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Objective: The aim of this study was to quantify costs of hospital-associated care for juvenile idiopathic arthritis (JIA), provide insights in patient-level variation in costs, and investigate costs over time from the moment of JIA diagnosis. Results were reported for all JIA patients in general and by subtype. Methods: This study was a single-center, retrospective analysis of prospective data from electronic medical records of children with JIA, ages 0–18 years, between April 1, 2011 and March 31, 2019. Patient characteristics (age, sex, JIA subtype) and hospital-based resource use (consultations, medication, radiology procedures, laboratory testing, surgeries, emergency department [ED] visits, hospital stays) were extracted and analyzed. Unit prices were obtained from Dutch reimbursement lists and pharmaceutical and hospital list prices. Results: The analysis included 691 patients. The mean total cost of hospital care was €3,784/patient/year, of which €2,103 (55.6%) was attributable to medication. Other costs involved pediatric rheumatologist visits (€633/patient/year [16.7%]), hospital stays (€439/patient/year [11.6%]), other within-hospital specialist visits (€324/patient/year [8.6%]), radiology procedures (€119/patient/year [3.1%]), laboratory tests (€114/patient/year [3.0%]), surgeries (€46/patient/year [1.2%]), and ED visits (€6/patient/year [0.2%]). Mean annual total costs varied between JIA subtypes and between individuals and were the highest for systemic JIA (€7,772/patient/year). Over the treatment course, costs were the highest in the first month after JIA diagnosis. Conclusion: Hospital care costs of JIA vary substantially between individuals, between subtypes, and over the treatment course. The highest annual costs were for systemic JIA, primarily attributable to medication (i.e., biologics). Costs of other hospital-associated care were comparable regardless of subtype.

Objectives Burden of comorbidities are largely unknown in JIA. From 2000, national and international patient registries were established to monitor biologic treatment, disease activity and adverse events in patients with JIA. The aim of this analysis was to investigate in parallel, for the first time, three of the largest JIA registries in Europe/internationally—UK JIA Biologic Registers (BCRD/BSPAR-ETN), German biologic registers (BiKeR/JuMBO), multinational Pharmachild—to quantify the occurrence of selected comorbidities in patients with JIA. Methods Information on which data the registers collect were compared. Patient characteristics and levels of comorbidity were presented, focussing on four key conditions: uveitis, MAS, varicella, and history of tuberculosis. Incidence rates of these on MTX/biologic therapy were determined. Results 8066 patients were registered into the three JIA registers with similar history of the four comorbidities across the studies; however, varicella vaccination coverage was higher in Germany (56%) vs UK/Pharmachild (16%/13%). At final follow-up, prevalence of varicella infection was lower in Germany (15%) vs UK/Pharmachild (37%/50%). Prevalence of TB (0.1–1.8%) and uveitis (15–19%) was similar across all registers. The proportion of systemic-JIA patients who ever had MAS was lower in Germany (6%) vs UK (15%) and Pharmachild (17%). Conclusion This analysis is the first and largest to investigate the occurrence of four important comorbidities in three JIA registries in Europe and the role of anti-rheumatic drugs. Combined, these three registries represent one of the biggest collection of cases of JIA worldwide and offer a unique setting for future JIA outcome studies.

Objective As young people enter adulthood, the interchangeable use of child and adult outcome measures may inaccurately capture changes over time. This study aimed to use item response theory (IRT) to model a continuous score for functional ability that can be used no matter which questionnaire is completed. Methods Adolescents (ages 11-17 years) in the UK Childhood Arthritis Prospective Study (CAPS) self-completed an adolescent Childhood Health Assessment Questionnaire (CHAQ) and a Health Assessment Questionnaire (HAQ). Their parents answered the proxy-completed CHAQ. Those children with at least 2 simultaneously completed questionnaires at initial presentation or 1 year were included. Psychometric properties of item responses within each questionnaire were tested using Mokken analyses to assess the applicability of IRT modeling. A previously developed IRT model from the Pharmachild-NL registry from The Netherlands was validated in CAPS participants. Agreement and correlations between IRT-scaled functional ability scores were tested using intraclass correlations and Wilcoxon's signed rank tests. Results In 303 adolescents, the median age at diagnosis was 13 years, and 61% were female. CHAQ scores consistently exceeded HAQ scores. Mokken analyses demonstrated high scalability, monotonicity, and the fact that each questionnaire yielded reliable scores. There was little difference in item response characteristics between adolescents enrolled in CAPS and Pharmachild-NL (maximum item residual 0.08). Significant differences were no longer evident between IRT-scaled HAQ and CHAQ scores. Conclusion IRT modeling allows the direct comparison of function scores regardless of different questionnaires being completed by different people over time. IRT modeling facilitates the ongoing assessment of function as adolescents transfer from pediatric clinics to adult services.

Background: This study aims to quantify medication costs in juvenile idiopathic arthritis (JIA), based on subtype. Research design and methods: This study is a single-center, retrospective analysis of prospective data from electronic medical records of JIA patients, aged 0–18 years between 1 April 2011 and 31 March 2019. Patient characteristics (age, gender, subtype) and medication use were extracted. Medication use and costs were reported as: 1) mean total annual costs; 2) between-patient heterogeneity in these costs; 3) duration of medication use; and, 4) costs over the treatment course. Results: The analysis included 691 patients. Mean total medication costs were €2,103/patient/year, including €1,930/patient/year (91.8%) spent on biologicals. Costs varied considerably between subtypes, with polyarticular rheumatoid-factor positive and systemic JIA patients having the highest mean costs (€5,020/patient/year and €4,790/patient/year, respectively). Mean annual medication costs over the patient’s treatment course ranged from €11,000/year (2.5% of patients). Etanercept and adalimumab were the most commonly used biologicals. Cost fluctuations over the treatment course were primarily attributable to biological use. Conclusions: Polyarticular rheumatoid-factor positive and systemic JIA patients had the highest mean total annual medication costs, primarily attributable to biologicals. Costs varied considerably between subtypes, individuals, and over the treatment course.

OBJECTIVE: To evaluate the efficacy and safety of 2 canakinumab monotherapy tapering regimens in order to maintain complete clinical remission in children with systemic juvenile idiopathic arthritis (JIA). METHODS: The study was designed as a 2-part phase IIIb/IV open-label, randomized trial. In the first part, patients received 4 mg/kg of canakinumab subcutaneously every 4 weeks and discontinued glucocorticoids and/or methotrexate as appropriate. Patients in whom clinical remission was achieved (inactive disease for at least 24 weeks) with canakinumab monotherapy were entered into the second part of the trial, in which they were randomized 1:1 into 1 of 2 treatment arms. In arm 1, the dose of canakinumab was reduced from 4 mg/kg to 2 mg/kg and then to 1 mg/kg, followed by discontinuation. In arm 2, the 4 mg/kg dose interval was prolonged from every 4 weeks, to every 8 weeks, and then to every 12 weeks, followed by discontinuation. In both arms, canakinumab exposure could be reduced provided systemic JIA remained in clinical remission for 24 weeks with each step. The primary objective was to assess whether >40% of randomized patients in either arm maintained clinical remission of systemic JIA for 24 weeks in the first part of the study. RESULTS: In part 1 of the study, 182 patients were enrolled, with 75 of those patients randomized before entering part 2 of the trial. Among the 75 randomized patients, clinical remission was maintained for 24 weeks in 27 (71%) of 38 patients in arm 1 (2 mg/kg every 4 weeks) and 31 (84%) of 37 patients in arm 2 (4 mg/kg every 8 weeks) (P ≤ 0.0001 for arm 1 versus arm 2 among those meeting the 40% threshold). Overall, 25 (33%) of 75 patients discontinued canakinumab, and clinical remission was maintained for at least 24 weeks in all 25 of these patients. No new safety signals were identified. CONCLUSION: Reduction of canakinumab exposure may be feasible in patients who have achieved clinical remission of systemic JIA, but consistent interleukin-1 inhibition appears necessary to maintain this response. ispartof: ARTHRITIS & RHEUMATOLOGY vol:73 issue:2 pages:336-346 ispartof: location:United States status: published

OBJECTIVE: To evaluate the long-term efficacy and safety of canakinumab and explore prediction of response in patients with systemic juvenile idiopathic arthritis (JIA) with or without fever at treatment initiation. METHODS: At enrollment, patients with active systemic JIA (ages 2 to

Objective To describe risk factors for IBD development in a cohort of children with JIA. Methods JIA patients who developed IBD were identified from the international Pharmachild register. Characteristics were compared between IBD and non-IBD patients and predictors of IBD were determined using multivariable logistic regression analysis. Incidence rates of IBD events on different DMARDs were calculated, and differences between therapies were expressed as relative risks (RR). Results Out of 8942 patients, 48 (0.54% ) developed IBD. These were more often male (47.9% vs 32.0%) and HLA-B27 positive (38.2% vs 21.0%) and older at JIA onset (median 8.94 vs 5.33 years) than patients without IBD development. They also had more often a family history of autoimmune disease (42.6% vs 24.4%) and enthesitis-related arthritis (39.6% vs 10.8%). The strongest predictors of IBD on multivariable analysis were enthesitis-related arthritis [odds ratio (OR): 3.68, 95% CI: 1.41, 9.40] and a family history of autoimmune disease (OR: 2.27, 95% CI: 1.12, 4.54). Compared with methotrexate monotherapy, the incidence of IBD on etanercept monotherapy (RR: 7.69, 95% CI: 1.99, 29.74), etanercept with methotrexate (RR: 5.70, 95% CI: 1.42, 22.77) and infliximab (RR: 7.61, 95% CI: 1.27, 45.57) therapy was significantly higher. Incidence on adalimumab was not significantly different (RR: 1.45, 95% CI: 0.15, 13.89). Conclusion IBD in JIA was associated with enthesitis-related arthritis and a family history of autoimmune disease. An increased IBD incidence was observed for etanercept therapy regardless of concomitant methotrexate use.

