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ObjectiveMajeed syndrome (MJS) is an autosomal recessive, systemic autoinflammatory disease (SAID) caused by biallelic loss-of-function variants in theLPIN2gene. It is characterized by early-onset chronic recurrent multifocal osteomyelitis (CRMO), dyserythropoietic anemia, and neutrophilic dermatosis. We analyzed a cohort of uncharacterized Indian patients for pathogenic variants inLPIN2and other genes associated with SAIDs.MethodsWe performed whole-exome sequencing (WES) for 1 patient and next-generation sequencing (NGS) targeted gene panel for SAIDs in 3 patients. One patient was a referral from neurology after clinical exome sequencing identified a novel variant inLPIN2. We reviewed the literature for all published studies of mutation-positive MJS patients and have summarized their clinical features and disease-causing variants.ResultsWe describe the largest series of patients with MJS outside of the Middle East. All 5 patients are homozygous for novel, possibly pathogenic variants in theLPIN2gene. Two of these variants are missense substitutions, and 3 are predicted to alter transcript splicing and create a truncated protein. In addition to the classical features of CRMO and anemia, patients exhibited previously unreported features, including abdominal pain, recurrent diarrhea/ear discharge, and erythema nodosum.ConclusionPatients with MJS may present initially to different specialists, and thus it is important to create awareness in the medical community. In India, consanguinity is a common sociocultural factor in many ethnic communities and an abbreviated NGS gene panel for autoinflammatory diseases should include MJS. The unavailability of interleukin 1 inhibitors in some countries poses a treatment challenge.

Objective Deficiency of adenosine deaminase 2 (DADA2) is a potentially fatal monogenic syndrome characterized by variable manifestations of systemic vasculitis, bone marrow failure, and immunodeficiency. Most cases are diagnosed by pediatric care providers, given the typical early age of disease onset. This study was undertaken to describe the clinical phenotypes and treatment response both in adults and in children with DADA2 in India. Methods A retrospective analysis of pediatric and adult patients with DADA2 diagnosed at various rheumatology centers across India was conducted. Clinical characteristics, diagnostic findings, and treatment responses were analyzed in all subjects. Results In total, 33 cases of DADA2 were confirmed in this cohort between April 2017 and March 2020. Unlike previous studies, nearly one-half of the confirmed cases presented during adulthood. All symptomatic patients exhibited features of vasculitis, whereas constitutional symptoms and anemia were more common in pediatric patients. Cutaneous and neurologic involvement were common, and 18 subjects had experienced at least one stroke. In addition, the clinical spectrum of DADA2 was expanded by recognition of novel features in these patients, including pancreatic infarction, focal myocarditis, and diffuse alveolar hemorrhage. Treatment with tumor necrosis factor inhibitors (TNFi) was initiated in 25 patients. All of the identified disease manifestations showed marked improvement after initiation of TNFi, and disease remission was achieved in 19 patients. Two cases were complicated by tuberculosis infection, and 2 deaths were reported. Conclusion This report presents the first case series of patients with DADA2 from India, diagnosed by adult and pediatric care providers. The findings raise awareness of this syndrome, particularly with regard to its presentation in adults.

OBJECTIVE: Utilizing data obtained from a prospective, international, juvenile systemic sclerosis (SSc) cohort, the present study was undertaken to determine if pulmonary screening with forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLco) is sufficient to assess the presence of interstitial lung disease (ILD) in comparison to high-resolution computed tomography (HRCT) in juvenile SSc. METHODS: The juvenile SSc cohort database was queried for patients enrolled from January 2008 to January 2020 with recorded pulmonary function tests (PFTs) parameters and HRCT to determine the discriminatory properties of PFT parameters, FVC, and DLco in detecting ILD. RESULTS: Eighty-six juvenile SSc patients had both computed tomography imaging and FVC values for direct comparison. Using findings on HRCT as the standard measure of ILD presence, the sensitivity of FVC in detecting ILD in juvenile SSc was only 40%, the specificity was 77%, and area under the curve (AUC) was 0.58. Fifty-eight juvenile SSc patients had both CT imaging and DLco values for comparison. The sensitivity of DLco in detecting ILD was 76%, the specificity was 70%, and AUC was 0.73. CONCLUSION: The performance of PFTs in juvenile SSc to detect underlying ILD was quite limited. Specifically, the FVC, which is one of the main clinical parameters in adult SSc to detect and monitor ILD, would miss ~60% of children who had ILD changes on their accompanying HRCT. The DLco was more sensitive in detecting potential abnormalities on HRCT, but with less specificity than the FVC. These results support the use of HRCT in tandem with PFTs for the screening of ILD in juvenile SSc.

Objective: To compare organ involvement and disease severity between male and female patients with juvenile onset systemic sclerosis. Methods: Demographics, organ involvement, laboratory evaluation, patient-reported outcomes and physician assessment variables were compared between male and female juvenile onset systemic sclerosis patients enrolled in the prospective international juvenile systemic sclerosis cohort at their baseline visit and after 12 months. Results: One hundred and seventy-five juvenile onset systemic sclerosis patients were evaluated, 142 females and 33 males. Race, age of onset, disease duration, and disease subtypes (70% diffuse cutaneous) were similar between males and females. Active digital ulceration, very low body mass index, and tendon friction rubs were significantly more frequent in males. Physician global assessment of disease severity and digital ulcer activity was significantly higher in males. Composite pulmonary involvement was also more frequent in males, though not statistically significantly. After 12 months, they are the pattern of differences changed female patients had significantly more frequent pulmonary involvement. Conclusion: In this cohort, juvenile onset systemic sclerosis had a more severe course in males at baseline and but the pattern changed after 12 months. Some differences from adult findings persisted, there is no increased signal of pulmonary arterial hypertension or heart failure in male pediatric patients. While monitoring protocols of organ involvement in juvenile onset systemic sclerosis need to be identical for males and females.

Optic Neuritis is the most common presentation of MOG Antibody Disease (MOG-AD). We share our experience with a 11-year-old boy who developed MOG associated Optic Neuritis temporally associated with SARS- CoV-2 infection. He responded well to intravenous methylprednisolone therapy followed by oral prednisolone. While various neurological and ophthalmological manifestations of COVID-19 have been described previously, there are few case reports of Optic neuritis associated with COVID-19. Our case further supports the evidence to suggest that SARS CoV-2 is another such virus that triggers MOG-AD.

