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Curcumin is a polyphenol present in the rhizomes of the species Curcuma longa L. ("turmeric," Zingiberaceae), which has been used for centuries as an anti-inflammatory. We aimed to evaluate the anti-inflammatory effects of C. longa in renal injury induced by doxorubicin (DOX, 3.5 mg.kg-1 IV). We studied four groups of Wistar rats: two groups with DOX-induced kidney injury, one fed with standard food and another with standard food mixed with C. longa (5 mg.g-1 ). Two other control groups without kidney injury were fed with the same foods. We measured albuminuria, body weight, and food intake every 2 weeks. After 8 weeks, treatment with C. longa did not change albuminuria, but it significantly attenuated the excretion of urinary inflammatory markers monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-β (TGF-β) and significantly attenuated immunostaining for desmin, vimentin, and ED-1+ cells in renal tissues of rats with DOX-induced kidney injury. In addition, treatment with C. longa resulted in significantly lower glomerular and tubule interstitial injury scores, compared with that in the DOX-STD group. In conclusion, administration of powdered rhizomes of C. longa for 8 weeks to rats with DOX-induced kidney injury did not reduce albuminuria but led to a significant decrease in urinary inflammatory markers MCP-1 and TGF-β and decreased histopathological alterations and immunostaining for desmin, vimentin, and ED-1+ cells kidneys tissues.

Made available in DSpace on 2021-06-25T10:38:01Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-11-01 Healthway Objective. To develop a composite disease activity score for systemic JIA (sJIA) and to provide preliminary evidence of its validity. Methods. The systemic Juvenile Arthritis Disease Activity Score (sJADAS) was constructed by adding to the four items of the original JADAS a fifth item that aimed to quantify the activity of systemic features. Validation analyses were conducted on patients with definite or probable/possible sJIA enrolled at first visit or at the time of a flare, who had active systemic manifestations, which should include fever. Patients were reassessed 2 weeks to 3 months after baseline. Three versions were examined, including ESR, CRP or no acute-phase reactant. Results. A total of 163 patients were included at 30 centres in 10 countries. The sJADAS was found to be feasible and to possess face and content validity, good construct validity, satisfactory internal consistency (Cronbach's alpha 0.64-0.65), fair ability to discriminate between patients with different disease activity states and between those whose parents were satisfied or not satisfied with illness outcome (P < 0.0001 for both), and strong responsiveness to change over time (standardized response mean 2.04-2.58). Overall, these properties were found to be better than those of the original JADAS and of DAS for RA and of Puchot score for adult-onset Still's disease. Conclusion. The sJADAS showed good measurement properties and is therefore a valid instrument for the assessment of disease activity in children with sJIA. The performance of the new tool should be further examined in other patient cohorts that are evaluated prospectively. UOC Clinica Pediatrica e Reumatologia IRCCS Istituto Giannina Gaslini Dipartimento di Neuroscienze Riabilitazione Oftalmologia Genetica e Scienze Materno-Infantili (DiNOGMI) Università degli Studi di Genova Dipartimento di Epidemiologia e Biostatistica IRCCS Istituto Giannina Gaslini Faculty of Medicine Ain Shams University Pediatric Rheumatology Division Institute of Child Health Section of Pediatric Rheumatology SRCC Children's Hospital Rheumatology Division Pediatric Department Faculty of Medicine Ramathibodi Hospital Mahidol University Pediatric Rheumatology Clinic R G Kar Medical College Division of Rheumatology IRCCS Ospedale Pediatrico Bambino Gesù Division of Pediatric Rheumatology Institute of Child Health Sir Ganga Ram Hospital Faculty of Medicine Benha University Faculty of Medicine Alexandria University Faculty of Medicine Tanta University Faculty of Medicine Cairo University Pediatric Rheumatology Division Adolescent Health Care Unit Universidade do Estado do Rio de Janeiro Department of Internal Medicine Universidade Federal do Rio de Janeiro Servicio de Inmunología y Reumatología Hospital de Pediatría Garrahan Department of Clinical Sciences and Community Health University of Milan Division of Rheumatology University Hospital Meyer Rheumatology Division National Medical Research Center of Children's Health Sechenov First Moscow State Medical University Department of Immunology Rheumatology and Allergy Queen Rania Children's Hospital Saint-Petersburg State Pediatric Medical University UOC Pediatria a Media Intensità di Cure Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Rheumatology Department Faculty of Medicine Suez Canal University Department of Pediatrics King Faisal Specialist Hospital and Research Center Dipartimento Promise G. D'Alessandro Università degli Studi di Palermo Pediatric Department Hospital das Clínicas Botucatu Medicine University UNESP UOC Pediatria Servizio di Immuno-Reumatologia Pediatrica Azienda Ospedaliera Universitaria Gaetano Martino Messina UO Nefrologia e Reumatologia Pediatrica Azienda Ospedaliera Universitaria Gaetano Martino Department of Pediatrics School of Medicine Institute of Medical Pharmaceutical and Health Sciences Kanazawa University Pediatric Unit Ospedale Vito Fazzi Pediatric Unit AON SS Antonio e Biagio e Cesare Arrigo Children's Hospital Pediatric Department Hospital das Clínicas Botucatu Medicine University UNESP

Systemic juvenile idiopathic arthritis (SJIA) is a disease of unknown etiology characterized by arthritis and systemic symptoms. Evidence shows that SJIA is probably not a single disease but a diverse group of clinically and genetically distinct illnesses. It is classified both as one of the Juvenile idiopathic arthritis (JIA) categories and also among the autoinflammatory diseases.

Made available in DSpace on 2019-10-06T16:19:22Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-08-01 In 2012, a European initiative called Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile localised scleroderma (JLS) is a rare disease within the group of paediatric rheumatic diseases (PRD) and can lead to significant morbidity. Evidence-based guidelines are sparse and management is mostly based on physicians' experience. This study aims to provide recommendations for assessment and treatment of JLS. Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was formed, mainly from Europe, and consisted of 15 experienced paediatric rheumatologists and two young fellows. Recommendations derived from a validated systematic literature review were evaluated by an online survey and subsequently discussed at two consensus meetings using a nominal group technique. Recommendations were accepted if ≥80% agreement was reached. In total, 1 overarching principle, 10 recommendations on assessment and 6 recommendations on therapy were accepted with ≥80% agreement among experts. Topics covered include assessment of skin and extracutaneous involvement and suggested treatment pathways. The SHARE initiative aims to identify best practices for treatment of patients suffering from PRDs. Within this remit, recommendations for the assessment and treatment of JLS have been formulated by an evidence-informed consensus process to produce a standard of care for patients with JLS throughout Europe. Pediatric Rheumatology University of Padova Pediatric Rheumatology Hospital and Institut de Recerca Sant Joan de Déu Pediatric Rheumatology University Children's Hospital Ljubljana Paediatric Rheumatology Alder Hey Children's NHS Foundation Trust Discipline of Paediatrics Women's and Children's Hospital University of Adelaide Pediatrics Sydney Children's Hospital Network Randwick and Westmead Unit of Paediatric Rheumatology Semmelweis University Pediatric Rheumatology Istanbul University Cerrahpasa Medical Faculty Instituto de Puericultura e Pediatria Martagao Gesteira Rheumatology Great Ormond Street Hospital NHS Trust Servicio de Inmunología/Reumatología Hospital de Pediatria Juan P Garrahan Department of Paediatric Immunology Wilhelmina Children's Hospital University Medical Center Utrecht Departamento de Pediatria Faculdade de Medicina de Botucatu Hospital das Clínicas UNESP Klinikum Eilbek Hamburger Zentrum für Kinder-und Jugendrheumatologie Departamento de Pediatria Faculdade de Medicina de Botucatu Hospital das Clínicas UNESP

The Brazilian collaborative registry for pediatric renal transplantation began in 2004 as a multicenter initiative aimed at analyzing, reporting, and disseminating the results of pediatric renal transplantation in Brazil. Data from all pediatric renal transplants performed from January 2004 to May 2018 at the 13 participating centers were analyzed. A total of 2744 pediatric renal transplants were performed in the thirteen participating centers. The median age at transplantation was 12.2 years, with the majority being male recipients (56%). The main underlying diseases were CAKUT (40.5%) and glomerulopathy (28%). 1981 (72%) of the grafts were from deceased donors (DD). Graft survival at one year (censored by death) was 94% in the live donor group (LD) and 91% in the DD group (log-rank test P

