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ObjectiveTo evaluate the long-term safety profile of anakinra in patients with systemic juvenile idiopathic arthritis (sJIA).MethodsData from patients with sJIA enrolled in the Pharmachild registry (ClinicalTrials.gov: NCT03932344) prior to September 30, 2018, and treated with anakinra were analyzed. The study endpoints were the occurrence of non-serious adverse events (SAEs) of at least moderate severity and SAEs, including macrophage activation syndrome (MAS), and the duration of anakinra treatment with reasons for discontinuation. All endpoints were analyzed overall by 6-month time windows, and in different treatment sets represented by those patients treated continuously with anakinra for at least 12, 18, and 24 months (set-12, -18, and -24, respectively).ResultsThree hundred six patients were enrolled. Of these patients, 46%, 34%, and 28% had been treated for at least 12, 18, and 24 months, respectively. Two hundred and one AEs, mostly represented by infections, were reported for 509.3 patient-years (PY) with an overall incidence rate (IR) of 39.5 per 100 PY. Among 56 SAEs (IR 11.0/100 PY), 23.2% were infections and 19.6% MAS episodes. The IR of AEs was higher during the first 6 months of anakinra treatment, followed by decreasing IRs in the long-term treatment sets. Treatment discontinuation occurred in 76% of patients, most frequently in the first 6 months, because of inefficacy (43%), remission (31%), or AEs/intolerance (15%). No deaths or malignancies occurred during anakinra treatment.ConclusionThe results of the present study confirm the long-term safety profile of anakinra in patients with sJIA and demonstrate an overall decreasing incidence of AEs over time. [ClinicalTrials.gov: NCT01399281 and NCT03932344]

To assess the possible impact conferred by co-existing variants in MEditerranean FeVer (MEFV) and other genes on systemic autoinflammatory disease (SAID) phenotype.Consecutive patients (n = 42) who underwent screening for SAIDs by next generation sequencing (NGS) targeting 26 genes, and carried at least one MEFV gene variant, were retrospectively studied. A total of 63 MEFV gene variants mainly located in exon 10 (n = 29) and exon 2 (n = 19) were identified in 21 patients with juvenile- and 21 with adult-onset disease.The candidate clinical diagnosis was Familial Mediterranean Fever (FMF) in 11, polygenic SAIDs (PFAPA, Still's disease, atypical SAPHO and inflammatory bowel disease) in 9, whereas the disease could not be clinically defined in 22 patients. Notably, 33 out of the 42 patients (79%) had at least one co-existing variants in 19 genes other than MEFV. NGS confirmed all clinical diagnoses and helped defining diagnosis in 59% of the remaining cases. Patients with undefined SAIDs (n = 9) or atypical FMF phenotype (n = 12) carried significantly more disease-causing variants in genes other than MEFV compared to patients with typical FMF (n = 9). More than one variants in these genes were significantly associated with adult-onset disease, while disease-causing variants in the same genes were also associated with an overall more severe SAID phenotype.Co-existing variants in SAID-related genes may explain the phenotypic variability of these diseases. Further studies should validate combined molecular and clinical data in order to better understand the cumulative gene dosage effect and improve the classification of these patients.

Objective To describe the clinical characteristics, treatment, and outcomes of a multinational cohort of patients with macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA). Study design International pediatric rheumatologists were asked to collect retrospectively the data of patients with the co-occurrence of MAS and TMA. Clinical and laboratory features of patients with systemic juvenile idiopathic arthritis (sJIA)-associated MAS and TMA were compared with those of an historical cohort of patients with sJIA and MAS. Results Twenty-three patients with MAS and TMA were enrolled: 17 had sJIA, 2 systemic lupus erythematosus, 1 juvenile dermatomyositis, 1 mixed connective tissue disease, and 2 undifferentiated connective tissue disease. Compared with the historical cohort of MAS, patients with sJIA with coexistent MAS and TMA had higher frequencies of renal failure and neurologic involvement, hemorrhage, jaundice, and respiratory symptoms, as well as more severe anemia and thrombocytopenia, higher levels of alanine aminotransferase, lactate dehydrogenase, bilirubin and D-dimer, and lower levels of albumin and fibrinogen. They also required admission to the intensive care unit more frequently. Among patients tested, complement abnormalities and reduced ADAMTS13 activity were observed in 64.3% and 44.4% of cases, respectively. All patients received glucocorticoids. Treatment for TMA included plasma-exchange, eculizumab, and rituximab. Conclusions The possible coexistence of MAS and TMA in rheumatic diseases may be underrecognized. This association should be considered in patients with MAS who develop disproportionate anemia, thrombocytopenia, and lactate dehydrogenase increase, or have multiorgan failure.

Objective.To develop and test shortened versions of the Manual Muscle Test-8 (MMT-8) in juvenile dermatomyositis (JDM).Methods.Construction of reduced tools was based on a retrospective analysis of individual scores of MMT-8 muscle groups in 3 multinational datasets. The 4 and 6 most frequently impaired muscle groups were included in MMT-4 and MMT-6, respectively. Metrologic properties of reduced tools were assessed by evaluating construct validity, internal consistency, discriminant ability, and responsiveness to change.Results.Neck flexors, hip extensors, hip abductors, and shoulder abductors were included in MMT-4, whereas MMT-6 also included elbow flexors and hip flexors. Both shortened tools revealed strong correlations with MMT-8 and other muscle strength measures. Correlations with other JDM outcome measures were in line with predictions. Internal consistency was good (0.88–0.96) for both MMT-4 and MMT-6. Both reduced tools showed strong ability to discriminate between disease activity states, assessed by the caring physician or a parent (P < 0.001), and between patients whose parents were satisfied or not satisfied with illness course (P < 0.001). Responsiveness to change (assessed by both standardized response mean and relative efficiency) of MMT-4 and, to a lesser degree, MMT-6, was slightly superior to that of MMT-8.Conclusion.Overall, the metrologic performance of MMT-4 and MMT-6 was comparable to that of the other established muscle strength tools, which indicates that they may be suitable for use in clinical practice and research, including clinical trials. The measurement properties of these tools should be further tested in other patient populations and evaluated prospectively.

