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Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease with both autoimmune and autoinflammatory components. Recently, familial cases of systemic-onset JIA have been attributed to mutations in LACC1/FAMIN. We describe three affected siblings from a Moroccan consanguineous family with an early-onset chronic, symmetric and erosive arthritis previously diagnosed as rheumatoid factor (RF)-negative polyarticular JIA. Autozygosity mapping identified four homozygous regions shared by all patients, located in chromosomes 3, 6 (n:2) and 13, containing over 330 genes. Subsequent whole exome sequencing identified two potential candidate variants within these regions (in FARS2 and LACC1/FAMIN). Genotyping of a cohort of healthy Moroccan individuals (n: 352) and bioinformatics analyses finally supported the frameshift c.128_129delGT mutation in the LACC1/FAMIN gene, leading to a truncated protein (p.Cys43Tyrfs*6), as the most probable causative gene defect. Additional targeted sequencing studies performed in patients with systemic-onset JIA (n:23) and RF-negative polyarticular JIA (n: 44) revealed no pathogenic LACC1/FAMIN mutations. Our findings support the homozygous genotype in the LACC1/FAMIN gene as the defect underlying the family here described with a recessively inherited severe inflammatory joint disease. Our evidences provide further support to the involvement of LACC1/FAMIN deficiency in different types of JIA in addition to the initially described systemic-onset JIA., The authors would like to thank the CRG Genomics Unit for assistance with whole exome sequencing. This work has been partially funded by: CERCA Programme/Generalitat de Catalunya (JIA, XE, SO), the PERIS program of the Generalitat de Catalunya grant SLT002/16/00310 (RR), the Spanish Ministry of Economy and Competitiveness co-financed by European Regional Development Fund (ERDF) grant SAF2015-68472-C2-1-R (JIA), the Instituto de Salud Carlos III/Transnational Research Projects on Rare Diseases (JIA) grant AC15/00027, the Spanish Society of Pediatric Rheumatology (JIA), the Secretaria d’Universitats i Recerca del Departament d’Economia grant 2009-SGR-1502 (XE) and the European Union Seventh Framework Programme (FP7/2007-2013) grant agreement no. 262055 (XE). We also acknowledge support of the Spanish Ministry of Economy and Competitiveness (MEIC) to the EMBL partnership, ‘Centro de Excelencia Severo Ochoa’.

OBJECTIVE: To identify biomarkers of articular and ocular disease activity in patients with Blau syndrome (BS). METHODS: Multiplex plasma protein arrays were performed in five BS patients and eight normal healthy volunteers (NHVs). Plasma S100A12 and S100A8/9 were subsequently measured by ELISA at baseline and 1-year follow-up in all patients from a prospective multicentre cohort study. CRP was measured using Meso Scale Discovery immunoassay. Active joint counts, standardization uveitis nomenclature for anterior uveitis cells and vitreous haze by Nussenblatt scale were the clinical parameters. RESULTS: Multiplex Luminex arrays identified S100A12 as the most significantly elevated protein in five selected BS vs eight NHVs and this was confirmed by ELISA on additional samples from the same five BS patients. In the patient cohort, S100A12 (n = 39) and S100A8/9 (n = 33) were significantly higher compared with NHVs (n = 44 for S100A12, n = 40 for S100A8/9) (P = 0.0000004 and P = 0.0003, respectively). Positive correlations between active joint counts and S100 levels were significant for S100A12 (P = 0.0008) and S100A8/9 (P = 0.015). CRP levels did not correlate with active joint count. Subgroup analysis showed significant association of S100 proteins with active arthritis (S100A12 P = 0.01, S100A8/9 P = 0.008). Active uveitis was not associated with increased S100 levels. CONCLUSION: S100 proteins are biomarkers of articular disease activity in BS and potential outcome measures in future clinical trials. As secreted neutrophil and macrophage products, S100 proteins may reflect the burden of granulomatous tissue in BS.

To develop recommendations on the transition from pediatric care to adult care in patients with chronic inflammatory rheumatic diseases with childhood onset based. Recommendations were generated following nominal group methodology and Delphi technique. A panel of 16 experts was established. A systematic literature review (on transitional care) and a narrative review were performed and presented to the panel in the first panel meeting to be discussed. A first draft of recommendations was generated and circulated. Focal groups with adolescents, young adults and parents were organized. In a second meeting, the focus group results along with the input from invited psychologist were used to establish definitive recommendations. Then, a Delphi process (two rounds) was carried out. A group of 72 pediatric and adult rheumatologists took part. Recommendations were voted from 1 (total disagreement) to 10 (total agreement). We defined agreement if at least 70 % voted ≥7. The level of evidence and grade or recommendation was assessed using the Oxford center for evidence-based medicine levels of evidence. Transition care was defined as a purposeful, planned process that addresses the medical, psychosocial and educational/vocational needs of adolescents and young adults with chronic inflammatory rheumatic diseases with childhood onset as they move from child-centered to adult-oriented healthcare systems. The consensus covers: transition needs, barriers and facilitators, transitional issues (objectives, participants, content, phases, timing, plans, documentation and responsibilities), physicians' and other health professionals' knowledge and skill requirements, models/programs, and strategies and guideline for implementation. Preliminary recommendations and agreement grade are shown in the Table (first Delphi round). These recommendations are intended to provide health professionals, patients, families and other stakeholders with a consensus on the transition process from pediatric to adult care.

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.