Background Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood and it causes short and long-term disability. Periodic assessment of functional capacity is important to determine the presence or absence of physical disability. Objectives To identify predictive factors of absence of functional disability after 24 months follow-up in a cohort of children with JIA treated at a tertiary referral hospital. Methods Longitudinal, retrospective, analytical, and observational study. Patients who met the following criteria were included in the study between 2013 and 2016:1 to 16 years old, diagnosis of JIA according to the International League of Associations for Rheumatology (ILAR); recently initiated (3 months) care at our clinic, complete C-HAQ (Childhood Health Assessment Questionnaire) records throughout the follow-up period. Patients were treated according to current guidelines for pharmacological and physical therapy. Functional capacity was assessed according to the C-HAQ every 3 months. For the analysis, the C-HAQ scores were divided into 3 categories: 0 - 0.49 (absence of disability), 0.5 - 1.5 (mild to moderate disability), and 1.51 - 3 (severe disability). Univariate comparisons were made to determine the relationship between different variables with the dependent variable “absence of functional disability at 24 months of follow-up”. Independent variables included: disease activity, functional capacity, and treatment-related outcome measures. Those with p values Results Of a total of 148 patients, 122 met the inclusion criteria. Median age: 7.4 years (1-16), 69 female (56.6%). Most patients had Polyarticular (44 patients, 36.1%) or Oligoarticular (33 patients, 27%) JIA. At the beginning of the study, 36 patients (29.5%) did not show functional disability; 70 (57.4%) exhibited mild-moderate disability and 16 (13.1%) severe disability. At 24 months, 73 patients (59.84%) had no disability, 37 (30.33%) moderate/mild disability, and 12 (9.84%) severe disability. In the multiple logistic regression model, performing regular physical therapy (PT) (adjOR 6.83 [95% CI 2.26 - 20.61], p = 0.001), starting PT within 12 months after diagnosis (adjOR 5.45 [95% CI 1.83 to 16.18], p = 0.002), baseline pain Visual Analogue Scale (pVAS, 0-10) less than 3 (adjOR 4.55 [95% CI 1.58 to 13.12], p = 0.005) and adherence to pharmacological treatment (adjOR 15.23 [95% CI 1.86 to 124.8], p = 0.011) were independent factors for not presenting functional disability at 24 months. The area under the model curve was 0.92 (95% CI 0.88 to 0.97). Conclusion The findings of this study reinforce the need of early and regular PT and medical treatment in children with JIA, in order to maintain or improve functional capacity over time.These results are not only statistically significant but clinically relevant since they reflect impact in functional skills in this population. Further studies are needed to confirm these outcomes in larger cohorts with longer follow – up. References [1] Magni-Manzoni S, Pistorio A. A longitudinal analysis of physical functional disability over the course of juvenile idiopathic arthritis Rheum Dis 2008; 67:1159–1164.i:10.1136/ard.2007.078121 [2 ] Ravelli A, Martini A. Early predictors of outcome in juvenile idiopathic arthritis. ClinExpRheumatol2003;21(Suppl 31):S89–93. Disclosure of Interests None declared

Annals of the rheumatic diseases 76(5), 906-913 (2017). doi:10.1136/annrheumdis-2016-210324, Published by BMJ Publ. Group, London

OBJECTIVES: Mevalonate kinase deficiency (MKD) is a rare metabolic disease characterized by recurrent inflammatory episodes. This study aimed to describe the genotype, phenotype and the response to treatment in an international cohort of MKD patients. METHODS: All MKD cases were extracted from the Eurofever registry (EAHC Project No. 2007332), an international, multicenter registry that retrospectively collects data on children and adults suffering from autoinflammatory diseases. RESULTS: One hundred and fourteen MKD patients were included in this study. The median age of onset was 0.5 years. Patients had on average 12 episodes per year. Most patients had gastrointestinal symptoms (n=112), mucocutaneous involvement (n=99), lymphadenopathy (n=102) or musculoskeletal symptoms (n=89). Neurological complaints included headache (n=43), but also cerebellar syndrome (n=2) and mental retardation (n=4). AA-amyloidosis was noted in five patients, almost twice as many as expected from previous cohorts. Macrophage activation syndrome occurred in one patient. Between attacks patients were generally well, but 10-20% patients suffered from constitutional symptoms, such as fatigue, between febrile attacks. Patients with p.V377I/p.I268T compound heterozygosity suffered significantly more often from AA-amyloidosis. Patients without a p.V377I mutation suffered more often from severe musculoskeletal involvement. Treatment with NSAIDs could relieve symptoms. Steroids given during attacks, anakinra and etanercept appeared to improve symptoms and could induce complete remission in MKD patients. CONCLUSION: This study described the clinical and genetic characteristics of 114 MKD patients, which is the largest cohort studied so far. The clinical manifestations confirm earlier reports. However, the prevalence of AA-amyloidosis was far higher than expected.

Made available in DSpace on 2019-10-04T11:56:51Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-02-01 International Leagues of Associations for Rheumatology (ILAR) Grant Juvenile idiopathic arthritis (JIA) is the most prevalent chronic rheumatic disease in children and young people (CYP) and a major cause of pain and disability. The vast majority of the world's children and their families live in less resourced countries (LRCs) and face significant socioeconomic and healthcare challenges. Current recommendations for standards of care and treatment for children with JIA do not consider children living in less resourced countries. In order to develop appropriate recommendations for the care of CYP with JIA in less resourced countries a meeting of experienced pediatric rheumatologists from less resourced countries was convened with additional input from a steering group of international pediatric rheumatologists with experience in developing recommendations and standards of care for JIA. Following a needs assessment survey of healthcare workers caring for CYP with JIA in LRC, a literature review was carried out and management recommendations formulated using Delphi technique and a final consensus conference. Responses from the needs assessment were received from 121/483 (25%) practitioners from 25/49 (51%) less resourced countries. From these responses, the initial 84 recommendations were refined and expanded through a series of 3 online Delphi rounds. A final list of 90 recommendations was proposed for evaluation. Evidence for each statement was reviewed, graded, and presented to the consensus group. The degree of consensus, level of agreement, and level of evidence for these recommendations are reported. Recommendations arrived at by consensus for CYP with JIA in less resourced countries cover 5 themes: (1) diagnosis, (2) referral and monitoring, (3) education and training, (4) advocacy and networks, and (5) research. Thirty-five statements were drafted. All but one statement achieved 100% consensus. The body of published evidence was small and the quality of evidence available for critical appraisal was low. Our recommendations offer novel insights and present consensus-based strategies for the management of JIA in less resourced countries. The emphasis on communicable and endemic diseases influencing the diagnosis and treatment of JIA serves as a valuable addition to existing JIA guidelines. With increasing globalization, these recommendations as a whole provide educational and clinical utility for clinicians worldwide. The low evidence base for our recommendations reflects a shortage of research specific to less resourced countries and serves as an impetus for further inquiry towards optimizing care for children with JIA around the world. Univ Cape Town, Dept Pediat & Child Hlth, Red Cross War Mem Childrens Hosp, Room 515,ICH Bldg, ZA-7700 Rondebosch, South Africa Univ British Columbia, BC Childrens Hosp, Dept Pediat, Vancouver, BC, Canada Univ Nairobi, Nairobi, Kenya Univ British Columbia, Dept Pediat, Vancouver, BC, Canada Univ Toronto, Hosp Sick Children, Toronto, ON, Canada Hosp Pediat Garrahan, Buenos Aires, DF, Argentina Muhimbili Univ Hlth & Allied Sci, Sch Med, Dar Es Salaam, Tanzania Univ Zambia, Dept Paediat & Child Hlth, Sch Med, Lusaka, Zambia Univ Witwatersrand, Wits Donald Gordon Med Ctr, Johannesburg, South Africa Univ Sao Paulo, Clin Res Ctr, Ribeirao Preto Med Sch, Sao Paulo, Brazil Sao Paulo State Univ, Div Pediat Rheumatol, Sao Paulo, Brazil Univ Hosp Leuven, Dept Microbiol & Immunol & Pediat Rheumatol, Leuven, Belgium Newcastle Univ, Great North Childrens Hosp, Newcastle, England Jaslok Hosp, Dept Pediat, Mumbai, India Ist Giannina Gaslini, PRINTO, Clin Pediat & Reumatol, Genoa, Italy Sao Paulo State Univ, Div Pediat Rheumatol, Sao Paulo, Brazil

Systemic-onset juvenile idiopathic arthritis is a complex, polygenic autoinflammatory disease affecting young individuals. It is an innate immunity-driven condition characterized by chronic, multiorganic inflammatory involvement. Typical clinical features including young age at presentation, fever, neutrophilic skin lesions, synovitis, serositis, organomegaly, as well as increased risk of amyloidosis are reminiscent of (and may mimic) certain monogenic autoinflammatory disorders. Strikingly high acute phase reactants, thrombocytosis, hyperferritinemia, and elevated serum levels of inflammatory-related proteins such as IL-1, IL-18, S100A8/9, and S100A12 characterize active phases. The disease may follow a relapsing or a continuous course into adulthood, frequently leading to joint damage, disability, and poorer quality of life. Major morbidity and mortality arise from the hypercytokinemic, hyperinflammatory stages called macrophage activation syndrome, a form of reactive hemophagocytic lymphohistiocytosis, which may occur in 50% of patients but become clinically overt only in a smaller proportion. Multidisciplinary teams are best fit to treat this complex disease. Decades after nonbiologic drugs and TNF inhibitors had consistently failed, the advent of biologic agents blocking IL-1 and IL-6 has proven dramatically efficacious for medical management.