© 2018, The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology. Objective: The implementation of value-based health care in inflammatory arthritis requires a standardized set of modifiable outcomes and risk-adjustment variables that is feasible to implement worldwide. Methods: The International Consortium for Health Outcomes Measurement (ICHOM) assembled a multidisciplinary working group that consisted of 24 experts from 6 continents, including 6 patient representatives, to develop a standard set of outcomes for inflammatory arthritis. The process followed a structured approach, using a modified Delphi process to reach consensus on the following decision areas: conditions covered by the set, outcome domains, outcome measures, and risk-adjustment variables. Consensus in areas 2 to 4 were supported by systematic literature reviews and consultation of experts. Results: The ICHOM Inflammatory Arthritis Standard Set covers patients with rheumatoid arthritis (RA), axial spondyloarthritis, psoriatic arthritis, and juvenile idiopathic arthritis (JIA). We recommend that outcomes regarding pain, fatigue, activity limitations, overall physical and mental health impact, work/school/housework ability and productivity, disease activity, and serious adverse events be collected at least annually. Validated measures for patient-reported outcomes were endorsed and linked to common reporting metrics. Age, sex at birth, education level, smoking status, comorbidities, time since diagnosis, and rheumatoid factor and anti-citrullinated protein antibody lab testing for RA and JIA should be collected as risk-adjustment variables. Conclusion: We present the ICHOM inflammatory arthritis Standard Set of outcomes, which enables health care providers to implement the value-based health care framework and compare outcomes that are important to patients with inflammatory arthritis.

To update the European League Against Rheumatism (EULAR) recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) published in 2011. Four systematic literature reviews were performed regarding the incidence/prevalence of vaccine-preventable infections among patients with AIIRD; efficacy, immunogenicity and safety of vaccines; effect of anti-rheumatic drugs on the response to vaccines; effect of vaccination of household of AIIRDs patients. Subsequently, recommendations were formulated based on the evidence and expert opinion. The updated recommendations comprise six overarching principles and nine recommendations. The former address the need for an annual vaccination status assessment, shared decision-making and timing of vaccination, favouring vaccination during quiescent disease, preferably prior to the initiation of immunosuppression. Non-live vaccines can be safely provided to AIIRD patients regardless of underlying therapy, whereas live-attenuated vaccines may be considered with caution. Influenza and pneumococcal vaccination should be strongly considered for the majority of patients with AIIRD. Tetanus toxoid and human papilloma virus vaccination should be provided to AIIRD patients as recommended for the general population. Hepatitis A, hepatitis B and herpes zoster vaccination should be administered to AIIRD patients at risk. Immunocompetent household members of patients with AIIRD should receive vaccines according to national guidelines, except for the oral poliomyelitis vaccine. Live-attenuated vaccines should be avoided during the first 6 months of life in newborns of mothers treated with biologics during the second half of pregnancy. These 2019 EULAR recommendations provide an up-to-date guidance on the management of vaccinations in patients with AIIRD.

Objective The objective of this study was to assess the relationship between adalimumab trough concentrations and treatment response in paediatric patients with JIA. Methods This was a monocentric cohort study of JIA patients treated with adalimumab. Clinical data and samples were collected during routine follow-up. Adalimumab trough concentrations were quantified by a novel liquid chromatography–tandem mass spectrometry assay. Anti-adalimumab antibodies were measured in samples with trough concentrations of ≤5mg/l. Disease activity was evaluated using the clinical Juvenile Arthritis DAS with 71-joint count (cJADAS71). Response to adalimumab was defined according to recent international treat-to-target guidelines. Results A total of 35 adalimumab trough samples were available from 34 paediatric patients with JIA. Although there was no significant difference in adalimumab dose, trough concentrations were significantly lower in patients with secondary failure [median 1.0 mg/l; interquartile range (IQR) 1.0–5.3] compared with patients with primary failure (median 13.97 mg/l; IQR 11.81–16.67) or an adequate response (median 14.94 mg/l; IQR 10.31–16.19) to adalimumab. Conclusion Adalimumab trough concentrations were significantly lower in JIA patients with secondary failure compared with patients with primary failure or an adequate response to adalimumab. Our results suggest that trough concentration measurements could identify JIA patients who require increased adalimumab doses to achieve or maintain therapeutic drug concentrations.

In view of the COVID-19 pandemic, there is an unmet clinical need for the guidelines on vaccination of patients with autoimmune inflammatory rheumatic diseases (AIIRD). This position paper summarises the current data on COVID-19 infection in patients with AIIRD and development of vaccines against COVID-19, discusses the aspects of efficacy and safety of vaccination, and proposes preliminary considerations on vaccination against COVID-19 in patients with AIIRD, mainly based on the expert opinion and knowledge on the use of other vaccines in this population of patients.

Background/Aims Younger and older people with rheumatic diseases may experience increased anxiety during the COVID-19 pandemic, due to the uncertainty regarding their likelihood of contracting the virus, its complications alongside their existing condition and whether their immunosuppressive treatments pose additional risks. This study explored trajectories of anxiety in parents of children and young people (CYP) with rheumatic diseases and adults with rheumatic diseases in the six months following March 2020 during the COVID-19 pandemic. Methods CYP and adults recruited to the international COVID-19 European Patient Registry, a parent-led, online, self-referred prospective cohort recruiting participants globally, were selected if enrolled within 20th March to 17th April 2020. Anxiety scores (0-10, 10=Highest anxiety) were collected weekly for up to 28 weeks and denoted parent anxiety in the CYP cohort and self-reported anxiety in the adult cohort. Group-based trajectory models explored anxiety clusters using censored-normal models in the CYP and adult populations, separately. Linear, quadratic and cubic polynomials were tested within 1 to 10 clusters and optimal models selected based on a combination of model fit (BIC), parsimony and clinical plausibility. Demographic (country, age, gender) and clinical (diagnosis, disease control, respiratory comorbidity, immunosuppressive therapy) information and COVID-19 mitigation behaviours (isolation, distancing, none) were collected at initial enrolment and compared between clusters using Chi-squared, Fisher’s exact and Kruskal-Wallis tests. Results Among 498 CYP and 2640 adults, most were female (65%, 89%) and from the UK (50%, 84%), respectively. The most common diagnoses were polyarticular JIA (37%) and oligoarticular JIA (29%) among CYP and RA among the adults (63%). Respiratory comorbidities were uncommon in the CYP (10%) and adult (17%) cohorts, and most were taking any immunosuppressive therapies (85%, 87%), respectively. As of March 2020, 88% and 79% were self-isolating, respectively. In both the parents of CYP and adult cohorts, four trajectory clusters were identified with similar patterns: Persistent extremely high anxiety (32%, 17%), persistent high anxiety (43%, 41%), high anxiety that marginally improved (25%, 32%) and moderate anxiety that improved (11%, 10%). Among CYP, few characteristics distinguished the clusters. However, in the adult cohort, clusters with greater and more persistent anxiety were associated with higher levels of respiratory comorbidities, higher use of immunosuppressive therapies, higher initial levels of self-isolation and slightly older age than those with lower or improving anxiety over time. Conclusion This study reports four trajectories of anxiety during the COVID-19 pandemic that are consistent across parents of CYP with rheumatic diseases and among adults with these conditions. Despite relatively lower risks for CYP, parental anxiety regarding COVID-19 was high and not associated with characteristics of their child or of their child's disease. Among adults with rheumatic diseases, greater anxiety was associated with risk factors potentially associated with COVID-19 morbidity and mortality. Disclosure S.J.W. Shoop-Worrall: None. S.M.M. Verstappen: None. W. Costello: None. S.P. Angevare: None. Y. Uziel: None. C. Wouters: None. N. Wulffraat: Honoraria; Sobi. Grants/research support; Abbvie. R. Beesley: None.

Background Pediatric patients with juvenile idiopathic arthritis (JIA) are at risk for a lower health-related quality of life compared to their healthy peers. Remote monitoring of health-related quality of life using electronic patient-reported outcomes could provide important information to treating physicians. The aim of this study was to investigate if self-assessment with the EuroQol five-dimensional ‘youth’ questionnaire with five levels (EQ-5D-Y-5 L) inside a mobile E-health application could identify JIA patients in need of possible treatment adjustments. Methods The EQ-5D-Y-5 L was completed via a mobile application (Reuma2Go) between October 2017 and January 2019. The clinical juvenile arthritis disease activity score with 71 joint count (cJADAS-71) was reported at every corresponding visit as reference for disease activity. Previously described cJADAS-71 thresholds were used to identify patients in possible need of treatment adjustments. Discriminatory power of the EQ-5D-Y-5 L was assessed by ROC-curves and diagnostic characteristics. Results Sixty-eight JIA patients completed the EQ-5D-Y-5 L questionnaire. Median cJADAS-71 indicated low disease activity overall in the studied population. ROC curves and diagnostic characteristics demonstrated that self-assessment with the EQ-5D-Y-5 L could distinguish between patients with inactive disease (or minimal disease activity) and moderate to high disease activity with good accuracy (87%), sensitivity (85%), specificity (89%) and negative predictive value (86%). Conclusions Results demonstrate that the EQ-5D-Y-5 L was able to identify JIA patients in need of possible treatment adjustments in our studied population. Remote monitoring of health-related quality of life and patient-reported outcomes via E-health applications could provide important additional information to determine the frequency of clinical visits, assess therapeutic efficacy and guide treat-to-target strategies in pediatric patients with JIA.

