Pierre Quartier

Hôpitaux Universitaires La Pitié salpêtrière - Charles Foix, Lutetia Parisorum, Île-de-France, France

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Publications (274)1340.65 Total impact


  • No preview · Article · Dec 2015 · Joint, bone, spine: revue du rhumatisme
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    ABSTRACT: Background: Macrophage activation syndrome (MAS) is a severe and potentially lethal complication of several inflammatory diseases but seems particularly linked to systemic juvenile idiopathic arthritis (sJIA). Standardized diagnostic and treatment guidelines for MAS in sJIA are currently lacking. The aim of this systematic literature review was to evaluate currently available literature on diagnostic criteria for MAS in sJIA and provide an overview of possible biomarkers for diagnosis, disease activity and treatment response and recent advances in treatment. Methods: A systematic literature search was performed in MEDLINE, EMBASE and Cochrane. 495 papers were identified. Potentially relevant papers were selected by 3 authors after which full text screening was performed. All selected papers were evaluated by at least two independent experts for validity and level of evidence according to EULAR guidelines. Results: 27 papers were included: 7 on diagnosis, 9 on biomarkers and 11 on treatment. Systematic review of the literature confirmed that there are no validated diagnostic criteria for MAS in sJIA. The preliminary Ravelli criteria, with the addition of ferritin, performed well in a large retrospective case-control study. Recently, an international consortium lead by PRINTO proposed a new set of diagnostic criteria able to distinguish MAS from active sJIA and/or infection with superior performance. Other promising diagnostic biomarkers potentially distinguish MAS complicating sJIA from primary and virusassociated hemophagocytic lymphohistiocytosis. The highest level of evidence for treatment comes from case-series. High dose corticosteroids with or without cyclosporine A were frequently reported as first-line therapy. From the newer treatment modalities, promising responses have been reported with anakinra. Conclusion: MAS in sJIA seems to be diagnosed best by the recently proposed PRINTO criteria, although prospective validation is needed. Novel promising biomarkers for sJIA related MAS are in need of prospective validation as well, and are not widely available yet. Currently, treatment of MAS in sJIA relies more on experience than evidence based medicine. Taking into account the severity of MAS and the scarcity of evidence, early expert consultation is recommended as soon as MAS is suspected.
    Full-text · Article · Dec 2015 · Pediatric Rheumatology
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    ABSTRACT: Background: Most data for treatment of dermatomyositis and juvenile dermatomyositis are from anecdotal, non-randomised case series. We aimed to compare, in a randomised trial, the efficacy and safety of prednisone alone with that of prednisone plus either methotrexate or ciclosporin in children with new-onset juvenile dermatomyositis. Methods: We did a randomised trial at 54 centres in 22 countries. We enrolled patients aged 18 years or younger with new-onset juvenile dermatomyositis who had received no previous treatment and did not have cutaneous or gastrointestinal ulceration. We randomly allocated 139 patients via a computer-based system to prednisone alone or in combination with either ciclosporin or methotrexate. We did not mask patients or investigators to treatment assignments. Our primary outcomes were the proportion of patients achieving a juvenile dermatomyositis PRINTO 20 level of improvement (20% improvement in three of six core set variables at 6 months), time to clinical remission, and time to treatment failure. We compared the three treatment groups with the Kruskal-Wallis test and Friedman's test, and we analysed survival with Kaplan-Meier curves and the log-rank test. Analysis was by intention to treat. Here, we present results after at least 2 years of treatment (induction and maintenance phases). This trial is registered with ClinicalTrials.gov, number NCT00323960. Findings: Between May 31, 2006, and Nov 12, 2010, 47 patients were randomly assigned prednisone alone, 46 were allocated prednisone plus ciclosporin, and 46 were randomised prednisone plus methotrexate. Median duration of follow-up was 35·5 months. At month 6, 24 (51%) of 47 patients assigned prednisone, 32 (70%) of 46 allocated prednisone plus ciclosporin, and 33 (72%) of 46 administered prednisone plus methotrexate achieved a juvenile dermatomyositis PRINTO 20 improvement (p=0·0228). Median time to clinical remission was 41·9 months in patients assigned prednisone plus methotrexate but was not observable in the other two treatment groups (2·45 fold [95% CI 1·2-5·0] increase with prednisone plus methotrexate; p=0·012). Median time to treatment failure was 16·7 months in patients allocated prednisone, 53·3 months in those assigned prednisone plus ciclosporin, but was not observable in patients randomised to prednisone plus methotrexate (1·95 fold [95% CI 1·20-3·15] increase with prednisone; p=0·009). Median time to prednisone discontinuation was 35·8 months with prednisone alone compared with 29·4-29·7 months in the combination groups (p=0·002). A significantly greater proportion of patients assigned prednisone plus ciclosporin had adverse events, affecting the skin and subcutaneous tissues, gastrointestinal system, and general disorders. Infections and infestations were significantly increased in patients assigned prednisone plus ciclosporin and prednisone plus methotrexate. No patients died during the study. Interpretation: Combined treatment with prednisone and either ciclosporin or methotrexate was more effective than prednisone alone. The safety profile and steroid-sparing effect favoured the combination of prednisone plus methotrexate. Funding: Italian Agency of Drug Evaluation, Istituto Giannina Gaslini (Genoa, Italy), Myositis Association (USA).
