ILD versus those with C-ILD (p = 0.011) and in healthy controls (p = 0.0004). The C-ILD group had significantly higher levels of BAFF versus controls (p ≤ 0.0001). Serum APRIL was markedly elevated in the RP-ILD group as compared with the C-ILD group (p = 0.003) and controls (p = 0.006). In patients with ILD, both BAFF and APRIL levels were correlated with serum Krebs von den Lungen-6 and interleukin 18. Subjects with high titer anti-MDA5 (> 200 U) had higher levels of BAFF and APRIL than those with low titer anti-MDA5 (< 100 U; p = 0.019 and p = 0.0029, respectively), which may have been due to a relationship between RP-ILD and high anti-MDA5 titer.Conclusion.Our findings of markedly elevated levels of BAFF and APRIL in patients with RP-ILD JDM suggest the potential importance of these cytokines in the diagnosis and treatment of RP-ILD accompanying JDM.

Objective.To identify macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (sJIA) undergoing tocilizumab (TCZ) treatment, and to confirm laboratory marker changes and responses to treatment in patients with MAS receiving TCZ.Methods.In Japan, 394 patients with sJIA were registered in an all-patient registry surveillance of TCZ as of January 15, 2012. TCZ (8 mg/kg) was administered every 2 weeks to patients with sJIA. MAS, hemophagocytic lymphohistiocytosis, or Epstein-Barr virus–associated hemophagocytic syndrome (EB-VAHS) was reported in 23 of these patients (25 events). The Safety Evaluation Committee of Tocilizumab for JIA reviewed these cases and clinically evaluated the data and laboratory findings using their own therapeutic experience. Events were categorized into 4 groups: definitive MAS, probable MAS, EB-VAHS, and non-MAS.Results.The committee’s review revealed 3 events of definitive MAS in 3 patients, 12 events of probable MAS in 11 patients, 2 events of EB-VAHS in 2 patients, and 8 events of non-MAS in 8 patients. There were 2 patients who developed 2 events: 2 events in 1 patient were classified into definitive MAS and probable MAS, and 2 events in another patient were classified into probable MAS. In patients with definitive or probable MAS, common clinical manifestations and laboratory findings of MAS were observed. Changes in laboratory data observed in patients with EB-VAHS were similar to those observed in patients with MAS.Conclusion.These results suggest that the clinical/laboratory features in the course of MAS appear to be similar among patients regardless of whether TCZ is administered. Similarities in the pathophysiological background of MAS and EB-VAHS were also suggested.

ObjectiveTo investigate the efficacy and safety of the interleukin-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK).MethodsPatients with TAK who had relapsed within the previous 12 weeks were induced into remission with oral glucocorticoid therapy. In this double-blind, placebo-controlled trial, patients were randomly assigned 1:1 to receive weekly tocilizumab 162 mg or placebo subcutaneously, and oral glucocorticoids were tapered 10 %/week from week 4 to a minimum of 0.1 mg/kg/day until 19 patients relapsed. The primary endpoint was time to relapse of TAK, defined as ≥2 of the following: objective systemic symptoms, subjective systemic symptoms, elevated inflammation markers, vascular signs and symptoms or ischaemic symptoms.ResultsThe intent-to-treat and safety populations included 18 tocilizumab-treated and 18 placebo-treated patients. The per-protocol set (PPS) included 16 tocilizumab-treated and 17 placebo-treated patients. HRs for time to relapse of TAK were 0.41 (95.41% CI 0.15 to 1.10; p=0.0596) in the intent-to-treat population (primary endpoint) based on relapse in eight tocilizumab-treated and 11 placebo-treated patients and 0.34 (95.41% CI 0.11 to 1.00; p=0.0345) in the PPS. The secondary endpoints, time to relapse assessed by Kerr’s definition and clinical symptoms only, were consistent with the primary endpoint. Serious adverse events were reported in one tocilizumab-treated and two placebo-treated patients. There were no serious infections and no deaths.ConclusionAlthough the primary endpoint was not met, the results suggest favour for tocilizumab over placebo for time to relapse of TAK without new safety concerns. Further investigation is warranted to confirm the efficacy of tocilizumab in patients with refractory TAK.Trial registration numberJapicCTI-142616.