Objective To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA). Methods A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of 28 experts was first asked to classify 428 patient profiles as having or not having MAS, based on clinical and laboratory features at the time of disease onset. The 428 profiles comprised 161 patients with systemic JIA-associated MAS and 267 patients with a condition that could potentially be confused with MAS (active systemic JIA without evidence of MAS, or systemic infection). Next, the ability of candidate criteria to classify individual patients as having MAS or not having MAS was assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The final criteria were selected in a consensus conference. Results Experts achieved consensus on the classification of 391 of the 428 patient profiles (91.4%). A total of 982 candidate criteria were tested statistically. The 37 best-performing criteria and 8 criteria obtained from the literature were evaluated at the consensus conference. During the conference, 82% consensus among experts was reached on the final MAS classification criteria. In validation analyses, these criteria had a sensitivity of 0.73 and a specificity of 0.99. Agreement between the classification (MAS or not MAS) obtained using the criteria and the original diagnosis made by the treating physician was high (κ = 0.76). Conclusion We have developed a set of classification criteria for MAS complicating systemic JIA and provided preliminary evidence of its validity. Use of these criteria will potentially improve understanding of MAS in systemic JIA and enhance efforts to discover effective therapies, by ensuring appropriate patient enrollment in studies.

Objectives: To develop a consensus document of recommendations for the use of methotrexate (MTX) in patients with juvenile idiopathic arthritis (JIA). Material and method: A group of eleven experts proposed several clinical questions on the use of MTX in patients with JIA. A systematic review was conducted and the evidence and recommendations for each question were extracted. The results were discussed and validated by the experts in a work session to establish the final recommendations. Results: MTX is recommended as the first drug for inducing remission in JIA, and its indication should be made according to the clinical category of the patient. Prior to treatment, it is recommended to perform a complete blood count, including white cells, levels of liver enzymes, serum creatinine, and other analytical parameters according to specific risk factors. Treatment should be initiated with a dose of 10–15 mg/m2/week. In cases of uveitis or polyarthritis, an initial dose of 15 mg/m2/week should be considered. For a better bioavailability and tolerability, it is preferable to administer MTX parenterally if the dose is ≥15 mg/m2/week. It is necessary to periodically perform an analytical monitoring of the patient and to assess possible alterations in liver enzymes to make changes if necessary. Combinations with biological agents may be necessary, as well as the concomitant addition of folic or folinic acid. Conclusions: This document describes the main recommendations for the appropriate use of MTX in JIA patients, according to scientific evidence and clinical experience. Resumen: Objetivos: Elaborar un documento de recomendaciones consensuadas para el uso de metotrexato (MTX) en pacientes con artritis idiopática juvenil (AIJ). Material y método: Un grupo de 11 expertos planteó diversos interrogantes clínicos en el uso de MTX en pacientes con AIJ. Se realizó una revisión sistemática y se extrajeron las evidencias y recomendaciones para cada pregunta. Los resultados fueron valorados y consensuados por los expertos en una sesión presencial para establecer las recomendaciones finales. Resultados: Se recomienda el MTX como primer fármaco inductor de remisión en AIJ, cuya indicación se realizará según la categoría clínica del paciente. Previo al tratamiento se recomienda evaluar un hemograma que incluya recuento leucocitario, niveles de enzimas hepáticas y creatinina sérica, así como otros parámetros analíticos conforme a factores de riesgo específicos. El tratamiento se iniciará con dosis de 10–15 mg/m2/semana. En casos de uveítis o poliartritis se valorará una dosis inicial de 15 mg/m2/semana. Para una mejor biodisponibilidad y tolerabilidad, se administrará preferentemente por vía parenteral si la dosis es ≥ 15 mg/m2/semana. Se deberá realizar un seguimiento analítico del paciente periódicamente y evaluar posibles alteraciones en enzimas hepáticas para realizar cambios si fuera preciso. La combinación con biológicos puede ser necesaria, además del uso concomitante de ácido fólico o folínico. Conclusiones: Este documento recoge las principales recomendaciones para el empleo adecuado de MTX en pacientes con AIJ, de acuerdo a la evidencia científica y a la experiencia clínica.

Resumen: Introducción: La cojera es un motivo de consulta frecuente. Nuestro objetivo es describir las características de los niños con cojera valorados en Reumatología. Material y Métodos: Estudio de corte transversal desde octubre de 2009 a junio de 2010. Las variables incluyeron: datos epidemiológicos, síntomas clínicos y pruebas de laboratorio e imagen. Resultados: Los 95 pacientes se clasificaron en cuatro grupos de acuerdo con su diagnóstico, inflamatorio 22%, infeccioso 17%, sinovitis transitoria de cadera 13% y miscelánea 48%. Había diferencias entre grupos en la edad (p