    No preview · Article · Nov 2015 · The Lancet

  • No preview · Article · Oct 2015 · Neuromuscular Disorders
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    ABSTRACT: Objective: Outcome of JDM is highly heterogeneous. Our objective was to determine clinical and muscle biopsy features associated with poor outcome and response to treatment. Methods: Clinical data and muscle biopsy were obtained from a monocentric cohort of 29 patients. Clinical subgroups were defined by latent class model analysis of initial and follow-up parameters. Myopathological features were analysed using validated scores. Capillary loss was determined on reconstructions of transversal sections and assessed in the different age groups to take into account variations of muscle capillarization during post-natal development. Regression models were used to identify initial predictors of therapeutic response. Results: Two distinct homogeneous subgroups of patients were identified according to clinical severity and pathological findings. The smallest group of patients (7/29) presented with severe JDM. Compared with the other group (22/29), patients had more severe muscle weakness at disease onset, low remission rate at 12 months, frequent subcutaneous limb oedema or gastrointestinal (GI) involvement and higher myopathological scores (capillary dropout, perifascicular necrosis/regeneration, fibres with internal myonuclei and fibrosis subscores). Relevance of capillary dropout to JDM severity was substantiated by age-based analysis, confirming its major role in JDM pathophysiology. Most of these manifestations could be related to vasculopathy (limb oedema, GI involvement, capillary dropout). Furthermore, Childhood Myositis Assessment Scale <34 with either GI involvement or muscle endomysial fibrosis at disease onset were the best predictors of poor response to treatment. Conclusion: Vasculopathy is prominent in severe JDM. Simple criteria can be used at initial evaluation to identify patients requiring a more intensive therapy.
    No preview · Article · Oct 2015 · Rheumatology (Oxford, England)
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    ABSTRACT: Objectives This three-year, international, multicentre, longitudinal, observational, cost-effectiveness study named RaDiCEA (RareDisease &Cost-EffectivenessAnalysis) will assess the economic evaluation (cost of illness - COI and cost-effectiveness analysis - CEA) of innovative therapies (i.e., anti IL-1 agents), quality of life (QoL) and effects of the prevention of otherwise irreversible central nervous system, eye, ear, kidney, and cartilage damages of different treatment strategies for cryopyrin-associated periodic syndromes (CAPS) of adults and children. Methods A virtual time-cohort approach and a Markov model simulating health states corresponding to different CAPS severity will be developed to assess the cost-effectiveness of two different treatment strategies: i.e., either anti IL-1 agents or other than anti IL-1. Due to the lack of a CAPS-specific severity index/damage score, a linear combination of existing indexes and damage scores will be used to rank patient's health status with respect to damages involving specific organs and systems. Coefficients of the resulting function will be assigned following both a top-down (Delphi) and an interim-ex post-bottom-up approach (principal component analysis) considering covariances of all the variables adopted to describe the disease evolution or response to therapies. The model uses relevant economic measures to quantify resource utilization for patients' care in the National Health Systems' perspectives and a broader societal perspective to take into account direct nonmedical costs and indirect costs, in addition to direct costs. QoL will be evaluated using EQ-5D questionnaires. To assess how the model reacts to changes in singular and multiple disease parameters, univariate and probabilistic sensitivity analyses will be performed. Expected results The RaDiCEA project will assess the long-term effectiveness of different potentially life-long treatment strategies and COI, while exploring the feasibility of a new CEA model to be generated from a rare disease (CAPS) observational study. The economic outcomes will be given as the number of years spent in each health state, the related yearly costs and QoL. Conclusions The importance and novelty of the model is twofold: i) in its application, adopting the cost-effectiveness approach for assessing the impact of CAPS therapies, and ii) in the methods, extending the analyses of the impact of CAPS therapies in reducing the speed of disease progression.
    No preview · Article · Sep 2015 · Pediatric Rheumatology
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    Full-text · Article · Sep 2015 · Pediatric Rheumatology
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    Full-text · Article · Sep 2015 · Pediatric Rheumatology
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    Full-text · Conference Paper · Sep 2015
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    ABSTRACT: To determine the type and frequency of musculoskeletal symptoms at onset and during follow-up of cryopyrin-associated periodic syndromes (CAPS). We retrospectively recorded the articular and muscular symptoms of patients with CAPS managed in French hospitals. Data were described as frequencies or median (range) and score groups were compared using the chi-square test, Fisher exact test, and Mann-Whitney test. 133 patients (33 children) were included, 20 with familial cold-induced auto-inflammatory syndrome, 88 with Muckle-Wells syndrome, 22 with chronic infantile neurologic cutaneous and articular syndrome, and 3 with unclassified CAPS. Median age was 35 (range 0-78) years at the time of the study, 1 (0-41) years at symptom onset, and 23 (0-58) years at diagnosis. The disease was sporadic in 17% of patients. Cutaneous symptoms predominated at onset (77%), followed by articular symptoms (30%). The p.Thr348Met and p.Arg260Trp NLRP3 mutations were significantly associated with presence and absence of articular symptoms at onset, respectively. During follow-up, 89% of patients had musculoskeletal symptoms; 88% had arthralgia and 58% arthritis, but only 9% had joint destruction. Tendinopathies occurred in 21.5% of patients, tender points in 16.5%, and myalgia in 33%. Only 3 patients had typical knee deformities. Radiographs were rarely performed. Except for bone deformities, osteoarticular symptoms occurred at similar frequencies in the different CAPS phenotypes. Joint manifestations were frequent in all CAPS phenotypes. Bone deformities were rare. Musculoskeletal manifestations varied within given families but tended to worsen over time. This article is protected by copyright. All rights reserved. © 2015, American College of Rheumatology.