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.

Although there are many reports on the resistance of Kawasaki disease (KD) to initial intravenous immunoglobulin (IVIg) therapy, risk factors for coronary artery lesions in such cases remain to be established. The objective of this study was to explore when additional therapies should be administered and to identify factors helpful for selecting a therapeutic option. Based on their written clinical records, we performed a retrospective review of KD patients who did not respond to initial IVIg therapy and who therefore then underwent plasma exchange (PE) therapy. This was a case-control study to compare the presence or absence of acute coronary lesions in patients treated by PE for IVIg-unresponsive KD at Yokohama City University Hospital or at Yokohama City University Medical Center. Fifteen of 44 patients had acute coronary artery lesions (CAL) correlating with high levels of white blood cells (WBC) (P = 0.045), D-dimer (P = 0.008), and fibrin/fibrinogen degradation products (P = 0.009) and lower levels of fibrinogen (P = 0.013) prior to PE therapy. There was a strong correlation between pre-PE levels of albumin and D-dimer (Pearson's correlation coefficient of 0.610). Multivariate analyses revealed that the odds ratio for CAL when D-dimer was ≥ 4.5 μg/mL was 25.06 (95% CI, 2.56-244.91, P = 0.006). D-dimer elevation and albumin decline in IVIg-unresponsive KD patients could be risk factors for acute CAL, suggesting the possibility that angitis has spread throughout the arterial system, as far as the coronary artery.

Aims At birth, dynamic changes occur in serum components and haemodynamics, such as closure of the ductus arteriosus (DA). A previous study demonstrated that, in full-term human neonates, serum osmolality decreased transiently after birth, but recovered over the next few days. However, the significance of this transient decrease in osmolality has never been addressed. The objective of the present study was to examine the role of changes in serum osmolality after birth in DA closure. Methods and results We found that rats exhibited a similar transient hypoosmolality after birth. Hypotonic stimulation induced constriction of DA rings and increased Ca2+ transient in DA smooth muscle cells, but not in the aorta. The hypoosmotic sensor transient receptor potential melastatin 3 (TRPM3) was highly expressed in the rat DA, and TRPM3 silencing abolished the Ca2+ response to hypoosmolality. Pregnenolone sulfate stimulation of TRPM3 induced rat DA constriction ex vivo and in vivo. Furthermore, hyper tonic fluid injection impaired rat DA closure. In humans, neonatal serum hypoosmolality was observed in relatively mature preterm infants (≥28 weeks). In extremely preterm infants (

Background Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common syndrome among the acute encephalopathies, and is associated with a high incidence of neurologic sequelae. This study examined the efficacy of cyclosporine (CsA) for the treatment of AESD. Methods Fourteen children with AESD were recruited and categorized as group A (not receiving CsA) and group B (receiving CsA). Clinical course, laboratory data, magnetic resonance imaging (MRI), and outcome were analyzed retrospectively. We divided the patients into three types according to the distribution of abnormalities on MRI: frontal lobe predominant type, unilateral cerebral hemisphere type, and diffuse type. We used the Pediatric Cerebral Performance Category scale (PCPC) and the Pediatric Overall Performance Category scale (POPC) as prognostic measures. Results Of the 14 children, five were boys (age range, 9–32 months). PCPC score was: 1 for seven patients, 2 for three patients, and 3 for four patients. There was no significant difference in PCPC between groups A and B (P = 0.293). POPC score was: 1 for six patients, 2 for five patients, and 3 for three patients. There was a significant difference in POPC between groups A and B when patients with the frontal lobe predominant type were excluded (P = 0.020). Conclusions CsA could improve the neurological prognosis of patients with AESD, except for those with frontal lobe predominant type.