Made available in DSpace on 2018-12-11T16:53:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-06-01 Recent therapeutic advances in juvenile idiopathic arthritis (JIA) have made remission an achievable goal for most patients. Reaching this target leads to improved outcomes. The objective was to develop recommendations for treating JIA to target. A Steering Committee formulated a set of recommendations based on evidence derived from a systematic literature review. These were subsequently discussed, amended and voted on by an international Task Force of 30 paediatric rheumatologists in a consensus-based, Delphi-like procedure. Although the literature review did not reveal trials that compared a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated development of recommendations. The group agreed on six overarching principles and eight recommendations. The main treatment target, which should be based on a shared decision with parents/patients, was defined as remission, with the alternative target of low disease activity. The frequency and timeline of follow-up evaluations to ensure achievement and maintenance of the target depend on JIA category and level of disease activity. Additional recommendations emphasise the importance of ensuring adequate growth and development and avoiding long-term systemic glucocorticoid administration to maintain the target. All items were agreed on by more than 80% of the members of the Task Force. A research agenda was formulated. The Task Force developed recommendations for treating JIA to target, being aware that the evidence is not strong and needs to be expanded by future research. These recommendations can inform various stakeholders about strategies to reach optimal outcomes for JIA. Clinica Pediatrica e Reumatologia Università degli Studi di Genova Istituto di Ricovero e Cura a Carattere Scientifico Istituto Giannina Department of Pediatrics Asklepios Klinik Sankt Augustin Department of Pediatric and Adolescents Medicine University Hospital of Cologne Division od Rheumatology University of Toronto Hospital for Sick Children Division of Rheumatology Cincinnati Children's Hospital Medical Center University of Cincinnati Department of Paediatric Immunology Wilhelmina Children's Hospital University Medical Center Utrecht University of Utrecht Rheumatology Unit Department of General Medicine Royal Children's Hospital Murdoch Children's Research Institute Department of Pediatric Rheumatology King Faisal Specialist Hospital and Research Center Alfaisal University Division of Pediatric Rheumatology Hospital Sant Joan de Déu Universitat de Barcelona Department of Allergology Rheumatology and Clinical Immunology University Medical Center Ljubljana Medical Faculty University of Ljubljana Division of Rheumatology Western University Children's Hospital London Health Sciences Centre Institute of Translational Medicine University of Liverpool Alder Hey Children's NHS Foundation Trust Rheumatology Department Hospital General de México Eduardo Liceaga Pediatric Rheumatology Azienda Ospedaliero Universitaria Meyer Division of Rheumatology Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesù Pediatric Rheumatology and Immunology University of Muenster Department of Pediatrics Nippon Medical School Institute of Clinical Medicine Children's Hospital Helsinki University Hospital Paris-Descartes University IMAGINE Institute RAISE 22 National Reference Centre Necker-Enfants Malades Hospital Assistance Publique Hopitaux de Paris Clinica Pediatrica e Reumatologia Istituto di Ricovero e Cura a Carattere Scientifico Istituto Giannina Gaslini Servicio de Inmunología y Reumatología Hospital de Pediatría Garrahan Reumatologia Pediátrica São Paulo State University (UNESP) Department of Rheumatology ISIC Superspeciality Hospital Sir Ganga Ram Hospital Red Cross War Memorial Children's Hospital University of Cape Town Pediatric Rheumatology Seattle Children's Hospital and Research Center University of Washington Pediatric Rheumatology Unit Department of Pediatrics Meir Medical Center Tel Aviv University Sackler School of Medicine Division of Rheumatology Department of Medicine3 Medical University of Vienna Reumatologia Pediátrica São Paulo State University (UNESP)

Background Diagnosis of Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) is currently based on a set of criteria proposed in 1999 modified from Marshall’s criteria. Nevertheless no validated evidence based set of classification criteria for PFAPA has been established so far. The aim of this study was to identify candidate classification criteria PFAPA syndrome using international consensus formation through a Delphi questionnaire survey. Methods A first open-ended questionnaire was sent to adult and pediatric clinicians/researchers, asking to identify the variables thought most likely to be helpful and relevant for the diagnosis of PFAPA. In a second survey, respondents were asked to select, from the list of variables coming from the first survey, the 10 features that they felt were most important, and to rank them in descending order from most important to least important. Results The response rate to the first and second Delphi was respectively 109/124 (88%) and 141/162 (87%). The number of participants that completed the first and second Delphi was 69/124 (56%) and 110/162 (68%). From the first Delphi we obtained a list of 92 variables, of which 62 were selected in the second Delphi. Variables reaching the top five position of the rank were regular periodicity, aphthous stomatitis, response to corticosteroids, cervical adenitis, and well-being between flares. Conclusion Our process led to identification of features that were felt to be the most important as candidate classification criteria for PFAPA by a large sample of international rheumatologists. The performance of these items will be tested further in the next phase of the study, through analysis of real patient data. Electronic supplementary material The online version of this article (10.1186/s12969-018-0246-9) contains supplementary material, which is available to authorized users.

Background: Paediatric musculoskeletal matters (PMM-www.pmmonline.org) is a free, evidence-based and peer reviewed open e-resource for paediatric musculoskeletal (MSK) medicine targeting non-MSK specialists. Since launch (Nov-2014) PMM has reached 190 countries with >78,000 users, >244,500 hits. Users who have declared their training background on the website are mainly non-MSK specialists. Feedback from users has requested further content to reflect international healthcare systems. PMM India was developed in collaboration with the Indian Academy of Paediatrics (IAP; Sept-2015, >3,700 users, 16,000 hits to date) and showcases successful partnership with local clinicians in developing PMM with local context. Further ‘internationalisation’ is now ongoing with additional global partners to develop PMM International. Here, we describe the process for international development. Methods: Paediatric rheumatologists in 11 countries around the world were approached to peer-review and identify additional PMM content to reflect paediatric MSK medicine in their health care systems (e.g., case mix, clinical presentations, care pathways), with a focus on knowledge relevant for non-MSK specialists. New content was developed by local teams identified by the paediatric rheumatologist(s) who then collated and provided expert overview before submission for editorial review. All contributions were provided in English. Additional cases and images were included with appropriate consent. Results: PMM International additions to the original website brings new content predominately focused on infections/infection-related disease with MSK features or as differential diagnoses for rheumatic disease. Most content is in English with requests for translation of some content (e.g., pGALS which is available in 11 languages to date). PMM International will be further peer reviewed with open access to all. A PMM app is planned to facilitate access where internet capacity is limited. Conclusion: Rapid globalisation necessitates appropriate e-resources with content that reflect international health care contexts. PMM International targets non-MSK specialist audiences to raise awareness and early recognition of MSK pathology. Our work reflects strong collaborative global partnerships within the paediatric rheumatology community. PMM has been endorsed by the Paediatric Rheumatology European Association (PReS) as an educational resource. Implementation of PMM International has yet to be formally evaluated (i.e., change in knowledge, practice), but data thus far supports wide reach and positive uptake from the target audience user groups.

Objective: To investigate the prevalence and associations with clinical manifestations of anti- P ribosomal antibodies in patients with juvenile-onset and adult-onset systemic lupus erythematosus (SLE). Methods: Clinical and serological data of 30 patients with juvenile-onset SLE (age at onset younger than 16 years old) were compared with data of 92 patients with adult-onset SLE. Symptoms occurring during the entire disease course were considered. Anti- P ribosomal antibodies were tested by ELISA.