    No preview · Article · Aug 2015 · Arthritis and Rheumatology
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    ABSTRACT: Few studies have assessed Health-Related Quality of Life (HR-QoL) in adults following juvenile idiopathic arthritis, and none since the advent of biotherapies. The aim of our study is to assess the impact of juvenile idiopathic arthritis on quality of life in a large transitional cohort, evaluate which factors influence quality of life in juvenile idiopathic arthritis, and determine which questionnaire should be used in practice. All consecutive juvenile idiopathic arthritis patients followed during adulthood in a transitional care program were included. Demographical, clinical and biological data were collected. The following quality of life questionnaires were administered: SF36 and EuroQoL. Age- and sex-matched controls (without rheumatic disease) were included. One hundred and sixty-one juvenile idiopathic arthritis (120 women and 41 men) and 76 (51/25) controls were included. Out of 161, sixty-five (40%) were considered to be in remission. Juvenile idiopathic arthritis had a large impact on the physical scales of quality of life. Pain seemed to be the most important factor affecting quality of life in cases of juvenile idiopathic arthritis. No significant difference was found between sub-types of juvenile idiopathic arthritis. In this large transitional cohort of patients at the era of biotherapies, juvenile idiopathic arthritis has a larger effect on physical than mental scale of quality of life measures. Pain was the main factor influencing quality of life. Sub-types of juvenile idiopathic arthritis do not seem to influence quality of life. Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.
    No preview · Article · Jul 2015 · Joint, bone, spine: revue du rhumatisme
  • F. Uettwiller · M. Rodero · G. Sarrabay · Y. Marot · P. Quartier · Y. Crow
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    ABSTRACT: Background Autosomal recessive loss of function mutations in CECR1 encoding adenosine deaminase 2 (ADA2) were newly reported to cause early-onset stroke and inflammatory vasculoapthy with polyarteritis nodosa as pathological feature. Overexpression of interferon stimulated genes (ISGs) has been suggested as part of the physiopathology and neutrophil related genes signature has been described in some patients. Objectives To describe the clinical and genetic features of two siblings; to measure ADA2 activity, secretion of inflammatory cytokines, interferon signature and expression of neutrophil related genes. Methods Double stranded DNA sequencing (NM_00128225.1) was performed. ADA2 activity in serum was assessed using a commercial kit. Methods for the assessment of the expression of a panel of ISGs and neutrophil stimulated genes have been previously published and validated. Cytokine secretion was assessed by ELISA. Results We report the case of a 9 years old girl of non consanguineous parents presenting at the age of 3 years with fever, systemic inflammation, lesions of cutaneous vasculitis and inflammatory muscles lesions. Muscular biopsy fund focal necroziting angeitis of a minor interfascicular artery compatible with a periarteritis nodosa. The girl experienced neurological ischemic transient attack with mild lymphocytic pleocytosis in the cerebrospinal fluid and two strokes leaving here with spasticity and a diminution of her mental performances. MRI showed pedoncular and mesencephalic lesions. She was resistant to steroids, cyclosporine and azathioprine. Pulses of cyclophosphamid allowed a transient clinical remission but she presented once more an aggravation and we decided to move to antiTNF (etanercept) Her sister was followed for anemia since age of one year, with mild unexplained inflammatory syndrome. She had no cutaneous or muscular expression and no fever. At the age of 3, she presented with transient paralysis of the third cranial nerve. At the age of 5, she presented with transient vestibulitis. Both were considered as viral but cerebral MRI revealed a lacunar stroke. Double stranded DNA sequencing showed an biallelic mutation: p.Tyr453Cys, already published and known to be pathogen by prediction analysis and a deletion of exon 6 predicted to shift the reading frame. ADA2 activity showed a significant reduction compared to control. In the two cases, interferon related genes signature was significantly elevated. Neutrophil genes showed no increased expression. Inflammatory cytokines were not significantly oversecreted. Conclusions We describe here a new mutation with a surprising clinical picture of the youngest girl: start in a very young age with no cutaneous expression, no fever and two transient neurological events. Association of inflammatory syndrome even mild with neurological unexplained event must lead to test for ADA2 mutation. ADA2 activity is probably not linked to the phenotype, as already suggested. If some patients seem to have a neutrophil signature with remarkable response to antiTNF, some are not, perhaps consistent with different sub classes of ADA2 deficiency. New therapeutics targeting the interferon pathways could be a novel approach to try. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background The long-term safety of anti-tumor necrosis factor (TNF) drugs is particularly important in pediatric patients (pts) who may require prolonged treatment of their inflammatory disease. Objectives To evaluate long-term rates of serious adverse events (AE) and anti-TNF AEs of special interest in adalimumab (ADA) clinical trials in pediatric pts with polyarticular or polyarticular course juvenile idiopathic arthritis (pJIA) or enthesitis-related arthritis (ERA). Methods Safety data from pts treated with ADA, either dosed 24 mg/m2 BSA every other week (eow) or 20 mg eow (<30 kg) to 40 mg eow (≥30 kg), in 4 clinical trials in pJIA and ERA were analyzed. Three studies in pJIA enrolled pts aged 2–17 years (yrs) treated with ADA for up to 8.5 yrs. One study enrolled pts with ERA aged 6–17 yrs who were treated with ADA for up to 52 wks in this analysis. AEs of special interest included malignancy, serious infections, tuberculosis (TB) and other opportunistic infections, and death. Events per 100 patient-years (PY) were calculated using AEs reported after first ADA dose through 70 days after last dose. Results ADA was administered to 274 pts, representing 769.0 PY of exposure. Infections, the most common AE, occurred in ≥10% of pts. Serious infection was the most frequently reported SAE (table). One case of latent TB was reported. No malignancies, opportunistic infections, or deaths were reported. 8.4% of pts (23/274) discontinued study due to AE (range, 5.1% in age <5 yr to 9.6% in ages 5 - <12 yrs). Other than uveitis, liver events, and injection site-related AEs, no differences in AE rates were observed between age groups.(table) Conclusions These data provide support for the long-term safety of ADA in pediatric pts aged 2–17 yrs with pJIA or ERA and demonstrate a safety profile consistent with ADA in adult pts and known information about the anti-TNF class. Acknowledgements AbbVie funded the studies (NCT00048542, NCT00690573, NCT00775437, and NCT01166282), contributed to their design and was involved in the collection, analysis, and interpretation of the data, and in the writing, review, and approval of the publication. Medical writing support was provided by Kathleen V. Kastenholz, PharmD, MS, of AbbVie. Disclosure of Interest N. Ruperto Grant/research support from: AbbVie, AstraZeneca, BMS, Janssen, “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences, Sobi, Xoma, and Wyeth for the PRINTO network paid to GASLINI Hospital, Consultant for: AbbVie, Amgen, Astellas, Alter, AstraZeneca, Biogen Idec, Boehringer, BMS, CD-Pharma, Celgene, Crescendo Bioscience, EMD Serono, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo-Nordisk, Pfizer, Roche, Sanofi Aventis, Servier, Sinergie, Takeda, and Vertex, Speakers bureau: AbbVie, Amgen, Astellas, Alter, AstraZeneca, Biogen Idec, Boehringer, BMS, CD-Pharma, Celgene, Crescendo Bioscience, EMD Serono, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo-Nordisk, Pfizer, Roche, Sanofi Aventis, Servier, Sinergie, Takeda, and Vertex, D. Lovell Consultant for: AbbVie, AstraZeneca, Boehringer Ingelheim, Celgene, Centocor, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Horizon Pharma, Janssen Biologics B.V., Novartis, Pfizer, Regeneron, Hoffman La-Roche, and UBC and served on data and safety monitoring boards for Forest Research, Speakers bureau: Genentech and Wyeth Pharmaceuticals, D. Kingsbury Grant/research support from: AbbVie, R. Burgos-Vargas Grant/research support from: AbbVie, Consultant for: AbbVie, BMS, Janssen, Pfizer, and Roche, Speakers bureau: AbbVie, BMS, Janssen, Pfizer, and Roche, T. Imagawa Grant/research support from: AbbVie/Eisai and Novartis, Consultant for: AbbVie/Eisai, Speakers bureau: AbbVie/Eisai, Chugai, and Mitsubishi Pharma, G. Horneff Grant/research support from: AbbVie, Pfizer, and Roche, Speakers bureau: AbbVie, Novartis, Pfizer, and Roche, P. Quartier Grant/research support from: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, and Swedish Orphan Biovitrum, Consultant for: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, and Swedish Orphan Biovitrum, S. Goodman Consultant for: Amgen, A. Reiff Consultant for: AbbVie and Amgen, Speakers bureau: AbbVie and Amgen, E. Giannini Consultant for: AbbVie, A. Cardoso Shareholder of: AbbVie, Employee of: AbbVie, J. Anderson Shareholder of: AbbVie, Employee of: AbbVie, N. Varothai Shareholder of: AbbVie, Employee of: AbbVie, J. Kalabic Shareholder of: AbbVie, Employee of: AbbVie, A. Martini Grant/research support from: AbbVie, AstraZeneca, BMS, Janssen, “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, and Wyeth for the PRINTO network paid to GASLINI Hospital, Consultant for: AbbVie, Amgen, Biogen Idec, Boehringer, BMS, Celgene, EMD Serono, Janssen, MedImmune, Medac, Novartis, Novo- Nordisk, Pfizer, Roche, Sanofi Aventis, Servier, Takeda, and Vertex, Speakers bureau: AbbVie, Amgen, Biogen Idec, Boehringer, BMS, Celgene, EMD Serono, Janssen, MedImmune, Medac, Novartis, Novo- Nordisk, Pfizer, Roche, Sanofi Aventis, Servier, Takeda, and Vertex
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases

  • No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Canakinumab (CAN) leads to improvement for patients (pts) with systemic juvenile idiopathic arthritis (SJIA)1. However, little is known about potential differences in response to CAN treatment between pts with vs. without SJIA associated fever at the time of the first CAN administration. Objectives To evaluate the long-term efficacy and safety profile of CAN-naïve children with SJIA pts with and without SJIA associated fever. Methods Pts aged 2-20 yrs with SJIA with and without SJIA associated fever at enrollment received open-label CAN 4mg/kg s.c. every 4 wks. Every 3 months, response to CAN was measured by adapted JIA ACR response criteria (aACR/JIA); juvenile arthritis disease activity score [JADAS]; clinical inactive disease; clinical remission on medication [6 months continuous clinical inactive disease]. Safety was assessed monthly. Results Data on 122/267 pts, 53 (43%) with and 69 (57%) without SJIA associated fever, were available for analysis with a median 94 wk study duration. At Wk4, ∼75% of both subgroups had responded (≥aACR/JIA30), increasing to 90% at Wk12. At Wk2, ∼21% of both subgroups had inactive disease; 44% at Wk8; 60% at Wk20 and then 60-70% for the remainder of the trial. Clinical remission on medication was achieved in about 29% of pts in both subgroups with ∼22% maintaining it for ≥12 consecutive months. At baseline, the median JADAS score was 21.5 with 8 (7.5%) and 99 (92.5%) pts meeting the criteria for moderate (JADAS >3.8 and ≤10.5) and high disease activity (JADAS >10.5), respectively. At Day15, the median JADAS was 6.8 and 1.5 at the last assessment. In addition, at the last assessment, 53 (48%) pts were rated as inactive disease (JADAS ≤1); 10 (9%) with low active disease activity (JADAS >1 and ≤3.8); while 14 (13%) had moderate and 31 (28%) with high disease activity. A similar long-term safety profile to the pivotal program in children with fever at enrollment was observed in these CAN-naïve pts with or without fever. The most common type of adverse event (AE) reported was infection (0.56 infections/100 PT-days) typically involving the upper respiratory tract. Fifteen pts discontinued due to an AE and 40 had >1 SAE (mostly infections, macrophage activation syndrome [MAS], or flare-associated) and no deaths. Eight cases of MAS (0.013 events/100 pt-days) were reported. Conclusions Canakinumab provides similar efficacy (inactive disease, clinical remission) in SJIA pts with and without SJIA associated fever at treatment onset. The long-term safety profile was acceptable and similar to the pivotal program in SJIA children with fever at enrollment. References Disclosure of Interest N. Ruperto Grant/research support from: Abbott, Bristol Myers and Squibb, Francesco Angelini S.P.A., Glaxo Smith & Kline, Janssen Biotech Inc Novartis,Pfizer Inc, Roche,Sanofi Aventis,Schwarz Biosciences GmbH: I declare that the GASLINI Hospital which is the public Hospital where I work as full time employee has received contributions to support the research activities of the network of PRINTO, Consultant for: Bristol Myers and Squibb, Centocor Research & Development,Glaxo Smith & Kline, Novartis, Pfizer Inc, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, I declare that the Gaslini Hospital which is the public Hospital where I work as full time employee has received contributions to support the PRINTO research activities from the industries above mentioned, Speakers bureau: Abbott, Abbvie, Amgen, Astellas, Biogenidec, Boehringer, Bristol MyersSquibb, Celgene, CrescendoBio, EMD Serono, Italfarmaco, Janssen, MedImmune, Novartis, NovoNordisk, Pfizer, Reumatic.com, Roche, Sanofi, Servier, Sinergie, Takeda, H. Brunner Consultant for: Novartis, Genentech, Pfizer, UCB, AstraZeneca, Biogen, Boehringer-Ingelheim, Regeneron, Speakers bureau: Novartis, Genentech, P. Quartier Grant/research support from: Abbvie, BMS, Chugai-Roche, Novartis, Pfizer, SOBI, Consultant for: Abbvie, Novartis, Servier, SOBI, Speakers bureau: Abbvie, BMS, Chugai-Roche, Medimmune, Novartis, Pfizer, SOBI, T. Constantin Consultant for: Pfizer, Abbvie, Roche, Novartis, Bristol-Myers Squibb, Speakers bureau: Pfizer, Abbvie, Roche, Novartis, Bristol-Myers Squibb, E. Alexeeva 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, I. Kone-Paut Grant/research support from: To my institution: SOBI, Roche, Novartis, Consultant for: Novartis, SOBI, Pfizer, CHUGAI, Abbvie, K. Marzan Grant/research support from: Novartis and Abbvie, Employee of: University of Southern California, N. Wulffraat Grant/research support from: Novartis, Pfizer, Abbvie, SOBI, Consultant for: Novartis, Pfizer, SOBI, R. Schneider Consultant for: Novartis, Roche, S. Padeh: None declared, V. Chasnyk: None declared, C. Wouters Grant/research support from: Unrestricted grant support GSK, Novartis, Roche, J. Kummerle Deschner Grant/research support from: Novartis, Consultant for: Novartis, T. Kallinich Speakers bureau: Novartis, BMS and Pfizer, B. Lauwerys: None declared, E. Haddad: None declared, E. Nasonov: None declared, M. Trachana Grant/research support from: Abbvie, Novartis, Pfizer, Consultant for: Novartis, Pfizer, Roche, Speakers bureau: Novartis, Pfizer, Roche, O. Vougiouka Grant/research support from: Novartis, K. Abrams Shareholder of: Novartis, Employee of: Novartis, K. Leon Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, A. Martini Grant/research support from: The Gaslini Hospital, which is the public Hospital where I work as a full time employee, has received contributions to support the research activities of the network of PRINTO from Bristol Myers and Squibb, Glaxo Smith & Kline, Janssen Biotech Inc, Novartis, Pfizer, Roche, Schwartz Bioscences GmbH, Speakers bureau: AbbVie, Boerhinger, Celgene, CrescendoBio, Janssen, Meddimune, Novartis, NovoNordisk, Pfizer, Sanofi Aventis, Vertex, Servier, D. Lovell Grant/research support from: National Institutes of Health, Consultant for: Astra-Zeneca, Bristol Meyers Squibb, AbbVee, Pfizer, Roche, Novartis, UBC, Forest Research Institute, Horizon, Johnson & Johnson, Biogen, Takeda, Genentech, Glaxo Smith Kline, Boehringer Ingelheim, Celgene, Jannsen, Speakers bureau: Genentech, Roche, Novartis