Aims/Introduction Brachial artery flow-mediated dilation (FMD) is a method of evaluating the function of vascular endothelial cells and is utilized for early diagnosis of atherosclerotic diseases. Only a few studies evaluated the risks for major vascular complications in youth with type 1 and 2 diabetes mellitus from the aspect of the early development of atherosclerosis. We studied whether there is a difference in vascular endothelial cell function between youth with type 1 and 2 diabetes mellitus. Materials and Methods We assessed %FMD of 24 patients with type 1 diabetes mellitus and 27 patients with type 2 diabetes mellitus aged 12–20 years along with glycated hemoglobin, lipid metabolism markers such as triglycerides, and inflammatory biomarkers such as total adiponectin levels in adolescent patients with type 1 or 2 diabetes mellitus. The significance of the difference in each factor between the type 1 and type 2 diabetes groups was assessed using Student's t-test. Results The %FMD was significantly lower in patients with type 2 diabetes. The body mass index and blood pressure were significantly higher, and total and high-molecular-weight adiponectin levels were significantly lower in patients with type 2 diabetes. %FMD significantly correlated with systolic blood pressure. Conclusions The results suggest that youth with type 2 diabetes have more advanced damage of the vascular endothelium and therefore are at higher risk for major vascular complications. Therefore, monitoring the progression of atherosclerosis would also be beneficial in youth with diabetes mellitus, and measurement of FMD could be further warranted.

A 14-year-old boy was admitted in the former hospital with remittent fever, erythematous rash, joint pain, and muscle pain. Antibiotics were ineffectively administered and then, methylprednisolone (mPSL) pulse therapy with methotrexate was introduced under the diagnosis of suspected systemic juvenile idiopathic arthritis (JIA). However, he still had clinical symptoms and signs, and was transferred to our hospital. Re-examination revealed no malignancies including acute leukemia by bone marrow aspiration, no infectious agents by septic work, and no significant increases of antibodies against several viruses including CMV, EBV, HSV, Parvovirus B19, adenovirus, and so forth. FDG-PET demonstrated the accumulation of (18)F-FDG in bone marrows suggesting systemic JIA. Laboratory findings were leukocytosis and granulocytosis, elevated levels of C-reactive protein, D-dimer, ferritin, and interleukin-6. He was finally diagnosed as having severe systemic JIA. Thus, soon after the additional mPSL pulse therapy, tocilizumab (TCZ) was successfully introduced. In conclusion, for systemic JIA patients with severe systemic inflammation, it will be reasonable to introduce tocilizumab earlier than the guideline suggested to reduce side effects of long-term and large amounts of steroids and to protect the transition to macrophage activation syndrome. Further studies will be needed to recommend appropriate timing of tocilizumab introduction.

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.

Associations between the severity of respiratory signs and symptoms and the respiratory viruses identified in 214 Japanese children with acute respiratory illness (ARI) enrolled between January and December 2012 were studied. Respiratory rate, wheezing, cyanosis, and the use of accessory muscles were used as indices of respiratory severity and phylogenetic analysis of the viruses identified in these children was performed. Respiratory viruses such as respiratory syncytial virus (RSV), human rhinovirus (HRV), human parainfluenza virus (HPIV), and human metapneumovirus (HMPV) were prevalent, being detected in approximately 70% of the patients (151/214 patients). Co-detection of viruses occurred in about 9% of patients. RSV was identified more frequently in cases scored as moderate/severe than in those scored as mild (P

The safety and efficacy of tocilizumab (TCZ), an anti-IL-6 receptor monoclonal antibody, have been reported in the treatment of children with systemic juvenile idiopathic arthritis (sJIA).Growth of children during the TCZ study was analyzed.Forty-five sJIA patients (8.1 ± 4.2 years) were enrolled. Mean standard deviation score (SDS) for height (HTSDS), height velocity (HVSDS) and changes in SDS from baseline (∆SDS) were determined. Correlation between ∆SDS and several factors such as age, disease duration and corticosteroid exposure were evaluated. Yearly height velocity was analyzed for 28 patients for whom we had data for 1 year prior to TCZ administration and who had received TCZ for more than 1 year.Of the 45 patients, 38 (84%) obtained a clinical response at week 144. The mean baseline HTSDS was - 2.7 ± 2.0 and inversely correlated with disease duration. Significant improvement was seen in change in HVSDS from 1 year prior to 1 year after baseline (- 6.0 ± 4.0 to - 2.5 ± 3.9, p = 0.0064). Reduction in corticosteroid exposure was significantly associated with improvement in HVSDS (p = 0.0027).Growth impairment evidenced by HTSDS was more prominent in patients with longer standing disease. Catch-up growth was observed in patients who required less or no corticosteroid during TCZ treatment.

