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Background Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory disease caused by loss-of-function mutations in both alleles of the ADA2 gene. Most patients with DADA2 exhibit systemic vasculopathy consistent with polyarteritis nodosa, but large phenotypic variability has been reported, and the pathogenesis of DADA2 remains unclear. Objectives This study sought to assess the clinical and genetic characteristics of Japanese patients with DADA2 and to gain insight into the pathogenesis of DADA2 by multi-omics analysis. Methods Clinical and genetic data were collected from 8 Japanese patients with DADA2 diagnosed between 2016 and 2019. ADA2 variants in this cohort were functionally analyzed by in vitro overexpression analysis. PBMCs from 4 patients with DADA2 were subjected to transcriptome and proteome analyses. Patient samples were collected before and after introduction of anti- TNF-α therapies. Transcriptome data were compared with those of normal controls and patients with other autoinflammatory diseases. Results Five novel ADA2 variants were identified in these 8 patients and were confirmed pathogenic by in vitro analysis. Anti-TNF-α therapy controlled inflammation in all 8 patients. Transcriptome and proteome analyses showed that upregulation of type II interferon signaling was characteristic of DADA2. Network analysis identified STAT1 as a key regulator and a hub molecule in DADA2 pathogenesis, a finding supported by the hyperactivation of STAT1 in patients’ monocytes and B cells after IFN-γ stimulation. Conclusions Type II interferon signaling and STAT1 are associated with the pathogenesis of DADA2.

Issues related to transitioning from paediatric to adult healthcare are currently receiving international attention. In Japan, 1000 patients with childhood-onset chronic rheumatological diseases reach adulthood every year and require transition from care by paediatric to care by adult rheumatologists. Here, we propose a guide for the latter, wherein the adult caregiver poses the clinical questions about transitional support that they need to have answered, and the paediatric caregiver mainly compiles the plans for the transition. To formulate the guide, we sought comments from both the Japan College of Rheumatology and the Pediatric Rheumatology Association of Japan and obtained their approval. Here, we present the outcome of this consultation in the form of a Guide for Supporting Transitional Care, aiming to provide essential knowledge to physicians in the fields of adult internal medicine and orthopaedics who may be involved in treating patients with rheumatic disease during the transition from paediatric to adult care. The features of transitional support that are common for patients with various different rheumatic diseases are presented in this guide, with the aim of informing policy and strategies to deliver optimal outcomes in transitional care by non-paediatric rheumatologists.

Background The European League Against Rheumatism (EULAR) Sjögren Syndrome Disease Activity Index (ESSDAI) has been utilized to assess Sjögren syndrome-related systemic involvement in adult patients. To date, however, the ESSDAI has not been validated in children with primary Sjögren’s syndrome. This study evaluated the applicability of the ESSDAI to Japanese children with primary Sjögren’s syndrome. Methods The medical records of children who had been diagnosed with Sjogren syndrome at age ≤ 16 years between June 2011 and October 2016 were collected, and their ESSDAIs at initial presentation were calculated. Clinical symptoms and treatment regimens were surveyed by questionnaire, and patients were divided into groups based on ESSDAI and glucocorticoid dosages. The associations of ESSDAI scores with treatment regimens were analyzed statistically. Results The study subjects included 31 children (3 boys, 28 girls) with primary Sjögren’s syndrome. Their median age at disease onset was 10 years (interquartile range [IQR], 8–13 years), and their median initial ESSDAI was 7.0 (IQR; 5.0–15.0). ESSDAI-determined disease activity was high in nine patients (29.0%), moderate in 15 (48.4%), and low in seven (22.6%). During the first year after their initial visit, 14 patients (45.2%) were treated with prednisolone (PSL) and six (19.4%) with immunosuppressants. Dose of PSL was significantly associated with ESSDAI score. Median ESSDAI score was significantly higher in patients treated with high/medium- than with no/low-dose PSL (16.5 [IQR 10.5–18.0] vs 5.0 [IQR 3.0–8.5]). Eight (66.7%) of 12 patients administered medium/high-dose PSL and one (5.3%) of 19 administered no/low-dose PSL had high disease activity on ESSDAI. Conclusion Disease activity assessed by ESSDAI tended to be consistent with disease activity assessed by pediatric rheumatologists in determining treatment regimens. ESSDAI is useful for assessing disease activity in Japanese children with primary Sjögren’s syndrome.