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Childhood-onset panniculitides are rare and classically include infectious, connective tissue, malignant, metabolic, and drugs, cold or trauma-induced panniculitis. Some specific types of panniculitis are only seen in neonates and very young infants, and include subcutaneous fat of the newborn, poststeroid panniculitis, sclerema neonatorum, and cold panniculitis. However, no specific discoverable etiology can be identified in many patients. Objectives To describe the spectrum of clinical and pathological manifestations of childhood-onset panniculitis of unknown cause Methods A retrospective single-center study of children presenting with panniculitis diagnosed by skin biopsy Results Eighteen patients were identified. The onset of symptoms occurred within the first two years of life in 15/18 patients (83%). Panniculitis was the revealing manifestation in 15/18 (83%) patients, and relapsed in 13/18 (72%) patients. Associated-non-cutaneous features occurred in 16/18 (89%) patients, especially autoinflammatory manifestations in 13/18 patients (72%), associated with immunodeficiency in 5 patients (low T or B cells count with hypogammaglobulinemia in 4 and 1 patients respectively). Autoinflammatory manifestations consisted in attacks of fever with an elevation of acute phase reactants associated with polyarthritis or polyarthralgia (2 patients), rash (2 patients) or aseptic adenitis (2 patients). Panniculitis was mostly lobular in 10 (55%) patients, septal in 3 (17%) patients or both in 5 patients (28%). Predominant infiltrate consisted of neutrophils, cytophagic histiocytes, lymphocytes, eosinophils in 8 (44%), 5 (28%), 3 (17%), and 1 (5.5%) patients respectively, and included granuloma in 1 patient. No relationship was found between clinical and pathological features. Genomic mutations were identified in 3 of the 4 patients who underwent genetic analysis: mutations in TRNT1, MVK (mevalonate kinase) and LCK genes. Conclusions This series underlines that auto-inflammatory diseases, possibly associated with inherited immunodeficiency, are a main cause of early-onset panniculitis. The identification of a monogenic cause in 3 patients and the early-onset presentation of the disease suggest that a subset of patients has a genetic predisposition to develop panniculitis, especially early-onset panniculitis. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background The long-term efficacy of canakinumab and changes in the daily lives of patients (and their caregivers) have not been thoroughly evaluated since its first use in France in 2007 and its approval for CAPS in 2010. Objectives A multicentre retrospective, observational study set up to assess the “real life” use of canakinumab in all French CAPS patients ever treated since 2007, to describe their clinical course on a long-term, and to analyse changes in their (and their caregiver's) quality of lives. Methods We targeted the 70-80 patients ever treated for CAPS in France, at least once and even during a clinical trial. Investigators were known experts in the field of CAPS in France who accepted to take part in the study. Data were collected through questionnaires by phone interviews and medical chart reviews, at treatment initiation, 6 months, 12 months and at the last medical visit. They included: clinical data, canakinumab use in real life conditions, impact on patients' (and caregivers') quality of life, and care consumption. The significance limit was set at 5% for all of the statistical tests. Results 68 CAPS patients, >90% of the target number, were enrolled (23 children, 45 adults). Sixteen patients (24%) had FCAS, 43 (63%) had MWS and 9 (13%) had NOMID-CINCA. The median duration of treatment was 5 years (from July 2007 to July 2014). >95% of patients remained on treatment. Doses were not modified in nearly half cases (31/68). For 37 patients, dosage adjustments (more often increase) were required (102 in total), especially in younger patients and those with the most severe phenotypes. The global activity of the disease, skin disorders and most of the symptoms were significantly better after canakinumab treatment (p<0.001) at the different study timepoints. The quality of life score also showed a significant improvement as median was 8 before canakinumab versus 2 (p<0.0001). Canakinumab treatment allowed also improvement in patient's daily activities, mood, and social life. Patients reported less school absences (79% versus 36%), and less sick leaves (48% versus 6%) after the initiation of canakinumab. The effect was weaker in CINCA patients; due in part to the late