Objective To investigate the prevalence and associations with clinical manifestations of anti-P ribosomal antibodies in patients with juvenile-onset and adult-onset systemic lupus erythematosus (SLE). Methods Clinical and serological data of 30 patients with juvenile-onset SLE (age at onset younger than 16 years) were compared with data of 92 patients with adult-onset SLE. Symptoms occurring during the entire disease course were considered. Anti-P ribosomal antibodies were tested by ELISA. Results Anti-P ribosomal antibodies were found significantly more often in pediatric-onset SLE patients (26.7% vs 6.5%; OR=5.21 [95% CI=1.6–16.5], P =.003). Alopecia (OR=10.11, 95% CI=1.25–97) and skin rash (non-discoid) (OR=4.1, 95% CI=1.25–13.89) were significantly associated with anti-P ribosomal antibodies. Conclusion Anti-ribosomal P antibodies are more often found in patients with juvenile SLE. Alopecia and skin rash were the only clinical manifestations associated to anti-ribosomal P antibodies.

OBJECTIVE: To determine whether systemic juvenile idiopathic arthritis (JIA) susceptibility loci that were identified by candidate gene studies demonstrate association with systemic JIA in the largest study population assembled to date. METHODS: Single-nucleotide polymorphisms (SNPs) from 11 previously reported systemic JIA risk loci were examined for association in 9 populations, including 770 patients with systemic JIA and 6,947 controls. The effect of systemic JIA-associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from the lymphoblastoid cell lines (LCLs) of 373 European subjects from the 1000 Genomes Project. Responses of systemic JIA-associated SNPs to anakinra treatment were evaluated in 38 US patients for whom treatment response data were available. RESULTS: We found no association between the previously reported 26 SNPs and systemic JIA. Expanded analysis of the regions containing the 26 SNPs revealed only 1 significant association: the promoter region of IL1RN (P < 1 × 10(-4) ). Systemic JIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between systemic JIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 [95% confidence interval 3.2-255.8]). CONCLUSION: In our study, IL1RN was the only candidate locus associated with systemic JIA. The implicated SNPs are among the strongest known determinants of IL1RN and interleukin-1 receptor antagonist levels, linking low expression with increased systemic JIA risk. Homozygous high expression alleles predicted nonresponsiveness to anakinra therapy, making them ideal candidate biomarkers to guide systemic JIA treatment. This study is an important first step toward the personalized treatment of systemic JIA.

IntroductionAutoinflammatory diseases can cause irreversible tissue damage due to systemic inflammation. Recently, the Autoinflammatory Disease Damage Index (ADDI) was developed. The ADDI is the first instrument to quantify damage in familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency and tumour necrosis factor receptor-associated periodic syndrome. The aim of this study was to validate this tool for its intended use in a clinical/research setting.MethodsThe ADDI was scored on paper clinical cases by at least three physicians per case, independently of each other. Face and content validity were assessed by requesting comments on the ADDI. Reliability was tested by calculating the intraclass correlation coefficient (ICC) using an ‘observer-nested-within-subject’ design. Construct validity was determined by correlating the ADDI score to the Physician Global Assessment (PGA) of damage and disease activity. Redundancy of individual items was determined with Cronbach’s alpha.ResultsThe ADDI was validated on a total of 110 paper clinical cases by 37 experts in autoinflammatory diseases. This yielded an ICC of 0.84 (95% CI 0.78 to 0.89). The ADDI score correlated strongly with PGA-damage (r=0.92, 95% CI 0.88 to 0.95) and was not strongly influenced by disease activity (r=0.395, 95% CI 0.21 to 0.55). After comments from disease experts, some item definitions were refined. The interitem correlation in all different categories was lower than 0.7, indicating that there was no redundancy between individual damage items.ConclusionThe ADDI is a reliable and valid instrument to quantify damage in individual patients and can be used to compare disease outcomes in clinical studies.

Objective To describe the clinical, laboratory, and histopathologic features, current treatment, and outcome of patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA). Methods In this multinational, multicenter study, pediatric rheumatologists and hemato-oncologists entered patient data collected retrospectively into a web-based database. Results A total of 362 patients, 22% of whom had MAS at the onset of systemic JIA, were included in the study by 95 investigators from 33 countries. The most frequent clinical manifestations were fever (96%), hepatomegaly (70%), and splenomegaly (58%). Central nervous system dysfunction and hemorrhages were recorded in 35% and 20% of the patients, respectively. Platelet count and liver transaminase, ferritin, lactate dehydrogenase, triglyceride, and d-dimer levels were the sole laboratory biomarkers showing a percentage change of >50% between the pre-MAS visit and MAS onset. Evidence of macrophage hemophagocytosis was found in 60% of the patients who underwent bone marrow aspiration. MAS occurred most frequently in the setting of active underlying disease, in the absence of a specific trigger. Nearly all patients were given corticosteroids, and 61% received cyclosporine. Biologic medications and etoposide were given to 15% and 12% of the patients, respectively. Approximately one-third of the patients required admission to the intensive care unit (ICU), and the mortality rate was 8%. Conclusion This study provides information on the clinical spectrum and current management of systemic JIA–associated MAS through the analysis of a very large patient sample. MAS remains a serious condition, as a sizeable proportion of patients required admission to the ICU or died.

Objective The myeloid-related proteins 8 and 14 (MRP-8/MRP-14) and neutrophil-derived S100A12 are biomarkers of inflammation. They can be used to determine the relapse risk in patients with juvenile idiopathic arthritis (JIA) after stopping antiinflammatory treatment. In this study, we tested the performance of different enzyme-linked immunosorbent assays (ELISAs) in order to validate systems available for routine use. Methods MRP-8/MRP-14 and S100A12 serum concentrations of 188 JIA patients in remission were analyzed. Commercially available test systems were compared to experimental ELISAs established in house. The ability of the assays to identify JIA patients at risk for relapse was analyzed. Results For MRP-8/MRP-14, the PhiCal Calprotectin and Buhlmann MRP8/14 Calprotectin ELISAs revealed hazard ratios of 2.3 and 2.1, respectively. For S100A12, the CircuLex S100A12/EN-RAGE ELISA revealed a hazard ratio of 3.1. The commercial assays allowed a JIA relapse prediction that was at least comparable to the experimental ELISAs. Conclusion For the prediction of JIA relapse after stopping medication, the biomarkers MRP-8/MRP-14 and S100A12 can be determined by using assays that are available for routine use. The tested commercial MRP-8/MRP-14 and S100A12 ELISAs showed a performance comparable to well-established experimental ELISA protocols when assay-specific cutoffs for the indication of relapse prediction are thoroughly applied.

BackgroundDifferent diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)—familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)—and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA.MethodsStep 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients’ diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria.ResultsThe panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94–1 and specificity of 0.95–1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98).ConclusionEurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.

OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. RESULTS: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from 99% for a score of =123. A cutoff value of =60 revealed the best performance in discriminating pHLH from MAS. CONCLUSION: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.

ObjectivesAutoinflammatory diseases cause systemic inflammation that can result in damage to multiple organs. A validated instrument is essential to quantify damage in individual patients and to compare disease outcomes in clinical studies. Currently, there is no such tool. Our objective was to develop a common autoinflammatory disease damage index (ADDI) for familial Mediterranean fever, cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic fever syndrome and mevalonate kinase deficiency.MethodsWe developed the ADDI by consensus building. The top 40 enrollers of patients in the Eurofever Registry and 9 experts from the Americas participated in multiple rounds of online surveys to select items and definitions. Further, 22 (parents of) patients rated damage items and suggested new items. A consensus meeting was held to refine the items and definitions, which were then formally weighted in a scoring system derived using decision-making software, known as 1000minds.ResultsMore than 80% of the experts and patients completed the online surveys. The preliminary ADDI contains 18 items, categorised in the following eight organ systems: reproductive, renal/amyloidosis, developmental, serosal, neurological, ears, ocular and musculoskeletal damage. The categories renal/amyloidosis and neurological damage were assigned the highest number of points, serosal damage the lowest number of points. The involvement of (parents of) patients resulted in the inclusion of, for example, chronic musculoskeletal pain.ConclusionsAn instrument to measure damage caused by autoinflammatory diseases is developed based on consensus building. Patients fulfilled a significant role in this process.