Juvenile fibromyalgia (JFM) is a disease in which patients complain of acute and chronic severe pain, an overt primary cause for which cannot be found or surmised. Although patients with JFM mainly complain of systemic pain or allodynia in the medical interview and physical examination, the concept of the disease is the total sum of painful illness, chronic fatigue, hypothermia and many other autonomic symptoms and signs. Many issues are interacting including individual traits (personality, temperament, sensitivity, memory of pain; age: early adolescence), individual states (self-esteem, anxiety, developmental level), and external stressors (parent especially mother, school environment). JFM is diagnosed on the combination of disease history, physical examination to determine the 18 tender points and allodynia, pain from gently touching their hair, and negative results of blood tests (inflammatory markers, thyroid function, myogenic enzymes). The goals of treatment are the following: restoration of function and relief of pain. Psychological support is advocated. Although the exact number of patients with JFM is still to be elucidated, it seems to be growing because pediatric rheumatologists in Japan encounter children with a wide variety of musculoskeletal pains. This guideline describes how to diagnose JFM in children and how to treat them appropriately.

Background Congenital cytomegalovirus (CMV) infection and neonatal herpes are major mother-to-child infections, and analyses of the important clinical issues, including risk factors for prognosis, are essential. Methods A secondary survey of congenital CMV infection and neonatal herpes was performed using questionnaires for cases reported in the primary survey between 2006 and 2008. Results Univariate analysis of 71 cases of congenital CMV infection showed that intrauterine growth restriction (IUGR) or other specific findings on fetal ultrasonography (US), microcephaly, intracranial calcification, disseminated intravascular coagulation, abnormal findings on computed tomography, and the use of i.v. gammaglobulin were all significantly correlated with poor outcome (death or severe sequelae). Multivariate analysis showed that only IUGR was significantly associated with poor outcome. Hearing impairment is one of the major abnormalities associated with congenital CMV infection. Automatic auditory brainstem response (automatic ABR) appeared to be useful for detection of hearing impairment in comparison with conventional ABR. Moreover, univariate analysis showed that specific fetal US or abnormal magnetic resonance imaging findings were correlated with sensorineural hearing loss. In 24 cases of neonatal herpes, fever and seizure were correlated with poor outcome on univariate analysis. All patients received acyclovir treatment, although substantial numbers of patients in severe clinical categories (disseminated or central nervous system diseases) received a low dose of acyclovir (

Ewing sarcoma (ES) is a primary bone malignant neoplasm and is the second most common primary malignancy of the bone found in childhood and adolescence after osteosarcoma. ES has an annual frequency in the population younger than 20 years of approximately 2.9 per million. ES occurs most frequently in the long bones of the extremities and pelvis and very rarely in the jaw. Recently, it was revealed that chromosomal translocation t(11;22)(q24;q12), which fuses the EWS gene on chromosome 22 and the FLI-1 gene on chromosome 11, occurs in most cases of ES. We report here a rare case of mandibular ES in a 10-year-old child with chromosomal translocation t(21;22)(q22;q12) in which the EWS gene is fused with the ERG gene on chromosome 21.

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.

Human parechovirus-3 (HPeV-3) has been reported to cause a sepsis-like illness in neonates and young infants. We experienced the occurrence of HPeV-3 infection in nine neonates and young infants (eight boys, one girl; aged 14-52 days, median 31 days). They were admitted to our hospital with the chief complaints of fever persisting for 3-5 days (median 4 days) and lethargy. Five infants presented with abdominal distension and six had a rash (including acral reddening), as was previously reported with this viral infection. Abdominal distension with navel protrusion and acral reddening during the course were characteristic. Laboratory data were characterized by elevated values for serum AST, LDH, FDP, D-dimer, ferritin, soluble IL-2 receptor, triglyceride, choline esterase, and urinary β(2)-microglobulin. Two of our nine patients presented with a hemophagocytic lymphohistiocytosis (HLH)-like illness and required specific therapy. These data suggest that HPeV-3 is an important virus that can cause hypercytokinemia, which sometimes leads to HLH, and systemic inflammatory response syndrome in neonates and young infants.