Objective To build a prediction model for uveitis in children with JIA for use in current clinical practice. Methods Data from the international observational Pharmachild registry were used. Adjusted risk factors as well as predictors for JIA-associated uveitis (JIA-U) were determined using multivariable logistic regression models. The prediction model was selected based on the Akaike information criterion. Bootstrap resampling was used to adjust the final prediction model for optimism. Results JIA-U occurred in 1102 of 5529 JIA patients (19.9%). The majority of patients that developed JIA-U were female (74.1%), ANA positive (66.0%) and had oligoarthritis (59.9%). JIA-U was rarely seen in patients with systemic arthritis (0.5%) and RF positive polyarthritis (0.2%). Independent risk factors for JIA-U were ANA positivity [odds ratio (OR): 1.88 (95% CI: 1.54, 2.30)] and HLA-B27 positivity [OR: 1.48 (95% CI: 1.12, 1.95)] while older age at JIA onset was an independent protective factor [OR: 0.84 (9%% CI: 0.81, 0.87)]. On multivariable analysis, the combination of age at JIA onset [OR: 0.84 (95% CI: 0.82, 0.86)], JIA category and ANA positivity [OR: 2.02 (95% CI: 1.73, 2.36)] had the highest discriminative power among the prediction models considered (optimism-adjusted area under the receiver operating characteristic curve = 0.75). Conclusion We developed an easy to read model for individual patients with JIA to inform patients/parents on the probability of developing uveitis.

Made available in DSpace on 2021-06-25T12:24:54Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-11-11 Background: Concerns about the safety and efficacy of vaccines in patients with autoimmune diseases (AID) have led to contradictions and low vaccination coverage in this population, who are at a higher risk of infections, including by human papillomavirus (HPV). Although HPV vaccines have been recommended for immunocompromised patients, there is still a lack of data to support its use for AID patients, such as juvenile dermatomyositis (JDM) patients. The aim of this study was to assess the safety and immunogenicity of the quadrivalent HPV (qHPV) vaccine in a cohort of JDM patients. Methods: JDM patients aged from 9 to 20 years and healthy controls (HC) were enrolled to receive a 3-dose schedule of qHPV vaccine from March/2014 to March/2016. Study visits were performed before the first dose, 1 month after the second and third doses, and 6 months after the third dose. Participants completed a diary of possible adverse events for 14 days following each dose of vaccination (AEFV). Disease activity and current therapy were analyzed at each visit for JDM patients. In addition, serum samples from all participants were collected to test antibody concentrations against HPV16 and 18 at each visit. Participant recruitment was conducted in ten Brazilian centres. From 47 eligible JDM patients and 41 HC, 42 and 35, respectively, completed the 3-dose schedule of the vaccine, given that five JDM patients and two HC had received doses prior to their inclusion in the study. Results: The AEFVs presented by the participants were mild and in general did not differ between JDM and HC groups. No severe AEFVs were related to the vaccination. Disease activity was stable, or even improved during the follow-up. One month after the third dose of the vaccine the JDM group presented seropositivity of 100% for HPV16 and 97% for HPV18, similarly to the HC group, who presented 100% for both serotypes (p = 1.000). Six months after the third dose the seropositivity for the patient group was 94% for both HPV types. Conclusions: The HPV vaccination in this cohort of JDM patients was safe and immunogenic. Since the seropositivity against HPV16 and 18 was very high after the 3-dose schedule, this regimen should be recommended for JDM patients. Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Paediat Immunol & Rheumatol, Utrecht, Netherlands Univ Fed Parana, Hosp Clin, Dept Pediat, Gen Carneiro St 68,181, BR-80060900 Curitiba, Parana, Brazil Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Paediat, Sao Paulo, Brazil Univ Fed Sao Paulo, Dept Prevent Med, Sao Paulo, Brazil Univ Sao Paulo, Fac Med, Hosp Clin, Dept Paediat Rheumatol,Inst Crianca, Sao Paulo, Brazil Univ Fed Sao Paulo, Dept Paediat Rheumatol, Sao Paulo, Brazil Hosp Estadual Infantil Nossa da Senhora, Dept Paediat Rheumatol, Vitoria, ES, Brazil Univ Fed Rio de Janeiro, Inst Puericultura & Pediat Martagao Gesteira IPPM, Dept Paediat Rheumatol, Rio De Janeiro, Brazil Univ Estado Rio De Janeiro, Dept Paediat Rheumatol, Rio De Janeiro, Brazil Hosp Infantil Albert Sabin, Dept Paediat Rheumatol, Fortaleza, Ceara, Brazil Univ Florida, Dept Paediat Immunol & Rheumatol, Coll Med, Gainesville, FL 32611 USA Hosp Crianca Brasilia Jose Alencar, Dept Paediat Rheumatol, Brasilia, DF, Brazil Univ Estadual Campinas, Dept Paediat Rheumatol, Sao Paulo, Brazil Univ Fed Rio de Janeiro, Dept Paediat Rheumatol, Rio De Janeiro, Brazil Univ Estadual Paulista, Dept Paediat Rheumatol, Botucatu, SP, Brazil Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Paediat Rheumatol, Sao Paulo, Brazil Natl Inst Publ Hlth & Environm RIVM, Ctr Infect Dis Control, Bilthoven, Netherlands Hosp Canc Barretos, Fac Ciencias Saude Dr Paulo Prata FACISB, Sao Paulo, Brazil Hosp Canc Barretos, Inst Ensino & Pesquisa IEP, Sao Paulo, Brazil Univ Estadual Paulista, Dept Paediat Rheumatol, Botucatu, SP, Brazil

Purpose Patients with juvenile idiopathic arthritis (JIA) are prone to developing chronic anterior uveitis (JIA-U+). Although several risk factors for JIA-U+ have been identified, the underlying etiology is poorly understood. Histopathological studies demonstrate B cell infiltrates in eye tissues of patients with JIA-U+. Methods We performed transcriptome profiling of peripheral blood CD19-positive B cells taken from 14 cases with JIA-U+, 13 JIA cases without uveitis (JIA-U-), and five healthy controls. Deconvolution-based estimation was used to determine the immune cell fractions for each sample. Results Deconvolution results revealed that naive B cells made up on average 71% of the CD19-positive cell fractions analyzed. Differential expression analysis identified 614 differentially expressed genes (DEGs) between the groups at nominal significance and six genes at a false discovery rate of 5% (FDR < 0.05). Head-to-head comparison of all JIA-U- versus JIA-U+ revealed no DEGs in the CD19+ B cell pool (FDR < 0.05). However, principal component analysis based on a panel of key genes for B cell subsets revealed that JIA-U+ cases bifurcate into distinct clusters, characterized by markedly disparate expression for genes associated with specific memory B cell populations. CIBERSORT analysis of the overall transcriptome of the new uveitis cluster identified an increased proportion of memory B cells. Conclusion These data show that JIA-U- and JIA-U+ have a globally similar transcriptome considering the global peripheral CD19-positive B cell pool. However, heterogeneity in B cell memory genes among cases with uveitis suggests a role for specific memory B cell subsets in the etiology of JIA-U+.

Fever of unknown origin (FUO) frequently presents a diagnostic challenge in the pediatric population despite of recent advances in diagnostic tools and techniques.(1, 2) FUO can be the primary manifestation of a broad spectrum of diseases, but the main causes in children are infections. Substantial progress has been achieved in the diagnosis of infectious and other causes of fever, due to new developments in nuclear medicine techniques, instrumental procedures and genetic testing for diagnosing rare hereditary auto-inflammatory conditions associated with fever. Nevertheless, there is no diagnostic checklist for children, and up to 200 conditions causing fever have to be ruled out, often leading to prolonged periods of hospitalization and treatment attempts which include various antibiotic regimens.(3, 4) An important differential diagnosis as a cause of FUO in children is Systemic onset Juvenile Idiopathic Arthritis (SJIA, Still’s disease, OMIM 604302), an aggressive auto-inflammatory disease that resembles sepsis.(5-7) Although the pathogenesis of SJIA remains poorly understood, overwhelming activation of the innate immune system due to an imbalance between pro-inflammatory cytokines and immune deactivators without evidence of involvement of the adaptive immune responses are seen in these patients.(8), (9) Unfortunately, characteristic signs of arthritis often do not develop before the later course of this disease and therefore at initial presentation the non-specific inflammatory pattern in SJIA patients cannot be differentiated from systemic infections by clinical or laboratory parameters, and suitable biomarkers are missing. In many cases an exploratory antibiotic treatment is initiated before a definitive diagnosis is made. This clinical uncertainty impedes early initiation of an appropriate anti-inflammatory therapy.(6, 7, 10) In previous studies we found high concentrations of S100A12 in serum from SJIA patients.(11) S100A12 is a calcium-binding protein expressed and secreted by activated phagocytes. Recently it has been assigned to the Damage Associated Molecular Pattern molecules (DAMPs), which represent endogenous ligands of pattern recognition receptors.(12) S100A12 has pro-inflammatory properties in vitro at concentrations found in SJIA serum in vivo.(11, 13) It is mainly expressed in granulocytes and binds to the Receptor for Advanced Glycation End-products (RAGE).(14) Activation of this receptor induces pro-inflammatory responses in leukocytes and endothelial cells via nuclear factor (NF)-κB.(15, 16) S100A12 is a useful marker protein for monitoring disease activity in several inflammatory diseases.(17) In the present study we assess the diagnostic value of S100A12 serum levels in differentiating between SJIA in the initial disease phase versus acute systemic infections and childhood leukemic malignancies as the most relevant differential diagnoses. Additionally we included sera from patients with other hereditary IL-1-driven diseases namely Familial Mediterranean Fever (FMF, OMIM 249100), Neonatal-onset Multisystem Inflammatory Disease (NOMID, OMIM 607115), and Muckle Wells Syndrome (MWS, OMIM 191900). All of these disorders typically present as FUO. To the best of our knowledge, this is the largest trial on a biomarker in FUO to date.

textabstractThe 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 Dutch 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 209 JIA patients (14.3% systemic, 39.7% oligoarticular, 25.8% RF negative polyarthritis, 20.2% other categories) and 107 healthy children were enrolled in two centres. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the Dutch 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.