Resumen: Introducción: La ecografía no distingue entre los diferentes tipos de sinovitis. El objetivo de este trabajo fue valorar su contribución junto a algunos datos clínicos en el diagnóstico de la artritis séptica (AS) y la sinovitis transitoria (ST) de cadera. Método: Estudio prospectivo de pacientes con ST o AS de cadera unilateral realizado entre diciembre 2006 y julio 2009. Las variables incluyeron manifestaciones clínicas y medidas ecográficas. Las ecografías fueron realizadas con un método estandarizado. Resultados: La muestra estaba compuesta por 26 niños, 22 diagnosticados de ST y 4 de AS. Se encontró diferencia en la historia de fiebre (p=0,002). La edad no era diferente, aunque la media y la mediana en ST fue 6 años, frente a media de 4,3 y mediana de 2,3 en AS. Tampoco fueron diferentes las medidas ecográficas.El valor predictivo positivo del criterio «mayor de 4 años y ausencia de fiebre» para el diagnóstico de sinovitis transitoria fue 100%, mientras que «menor de 4 años e historia de fiebre» para el diagnóstico de artritis séptica era del 75%, siempre que la radiología hubiese excluido procesos ortopédicos y la ecografía mostrara derrame. Conclusiones: Pese a las limitaciones del estudio (tamaño de la muestra y baja prevalencia) la combinación de edad e historia de fiebre parece útil para diferenciar la sinovitis transitoria de la artritis séptica. La contribución de la ecografía fue confirmar la presencia de derrame articular. Abstract: Introduction: Ultrasound does not distinguish between different types of synovitis. The aim of this study was to evaluate its contribution, together with several clinical data, in the diagnosis of septic arthritis (SA) and transient synovitis (TS) of the hip. Methods: Prospective study of patients diagnosed with unilateral SA or TS of the hip carried out between December 2006 and July 2009. A set of clinical variables and ultrasound measurements were analysed. The ultrasound examinations were performed using a standardised procedure. Results: The sample included 26 children, 22 diagnosed with TS and 4 with SA. A difference was found in the history of fever (P=0.002). On the other hand, no differences were detected in the age of the children, although mean and median in the TS group were 6 years vs a mean of 4.3 with a median of 2.3 years in the SA group. There were no differences in the ultrasound measurements either.The positive predictive value of the criterion “older than 4 years of age and no history of fever” for the diagnosis of transient synovitis was 100%, while “younger than 4 years and history of fever” for the diagnosis of septic arthritis was 75%, once radiology had excluded orthopaedic processes and ultrasound showed an effusion. Conclusions: In spite of the study limitations (sample size and low prevalence) the combination of age and history of fever appears to be useful in distinguishing transient synovitis from septic arthritis. The contribution of ultrasound was to confirm the presence of joint effusion.

Objective To study the phenotype characteristics of the largest to date cohort of patients with pediatric granulomatous arthritis (PGA) and documented mutations in the NOD2 gene. Methods We analyzed merged data from 2 prospective cohorts of PGA patients, the International PGA Registry and a Spanish cohort. A systematic review of the medical records of interest was performed to identify phenotype characteristics. Results Forty-five patients with PGA (23 sporadic cases and 22 from familial pedigrees) and documented NOD2 mutations were identified and formed the basis of the study. Of these 45 patients, 18 had the R334W-encoding mutation, 18 had R334Q, 4 had E383K, 3 had R587C, 1 had C495Y, and 1 had W490L. The majority of patients manifested the typical triad of dermatitis, uveitis, and arthritis. In contrast, in 13 patients, the following “atypical” manifestations were noted: fever, sialadenitis, lymphadenopathy, erythema nodosum, leukocytoclastic vasculitis, transient neuropathy, granulomatous glomerular and interstitial nephritis, interstitial lung disease, arterial hypertension, hypertrophic cardiomyopathy, pericarditis, pulmonary embolism, hepatic granulomatous infiltration, splenic involvement, and chronic renal failure. In addition, 4 individuals who were asymptomatic carriers of a disease-causing mutation were documented. Conclusion NOD2-associated PGA can be a multisystem disorder with significant visceral involvement. Treating physicians should be aware of the systemic nature of this condition, since some of these manifestations may entail long-term morbidity.

Objective Blau syndrome and early-onset sarcoidosis are NOD2 gene–associated chronic autoinflammatory diseases characterized by skin rash, arthritis, and/or eye involvement, with noncaseating granulomata as their pathologic hallmark. This study was undertaken to describe the expanded clinical phenotype, treatment outcomes, and NOD2 gene mutation analysis in a Spanish cohort with pediatric granulomatous arthritis, a chronic disease resembling Blau syndrome/early-onset sarcoidosis. Methods Clinical, laboratory, and treatment data on the 12 patients in the cohort were obtained through direct interviews. NOD2 gene analysis was performed in a central laboratory, by bidirectional sequencing. Cytokine levels were measured using the human Flex-Set cytokine bead array. Results The classic Blau syndrome/early-onset sarcoidosis triad of skin rash, arthritis, and recurrent uveitis was identified in 5 patients (41.7%), whereas 7 patients (58.3%) presented with fewer than 3 of the classic features. Novel atypical manifestations such as persistent fever and myocardiopathy were also observed. NOD2 analysis revealed 1 heterozygous mutation in each patient, and familial studies confirmed its full penetrance. Of the 12 cases, 58.3% were sporadic, due to de novo mutations. Four different missense mutations on exon 4 were detected. Two of them (R334W and R334Q) were recurrent mutations and were found in 77.8% of the Spanish families, whereas the other 2 (C495Y and R587C) were novel. In the patient who received anakinra treatment, all clinical inflammatory symptoms improved and plasma cytokine levels normalized. Conclusion These findings indicate that the expanding clinical heterogeneity of the disease (that is, the presentation of incomplete forms of the classic triad and atypical manifestations) and the high prevalence of sporadic cases should alert clinicians to the possible genetic basis of the condition and support the inclusion of DNA analysis as a diagnostic test. The positive response to anakinra observed in 1 patient suggests a new potential therapeutic approach that merits further investigation, and suggests that the pathogenesis of pediatric granulomatous arthritis may involve interleukin-1–mediated events.

Preliminary response to Janus kinase inhibition with baricitinib in chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) G Montealegre, A Reinhardt, P Brogan, Y Berkun, A Zlotogorski, D Brown, P Chira, L Gao, J Dare, S Schalm, R Merino, D Chapelle, H Kim, S Judd, M O’Brien, A Almeida De Jesus, Y Kim, B Kost, Y Huang, S Paul, A Brofferio, C-C Lee, C Hadigan, T Heller, C Minniti, K Rother, R Goldbach-Mansky

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.