BackgroundIn 2012, a European initiative calledSingleHub andAccess point for pediatricRheumatology inEurope (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile dermatomyositis (JDM) is a rare disease within the group ofpaediatric rheumatic diseases(PRDs) and can lead to significant morbidity. Evidence-based guidelines are sparse and management is mostly based on physicians' experience. Consequently, treatment regimens differ throughout Europe.ObjectivesTo provide recommendations for diagnosis and treatment of JDM.MethodsRecommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was constituted, consisting of 19 experienced paediatric rheumatologists and 2 experts in paediatric exercise physiology and physical therapy, mainly from Europe. Recommendations derived from a validated systematic literature review were evaluated by an online survey and subsequently discussed at two consensus meetings using nominal group technique. Recommendations were accepted if >80% agreement was reached.ResultsIn total, 7 overarching principles, 33 recommendations on diagnosis and 19 recommendations on therapy were accepted with >80% agreement among experts. Topics covered include assessment of skin, muscle and major organ involvement and suggested treatment pathways.ConclusionsThe SHARE initiative aims to identify best practices for treatment of patients suffering from PRD. Within this remit, recommendations for the diagnosis and treatment of JDM have been formulated by an evidence-informed consensus process to produce a standard of care for patients with JDM throughout Europe.

Objective.Systemic juvenile idiopathic arthritis (SJIA) frequently leads to disability and damage. Predictive factors for a poor outcome include persistent systemic features and younger age at onset. We describe and analyze disease features in patients with early-onset (EO) SJIA (disease onset before age 18 mo) and compare them to patients with later-onset (LO) disease.Methods.Clinical features at onset, activity measures (occurrence of macrophage activation syndrome, remission), and outcome measures for disability [Childhood Health Assessment Questionnaire (CHAQ) ≥ 0.5] and damage [radiographic joint destruction, Juvenile Arthritis Damage Index (JADI) score, growth retardation] observed during followup were analyzed retrospectively in patients with SJIA followed for ≥ 3 years since disease onset.Results.In total 132 patients were included. SJIA started at age ≤ 18 months in 19 (14%) patients and at a later age in 113 (86%) children. At onset, serositis (p < 0.01) and hepatomegaly (p < 0.05) were more frequent in EO patients, who also exhibited lower hemoglobin levels (p < 0.03) and higher platelet counts (p < 0.03) than patients with LO. Macrophage activation syndrome occurred in 20 patients (11 EO and 9 LO; p < 0.0001). Remission was achieved by 49 patients (37%; 4 EO and 45 LO). At last visit, destructive hip disease (p < 0.04), growth retardation (p < 0.01), radiographic damage (p < 0.02), and disability (p < 0.04) were more frequent in patients with EO disease, who had higher JADI scores (p < 0.003).Conclusion.Patients with EO exhibited a more aggressive and destructive disease course than patients with LO SJIA.

Takayasu's arteritis is a chronic inflammatory disease that primarily affects the large vessels, such as the aorta and its branches. It represents the third most frequent vasculitis during pediatric age. Our objective was to describe clinical and complementary exams features as well as treatment modalities of a case series of pediatric patients. We present 11 patients (10 girls) with median age at onset of 8 years (range: 2-15). The median diagnosis delay was 16 months (range: 2-96). Clinical presentations were lower limb claudication, arterial hypertension, CNS involvement, presence of murmurs, systemic symptoms, lymphadenopathy, chest pain, abdominal pain and arthritis. Laboratory tests showed: elevated ESR, anemia and trombocytosis. Vascular imaging studies exhibited stenosis, dilatation, occlussion and aneurysms. The outcome of the disease was persistent active condition (1 patient), relapse (4 patients), remission (3 patients), motor sequelae (1 patient) and death (2 patients). All patients were treated with steroids and immunosuppressants. Takayasu 's arteritis is a condition that can potentially be life-threatening. The diagnosis should be suspected in a variety of clinical manifestations during childhood.

The standardization of the criteria to evaluate improvement in rheumatic diseases has been a goal of numerous research groups. This work led to establishment of definition of response in rheumatoid arthritis (1), juvenile arthritis (2–4), systemic lupus erythematosus (SLE) both in adults (5–7) and children (8–10). The International Myositis Outcome Assessment and Clinical Studies (IMACS) group proposed a core set of outcome variables for inclusion in clinical trials in adult and juvenile inflammatory myopathies and defined the degree of change in each core set variables that is clinically meaningful, as well as guidelines for performing clinical trials (11–14). However, until now these proposals have not yet been formally validated in the context of external prospective pediatric studies or clinical trials. Although children/adolescents and adults with DM share many signs and symptoms of disease, they differ in the clinical features and outcome (15–17), and treatment approaches should consider the peculiarities of juvenile patients as well as their longer life expectancy. Therefore, all outcome measures developed for adults need to be subjected to a critical evidence-based evaluation of their measurement properties in children and adolescents. To help standardize the conduct and reporting of juvenile dermatomyositis (JDM) clinical trials and enhance identification of new therapeutic agents, the Pediatric Rheumatology International Trials Organization (PRINTO) (18), in collaboration with the Pediatric Rheumatology Collaborative Study Group (PRCSG) and with the support of the European Union and the U.S. National Institutes of Health, undertook in year 2000 a multinational effort to develop, and promulgate a core set of outcome variables and a definition of clinical improvement to evaluate response to therapy in patients with JDM and in juvenile SLE. The first two phases of the project, previously published (8;19), led to the development of a prospectively evidence-based validated core set of six variables for the evaluation of response to therapy that is now known as the provisional PRINTO/American College of Rheumatology/European League Against Rheumatism Disease Activity Core Set for the evaluation of response to therapy in JDM (PRINTO/ACR/EULAR JDM core set) (Table 1). Table 1 Final domains and suggested variables included in the final PRINTO/ACR EULAR core set for the evaluation of response to therapy in JDM (adapted from ref. (19)). In this paper we report the results of the third phase of the project, which was aimed at developing a provisional validated definition of improvement to aid in the classification of individual patients in future therapeutic trials and in current clinical practice as either improved or not improved.

To analyse the effectiveness and safety of adalimumab in a group of patients with juvenile idiopathic arthritis (JIA) who had failed treatment with etanercept and/or infliximab in a single paediatric rheumatology clinic. Patients with JIA with active polyarthritis refractory to metotrexate (MTX) (or =20 mg/m2/week) for at least 3 months and to etanercept (up to 1 mg/kg twice weekly) and/or infliximab (up to 10 mg/kg every 4 weeks) for at least 6 months were included. All patients received adalimumab 24 mg/m2/week concomitantly with MTX 7.5-10 mg/week. Evaluation of efficacy included improvement as defined by the ACR paediatric 30 criteria, 50% and 70% improvement and remission. Six patients were included. Three patients met improvement criteria; 50% and 70% improvement occurred in two children. Improvement was sustained for 12, 24 and 36 months, respectively. Remission occurred in one patient. Adalimumab was discontinued due to lack of efficacy in three patients. No side effects were observed. Adalimumab appears to be effective and safe in patients with JIA refractory to other anti-TNF agents. Further controlled studies are needed in order to assess efficacy of adalimumab in children with refractory JIA.

UNLABELLED CINCA/IOMID is a systemic inflammatory disorder of unknown aetiology that resembles congenital infection and systemic juvenile chronic arthritis (JCA). This disorder is characterized by neonatal onset, persistent rash, ocular inflammatory lesions, and progressive articular and neurological involvement. We report two new patients with this syndrome. Both children presented periodic bouts of cutaneous rash, fever, organomegaly, articular involvement with typical radiological features, and developmental delay. One of the patients presented neonatal jaundice and elevation of liver enzymes; inflammatory infiltrates were observed in the liver biopsy. The other patient showed retinal vasculitis detected at age 18 mo on fundoscopy and fluorescent angiography. Therapy with azathioprine was associated with prolonged remission of this complication. In both cases, the disease was diagnosed after some delay. CONCLUSION Early hepatitis and retinal vasculitis are rare features of CINCA/IOMID that may help differentiate this syndrome from JRA. Azathioprine may have induced the remission of vasculitis in one case.

Aim: To describe two children with hypertrophic osteoarthropathy associated with cholestatic hepatic disease. Both patients suffered from chronic progressive cholestatic liver disease and developed digital clubbing, polyarthritis and periosteal reaction. In one of them, clinical and radiological features normalized after liver transplant. Conclusion: Hepatic hypertrophic osteoarthropathy is a rare disabling condition that responds poorly to conservative management, while liver transplantation appears to be the only effective therapeutic intervention.