Objectives Colchicine is the main treatment for FMF. Although a number of individuals with FMF are intolerant/resistant to colchicine, there is no standard definition of colchicine resistance/intolerance. We developed a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF that may serve as a guide for clinicians and health authorities. Methods A set of statements was identified using a modified-Delphi consensus-based approach. The process involved development of an initial colchicine resistance/intolerance-related questionnaire derived from a systematic literature review. The questionnaire, which was completed by an international panel of 11 adult and paediatric rheumatologists with expertise in FMF, was analysed anonymously. The results informed draft consensus statements that were discussed by a round-table expert panel, using a nominal group technique to agree on the selection and wording of the final statements. Results Consensus among the panel was achieved on eight core statements defining colchicine resistance/intolerance in patients with FMF. A definition of resistance was agreed upon that included recurrent clinical attacks (average one or more attacks per month over a 3-month period) or persistent laboratory inflammation in between attacks. Other core statements recognize the importance of assessing treatment adherence, and the impact of active disease and intolerance to colchicine on quality of life. Conclusion Based on expert opinion, a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF were identified to help guide clinicians and health authorities in the management of patients with FMF.

Introduction: ABIRISK is a project funded by Innovative Medicine Initiative, with the aim to investigate anti-drug antibody (ADA) formation in the treatment of JIA with biologics (BPs). A major limitation to the use of biologics is the development of ADA that may decrease the efficacy of BPs. Objectives: The aim of this project is to improve the capability to predict biologic immunogenicity in JIA patients. Methods: JIA Patients (by ILAR criteria) followed by 24 PRINTO centres in 12 countries were prospectively enrolled and treated with Etanercept, Adalimumab or Tocilizumab. Patient’s data were obtained from Pharmachild, a pharmacovigilance data registry of JIA patients. For each patient detailed demographic and clinical information were reported; biologic samples were collected for PK and ADA detection before therapy start as well as at periodic visits up to month 18 of follow-up. Disease activity was assessed with Juvenile Arthritis Disease Activity Score-10 (JADAS10) and JIA American College of Rheumatology (JIA ACR) criteria. Results: 148 patients were included in the analysis. Five patients were considered twice because treated with 2 different sequential biologics. Demographic and clinical data by therapy are represented in the table. 54% of the patients were treated with Adalimumab. Disease duration was higher in the group receiving Tocilizumab. Disease activity showed a pattern of improvement over time both globally and for each treatment group (Table 1). Anti-adalimumab and antitocilizumab antibodies were detected respectively in 14 and 3 patients, while no patient developed antibodies anti-etanercept. Conclusion: Preliminary data show a global improvement of disease activity during follow-up period. Analysis of the correlation between drug concentration/ADA development and clinical information will help to determine which patients will respond best to which biologic.

OBJECTIVE: To develop a composite DAS for JDM and provide preliminary evidence of its validity. METHODS: The Juvenile DermatoMyositis Activity Index (JDMAI) is composed of four items: physician's global assessment of overall disease activity ; parent's/child's global assessment of child's wellbeing ; measurement of muscle strength ; and assessment of skin disease activity. The score of the JDMAI is the arithmetic sum of the scores of each individual component. Six versions of the JDMAI were tested, which differed in the tools used to assess the third and fourth items. Validation procedures were conducted using three large multinational patient samples including a total of 627 patients. RESULTS: The JDMAI was found to possess face and content validity, good construct validity, satisfactory internal consistency (Cronbach's alpha = 0.58- 0.89), fair responsiveness to clinically important change (standardized response mean = 0.82-3.12 among patients improved) and strong capacity to discriminate patients judged as being in the state of inactive disease or low, moderate or high disease activity by the physician (P < 0.001) or whose parents were satisfied or not satisfied with the course of their child's illness (P < 0.001). Overall, the six versions of the JDMAI showed similar metrological performances in validation analyses. CONCLUSION: The JDMAI was found to possess good measurement properties in a large population of patients with a wide range of disease activity, and is, therefore, suitable for use in both clinical and research settings. The final version of the JDMAI will be selected after its prospective validation

Background Assessment of muscle strength is a fundamental component of the clinical evaluation of children with juvenile dermatomyositis (JDM). Regular measurement of muscle strength in daily care requires the availability of simple and quick muscle assessment tools. Objectives To investigate whether reduced versions of the MMT8 and CMAS are equally reliable as the original tools. Methods The following 4 reduced instruments were devised: 1) MMT4 (score 0-40), including 4 items of MMT8 (neck flexors, deltoid middle, gluteus maximus, and gluteus medius); 2) MMT6 (score 0-60), composed of the same items of MMT4 plus biceps brachii and quadriceps; 3) head lift time of CMAS (0-120 seconds or 0-5 points); 4) sum of CMAS head lift time in points and the 6 sit-ups maneuvers of CMAS (score 0-11). Validation was conducted according to OMERACT filter on 213 patients followed in standard clinical care at 13 international pediatric rheumatology centers and evaluated at baseline and after a median of 5.9 months. Results All reduced instruments revealed strong correlations (r > 0.7) with muscle activity VAS and total DAS, moderate correlations (r = 0.4-0.7) with physician’s global VAS, muscle DAS, skin activity VAS, pain VAS, parent’s overall wellbeing VAS, and CK. Correlations with skin DAS and fatigue VAS were low (r Conclusion We found that reduced versions of the MMT8 and CMAS have good metrologic properties and perform similarly to the original tools in a population of patients followed in standard clinical care. Our results suggest that these simplified and shortened instruments could serve as surrogate for the complete measures in routine practice, particularly in a busy clinical setting. References [1] Measures of adult and juvenile dermatomyositis, polimyositis, and inclusion body myositis. Rider LG, Werth VP, Huber AM, Alexanderson H, Rao AP, et al. Arthritis Care Res (Hoboken)2011;63:S118-57. [2] Clinical assessment in juvenile dermatomyositis. Ravelli A, Ruperto N, Trail L, Felici E, Sala E, et al. Autoimmunity2006;39:197-203. Disclosure of Interests Silvia Rosina: None declared, Giulia Camilla Varnier: None declared, Angela Pistorio: None declared, Alessandro Consolaro Grant/research support from: AbbVie, Pfizer, Clarissa Pilkington: None declared, Susan Maillard: None declared, Adele Civino: None declared, Elena Tsitsami: None declared, Jaime de Inocencio: None declared, Marija Jelusic: None declared, Jelena Vojinovic: None declared, Graciela Espada: None declared, Balahan Makay Speakers bureau: Enzyvant, Novartis, Roche, Abbvie, Maria Katsikas: None declared, Polixeni Pratsidou-Gertsi: None declared, Dragana Lazarevic: None declared, Anand Prahalad Rao: 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 (