ObjectivesTo assess if the Juvenile Arthritis Disease Activity Score (JADAS71) could be used to correctly identify patients with juvenile idiopathic arthritis (JIA) in need of antitumour necrosis factor therapy (anti-TNF) therapy 3 and 6 months after start of methotrexate (MTX).MethodsMonocentric retrospective cohort study from 2011 to 2015 analysing all patients with oligoarticular JIA (OJIA) (n=39) and polyarticular course JIA (PJIA) (n=74) first starting MTX. Three and 6 months after MTX start, clinical and laboratory features and the 2011 American College of Rheumatology (ACR) JIA treatment recommendations (ACR clinical practice guideline (ACR-CPG)) were compared between groups starting and not starting anti-TNF therapy. The sensitivity and specificity of the ACR-CPG, JADAS71 and the clinical JADAS to identify non-responders after 12 months were calculated.ResultsPhysicians escalated patients with significantly higher physician global assessment, clinical JADAS (cJADAS) and patient Visual Analogue Scale (VAS). The decision not to escalate was correct in 70%–75% as shown by MTX response. The implementation of the ACR-CPG would increase the current anti-TNF use from 12% to 65%. The use of (c)JADAS in identifying patients in need of anti-TNF therapy outperformed the ACR-CPG with a much higher sensitivity, specificity and accuracy. The cJADAS threshold for treatment escalation at month 3 and 6 was >5 and >3 for OJIA and >7 and >4 for PJIA, respectively. The performance of the cJADAS decreased when the patient VAS contribution to the total score was restricted and overall did not improve by adding the erythrocyte sedimentation rate.ConclusionsThe cJADAS identifies patients in need of anti-TNF and is a user-friendly tool ready to be used for treat to target in JIA. The patient VAS is a critical item in the cJADAS for the decision to escalate to anti-TNF.

Lupus nephritis (LN) occurs in 50%–60% of patients with childhood-onset systemic lupus erythematosus (cSLE), leading to significant morbidity. Timely recognition of renal involvement and appropriate treatment are essential to prevent renal damage. The Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative aimed to generate diagnostic and management regimens for children and adolescents with rheumatic diseases including cSLE. Here, we provide evidence-based recommendations for diagnosis and treatment of childhood LN. Recommendations were developed using the European League Against Rheumatism standard operating procedures. A European-wide expert committee including paediatric nephrology representation formulated recommendations using a nominal group technique. Six recommendations regarding diagnosis and 20 recommendations covering treatment choices and goals were accepted, including each class of LN, described in the International Society of Nephrology/Renal Pathology Society 2003 classification system. Treatment goal should be complete renal response. Treatment of class I LN should mainly be guided by other symptoms. Class II LN should be treated initially with low-dose prednisone, only adding a disease-modifying antirheumatic drug after 3 months of persistent proteinuria or prednisone dependency. Induction treatment of class III/IV LN should be mycophenolate mofetil (MMF) or intravenous cyclophosphamide combined with corticosteroids; maintenance treatment should be MMF or azathioprine for at least 3 years. In pure class V LN, MMF with low-dose prednisone can be used as induction and MMF as maintenance treatment. The SHARE recommendations for diagnosis and treatment of LN have been generated to support uniform and high-quality care for all children with SLE.

Reticular dysgenesis (RD) is a rare congenital disorder defined clinically by the combination of severe combined immunodeficiency (SCID), agranulocytosis, and sensorineural deafness. Mutations in the gene encoding adenylate kinase 2 were identified to cause the disorder. Hematopoietic stem cell transplantation (HSCT) is the only option to cure this otherwise fatal disease. Retrospective data on clinical presentation, genetics, and outcome of HSCT were collected from centers in Europe, Asia, and North America for a total of 32 patients born between 1982 and 2011. Age at presentation was

Background Methotrexate (MTX) therapy has proven to be a successful and safe treatment for Juvenile Idiopathic Arthritis (JIA). Despite the high efficacy rates of MTX, treatment outcomes are often complicated by burdensome gastro-intestinal side effects. Intolerance rates for MTX in children are high (approximately 50%) and thus far no conclusive effective treatment strategies to control for side effects have been found. To address this need, this article proposes an innovative research approach based on pharmacological conditioning, to reduce MTX intolerance. Presentation of the hypothesis A collaboration between medical psychologists, pediatric rheumatologists, pharmacologists and patient groups was set up to develop an innovative research design that may be implemented to study potential improved control of side effects in JIA, by making use of the psychobiological principles of pharmacological conditioning. In pharmacological conditioning designs, learned positive associations from drug therapies (conditioning effects) are integrated in regular treatment regimens to maximize treatment outcomes. Medication regimens with immunosuppressant drugs that made use of pharmacological conditioning principles have been shown to lead to optimized therapeutic effects with reduced drug dosing, which might ultimately cause a reduction in side effects. Testing the hypothesis This research design is tailored to serve the needs of the JIA patient group. We developed a research design in collaboration with an interdisciplinary research group consisting of patient representatives, pediatric rheumatologists, pharmacologists, and medical psychologists. Implications of the hypothesis Based on previous experimental and clinical findings of pharmacological conditioning with immune responses, we propose that the JIA patient group is particularly suited to benefit from a pharmacological conditioning design. Moreover, findings from this study may potentially also be promising for other patient groups that endure long-lasting drug therapies.

The Rare Immunodeficiency, AutoInflammatory and AutoImmune Disease (RITA) network is a European Research Network (ERN) that brings together the leading centres for rare immune disorders. On April 2018 an online survey was sent to all RITA members in order to facilitate the harmonization of data collection in rare immune disorders registries. Currently, as many as 52 different registries collect data on rare immune disorders, of whom 30 (58%) are dedicated primarily to autoimmune diseases, 15 (29%) to primary immunodeficiencies and 12 (23%) to autoinflammatory disorders. Improving data on patient safety, outcome, and quality of life measures is warranted to unfold the full potential of RITA registries.

Purpose To collect retrospective data of patients with Juvenile Idiopathic Arthritis (JIA) and other rheumatic diseases who received live attenuated booster measles-mumps-rubella (MMR) or measles-mumps-rubella-varicella (MMR/V) during treatment with immunosuppressive therapy. Results Data from 13 pediatric rheumatology centers in 10 countries, including 234 patients, were collected. Mean age at diagnosis was 5 ± 2.7 years, 67% were girls. Among them, 211 (90.2%) had JIA and 110 (47%) were in remission on medication. Disease activity was low in 37%, high in 8%, and moderate in 8%. One hundred-twenty-four received MMR/V booster while on methotrexate (MTX); 3 reported local mild adverse events (AE). Among 62 on MTX + biologics and 9 patients who received a combination of 2 disease modifying antirheumatic drugs (DMARDs), 9 reported mild AE. Among 39 on biologics, 1 reported fever one day after booster vaccination. No vaccine-related infection of measles, rubella, mumps or varicella was reported, none of the patients developed disease flare, including those with high disease activity. Conclusions In this retrospective study, live-attenuated MMR/V booster vaccines were safe for children with rheumatic diseases, on immunosuppressive therapies. This strengthens the Paediatric Rheumatology European Society (PReS) recommendation that vaccination with live attenuated vaccines in patients on immunosuppressive therapies can be considered individually, weighing the benefit of vaccination against the risk of inducing infection through vaccination. These data provide the basis for a prospective data collection study, planned by the PReS vaccination study group.

Objectives IgA vasculitis (IgAV, formerly known as Henoch–Schönlein purpura) is the most common cause of systemic vasculitis in childhood. To date, there are no internationally agreed, evidence-based guidelines concerning the appropriate diagnosis and treatment of IgAV in children. Accordingly, treatment regimens differ widely. The European initiative SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) aims to optimize care for children with rheumatic diseases. The aim therefore was to provide internationally agreed consensus recommendations for diagnosis and treatment for children with IgAV. Methods Recommendations were developed by a consensus process in accordance with the EULAR standard operating procedures. An extensive systematic literature review was performed, and evidence-based recommendations were extrapolated from the included papers. These were evaluated by a panel of 16 international experts via online surveys and subsequent consensus meeting, using nominal group technique. Recommendations were accepted when ⩾80% of experts agreed. Results In total, 7 recommendations for diagnosis and 19 for treatment of paediatric IgAV were accepted. Diagnostic recommendations included: appropriate use of skin and renal biopsy, renal work-up and imaging. Treatment recommendations included: the importance of appropriate analgesia and angiotensin-converting enzyme inhibitor use and non-renal indications for CS use, as well as a structured approach to treating IgAV nephritis, including appropriate use of CS and second-line agents in mild, moderate and severe disease along with use of angiotensin-converting enzyme inhibitors and maintenance therapy. Conclusion The SHARE initiative provides international, evidence-based recommendations for the diagnosis and treatment of IgAV that will facilitate improvement and uniformity of care.