Background Intraarticular injections (IAI) were first reported in adult rheumatology in the 1950s and subsequently gained acceptance as a safe and efficacious treatment in Juvenile idiopathic arthritis (JIA). IAIs are now widely performed and recommended as the initial or only treatment of oligoarticular JIA and ancillary treatment of actively inflamed joints in other varieties of JIA. However, the performance of the procedure is currently not guided by standardized recommendations, and several practice variations are observed. Methods This worldwide survey of pediatric rheumatologists (with 48.5% response from Pediatric Rheumatology International Trials Organization [PRINTO and Pediatric Rheumatology Collaborative Study Group [PRCSG] members) captures the differences in pre-procedural, procedural and post-procedural protocols and practices observed across the globe and asks the necessity of developing consensus in this area of Pediatric Rheumatology. Results This worldwide survey of Pediatric Rheumatologists had a response rate of just under 50% and the views of about 42% who routinely performed the procedure. It captured the differences in IAI protocols and practices observed across the globe. Significant variations in practice were noted in use of Local anesthesia, choice, and dose of therapeutic agent for the intraarticular injection and use of ultrasound to guide injections. While some practice variations may be explained by institutional protocols in different parts of the world, the clinical implications of these are largely unknown and beg the need for further studies. Conclusions Given these practice variations, the authors recommend further studies to explore the cost and clinical implications and subsequently work towards developing consensus plans to ensure uniformity in this widely used procedure in Pediatric Rheumatology.

Background: Intraarticular injections (IAI) were first reported in adult rheumatology in the 1950s and subsequently gained acceptance as a safe and efficacious treatment in Juvenile Idiopathic arthritis (JIA). IAIs are now widely performed and recommended as the initial or only treatment of Oligoarticular JIA and ancillary treatment of actively inflamed joints in other varieties of JIA. However, the performance of the procedure is not currently guided by standardized recommendations, thereby several practice variations are observed.Methods: This worldwide survey of pediatric rheumatologists (with 50% response from Pediatric Rheumatology International Trials Organization: PRINTO and Pediatric Rheumatology Collaborative Study Group: PRCSG members) captures the differences in pre-procedural, procedural and post procedural protocols observed across the globe and asks the necessity of developing consensus in this area of Pediatric Rheumatology. Results: This worldwide survey of Pediatric Rheumatologists had a response rate of almost 50% and captured the differences in IAI protocols observed across the globe. Conclusions: Consensus plans are needed to ensure uniformity in this widely used procedure in Pediatric Rheumatology.

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

Summary TANK binding kinase 1 (TBK1) regulates IFN-I, NF-κB, and TNF-induced RIPK1-dependent cell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discovered four humans, ages 32, 26, 7, and 8 from three unrelated consanguineous families with homozygous loss-of-function mutations in TBK1. All four patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We demonstrate that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-κB. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD.

To assess the course, outcome and complications in a mono-centric cohort of 53 patients with systemic onset juvenile idiopathic arthritis (s-JIA). In an observational study, 53 consecutive patients diagnosed with s-JIA on or before October 2009 were enrolled and followed up between October 2009 and September 2012. At each 6–12 weekly visit, clinical examination, laboratory investigations and details of on-going treatment were recorded. Disease course was classified as monocyclic, intermittent and persistent. At last visit, outcome was studied with respect to remission (Wallace criteria) and Steinbrocker functional classification. Juvenile Arthritis Damage Index (JADI) was measured on a subset. In 53 patients analysed, the mean follow-up period was 5.5 ± 1.85 y, with a cumulative follow-up period of 291.5 patient-years. The mean age at diagnosis was 6.3 ± 3.4 y. Thirty-three patients suffered from disease and/or drug related complications. Infections were observed in 16 (30%) and macrophage activation syndrome in 5 (9.4%). Nine (17%) had a monocyclic course, 31 (58.5%) had an intermittent course and 13 (24.5%), a persistent course. At last visit, 9/9 patients of the monocyclic group, 17/31 in the intermittent group and 3/13 in the persistent group were in remission. At the end of the study, 96.2% of the index patients were Steinbrocker functional class I and II with the monocyclic group having the best functional outcome. JADI was performed on 20/53 patients. Nine had significant articular damage. The range of Juvenile arthritis damage index-articular (JADI-A) was 0–25/72 (median-6) and of Juvenile arthritis damage index-extra articular (JADI-EA) was 0–4/17 (median-1). The outcome of patients with s-JIA in a resource limited setting where early diagnosis, multidisciplinary care and availability of biologics are hurdles, is further altered by complications related to longstanding disease and over use of steroids.

Long standing hypothyroidism presenting as an ovarian mass has been well described in literature as the Van Wyk Grumbach syndrome (hypothyroidism, isosexual precocious puberty and ovarian mass). Here, authors report this entity in a 11 y 7 mo old girl child who was referred to a surgeon in view of intestinal obstruction along with a multiloculated ovarian cyst. On evaluation, she was found to have raised serum creatinine, short stature, delayed bone age and pituitary enlargement. She was diagnosed with autoimmune thyroiditis and was started on replacement therapy with thyroxine, after which the ovarian cysts regressed. This entity should be kept in mind in cases of ovarian cysts, especially those with isosexual precocity, to prevent unnecessary evaluation and surgical misadventures.

Background: Data on immunisation practices in Paediatric Rheumatology are scarce. EULAR recommendations for vaccination in paediatric patients with rheumatic disease (RD) were published in 2011. In some countries national recommendations for vaccination of immunocompromised patients are available. Objectives: To ascertain the opinion and current practices of paediatric rheumatologists with regards to immunisation of children with rheumatic diseases (RD), and to establish their confidence to immunise the patients with RD on immunosuppressive medication with live vaccines in light of the evidence available. Methods: An online survey of practices and opinions towards immunisations with a focus on immunisation of the immunocompromised child with RD was distributed to paediatric rheumatologists across the globe. Responses were collected via SurveyMonkey and descriptive analysis was performed. Responses were anonymous with the exception of identification of the country and length of practice. Results: 289 responses were received from 53 countries in Europe, North and South America, Australia and Asia. 35% of the respondents had over 15 years of practice in Paediatric Rheumatology, while 42% had 5 -15 years. 57% responded that all immunisations or at least part of them are given in their paediatric rheumatology unit, and 60% that the vaccinations are mandatory in their country. 93% of respondents support the immunisation of paediatric patients with RD, 6.9% responded that they are either not supportive/not sure/support only vaccinations with inactivated vaccines. 53% reported that national recommendations for immunisations of immunosuppresed child are available but not specific to Paediatric Rheumatology. 41% of respondents inform their practice on immunisation of patients with RD based exclusively on the EULAR recommendations, 37.5% based on national guidelines, 8.5% on local guidelines and 10% on combinations of the above. 48% of clinicians would postpone vaccinations in all cases if disease is active. In terms of immunisations with live vaccines of patients with JIA on immunosuppresive treatment, 41% of respondents would recommend the first dose of MMR or Varicella vaccines to patients with stable disease on Prednisolone 48% of the respondents identified the reluctance of other health professionals involved in the process of immunisations as the main reason hampering the vaccination of paediatric patients with RD, whilst 22% indicated parental refusal or hesitancy. Conclusion: There is variation in practice and opinions worldwide with regards to immunisations in paediatric patients with RD, and this likely reflects the discrepancies between national guidelines for immunisation of immunosuppressed child and also national policies. More studies are required, but there is an increasing vote of confidence towards immunisation of patients on lower grade immunosuppression with MMR or varicella vaccines Disclosure of Interests: None declared