There are a considerable number of pediatric patients with Sjogren's syndrome (SS); however, SS is generally considered rare among children. Pediatric patients with SS report fewer sicca symptoms; therefore, many are under-diagnosed and cannot access appropriate medical management. Therefore, we propose a newly developed guidance for the diagnosis, treatment, and management of pediatric SS, including epidemiology, clinical features, and diagnostic examination methodology. The aim of this guidance was to standardize the medical care of pediatric SS in Japan, and we published the Japanese version by YODOSHA in 2018. This article is the English version, which is summarized and updated. This guidance will need to be revised in the near future as additional clinical data become available.

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

Background This study aimed to determine the influence of tocilizumab (TCZ) in modifying the clinical and laboratory features of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s-JIA). Furthermore, we assessed the performance of the 2016 MAS classification criteria for patients with s-JIA-associated MAS while treated with TCZ. Methods A panel of 15 pediatric rheumatologists conducted a combination of expert consensus and analysis of real patient data. Clinical and laboratory features of s-JIA-associated MAS in 12 TCZ-treated patients and 18 untreated patients were evaluated. Possible MAS was defined as having characteristic laboratory features but lack of clinical features of MAS, or atypical MAS, or early treatment that prevented full-blown MAS. Results Clinically, the TCZ-treated patients with s-JIA-associated MAS were less likely febrile and had significantly lower ferritin, triglyceride, and CRP levels than the untreated patients with s-JIA-associated MAS. Other laboratory features of MAS including lower platelet counts and lower fibrinogen were more pronounced in TCZ-treated patients. The TCZ-treated patients with s-JIA-associated MAS were less likely to be classified as MAS based on the MAS classification criteria (25% vs 83.3%, p Conclusion TCZ could modify the clinical and laboratory features of s-JIA-associated MAS. When evaluating the s-JIA patients while treated with TCZ, it is not applicable to use MAS classification criteria. Care must be taken to not underdiagnose MAS based on the MAS classification criteria.

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.

Objective To validate whether the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA) is practical in the real world. Methods A combination of expert consensus and analysis of real patient data was conducted by a panel of 15 pediatric rheumatologists. A total of 65 profiles comprised 18 patients with systemic JIA-associated MAS and 47 patients with active systemic JIA without evidence of MAS. From these profiles, 10 patient data points for full-blown MAS, 11 patient data points for MAS onset, and 47 patient data points for acute systemic JIA without MAS were evaluated. Results Evaluation of the classification criteria to discriminate full-blown MAS from acute systemic JIA without MAS showed a sensitivity of 1.000 and specificity of 1.000 at the time of full-blown MAS. Sensitivity was 0.636 and specificity was 1.000 at the time of MAS onset. The number of measurement items that fulfilled the criteria increased in full-blown MAS compared to that at MAS onset. At MAS onset, the positive rates of patients who met the criteria for platelet counts and triglycerides were low, whereas those for aspartate aminotransferase were relatively high. At full-blown MAS, the number of patients who met the criteria for each measurement item increased. Conclusion The classification criteria for MAS complicating systemic JIA had a very high diagnostic performance. However, the diagnostic sensitivity for MAS onset was relatively low. For the early diagnosis of MAS in systemic JIA, the dynamics of laboratory values during the course of MAS should be further investigated.

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.