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

Objective: Systemic juvenile idiopathic arthritis (JIA) is a multifactorial autoinflammatory disease with a historically poor prognosis. With current treatment regimens, approximately half of patients still experience active disease after 1 year of therapy. This study was undertaken to evaluate a treat-to-target approach using recombinant interleukin-1 receptor antagonist (rIL-1Ra; anakinra) as first-line monotherapy to achieve early inactive disease and prevent damage. Methods: In this single-center, prospective study, patients with new-onset systemic JIA with an unsatisfactory response to nonsteroidal antiinflammatory drugs received rIL-1Ra monotherapy according to a treat-to-target strategy. Patients with an incomplete response to 2 mg/kg rIL-1Ra subsequently received 4 mg/kg rIL-1Ra or additional prednisolone, or switched to alternative therapy. For patients in whom inactive disease was achieved, rIL-1Ra was tapered after 3 months and subsequently stopped. Results: Forty-two patients, including 12 who had no arthritis at disease onset, were followed up for a median of 5.8 years. The median time to achieve inactive disease was 33 days. At 1 year, 76% had inactive disease, and 52% had inactive disease while not receiving medication. High neutrophil counts at baseline and a complete response after 1 month of rIL-1Ra were highly associated with inactive disease at 1 year. After 5 years of follow-up, 96% of the patients included had inactive disease, and 75% had inactive disease while not receiving medication. Articular or extraarticular damage was reported in

Background: O ver the years, awareness of vaccine-preventable infection in rheumatic diseases has increased. At the same time, the safety of vaccines is still a hot topic in the public arena. Large-scale registries with data on juvenile idiopathic arthritis or RA taking the combination of methotrexate and biologics have demonstrated an increased incidence of infections. EULAR recommendations for both vaccination in pediatric patients and adults with rheumatic diseases, provide evidence-based guidance based on data from published studies on safety and efficacy of vaccinations in adults and children with rheumatic conditions. Especially in children, few data exist on safety and efficacy of live-attenuated vaccines such as MMR. This is relevant given the decreasing vaccination coverage and occurrence of measles outbreakes Objectives: To provide an overview of vaccines used in patients groups with rheumatic conditions under medication such as MTX and or biologicals. Also we seek for evidence on adverse events, protection rates and persistence of protective antibody titers over time. From these studies general guidelines are proposed. Methods: Literature review of vaccination studies performed in adults and children. In addition the clinical practice of boostering of MMR in JIA patients under immunosuppressive therapy was investigated in several large academic pediatric centers across Europe. Thus 234 JIA patients were identified that received a MMR booster under MTX and or biologicals. Results: EULAR recommendations are updated for children and adults. For most vaccines it is adivised to follow the national vaccination guidelines. Non-live vaccines can be safely provided to AIIRD patients under immunomodulating treatments, whereas the administration of live attenuated vaccines should be avoided under immunomodulating treatment, with the possible exceptions of herpes zoster and MMR. In 234 children with JIA who received the MMR booster while using MTX and or a Biological only 7 of adverse events were reported. Adverse events reported were mild (skin reaction, mild fever, urinary tract infection. There was no relation between disease activity, disease type or duration, sex, age and outcome of vaccinations. Vaccination status of patients with rheumatic conditions should be assessed annually. Live attenuated vaccines should be avoided during the first 6 months of life in newborns of mothers treated with biologics during the second half of pregnancy. Conclusion: The EULAR recommendations of 2011 are currently updated and will provide an up-to-date guidance on the management of vaccinations in patients with inflammatory rheumatic conditions. There is still a scartity of data on safety and efficay of live attenuated vaccines under biologicals. The next challenge is the implementation into the clinical practice of health professionals across Europe. Disclosure of Interests: None declared

Background Common practice is to withhold vaccination with live-attenuated vaccines in patients with rheumatic diseases on high-dose DMARDs, glucocorticosteroids or biological agents, due to limited safety data, and the (theoretical) risk of introducing an infectious disease to the patient. Evidence for this approach is low. We collected data from pediatric rheumatologists who vaccinate these patients, to obtain additional safety data, which might update and revise this approach. Objectives To collect retrospective data in patients with JIA and other diseases who received live booster MMR or MMRV while on DMARDs, glucocorticosteroids or biological agents. Methods Data from 13 pediatric rheumatology centers in 10 countries were collected. Results 234 patients were reported; mean age 5± 2.7, 70% girls. 206 had JIA;. 46% oligoarticular, 36% polyarticular, 8% systemic, 5% SPA types, 5% JIA and uveitis. 48% of JIA patients were in remission on medication. Disease activity was low in 38%, high in 2%, moderate in 7%; 11 patients had juvenile dermatomyositis, 3 systemic and 2 localized scleroderma, 4 isolated idiopathic uveitis, 1 CINCA syndrome, 1 MKD, and 1 FMF. 110 patients had MMR/V booster while on MTX; 3 reported mild side-effects of local skin reaction and pain, none had disease flare. 76 had booster while on MTX+ anti-TNF; 7 reported mild and transient adverse events of local skin reaction, fever and URTI. 39 had booster while on anti-TNF alone; 1 reported fever. 3 had booster while on tocilizumab, 7 on anakinra, and 5 on canakinumab. There was no relation between disease activity, type or duration, sex, age and outcome of vaccinations. No vaccine infection related to measles, rubella, mumps and varicella were reported. Conclusion This large, retrospective data collection demonstrates that live-attenuated booster vaccine is probably safe in children with rheumatic diseases, on immunosuppressive therapies. This strengthens the new PRES recommendation: “Vaccination of live-attenuated vaccines in patients on high-dose DMARD, high-dose glucocorticosteroids or biological agents can be considered on a case-by-case basis, weighing the risk of infections against the hypothetical risk of inducing infection through vaccination.” These data provide the basis for a large, prospective data collection study that is planned by the PReS vaccination study group. It will increase the current level of evidence for the safety of vaccinations in our pediatric rheumatology population. Disclosure of Interests Yosef Uziel: None declared, Veronica Moshe Bergonzo: None declared, Beata Onozo: None declared, Andrea Kulcsar: None declared, Diana Trobert-Sipos : None declared, Jonathan Akikusa: None declared, Gecilmara Salviato Pileggi : None declared, Despoina Maritsi: None declared, Ozgur KASAPCOPUR: None declared, Roubini Smerla: None declared, Donato Rigante: None declared, Erato Atasali: None declared, Mariana Rodrigues: None declared, Balahan Makay Speakers bureau: Enzyvant, Novartis, Roche, Abbvie, Nico Wulffraat: None declared, Natasa Toplak: None declared

Background: Heterogeneity in response to biological medication is a major challenge in the management of Juvenile Idiopathic Arthritis (JIA) (1). Biomarkers such as cytokines or whole blood RNA expression profiles that predict therapy efficacy prior to treatment pose a solution and could enable precision medicine. It was previously demonstrated that whole blood gene expression profiles can predict response to anti-TNF-α therapy in patients with JIA (2). These findings currently await validation in a multicenter prospective cohort study. Harmonization of data from different cohorts, however, is often hampered by site-dependent differences in biological sample collection and processing (3). For instance, the biological material that is retrospectively available from biobanks depends on what is stored exactly, e.g. whole blood versus peripheral blood mononuclear cells (PBMC). Furthermore, different blood collection tubes containing different additives can affect sample quality at an early stage and make interchangeability or comparability of data impossible. Objectives: We evaluated the comparability of gene expression profiles when whole blood from patients with JIA is collected in different RNA collection tubes and processed accordingly. Next, we will investigate the predictive capacity for therapy response of RNA expression profiles from frozen PBMC of 63 JIA patients. Methods: Peripheral blood from 11 children with non-systemic JIA with active disease was collected in PAXgene (PreAnalytiX) and Tempus (Applied Biosystems) tubes. All tubes were subsequently stored in the freezer at -80 °C. After thawing, RNA from the PAXgene tubes was extracted with use of the PAXgene Blood RNA Kit and RNA from the Tempus tubes was isolated by using the Tempus Preserved Blood RNA Purification Kit I. Gene expression of CSNK1D, C1D, ASAP2, SRRD, PPP1R3B, HLA-DQA1, PDZK1IP1 and MZB1 was determined with qPCR. For our next experiment, frozen PBMC derived from patients with non-systemic JIA who are included in our longitudinal Pharmachild registry biobank will be used. Of the 63 patients, 28 (44.4%) children were diagnosed with oligo articular JIA, 19 (30.2%) with poly articular JIA, 9 (14.3%) with enthesitis-related JIA, 4 (6.3%) with psoriatic JIA and 3 (4.8%) with undifferentiated JIA. The average age at sampling was 11.5 years ± 4.0 and 65% of the patients was female. These samples will be run on a 96-analyte NanoString panel and associated with clinical response at time points 3 and 6 months after start of TNF-α blockade. Results: Both RNA blood collection systems yielded high-quality RNA, with overall higher RNA concentrations for blood collected in Tempus tubes in comparison to PAXgene tubes. qPCR data showed that gene expression of all measured genes is affected by the method of blood collection and processing. However, the inter-individual variation was similar between both collection tubes, indicating that similar RNA profiles were observed. Conclusion: Gene expression profiles derived from whole blood collected in PAXgene or Tempus tubes are comparable, but are not interchangeable. References: [1] Swart JF, de Roock S, & Prakken BJ. Understanding inflammation in juvenile idiopathic arthritis: How immune biomarkers guide clinical strategies in the systemic onset subtype. Eur J Immunol 2016;46(9):2068-2077. [2] Cui A, Quon G, Rosenberg AM et al. Gene Expression Deconvolution for Uncovering Molecular Signatures in Response to Therapy in Juvenile Idiopathic Arthritis. PloS one 2016;11(5):1-17. [3] Yeung RS, Albani S, Feldman BM et al. Enhancing translational research in paediatric rheumatology through standardization. Nature Reviews Rheumatology 2016;12(11):684. Disclosure of Interests: None declared