Background Juvenile Arthritis Disease Activity Score (JADAS) has gained increasing popularity for the measurement of the level of disease activity in patients with juvenile idiopathic arthritis (JIA). However, so far the JADAS has been validated only in children with the non-systemic categories of JIA. Objectives To develop and validate the systemic JADAS (sJADAS), a new version of the JADAS specific to systemic JIA (sJIA). Methods The sJADAS is made up by adding a fifth item, named Systemic Manifestation Score (SMS), to the four items included in the original tool (physician global assessment of disease activity, parent/patient global assessment of well-being, active joint count and erythrocyte sedimentation rate). The SMS ranges from 0 to 10 and is aimed to quantify the activity of systemic features. The sJADAS score ranges from 0 to 50. The validation sample included patients with definite and possible/probable sJIA with active systemic manifestations, which should comprise fever, who were assessed at baseline and then at a subsequent visit, 2 weeks to 3 months after initial evaluation. Validation procedures included assessment of concurrent, construct and discriminant validity, internal consistency and responsiveness to clinical change. Results A total of 161 patients, 86.7% (n=137) with definite sJIA and 13.3% (n=21) with possible/probable sJIA, assessed at disease onset (n=90; 56.6%) or at time of a disease flare (n=69; 43.4%), were enrolled at 57 centers in 10 countries from February 2017 to December 2018. Median age at disease onset was 5.0 years (interquartile range, IQR 2.8 - 8) and median age at study entry was 6.9 years (IQR 3.8–10.8). Median disease duration from onset to study entry was 0.2 years (IQR 0.1–1.9). The median sJADAS at baseline visit was 28.2 (IQR 22.8–35.0). The sJADAS correlated strongly with JADAS10 (rs=0.98) and clinical JADAS10 (cJADAS10) (rs=0.91); moderately with functional ability scales (JAFS and CHAQ) (rs=0.69; rs=0.62) and total score (rs=0.57) and physical (rs=0.60) and psychosocial (rs=0.40) subscale scores of the health-related quality of life tool (PRQL) and with pain VAS (rs=0.57); and mildly with the CRP (rs=0.42). The sJADAS discriminated well between patients with or without morning stiffness (p Conclusion The sJADAS was found to be a valid instrument for the assessment of disease activity in sJIA. This composite score is feasible and easily applicable in standard clinical practice, which should result in its widespread acceptance and use. The strong responsiveness to clinical change over time indicates that the sJADAS is suitable to assess therapeutic response in sJIA clinical trials. Disclosure of Interests Jessica Tibaldi: None declared, Yasser El Miedany: None declared, Priyankar Pal : None declared, Soamarat Vilaiyuk: None declared, Raju Khubchandani: None declared, Claudia Bracaglia: None declared, Tapas K Sabui : None declared, Sujata Sawhney: None declared, Riccardo Russo Speakers bureau: Novartis, Abbvie, Flavio R. Sztajnbok: None declared, Rolando Cimaz: None declared, Francesca Minoia: None declared, Motasem O. Alsuweiti: None declared, Ekaterina Alexeeva: None declared, Mikhail Kostik: None declared, Maria Cristina Maggio: None declared, Nicolino Ruperto Grant/research support from: The Gaslini Hospital, where NR works as full-time public employee, has received contributions (> 10.000 USD each) from the following industries in the last 3 years: BMS, Eli-Lilly, GlaxoSmithKline, F Hoffmann-La Roche, Janssen, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties., Consultant for: Received honoraria for consultancies or speaker bureaus (

Objective.To revise the current juvenile idiopathic arthritis (JIA) International League of Associations for Rheumatology (ILAR) classification criteria with an evidence-based approach, using clinical and routine laboratory measures available worldwide, to identify homogeneous clinical groups and to distinguish those forms of chronic arthritis typically seen only in children from the childhood counterpart of adult diseases.Methods.The overall project consists of 4 steps. This work represents Step 1, a Delphi Web-based consensus and Step 2, an international nominal group technique (NGT) consensus conference for the new provisional Pediatric Rheumatology International Trials Organization JIA classification criteria. A future large data collection of at least 1000 new-onset JIA patients (Step 3) followed by analysis and NGT consensus (Step 4) will provide data for the evidence-based validation of the JIA classification criteria.Results.In Step 1, three Delphi rounds of interactions were implemented to revise the 7 ILAR JIA categories. In Step 2, forty-seven questions with electronic voting were implemented to derive the new proposed criteria. Four disorders were proposed: (a) systemic JIA; (b) rheumatoid factor–positive JIA; (c) enthesitis/spondylitis-related JIA; and (d) early-onset antinuclear antibody–positive JIA. The other forms were gathered under the term “others.” These will be analyzed during the prospective data collection using a list of descriptors to see whether the clustering of some of them could identify homogeneous entities.Conclusion.An international consensus was reached to identify different proposed homogeneous chronic disorders that fall under the historical termJIA. These preliminary criteria will be formally validated with a dedicated project.