Background:Still’s disease is a systemic auto-inflammatory disease with a pediatric form, sJIA, and an analogous condition in adults, adult-onset Still’s disease (AOSD). The role of interleukin-1 (IL-1) in the pathophysiology of Still’s disease is well established. Canakinumab, a monoclonal antibody against IL-1ß, is approved to treat patients with Still’s disease in Europe (sJIA and AOSD) and the United States (sJIA).Objectives:To study the efficacy of canakinumab in sJIA patients categorized by age, we performed an intention-to-treat analysis of pooled data from 5 clinical trials, as an addition to a previously communicated analysis including 3 of the studies1Methods:The age categories were children (2-Results:302 children, 82 young adolescents and 34 older adolescents and young adults were included in the analysis, with a mean disease duration of 922, 1708 and 2615 days, respectively. Prior therapy with other biologics was common, with anakinra used in 33%, 35% and 47% of patients in each group. Disease severity was comparable among groups, with the mean number of active joints ranging from 11.8 to 13.7. Adapted pediatric ACR responses revealed a rapid response to canakinumab, with all groups showing similar rates of responders at most time points (Table 1). In each age group, the proportion of patients with inactive disease progressively increased to Day 57. At all time points after Day 15, the 16-Table 1.Percentages of patients with Adapted pediatric ACR responses and inactive disease status over time*Time of treatment(Days)2 - a12 - b16-cACR301572.781.783.9 (%)2977.584.182.45776.282.988.28565.574.583.3ACR701551.558.364.5 (%)2961.962.270.65765.258.579.48558.661.875.0ACR1001521.625.012.9 (%)2929.530.535.35736.134.138.28534.130.933.3Inactive disease1519.030.019.4 (%)2934.134.147.15739.436.655.98536.743.452.2*Some studies did not include visits at Day 15 and/or 85. For Day 15, 29, 57 and 85 the respective denominators for each age group were:aN = 231, 302, 302, 232;bN = 60, 82, 82, 55;cN = 31, 34, 34, 24.Conclusion:The efficacy and safety profile of canakinumab was consistent in children, adolescents and young adults with sJIA. Since sJIA and AOSD represent pediatric- and adult- onset variants of the Still’s disease continuum, these results further support the therapeutic effect of canakinumab 4 mg/kg every 4 weeks in both children and adults with Still’s disease.References:[1]Feist et al.Clin Exp Rheumatol.2018;36(4):668-75.Disclosure of Interests:Pierre Quartier Consultant of: AbbVie, Chugai-Roche, Lilly, Novartis, Sanofi, Sobi, Speakers bureau: AbbVie, BMS, Chugai-Roche, Novartis, Pfizer, Sobi, Eugen Feist Consultant of: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Speakers bureau: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Daniel J Lovell Consultant of: Abbott (consulting and PI), AbbVie (PI), Amgen (consultant and DSMC Chairperson), AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb (PI), Celgene, Forest Research (DSMB Chairman), GlaxoSmithKline, Hoffman-La Roche, Janssen (co-PI), Novartis (consultant and PI), Pfizer (consultant and PI), Roche (PI), Takeda, UBC (consultant and PI), Wyeth, Employee of: Cincinnati Children’s Hospital Medical Center, Speakers bureau: Wyeth, Hiroaki Umebayashi: None declared, Nicolino Ruperto Grant/research support from: Bristol-Myers Squibb, Eli Lily, F Hoffmann-La Roche, GlaxoSmithKline, Janssen, Novartis, Pfizer, Sobi (paid to institution), Consultant of: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Speakers bureau: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Hermine Brunner Consultant of: Hoffman-La Roche, Novartis, Pfizer, Sanofi Aventis, Merck Serono, AbbVie, Amgen, Alter, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer, Bristol-Myers Squibb, Celgene, EMD Serono, Janssen, MedImmune, Novartis, Pfizer, and UCB Biosciences, Speakers bureau: GSK, Roche, and Novartis, Cornelia Dunger-Baldauf Employee of: Novartis, Stephanie Noviello Employee of: Novartis, sarah whelan Employee of: Novartis

