M. Najafzadeh, S. Schneeweiss, N. Choudhry, K. Bykov, K. H. Kahler et al., A unified framework for classification of methods for benefitrisk assessment, Value Health J Int Soc Pharmacoeconomics Outcomes Res, vol.18, issue.2, pp.250-259, 2015.

M. Boers, P. Brooks, J. F. Fries, L. S. Simon, V. Strand et al., A first step to assess harm and benefit in clinical trials in one scale, J Clin Epidemiol, vol.63, issue.6, pp.627-659, 2010.

E. H. Giannini, N. Ruperto, A. Ravelli, D. J. Lovell, D. T. Felson et al., Preliminary definition of improvement in juvenile arthritis, Arthritis Rheum

A. Consolaro, B. Schiappapietra, S. Dalprà, C. S. Martini, A. Ravelli et al., Optimisation of disease assessments in juvenile idiopathic arthritis

, Clin Exp Rheumatol, vol.32, issue.5, 2014.

S. J. Balevic, M. L. Becker, M. Cohen-wolkowiez, and L. E. Schanberg, Clinical Trial Design in Juvenile Idiopathic Arthritis. Paediatr Drugs, vol.19, pp.379-89, 2017.

J. B. Schroll, E. Maund, and P. C. Gøtzsche, Challenges in coding adverse events in clinical trials: a systematic review, PloS One, vol.7, issue.7, p.41174, 2012.

S. Crépin, C. Villeneuve, and M. L. , Quality of serious adverse events reporting to academic sponsors of clinical trials: far from optimal, Pharmacoepidemiol Drug Saf, vol.25, issue.6, pp.719-743, 2016.

J. Higgins and S. Green, Cochrane handbook for systematic reviews of interventions, 2008.

, Cochrane book series)

D. Moher, A. Liberati, J. Tetzlaff, D. G. Altman, R. E. Petty et al., International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, J Rheumatol, vol.6, issue.7, pp.390-392, 2001.

J. Higgins, D. G. Altman, P. C. Gøtzsche, P. Jüni, D. Moher et al., The Cochrane Collaboration's tool for assessing risk of bias in randomised trials, BMJ, vol.343, p.5928, 2011.

M. J. Bradburn, J. J. Deeks, J. A. Berlin, R. Localio, and A. , Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events, Stat Med, vol.26, issue.1, pp.53-77, 2007.

J. Higgins and S. G. Thompson, Quantifying heterogeneity in a meta-analysis, Stat Med, vol.21, issue.11, pp.1539-58, 2002.

M. Egger, D. Smith, G. Schneider, M. Minder, and C. , Bias in meta-analysis detected by a simple, graphical test, BMJ, vol.315, issue.7109, pp.629-663, 1997.

S. Visvanathan, C. Wagner, J. C. Marini, D. J. Lovell, A. Martini et al., The effect of

, Asia Pac Leag Assoc Rheumatol Congr APLAR China Conf, 2016.

Z. Ping and . Zh, Efficacy and safety of Infliximab in juvenile idiopathic arthritis and juvenile ankylosing spondylitis: a randomized, double-blind, controlled study, Int J Rheum Conf 18th Asia Pac Leag Assoc Rheumatol Congr APLAR China Conf, 2016.

A. V. Ramanan, A. D. Dick, A. P. Jones, A. Mckay, P. R. Williamson et al., Adalimumab plus Methotrexate for Uveitis in Juvenile Idiopathic Arthritis, N Engl J Med, vol.376, issue.17, pp.1637-1683, 201727.

J. A. Smith, D. Thompson, S. M. Whitcup, E. Suhler, G. Clarke et al.,

P. Tynjala, P. Vahasalo, M. Tarkiainen, L. Kroger, K. Aalto et al., Aggressive combination drug therapy in very early polyarticular juvenile idiopathic arthritis (ACUTE-JIA): a multicentre randomised open-label clinical trial

, Ann Rheum Dis, vol.70, pp.1605-1617, 2011.

C. A. Wallace, E. H. Giannini, S. J. Spalding, P. J. Hashkes, O. Neil et al., Trial of Early Aggressive Therapy in Polyarticular Juvenile Idiopathic Arthritis, Arthritis Rheum, vol.64, issue.6, pp.2012-2033, 2012.

R. Burgos-vargas, S. Tse, G. Horneff, A. L. Pangan, J. Kalabic et al., Double-Blind, Placebo-Controlled Multicenter Study of Adalimumab in Pediatric Patients With Enthesitis-Related Arthritis, Arthritis Care Res

D. Benedetti, F. Brunner, H. I. , R. N. Kenwright, A. Wright et al.,

P. D. Joseph, J. C. Craig, and P. H. Caldwell, Clinical trials in children, Br J Clin Pharmacol, vol.79, pp.357-69, 2015.

D. J. Lovell, E. H. Giannini, and A. Reiff, Etanercept in children with polyarticular juvenile rheumatoid arthritis, N Engl J Med, vol.342, pp.763-772, 2000.

N. Ruperto, D. J. Lovell, and R. Cuttica, A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis, Arthritis Rheum, vol.56, pp.3096-106, 2007.

N. Ruperto, D. J. Lovell, and P. Quartier, Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial, Lancet Lond Engl, vol.372, pp.383-91, 2008.

G. Horneff, I. Foeldvari, and K. Minden, Efficacy and safety of etanercept in patients with the enthesitis-related arthritis category of juvenile idiopathic arthritis: results from a phase III randomized, double-blind study, Arthritis Rheumatol Hoboken NJ, vol.67, pp.2240-2249, 2015.