Made available in DSpace on 2019-10-05T16:54:20Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-04-01 IRCCS Istituto Giannina Gaslini Background To our knowledge, the characteristics and burden of childhood arthritis have never been studied on a worldwide basis. We aimed to investigate, with a cross-sectional study, the prevalence of disease categories, treatment methods, and disease status in patients from across different geographical areas and from countries with diverse wealth status. Methods In this multinational, cross-sectional, observational cohort study, we asked international paediatric rheumatologists from specialised centres to enrol children with a diagnosis of juvenile idiopathic arthritis, according to International League of Associations for Rheumatology criteria, who were seen consecutively for a period of 6 months. Each patient underwent retrospective and cross-sectional assessments, including measures of disease activity and damage and questionnaires on the wellbeing and quality of life of the children. We qualitatively compared the collected data across eight geographical areas, and we explored an association between disease activity and damage and a country's gross domestic product (GDP) with a multiple logistic regression analysis. Findings Between April 4, 2011, and Nov 21, 2016, 9081 patients were enrolled at 130 centres in 49 countries, grouped into eight geographical areas. Systemic arthritis (125 [33.0%] of 379 patients) and enthesitis-related arthritis (113 [29.8%] of 379) were more common in southeast Asia, whereas oligoarthritis was more prevalent in southern Europe (1360 [56.7%] of 2400) and rheumatoid factor-negative polyarthritis was more frequent in North America (165 [31.5%] of 523) than in the other areas. Prevalence of uveitis was highest in northern Europe (161 [19.1%] of 845 patients) and southern Europe (450 [18.8%] of 2400) and lowest in Latin America (54 [6.4%] of 849), Africa and Middle East (71 [5.9%] of 1209), and southeast Asia (19 [5.0%] of 379). Median age at disease onset was lower in southern Europe (3.5 years, IQR 1.9-7.3) than in other regions. Biological, disease-modifying antirheumatic drugs were prescribed more frequently in northern Europe and North America than in other geographical settings. Patients living in countries with lower GDP had greater disease activity and damage than those living in wealthier countries. Damage was associated with referral delay. Interpretation Our study documents a variability in prevalence of disease phenotypes and disparities in therapeutic choices and outcomes across geographical areas and wealth status of countries. The greater disease burden in lowerresource settings highlights the need for public health efforts aimed at improving equity in access to effective treatments and care for juvenile idiopathic arthritis. Copyright (C) 2019 Elsevier Ltd. All rights reserved. Univ Genoa, Ist Giannina Gaslini, IRCCS, Clin Paediat & Rheumatol, Genoa, Italy Univ Genoa, Ist Giannina Gaslini, IRCCS, Epidemiol & Biostat Serv, Genoa, Italy Univ Genoa, Ist Giannina Gaslini, IRCCS, Sci Directory, Genoa, Italy Univ Genoa, PRINTO, IRCCS, Ist Giannina Gaslini, Genoa, Italy Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet & Maternal, Genoa, Italy Wilhelmina Childrens Hosp, Dept Pediat Immunol & Rheumatol, Utrecht, Netherlands Sanjay Gandhi Postgrad Inst Med Sci, Lucknow, Uttar Pradesh, India Univ Hosp 12 Octubre, Dept Pediat Rheumatol, Madrid, Spain Alfaisal Univ, Dept Pediat Rheumatol, King Faisal Specialist Hosp, Riyadh, Saudi Arabia Alfaisal Univ, Res Ctr, Riyadh, Saudi Arabia Western Univ Childrens Hosp, Hlth Sci Ctr, London, ON, Canada Oslo Univ Hosp, Dept Rheumatol, Oslo, Norway Oslo Univ Hosp, Med Fac, Oslo, Norway Univ Oslo, Oslo, Norway Oslo Univ Hosp, Norwegian Natl Advisory Unit Rheumat Dis Children, Oslo, Norway Univ Hosp Munster, Dept Pediat Rheumatol & Immunol, Munster, Germany Hosp Sor Maria Ludovica, Rheumatol Serv, La Plata, Buenos Aires, Argentina Bucharest Emergency Hosp, Cluj Napoca, Romania Childrens Emergency Hosp, Cluj Napoca, Romania Cincinnati Childrens Hosp Med Ctr, Div Rheumatol, Cincinnati, OH 45229 USA Alberta Childrens Prov Gen Hosp, Div Pediat Rheumatol, Dept Pediat, Calgary, AB, Canada Sofiamed, Pediat Dept, Sofia, Bulgaria Rigshosp, Juliane Marie Ctr, Paediat Rheumatol Unit, Copenhagen, Denmark Natl Inst Rheumatism & Physiotherapy, Clin Immunol Adult & Paediat Rheumatol Dept, Budapest, Hungary Univ Latvia, Pediat Dept, Riga, Latvia Univ Latvia, Univ Childrens Hosp, Riga, Latvia Univ Estadual Paulista, Botucatu Fac Med, Botucatu, SP, Brazil Shariati Hosp, Rheumatol Res Ctr, Dept Pediat & Rheumatol, Tehran, Iran Inst Rheumatol Belgrade, Div Pediat Rheumatol, Belgrade, Serbia Thessaloniki Univ, Dept Pediat 1, Hippokrat Gen Hosp, Sch Med, Thessaloniki, Greece Univ Estadual Paulista, Botucatu Fac Med, Botucatu, SP, Brazil

Background:Juvenile systemic sclerosis (jSSc) is an orphan disease with a prevalence of around 3 in 1, 000,000 children. It is known that in pediatric jSSc cohorts, there are a significant number of patients with overlap features, such as arthritis and myositis. However, the disease burden between those with and without overlap features in jSSc has not been defined.Objectives:Compare the clinical phenotype between children with and without overlap features in the juvenile systemic scleroderma inception cohort (jSScC).Methods:A cross-sectional study was performed using baseline visit data. Demographic, organ system evaluation, autoantibody profile, treatment, and patient and physician reported outcome variables were extracted from jSScC. Comparison between patients with and without overlap features was performed using chi-square test and Mann Whitney U-test.Results:At the time of data extraction, 175 jSSc patients were enrolled in the cohort, 81% were Caucasian and 81% female. Mean disease duration was 3.1 year (±2.7). Mean age at Raynaud´s onset was 10 years (±3.8) and mean age of first non-Raynaud´s was 10.2 years (±3.8). Overlap features occurred 17% (n=30) of the cohort, 12.5% in the diffuse cutaneous (dc) jSSc and in 30% in the limited cutaneous (lc) jSSc. Significant differences in clinical characteristics were found between those patients with compared to without overlap characteristics. Patients with overlap features presented more frequently with Gottron papules (p=0.007), swollen joints (p=0.019), muscle weakness (p=0.003), and lung involvement documented by decreased DLCO < 80% (p=0.06) and/or abnormal high resolution computed tomography (p=0.049). Anti-PM/Scl autoantibodies were also more common in this group (p=0.001). Significantly more patients without overlap features had Raynaud´s (p=0.006). Physician Global Assessment of disease activity was significantly higher in patients with overlap features (41 vs 34; p=0.041). (Table 1.)Table 1.Demographic and clinical characteristics of jSSc patients with and without overlap features.Whole CohortN=175Patients without overlapN=145Patients with overlapN=30P valueFemale to Male Ratio 4.3:1(142/33)4:1(116/29)6.5:1(26/4)0.395Cutaneous subtypeDiffuse subtype (N)73% (128)11216Limited subtype (N)27% (47)3317Mean disease duration (years)3.1 (± 2.7)3.2 (± 2.8)3.1 (± 2.2)0.291Mean age of onset of Raynaud´s (years)10.0 (± 3.8)17 non-Raynaud10.0 (± 3.8)10 non-Raynaud10.0 (± 3.7)7 non-Raynaud0.931Mean age of onset of non-Raynaud´s (years)10.2 (± 3.8)10.2 (± 3.9)9.8 (± 3.7)Disease modifying drugs (N)88% (154) 89% (129)83% (25)0.388Raynaud´s phenomenon90% (158)93% (135)77% (23)0.006Anti-PMScl18% (12/68)9% (5/53)47% (7/15)0.001Gottron Papules (N)27% (46/171)23% (33/144)48% (13/27)0.007DLCO 44% (39/88)39% (28/71)65% (11/17)0.06Abnormal findings in HRCT (N)44% (59/133)40% (43/107)62% (16/26)0.049Proportion of patients with swollen joints 18% (32) 14% (21) 37% (11)0.019Muscle Weakness (N) 21% (31/149)16% (20/123) 42% (11/26)0.003Physician global disease activity(0-100) min -max35 (0-90) n=14134 (0-90) n=11441 (0-80) n=270.041Conclusion:Results from this large international cohort of jSSc patients demonstrate significant differences between patients with and without overlap features. Patients with overlap have significantly more interstitial lung disease and more physician rated disease activity and should not be considered to have more “mild disease”.Supported by the “Joachim Herz Stiftung”Disclosure of Interests:None declared