Background Previous studies including a systematic literature review revealed clinical manifestations and laboratory features of systemic juvenile idiopathic arthritis (s-JIA) associated macrophage activation syndrome (MAS) could be modified in patients treated with tocilizumab (TCZ) 1,2. Objectives To clarify whether TCZ modifies clinical manifestations and laboratory features of s-JIA associated MAS, and to assess performance of the 2016 MAS classification criteria for patients with s-JIA associated MAS while treated with TCZ in the real world. Methods A combination of expert consensus and analysis of real patient data was conducted by a panel of 15 pediatric rheumatologists. Clinical manifestations and laboratory features of s-JIA associated MAS at the MAS diagnosis in 12 patients while treated with TCZ and 18 patients not treated with TCZ were evaluated. Possible MAS was defined as having characteristic laboratory features but lack of clinical features of MAS, or atypical MAS, or early treatment that prevented fulminant MAS 3,4. Results Among 12 patients while treated with TCZ, only 2 patients were diagnosed with definite MAS, and other 10 patients were diagnosed with possible MAS. On the other hand, among 18 patients not treated with TCZ, 10 patients were diagnosed with definite MAS, and other 8 patients were diagnosed with possible MAS. MAS classification criteria could classify the patients diagnosed with definite MAS while treated with TCZ as having MAS as well as the patients not treated with TCZ (100% and 100%, respectively). However, this criteria were less likely to classify the patients diagnosed with possible MAS while treated with TCZ as well as the patients not treated with TCZ (60% and 75%, respectively). Furthermore, the patients with possible MAS while treated with TCZ were less likely febrile and significantly less often had rash, and had notably lower ferritin levels (587 versus 8518 ng/ml; P=0.0021), compared to the patients with possible MAS not treated with TCZ. Other laboratory features of MAS including lower platelet counts, lower fibrinogen were more pronounced in patients treated with TCZ. Conclusion These findings show TCZ could modify clinical manifestations and laboratory features of s-JIA associated MAS. When evaluating s-JIA patients while treated with TCZ, care must be taken to not underdiagnose MAS based on MAS classification criteria. References [1] Shimizu M, et al. Cytokine 2012;58:287-294. [2] Sculert GS, et al. Arthritis Care Res 2018;70:409-419 [3] Grom AA, et al. Arthritis Rheumatol 2016;68:218-228. [4] Yokota S, et al. J Rheumatol 2015;42:712-722. Disclosure of Interests Masaki Shimizu: None declared, Mao Mizuta: None declared, Takahiro Yasumi Shareholder of: Takeda, Speakers bureau: AbbVie, Novartis, CSL Behring, Naomi Iwata: None declared, Yuka Okura: None declared, Noriko Kinjo: None declared, Hiroaki Umebayashi Speakers bureau: AbbVie, Eisai, Novartis, Ono, Chugai, Tomohiro Kubota: None declared, Yasuo Nakagishi: None declared, Kenichi Nishimura: None declared, Masato Yashiro: None declared, Junko Yasumura: None declared, Hiroyuki Wakiguchi: None declared, Nami Okamoto: None declared, Masaaki Mori Grant/research support from: Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Japan Blood Products Organization, Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku Co., Ltd., Ono Pharmaceutical Co., Ltd., Towa Pharmaceutical Co., Ltd., UCB Japan Co. Ltd.