Vaccination is the most powerful way to prevent human beings from contracting infectious diseases including viruses. In the case of the human papillomavirus (HPV) vaccine, an unexpectedly novel disease entity, HPV vaccination associated neuro-immunopathetic syndrome (HANS), has been reported and remains to be carefully verified. To elucidate the mechanism of HANS, we applied a strategy similar to the active experimental autoimmune encephalitis (EAE) model - one of the most popular animal models used to induce maximum immunological change in the central nervous system. Surprisingly, mice vaccinated with pertussis toxin showed neurological phenotypes that include low responsiveness of the tail reflex and locomotive mobility. Pathological analyses revealed the damage to the hypothalamus and circumventricular regions around the third ventricle, and these regions contained apoptotic vascular endothelial cells. These data suggested that HPV-vaccinated donners that are susceptible to the HPV vaccine might develop HANS under certain environmental factors. These results will give us the new insight into the murine pathological model of HANS and help us to find a way to treat of patients suffering from HANS.

Autosomal dominant hyper-IgE syndrome (AD-HIES) is included among primary immunodeficiencies, and results from heterozygous mutations in the signal transduction and activator of transcription 3 (STAT3) gene. AD-HIES leads to impaired Th17 cell differentiation and IL-17 production, and is associated with increased susceptibility to bacteria and fungi. It was reported that several patients with AD-HIES were treated with hematopoietic stem cell transplantation (HSCT). The efficacy of HSCT in treating AD-HIES is variable. This study aims to evaluate the long-term clinical and immunological efficacy of HSCT for AD-HIES. We have followed for more than 8 years two patients with AD-HIES who were treated with HSCT. Their ability of IL-17 production was evaluated by flow cytometry. Both patients indicated the normal ability of IL-17 production and their serum IgE levels decreased after HSCT. On the other hand, they suffered from pulmonary complications of AD-HIES such as pneumatoceles and bronchiectasis even after HSCT; however, the frequency of infections was decreased. Although the dysfunction of STAT3 in non-hematological tissues such as the lungs could not be corrected by HSCT, AD-HIES patients with risk factors for pulmonary complications may benefit from immunological correction by HSCT before severe pulmonary complications occur. Future studies should investigate risk factors for pulmonary complications in AD-HIES patients.

We report the case of a 15-year-old Japanese girl with myopathy associated with antibodies to a signal recognition particle (anti-SRP myopathy). The patient presented with progressive symmetrical proximal muscle weakness that caused difficulty in walking within 3 months, and marked elevation of the serum creatine kinase levels. A skeletal muscle biopsy revealed active necrotic and regenerating processes, with mild inflammatory changes. Based on the above findings, the patient was diagnosed as having anti-SRP myopathy. Only a limited number of pediatric patients with anti-SRP myopathy has been reported previously, with usually a poor prognosis. Early diagnosis is important for obtaining a better prognosis in patients with anti-SRP myopathy.

We investigated the safety and efficacy of administering influenza vaccines to patients with systemic-onset juvenile idiopathic arthritis (sJIA) treated with tocilizumab. The subjects were 27 sJIA patients treated with tocilizumab and 17 healthy age- and sex-matched volunteers. Serum samples were collected prior to and 4–7 weeks after vaccination. Hemagglutination inhibition values of the vaccine were taken as the antibody titers. The duration of tocilizumab administration and the daily doses of prednisolone per unit body weight were analyzed to identify factors affecting the responses of the sJIA patients to influenza vaccination. We questioned all the subjects about whether they had contracted influenza and whether they had had adverse reactions to the influenza vaccination. We compared steroid doses in sJIA patients before and after vaccination to document any worsening of the underlying disease. The efficacy of influenza vaccination did not differ significantly between the sJIA group and the healthy controls. The duration of tocilizumab administration did not affect the response of the sJIA patients to the influenza vaccination. None of the sJIA patients experienced either severe adverse reactions or disease exacerbation after the influenza vaccination. We found that sJIA patients treated with tocilizumab could be effectively and safely immunized with the influenza vaccine.

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