H. I. Brunner, N. Ruperto, and Z. Zuber, Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial, Ann Rheum Dis, vol.74, pp.1110-1117, 2015.

A. V. Ramanan, A. D. Dick, and A. P. Jones, Adalimumab plus methotrexate for uveitis in juvenile idiopathic arthritis, N Engl J Med, vol.376, pp.1637-1683, 2017.

H. J. Lachmann, I. Kone-paut, and J. B. Kuemmerle-deschner, Use of canakinumab in the cryopyrin-associated periodic syndrome, N Engl J Med, vol.360, pp.2416-2441, 2009.

I. Koné-paut, H. J. Lachmann, and J. B. Kuemmerle-deschner, Sustained remission of symptoms and improved health-related quality of life in patients with cryopyrin-associated periodic syndrome treated with canakinumab: results of a double-blind placebo-controlled randomized withdrawal study, Arthritis Res Ther, vol.13, p.202, 2011.

J. Merrill, J. Buyon, and R. Furie, Assessment of flares in lupus patients enrolled in a phase II/III study of rituximab (EXPLORER), Lupus, vol.20, pp.709-725, 2011.

B. H. Rovin, R. Furie, and K. Latinis, Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab study, Arthritis Rheum, vol.64, pp.1215-1241, 2012.

J. Anton, I. Calvo, and J. Fernández-martin, Efficacy and safety of canakinumab in cryopyrin-associated periodic syndromes: results from a Spanish cohort, Clin Exp Rheumatol, vol.33, pp.67-71, 2015.

M. Tarkiainen, P. Tynjälä, and P. Vähäsalo, Occurrence of adverse events in patients with JIA receiving biologic agents: long-term follow-up in a real-life setting, Rheumatol Oxf Engl, vol.54, pp.1170-1176, 2015.

M. H. Otten, J. Anink, and F. Prince, Trends in prescription of biological agents and outcomes of juvenile idiopathic arthritis: results of the Dutch national arthritis and biologics in children register, Ann Rheum Dis, vol.74, pp.1379-86, 2015.

J. B. Kuemmerle-deschner, F. Hofer, and T. Endres, Real-life effectiveness of canakinumab in cryopyrin-associated periodic syndrome, Rheumatol Oxf Engl, vol.55, pp.689-96, 2016.

G. Horneff, A. Klein, and J. Klotsche, Comparison of treatment response, remission rate and drug adherence in polyarticular juvenile idiopathic arthritis patients treated with etanercept, adalimumab or tocilizumab, Arthritis Res Ther, vol.18, p.272, 2016.

A. Boneparth, S. E. Wenderfer, and L. N. Moorthy, Clinical characteristics of children with membranous lupus nephritis: the childhood arthritis and rheumatology research alliance legacy registry, Lupus, vol.26, pp.299-306, 2017.

G. Amarilyo, S. Tarp, and I. Foeldvari, Biological agents in polyarticular juvenile idiopathic arthritis: A meta-analysis of randomized withdrawal trials, Semin Arthritis Rheum, vol.46, pp.312-320, 2016.

S. Tarp, G. Amarilyo, and I. Foeldvari, Efficacy and safety of biological agents for systemic juvenile idiopathic arthritis: a systematic review and meta-analysis of randomized trials, Rheumatol Oxf Engl, vol.55, pp.669-79, 2016.

J. Klotsche, M. Niewerth, and J. Haas, Long-term safety of etanercept and adalimumab compared to methotrexate in patients with juvenile idiopathic arthritis (JIA), Ann Rheum Dis, vol.75, pp.855-61, 2016.

T. Beukelman, K. Haynes, and J. R. Curtis, Rates of malignancy associated with juvenile idiopathic arthritis and its treatment, Arthritis Rheum, vol.64, pp.1263-71, 2012.

Z. Niaki, O. Clarke, A. E. Ramsey-goldman, and R. , Malignancy incidence in 5294 patients with juvenile arthritis, RMD Open, vol.2, p.212, 2016.

J. F. Swart, S. De-roock, and N. M. Wulffraat, What are the immunological consequences of long-term use of biological therapies for juvenile idiopathic arthritis? Arthritis, Res Ther, vol.15, p.213, 2013.

S. Crépin, C. Villeneuve, and M. L. , Quality of serious adverse events reporting to academic sponsors of clinical trials: far from optimal, Pharmacoepidemiol Drug Saf, vol.25, pp.719-743, 2016.

R. E. Petty, T. R. Southwood, and P. Manners, International league of associations for rheumatology classification of juvenile idiopathic arthritis: second revision, J Rheumatol, vol.31, pp.390-392, 2001.

G. Horneff, H. Schmeling, and T. Biedermann, The German etanercept registry for treatment of juvenile idiopathic arthritis, Ann Rheum Dis, vol.63, pp.1638-1682, 2004.

F. Prince, M. Twilt, and R. Ten-cate, Long-term follow-up on effectiveness and safety of etanercept in juvenile idiopathic arthritis: the Dutch national register

, Ann Rheum Dis, vol.68, pp.635-676, 2009.

D. Windschall, T. Müller, and I. Becker, Safety and efficacy of etanercept in children with the JIA categories extended oligoarthritis, enthesitis-related arthritis and psoriasis arthritis, Clin Rheumatol, vol.34, pp.61-70, 2015.

M. Trachana, P. Pratsidou-gertsi, and G. Pardalos, Safety and efficacy of adalimumab treatment in Greek children with juvenile idiopathic arthritis, Scand J Rheumatol, vol.40, pp.101-108, 2011.