BACKGROUND: Most data for treatment of dermatomyositis and juvenile dermatomyositis are from anecdotal, non-randomised case series. We aimed to compare, in a randomised trial, the efficacy and safety of prednisone alone with that of prednisone plus either methotrexate or ciclosporin in children with new-onset juvenile dermatomyositis.METHODS: We did a randomised trial at 54 centres in 22 countries. We enrolled patients aged 18 years or younger with new-onset juvenile dermatomyositis who had received no previous treatment and did not have cutaneous or gastrointestinal ulceration. We randomly allocated 139 patients via a computer-based system to prednisone alone or in combination with either ciclosporin or methotrexate. We did not mask patients or investigators to treatment assignments. Our primary outcomes were the proportion of patients achieving a juvenile dermatomyositis PRINTO 20 level of improvement (20% improvement in three of six core set variables at 6 months), time to clinical remission, and time to treatment failure. We compared the three treatment groups with the Kruskal-Wallis test and Friedman's test, and we analysed survival with Kaplan-Meier curves and the log-rank test. Analysis was by intention to treat. Here, we present results after at least 2 years of treatment (induction and maintenance phases). This trial is registered with ClinicalTrials.gov, number NCT00323960.FINDINGS: Between May 31, 2006, and Nov 12, 2010, 47 patients were randomly assigned prednisone alone, 46 were allocated prednisone plus ciclosporin, and 46 were randomised prednisone plus methotrexate. Median duration of follow-up was 35·5 months. At month 6, 24 (51%) of 47 patients assigned prednisone, 32 (70%) of 46 allocated prednisone plus ciclosporin, and 33 (72%) of 46 administered prednisone plus methotrexate achieved a juvenile dermatomyositis PRINTO 20 improvement (p=0·0228). Median time to clinical remission was 41·9 months in patients assigned prednisone plus methotrexate but was not observable in the other two treatment groups (2·45 fold [95% CI 1·2-5·0] increase with prednisone plus methotrexate; p=0·012). Median time to treatment failure was 16·7 months in patients allocated prednisone, 53·3 months in those assigned prednisone plus ciclosporin, but was not observable in patients randomised to prednisone plus methotrexate (1·95 fold [95% CI 1·20-3·15] increase with prednisone; p=0·009). Median time to prednisone discontinuation was 35·8 months with prednisone alone compared with 29·4-29·7 months in the combination groups (p=0·002). A significantly greater proportion of patients assigned prednisone plus ciclosporin had adverse events, affecting the skin and subcutaneous tissues, gastrointestinal system, and general disorders. Infections and infestations were significantly increased in patients assigned prednisone plus ciclosporin and prednisone plus methotrexate. No patients died during the study.INTERPRETATION: Combined treatment with prednisone and either ciclosporin or methotrexate was more effective than prednisone alone. The safety profile and steroid-sparing effect favoured the combination of prednisone plus methotrexate.FUNDING: Italian Agency of Drug Evaluation, Istituto Giannina Gaslini (Genoa, Italy), Myositis Association (USA).

Autoinflammatory diseases are characterised by fever and systemic inflammation, with potentially serious complications. Owing to the rarity of these diseases, evidence-based guidelines are lacking. In 2012, the European project Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate regimens for the management of children and young adults with rheumatic diseases, facilitating the clinical practice of paediatricians and (paediatric) rheumatologists. One of the aims of SHARE was to provide evidence-based recommendations for the management of the autoinflammatory diseases cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). These recommendations were developed using the European League Against Rheumatism standard operating procedure. An expert committee of paediatric and adult rheumatologists was convened. Recommendations derived from the systematic literature review were evaluated by an online survey and subsequently discussed at a consensus meeting using Nominal Group Technique. Recommendations were accepted if more than 80% agreement was reached. In total, four overarching principles, 20 recommendations on therapy and 14 recommendations on monitoring were accepted with >= 80% agreement among the experts. Topics included (but were not limited to) validated disease activity scores, therapy and items to assess in monitoring of a patient. By developing these recommendations, we aim to optimise the management of patients with CAPS, TRAPS and MKD.

Objective. To report baseline articular, functional and ocular findings of the first international prospective cohort study of Blau syndrome (BS). Methods. Three-year, multicentre, observational study on articular, functional (HAQ, Childhood HAQ and VAS global and pain), ophthalmological, therapeutic and radiological data in BS patients. Results. Baseline data on the first 31 recruited patients (12 females and 19 males) from 18 centres in 11 countries are presented. Of the 31 patients, 11 carried the p.R334W NOD2 mutation, 9 the p.R334Q and 11 various other NOD2 missense mutations; 20 patients were sporadic and 11 from five BS pedigrees. Median disease duration was 12.8 years (1.1-57). Arthritis, documented in all but one patient, was oligoarticular in 7, polyarticular in 23. The median active joint count was 21. Functional capacity was normal in 41%, mildly impaired in 31% and moderate-severe in 28% of patients. The most frequently involved joints at presentation were wrists, ankles, knees and PIPs. On radiographs, a symmetrical non-erosive arthropathy was shown. Previously unknown dysplastic bony changes were found in two-thirds of patients. Ocular disease was documented in 25 of 31 patients, with vitreous inflammation in 64% and moderate-severe visual loss in 33%. Expanded manifestations (visceral, vascular) beyond the classic clinical triad were seen in 52%. Conclusion. BS is associated with severe ocular and articular morbidity. Visceral involvement is common and may be life-threatening. Bone dysplastic changes may show diagnostic value and suggest a previously unknown role of NOD2 in bone morphogenesis. BS is resistant to current drugs, suggesting the need for novel targeted therapies.

OBJECTIVE: Juvenile localized scleroderma is usually considered a disease that is confined to the skin and subcutaneous tissue. We studied the prevalence and clinical features of extracutaneous manifestations in a large cohort of children with juvenile localized scleroderma. METHODS: Data from a multinational study on juvenile scleroderma was used for this in-depth study. Clinical features of patients with extracutaneous manifestations were compared with those of patients who had exclusively skin involvement. RESULTS: Seven hundred fifty patients entered the study. One hundred sixty-eight patients (22.4%) presented with a total of 193 extracutaneous manifestations, as follows: articular (47.2%), neurologic (17.1%), vascular (9.3%), ocular (8.3%), gastrointestinal (6.2%), respiratory (2.6%), cardiac (1%), and renal (1%). Other autoimmune conditions were present in 7.3% of patients. Neurologic involvement consisted of epilepsy, central nervous system vasculitis, peripheral neuropathy, vascular malformations, headache, and neuroimaging abnormalities. Ocular manifestations were episcleritis, uveitis, xerophthalmia, glaucoma, and papilledema. In more than one-fourth of these children, articular, neurologic, and ocular involvements were unrelated to the site of skin lesions. Raynaud's phenomenon was reported in 16 patients. Respiratory involvement consisted essentially of restrictive lung disease. Gastrointestinal involvement was reported in 12 patients and consisted exclusively of gastroesophageal reflux. Thirty patients (4%) had multiple extracutaneous features, but systemic sclerosis (SSc) developed in only 1 patient. In patients with extracutaneous involvement, the prevalence of antinuclear antibodies and rheumatoid factor was significantly higher than that among patients with only skin involvement. However, Scl-70 and anticentromere, markers of SSc, were not significantly increased. CONCLUSION: Extracutaneous manifestations of juvenile localized scleroderma developed in almost one-fourth of the children in this study. These extracutaneous manifestations often were unrelated to the site of the skin lesions and sometimes were associated with multiple organ involvement. The risk of developing SSc was very low. This subgroup of patients with juvenile localized scleroderma should be evaluated extensively, treated more aggressively, and monitored carefully.