Uveitis associated with juvenile idiopathic arthritis (JIA) typically involves the anterior chamber segment, follows an indolent chronic course, and presents a high rate of uveitic complications and a worse outcome as compared to other aetiologies of uveitis. Disease assessment, treatment, and outcome measures have not been standardized. Collaboration between pediatric rheumatologists and ophthalmologists is critical for effective management and prevention of morbidity, impaired vision, and irreparable visual loss. Although the Standardization of Uveitis Nomenclature Working Group recommendations have been a great advance to help clinicians to improve consistency in grading and reporting data, difficulties arise at the time of deciding the best treatment approach in the individual patient in routine daily practice. For this reason, recommendations for a systematized control and treatment strategies according to clinical characteristics and disease severity in children with JIA-related uveitis were developed by a panel of experts with special interest in uveitis associated with JIA. A clinical management algorithm organized in a stepwise regimen is here presented.

This is a consensus document of the Sociedad Española de Infectología Pediátrica, Sociedad Española de Reumatología Pediátrica and Sociedad Española de Ortopedia Pediátrica on the aetiology and diagnosis of uncomplicated acute osteomyelitis and septic arthritis.A review is presented of the aetiopathogenesis and pathophysiology of acute osteoarticular infection defined as a process with less than 14 days of symptomatology, uncomplicated, and community-acquired. The diagnostic approach to these conditions is summarised based on the best available scientific knowledge. Based on this evidence, a number of recommendations for clinical practice are provided. Resumen: Se presenta el Documento de Consenso sobre etiopatogenia y diagnóstico de la osteomielitis aguda y la artritis séptica no complicadas elaborado por la Sociedad Española de Infectología Pediátrica, la Sociedad Española de Reumatología Pediátrica y la Sociedad Española de Ortopedia Pediátrica.En este documento se revisan la etiopatogenia y la fisiopatología de la infección osteoarticular aguda en niños, considerada como aquella no complicada, de origen comunitario, que presenta una evolución inferior a 14 días, así como la aproximación clínico-diagnóstica a estas entidades, basándonos en las mejores evidencias científicas disponibles. En función de dichas evidencias, se aportan una serie de recomendaciones para la práctica clínica.

BS is an autosomal dominant monogenic granulomatous disease due to gain of function mutations at or near the NACHT domain of NOD2. It is characterized by a triad of granulomatous polyarthritis, uveitis and rash. Retrospective work by our group showed a life time risk of ocular involvement of 60% with significant morbidity and poor visual outcome. Prospective studies on natural history of visual outcome are not available. In view of current lack of effective therapies, research on relevant pathways downstream NOD2 is essential and may lead to appropriate targeted drug development.

Objective. To propose a reduced joint power Doppler US (PDUS) assessment and provide preliminary evidence of its validity, feasibility, reliability and sensitivity to change compared with a comprehensive (i.e. 44 joints) PDUS assessment in evaluating synovitis in JIA. Methods. This multicentre study included 42 children with active JIA with 54 clinically involved joints requiring modified therapy. At each visit, clinical and PDUS assessments were performed blinded. Each joint was scored for greyscale (GS) synovitis and power Doppler signal according to a 4-point semiquantitative scale with calculation of US composite indices and US composite joint counts. A process of data reduction based on the frequency of US joint involvement was performed to obtain a reduced PDUS assessment. The relationship between the comprehensive and the reduced PDUS assessments was investigated by Spearman’s coefficient at all visits, as well as the relationship between changes in the two PDUS assessments during follow-up. In addition, the metric properties of the comprehensive and the reduced PDUS assessments were tested. Results. The 10-joint PDUS assessment, including bilateral knee, ankle, wrist, elbow and the second MCP joints, detected 100% of children with GS synovitis and power Doppler signal. The two PDUS assessments were highly correlated at all visits. The reduced model had a higher responsiveness than the comprehensive model. Intraobserver and interobserver agreement was good for both US findings. Conclusion. The 10-joint PDUS assessment is valid and feasible for assessment of synovitis in JIA in clinical practice.

Intra-articular corticosteroid injections (IACI) are one of the mainstays of treatment for children with juvenile idiopathic arthritis. The most important disadvantage of IACI is the pain associated with the procedure. Little is known about the children or parents' perception of this pain. This study was undertaken to determine whether patients and their parents prefer sedation to receive IACI or not and why. A survey form was presented to patients and/or their parents from January to March 2010 to evaluate their choice of anesthesiologist-controlled deep sedation (with sevoflurane) vs. no sedation–no local anesthesia and the reasons for it. All participants had experienced the two options. In addition, there were two visual analog scales (VAS) to evaluate pain associated with blood draws and IACI, respectively. A total of 45 patients and their parents filled out the survey form. There were 34 females; the median age was 10.6 years, and the median duration of the disease was 6.4 years. Median VAS score was 1.3 for pain associated with blood draws, and 6, for IACI. Most children preferred sedation for IACI (26 vs. 15), although four did not show preference for either method. Children who preferred sedation for IACI were younger (p = 0.03) and had a shorter course of disease (p = 0.04). Conclusions: While most children prefer to receive IACI under sedation, a majority of parents prefer to avoid its risks. Children who prefer IACI without sedation are significantly older and have a longer course of disease.

Purpose To report the results of adalimumab therapy in a cohort of children with refractory noninfectious uveitis. Methods The medical records of patients diagnosed with uveitis and treated with biweekly adalimumab injections for a period of at least 3 months at the University Hospital of La Paz from 2007-2012 were retrospectively reviewed. Improvement in inflammatory activity was graded according to grading schema of the Standardization of Uveitis Nomenclature Working Group. Results A total of 15 patients participated in the study (12 girls; mean patient age, 12 years). Diagnoses included juvenile idiopathic arthritis in 10 patients, idiopathic uveitis in 4, and familial juvenile systemic granulomatosis or Blau syndrome in 1. Mean follow-up was 32 months (median, 36; range, 15-58 months). Improvement in inflammatory activity was initially observed in 12 (86%) of 14 children, with a mean time to achieve response of 6 weeks (median, 4; range, 1-18). Treatment was effective in 9 patients (60%), mildly effective in 2 (13%), ineffective in 2 (13%), and resulted in worsening in 2 (13%). In the juvenile idiopathic arthritis patients, response was effective in 6 cases (60%), mildly effective in 2 (20%), and ineffective in 2 (20%). Adalimumab therapy was discontinued in 4 patients. Conclusions Adalimumab was effective in most patients in the initial control of acute inflammatory activity in children with refractory uveitis, although therapy appears to become less effective in the long term.