H. Schmeling, K. Minden, and I. Foeldvari, Efficacy and safety of adalimumab as the first and second biologic agent in juvenile idiopathic arthritis: the German biologics JIA registry, Arthritis Rheumatol, vol.66, pp.2580-2589, 2014.

J. A. Singh, G. A. Wells, and R. Christensen, Adverse effects of biologics: a network meta-analysis and Cochrane overview, Cochrane Database Syst Rev, vol.16, p.8794, 2011.

J. N. Hoes, J. Jacobs, and S. Verstappen, Adverse events of low-to medium-dose oral glucocorticoids in inflammatory diseases: a meta-analysis

, Ann Rheum Dis, vol.68, pp.1833-1841, 2009.

K. L. Hyrich, M. Lunt, and K. D. Watson, Society for rheumatology biologics register. Outcomes after switching from one anti-tumor necrosis factor alpha agent to a second anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort study, Arthritis Rheum, vol.56, pp.13-20, 2007.

A. Céspedes-cruz, R. Gutiérrez-suárez, and A. Pistorio, Methotrexate improves the health-related quality of life of children with juvenile idiopathic arthritis

, Ann Rheum Dis, vol.67, pp.309-323, 2008.

J. Wipff, L. Sparsa, and A. Lohse, Impact of juvenile idiopathic arthritis on quality of life during transition period at the era of biotherapies, J Bone Spine Rev Rhum, vol.83, pp.69-74, 2016.

A. F. Mourão, M. J. Santos, M. Gomes, and J. A. , Effectiveness and long-term retention of anti-tumour necrosis factor treatment in juvenile and adult patients with juvenile idiopathic arthritis: data from Reuma.pt, Rheumatol Oxf Engl, vol.55, pp.697-703, 2016.

P. Tynjälä, P. Vähäsalo, and M. Tarkiainen, Aggressive combination drug therapy in very early polyarticular juvenile idiopathic arthritis (ACUTE-JIA): a multicentre randomised open-label clinical trial, Ann Rheum Dis, vol.70, pp.1605-1617, 2011.

C. A. Wallace, E. H. Giannini, and S. J. Spalding, Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis, Arthritis Rheum, vol.64, pp.2012-2033, 2012.

C. Hinze, F. Gohar, and D. Foell, Management of juvenile idiopathic arthritis: hitting the target, Nat Rev Rheumatol, vol.11, pp.290-300, 2015.

H. D. Davies, Infectious complications with the use of biologic response modifiers in infants and children, Pediatrics, vol.138, p.20161209, 2016.

D. Bandt, M. Sibilia, J. , L. Loët, and X. , Systemic lupus erythematosus induced by anti-tumour necrosis factor alpha therapy: a French national survey, Arthritis Res Ther, vol.7, pp.545-51, 2005.

N. Ruperto, D. J. Lovell, and R. Cuttica, Long-term efficacy and safety of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis: findings from an open-label treatment extension, Ann Rheum Dis, vol.69, pp.718-740, 2009.

G. Horneff, F. D. Bock, and I. Foeldvari, Safety and efficacy of combination of etanercept and methotrexate compared to treatment with etanercept only in patients with juvenile idiopathic arthritis (JIA): preliminary data from the German JIA registry, Ann Rheum Dis, vol.68, pp.519-544, 2009.

V. Devauchelle-pensec, M. Thepaut, and R. Pecquery, Managing monoarthritis in children, J Bone Spine Rev Rhum, vol.83, pp.25-30, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01353495

R. A. Berard and R. M. Laxer, Learning the hard way: clinical trials in juvenile idiopathic arthritis

, Ann Rheum Dis, vol.77, issue.1, pp.1-2, 2018.

J. Swart, G. Giancane, G. Horneff, B. Magnusson, M. Hofer et al., Pharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15,000 patients from Pharmachild and national registries, Arthritis Res Ther, vol.20, issue.1, p.285, 201827.

J. F. Swart, S. De-roock, and N. M. Wulffraat, What are the immunological consequences of long-term use of biological therapies for juvenile idiopathic arthritis?, Arthritis Res Ther, vol.15, issue.3, p.213, 2013.

. Fda-o-of-the, What is a Serious Adverse Event? FDA, 2019.

E. Mayo-wilson, N. Fusco, T. Li, H. Hong, J. K. Canner et al., Harms are assessed inconsistently and reported inadequately Part 2: nonsystematic adverse events, J Clin Epidemiol

B. Delcoigne, A. Horne, and J. Askling, OP0001 Risk of malignancy in children with juvenile idiopathic arthritis: a register-based cohort study

, Ann Rheum Dis, vol.77, issue.2, pp.50-50, 2018.

S. Bernatsky and O. , Cancer Risk in 5,108 Patients with Juvenile Idiopathic Arthritis (JIA). ACR Meeting Abstracts

G. Horneff, Biologic-associated infections in pediatric rheumatology, Curr Rheumatol Rep, vol.17, issue.11, p.66, 2015.

D. F. Stroup, J. A. Berlin, S. C. Morton, I. Olkin, G. D. Williamson et al., Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group, JAMA, vol.283, issue.15, pp.2008-2020, 2000.

Z. Munn, S. Moola, K. Lisy, D. Riitano, and C. Tufanaru, Methodological guidance for systematic reviews of observational epidemiological studies reporting prevalence and cumulative incidence data

, Int J Evid Based Healthc, vol.13, issue.3, pp.147-53, 2015.