Juvenile idiopathic arthritis (JIA) is the most common chronic condition in pediatric rheumatology. Corticosteroids have been used for the treatment of JIA since the 1950s. Although biologic agents have revolutionized the management of JIA in the past 15 years, corticosteroids still have a significant place in the pharmacological treatment of the disease. Each JIA category (systemic, rheumatoid factor–negative and –positive polyarthritis, oligoarthritis, psoriatic arthritis, enthesitis-related arthritis, and undifferentiated arthritis) exhibits a distinctive response to corticosteroid treatment. Methylprednisolone and prednisone are the most commonly used systemically active agents in JIA. The most frequent indications are anemia, serositis, pneumonitis, and the macrophage activation syndrome, which are usually encountered in patients with systemic arthritis. Pulsed, intravenous higher-dose corticosteroid (methylprednisolone) is often required to control these severe manifestations of JIA. Systemic corticosteroids are also used as a bridging therapy until disease-modifying drugs become effective in certain patients. The evidence supporting the efficacy and safety of systemic steroids in JIA is scarce and limited to uncontrolled, open trials. Corticosteroids are also frequently used as intra-articular therapy in oligoarthritis (and psoriatic, polyarticular, enthesitis-related, and undifferentiated arthritis). The drug of choice for intra-articular therapy is triamcinolone hexacetonide, which has shown high effectiveness in oligoarthritis. JIA-related refractory uveitis is another indication for the use of topical and systemic corticosteroids. The advent of new, biological therapies has restricted the use of systemic corticosteroids to particular situations and allowed for the earlier tapering of dosing in JIA.

Objective Neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) is characterized by fever, chronic meningitis, uveitis, sensorineural hearing loss, urticarial skin rash, and a characteristic deforming arthropathy. We investigated whether patients with this disorder have mutations in CIAS1, the gene which causes Muckle-Wells syndrome and familial cold autoinflammatory syndrome, two dominantly inherited disorders with some similarities to NOMID/CINCA syndrome. Methods Genomic DNA from 13 patients with classic manifestations of NOMID/CINCA syndrome and their available parents was screened for CIAS1 mutations by automated DNA sequencing. Cytokine messenger RNA (mRNA) levels were assessed by real-time polymerase chain reaction on peripheral blood leukocyte mRNA, and serum cytokine levels were assayed by enzyme-linked immunosorbent assay. Protein expression was assessed by Western blotting of lysates from plastic-adherent peripheral blood mononuclear cells. Results In 6 of the 13 patients, we found 6 heterozygous missense substitutions in CIAS1. Five of the 6 mutations are novel. None of these sequence changes was observed in a panel of >900 chromosomes from healthy controls. Two distinct nucleotide changes in a single codon in unrelated patients resulted in the same amino acid change. In 4 mutation-positive children whose parental DNA was available, no mutation was found in the parental DNA, supporting the conclusion that the mutations arose de novo. Consistent with the recently discovered role of CIAS1 in the regulation of interleukin-1 (IL-1), we found evidence of increased IL-1β, as well as tumor necrosis factor, IL-3, IL-5, and IL-6, but not transforming growth factor β, in a mutation-positive patient compared with normal controls. Conclusion Our data increase the total number of known germline mutations in CIAS1 to 20, causing a spectrum of diseases ranging from familial cold autoinflammatory syndrome to Muckle-Wells syndrome to NOMID/CINCA syndrome. Mutations in CIAS1 were only found in ∼50% of the cases identified clinically as NOMID/CINCA syndrome, which raises the possibility of genetic heterogeneity. IL-1 regulation by CIAS1 suggests that IL-1 receptor blockade may constitute a rational approach to the treatment of NOMID/CINCA syndrome.

The juvenile spondyloarthropathies (JSpA) are a group of related seronegative rheumatic diseases characterized by involvement of the axial joints, peripheral large joints and entheses. JSpA and adult SpA are probably parts of the same disease continuum. JSpA are represented by enthesitis related arthritis (ERA). juvenile psoriatic arthritis (JPsA) and probably undifferentiated arthritis (UA) in the ILAR criteria. Sets of classification criteria have been developed in adult patients with SpA. The ASAS classification criteria for axial and peripheral SpA have not been validated in pediatric populations.

Juvenile Localized Scleroderma (JLS) and Juvenile Systemic Sclerosis (JSSc) form a group of rare pediatric diseases that can lead to significant morbidity. Evidence-based guidelines are sparse and management is mostly based on physician’s experience. Consequently, treatment regimens differ throughout Europe. In 2012, a European initiative called SHARE (Single Hub and Access point for pediatric Rheumatology in Europe) was launched to optimize and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases.

During the past 15 years, a growing number of monogenic inflammatory diseases have been described and their respective responsible genes identified. The proteins encoded by these genes are involved in the regulatory pathways of inflammation and are mostly expressed in cells of the innate immune system. Diagnosis remains clinical, with genetic confirmation where feasible. Although a group of patients exhibit episodic systemic inflammation (periodic fevers), these disorders are mediated by continuous overproduction and release of pro-inflammatory mediators, such as IL-1 and IL-6, and TNF and are best considered as autoinflammatory diseases rather than periodic fevers. Treatment with biologic agents that block these cytokines, particularly IL-1, has proved to be dramatically effective in some patients. Still, in many cases of autoinflammation no genetic abnormalities are detected and treatment remains suboptimal, raising the question of novel pathogenic mutations in unexplored genes and pathways.

This report describes 3 cases of juvenile dermatomyositis (juvenile DM) complicated by cholestasis. All 3 patients had typical features of juvenile DM, and all developed a cholestatic syndrome within the initial months of their disease. Liver biopsy revealed mixed (cytoplasmic and ductal) cholestasis with no abnormalities in the intrahepatic ducts in all 3 cases. Cholestasis improved or was completely reversible upon treatment with prednisone. In the 2 patients who could be followed up long term, no sequelae remained. The possible role of inflammation in the pathogenesis of cholestasis in juvenile DM is discussed.

Background: Most of the available documentation in the literature on ocular involvement in localised scleroderma (LS) are descriptions of single cases in adult patients. This article reports the frequency and specific features of ocular involvement in a large cohort of children with juvenile LS (JLS). Methods: Data from a large, multi-centre, multinational study of children with LS were used to collect and analyse specific information on ocular involvement. Results: 24 out of 750 patients (3.2%) revealed a significant ocular involvement. 16 were female and 8 male. 16 patients (66.7%) had scleroderma “en coup de sabre” (ECDS) of the face, 5 (20.8%) had the linear subtype, 2 (8.3%) had generalised morphea (GM) and one (4.2%) had plaque morphea (PM). Of the 24 patients with eye involvement, 10 patients (41.7%) reported adnexa (eyelids and eyelashes) abnormalities, 7 (29.2%) anterior segment inflammation (5 anterior uveitis, 2 episcleritis) and 3 central nervous system-related abnormalities. 4 patients presented single findings such as paralytic strabismus (1), pseudopapilloedema (1) and refractive errors (2). Other extracutaneous manifestations were detected in a significantly higher number of patients with ocular involvement and were mostly neurological. Conclusion: Ocular abnormalities are not unusual in patients with JLS, especially in the ECDS subtype. They are frequently associated with other internal organ involvement, particularly the central nervous system (CNS). Careful ophthalmic monitoring is recommended for every patient with JLS, but is mandatory in those with skin lesions on the face and/or concomitant CNS involvement.

Objectives. To translate into Argentine Spanish and cross-culturally adapt the Childhood Health Assessment Questionnaire (CHAQ) and validate the adapted instrument in Argentine patients with juvenile rheumatoid arthritis (JRA). Methods. Five bilingual Argentine pediatric rheumatologists translated into Argentine Spanish and cross-culturally adapted the United States English CHAQ. Pretesting was done in a sample of 23 parents using a probe question technique. Parents of 70 patients with JRA and 21 healthy children (controls) participated in the validation phase. All were from Argentina. Results. The mean disability index (DI) scores for patients with systemic, polyarticular, or pauciarticular onset JRA were 0.64, 0.32, and 0.1, respectively. Healthy controls averaged 0.2. Intercomponent correlations were between 0.4 and 0.9, suggesting internal consistency, but also some redundancy. Test-retest reliability, studied at a 1-week interval, was moderate (mean DI 0.44 [in clinic] and 0.29 [one week later], Pearson's correlation = 0.82). We compared CHAQ scores from 15 parents with those of their children >10 years of age. Significantly higher DI scores were given by patients than their respective parents (P > 0.019), but the pairwise scores (parent–patient) were highly correlated (r = 0.986). Conclusions. Cross-cultural adaptation of the US CHAQ to Argentina required few changes. Although DI scores for all patient subgroups were higher than for controls subjects, the scores were low, particularly for those with pauciarticular disease. Prospective studies designed to examine the sensitivity to change and predictive validity will help to assess further the usefulness of the adapted CHAQ in the Argentine population.