Background Systemic juvenile idiopathic arthritis (JIA) is the most severe subtype of JIA; treatment options are limited. Interleukin-6 plays a pathogenic role in systemic JIA. Methods We randomly assigned 112 children, 2 to 17 years of age, with active systemic JIA (duration of ≥6 months and inadequate responses to nonsteroidal antiinflammatory drugs and glucocorticoids) to the anti–interleukin-6 receptor antibody tocilizumab (at a dose of 8 mg per kilogram of body weight if the weight was ≥30 kg or 12 mg per kilogram if the weight was

Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome (MIM no. #607715), also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly-inherited autoinflammatory disease that is characterized by neonatal onset and the triad of urticarial-like skin rash, neurologic manifestations, and arthritis/arthropathy. Patients often experience recurrent fever and systemic inflammation. NOMID/CINCA syndrome is the most severe clinical phenotype of the cryopyrin-associated periodic syndromes (CAPS) that also include the 2 less severe but phenotypically similar syndromes familial cold autoinflammatory syndrome (FCAS; MIM no. #120100) and Muckle-Wells syndrome (MIM no. #191900). CAPS are caused by mutations in the NLRP3 gene, which is a member of the nucleotide-binding oligomerization domain–like receptor (NLR) family of the innate immune system (1, 2). NLRP3 is an intracellular “sensor” of danger signals arising from cellular insults, such as infection, tissue damage, and metabolic deregulation, and it has been highly conserved throughout evolution. NLRP3 associates with ASC and procaspase 1 to constitute a large multiprotein complex termed the NLRP3 inflammasome. When activated, the NLRP3 inflammasome converts the biologically inactive procaspase 1 into active caspase 1. Caspase 1 produces the cytokines interleukin-1β (IL-1β) and IL-18, which are mainly involved in the inflammatory response (3). Available research suggests that mutated NLRP3 induces autoactivation of the NLRP3 inflammasome in CAPS patients, resulting in an uncontrolled overproduction of IL-1β. Most CAPS patients carry heterozygous germline missense mutations in the NLRP3 coding region (“mutation-positive” patients) (4, 5). More than 80 different disease-causing mutations have been reported to date (6). However, ~40% of clinically diagnosed NOMID/CINCA syndrome patients show no heterozygous germline NLRP3 mutation during conventional Sanger-sequencing-based genetic analyses (“mutation-negative” patients). Comparisons of NOMID/CINCA syndrome patients with and without heterozygous germline NLRP3 mutations have revealed no differences in clinical features or response to treatment (4, 7). In a previous study, we identified a high incidence of somatic NLRP3 mosaicism in “mutation-negative” NOMID/CINCA syndrome patients in Japan (8). We therefore hypothesized that somatic NLRP3 mosaicism may be implicated in the etiology of the disorder, although its precise contribution remains unclear. The aim of the present study was to evaluate both the frequency of NLRP3 somatic mosaicism in NOMID/CINCA syndrome patients and the association between somatic mosaicism and clinical phenotype using an international cohort of mutation-negative NOMID/CINCA syndrome patients.

Resumen: Se presenta el Documento de Consenso sobre etiopatogenia y diagnóstico de la osteomielitis aguda y la artritis séptica no complicadas elaborado por la Sociedad Española de Infectología Pediátrica, la Sociedad Española de Reumatología Pediátrica y la Sociedad Española de Ortopedia Pediátrica.En este documento se revisan la etiopatogenia y la fisiopatología de la infección osteoarticular aguda en niños, considerada como aquella no complicada, de origen comunitario, que presenta una evolución inferior a 14 días, así como la aproximación clínico-diagnóstica a estas entidades, basándonos en las mejores evidencias científicas disponibles. En función de dichas evidencias, se aportan una serie de recomendaciones para la práctica clínica. Abstract: This is a Consensus Document of the Sociedad Española de Infectología Pediátrica, Sociedad Española de Reumatología Pediátrica and Sociedad Española de Ortopedia Pediátrica on the aetiology and diagnosis of uncomplicated acute osteomyelitis and septic arthritis.A review is presented of the aetiopathogenesis and pathophysiology of acute osteoarticular infection defined as a process with less than 14 days of symptomatology, uncomplicated, and community-acquired. The diagnostic approach to these conditions is summarised based on the best available scientific knowledge. Based on this evidence, a number of recommendations for clinical practice are provided.

This is a Consensus document of the Spanish Society of Paediatric Infectious Diseases (Sociedad Española de Infectología Pediatrica), the Spanish Society of Paediatric Rheumatology (Sociedad Española de Reumatología Pediátrica) and the Spanish Society of Paediatric Orthopaedics (Sociedad Española de Ortopedia Pediátrica), on the treatment of uncomplicated acute osteomyelitis and septic arthritis.A review is presented on the medical and surgical treatment of acute osteoarticular infection, defined as a process with