Background:Juvenile systemic sclerosis (jSSc) is a rare disease with a prevalence of around 3 in 1,000,000 children. To better capture the clinical manifestations of jSSc the juvenile systemic sclerosis inception cohort (jSScC) has been prospectively enrolling patients with predetermined clinical variables over the past 12 years. One of the goals is to study the demographic, clinical features, and physician and patient reported outcome differences between those with juvenile limited cutaneous (lc) compared to diffuse cutaneous (dc) disease subtypes, to determine if characteristics are similar or different between dc and lc jSSc.Objectives:Evaluation of the baseline clinical characteristics of jSSc patients in the jSScC. Compare clinical phenotype between diffuse (dcjSSc) and limited cutaneous (lcjSSc) subtypes.Methods:Demographic, physical examination, organ system evaluation, autoantibody profile, treatment, and patient and physician reported outcome variables were evaluated from the jSSc Inception cohort and summary statistics applied using chi-square test and Mann Whitney U-test comparing lcjSSc and dcjSSc subtypes.Results:At the time of data extraction, 175 jSSc patients were enrolled in the cohort, 81% were Caucasian and 81% female. Diffuse cutaneous jSSc subtype predominated (73%). Mean disease duration was 3.1 year (±2.7). Mean age at Raynaud´s was 10 years (+3.8) and mean age of first non-Raynaud´s was 10.2 years (±3.8). Significant differences were found between dcjSSc versus lcjSSc, regarding several clinical characteristics. Patients with diffuse cutaneous subtype had significantly higher modified Rodnan skin score (p=0.001), presence of sclerodactyly (p=0.02), presence of Gottron’s papules (p=0.003), presence of telangiectasia (p=0.001), history of digital tip ulceration (p=0.01), and frequency of elevated CK value (p=0.04). Cardiac involvement was significantly higher in limited cutaneous jSSc subtype (p=0.02). Diffuse cutaneous jSSc patients had significantly worse scores for Physician Global Assessment of disease activity (38 vs 25; p=0.002) and disease damage (34 vs 19; p=0.008).Table 1.Comparison of demographic data and significant differences between dcjSSc and lcjSSc at time of inclusionWhole CohortN=175Diffuse SubtypeN=128Limited SubtypeN=47P valueFemale to Male Ratio4.3:1 (142/33)4.1:1 (103/25)4.8:1 (39/8)0.829Cutaneous subtypeDiffuse subtype73% (128)1280Limited subtype27% (47)047Mean Disease duration (years)3.1 (± 2.7)3.3 (± 2.9)2.6 (± 2.2)0.135Mean age of onset of Raynaud´s (years)10.0 (± 3.8)17 non-Raynaud9.8 (± 3.6)10 non-Raynaud10.6 (± 4.3)7 non-Raynaud0.219Mean age of onset of non-Raynaud´s (years)10.2 (± 3.9)10.0 (± 3.7)10.9 (± 4.3)0.173Disease modifying drugs88% (154)89% (114)85% (40)0.446CutaneousMean modified Rodnan skin score14.3 (0-51)17.4 (0-51)6.1 (0-24)0.001Gottron Papules27% (46/171)33% (41/124)11% (5)0.003Sclerodactyly78% (126/162)82% (98/119)65% (28/43)0.020Laboratory valuesElevated CK25% (30/122)30% (26/88)12% (4/34)0.041VascularTelangiectasia36% (56/154)44% (49/111)16% (7/43)0.001History of ulceration53% (91/173)61% (77/127)30% (14/46)0.001CardiacCardiac Involvement6% (10)2% (3)15% (7)0.002Patient Related OutcomesPhysician global disease activity(0-100) min -max35(0-90) n=14138(0-90) n=10825(0-80) n=330.002Physician global disease damage(0-100) min -max31(0-85) n=14034(0-85) n=10819(0-60) n=320.008Conclusion:Results from this large international cohort of jSSc patients demonstrate significant differences between dcjSSc and lcjSSc patients. According to the general organ involvement and physician global scores, the dcjSSc patients had significantly more severe disease. These observations strengthen our previous findings of the unique organ pattern of pediatric patients.Supported by the “Joachim Herz Stiftung”Disclosure of Interests:None declared.