Background Last year the International League of Associations for Rheumatology (ILAR) classification criteria for juvenile idiopathic arthritis (JIA), [1] were challenged by the provisional Paediatric Rheumatology International Trials Organisation (PRINTO) classification criteria.[2] Four disorders were proposed: (a) systemic JIA; (b) rheumatoid factor (RF)-positive JIA; (c) enthesitis/spondylitis-related JIA; and (d) early-onset antinuclear antibody (ANA)-positive JIA. Early-onset ANA-positive JIA is defined by: arthritis for ≥ 6 weeks, and early-onset (≤ 6 yrs), and presence of 2 positive ANA tests with a titer ≥ 1/160 at least 3 months apart with the exclusions of having systemic JIA, RF-positive arthritis, or enthesitis/spondylitis-related JIA. Objectives To evaluate the shifts from the original subtypes of JIA in the new disorder of early-onset ANA–positive JIA. Methods This study used data from the international PRINTO based registry regarding pharmacovigilance in JIA called Pharmachild.[3] For this analysis we used the data of 4,165 patients completely categorized following the ILAR ‘oligoarthritis’, ‘RF-negative polyarthritis’, ‘psoriatic arthritis’ and ‘undifferentiated JIA’ (UJIA) subtypes and with complete determination of ANA status. These patients were if possible reclassified in the early-onset ANA–positive JIA according to the provisional PRINTO classification criteria. Results Table 1 shows the characteristics of all 4,165 patients according to the ILAR criteria. Of this final set of 4165 patients, 1279 (30.7%) were ANA-positive and 957 (74.8%) classified into the PRINTO ‘early onset ANA-positive JIA’ category. Of these 957, 2 patients were RF-positive, which is an exclusion criterion for the ‘early onset ANA-positive JIA’ category and therefore were not categorized as early onset ANA-positive JIA. The female proportion was higher than in any ILAR subtype being 83.0% (793/955). The origin (ILAR categories) of the 955 patients in the ‘early onset ANA-positive JIA’ category consisted of 33.7% patients with persistent oligoarthritis (322/955), 24.7% (236/955) with extended oligoarthritis, 28.0% with RF-negative polyarthritis (267/955), 4.2% with psoriatic arthritis (40/955) and 9.4% with UJIA (90/955). Conclusion This study shows that of all ANA-positive JIA patients belonging to the ‘oligoarthritis’, ‘RF-negative polyarthritis’, ‘psoriatic arthritis’ and ‘UJIA’ ILAR subtypes, 74.8% met the criteria for the PRINTO ‘early onset ANA-positive’ category. The female proportion was higher than in any ILAR subtype being 83.0%. This new category consists largely of 3 ILAR subtypes: persistent oligoarthritis (34%), extended oligoarthritis (25%) and RF negative polyarthritis (28%). Further studies on these provisional criteria are ongoing. References [1] Petty RE, Southwood TR, Manners P et al. International League of Associations for Rheumatology Classification of Juvenile Idiopathic Arthritis: Second Revision, Edmonton, 2001. J Rheumatol. 2014 [2] Martini A, Ravelli A, Avcin T et al. Toward New Classification Criteria for Juvenile Idiopathic Arthritis: First Steps, PRINTO International Consensus. J Rheumatol. 2018 Oct 1 [3] Swart J, Giancane G, Horneff G et al. Pharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15,000 patients from Pharmachild and national registries. Arthritis Res Ther. 2018 Dec 27 Disclosure of Interests Vera Mars: None declared, Joost F. Swart: None declared, Gabriella Giancane: None declared, Sytze De Roock: None declared, Anne Estmann: None declared, Marija Jelusic: None declared, Estefania Moreno Ruzafa: None declared, Jaime de Inocencio: None declared, Jelena Vojinovic: None declared, Agustin Remesal: None declared, M Laday: None declared, Rolando Cimaz: None declared, A V Cochino: None declared, Inmaculada Calvo Grant/research support from: received research grants from Pfizer, Roche, Novartis, Clementia, Sanofi, MSD, BMS and GSK, Consultant for: Advisory boards: Novartis, AbbVie, Speakers bureau: AbbVie, Roche, Novartis, SOBI, M Harjacek: None declared, Nico Wulffraat: 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 (

Background Juvenile idiopathic arthritis (JIA) has a reported prevalence varying from 16 to 150 per 100,000 patients and it thereby is the most frequent chronic rheumatologic disease presenting in childhood. Inflammatory bowel disease (IBD) is an auto-inflammatory disease that can develop in patients with JIA. Results from multiple studies suggest an association between therapy with Etanercept (ETN) and occurrence of IBD in patients with JIA, which may or may not be counteracted by methotrexate. Objectives The aim of this study was to describe characteristics of JIA patients who developed IBD and to evaluate a possible relationship between IBD onset and medication use at IBD onset. Methods Pharmachild, the largest international JIA registry, was used for this study. Patients were enrolled via members of the Paediatric Rheumatology INternational Trials Organisation (PRINTO). The registry contains both retrospective and prospective data. Results A total of 8,309 patients were included in this study. 290 gastrointestinal disorders were reported in 260 patients. 50 cases in 47 patients were classified as IBD or suspected IBD. Age at JIA onset was significantly higher in patients who developed IBD (9.1 vs 7.1 years p=0.002), and female predominance was lower (48.9% versus 67.6% p=0.011). Enthesitis related arthritis (ERA) was the JIA subtype in 40.4% of the patients who developed IBD. In 14 out of 47 patients more detailed information about IBD disease onset was available, such as date of disease onset and medication used at that time. 71.4% of all 14 patients used etanercept and 50.0% used MTX 3 months prior or at IBD onset. Etanercept exposure prior to IBD onset varied from no exposure to 6.39 years with a median of 1.3 years. Methotrexate exposure prior to disease onset varied from no exposure to 8.10 years with a median of 2.9 years. Information regarding quality of life was available for 2,752 patients of which 17 IBD patients. Quality of life, both physical and psychosocial, was significantly lower in patients who developed IBD patients (p=0.018 and p=0.046 respectively). Conclusion In this study ERA patients were more at risk of developing IBD and 71.4% used etanercept while developing IBD. We did not find a protective role of MTX since 50.0% of patients with available data developed IBD while using MTX. Lastly, IBD has an important physical and psychosocial impact on quality of life. Reference [1] Swart JF; Giancane G; Horneff G; Magnusson B; Hofer M; Alexeeva E; Panaviene V; Bader-Meunier B; Anton J; Nielsen S; De Benedetti F; Kamphuis S; Stanevicha V; Trachana M; Ailioaie LM; Tsitsami E; Klein A; Minden K; Foeldvari I; Haas JP; Klotsche J; Horne. Pharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15,000 patients from pharmachild and national registries. Arthritis Res Ther. 2018; Disclosure of Interests Roline Krol: None declared, Joost F. Swart: None declared, Gabriella Giancane: None declared, Sytze De Roock: None declared, Troels Herlin: None declared, Pavla Dolezalova: None declared, Helga Sanner: None declared, Gordana Susic: None declared, Flavio R. Sztajnbok: None declared, D Maritsi: None declared, Tamas Constantin: None declared, V Vargova: None declared, Sujata Sawhney: None declared, Marite Rygg: None declared, SHEILA KNUPP DE OLIVEIRA: None declared, Marco Cattalini: None declared, Ellen Nordal: None declared, Claudia Magalhaes: None declared, Alberto Martini Consultant for: I do not have any conflict of interest to declare since starting from 1 March 2016 I became the Scientific Director of the G. Gaslini Hospital; therefore, my role does not allow me to render private consultancies resulting in personal income. I perform consultancy activities on behalf of the Gaslini Institute for the companies listed below: AbbVie, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, EMD Serono, Janssen, Novartis, Pfizer, R-Pharm. The money received for these activities are directly transferred to the Gaslini Institute’s bank account. Before March 2016, I was the head of the Pediatric Rheumatology Department at the G. Gaslini Hospital, where the PRINTO Coordinating Centre is located. For the coordination activity of the PRINTO network, the Gaslini Hospital received contributions from the industries listed in this section. This money has been reinvested for the research activities of the hospital in fully independent manners besides any commitment with third parties., Nico Wulffraat: 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 (

Background: In recent years, juvenile idiopathic arthritis (JIA) research has shifted towards treat-to-target therapy based on clinical assessments and patient-reported outcomes (1). A well-known measurement of quality of life is the EQ-5D-5L (2). Herewith, we report preliminary results of a retrospective study using the child-friendly ‘EQ-5D-5L-Y’ with an E-health application (Reuma2GO) to monitor children with JIA in an outpatient setting. Objectives: To assess the relationship between dimensions of the health-related quality of life ‘EQ-5D-5L-Y’ questionnaire and conventional assessments for children with JIA, including the Juvenile Arthritis Multidimensional Assessment Report (JAMAR) and active joint count (AJC), and to investigate the potential of the EQ-5D-5L-Y as instrument for outpatient management. Methods: The study was designed as monocentric retrospective cohort study. Data from October 2017 to January 2019 were available for 70 patients with JIA. The relationships between individual dimensions of the EQ-5D-5L-Y, JAMAR and several clinical assessments were investigated. Furthermore, dimensions of the EQ-5D-5L-Y were investigated as possible predictors for binary disease activity using AJC > 0 as reference standard for active disease. Results: Seventy patients with JIA completed 115 EQ-5D-5L-Y and JAMAR questionnaires within two weeks before a clinical visit. Moderate to high correlations were found between the EQ-5D-5L-Y and JAMAR. Moreover, the best possible EQ-5D-5L-Y score, with and without health-related visual analogue scale (EQ-VAS), demonstrated high sensitivity (81.1%) and negative predictive value (84.8%) for active disease (Table 1). The few patients who were incorrectly classified as having inactive disease (false-negatives) did not have their medication changed at the clinical visit and experienced little to no impact of disease activity on their quality of life, as indicated by the JAMAR questionnaire. PPV: positive predictive value; NPV: negative predictive value. Conclusion: These results demonstrate the discriminatory value of the EQ-5D-5L-Y between active and inactive disease in our cohort of patients with JIA. High negative predictive value was found for the total EQ-5D-5L-Y score, with and without EQ-VAS. In conclusion, the EQ-5D-5L-Y could be a valuable instrument for monitoring children with JIA in an outpatient setting which could aid physicians with deciding whether a clinical visit is necessary or not. References [1] Filocamo G, et al. A new approach to clinical care of juvenile idiopathic arthritis: The juvenile arthritis multidimensional assessment report. J Rheumatol2011;38:938–953. [2] Janssen MF, et al. Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study. Qual Life Res2013;22:1717–1727. Disclosure of Interests: Martijn J.H. Doeleman: None declared, Sytze De Roock: None declared, Nathan Buijsse: None declared, Mark Klein: None declared, Gouke J. Bonsel: None declared, V. Seyfert Shareholder of: VS is CEO and founder at MyOwnMed, Inc., Employee of: VS is CEO and founder at MyOwnMed, Inc., Nico Wulffraat: None declared, Joost F. Swart: None declared