Background The transition from pediatric to adult healthcare systems has recently received worldwide attention, and it is “the purposeful, planned movement of adolescents and young adults with chronic physical and medical conditions from child-centered to adult-oriented healthcare systems.” In Japan, 1,000 patients with childhood-onset chronic disease reach adulthood every year, and many of them survive without serious sequelae or disabilities. The Japan Pediatric Society convened a committee of healthcare transition, summarized their statements, and the working group launched its activities in 2013. Objectives A clinical practice guidance for the transitional care of young people with childhood-onset rheumatic disorders has been established in Japan. Methods The guidance was designed to support pediatric and non-pediatric rheumatologic health care professionals make decisions about appropriate transitional health care for childhood-onset rheumatic disorders. It offered statements and recommendations addressing key clinical questions regarding transitional care proposed by leading pediatric and non-pediatric rheumatology medical experts and consisted of general core and disease-specific guidance. Results Category of clinical questions in the general core guidance involved the following: (1) initial statement of transitional care in rheumatology; (2) management of social life environment and public funded health care; (3) issues specific to adolescence; (4) risk management in childhood-onset rheumatic disorders; and (5) decision-making, privacy and consent, access to information, adherence to care, and preferred methods of communication, including attending to health literacy needs. In the disease-specific guidance, issues focused on each rheumatic disorder such as juvenile idiopathic arthritis, childhood-onset systemic lupus erythematosus, juvenile dermatomyositis, and Sjogren’s syndrome were brought up. Conclusion The guidance informs policy and strategies to reach optimal outcomes in transitional care for both pediatric and non-pediatric rheumatologists based on available evidence and expert opinion. References [1] Miyamae T, et al. Survey of attitudes of non-pediatric rheumatologists among councilors of the Japan College of Rheumatology regarding transitional care. Mod Rheumatol. 2017;27(6):1047-1050. [2] Matsui T, et al. Survey of the awareness of adult rheumatologists regarding transitional care for patients with juvenile idiopathic arthritis in Japan. Mod Rheumatol. 2018;28(6):981-985. Disclosure of Interests Takako Miyamae Speakers bureau: AbbVie, Eisai, Bristol-Meyers, Novartis, Ayumi, Taisyo-Toyama, Chugai, Shinji Akioka Grant/research support from: Eli Lily, Speakers bureau: Pfizer, Maruho, CSL Behring, Astellas, Chugai, Toru Igarashi: None declared, Yuzaburo Inoue Grant/research support from: MSD, Speakers bureau: Novartis, CSL Behring, MSD, Taishotoyama, Ono, Motomu Hashimoto Grant/research support from: Astellas, Brystol-Meyers, Eisai, Employee of: M. H. is affiliated with the department (Department of Advanced Medicine for Rheumatic Diseases, Kyoto University), which is financially supported by four pharmaceutical companies (Tanabe-Mitsubishi, Chugai, Ayumi, UCB Japan), Speakers bureau: Tanabe Mitsubishi, Brystol-Meyers, Toshihiro Matsui Speakers bureau: Takeda, Chugai, Eisai, Pfizer, Astellas, Eli Lilly, Ono, AbbVie, Mitsubishi Tanabe, AsahiKASEI, UCB, Teijin, Susumu Nishiyama Paid instructor for: Kissei Pharmaceutical Co., Ltd, Takeda Pharmaceutical Company, Mitsubishi Tanabe Pharma, Astellas Pharma, Eisai Pharmaceutical company, AbbVie Inc., TEIJIN Pharma, Asahi Kasei Corporation, Bristol- Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Santen Pharmaceutical Co., Ltd., AYUMI Pharmaceutical Corporation, Speakers bureau: Kissei Pharmaceutical Co., Ltd, DAIICHI SANKYO COMPANY, LIMITED, Shiro Ohshima Grant/research support from: AbbVie, Eisai, Asahikasei, Speakers bureau: AbbVie, Eisai, Bristol-Meyers, Novartis, Astellas, Nippon-Kayaku, Pfizer, UCB, Ayumi, Daiichi-Sankyo, Takeda, Tanabe-Matsubishi, Chugai, Hiroaki Umebayashi Speakers bureau: AbbVie, Eisai, Novartis, Ono, Chugai, Takahiro Yasumi Shareholder of: Takeda, Speakers bureau: AbbVie, Novartis, CSL Behring, Masaaki Mori Grant/research support from: Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Japan Blood Products Organization, Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku Co., Ltd., Ono Pharmaceutical Co., Ltd., Towa Pharmaceutical Co., Ltd., UCB Japan Co. Ltd.