G. Schwarzer and H. Chemaitelly,

M. J. Spittal, J. Pirkis, L. C. Gurrin, and -. Meta,

S. G. Thompson and J. Higgins, How should meta-regression analyses be undertaken and interpreted? Stat Med, vol.21, pp.1559-73, 2002.

J. Higgins and S. G. Thompson, Quantifying heterogeneity in a meta-analysis, Stat Med, vol.21, issue.11, pp.1539-58, 2002.

M. Egger, D. Smith, G. Schneider, M. Minder, and C. , Bias in meta-analysis detected by a simple, graphical test, BMJ, vol.315, issue.7109, pp.629-663, 1997.

D. Windschall, T. Müller, I. Becker, and . Horneff,

, Clin Rheumatol, vol.35, issue.12, pp.2925-2956, 2016.

N. Tzaribachev, J. Kuemmerle-deschner, M. Eichner, and G. Horneff, Safety and efficacy of etanercept in children with juvenile idiopathic arthritis below the age of 4 years, Rheumatol Int

M. H. Otten, F. Prince, and W. Armbrust,

R. Cate, E. Hoppenreijs, and M. Twilt,

P. Lahdenne, P. Vähäsalo, and V. Honkanen, Infliximab or etanercept in the treatment of children with refractory juvenile idiopathic arthritis: an open label study, Ann Rheum Dis, vol.62, issue.3, p.245, 2003.

T. Imagawa, S. Takei, H. Umebayashi, K. Yamaguchi, Y. Itoh et al., Efficacy, pharmacokinetics, and safety of adalimumab in pediatric patients with juvenile idiopathic arthritis in Japan, Clin Rheumatol, vol.31, issue.12, pp.1713-1734, 2012.

E. I. Alexeeva, S. I. Valieva, T. M. Bzarova, E. L. Semikina, K. B. Isaeva et al.,

, Events Associated with Anti-Tumor Necrosis Factor Alpha Agents in Pediatric-Onset Inflammatory Bowel Disease and Juvenile Idiopathic Arthritis in A Real-Life Setting, Paediatr Drugs, 2018.

, Apr, vol.20, issue.2, pp.165-71

T. Beukelman, Y. Kimura, N. T. Ilowite, K. Mieszkalski, M. D. Natter et al., The new Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry: design, rationale, and characteristics of patients enrolled in the first 12 months, Pediatr Rheumatol Online J, vol.15, issue.1, p.30, 2017.

M. Bielak, E. Husmann, N. Weyandt, J. Haas, B. Hügle et al.,

V. Gerloni, I. Pontikaki, M. Gattinara, and F. ,

, Ann Rheum Dis, 2008.

M. Mori, N. Sugiyama, Y. Morishima, N. Sugiyama, T. Kokubo et al., Safety and effectiveness of etanercept for treatment of juvenile idiopathic arthritis: Results from a postmarketing surveillance, Mod Rheumatol, vol.28, issue.1, p.101, 2018.

Z. Zuber, L. Rutkowska-sak, J. Post?pski, B. Dobrzyniecka, V. Opoka-winiarska et al., Etanercept treatment in juvenile idiopathic arthritis: the Polish registry, Med Sci Monit Int Med J Exp Clin Res, vol.17, issue.12, pp.35-42, 2011.

N. Cabrera, J. Lega, B. Kassai, C. Wouters, A. Kondi et al., Safety of biological agents in paediatric rheumatic diseases: A real-life

M. Mori, M. Nakagawa, N. Tsuchida, K. Kawada, J. Sato et al., Proposal for the development of biologics in pediatric rheumatology, Pediatr Int Off J Jpn Pediatr Soc

, Feb, vol.60, issue.2, pp.108-122

P. A. Nigrovic, M. Mannion, F. Prince, A. Zeft, C. E. Rabinovich et al., Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of fortysix patients from an international multicenter series, Arthritis Rheum, vol.63, issue.2, pp.545-55, 2011.

N. Ruperto, D. J. Lovell, R. Cuttica, N. Wilkinson, P. Woo et al., A randomized, placebocontrolled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis, Arthritis Rheum, vol.56, issue.9, pp.3096-106, 2007.

P. Tynjälä, P. Vähäsalo, M. Tarkiainen, L. Kröger, K. Aalto et al., Aggressive Combination Drug Therapy in Very Early Polyarticular Juvenile Idiopathic Arthritis (ACUTE-JIA): a multicentre randomised open-label clinical trial, Ann Rheum Dis, vol.70, issue.9, pp.1605-1617, 2011.

P. Quartier, F. Allantaz, R. Cimaz, P. Pillet, C. Messiaen et al., A multicentre, randomised, double-blind

D. Benedetti, F. Brunner, H. I. , R. N. Kenwright, A. Wright et al., Randomized Trial of Tocilizumab in Systemic Juvenile Idiopathic Arthritis, N Engl J Med, vol.367, issue.25, pp.2385-95, 2012.

G. Horneff, S. Fitter, I. Foeldvari, K. Minden, J. Kuemmerle-deschner et al., Double-blind, placebo-controlled randomized trial with adalimumab for treatment of juvenile onset ankylosing spondylitis (JoAS): significant short term improvement, Arthritis Res Ther, vol.14, issue.5, p.230, 2012.

R. Burgos-vargas, S. Tse, G. Horneff, A. L. Pangan, J. Kalabic et al., Double-Blind, Placebo-Controlled Multicenter Study of Adalimumab in Pediatric Patients With Enthesitis-Related Arthritis, Arthritis Care Res

A. V. Ramanan, A. D. Dick, A. P. Jones, A. Mckay, P. R. Williamson et al., Adalimumab plus Methotrexate for Uveitis in Juvenile Idiopathic Arthritis, N Engl J Med, vol.376, issue.17, pp.1637-1683, 201727.