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

Background:Systemic juvenile idiopathic arthritis (SJIA) is characterized by extra-articular manifestations, as fever and rash, and rarely associated by a potentially lethal complication as macrophage activation syndrome (MAS). Anakinra is a recombinant human interleukin (IL)-1 receptor antagonist whose efficacy and safety profile has been studied for patients with SJIA.Objectives:To evaluate the long-term safety profile of anakinra in patients with SJIA.Methods:Data from patients with SJIA enrolled in the Pharmachild registry before 30 September 2018 and treated with anakinra were analyzed. The study endpoints were the occurrence of non-serious adverse events (AEs) of at least moderate severity and serious AEs (SAEs), including macrophage activation syndrome (MAS), and the duration of anakinra treatment with reasons for discontinuation. All endpoints were analyzed overall, by 6 month-time windows and in different treatment sets represented by those patients continuously treated with anakinra for at least 12, 18 and 24 months (set-12, -18, -24, respectively).Results:306 patients were enrolled. 46%, 34% and 28% of them had been treated for at least 12, 18 and 24 months, respectively. 201 AEs, mostly represented by infections, were reported for 509.3 patient-years (py) with an overall incidence rate (IR) of 39.5/100 py. Among 56 SAEs (IR 11.0/100 py), (Table 1) 23.2% were infections and 19.6% MAS episodes. The IR of AEs was higher during the first 6 months of anakinra, followed by decreasing IR in the different long-term treatment sets. Treatment discontinuation occurred in 76% of patients, most in the first 6 months, due to inefficacy (43%), remission (31%) or AEs/intolerance (15%). No deaths or malignancies occurred during anakinra treatment.Table 1.Number of SAEs and incidence rates (95% CI) by overall PT decreasing order and time window in the complete set (events with a frequency >1 by overall SOC and >1 by overall PT were reported) Only time windows Time window1-6 months7-12 monthsOverallN306194306Patient-time (years)117.380.2509.3SOCPTnRate (95% CI)nRate (95% CI)nRate(95% CI)AllAll3328.1 (19.1-41.5)45.0 (1.9-13.2)5611.0 (7.9-15.2)Infections and infestationsAll76.0 (2.9- 12.4)11.2 (0.2- 8.8)132.6 (1.4- 4.8)Pneumonia21.7 (0.4- 6.8)11.2 (0.2- 8.8)40.8 (0.3- 2.1)Immune system disordersAll76.0 (2.8- 12.5)11.2 (0.2- 8.8)112.2 (1.1- 4.1)Haemophagocytic lymphohistiocytosis76.0 (2.8- 12.5)11.2 (0.2- 8.8)112.2 (1.1- 4.1)Injury, poisoning and procedural complicationsAll54.3 (1.8- 10.2)--91.8 (0.9- 3.4)Infusion related reaction10.9 (0.1- 6.0)--20.4 (0.1- 1.6)Injection related reaction43.4 (1.3- 9.1)--61.2 (0.5- 2.6)Metabolism and nutrition disordersAll32.6 (0.8- 7.9)--40.8 (0.3- 2.1)Skin and subcutaneous tissue disordersAll32.6 (0.8- 7.9)11.2 (0.2- 8.8)40.8 (0.3- 2.1)Blood and lymphatic system disordersAll10.9 (0.1- 6.1)--20.4 (0.1- 1.6)General disorders and administration site conditionsAll10.9 (0.1- 6.1)11.2 (0.2- 8.8)20.4 (0.1- 1.6)InvestigationsAll21.7 (0.4- 6.8)--20.4 (0.1- 1.6)Nervous system disordersAll10.9 (0.1- 6.0)--20.4 (0.1- 1.6)Surgical and medical proceduresAll10.9 (0.1- 6.0)--20.4 (0.1- 1.5)Abbreviations: SAE, serious adverse event; SOC, system organ class; PT, preferred term, MedDRA version 21.1; N, number of patients ever treated with anakinra during the time window irrespectively of the length of any unexposed periods; 95% CI, 95% Confidence Interval.Conclusion:The results of the present study confirm the long-term safety profile of anakinra in SJIA patients and show a decreasing overall incidence rate of AEs over time.Disclosure of Interests:Gabriella Giancane Grant/research support from: The study was funded by SOBI Swedish, Riccardo Papa Grant/research support from: The study was funded by SOBI Swedish, Sebastian Vastert Grant/research support from: The study was funded by SOBI Swedish, Francesca Bagnasco Grant/research support from: The study was funded by SOBI Swedish, Joost F. Swart Grant/research support from: The study was funded by SOBI Swedish, Pierre Quartier Grant/research support from: The study was funded by SOBI Swedish, michael hofer Grant/research support from: The study was funded by SOBI Swedish, Jordi Anton Grant/research support from: The study was funded by SOBI Swedish, Sylvia Kamphuis Grant/research support from: The study was funded by SOBI Swedish, Helga Sanner Grant/research support from: The study was funded by SOBI Swedish, Mia Glerup Grant/research support from: The study was funded by SOBI Swedish, Fabrizio De Benedetti Grant/research support from: The study was funded by SOBI Swedish, Elena Tsitsami Grant/research support from: The study was funded by SOBI Swedish, Agustin Remesal Grant/research support from: The study was funded by SOBI Swedish, Estefania Moreno Ruzafa Grant/research support from: The study was funded by SOBI Swedish, Jaime de Inocencio Grant/research support from: The study was funded by SOBI Swedish, Charlotte Myrup Grant/research support from: The study was funded by SOBI Swedish, Chiara Pallotti Grant/research support from: The study was funded by SOBI Swedish, Isabelle Koné-Paut Grant/research support from: The study was funded by SOBI Swedish, Karin Franck-Larsson Employee of: I am employee of SOBI pharmaceutical company, Hakan Malmstrom Employee of: I am employee of SOBI pharmaceutical company, Susanna Cederholm Employee of: I am employee of SOBI pharmaceutical company, Angela Pistorio Grant/research support from: The study was funded by SOBI Swedish, Nico Wulffraat Grant/research support from: The study was funded by SOBI Swedish, Nicolino Ruperto Speakers bureau: NR has received honoraria for consultancies or speaker bureaus (< 10.000 USD each) from the following pharmaceutical companies in the past 3 years: Ablynx, Astrazeneca-Medimmune, Bayer, Biogen, Boehringer, Bristol Myers and Squibb, Celgene, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Hoffmann-La Roche,Janssen, Merck, Novartis, Pfizer, R-Pharma, Sinergie, Sobi and UCB., Consultant of: NR has received honoraria for consultancies or speaker bureaus (< 10.000 USD each) from the following pharmaceutical companies in the past 3 years: Ablynx, Astrazeneca-Medimmune, Bayer, Biogen, Boehringer, Bristol Myers and Squibb, Celgene, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Hoffmann-La Roche,Janssen, Merck, Novartis, Pfizer, R-Pharma, Sinergie, Sobi and UCB., Grant/research support from: The IRCCS Istituto Giannina Gaslini (IGG), 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.