Background:It has been published that the presence of NXP2 autoantibodies presents a risk for calcinosis in patients with JDM.Objectives:To investigate the incidence of calcinosis and response to the treatment in NXP2 positive JDM patients with calcinosis.Methods:The study design is a retrospective, multinational, multicenter study. Data on gender, race, age at disease onset and age at disease diagnosis, age at inclusion in the study, clinical presentation, muscle function tests, laboratory results, imaging, data on treatment and outcome of disease were collectedResults:we collected 26 patients (19 F, 7 M) with JDM and positive NXP2 antibodies. Fourteen patients were white, eight asian, three black and one Hispanic ethnicity. The mean age at disease presentation was 6.5 years (SD 3.7), the median diagnosis delay was 4 months (range 0.5- 27 months). Patients were divided in two groups (A and B) based on the presence of calcinosis.Eleven patients (42%) developed calcinosis (group A) in the course of the disease, 10 females and 1 male. Four patients already had calcinosis at presentation, 1 developed after 4 months, and 6 developed calcinosis later in disease course (median 2 years, range 0,8- 7,8). Four patients developed lipodystrophy in group A (1 in group B). In group A, 3 patients developed skin ulcerations (1 in group B), 2 patients had polyarthritis (1 in group B), 2 patients had gut involvement (1 in group B) and 1 patient had lung involvement (2 in group B).The mean age at disease presentation (5.2 / 7.5 y) and mean CK level (1548.6 / 1811.6 U/L) were lower in group A. The platelet count (306.5 / 258 109/L), and mean values of AST (111.4 / 103.8 U/L), ALT (72.2 / 50.8 U/L), LDH (1048.3 / 808 IU/L), and IgG (11.8 / 9.9 g/L) were higher in group A. However, the differences were not statistically significant. ANA antibodies were positive in 9/11 in group A and 12/15 in group B. One patient in group A was also positive for anti-MDA5 antibody. The data on muscle strength measurement (MMT/CMAS) were available only in a few patients.Treatments used for patients with calcinosis includes, methotrexate and glucocorticosteroids (GCS) (all patients), hydroxychloroquine (9), IVIG (7), cyclosporine (4), bisphosphonate (4), MMF (5), rituximab (4), cyclophosphamide (1), abatacept (1) and TNF alpha blocker (1).Disease outcome (by evaluation of the treating physician) was excellent in 4, good in 2, stable in 2 and poor in 3 patients. None of the patients from group B had a poor disease outcome. Patients with excellent disease outcomes from group A were treated with GCS and methotrexate (4), hydroxychloroquine (3), IVIG (1) and cyclosporine (1). Out of two patients who had good outcomes, one was additionally treated with MMF, bisphosphonates and rituximab and the second was treated with cyclophosphamide and rituximab. One patient with calcinosis at the presentation (age 4 years) was treated also with anti-TNF alpha therapy which not only stopped progression but partially dissolved the calcinosis. However, after 2 years of anti-TNF alpha therapy the calcinosis start to progress and the therapy was changed to MMF and rituximab, which stopped the progression of calcinosis.Conclusion:Our preliminary results showed that calcinosis occurred in 42% of NXP2 positive JDM patients. Children with calcinosis were treated with several combinations of drugs. In four cases, rituximab and in one case, for limited time of 2 years, anti-TNF alpha agent, were used successfully.References:[1]Chung MP, Richardson C, Kirakossian D, Orandi AB, Saketkoo LA, et al. Calcinosis biomarkers in adult and juvenile dermatomyositis. Autoimmun Rev 2020; 19(6):102533.Disclosure of Interests:Natasa Toplak: None declared, Pallavi Pimpale Chavan: None declared, Silvia Rosina: None declared, Tomas Dallos Consultant of: Abbvie, Novartis, Rotem Semo Oz: None declared, Cassyanne Aguiar: None declared, Raju Khubchandani: None declared, Angelo Ravelli: None declared, Anjali Patwardhan: None declared.

Objective To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). Methods The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. Results In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. Conclusion Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.

Objective To assess the quality of medical care in childhood-onset systemic lupus erythematosus (SLE) at tertiary pediatric rheumatology centers as measured by observance of SLE quality indicators (SLE-QIs). Methods International consensus has been achieved for childhood-onset SLE-QIs capturing medical care provision in 9 domains: diagnostic testing, education of cardiovascular (CV) risk and lifestyles, lupus nephritis (LN), medication management, bone health, ophthalmologic surveillance, transition, pregnancy, and vaccination. Using medical record information, the level of performance of these childhood-onset SLE-QIs was assessed in childhood-onset SLE populations treated at 4 tertiary pediatric rheumatology centers in the US, 2 in Brazil, and 1 center in India. Results A total of 483 childhood-onset SLE patients were assessed. Care for the 310 US patients differed markedly for childhood-onset SLE-QIs addressing LN, bone health, vaccinations, education on CV risk, and transition planning. Performance of safety blood testing for medications was high at all centers. Despite often similar performance on the childhood-onset SLE-QI, access to kidney biopsies was lower in Brazil than in the US. Irrespective of the country of practice, larger centers tended to meet the childhood-onset SLE-QIs more often than smaller centers. Conclusion The childhood-onset SLE-QIs, evidence-based minimum standards of medical care, are not consistently met in the US or some other countries outside the US. This has the potential to contribute to suboptimal childhood-onset SLE outcomes.

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between ADA2 mutations and clinical phenotype remains unavailable. OBJECTIVE: We tested whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation. METHODS: DADA2 patients with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion and deletion genotypes from 152 patients across the DADA2 spectrum. RESULTS: We identified DADA2 patients presenting with pure red cell aplasia (PRCA, n = 5) or bone marrow failure syndrome (BMF, n = 10). Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly and gingivitis were common in patients with BMF, of whom half died from infection. Unlike DADA2 patients with vasculitis, patients with PRCA and BMF proved largely refractory to tumor necrosis factor inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. By contrast, PRCA and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions / deletions resulting in complete loss of function. CONCLUSION: Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2. CLINICAL IMPLICATIONS: Genotype correlates with clinical phenotype and therapeutic response in DADA2.

To describe the frequency and types of disease damage occurring with childhood-onset systemic lupus erythematosus (SLE) as measured by the 41-item Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), and to assess the SDI's ability to reflect damage severity.Information for the SDI was prospectively collected from 1,048 childhood-onset SLE patients. For a subset of 559 patients, physician-rated damage severity measured by visual analog scale (MD VAS damage) was also available. Frequency of SDI items and the association between SDI summary scores and MD VAS damage were estimated. Finally, an international consensus conference, using nominal group technique, considered the SDI's capture of childhood-onset SLE-associated damage and its severity.After a mean disease duration of 3.8 years, 44.2% of patients (463 of 1,048) already had an SDI summary score0 (maximum 14). The most common SDI items scored were proteinuria, scarring alopecia, and cognitive impairment. Although there was a moderately strong association between SDI summary scores and MD VAS damage (Spearman's r = 0.49, P0.0001) in patients with damage (SDI summary score0), mixed-effects analysis showed that only 4 SDI items, each occurring in2% of patients overall, were significantly associated with MD VAS damage. There was consensus among childhood-onset SLE experts that the SDI in its current form is inadequate for estimating the severity of childhood-onset SLE-associated damage.Disease damage as measured by the SDI is common in childhood-onset SLE, even with relatively short disease durations. Given the shortcomings of the SDI, there is a need to develop new tools to estimate the impact of childhood-onset SLE-associated damage.

Paediatric leg pains, long described as ‘growing pains’, frequently present to clinicians, are prevalent in early childhood, disrupt sleep, and distress affected children and parents. There are many cited associations, but no defined leg pain sub-types, nor revealed predictive factors. We explored the implicated factors (viz. foot arches, foot strength, joint mobility, vitamin D, iron) in children with leg pain versus a control group. Leg pain sub-groups—growing pains (GP), restless legs (RLS), both (mixed)—are defined for the first time. A case controlled study design, in a primary care setting, Mumbai, India. A total of 77 children with leg pains (n = 64) and controls (n = 13), aged 3–12 years, identified by paediatricians, completed data collection. Blood assays for iron and vitamin D, pain, Beighton score, foot arch, foot strength and anthropometrical data were collected. All outcome measures were validated, with standardised protocols. Leg pain (all groups) was predicted by increased joint mobility and increased ankle dorsiflexion strength (β = 0.56, P

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.