N. Ruperto, H. I. Brunner, P. Quartier, T. Constantin, N. Wulffraat et al., Two Randomized Trials of Canakinumab in Systemic Juvenile Idiopathic Arthritis, N Engl J Med, 2012.

D. J. Lovell, E. H. Giannini, A. O. Reiff, Y. Kimura, S. Li et al., Long-term safety and efficacy of rilonacept in patients with systemic juvenile idiopathic arthritis, Arthritis Rheum, vol.65, issue.9, pp.2486-96, 2013.

N. T. Ilowite, K. Prather, Y. Lokhnygina, L. E. Schanberg, M. Elder et al., Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis. Arthritis Rheumatol Hoboken NJ, vol.66, pp.2570-2579, 2014.

H. Muller, P. Brinkman, D. Schonenberg, D. Koopman-keemink, Y. Brederije et al.,

D. J. Lovell, E. H. Giannini, A. Reiff, G. D. Cawkwell, E. D. Silverman et al., Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group, N Engl J Med, vol.342, issue.11, pp.763-772, 2000.

D. J. Lovell, N. Ruperto, S. Goodman, A. Reiff, L. Jung et al., Adalimumab with or without methotrexate in juvenile rheumatoid arthritis, N Engl J Med, vol.359, issue.8, pp.810-830, 2008.

N. Ruperto, D. J. Lovell, P. Quartier, E. Paz, N. Rubio-pérez et al., Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis, Arthritis Rheum, vol.62, issue.6, pp.1792-802, 2010.

S. Yokota, T. Imagawa, M. Mori, T. Miyamae, Y. Aihara et al., Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial, Lancet Lond Engl, vol.371, issue.9617, pp.998-1006, 2008.

N. Ilowite, O. Porras, A. Reiff, S. Rudge, M. Punaro et al.,

N. Ruperto, H. I. Brunner, P. Quartier, T. Constantin, N. Wulffraat et al., Two Randomized Trials of Canakinumab in Systemic Juvenile Idiopathic Arthritis, N Engl J Med, 2012.

H. I. Brunner, N. Ruperto, Z. Zuber, C. Keane, O. Harari et al., Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial, Ann Rheum Dis, vol.74, issue.6, pp.1110-1117, 2015.

G. Horneff, I. Foeldvari, K. Minden, R. Trauzeddel, J. B. Kümmerle-deschner et al., Efficacy and safety of etanercept in patients with the enthesitis-related arthritis category of juvenile idiopathic arthritis: results from a phase III randomized, double-blind study, Arthritis Rheumatol Hoboken NJ, vol.67, issue.8, pp.2240-2249, 2015.

J. Lau, J. Ioannidis, N. Terrin, C. H. Schmid, and I. Olkin, The case of the misleading funnel plot, BMJ, vol.333, issue.7568, pp.597-600, 2006.

P. D. Joseph, J. C. Craig, and P. Caldwell, Clinical trials in children, Br J Clin Pharmacol, vol.79, issue.3, pp.357-69, 2015.

A. Hurd and T. Beukelman,

G. R. Burmester, R. Panaccione, K. B. Gordon, M. J. Mcilraith, and A. Lacerda, Adalimumab: longterm safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease, Ann Rheum Dis, 2012.

D. J. Lovell, E. H. Giannini, A. Reiff, G. D. Cawkwell, E. D. Silverman et al., Etanercept in Children with Polyarticular Juvenile Rheumatoid Arthritis, N Engl J Med, vol.342, issue.11, p.763, 2000.

M. Hooper, D. Wenkert, B. Bitman, and V. C. Dias,

W. G. Dixon, L. Carmona, A. Finckh, M. L. Hetland, T. K. Kvien et al., EULAR points to consider when establishing, analysing and reporting safety data of biologics registers in rheumatology

, Ann Rheum Dis, vol.69, issue.9, pp.1596-602, 2010.

H. I. Brunner, L. G. Rider, D. J. Kingsbury, D. Co, R. Schneider et al.,

, Heterogeneity: I 2 = 86%, ? 2 = 0.0116, p.1

, Heterogeneity: I 2 = 95%, ? 2 = 0.0104, p.1

, Heterogeneity: I 2 = 91%, ? 2 = 0.0130, p.1

T. Lequerre, , 2008.

P. A. Nigrovic, , 2011.

G. Horneff, , 2015.

G. Horneff, , 2017.

G. Horneff, , 2017.

M. Bielak, , 2018.

P. Quartier, , 2003.

P. Lahdenne, , 2003.

N. Tzaribachev, , 2008.

J. De-inocencio-arocena, , 2009.

T. R. Southwood, , 2011.

M. H. Otten, , 2011.

. Zuber, , 2011.

E. I. Alexeeva, , 2011.

M. Trachana, , 2011.

C. Bracaglia, , 2012.

M. Tarkiainen, , 2015.

D. Windschall, , 2015.

S. Verazza, , 2016.

J. Klotsche, , 2016.

J. Klotsche, , 2016.

S. Pastore, , 2017.

N. Cabrera, , 2018.

N. Cabrera, , 2018.

N. Cabrera, , 2018.

N. Cabrera, , 2018.

N. Cabrera, , 2018.

M. Mori, , 2018.

J. Y. Choi, , 2018.

G. Horneff, , 2016.

M. Bielak, , 2018.

N. Cabrera, , 2018.

P. Quartier, , 2003.

V. Gerloni, , 2008.

N. Tzaribachev, , 2008.

J. De-inocencio-arocena, , 2009.

T. R. Southwood, , 2011.

M. H. Otten, , 2011.

. Zuber, , 2011.