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 Although there are many reports on Juvenile Idiopathic arthritis-associated uveitis (JIA-U) from various countries, especially from Europe and North America, there are few reports from Asia. Our aim was to investigate the epidemiology, characteristics and predictors of JIA-U in Japan. Methods Data were retrospectively collected on 726 patients with JIA from medical records as of April 2016 at 15 medical centers specialized in pediatric rheumatic diseases. Of these, patients with uveitis were further investigated for the specific characteristics of this manifestation. Results The prevalence of uveitis was 6.1% in the 726 JIA patients examined. Incidence of uveitis was significantly higher in patients with an earlier arthritis onset (2.6-vs.-5.8 years, P

Background Systemic juvenile idiopathic arthritis (SJIA) is a distinct form of juvenile idiopathic arthritis (JIA), accounting for approximately 4% to 17% of JIA1. In Japan, a higher frequency of SJIA, 41.7% of JIA2 has been reported compared to Europe and United States. Tocilizumab (TCZ) is the only approved biologic for SJIA treatment in Japan. However, some patients (pts) demonstrate persistently high disease activity and/or drug intolerabiliy. Therefore, new treatment options are required. Here, we evaluated the efficacy and safety of canakinumab (CAN), a human anti-interleukin-1s monoclonal antibody, in Japanese SJIA pts. Objectives To report the results of a 28 week (Wk) interim whole analysis of Phase III data (NCT02396212) of CAN, and the subgroup analysis of pts with or without prior use of TCZ. Methods Patients (age ≥2- Results The trial enrolled 19 pts who had insufficient response to prior treatment; the majority (15/19, 78.9%) had received TCZ (table 1). Of the 19 pts, 3 discontinued CAN due to lack of efficacy or adverse events (AE) by Wk28 and 16 completed the assessment of Wk28. All pts (19/19) achieved aACR 30/50/70 at Wk8 (figure 1). Overall, 73.7% (14/19) pts achieved corticosteroid tapering at Wk28 and 2 pts (10.5%) achieved ”steroid free”. Of 15 pts with prior use of TCZ, 12 pts (80.0%) achieved aACR 100 at Wk8 and 11 pts (73.7%) achieved corticosteroid tapering (26.3%, 5/19). Serious AE (SAE) was seen in 41.1% (8/19) pts, and the most frequent SAE was JIA (flare or worsening of SJIA, 21.1%, 4/19). One macrophage activation syndrome (MAS) but no death was reported. Conclusions CAN 4 mg/kg q4w s.c. provided improvement in disease activity and a redution of oral steroid dose in Japanese SJIA pts, including those who were not well-controlled with TCZ. No new safety concerns were reported. References [1] Ravelli A, Martini. Lancet2007; 369(9563):767–78. [2] Takei S, et al. Annual Report on children with chronic refractory diseases from the Japanese Ministry of Health, Labor and Welfare2008;102–13. Disclosure of Interest None declared

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

【目的】アレルギー疾患を有する小児が東日本大震災によってどのような影響を受けたかを調査し，今後の対応を検討する． 【対象と方法】対象は，宮城県立こども病院総合診療科，仙台医療センター小児科，森川小児科アレルギー科を定期受診した402名のアレルギー疾患の小児の保護者．口頭で同意を得た後，外来の待ち時間にアンケート記入を行い，診察時に回収した． 【結果】困った事で最も多かった回答は，それぞれ，気管支喘息では「停電のため電動式吸入器が使用できなかった」，アトピー性皮膚炎では「入浴できず湿疹が悪化した」，食物アレルギーでは「アレルギー用ミルクやアレルギー対応食品を手に入れるのが大変だった」であった． 【まとめ】大震災に対する今後の対応として，気管支喘息では停電の時でも吸入できるような吸入薬や吸入器の備え，アトピー性皮膚炎では入浴できない時のスキンケアの指導，食物アレルギーではアレルギー用ミルクを含めたアレルギー対応食品の備蓄や避難所などの公的機関で食物アレルギーへの理解を深める啓蒙活動が必要と考えた．

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.

Familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in approximate to 35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes. Objective To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative. Methods NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-kappa B) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants. Results A variable degree (5.5-34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses. Conclusions We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tools.

We reported three cases of childhood-onset male systemic lupus erythematosus (SLE), all of whom successfully treated with a combination of pulse methylprednisolone (mPSL) and pulse cyclophosphamide (IVCY). All of them had severe lupus nephritis and were complicated with other collagen diseases. Two cases were complicated with Sjögren syndrome (SS) and the other was complicated with both SS and anti-phospholipid syndrome (APS). After a combination of pulse mPSL and IVCY for a year, followed by oral predonisolone (PSL) and azathioprine (AZA), following up renal biopsy were performed in all cases, which showed histological improvement in glomerulonephritis. One case had flares a year later, but no flares were observed either in clinical symptoms or in laboratory examinations in the others. Their autoantibodies except anti-nuclear antibody (ANA) were eliminated. We suggest a combination of pulse mPSL and IVCY is effective for the patients who are suffering with severe lupus nephritis complicated with the other collagen diseases.

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.

An afebrile 8-year-old Japanese girl was referred with hypotensive shock and respiratory distress. She presented with a cough of 1-week duration followed by lethargy, dyspnea, and anuria, with which she was admitted to a previous hospital. She was intubated and given intravenous catecholamines, which did not improve her symptoms. Then, she was transferred to our hospital. Physical examination revealed a right arm blood pressure of 128/64 mm Hg and a left arm blood pressure of 94/56 mm Hg while on 4.6 μg/kg per min of dopamine and dobutamine. However, no blood pressure was obtained in the lower limbs. The heart sounds were distant with no murmur audible. Coarse crackles were prominent in both lungs. Laboratory data showed the following values: creatine kinase of …

The patient was a 7-year-old girl. At the age of 6, deposits of pigment had appeared on the skin of her face and limbs, the skin had become sclerosed, and she had developed dyspnea on exertion. Her previous physician had hospitalized her. She was diagnosed as systemic scleroderma that accompanied pulmonary hypertension by her symptoms and laboratory findings. She was referred to our hospital at 7 years of age, and she was hospitalized. At that time, the entire skin showed deposition of brown pigment, the skin of the limbs was sclerotic. And the face was mask-like, flexion of the joints of the fingers and knees was limited, and the fingertips were ulcerated. Raynaud's phenomenon was present. She was positive for antinuclear antibodies, and negative for other autoantibodies. Echocardiography revealed pulmonary hypertension. After admission, steroid pulse therapy and cyclophosphamide (CY) pulse therapy were initiated, and for aftercare, 15 mg/day of prednisolone (PSL) and mizolibin (MZB) were administered orally. After several months, the sclerosis of the skin improved and the restriction of limb flexion was almost eliminated. The pulmonary hypertension advanced temporarily (maximum: 70 mmHg), but after oral administration of a PGI2 preparation and low-flow supplemental oxygen therapy and the initiation of anticoagulant therapy, the systolic pressure of the pulmonary artery improved to 34 mmHg. The CY pulse therapy was terminated after two years, and internal use of PSL and MZB was continued. The patient's condition is now stable. This case was treated from an early stage with steroid pulse therapy and CY pulse therapy, accompanied with oral administration of a PGI2 preparation for the pulmonary hypertension. The dermal symptoms improved, and it was possible to maintain a state of remission.

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. …