initiation of anti -IL1β treatment. Caregivers (49) were mostly family members and 35% of them had CAPS. They dedicated a mean of 7 hours/week to the CAPS patients before treatment and 4 hours during the last year. They spent on average 11.1 days per year of their job before canakinumab treatment versus 3 days after. The trend was less pronounced for caregivers of NOMID-CINCA patients. Conclusions ENVOL study showed real-life results similar to those obtained during the phase III clinical trials with canakinumab, reinforcing its sustained activity. The maintenance of more than 95% of patients on therapy confirmed its major benefit to CAPS patients, which was demonstrated herein by the positive impact of canakinumab in patients (and their caregivers) social, emotional, educational and professional lives. Disclosure of Interest I. Kone-Paut Grant/research support from: SOBI, Novartis, Roche, Consultant for: SOBI, Novartis, Pfizer, Abbvie, Chugai, Speakers bureau: Novartis, SOBI, P. Quartier Grant/research support from: Abbvie, Novartis, Pfizer, Consultant for: Abbvie, Novartis, Servier, SOBI, Speakers bureau: Abbvie, Chugai Roche, Medimmune, Novartis, Sobi, O. Fain Consultant for: Shire et CSL Behring, G. Grateau Grant/research support from: Abbvie, Novartis, Pfizer, Consultant for: Abbvie, Novartis, Servier, SOBI, Speakers bureau: Abbvie, Chugai Roche, Medimmune, Novartis, Sobi, P. Pillet: None declared, V. Despert: None declared, K. STANKOVIC STOJANOVIC: None declared, S. quere Employee of: Novartis employee, L. willemins Employee of: Novartis employee, O. Reigneau Employee of: novartis employee, E. Hachulla Consultant for: Novartis, SOBI
    Full-text · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Juvenile idiopathic arthritis (JIA) is one of the most common childhood rheumatic diseases. Adalimumab (ADA) is approved for moderate to severe polyarticular JIA (pJIA) in patients (pts) ≥4 yrs in Australia and Japan and for pts ≥2 yrs in the US and EU. Objectives To evaluate long-term safety and effectiveness of ADA in pts with moderately to severely active pJIA who are prescribed and treated with ADA in routine clinical practice. Methods This is an ongoing, multicenter, non-interventional, observational registry of pts with moderately to severely active pJIA who are treated with either ADA ± methotrexate (MTX) or MTX alone as part of their routine clinical care. 800 pts (500 ADA/300 MTX) were to be enrolled in the US, EU, and Australia. The follow-up observational period is 10 yrs from enrollment into one of the treatment arms. Observational adverse events (AEs) were recorded from the first day in the registry through last contact, irrespective of registry treatment duration. Clinical outcomes were assessed by 27-joint juvenile arthritis disease activity score (JADAS27), based on CRP. 5 yr interim data are presented. Results As of January 2014, enrollment is complete. 842 pts (540 ADA/302 MTX) were treated as of the March 28, 2014 cutoff. Mean pJIA disease duration at enrollment was 1.3 and 3.7 yrs and mean duration of study exposure was 643 and 653 days for MTX and ADA arms, respectively. Baseline mean AJC73 was 5.8 and 5.4 for MTX and ADA, respectively, and CHAQ-DI was 0.6 for both groups. Overall, 153 pts (50.7%) in the MTX arm and 132 pts (24.4%) in the ADA arm discontinued registry drug. Of those, 22 (7.3%) and 23 (4.3%) in the MTX and ADA arm, respectively, discontinued due to an AE, and 39 of the 153 pts in the MTX arm discontinued as they switched to the ADA arm. The observational AEs are summarized (Table). No deaths, malignancies, or opportunistic infections were reported. In the ADA arm, there were 13 (2.4%) pts with serious infectious AEs (abdominal abscess, acute tonsillitis, appendicitis, cellulitis, gastroenteritis, mononucleosis, viral meningitis, pneumonia, pyelonephritis, scarlet fever, subcutaneous abscess, tonsillitis, urinary tract infection, and varicella). Frequencies and rates of treatment-emergent AEs were similar to those reported for observational AEs. Mean JADAS27 improved from 12.1 at baseline to 9.4, 6.1, 5.1, 4.4 at months 1, 3, 6, and 12 for pts in the MTX arm and from 12.1 at baseline to 7.4, 5.5, 4.4, 4.5 in the ADA arm, respectively (observed data). Conclusions Overall, ADA is well-tolerated in these pts with active pJIA. No new safety signals were observed, and based on this interim analysis, the known safety profile of ADA remains unchanged. Acknowledgements AbbVie sponsored the study (NCT00783510), contributed with PRINTO and PRCSG to the design, and participated in data collection, analysis, and interpretation, and in the writing, review, and approval of the abstract. Medical writing support was provided by Jessica L. Suboticki, PhD, of AbbVie. Disclosure of Interest N. Ruperto Employee of: GASLINI Hospital, which has received contributions to support the research activities of the network of PRINTO from AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals. NR has served on speaker's bureau for Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, Janssen Biologics B.V., MedImmune, Roche, and Wyeth/Pfizer, H. Brunner Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Boehringer-Ingelheim, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UCB, and Genentech, Speakers bureau: Genentech