D. Windschall, , 2015.

S. Verazza, , 2016.

G. Horneff, , 2016.

J. Klotsche, , 2016.

D. Windschall, , 2016.

N. Cabrera, , 2018.

J. Y. Choi, , 2018.

M. Trachana, , 2011.

C. Bracaglia, , 2012.

T. Imagawa, , 2012.

G. Horneff, , 2016.

J. Klotsche, , 2016.

D. Windschall, , 2016.

N. Cabrera, , 2018.

V. Gerloni, , 2008.

A. Tambralli, , 2013.

N. Cabrera, , 2018.

T. Lequerre, , 2008.

P. A. Nigrovic, , 2011.

N. Cabrera, , 2018.

, Heterogeneity: I 2 = 78%, ? 2 = 0.0133, p.1

, Heterogeneity: I 2 = 66%, ? 2 = 0.0024, p.1

, Heterogeneity: I 2 = 76%, ? 2 = 0.0015, p.1

T. Lequerre, , 2008.

P. A. Nigrovic, , 2011.

M. Bielak, , 2018.

T. Imagawa, , 2012.

A. Tambralli, , 2013.

G. Horneff, , 2016.

G. Horneff, , 2016.

G. Horneff, , 2016.

D. Windschall, , 2016.

D. Windschall, , 2016.

P. Quartier, , 2003.

P. Lahdenne, , 2003.

V. Gerloni, , 2008.

V. Gerloni, , 2008.

N. Tzaribachev, , 2008.

J. De-inocencio-arocena, , 2009.

T. R. Southwood, , 2011.

M. H. Otten, , 2011.

. Zuber, , 2011.

M. Trachana, , 2011.

C. Bracaglia, , 2012.

M. Tarkiainen, , 2015.

D. Windschall, , 2015.

S. Verazza, , 2016.

J. Klotsche, , 2016.

J. Klotsche, , 2016.

S. Pastore, , 2017.

N. Cabrera, , 2018.

N. Cabrera, , 2018.

N. Cabrera, , 2018.

N. Cabrera, , 2018.

N. Cabrera, , 2018.

W. J. Lee, , 2018.

J. Y. Choi, , 2018.

P. Quartier, , 2003.

P. Lahdenne, , 2003.

V. Gerloni, , 2008.

V. Gerloni, , 2008.

N. Tzaribachev, , 2008.

T. Lequerre, , 2008.

J. De-inocencio-arocena, , 2009.

T. R. Southwood, , 2011.

M. H. Otten, , 2011.

. Zuber, , 2011.

E. I. Alexeeva, , 2011.

P. A. Nigrovic, , 2011.

M. Trachana, , 2011.

C. Bracaglia, , 2012.

T. Imagawa, , 2012.

A. Tambralli, , 2013.

M. Tarkiainen, , 2015.

D. Windschall, , 2015.

S. Verazza, , 2016.

G. Horneff, , 2016.

G. Horneff, , 2016.

G. Horneff, , 2016.

J. Klotsche, , 2016.

J. Klotsche, , 2016.

D. Windschall, , 2016.

D. Windschall, , 2016.

S. Pastore, , 2017.

G. Horneff, , 2017.

G. Horneff, , 2017.

M. Bielak, , 2018.

N. Cabrera, , 2018.

N. Cabrera, , 2018.

N. Cabrera, , 2018.

N. Cabrera, , 2018.

N. Cabrera, , 2018.

W. J. Lee, , 2018.

M. Mori, , 2018.

J. Y. Choi, , 2018.

P. Quartier, , 2003.

P. Lahdenne, , 2003.

V. Gerloni, , 2008.

V. Gerloni, , 2008.

N. Tzaribachev, , 2008.

T. Lequerre, , 2008.

J. De-inocencio-arocena, , 2009.

T. R. Southwood, , 2011.

M. H. Otten, , 2011.

. Zuber, , 2011.

E. I. Alexeeva, , 2011.

P. A. Nigrovic, , 2011.

M. Trachana, , 2011.

C. Bracaglia, , 2012.

T. Imagawa, , 2012.

A. Tambralli, , 2013.

M. Tarkiainen, , 2015.

D. Windschall, , 2015.

S. Verazza, , 2016.

G. Horneff, , 2016.

G. Horneff, , 2016.

G. Horneff, , 2016.

J. Klotsche, , 2016.

J. Klotsche, , 2016.

D. Windschall, , 2016.

D. Windschall, , 2016.

S. Pastore, , 2017.

G. Horneff, , 2017.

G. Horneff, , 2017.

M. Bielak, , 2018.

N. Cabrera, , 2018.

N. Cabrera, , 2018.

N. Cabrera, , 2018.

N. Cabrera, , 2018.

N. Cabrera, , 2018.

W. J. Lee, , 2018.

M. Mori, , 2018.

J. Y. Choi, , 2018.

N. Cabrera, P. Nakhleh, and M. Desjonqueres,

J. Harris, Improving Care Delivery Outcomes in Pediatric Rheumatic Diseases, Curr Opin Rheumatol, vol.28, issue.2, pp.110-116, 2016.

, Disclosure of Interests: None

, AB0947 TREATMENT WITH SIMULTANEOUS BIOLOGICAL AGENTS IN JUVENILE IDIOPATHIC ARTHRITIS: SINGLE-CENTER CASE SERIES AND REVIEW OF LITERATURE

, Hospital Woman Mère Enfant -Hcl, Paediatric Rheumatology, vol.2

R. Cimaz, A. Marino, and A. Martini, How I treat juvenile idiopathic arthritis: A state of the art review, Autoimmun Rev, vol.16, issue.10, pp.1008-1023, 2017.