Neonatal-Onset Multisystem Inflammatory Disease (NOMID) or Chronic Infantile Neurologic Cutaneous Articular (CINCA) syndrome is a monogenic autoinflammatory disorder characterized by urticarial skin rash, fever, chronic meningitis and joint manifestations. Here we report a case of an Indian male child who presented at the age of 9 months with fever, respiratory distress, urticarial skin rash, arthritis, and neuroregression. Suspecting NOMID/CINCA syndrome, the child's blood was sent to the Jaslok Hospital and Research Centre for mutation analysis of the CIAS1/NLRP3 gene. The DNA was screened for mutations in exon 3 of CIAS1/NLRP3 gene by automated Sanger sequencing. DNA sequencing showed a novel heterozygous c.1813A➔G, p.R605G mutation in exon 3 of CIAS1/NLRP3 gene (ref no NM_001243133.1). His parents tested negative for this mutation. We therefore identified a novel de novo mutation in this family in the CIAS1/NLRP3 gene responsible for the child's clinical features.

Kawasaki disease (KD) is recognized as a leading cause of acquired heart disease in children in developed countries. Although global in distribution, Japan records the highest incidence of KD in the world. Epidemiological reports from the two most populous countries in the world, namely China and India, indicate that KD is now being increasingly recognized. Whether this increased reporting is due to increased ascertainment, or is due to a true increase in incidence, remains a matter of conjecture. The diagnosis and management of KD in developing countries is a challenging proposition. In this review we highlight some of the difficulties faced by physicians in managing children with KD in resource-constrained settings.

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient-reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Hindi language. The reading comprehension of the questionnaire was tested in ten JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach’s alpha, interscale correlations, test–retest reliability, and construct validity (convergent and discriminant validity). A total of 275 JIA patients (28.4% systemic, 10.9% oligoarticular, 13.8% RF negative polyarthritis, 46.9% other categories) and 98 healthy children were enrolled in three centres. The JAMAR components discriminated well healthy subjects from JIA patients. Notably, there is no significant difference between the healthy subjects and their affected peers in the school-related problems variable. All JAMAR components revealed good psychometric performances. In conclusion, the Hindi version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

Aims To explore knowledge, attitudes, and practices relating to musculoskeletal examination (MSKe) in one state of India. Methods Pediatricians from the state of Maharashtra (capital – Mumbai) were invited to complete an 11-item web-based survey. Participation implied consent and the survey was based on a similar UK study. All pediatricians from the state of Maharashtra ( n = 1523) were invited to participate; 223 pediatricians responded (response rate: 14.64%) with variable training in pediatrics and experience. Results Respondents reported similar time devoted within their consultations to management plan, history, and physical examination. Most ( n = 166, 74.44%) had been taught to examine the musculoskeletal system in children ( n = 82, 36.77%) or in both adults and children ( n = 84, 37.67%). However, MSKe was not part of their current routine practice, despite many ( n = 115, 51.57%) deeming this an important part of assessment. The majority ( n = 207, 92.82%) were very confident ( n = 7, 3.14%), or confident in some ( n = 120, 53.81%) or most ( n = 80, 35.87%) aspects of performing a structured MSKe, but were less confident with MSKe compared to other systems. Most ( n = 158, 70.85%) were unaware of pGALS (Pediatric Gait Arms Legs Spine) prior to the survey but many ( n = 204, 91.48%) were supportive of its inclusion within the curriculum for undergraduates and/or postgraduates, and expressed a desire to receive more information. Conclusions Many pediatricians are not confident in MSKe and are less confident compared to other bodily systems. There is need for greater training and awareness about the importance of MSKe at both undergraduate and postgraduate level. As a simple validated clinical skill, there is considerable potential to increase teaching of pGALS and thereby ultimately potentially improve MSKe performance in clinical practice.

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.

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.

Thrombotic thrombocytopenic purpura (TTP) and systemic lupus erythematosus (SLE) very rarely present simultaneously and pose a diagnostic and therapeutic dilemma to the physician. Prompt diagnosis and management with plasma exchange and immunosuppression is life-saving. To describe the effectiveness of cryosupernatant and steroids in pediatric SLE with TTP. We describe three children aged 12–14 years with SLE who were diagnosed with TTP based on fever, CNS manifestations, ANA, anti-dsDNA, anti-sm positivity, hypocomplementemia, and microangiopathic anemia with thrombocytopenia. All three children were managed with cryosupernatant and steroids without plasmapheresis. All children improved with cryosupernatant and steroids. All attained remission within 10 days. They were doing well at last follow up without relapse or flare. Cryosupernatant and steroids may be an effective therapy for Thrombotic thrombocytopenic purpura with systemic lupus erythematosus

Background Pertussis and measles infection as well as vaccination have been suspected as possible mediating factors of allergic disease in childhood. Methods Between 1995 and 2005 cross-sectional studies were performed in 29 centers in 21 countries. Parental questionnaires were used to collect information on allergic diseases and exposures. We analyzed data from 54,943 randomly selected schoolchildren aged 8–12 yr. A subgroup of 31,759 children was also skin prick tested (SPT) to common environmental allergens. Combined odds ratios were calculated by random effect models for meta-analysis. Results Pertussis and measles vaccination were not significantly associated with any of the allergy outcomes or SPT positivity. However, pertussis infection was associated with wheeze (ORad 1.68; 95% CI 1.44–1.97) and rhinoconjunctivitis (ORad 1.63; 95% 1.33–2.00). Pertussis infection was also significantly associated with a higher prevalence of reported eczema during the past year in non-affluent countries. Measles infection was associated with a higher prevalence of wheeze (ORad 1.26; 95% 1.10–1.43) and reported eczema (ORad 1.22; 95% 1.08–1.39). No association with SPT positivity was found, suggesting that these associations are unlikely to be mediated by an allergic component. Conclusions Associations of pertussis and measles infection with symptoms of asthma, rhinoconjunctivitis and eczema were found in both affluent and non-affluent countries and are unlikely to be mediated by IgE.

Objective.To put forward a new concept — Blau arteritis, a form of large-vessel vasculitis phenotypically related to Takayasu disease but genetically and clinically part of an expanded phenotype of Blau syndrome.Methods.We provide a clinical description of a new case and summarize previously published cases of arteritis associated with Blau syndrome. Genetic testing was performed by direct sequencing of exon 4 of the NOD2 gene.Results.The case described and those reviewed from the literature demonstrate the emerging phenotype of Takayasu-like arteritis in patients with Blau syndrome. Although most patients described to date depict an otherwise classic Blau syndrome phenotype, the current case was atypical in that the predominant features were arteritic. A novel substitution, G464W, in a highly conserved position near the nucleotide oligomerization domain of the NOD2 protein is also described.Conclusion.Blau arteritis can be observed in the context of both typical and atypical (incomplete) Blau syndrome. The associated mutation in the NOD2 gene raises the question of the potential importance of this gene among patients with “primary” forms of Takayasu arteritis.