Objective.To assess the efficacy and safety of the interleukin-1β (IL-1β) inhibitor canakinumab in all adolescent and adult patients with familial Mediterranean fever (FMF) identified from the Greek National Registry for off-label drug use between 2010 and 2015.Methods.In this retrospective longitudinal outcome study, clinical and laboratory data were collected from 14 patients (7 men) aged median 38.5 years (range 13–70), with median disease duration of 14 years, and active FMF despite colchicine (n = 9) or both colchicine and anakinra (n = 5).Results.All patients continued to receive canakinumab at last visit (median of 18 mos, range 13–53), which was initially given as monotherapy (n = 8) or in combination with colchicine and/or corticosteroids, every 4 (n = 7), 6 (n = 2), or 8 weeks (n = 5). Eleven patients (79%), including 6 receiving monotherapy, achieved complete clinical remission within 2 months (median), while normalization of all laboratory variables denoting inflammation occurred in 92% at 3 months (median). The remaining 3 patients achieved partial responses. Responses were sustained in all but 4 patients, who relapsed. Reducing the canakinumab administration interval from 8 or 6 weeks to 4 weeks led to suppression of disease activity in the relapsing patients. On the other hand, drug administration interval could be safely increased in 2 patients in remission. Corticosteroid doses were significantly reduced during followup. Canakinumab was well tolerated; 1 patient experienced a urinary tract infection and another one a viral gastroenteritis.Conclusion.Treatment with canakinumab in an individualized dosing scheme results in rapid and sustained remission in colchicine-resistant FMF.

Objective To develop and test a hybrid measure of muscle strength for juvenile dermatomyositis (JDM), which is based on the combination of the Manual Muscle Testing 8 (MMT8) and the Childhood Myositis Assessment Scale (CMAS), but is more comprehensive than the former and more feasible than the latter. Methods The hybrid MMT/CMAS (hMC) is composed of all 8 items of the MMT8 and 3 items of the CMAS: 1) time of head lift; 2) assessment of abdominal muscles; 3) floor rise. The score ranges from 0 to 100, with 100 indicating normal muscle strength. Validation procedures were conducted using three large multinational patient samples including a total of 810 JDM patients. Results The hMC revealed face and content validity, good construct validity, excellent test-retest reliability (intraclass correlation coefficient = 0.99) and internal consistency (Chronbach's alpha = 0.94), strong responsiveness to clinical change over time (standardized response mean = 0.8 among patients judged as improved by the caring physician), and satisfactory capacity to discriminate patients judged as being in the states of inactive disease or low, moderate, or high disease activity by the physician (p < 0.001) or patients whose parents were satisfied or not satisfied with illness course (p < 0.001). Conclusion The hMC was found to possess good measurement properties in a large population of patients with a wide range of disease activity and severity. The new tool, which is primarily intended for use in routine clinical care, should be further tested in other populations of patients evaluated prospectively. This article is protected by copyright. All rights reserved.

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient-reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Greek language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographics, clinical data, and the JAMAR from 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). The Greek JAMAR was fully cross-culturally adapted with two forward and three backward translations. A total of 272 JIA patients (5.9% systemic, 57.7% oligoarticular, 21.3% RF negative poly-arthritis, 15.1% other categories), and 100 healthy children were enrolled in all centres. The JAMAR components discriminated well-healthy subjects from JIA patients; notably, there was no significant difference between healthy subjects and their affected peers in psychosocial quality of life and school-related items. All JAMAR components revealed good psychometric performances. In conclusion, the Greek 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 in clinical research.

Sialic acid acetylesterase (SIAE) deficiency was suggested to lower the levels of ligands for sialic acid-binding immunoglobulin-like receptors, decreasing the threshold for B-cell activation. In humans, studies of rare heterozygous loss-of-function mutations in SIAE gene in common autoimmune diseases, including juvenile idiopathic arthritis (JIA), yielded inconsistent results. Considering the distinct pathogenesis of the two main subtypes of JIA, autoinflammatory systemic (sJIA) and autoimmune oligo/polyarticular (aJIA), and a predisposition to autoimmunity displayed by patients and families with primary antibody deficiencies (PADs), the aim of our study was to analyze whether SIAE rare variants are associated with both the phenotype of JIA and the autoimmunity risk in families with PADs. A cohort of 69 patients with JIA, 117 healthy children, 54 patients, and family members with PADs were enrolled in the study. Three novel SIAE variants (p.Q343P, p.Y495X, and c.1320+33T>C) were found only in patients with aJIA but interestingly also in their healthy relatives without autoimmunity, while none of PAD patients or their relatives carried SIAE defects. Our results show that SIAE rare variants are not causative of autoimmunity as single defects.