J. L. Record, T. Beukelman, and R. Q. Cron, Combination Therapy of Abatacept and Anakinra in Children with Refractory Systemic Juvenile Idiopathic Arthritis: A Retrospective Case Series, J Rheumatol, vol.38, issue.1, pp.180-181, 2011.

F. Osório, F. Magro, C. Lisboa, S. Lopes, G. Macedo et al., Anti-TNF-Alpha induced psoriasiform eruptions with severe scalp involvement and alopecia: report of five cases and review of the literature, Dermatology, vol.225, issue.2, pp.163-170, 2012.

J. Ettler, D. A. Wetter, and M. R. Pittelkow, Pityriasis amiantacea: a distinctive presentation of psoriasis associated with tumour necrosis factor-a inhibitor therapy, Gabriele Simonini Grant/research support from: Abbvie, Speakers bureau: Abbvie, Rolando Cimaz: None declared, vol.37, pp.639-680, 2012.

A. India,

H. Chaudhary, P. Vignesh, A. Jindal, D. Suri, A. Gupta et al., Post Graduate Institute of, Medical Education and Research

R. Tocilizumab-;-davies, G. D. Hyrich, K. L. Pain, and C. E. , ESR: erythrocyte sedimentation rate, GH : growth hormone, IVIG: intravenous immunoglobulin, JIA: juvenile idiopathic arthritis, MTX: methotrexate, Neg: negative, NSAIDs: non-steroidal anti-inflammatory drugs, P: patient, Pos: positive, RF: Rheumatoid factor, So JIA (systemic-onset juvenile idiopathic arthritis) a: genu valgus bilateral, b: serious adverse event: Acute cholestatic hepatitis, tocilizumab was stopped (liver biopsy reveal ed an inflammatory infiltrate with hepatocellular drop out suggesting drug induced liver injury), c: complicated therapeutic compliance by the family, d: substitutive dose (replacement therapy), e: stopped during treatment with anakinra, f: infiltrations at knees, ankles and elbows, g: serious adverse event: No clinical (vomiting) and biological (hepatic cytolysis) tolerance. 6 : Bibliographie 1, Rituximab (10.7)* in years, *bDMARD combined. ACE: angiotensin-converting-enzyme, ANA: antinuclear antibodies, Aredia : pamidronate disodium pentahydrate, bDMARDs: biological disease-modifying antirheumatic drugs, CIO: corticosteroid-induced osteoporosis, CRP: C reactive protein, vol.46, pp.584-93, 2017.

H. I. Brunner, L. G. Rider, D. J. Kingsbury, D. Co, R. Schneider et al.,

A. Bettiol, E. Silvestri, D. Scala, G. Amedei, A. Becatti et al.,

A. Bettiol, G. Lopalco, G. Emmi, L. Cantarini, M. L. Urban et al.,

, Unveiling the Efficacy, Safety, and Tolerability of Anti-Interleukin-1 Treatment in Monogenic and Multifactorial Autoinflammatory Diseases, Int J Mol Sci, vol.20, issue.8, 2019.

S. P. Ardoin, R. P. Daly, L. Merzoug, K. Tse, K. Ardalan et al.,

P. D. Joseph, J. C. Craig, and P. Caldwell, Clinical trials in children, Br J Clin Pharmacol, vol.79, issue.3, pp.357-69, 2015.

N. Ruperto, R. Vesely, A. Saint-raymond, and A. Martini, Impact of the European paediatric legislation in paediatric rheumatology: past, present and future, Ann Rheum Dis, vol.72, issue.12, pp.1893-1899, 2013.

S. Monti, V. Grosso, M. Todoerti, and R. Caporali, Randomized controlled trials and real-world data: differences and similarities to untangle literature data

D. J. Lovell, E. H. Giannini, A. Reiff, G. D. Cawkwell, E. D. Silverman et al., Etanercept in Children with Polyarticular Juvenile Rheumatoid Arthritis, N Engl J Med

J. A. Smith, D. Thompson, S. M. Whitcup, E. Suhler, G. Clarke et al.,

C. A. Wallace, E. H. Giannini, S. J. Spalding, P. J. Hashkes, O. Neil et al.,

. Rheum, , vol.64, pp.2012-2033, 2012.

D. J. Lovell, N. Ruperto, S. Goodman, A. Reiff, L. Jung et al.,

, Adalimumab with or without Methotrexate in Juvenile Rheumatoid Arthritis, N Engl J Med, vol.359, issue.8, pp.810-830, 2008.

G. Horneff, S. Fitter, I. Foeldvari, K. Minden, J. Kuemmerle-deschner et al.,

N. , Double-blind, placebo-controlled randomized trial with adalimumab for treatment of juvenile onset ankylosing spondylitis (JoAS): significant short term improvement, Arthritis Res Ther, vol.14, issue.5, 2012.

D. Randomized, Placebo-Controlled Multicenter Study of Adalimumab in Pediatric Patients With Enthesitis-Related Arthritis, Arthritis Care Res, vol.67, issue.11, pp.1503-1515, 2015.

N. Ruperto, D. J. Lovell, R. Cuttica, N. Wilkinson, P. Woo et al.,

P. Tynjälä, P. Vähäsalo, M. Tarkiainen, L. Kröger, K. Aalto et al.,

, Aggressive combination drug therapy in very early polyarticular juvenile idiopathic arthritis (ACUTE-JIA): a multicentre randomised open-label clinical trial, Ann Rheum Dis, 2011.