Background Rare Immunodeficiency, AutoInflammatory and AutoImmune Disease (RITA) network is a European Research Network that brings together the leading centres for rare immune disorders (RID). Objectives To know the state of the art about diseases registries and research networks in Europe regarding patients with RID. Methods On April 2018 an on-line survey was sent to all 126 RITA members, of whom 45 are healthcare providers and 8 patients/family organizations. All data were collected and analysed using Excel program. Results Ninety RITA members (71%) replied. Collectively, 27 members are coordinating 25 registries, 53 members are participating in 38 registries, and 27 members knew the existence of 16 registries without participating. Only two members are not involved in any registries. Data about 53 different registries were collected across 14 European countries. Almost 50% of registries collect data on autoimmune disorders, while others are dedicated to primary immunodeficiencies and autoinflammatory diseases (respectively 15 registries, 28%, and 12 registries, 23%). Fifteen registries (28%) enrolled patients with a single specific disorder: in particular, three registries are devoted to systemic lupus erythematosus, two registries to Kawasaki disease or Behcet disease, and single registry to juvenile dermatomyositis, juvenile systemic sclerosis, juvenile idiopathic arthritis (JIA)-related uveitis, systemic JIA, Blau syndrome, sarcoidosis, Guillain-Barre syndrome, and myasthenia gravis. More than 55000 patients with RID are enrolled. The majority of registries (36; 68%) enrol only patients from national territories. Among the internationals, six collect data on autoimmune disorders (Pharmachild, BrainWorks, EuroMyositis, EULAR web library, UKIVAS registry and JIR cohort), five on primary immunodeficiencies (ESID, EBMT, SCETIDE, PCID and HLH registry), and three are devoted to autoinflammatory diseases (Eurofever, Infevers, and ImmunAID), despite also ESID registry and JIR cohort collect data on autoinflammatory diseases. Data usually collected in these registries are demography, diagnosis, clinical manifestations, laboratory tests and treatment, while genetic and imaging data are less frequently reported (respectively in 38% and 9% of registries). A treatment safety profile is reported in 29 registries (55%). Collectively, fifteen biobanks are counted. Conclusion The survey highlighted the pivotal role of national and international organizations in Europe to collect and organize clinical data on immune diseases, allowing the rapidly growing knowledge on these rare disorders, creating research networks and providing significant numbers of data to support new discoveries in the field. RITA network could improve the coordination of these numerous entities, supporting initiatives of collaboration. As a first attempt, the present survey revealed that the collection of key parameters about patient safety, as well as outcome data and quality of life measures should be improved among the registries of RITA network. References [1] Beukelman T, Anink J, Duffy C, et al. A survey of national and multi-national registries and cohort studies in juvenile idiopathic arthritis: challenges and opportunities. Pediatric Rheumatology 2017;15(1):31. Disclosure of Interests Riccardo Papa: None declared, Andrew Cant: None declared, Christoph Klein: None declared, Mark Little: None declared, Nico M Wulffraat: None declared, Marco Gattorno Grant/research support from: MG has received unrestricted grants from Sobi and Novartis, 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 (

Childhood-onset systemic lupus erythematosus (cSLE) is a rare, multisystem and potentially life-threatening autoimmune disorder with significant associated morbidity. Evidence-based guidelines are sparse and management is often based on clinical expertise. SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) was launched to optimise and disseminate management regimens for children and young adults with rheumatic diseases like cSLE. Here, we provide evidence-based recommendations for diagnosis and treatment of cSLE. In view of extent and complexity of cSLE and its various manifestations, recommendations for lupus nephritis and antiphospholipid syndrome will be published separately. Recommendations were generated using the EULAR (European League Against Rheumatism) standard operating procedure. An expert committee consisting of paediatric rheumatologists and representation of paediatric nephrology from across Europe discussed evidence-based recommendations during two consensus meetings. Recommendations were accepted if >80% agreement was reached. A total of 25 recommendations regarding key approaches to diagnosis and treatment of cSLE were made. The recommendations include 11 on diagnosis, 9 on disease monitoring and 5 on general treatment. Topics included: appropriate use of SLE classification criteria, disease activity and damage indices; adequate assessment of autoantibody profiles; secondary macrophage activation syndrome; use of hydroxychloroquine and corticosteroid-sparing regimens; and the importance of addressing poor adherence. Ten recommendations were accepted regarding general diagnostic strategies and treatment indications of neuropsychiatric cSLE. The SHARE recommendations for cSLE and neuropsychiatric manifestations of cSLE have been formulated by an evidence-based consensus process to support uniform, high-quality standards of care for children with cSLE.

In 1951, Barbara Ansell, a young 28-year-old physician and aspiring cardiologist, was encouraged by Professor Eric Bywaters to join him in the Special Unit for Juvenile Rheumatism, recently created by the Medical Research Council (MRC) of UK, located at the Canadian Red Cross Memorial Hospital in Taplow, Buckinghamshire, UK. She had been advised that cardiology ‘was a man’s world’. Although initially aimed at research and treatment of rheumatic fever, this unit of pathologists and clinicians morphed into a unit for juvenile chronic arthritis as the incidence of rheumatic fever gradually waned. At that time, a child with chronic arthritis would mostly be confined to bed at home, perhaps with aspirin and/or cortisone medication and bore a grim prognosis regarding both function and survival. She began her pioneering work there with her MD thesis (1965) on the classification of children with chronic arthritis. Her clinical skill and experience were legendary. Her major clinical achievements are listed in box 1. She also was actively engaged with scientists in the search for the causes of the diseases she encountered. She was ideally placed in the shared environment of MRC facilities next to a general hospital. Box 2 is a short summary of the main milestones and breadth of her work. In 1988, the world-renowned paediatric rheumatologist, Barbara Ansell CBE, FRCP, FRCS, FRCPCH, retired as director of the MRC Division of Rheumatology at Northwick Park, Harrow, UK. She left as a legacy an army of former colleagues, protegees and friends from all areas of healthcare, dedicated to children and adolescents with rheumatic diseases. By then the outcome for such young patients had improved dramatically. Gratifyingly, Barbara did see the fulfilment of her long-held dream, expressed passionately at her retirement Festschrift: the beginning of truly effective therapies. Box 1 ### Barbara Ansell: Key achievements

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.

Background To describe the 6-year safety and efficacy of etanercept (ETN) in children with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA) Methods Patients who completed the 2-year, open-label, phase III CLinical Study In Pediatric Patients of Etanercept for Treatment of ERA, PsA, and Extended Oligoarthritis (CLIPPER) were allowed to enroll in its 8-year long-term extension (CLIPPER2). Children received ETN at a once-weekly dose of 0.8 mg/kg, up to a maximum dose of 50 mg/week. Efficacy assessments included the JIA core set of outcomes, the JIA American College of Rheumatology response criteria (JIA-ACR), and the Juvenile Arthritis Disease Activity Score (JADAS). Efficacy data are reported as responder analyses using a hybrid method for missing data imputation and as observed cases. Safety assessments included treatment-emergent adverse events (TEAEs). Results Out of 127 patients originally enrolled in CLIPPER, 109 (86%) entered CLIPPER2. After 6 years of trial participation (2 years in CLIPPER and 4 years in CLIPPER2), 41 (32%) patients were still taking ETN, 13 (11%) entered the treatment withdrawal phase after achieving low/inactive disease (of whom 7 had to restart ETN), 36 (28%) discontinued treatment for other reasons but are still being observed, and 37 (29%) discontinued treatment permanently. According to the hybrid imputation analysis, proportions of patients achieving JIA ACR90, JIA ACR100, and JADAS inactive disease after the initial 2 years of treatment were 58%, 48%, and 32%, respectively. After the additional 4 years, those proportions in patients who remained in the trial were 46%, 35%, and 24%. Most frequently reported TEAEs [n (%), events per 100 patient-years] were headache [28 (22%), 5.3], arthralgia [24 (19%), 4.6], and pyrexia [20 (16%), 3.8]. Number and frequency of TEAEs, excluding infections and injection site reactions, decreased over the 6-year period from 193 and 173.8, respectively, during year 1 to 37 and 61.3 during year 6. A single case of malignancy (Hodgkin’s lymphoma) and no cases of active tuberculosis, demyelinating disorders, or deaths were reported. Conclusions Open-label etanercept treatment for up to 6 years was safe, well tolerated, and effective in patients with eoJIA, ERA, and PsA. Trial registration ClinicalTrials.gov: CLIPPER, NCT00962741, registered 20 August, 2009, CLIPPER2, NCT01421069, registered 22 August, 2011. Electronic supplementary material The online version of this article (10.1186/s13075-019-1916-9) contains supplementary material, which is available to authorized users.

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

OBJECTIVE: The objective was to predict insufficient response to 3 months methotrexate (MTX) in DMARD naïve rheumatoid arthritis patients.METHODS: A Multivariable logistic regression model of rheumatoid arthritis patients starting MTX was developed in a derivation cohort with 285 patients starting MTX in a clinical multicentre, stratified single-blinded trial, performed in seven secondary care clinics and a tertiary care clinic. The model was validated in a validation cohort with 102 patients starting MTX at a tertiary care clinic. Outcome was insufficient response (disease activity score (DAS)28 >3.2) after 3 months of MTX treatment. Clinical characteristics, lifestyle variables, genetic and metabolic biomarkers were determined at baseline in both cohorts. These variables were dichotomized and used to construct a multivariable prediction model with backward logistic regression analysis.RESULTS: The prediction model for insufficient response in the derivation cohort, included: DAS28>5.1, Health Assessment Questionnaire>0.6, current smoking, BMI>25 kg/m2, ABCB1 rs1045642 genotype, ABCC3 rs4793665 genotype, and erythrocyte-folateCONCLUSIONS: A prognostics prediction model for insufficient response to MTX in 2 prospective RA cohorts by combining genetic, metabolic, clinical and lifestyle variables was developed and validated. This model satisfactorily identified RA patients with high risk of insufficient response to MTX.