Background Musculoskeletal (MS) involvement and clinically evident arthritis occurs in up to 65% of patients with Juvenile Systemic or localized Scleroderma (JSc). It may be the first manifestation preceding even the onset of Raynaud or skin manifestations; patients presenting with arthritis, tenosynovitis or enthesistis may suffer from Sc. On the other hand clinical examination often underestimates MS involvement in Sc. US and MRI can help distinguish arthritis with effusion from dry tenosynovitis of Sc, define whether loss of range of motion (LOM) derives only from skin thickening or from bone and joint involvement and monitor disease progression. Objectives To describe the spectrum of MRI and US features in juvenile scleroderma with musculoskeletal involvement. Methods We describe MRI and color Doppler MSUS findings of clinically affected (with arthritis and/or LOM and/or overlying skin with edema or sclerosis) lower or upper extremities from 4 males and 2 females;2 with systemic sc (ssc), 2 with linear scleroderma, 1 with generalized morphea, 1 with mixed morphea (median age 8,5 years, range 7–10,5; median time from symptom onset to MRI 11 months, range 2–24). MRI sequences;T1, fluid-sensitive, and T1-FS contrast-enhanced. Comparisons were made to uninvolved areas of the extremity, and the contralateral extremity. Findings guiding diagnosis and evaluation of disease extent are depicted in the Figure. Results Thickening of the dermis and infiltration of the subcutaneous fat with increase in signal intensity on fluid sensitive sequences and contrast-enhanced T1w images and hypointense signal lesions on unenhanced T1w images (asterisks) was apparent in 4 patients. In 2 male patients with generalized scleroderma, clinical LOM of fingers and wrists preceded skin sclerosis by 2 months. Joint and tendon sheath synovitis, indicated by initial MSUS, was detected in fluid sensitive and T1w enhanced images (white arrows). The combination of tendon-sheath synovitis and muscular fascia thickening and enhancement (black arrows), and contractures (thin white arrow) very characteristic of scleroderma, helped identify sclerodermatous musculoskeletal involvement in the absence of skin induration. Focal bone marrow edema depicted as high signal intensity in fluid sensitive sequences (curved arrow) was found in 2 cases; 1 with generalized morphea without apparent overlying skin sclerodermatous lesion, 1 with linear scleroderma with atrophic lesions in all overlying structures Conclusions Musculoskeletal imaging features of juvenile scleroderma involving the skin, fascia, musculature and bones reflect pathomorphologic changes of this rare disorder and enable a complete assessment of the disease extent, including depth of infiltration and disease activity.In the described cases implementation of MSUS and MRI in Juvenile scleroderma led to earlier definition of the diagnosis and assisted the evaluation of disease extension. References Zulian F et al. Arthritis and Rheumatism 2007 Mar 15;57(2):203–12. Eusler E et al. Pediatr Radiol 2017 Jan 14. Schannz S et al. RSNA 2011. Torok K Pediatr Clin North Am. 2012 April;59(2):381–405. Disclosure of Interest None declared

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

Objective To compare the capacity of the 2004 diagnostic guidelines for hemophagocytic lymphohistiocytosis (HLH-2004) with the capacity of the preliminary diagnostic guidelines for systemic juvenile idiopathic arthritis (JIA)–associated macrophage activation syndrome (MAS) to discriminate MAS complicating systemic JIA from 2 potentially confusable conditions, represented by active systemic JIA without MAS and systemic infection. Methods International pediatric rheumatologists and hemato-oncologists were asked to retrospectively collect clinical information from patients with systemic JIA–associated MAS and confusable conditions. The ability of the guidelines to differentiate MAS from the control diseases was evaluated by calculating the sensitivity and specificity of each set of guidelines and the kappa statistics for concordance with the physician's diagnosis. Owing to the fact that not all patients were assessed for hemophagocytosis on bone marrow aspirates and given the lack of data on natural killer cell activity and soluble CD25 levels, the HLH-2004 guidelines were adapted to enable the diagnosis of MAS when 3 of 5 of the remaining items (3/5-adapted) or 4 of 5 of the remaining items (4/5-adapted) were present. Results The study sample included 362 patients with systemic JIA and MAS, 404 patients with active systemic JIA without MAS, and 345 patients with systemic infection. The best capacity to differentiate MAS from systemic JIA without MAS was found when the preliminary MAS guidelines were applied. The 3/5-adapted HLH-2004 guidelines performed better than the 4/5-adapted guidelines in distinguishing MAS from active systemic JIA without MAS. The 3/5-adapted HLH-2004 guidelines and the preliminary MAS guidelines with the addition of ferritin levels ≥500 ng/ml discriminated best between MAS and systemic infections. Conclusion The preliminary MAS guidelines showed the strongest ability to identify MAS in systemic JIA. The addition of hyperferritinemia enhanced their capacity to differentiate MAS from systemic infections. The HLH-2004 guidelines are likely not appropriate for identification of MAS in children with systemic JIA.

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

This study constitutes the first molecular analysis of hereditary angioedema (HAE) in Greece, where 11 patients from three unrelated families with recurrent angioedema attacks and decreased C1 inhibitor antigenic levels were analyzed for SERPING1 mutations. Interestingly, one family displayed a novel SERPING1 alteration, characterized by the substitution of two consecutive nucleotides TC to AA, resulting in a termination codon (F225X). To the best of our knowledge, this is the first report of such a mutation in SERPING1, causing HAE. The second family displayed the nonsense mutation W482X, and the third the missense mutation M1V, already described in the literature. The type of mutation did not predict clearly the disease phenotype, since even members of the same family displayed a variety of the frequency and the severity of angioedema attacks. Our study identified a novel mutagenesis mechanism for HAE pathogenesis, providing additional evidence for the genetic heterogeneity of the disease.