H. I. Brunner, N. Ruperto, N. Tzaribachev, G. Horneff, V. G. Chasnyk et al., Subcutaneous golimumab for children with active polyarticular-course juvenile idiopathic arthritis: results of a multicentre, double-blind, randomised-withdrawal trial, Ann Rheum Dis

P. Quartier, F. Allantaz, R. Cimaz, P. Pillet, C. Messiaen et al., A multicentre, randomised, double-blind

, Ann Rheum Dis, vol.70, issue.5, pp.747-54, 2011.

N. Ilowite, O. Porras, A. Reiff, S. Rudge, M. Punaro et al., Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study, Clin Rheumatol, vol.28, issue.2, pp.129-166, 2009.

N. Ruperto, H. I. Brunner, P. Quartier, T. Constantin, N. Wulffraat et al.,

, Two Randomized Trials of Canakinumab in Systemic Juvenile Idiopathic Arthritis, N Engl J

. Med, , vol.367, pp.2396-406, 2012.

D. J. Lovell, E. H. Giannini, A. O. Reiff, Y. Kimura, S. Li et al.,

N. T. Ilowite, K. Prather, Y. Lokhnygina, L. E. Schanberg, M. Elder et al., Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis, Arthritis Rheumatol Hoboken NJ, vol.65, issue.9, pp.2486-96, 2013.

H. I. Brunner, N. Ruperto, Z. Zuber, C. Keane, O. Harari et al., , vol.66, pp.2570-2579

, Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial, Ann Rheum Dis

S. Yokota, T. Imagawa, M. Mori, T. Miyamae, Y. Aihara et al., Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial, Lancet Lond Engl, vol.74, issue.6, pp.1110-1117

N. Ruperto, D. J. Lovell, P. Quartier, E. Paz, N. Rubio-pérez et al., , vol.371, pp.998-1006

. Rheum, C. Smith, P. R. Williamson, and M. W. Beresford, Varnier GC, Ciurtin C. Paediatric and adolescent rheumatic diseases: measures of disease activity, Best Pract Res Clin Rheumatol, vol.62, issue.6, pp.338-380, 2005.

G. Horneff, K. Minden, I. Foeldvari, N. Onken, D. Windschall et al.,

S. Kamphuis, W. Armbrust, T. Cate, R. Hoppenreijs, and E. P. , Prince FHM, Ferket IS, vol.73, pp.897-906, 2014.

H. , Development of a web-based register for the Dutch national study on biologicals in JIA: www.ABC-register.nl. Rheumatol Oxf Engl, vol.47, pp.1413-1419, 2008.

T. Beukelman, Y. Kimura, N. T. Ilowite, K. Mieszkalski, M. D. Natter et al., The new Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry

C. Hinze, F. Gohar, D. Foell, J. Rodriguez-smith, H. I. Brunner et al., Update on the treatment and outcome of systemic lupus erythematous in children, Curr Opin Rheumatol, vol.11, issue.5, pp.290-300, 2015.

F. Vanoni, F. Minoia, and C. Malattia, Biologics in juvenile idiopathic arthritis: a narrative review, Eur J Pediatr, vol.176, issue.9, pp.1147-53, 2017.

G. M. Bartelds, C. A. Wijbrandts, M. T. Nurmohamed, S. Stapel, and W. F. Lems,

L. , Anti-infliximab and anti

G. Horneff, S. Crépin, C. Villeneuve, and M. L. , Quality of serious adverse events reporting to academic sponsors of clinical trials: far from optimal, Pharmacoepidemiol Drug Saf, vol.17, issue.11, pp.719-743, 2015.

J. B. Schroll, E. Maund, P. C. Gøtzsche, E. Mayo-wilson, N. Fusco et al., Harms are assessed inconsistently and reported inadequately Part 2: nonsystematic adverse events, PloS One, vol.7, issue.7, 2012.

, Learning the hard way: clinical trials in juvenile idiopathic arthritis, Clin Epidemiol, vol.113, issue.1, pp.1-2, 2018.

G. Morley, Adverse event reporting: A brief overview of MedDRA

J. B. Schroll, E. Maund, P. C. Gøtzsche, M. H. Otten, J. Anink et al., Efficacy of biological agents in juvenile idiopathic arthritis: a systematic review using indirect comparisons, Ann Rheum Dis, vol.7, issue.7, pp.1806-1818, 2012.

G. Giancane, A. Alongi, and A. Ravelli, Update on the pathogenesis and treatment of juvenile idiopathic arthritis, Curr Opin Rheumatol, vol.29, issue.5, pp.523-532, 2017.

E. I. Alexeeva, S. I. Valieva, T. M. Bzarova, E. L. Semikina, K. B. Isaeva et al.,

G. Horneff, N. Ruperto, H. Brunner, P. Quartier, T. Constantin et al.,

P. Tynjälä, P. Vähäsalo, M. Tarkiainen, L. Kröger, K. Aalto et al.,

, Aggressive Combination Drug Therapy in Very Early Polyarticular Juvenile Idiopathic Arthritis (ACUTE-JIA): a multicentre randomised open-label clinical trial, Ann Rheum Dis

A. Ravelli, A. Consolaro, G. Horneff, R. M. Laxer, D. J. Lovell et al., , vol.70, pp.1605-1617

, Treating juvenile idiopathic arthritis to target: recommendations of an international task force

, Ann Rheum Dis, vol.77, issue.6, pp.819-847, 2018.