The concept of paediatric rheumatology clinics is relatively new to India. With the specialty still in its formative years, referrals are still delayed and children usually present after having visited multiple facilities. Our centre, which has been one of the “early birds” in setting up a paediatric rheumatology clinic in a tertiary hospital in Mumbai, reports on the spectrum of cases seen since its inception in 2003 and thereby provides a framework for those wanting to open such centres in India or for that matter in countries where paediatric rheumatology is coming of age.

Some have suggested a protective effect of tuberculosis (TB) infection on allergic disease risk, but few studies have examined the association between the two. We therefore investigated whether TB disease and bacillus Calmette-Guerin (BCG) vaccination in early life protect against allergic disease. Information on allergic disease symptoms, past TB disease, and BCG vaccination as well as potential confounding factors was gathered by parental questionnaire from a randomly selected subset of 23,901 8- to 12-yr-old schoolchildren in 20 centers in both developed and developing countries. Children were also physically examined for flexural eczema and underwent skin prick testing. Pooled odds ratio (OR) estimates and corresponding 95% confidence intervals (CIs) across study centers were calculated, using random effects meta-analysis models. There were 245 (1.0%) reported cases of TB disease, and 66.3% (15,857) of all children received the BCG vaccine. Asthma, hay fever, and flexural eczema symptoms in the past year as well as flexural eczema on skin examination were all positively linked to a history of TB (adjusted pooled OR 'wheeze in the past year' = 2.27, 95% CI 1.52-3.41; adjusted pooled OR 'hay fever symptoms in the past year' = 2.23, 1.22-4.09; adjusted pooled OR 'flexural eczema symptoms in the past year' = 3.21, 2.01-5.12; adjusted pooled OR 'flexural eczema on skin examination' = 4.04, 1.71-9.56). Even higher risk estimates were seen for severe asthma and eczema symptoms [adjusted OR = 4.02 (2.17-7.47) and adjusted OR = 6.31 (2.19-18.17), respectively]. There was no significant association between past TB and skin prick test positivity (adjusted pooled OR = 1.32, 0.87-2.02). BCG vaccination during the first year of life was also not associated with any of the allergy outcomes. We found a uniform positive association between TB and all allergic disease outcomes, including eczema on skin examination. As this was a cross-sectional study, it is unclear whether this positive association is attributable to a causal relationship, and further longitudinal studies are required.

Summary Background Exclusive breastfeeding for at least 4 months is recommended by many governments and allergy organizations to prevent allergic disease. Objectives To investigate whether exclusive breastfeeding protects against childhood eczema. Methods Study subjects comprised 51 119 randomly selected 8- to 12-year-old schoolchildren in 21 countries. Information on eczema and breastfeeding was gathered by parental questionnaire. Children were also examined for flexural eczema and underwent skin prick testing. Odds ratios (ORs) were calculated for each study centre and then pooled across populations. Results There was a small increase in the risk of reported ‘eczema ever’ in association with ‘breastfeeding ever’ and breastfeeding 6 months (pooled adjusted OR 1·09, 95% CI 0·94–1·26). Risk estimates were very similar for exclusive breastfeeding 4 months and for eczema symptoms in the past 12 months and eczema on skin examination. As for more severe eczema, breastfeeding per se conveyed a risk reduction on sleep disturbed eczema (pooled adjusted OR 0·71, 95% CI 0·53–0·96), but this effect was lost where children had been exclusively breastfed for > 4 months (pooled adjusted OR 1·02, 95% CI 0·67–1·54). Allergic sensitization and a history of maternal allergic disease did not modify any of these findings. Conclusions Although there was a protective effect of ever having been breastfed on more severe disease, we found no evidence that exclusive breastfeeding for 4 months or longer protects against eczema. Our results are consistent with findings from a recent systematic review of prospective studies. The U.K. breastfeeding guidelines with regard to eczema should be reviewed. Intervention studies are now required to explore how and when solids should be introduced alongside breastfeeding to aid protection against eczema and other allergic diseases.

Objective To evaluate response to therapy over a 24-month period in a large prospective international cohort of patients with juvenile dermatomyositis (DM). Methods The study included 145 patients with recent-onset juvenile DM and 130 juvenile DM patients experiencing disease flare, all of whom were

In children with Crouzon syndrome, craniofacial dysmorphism predisposes them to sleeprelated breathing disorders. In this review, we have discussed the clinical manifestation, consequences, and need for management with both temporary and definitive measures of Obstructive sleep apnea syndrome (OSAS).

RATIONALE: Bronchial responsiveness is an objectively measurable trait related to asthma. Its prevalence and association with asthma symptoms among children in many countries are unknown. OBJECTIVES: To investigate international variations in bronchial responsiveness (BR) and their associations with asthma symptoms and atopic sensitization. METHODS: Bronchial challenge tests were conducted in 6,826 schoolchildren (aged 8-12 years) in 16 countries using hypertonic (4.5%) saline. FEV(1) was measured at baseline and after inhalation for 0.5, 1, 2, 4, and 8 min. BR was analyzed both as a dichotomous (bronchial hyperreactivity, BHR, at least 15% decline in FEV(1)) and as a continuous variable (time-response slope, BR slope, individual decline in FEV(1) per log(min)). RESULTS: Prevalence of wheeze last year ranged from 4.4% in Tirana (Albania) to 21.9% in Hawkes Bay (New Zealand) and of BHR from 2.1% in Tirana to 48% in Mumbai (India). The geometric mean BR slope varied between 3.4%/log(min) in Tirana and 12.8%/log(min) in Mumbai and Rome (Italy). At the individual level, BHR was positively associated with wheeze during the past 12 months both in affluent countries (OR = 3.6; 95% CI: 2.7-5.0) and non-affluent countries (OR = 3.0; 1.6-5.5). This association was more pronounced in atopic children. There was a correlation (rho = 0.64, P = 0.002) between center-specific mean BR slope and wheeze prevalence in atopic, but not in non-atopic children. CONCLUSIONS: BR to saline in children varied considerably between countries. High rates of BR were not confined to affluent countries nor to centers with high prevalences of asthma symptoms. The association between wheeze and BHR at the individual level differed across centers and this heterogeneity can be largely explained by effect modification by atopy. Pediatr. Pulmonol. 2010; 45:796-806. (c) 2010 Wiley-Liss, Inc.