The objective of this study was to assess the frequency ofMBL2genotypes and their associations with MBL levels and various morbidities of a neonatal intensive care unit (NICU). One hundred and thirty-four (134) NICU (83 term and 51 preterm) and 150 healthy neonates were enrolled in the study.MBL2genotype and MBL serum levels at birth were determined prospectively by PCR-RFLP-sequencing and enzyme-linked immunosorbent assay, respectively. NICU neonates displayed significantly lower MBL serum levels compared to healthy ones. MBL deficiency, defined as the lowMBL2expression group (XA/O and O/O), was significantly associated with an increased risk of respiratory morbidity, especially transient tachypnea of the newborn and respiratory distress syndrome (RDS). Moreover, an increase of 100 ng/mL of serum MBL levels decreases by 5% the risk of total respiratory morbidity and by 7% the risk of RDS, after correction for prematurity and sex and regardless of the presence of infections. Our study further supports the notion that neonates with MBL deficiency and low MBL serum levels at birth may be at higher risk of developing severe respiratory complications.

To identify preliminary core sets of outcome variables for disease activity and damage assessment in juvenile systemic lupus erythematosus (JSLE) and juvenile dermatomyositis (JDM).Two questionnaire surveys were mailed to 267 physicians from 46 different countries asking each member to select and rank the response variables used when assessing clinical response in patients with JSLE or JDM. Next, 40 paediatric rheumatologists from 34 countries met and, using the nominal group technique, selected the domains to be included in the disease activity and damage core sets for JSLE and JDM.A total of 41 response variables for JSLE and 37 response variables for JDM were selected and ranked through the questionnaire surveys. In the consensus conference, domains selected for both JSLE and JDM activity or damage core sets included the physician and parent/patient subjective assessments and a global score tool. Domains specific for JSLE activity were the immunological tests and the kidney function parameters. Concerning JDM, functional ability and muscle strength assessments were indicated for both activity and damage core sets, whereas serum muscle enzymes were included only in the activity core set. A specific paediatric domain called 'growth and development' was introduced in the disease damage core set for both diseases and the evaluation of health-related quality of life was advised in order to capture the influence of the disease on the patient lifestyle.We developed preliminary core sets of measures for disease activity and damage assessment in JSLE and JDM. The prospective validation of the core sets is in progress.

Evidence from case reports/series, one controlled study, and one phase II, open-label, single-arm study supports IL-1β blockage as a potential treatment for colchicine resistant Familial Mediterranean Fever (FMF).

To compare the capacity of the 2004 diagnostic guidelines for hemophagocytic lymphohistiocytosis (HLH-2004) with the capacity of the preliminary diagnostic guidelines for systemic juvenile idiopathic arthritis (JIA)-associated macrophage activation syndrome (MAS) to discriminate MAS complicating systemic JIA from 2 potentially confusable conditions, represented by active systemic JIA without MAS and systemic infection.International pediatric rheumatologists and hemato-oncologists were asked to retrospectively collect clinical information from patients with systemic JIA-associated MAS and confusable conditions. The ability of the guidelines to differentiate MAS from the control diseases was evaluated by calculating the sensitivity and specificity of each set of guidelines and the kappa statistics for concordance with the physician's diagnosis. Owing to the fact that not all patients were assessed for hemophagocytosis on bone marrow aspirates and given the lack of data on natural killer cell activity and soluble CD25 levels, the HLH-2004 guidelines were adapted to enable the diagnosis of MAS when 3 of 5 of the remaining items (3/5-adapted) or 4 of 5 of the remaining items (4/5-adapted) were present.The study sample included 362 patients with systemic JIA and MAS, 404 patients with active systemic JIA without MAS, and 345 patients with systemic infection. The best capacity to differentiate MAS from systemic JIA without MAS was found when the preliminary MAS guidelines were applied. The 3/5-adapted HLH-2004 guidelines performed better than the 4/5-adapted guidelines in distinguishing MAS from active systemic JIA without MAS. The 3/5-adapted HLH-2004 guidelines and the preliminary MAS guidelines with the addition of ferritin levels ≥500 ng/ml discriminated best between MAS and systemic infections.The preliminary MAS guidelines showed the strongest ability to identify MAS in systemic JIA. The addition of hyperferritinemia enhanced their capacity to differentiate MAS from systemic infections. The HLH-2004 guidelines are likely not appropriate for identification of MAS in children with systemic JIA.

SIAE is involved in the maintenance of immunological tolerance through negative regulation of Β-cell receptor (BCR) signaling. Recent evidences, though conflicting, indicate that rare loss-of-function SIAE variants are associated with susceptibility to various autoimmune diseases. Advances in understanding JIA pathophysiology have led to the consensus that systemic JIA (SJIA) is an autoinflammatory disorder while oligo/polyarticular JIA (O/PJIA) is an antigen-driven lymphocyte-mediated autoimmune disease.