Objective To validate and promulgate a core set of outcome measures for the evaluation of response to treatment in patients with juvenile systemic lupus erythematosus (SLE). Methods In 2001, a preliminary consensus-derived core set of measures for evaluating the response to therapy in juvenile SLE was established. In the present study, the core set was validated through an evidence-based, large-scale data collection process that led to the enrollment of 557 patients from 39 different countries. Consecutive patients with active disease were assessed at baseline and after 6 months. The validation procedures included assessment of feasibility, responsiveness, discriminant and construct ability, agreement in the evaluation of response to therapy between physicians and parents, redundancy, internal consistency, and ability to predict a therapeutic response. Results The following clinical measures were found to be feasible and to have good construct validity, discriminative ability, and internal consistency; furthermore, they were not redundant, proved responsive to clinically important changes in disease activity, and were associated strongly with treatment outcome and thus were included in the final core set: 1) physician's global assessment of disease activity, 2) global disease activity measure, 3) 24-hour proteinuria, 4) parent's global assessment of the patient's overall well-being, and 5) health-related quality of life assessment. Conclusion The members of PRINTO propose a core set of criteria for the evaluation of response to therapy that is scientifically and clinically relevant and statistically validated. The core set will help standardize the conduct and reporting of clinical trials and assist practitioners in deciding whether a patient with juvenile SLE has responded adequately to therapy.

Sarcoidosis is a rare multisystemic granulomatous disease. Pulmonary involvement is common in adults, but any organ can be affected.

Background Many young people with rheumatic childhood-onset diseases continue to require medical care into adult life. There are many differences between pediatric and adult care. Although there is an extensive evidence base for the need of transitional care, there is a paucity of robust outcome data and a great variability on the models of transitional care. Objectives To develop recommendations on the transition from pediatric care to adult care in patients with chronic inflammatory rheumatic diseases with childhood-onset based on the best evidence and experience. Methods Recommendations were generated following nominal group methodology and Delphi technique. A panel of experts was established (8 pediatricians, 8 rheumatologists). A systematic literature review (on) and a narrative review (websites, clinical guidelines and other relevant documentation) were performed and presented to the panel in the 1st panel meeting to be discussed and to help define recommendations. A first draft of recommendations was generated and circulated for comments and wording refinements. Focal groups with adolescents, young adults and parents were separately. In a 2nd panel meeting the focus group results along with the input from invited nurses and psychologists were used to established definitive recommendations. A Delphi process (2 rounds) was carried out. A large group of pediatricians and rheumatologits took part. Recommendations were voted from 1 (total disagreement) to 10 (total agreement). We defined agreement if at least 70% voted ≥7. The level of evidence and grade or recommendation was assessed using the Oxford Centre for Evidence-based Medicine Levels of Evidence. Results Transition care was defined as a purposeful, planned process that addresses the medical, psychosocial and educational/vocational needs of adolescents and young adults with chronic inflammatory rheumatic diseases with childhood-onset as they move from child-centred to adult-oriented health care systems. The consensus covers: transition needs, barriers and facilitators, transitional issues (objectives, participants, content, phases, timing, plans, documentation, and responsibilities), physicians and other health professionals knowledge and skills requirements, models/programs, strategies and guideline for implementation. Conclusions These recommendations are intended to provide pediatricians, rheumatologists, patients, families and other stakeholders with a consensus on the transition process from pediatric care to adult care in patients with chronic inflammatory rheumatic diseases with childhood-onset. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5689

To the Editor: Etanercept (ETN) has been used to treat patients with juvenile idiopathic arthritis (JIA) with demonstrated efficacy and safety1,2. However, few studies have addressed the appropriate time and the way to discontinue the drug once the disease is inactive. We analyzed the progress of patients with JIA after discontinuation of ETN and the clinical response to reintroduction of the drug in those who relapsed. A retrospective chart review 2004 to 2009 revealed that therapy with ETN had been discontinued in 26 patients with JIA due to inactive disease (16 female, 10 male). The mean age at discontinuation of drug was 11 ± 2 (range 2.6–18.8) years. The clinical subtypes of JIA were 11 cases of enthesitis-related arthritis, 7 rheumatoid factor-negative polyarthritis, 2 systemic JIA with polyarticular involvement, 1 psoriatic arthritis, and 1 persistent oligoarticular arthritis. Inactive disease was defined according to the criteria of Wallace, et al 3, which required no joints with active arthritis, no … Address correspondence to Dr. Remesal; E-mail: agusremesal{at}hotmail.com

TRAPS is a rare lifelong disease. Optimal treatment is not established but tends to rely either on corticosteroids with risks of known short and long term side effects or anti cytokine agents which are expensive, and both types of agents lead to higher risk of infection.

Background TNF receptor associated periodic syndrome (TRAPS) is an autoinflammatory syndrome. Diagnosis relies on genetic testing. More than 70 TNFRSF1A pathogenic sequence variants (PSV) have been reported but it is not known if there are phenotype genotype correlations and interpretation of the significance of R92Q, a common variant of unknown significance (VUS), is often problematic. Objectives To analyse the presenting clinical features of patients with TNFRSF1A PSV and of those with inflammatory symptoms and the R92Q VUS. Methods Anonymised data derived from patient recall and case records were entered by specialist physicians to a web-based registry (www.printo.it). Results 46 TNFRSF1A PSV were identified in 86 patients; 11 (13%) carried the T50M PSV and in 40 (47%) a cysteine residue was affected; 61% patients reported a family history of similar symptoms; 52% were male; 94% were Caucasian and the mean age at symptom onset was 7.6 yrs (range: neonatal to 49 yrs). In 9% symptoms onset after aged 30 yrs. Median attack duration was 10 days and the median number of symptomatic days/yr was 51.5 (range: 8 – 365). Patients with the R92Q VUS were 98% Caucasian, 46% male and 17% reported a family history. Symptoms onset at a median of 10 yrs (range: neonatal to 52.6 yrs). Median attack duration was 6.5 days and the median number of symptomatic days/yr was 57. Clinical features seen in attacks are summarised in the table. Patients with the R92Q VUS were significantly less likely to have rash and more likely to have attacks features of headache, cervical adenopathy, headache and/or pharyngitis than patients with TNFRSF1A PSV. AA amyloidosis complicated 16 cases (19%) including 7 cysteine PSV (17.5%), 2 (18%) T50M and no patients with R92Q. Among patients with clear TNFRSF1A PSV no phenotype genotype correlations were identified. Conclusions The phenotype of PSV confirmed TRAPS is very variable with no pathognomonic pattern and no increased severity with cysteine or the T50M PSVs; musculoskeletal pain, fever, gastrointestinal symptoms and constitutional upset are most frequent. Even though there may have been a bias to entering patients with severe R92Q associated disease into the registry there are significant differences compared to patients with PSVs with a later presentation and more upper respiratory tract type symptoms reminiscent of those seen in PFAPA. Disclosure of Interest None Declared