Objective. The aim of this study was to determine the short- and long-term efficacy and safety of 8-weekly canakinumab therapy in children with cryopyrin-associated periodic syndromes (CAPS) in routine clinical practice. Methods. A single-centre observational study was performed. Patients were assessed every 8 weeks at a dedicated clinic. Standardized assessments were the 10-domains DAS for CAPS, acute phase reactants (APRs), physician’s global assessment of disease activity, Child Health Assessment Questionnaire (CHAQ) and Child Health Questionnaire Parent Form 28 (CHQPF-28). The primary endpoint was clinical improvement, defined as a reduction of DAS score 8 weeks after commencing therapy. Secondary endpoints included sustained clinical improvement in APRs, relapses, CHAQ score and CHQPF-28 score. Results. Ten children with CAPS [eight Muckle-Wells syndrome (MWS), two chronic infantile cutaneous neurological articular (CINCA); median age 6.3 years] received 8-weekly canakinumab treatments at 28.7 mg/kg for a median of 21 months (range 1231 months). Nine of 10 patients improved after the first dose: baseline median DAS of 7.5/20 decreased to 3.5/20 at 8 weeks (P = 0.04). This clinical improvement was sustained at a median follow-up of 21 months (range 1231 months). Children with CINCA required higher doses of canakinumab than those with MWS. CHAQ and CHQ scores indicated improvement in functioning and health-related quality of life (HRQoL). Treatment was well tolerated, with no injection site reactions and no serious infections. Conclusion. Canakinumab, although costly, is a safe and effective treatment for CAPS in children, leading to sustained improvement in disease activity, serological markers, functional ability and HRQoL.

Educational strategies and contents developed in the First World are not always adapted to the needs and challenges of developing countries. Cooperation and collaboration between developing countries can be mutually beneficial and create the basis for a longstanding, Third World-centered educational program aimed at increasing the pediatric support for Pediatric Rheumatology (PR).

The conduct of Clinical Research in rare diseases, such as Juvenile Systemic Sclerosis (jssc) and Juvenile Localized Scleroderma (JLS), requires an adequate number of patients and a fruitful collaboration between international centers. The clinical management of young patients suffering from these diseases is also often difficult to achieve in an effective and shared matter.

Methods Retrospective analysis of clinical data. Early-onset (EO) was defined as the start of SJIA prior to age 18 months. Variables included: demographic and clinical features at onset and outcome variables during disease course (pattern of course, presence of clinical joint damage [using the Juvenile Arthritis Damage Index or JADI], radiographic joint damage [erosions], destructive hip disease, disability [CHAQ > 0.5], growth retardation, development of macrophage activation syndrome [MAS], need for biologic agents, and death). Patients with EO were compared with patients with disease onset at age ≥ 18 months. Chi square and Mann-Whitney tests were used for comparisons.

Background Tocilizumab (TCZ), an IL-6 receptor inhibitor, improves arthritis and systemic symptoms associated with systemic JIA. It may be a valuable option in patients with JIA who show inadequate response to anti-TNF agents. Aim

Objective To develop a preliminary disease severity score for juvenile systemic sclerosis (SSc). Methods We conducted an evidence- and consensus-based study that included the following 5 phases: 1) prospective collection of data regarding the demographic and clinical characteristics of patients with diffuse juvenile SSc who were followed up for at least 4 years or until death; 2) blinded evaluation of the disease course profiles of these patients by experts in juvenile SSc, so that patient profiles with a defined clinical course could be used as the gold standard for the score validation phase; 3) definition of candidate severity indices to be included in potential scores; 4) selection of the pediatric severity score with the best statistical performance, as determined by its ability to classify individual patients as having improvement or worsening of disease compared with baseline values or the previous evaluation; 5) validation of the efficiency of the selected score in patients with a mild, moderate, or severe disease course and comparison with the Medsger severity score for adults with SSc. Results Thirty-five patients classified as having a mild (n = 17), moderate (n = 10), or severe (n = 8) disease course entered the study. The selected pediatric SSc score, defined as the Juvenile Systemic Sclerosis Severity Score (J4S), included indices of 9 organ systems each scored on a scale of 0–4. To weight the importance of the involvement of different organ systems, a coefficient of severity was introduced. Compared with the modified Medsger severity score, the J4S performed significantly better in detecting change in severity, both in patients with a moderate disease course (0.89 versus 0.52) and in patients with a severe disease course (0.82 versus 0.75). Conclusion The J4S is a valid instrument to assess disease severity in juvenile SSc.

OBJECTIVES: To report methodology and overall clinical, laboratory and radiographic characteristics for Henoch-Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA) classification criteria. METHODS: The preliminary Vienna 2005 consensus conference, which proposed preliminary criteria for paediatric vasculitides, was followed by a EULAR/PRINTO/PRES - supported validation project divided into three main steps. Step 1: retrospective/prospective web-data collection for HSP, c-PAN, c-WG and c-TA, with age at diagnosis

Made available in DSpace on 2013-08-12T19:10:16Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-01-15 Made available in DSpace on 2013-09-30T19:20:41Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-01-15 Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-20T15:33:16Z No. of bitstreams: 0 Made available in DSpace on 2014-05-20T15:33:16Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-01-15 Myositis Association European Union Objective. To investigate the long-term outcome and prognostic factors of juvenile dermatomyositis (DM) through a multinational, multicenter study.Methods. Patients consisted of inception cohorts seen between 1980 and 2004 in 27 centers in Europe and Latin America. Predictor variables were sex, continent, ethnicity, onset year, onset age, onset type, onset manifestations, course type, disease duration, and active disease duration. Outcomes were muscle strength/endurance, continued disease activity, cumulative damage, muscle damage, cutaneous damage, calcinosis, lipodystrophy, physical function, and health-related quality of life (HRQOL).Results. A total of 490 patients with a mean disease duration of 7.7 years were included. At the cross-sectional visit, 41.2-52.8% of patients, depending on the instrument used, had reduced muscle strength/endurance, but less than 10% had severe impairment. Persistently active disease was recorded in 41.2-60.5% of the patients, depending on the activity measure used. Sixty-nine percent of the patients had cumulative damage. The frequency of calcinosis and lipodystrophy was 23.6% and 9.7%, respectively. A total of 40.7% of the patients had decreased functional ability, but only 6.5% had major impairment. Only a small fraction had decreased HRQOL. A chronic course, either polycyclic or continuous, consistently predicted a poorer outcome. Mortality rate was 3.1%.Conclusion. This study confirms the marked improvement in functional outcome of juvenile DM when compared with earlier literature. However, many patients had continued disease activity and cumulative damage at followup. A chronic course was the strongest predictor of poor prognosis. These findings highlight the need for treatment strategies that enable a better control of disease activity over time and the reduction of nonreversible damage. Ist Ricovero & Cura Carattere Sci G Gaslini, Genoa, Italy Univ Genoa, Genoa, Italy Great Ormond St Hosp Sick Children, London WC1N 3JH, England UCL, Inst Child Hlth, London, England Univ Fed Rio de Janeiro, Rio de Janeiro, Brazil Universidade do Estado do Rio de Janeiro (UERJ), BR-20550011 Rio de Janeiro, Brazil Hosp Gen Ninos Pedro de Elizalde, Buenos Aires, DF, Argentina Fdn IRCCS Policlin, Milan, Italy Hosp Pediat Juan P Garrahan, Buenos Aires, DF, Argentina Univ São Paulo, Fac Med Ribeirao Preto, Hosp Clin, Ribeirao Preto, Brazil Hosp Gen Mexico City, Mexico City, DF, Mexico Fdn Ist Ricovero & Cura Carattere Sci Policlin S, Pavia, Italy Ctr Med Natl La Raza, Mexico City, DF, Mexico Hosp Pequeno Principe, Curitiba, Parana, Brazil Clin Pediat 1, Padua, Italy Ctr Med Nacl Siglo XXI, Mexico City, DF, Mexico Osped Pediat Bambino Gesu, Rome, Italy Osped Villa Monna Tessa, Florence, Italy Univ Naples Federico 2, Naples, Italy Ist Ortoped Gaetano Pini, Milan, Italy Univ estadual Paulista, Botucatu, SP, Brazil II Clin Pediat, Cagliari, Italy Univ São Paulo, São Paulo, Brazil Ist Ricovero & Cura Carattere Sci Burlo Garofalo, Trieste, Italy Univ estadual Paulista, Botucatu, SP, Brazil EU: AML/B7-311/970666/II-0246-FI