Background The Pharmachild study is aimed at observing children with JIA undergoing treatment primarily with biologics±methotrexate (MTX). It is conducted by the participating centres of over 60 countries belonging to PRINTO and PReS. Objectives Primary endpoint of the study is safety in JIA patients undergoing immunosuppressive therapy. A preliminary analysis of infections has been performed by an independent Safety Ajudication Committee of 6 experts (3 pediatric rheumatologists and 3 pediatric infectious disease specialists). Methods The centres were asked to report all infections encountered by the patients followed for JIA. Data were checked by PRINTO and the medical monitor based on MedDRA dictionary. Upon completion of these steps, all eligible cases for adjudication, represented by serious/severe/very severe infections, were submitted to the expert Committee. The experts were asked to answer 6 questions. The events with consensus of at least 4/6 experts on more than 3/6 questions were considered. An additional analysis was performed on opportunistic infections, with referral to the recommendations by Withrop et al.1, and on the correlation between infections and 3 treatment phases: MTX only, first biologic±MTX and at least 2 sequential biologics±MTX after failure of the first biologic. Results 7817 patients were enrolled in Pharmachild at the time of preliminary analysis, with 27% of total safety events reported as infections. 360 events were submitted to the Safety Adjudication Committee. 94 infections (26.1%) achieved maximum consensus among the experts (6/6 questions), 237 (65.8%) consensus on 4/6 or 5/6 questions, the remaining events were discarded. 330 infections were finally retained for the analysis, mostly represented by serious infections of moderate/severe intensity. With regard to the other questions, 74.2% infections were adjudicated as common, appropriately treated, with no clear correlation to the immunosuppressive therapy. The experts achieved consensus on 18 infections adjudicated as opportunistic. Referring to the list of opportunistic infections provided by Winthrop et al.1, we identified 89/330 (27%) opportunistic infections, mostly represented by EBV and herpes zoster infections. 98.8% of events were not recoded. A doubled risk of infections was found in the group of patients who were started on their first biologic±MTX or who had been treated with at least 2 sequential biologics±MTX (1.3 and 1.9 infectious events per 100 py, respectively), compared to the MTX only group (0.8 infectious events per 100 py). The same was found for serious and opportunistic infections. Conclusions Our preliminary analysis showed a significant number of infections in JIA patients on immunosuppressive therapy, with one third classified as opportunistic infection. The introduction of biologics in therapy increased the risk of opportunistic and serious infection. References Winthrop et al. Ann Rheum Dis. 2015;74:2107–16. Disclosure of Interest None declared

We report a case of a 13-year-old girl with chronic recurrent multifocal osteomyelitis (CRMO) who developed severe arthritis in four different joints within the first year from the onset of the disease. Her multiple vertebrae lesions showed significant amelioration after a 2-month treatment with prednisolone. In parallel, the initial severe symmetrical arthritis of both knees showing overt synovitis and joint effusion, in the absence of lesions in the metaphyses of the femur or the tibia, responded remarkably well in intra-articular triamcinolone hexacetonide injections. However, upon discontinuation of prednisolone, the patient developed severe arthritis of her right ankle and the proximal interphalangeal joint of her right middle finger. Thus, prednisolone was reinitiated combined with methotrexate, and the patient went into remission, which persists one year after prednisolone tapering. The appearance of arthritis in both knees in the absence of bone lesions and the emergence of severe arthritis of the ankle after remission of spinal bone lesions suggest that CRMO and juvenile idiopathic arthritis may coexist and be causally related.

NOMID/CINCA is the most severe phenotype of cryopyrin-associated periodic syndrome (CAPS), characterized by persistence of inflammation-mediated symptoms and overproduction of interleukin (IL)-1β, associated with significant morbidity, if untreated. In CAPS-patients early initiation of anti-IL1β-treatment appears to prevent severe disease sequelae. However, canakinumab as a 1st-line treatment in young infants suffering from NOMID has been scarcely reported.

Background Juvenile systemic sclerosis (jSSc) is an orphan disease. We have currently new promising effective medication to treat systemic sclerosis, but no valid outcome measures to assess the activity of the disease. Objectives In the frame of the juvenile scleroderma working group of Paediatric Rheumatology European Society (PRES JSWG), we developed a provisional response index for jSSc. Methods The facilitating committee designed a 3-round Delphi-exercise to obtain a core set of disease activity measures in jSSc. In Round 1, they were asked to add unique items in 21 preleminary domains. Round 2 judged the items9 applicability and importance using a 1-10 scale. Previous respondents were asked to re-rate uncertain (score 4-7) items in Round 3. The aforementioned were followed by a face-to-face Nominal Group discussion to decide final items and domain structure. Results 52 participants of Round 1 suggested a total of 131 items for the 21 domains. In round 2, 56 responders rated the significance of the items. The Nominal Group accepted 11 main domains for further validation containing 41 items (see table 1). Conclusions We reached consensus and developed a Response Index, which should help to conduct clinical trials in jSSc. The validation of the JSSRI is planned in the frame of the Juvenile Scleroderma Inception Cohort. Disclosure of Interest None declared