Background Juvenile idiopathic arthritis (JIA) is a heterogeneous group of arthritides that all present with chronic joint inflammation that can lead to structural damage. The advances in therapeutic effectiveness have created a need for looking for imaging tools that describe more precisely the clinical state of disease inactivity. The well-known advantages of ultrasonography with power Doppler (PDUS) makes that this technique is ideal for evaluation of the pediatric population in the clinical setting and lets clinicians choose an appropriate treatment to induce remission. Objectives The purpose of this study was to determine the prevalence of abnormalities detected by ultrasonography (US) in JIA patients presenting clinically inactive disease (ID) –on medication and off medication – and to compare between two groups. Methods Study design: Cross-sectional, multicenter study. Patients: Inclusion criteria: 1) JIA patients, age from 4 to 16 years old, 2) remission according to clinical assessment by their consultant doctor for a minimum of 6 months prior to the screening, 3) taking stable disease modified anti-rheumatic drugs (DMARDs) therapy or have discontinued medications for JIA for a minimum of 6 months, 4) biologics naive patients. Exclusion criteria: Intra-articular steroid injection in the last 6 months. Data collected: Clinical and PDUS assessments were performed blindly on 44 joints. Other clinical and laboratory markers of activity disease were collected. For the analysis the Outcome Measure in Rheumatology in Clinical Trials (OMERACT) definitions for rheumatoid arthritis of synovitis and tenosynovitis were applied in our patients. The presence of Doppler signal inside the intraarticular synovium or in the synovial sheath was considered as inflammatory activity. Results 34 patients, of whom 23 patients have attained clinical remission on medication (CRM) with DMARD therapy and 11 patients have attained inactivity disease off medication (CR) (1). The mean (SD) disease duration was 48 (35) months. Half of the study patients have attained one or more previous inactivity disease state, but there was no significant difference between the 2 groups. Thirteen (38.2%) patients had evidence of ≥1 US findings, although the number of US abnormalities detected in CRM patients was higher than CR group, there were no significant differences between the 2 groups in detecting GS synovitis (p=0.86) and PD signal (p=0.38). US examination showed 37 joints presented GS synovial hypertrophy and 18 (48 %) of 37 joints with GS synovitis presented increased PD signal. Conclusions Our study shows that a proportion of patients presenting clinically inactive disease presented GS synovitis and some of them seem to present inflammatory activity detected by PDUS. The significance of these findings has importance in order to obtain an accurate definition of disease status in the growing skeleton of JIA patients. References Wallace CA, Ruperto N, Giannini EH. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol 2004; 31:2290-4 Disclosure of Interest P. Collado Grant/research support from: Pfiser, M. L. Gamir Grant/research support from: Pfiser, R. Merino Grant/research support from: Pfiser, C. Modesto Grant/research support from: Pfiser, I. Monteagudo Grant/research support from: Pfiser, J. C. Lopez-Robledillo Grant/research support from: Pfiser

Background Anakinra (ANK) is a recombinant interleukin-1 receptor antagonist currently used for treating autoinflammatory syndromes. Objectives To describe patient characteristics and their response to ANK in a tertiary centre between 2004 and 2011. Methods Retrospective study of 35 children treated with ANK. Demographic, clinical, analytical and genetic data were recorded. They were considered as responders when they reached analytic and clinical normalization and corticosteroids could then be discontinued. Results The sample included 21 boys and 14 girls, aged 3 days - 13 years old. Patient characteristics and response to ANK are summarised in the table [(values are expressed as n (%), median, mean (minimum-maximum)]. Responders were older at disease onset (p=0.032) and showed a high number of neutrophils (p=0.002). Nineteen (54%) cases met the criteria for systemic-onset juvenile idiopathic arthritis (SoJIA), 10 of them responded and their median time to start treatment was 1.6 years, being 4.5 for non-responders. Sixteen (46%) children did not meet the criteria for SoJIA, and 8 responded. The median time to start ANK in this group was 0.9 years for responders and 1.1 for non-responders respectively. Genetic testing performed in 27 patients showed mutation in 14 (8 MEFV, 2 TNRFSF1A, 2 NLRP3, 1 MVK y 1 NOD2), 6 of them were responders (4 MEFV, 1 NLRP3 y 1 MVK). Conclusions In spite of study limitations, responders were older at disease onset and showed a higher number of neutrophils. Moreover, it seems that patients with SoJIA who had the shortest time of evolution responded better than those with longer disease duration. References The pattern of response to anti-interleukin-1 treatment distinguishes two subsets of patients with systemic-onset juvenile idiopathic arthritis. Gattorno M et al. Arthritis Rheum 2008;58:1505-15. Anakinra: a safe and effective first-line treatment in systemic onset juvenile idiopathic arthritis (SoJIA). Hedrich CM et al. Rheumatol Int 2011 Nov 15 (Epub ahead of print). Disclosure of Interest None Declared