ObjectivesTo evaluate the long-term efficacy and safety of canakinumab in patients with active systemic juvenile idiopathic arthritis (JIA).MethodsPatients (2–19 years) entered two phase III studies and continued in the long-term extension (LTE) study. Efficacy assessments were performed every 3 months, including adapted JIA American College of Rheumatology (aJIA-ACR) criteria, Juvenile Arthritis Disease Activity Score (JADAS) and ACR clinical remission on medication criteria (CRACR). Efficacy analyses are reported as per the intent-to-treat population.Results144 of the 177 patients (81%) enrolled in the core study entered the LTE. Overall, 75 patients (42%) completed and 102 (58%) discontinued mainly for inefficacy (63/102, 62%), with higher discontinuation rates noted in the late responders group (n=25/31, 81%) versus early responders (n=11/38, 29%). At 2 years, aJIA-ACR 50/70/90 response rates were 62%, 61% and 54%, respectively. CRACR was achieved by 20% of patients at month 6; 32% at 2 years. A JADAS low disease activity score was achieved by 49% of patients at 2 years. Efficacy results were maintained up to 5 years. Of the 128/177 (72.3%) patients on glucocorticoids, 20 (15.6%) discontinued and 28 (22%) tapered to 0.150 mg/kg/day. Seven patients discontinued canakinumab due to CR. There were 13 macrophage activation syndrome (three previously reported) and no additional deaths (three previously reported). No new safety findings were observed.ConclusionResponse to canakinumab treatment was sustained and associated with substantial glucocorticoid dose reduction or discontinuation and a relatively low retention-on-treatment rate. No new safety findings were observed on long-term use of canakinumab.Trial registration numbersNCT00886769, NCT00889863, NCT00426218 and NCT00891046.

Objectives The European initiative Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) aimed to optimize care for children with rheumatic diseases. Systemic vasculitides are very rare in children. Consequently, despite recent advances, paediatric-specific information is sparse. The lack of evidence-based recommendations is an important, unmet need. This study aimed to provide recommendations for diagnosing and treating children with rare forms of childhood systemic vasculitis. Methods Recommendations were developed by a consensus process in accordance with the European League Against Rheumatism standard operating procedures. A systematic literature review informed the recommendations, which were devised and evaluated by a panel of experts via an online survey, and two consensus meetings using nominal group technique. Recommendations were accepted when ⩾ 80% of experts agreed. Results Ninety-three relevant articles were found, and 78 recommendations were accepted in the two consensus meetings. General, cross-cutting recommendations and disease-specific statements regarding the diagnosis and treatment of childhood-onset PAN, granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and Takayasu arteritis are provided. Conclusion These Single Hub and Access point for paediatric Rheumatology in Europe recommendations were formulated through an evidence-based consensus process to support uniform, high-quality standard of care for children with rare forms of paediatric systemic vasculitis.

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

OBJECTIVES: To determine the prevalence of severe fatigue and fatigue-related limitations among adolescents with juvenile idiopathic arthritis (JIA) and other pediatric rheumatic diseases (PRD). In addition, we assessed the effect of disease activity and pain on the severity of fatigue. METHODS: This cross-sectional study included 175 patients (10-18 years of age) who visited the pediatric rheumatology and immunology outpatient clinic at Wilhelmina Children's Hospital from April through July 2013. Patients completed validated questionnaires regarding fatigue, physical functioning, and school attendance. Disease activity in JIA patients was measured using the Juvenile Arthritis Disease Activity Score (JADAS-27). The results were compared against a healthy control group. RESULTS: The prevalence of severe fatigue among patients with PRD was 25.1%, which was significantly higher than the healthy control group (p

INTRODUCTION: Interleukin-1 (IL-1) is the key molecule of a strong pro-inflammatory pathway in the innate immune system. The IL-1 family harbors components with pro- and anti-inflammatory effects essential for the regulation of the inflammation process. Auto-inflammatory diseases and systemic onset juvenile idiopathic arthritis (JIA) are examples of chronic inflammatory diseases that are IL-1 dependent. IL-1 blockade has proven to be very effective and has greatly improved the outcome of these disorders. Areas covered: This review describes the components of the IL-1 family and the available IL-1 blocking agents for clinical practice. Among them, canakinumab was more recently introduced. Based on the published clinical trials one can conclude that the clinical efficacy in auto-inflammatory diseases is at least as good as other IL-1 blocking agents. The safety data are limited to those registration studies (Phase 2 and 3). In short term the adverse events described are not very different from the other IL-1 blockers. Expert opinion: Longer term use in larger numbers of patients and adequate data collection using large-scale registries are necessary to provide us with a well-balanced overview of safety issues of canakinumab. Registration studies and open label extension studies show an acceptable safety profile so far.

Background: In 2012, a European initiative called Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and uveitis is possibly its most devastating extra-articular manifestation. Evidence-based guidelines are sparse and management is mostly based on physicians' experience. Consequently, treatment practices differ widely, within and between nations. Objectives: To provide recommendations for the diagnosis and treatment of JIA-associated uveitis. Methods: Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was constituted, consisting of nine experienced paediatric rheumatologists and three experts in ophthalmology from Europe. Recommendations derived from a validated systematic literature review were evaluated by an Expert Committee and subsequently discussed at two consensus meetings using nominal group techniques. Recommendations were accepted if >80% agreement was reached (including all three ophthalmologists). Results: In total, 22 recommendations were accepted (with >80% agreement among experts): 3 on diagnosis, 5 on disease activity measurements, 12 on treatment and 2 on future recommendations. Conclusions: The SHARE initiative aims to identify best practices for treatment of patients suffering from JIA-associated uveitis. Within this remit, recommendations for the diagnosis and treatment of JIA-associated uveitis have been formulated by an evidence-informed consensus process to suggest a standard of care for JIA-associated uveitis patients throughout Europe. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved.

Background: The availability of methotrexate and the introduction of multiple biological agents have revolutionized the treatment of juvenile idiopathic arthritis (JIA). Several international and national drug registries have been implemented to accurately monitor the long-term safety/efficacy of these agents. This report aims to present the combined data coming from Pharmachild/PRINTO registry and the national registries from Germany (BiKeR) and Sweden.Methods: Descriptive statistics was used for demographic, clinical data, drug exposure, adverse events (AEs) and events of special interest (ESIs). For the Swedish register, AE data were not available.Results: Data from a total of 15,284 patients were reported: 8274 (54%) from the Pharmachild registry and 3990 (26%) and 3020 (20%) from the German and the Swedish registries, respectively. Pharmachild children showed a younger age (median of 5.4 versus 7.6 years) at JIA onset and shorter disease duration at last available visit (5.3 versus 6.1–6.8) when compared with the other registries. The most frequent JIA category was the rheumatoid factor–negative polyarthritis (range of 24.6–29.9%). Methotrexate (61–84%) and etanercept (24%–61.8%) were the most frequently used synthetic and biologic disease-modifying anti-rheumatic drugs (DMARDs), respectively. There was a wide variability in glucocorticoid use (16.7–42.1%). Serious AEs were present in 572 (6.9%) patients in Pharmachild versus 297 (7.4%) in BiKeR. Infection and infestations were the most frequent AEs (29.4–30.1%) followed by gastrointestinal disorders (11.5–19.6%). The most frequent ESIs were infections (75.3–89%).Conclusions: This article is the first attempt to present a very large sample of data on JIA patients from different national and international registries and represents the first proposal for data merging as the most powerful tool for future analysis of safety and effectiveness of immunosuppressive therapies in JIA.Registry registration: The Pharmachild registry is registered at ClinicalTrials.gov (NCT01399281) and at the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) (http://www.encepp.eu/encepp/viewResource.htm?id=19362). The BiKeR registry is registered at ENCePP (http://www.encepp.eu/encepp/viewResource.htm?id=20591).

Background Withholding live-attenuated vaccines in patients using interleukin (IL)-1 or IL-6 blocking agents is recommended by guidelines for both pediatric and adult rheumatic diseases, since there is a risk of infection in an immune suppressed host. However, this has never been studied. This retrospective, multicenter survey aimed to evaluate the safety of live-attenuated vaccines in patients using IL-1 or IL-6 blockade. Methods We contacted physicians involved in the treatment of autoinflammatory diseases to investigate potential cases. Patients were included if a live-attenuated vaccine had been administered while they were on IL-1 or IL-6 blockade. Results Seventeen patients were included in this survey (7 systemic juvenile idiopathic arthritis (sJIA), 5 cryopyrin associated periodic syndrome (CAPS), 4 mevalonate kinase deficiency (MKD) and 1 familial Mediterranean fever (FMF). Three patients experienced an adverse event, of which two were serious adverse events (a varicella zoster infection after varicella zoster booster vaccination, and a pneumonia after MMR booster). One additional patient had diarrhea after oral polio vaccine. Further, seven patients experienced a flare of their disease, which were generally mild. Eight patients did not experience an adverse event or a flare. Conclusion We have described a case series of seventeen patients who received a live-attenuated vaccine while using IL-1 or IL-6 blocking medication. The findings of this survey are not a reason to adapt the existing guidelines. Prospective trials are needed in order to acquire more evidence about the safety and efficacy before considering adaptation of guidelines.