Background Treatment of juvenile idiopathic arthritis (JIA) has greatly changed in the past 15 years thanks to the introduction of biologic agents but little is known on the long-term safety profiles. Objectives To evaluate the long-term safety profile of a large cohort of JIA patients treated with methotrexate (MTX) alone or in combination with one or more biologic agents in the Pharmachild registry. Methods Pharmachild is an ongoing, multicenter, non-interventional, retrospective/prospective observational registry of patients with JIA treated with either MTX alone or in combination with one or more biologic agents as part of their standard clinical care. 3 treatment groups of patients were considered: treated with MTX only, treated with MTX+1 biologic agent (MTX+1B) and treated with MTX+>1 subsequentially given biologic agent (MTX+>1B). Safety was re-coded by certified assessors according to the Medical Dictionary for Regulatory Activities (MedDRA). True incidence rate events9 100 patient-years (PY) for events at least moderate other adverse events (AE) including events of special interest (ESI) or were calculated for all MedDRA System Organ Class (SOC). Results Out of 5882 JIA patients: 1715 (29%, 3832 PY, median disease duration, DD, 2.9 years) treated primarily with MTX (no biologics), 3007 (51%, 7013 PY, DD 4.7 years) treated with MTX+1B (67% etanercept, 18% adalimumab, infliximab/tocilizumab 5% each) and 1117 (19%, 4892 PY, DD 7.1 years) treated with MTX+>1B (31% etanercept, 27% adalimumab, 15% infliximab, 9% tocilizumab). 2355 (40%) children were treated also with corticosteroids (82% in systemics) and 1176 (20%) with other DMARDS. There were 609 (10.4%) systemic, 1195 (20.3%) oligo persistent, 2914 (49.5%) extended/poly RF pos or neg and 1164 (19.8%) other JIA categories. The incidence rates (Table) of serious AE increases with the addition of ≥1 biologic agents (2.1, 3.2, 8.9). A similar trend was observed for infections (3.2, 3.3, 4.4); serious infections rates were 0.5, 1, 1.9 respectively. The incidence rates for varicella were 0.55, 0.34, 0.41 and for herpes zoster 0.08, 0.24, 0.51 in the 3 groups, respectively. Incidence rates for injury, poisoning and procedural complications, blood and lymphatic system, eye and other were higher in the group treated with more than 1 biologic agent. Incidence rates for gastrointestinal and hepatobiliary disorders were higher for the MTX only group when compared to the other 2. Patients who discontinued the MTX or biologics for AE or drug intolerance were 75 (4%), 483 (16%) and 210 (18%). There were a total of 4 malignancies (2 acute lymphocytic leukemia, 1 thyroid cancer, 1 fibroadenoma of breast). There were 12 deaths (1, 5 and 6 in each of the 3 groups). Conclusions The introduction of one or more sequential biologic agent increase the rate of serious adverse events, infection when compared to the treatment with MTX alone. Disclosure of Interest J. Swart: None declared, A. Pistorio: None declared, F. Bovis: None declared, E. Alekseeva Grant/research support from: Roche, Abbott, Pfizer, Bristol-Myers Squibb, Centocor, Novartis, Speakers bureau: Roche, Merck Sharp & Dohme, Abbott, Bristol Myers Squibb, Medac, Novartis, Pfizer, M. Hofer: None declared, S. Nielsen: None declared, J. Anton Grant/research support from: Pfizer, abbvie, Novartis, Roche and Sobi, Speakers bureau: Pfizer, abbvie, Novartis, Roche and Sobi, A. Consolaro: None declared, V. Panaviene: None declared, V. Stanevicha: None declared, M. Trachana Grant/research support from: Abbvie, Novartis, Pfizer, Consultant for: Novartis, Pfizer, Roche, Speakers bureau: Novartis, Pfizer, Roche, C. Ailioaie: None declared, P. Quartier: None declared, F. De Benedetti: None declared, E. Tsitsami: None declared, B. Flato: None declared, P. Dolezalova Grant/research support from: Novartis, Speakers bureau: Novartis, Pfizer, Roche, Abbvie, T. Constantin Speakers bureau: Pfizer, Abbvie, Novartis, Roche, Bristol-Myers Squibb, T. Herlin: None declared, S. Kamphuis: None declared, S. Sawhney: None declared, D. Maritsi: None declared, V. Vargova: None declared, L. Villa: None declared, C. Pallotti: None declared, A. Ravelli Consultant for: Roche, Speakers bureau: Abbvie, Novartis, Pfizer, A. Martini Shareholder of: Abbott, BMS, “Francesco Angelini”, GlaxoSmithKline (GSK), Hoffman-La Roche, Italfarmaco, Janssen, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Sobi, Xoma, Wyeth. The Gaslini Hospital, which is the public Hospital where I work as full time public employee, has received contributions from the industries mentioned in this section. This money has been reinvested for the research activities of the hospital in a fully independent manners besides any committment with third parties., Consultant for: Honoraria for consultancy: Abbott, AbbVie, Amgen, Biogenidec, Astellas, Alter, AstraZeneca, Boehringer, BMS, CD-Pharma,Celgene, CrescendoBio, EMD Serono,Hoffman-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Servier, Vertex., Speakers bureau: Honoraria for speaker9s bureau from: Abbvie, Medimmune, Novartis, Roche, Takeda, N. Wulffraat: None declared, N. Ruperto Shareholder of: Abbott, BMS, “Francesco Angelini”, GlaxoSmithKline (GSK), Hoffman-La Roche, Italfarmaco, Janssen, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Sobi, Xoma, Wyeth. The Gaslini Hospital, which is the public Hospital where I work as full time public employee, has received contributions from the industries mentioned in this section. This money has been reinvested for the research activities of the hospital in a fully independent manners besides any committment with third parties., Consultant for: Honoraria for consultancy: Abbott, AbbVie, Amgen, Biogenidec, Astellas, Alter, AstraZeneca, Boehringer, BMS, CD-Pharma,Celgene, CrescendoBio, EMD Serono,Hoffman-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Servier, Takeda, Vertex., Speakers bureau: Honoraria for bureau speaker: Abbott, AbbVie, Amgen, Biogenidec, Astellas, BMS, CD-Pharma, Hoffman-La Roche, Pfizer

Posterior reversible encephalopathy syndrome (PRES) is a distinct clinical entity presenting with a constellation of neurological symptoms and characteristic neuroimaging findings of posterior cerebral white matter edema. In adults, PRES has been associated with a variety of conditions and predisposing factors, including acute hypertension, preeclampsia or eclampsia, renal disease, sepsis, and exposure to immunosuppressants. The syndrome has been reported less frequently in children, with only one publication reporting the association of PRES with macrophage activation syndrome (MAS) in a patient with systemic onset juvenile idiopathic arthritis (SoJIA).

Objective In the 1997 revision of the International League of Associations for Rheumatology (ILAR) criteria for juvenile idiopathic arthritis (JIA), a family history of psoriasis is an exclusion for the oligoarthritis category. We investigated whether psoriasis in a first or second degree relative influences the clinical expression and course of JIA patients with oligoarthritis. Methods In a cross-sectional study, consecutive oligoarticular-onset JIA patients were investigated. Clinical evaluations included confirmation of a family history of psoriasis and assessment of nail abnormalities, dactylitis, psoriatic rash, variables of JIA activity, and laboratory indicators of inflammation. Retrospective assessments included sex, onset age, disease duration, antinuclear antibodies, HLA–B27, uveitis, ocular complications, second-line therapies, intraarticular corticosteroid injections, radiographic joint lesions, joint involvement over time, and laboratory investigations at disease presentation and first observation. Results A total of 185 patients were included. Thirty-three had a positive family history of psoriasis (group 2) and 139 did not (group 1). Thirteen patients fulfilled the ILAR criteria for juvenile psoriatic arthritis (group 3). Patients in groups 1 and 2 were comparable for all parameters, except for a higher frequency of females in group 1 (P = 0.04). As compared with group 2, patients in group 3 were less frequently antinuclear antibody positive and had a more severe arthritis and a different distribution of joint involvement. Conclusion We found close similarities in the clinical features and course among patients with oligoarthritis who had a positive family history for psoriasis and those who did not. These findings argue against the exclusion of the former patients from the oligoarthritis category of JIA.