Background Musculoskeletal ultrasonography (US) has been routinely used to confirm synovial effusion in children with arthritis. Recent studies show that US is more sensitive than clinical examination in detecting synovitis in juvenile idiopathic arthritis (JIA). In addition, given the high sensitivity of US in detecting subclinical synovitis, minimal effusion or even age-related variations, it remains important for the interpretation of US abnormalities in the clinical context. Since mostly data focusing on US detection of JIA synovitis include grey-scale (i.e. B-mode) US, the actual significance of US-detected subclinical synovitis in asymptomatic joints remains unclear. Objectives To investigate the usefulness of ultrasonography with power Doppler (PDUS) for detecting synovitis compared with clinical examination on large number of joints in JIA. Methods This multicenter study included 42 children with active JIA. Clinical and PDUS assessments were performed blindly on 44 joints. Active disease was defined by high acute phase reactants with clinically active arthritis. Active arthritis on US was defined as synovial hypertrophy, effusion, or increased vascularity on power Doppler (PD) scan. For the US-image analysis the OMERACT definitions for Rheumatoid Arthritis of synovitis was applied [[1][1]]. McNemar test was used to compare the percentage of joints showing synovitis detected by clinical examination and by PDUS. Results In total, 1848 joints were examined both clinically and by PDUS. Physical examination showed 277 joints (15.0%) having clinically active synovitis, and of these, 184 (10%) had synovitis confirmed by US. Furthermore, up to 177 joints (9.6%) were shown to have synovitis on US examination alone. The percentage of joints with synovitis confirmed by PDUS (19.5%, n=361 joints) was statistically higher than the percentage of joints having clinically active synovitis, 15.0% ( p < 0.0005). Of the 361 joints with GS synovitis detected by US examination, 116 (32.1%) joints were shown to have inflammatory activity by PD signal detected in SH. Subclinical active synovitis was confirmed by PDUS in 51/177 joints (28.8%) that only seemed to have synovitis on US examination. Conclusions The study shows that the PD-technique along with GS examination increases the sensitivity of US for detecting subclinical synovitis in JIA. However, longitudinal studies in children are required to know subsequent structural damage. References 1. Wakefield RJ, Balin PV, Szkudlarek M et al. OMERACT 7 Special Interest Group: Diagnosed musculoskeletal ultrasound including definitions for ultrasonography patology. J Rheumatol 2005;32:2485-2487 References Disclosure of Interest None Declared [1]: #p-7

To study the ovarian toxicity associated with cyclophosphamide in girls with systemic lupus erythematosus (SLE), we retrospectively reviewed the charts of 30 SLE girls aged 16 yr or younger at diagnosis, followed at three university hospitals. Gynaecological history was extracted from the charts or obtained prospectively. Ten had not received cyclophosphamide therapy, six were treated with daily oral cyclophosphamide, 10 with intravenous pulses and four with daily oral and intravenous pulses. Median oral cyclophosphamide dose was 38 g (inter-quartile range 75) and median intravenous dose 12.95 g (inter-quartile range 6.2). Six girls had oligomenorrhoea (20%) and one amenorrhoea (3%). Two treated with oral cyclophosphamide had oligomenorrhoea (33%) and one amenorrhoea (17%), two treated with both oral and intravenous pulses had oligomenorrhoea (50%), and none of those treated with intravenous pulses alone had menstrual disturbances (50% oral vs 0% intravenous pulses ; P = 0.016). Girls who had menstrual disturbances had received higher doses of cyclophosphamide than those who did not (medians : 63 vs 15 g ; P < 0.05). In summary, menstrual disturbances in SLE girls treated with cyclophosphamide are related to the total dose and perhaps to the administration method.

Initial* End* ۵ p Initial* End* ۵ p Initial* End* ۵ p ETA 3.25 0.5 -6 0.00 28 12 -5 0.00 13.2 2.3 -5 0.00 ADA 2.42 0.4 -3 0.01 17 13 -1 0.26 5.58 1.2 -2 0.06 AK 5.36 0.00 -3 0.01 62 9 -2 0.02 69.5 2.9 -2 0.03 TCZ 6.45 0.86 -3 0.01 46 4 -3 0.01 95.6 0.6 -3 0.01 IFX 4.9 0.00 47 6

We identified a consanguineous Moroccan family with three affected siblings diagnosed with rheumatoid factor-negative polyarticular juvenile idiopathic arthritis. They all suffered from an early-onset (2-4 years-old) chronic and symmetric polyarthritis affecting both large and small joints. The joint involvement was markedly erosive in two siblings, with the older sister requiring hip prosthetic replacement at the age of 18 years. None of the patients had fever, skin rash, uveitis or other extra-articular manifestations. Laboratory analyses revealed leukocytosis, thrombocytosis, severe anaemia, marked increase of inflammatory markers and negative results for rheumatoid factor, anti-nuclear antibodies and HLA-B27.

Early diagnosis of macrophage activations syndrome (MAS) in systemic juvenile idiopathic arthritis (sjia) may be challenging because it may mimic the clinical features of the underlying disease or be confused with an infectious complication. However, the diagnostic value of the guidelines for hemophagocytic lymphohistiocytosis (HLH) or sjia-associated MAS has seldom been examined.

Blau syndrome is an autosomal dominant monogenic granulomatous disease associated with gain of function mutations at or near the NACHT domain of NOD2; it is the only form of granulomatous arthritis with a known gene mutation. Although its phenotype has been amply described as a triad of arthritis, uveitis and dermatitis in case series and retrospective cohorts, prospective studies on natural history and outcome have not been done.

Many young people with childhood-onset diseases, including rheumatic diseases, continue to require medical care into adult life. Although there is an extensive evidence base for the need of transitional care, there is a paucity of robust outcome data and a great variability on the models of transitional care.