Pharmaceuticals, C. Wallace Grant/research support from: Pfizer, Amgen, Consultant for: Amgen, Novartis, M. Toth: None declared, I. Foeldvari Consultant for: AbbVie, Novartis, J. Bohnsack Consultant for: Novartis, D. Milojevic Consultant for: Genentech, Novartis, E. Rabinovich Grant/research support from: UCB Pharma, Janssen Research & Development, LLC, Hoffmann-La Roche Inc., AbbVie, P. Vavrincova: None declared, D. Kingsbury Grant/research support from: AbbVie, K. Marzan Grant/research support from: AbbVie, P. Quartier Grant/research support from: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, Swedish Orphan Biovitrum; Participates on a data management committee of a phase 3 trial by Sanofi, Consultant for: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, Swedish Orphan Biovitrum, K. Minden Grant/research support from: Pfizer, Abbvie, Consultant for: Pfizer, Abbvie, Roche/Chugai, Novartis, Medac, Pharm-Allergan, Speakers bureau: Pfizer, Abbvie, Roche/Chugai, Novartis, Medac, Pharm-Allergan, E. Chalom Speakers bureau: AbbVie, G. Horneff Grant/research support from: AbbVie, Pfizer, and Roche and speaker's fees from AbbVie, Novartis, Pfizer, Roche, R.-M. Kuester Grant/research support from: AbbVie, Wyeth/Pfizer, J. Dare Grant/research support from: AbbVie, AstraZeneca, Bristol-Myers Squibb, Horizon Pharma, Medac GmbH, UCB Biosciences, M. Bereswill Shareholder of: AbbVie, Employee of: AbbVie, H. Kupper Shareholder of: AbbVie, Employee of: AbbVie, J. Kalabic Shareholder of: AbbVie, Employee of: AbbVie, A. Martini Employee of: GASLINI Hospital, which has received contributions to support the research activities of the network of PRINTO from AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuticals, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, MedImmune, D. Lovell Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UBC, Xoma, Genentech; served on data and safety monitoring boards for Amgen, Forest Research, Speakers bureau: Wyeth Pharmaceuticals
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Objective To evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis ( pcJIA). Methods This three-part, randomised, placebocontrolled, double-blind withdrawal study (NCT00988221) included patients who had active pcJIA for ≥6 months and inadequate responses to methotrexate. During part 1, patients received open-label tocilizumab every 4 weeks (8 or 10 mg/kg for body weight (BW) <30 kg; 8 mg/kg for BW ≥30 kg). At week 16, patients with ≥JIA-American College of Rheumatology (ACR) 30 improvement entered the 24- week, double-blind part 2 after randomisation 1:1 to placebo or tocilizumab (stratified by methotrexate and steroid background therapy) for evaluation of the primary end point: JIA flare, compared with week 16. Patients flaring or completing part 2 received open-label tocilizumab. Results In part 1, 188 patients received tocilizumab (<30 kg: 10 mg/kg (n=35) or 8 mg/kg (n=34); ≥30 kg: n=119). In part 2, 163 patients received tocilizumab (n=82) or placebo (n=81). JIA flare occurred in 48.1% of patients on placebo versus 25.6% continuing tocilizumab (difference in means adjusted for stratification: -0.21; 95% CI -0.35 to -0.08; p=0.0024). At the end of part 2, 64.6% and 45.1% of patients receiving tocilizumab had JIA-ACR70 and JIAACR90 responses, respectively. Rates/100 patient-years (PY) of adverse events (AEs) and serious AEs (SAEs) were 480 and 12.5, respectively; infections were the most common SAE (4.9/100 PY). Conclusions Tocilizumab treatment results in significant improvement, maintained over time, of pcJIA signs and symptoms and has a safety profile consistent with that for adults with rheumatoid arthritis.
    No preview · Article · Jun 2015
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    ABSTRACT: 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 events' 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 speaker's 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
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases

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6k Citations
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Institutions

  • 2015
    • Hôpitaux Universitaires La Pitié salpêtrière - Charles Foix
      Lutetia Parisorum, Île-de-France, France
  • 2009-2015
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
  • 2008-2015
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2003-2015
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands
  • 2011-2014
    • IRCCS Istituto G. Gaslini
      • Department of Experimental and Laboratory Medicine
      Genova, Liguria, Italy
  • 2001-2014
    • Hôpital Universitaire Necker
      Lutetia Parisorum, Île-de-France, France
  • 2013
    • Institut Imagine
      Lutetia Parisorum, Île-de-France, France
    • Hacettepe University
      • Department of Pediatrics
      Ankara, Ankara, Turkey
  • 2012
    • Université Paris-Sorbonne - Paris IV
      Lutetia Parisorum, Île-de-France, France
  • 2010
    • Università degli Studi di Genova
      Genova, Liguria, Italy
    • CHU de Lyon - Hôpital Femme-Mère-Enfant
      Lyons, Rhône-Alpes, France
  • 2003-2005
    • Imperial College London
      • Department of Medicine
      Londinium, England, United Kingdom
  • 1999
    • Karolinska Institutet
      Сольна, Stockholm, Sweden