Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2025 Feb 20;2(2):CD013715.
doi: 10.1002/14651858.CD013715.pub2.

Tumor necrosis factor (TNF) inhibitors for juvenile idiopathic arthritis

Giovanni Cagnotto  1   2 , Carsten B Juhl  3   4 , Fredrik Ahlström  5 , Filip Wikström  6 , Matteo Bruschettini  7   8 , Ingemar Petersson  9   10 , Lene Dreyer  11 , Michele Compagno  1   2
Affiliations
Meta-Analysis

Tumor necrosis factor (TNF) inhibitors for juvenile idiopathic arthritis

Giovanni Cagnotto et al. Cochrane Database Syst Rev. .

Abstract

Background: Juvenile idiopathic arthritis (JIA) is a rheumatic disorder that causes chronic joint inflammation beginning before the age of 16 years. Pharmacological treatment necessary to prevent joint destruction and functional impairment includes non-steroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroids, conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) like methotrexate (MTX), and biologic DMARDs (bDMARDs) such as tumor necrosis factor inhibitors (TNFi), abatacept, anakinra, and tocilizumab. More recently, targeted synthetic DMARDs (tsDMARDs) like tofacitinib, baricitinib, and upadacitinib have been approved for the treatment of JIA.

Objectives: To assess the benefits and harms of TNFi in children with JIA.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via Ovid), Embase (via Ovid), and ClinicalTrials.gov and the WHO ICTRP from inception to 28 February 2024, with no language restrictions.

Selection criteria: We included randomized controlled trials (RCTs), quasi-RCTs, and data from the randomized part of withdrawal trials conducted in individuals with JIA where TNFi were compared to placebo, MTX, NSAIDs, other bDMARDs, tsDMARDs, or other TNFi. Our major outcomes were treatment response, pain, function, participant global assessment of well-being (disease activity), remission, withdrawals due to adverse events, and serious adverse events.

Data collection and analysis: We used standard Cochrane methods. At least two review authors performed study selection, data extraction, and risk of bias and GRADE assessment. The primary comparison was TNFi versus placebo. The primary time point was up to 16 weeks and up to the end of the trials for efficacy and safety outcomes, respectively.

Main results: We included nine studies with 678 participants (80% females) with JIA. The mean age of participants ranged from 8 to 15 years, and the mean duration of symptoms ranged from 0.8 years to 6.7 years. Seven studies compared TNFi to placebo (570 participants), and two studies compared TNFi combined with MTX to MTX alone (108 participants). We identified no studies investigating the other predefined comparisons. Only two studies had a low risk of bias in all domains, while five studies had a high risk of bias in at least one domain, predominantly other bias. Two studies were at unclear risk of selection bias, and two studies were at unclear risk of detection bias. TNFi versus placebo Benefits at up to 16 weeks Low-certainty evidence (downgraded for risk of bias and imprecision) suggests that treatment with TNFi may increase the likelihood of achieving a treatment response, defined as pedACR70 (34% compared to 14% with placebo) (risk ratio [RR] 2.47, 95% confidence interval [CI] 1.48 to 4.14; 4 studies, 245 participants). The evidence is very uncertain (downgraded for indirectness and imprecision) for the effect of TNFi on pain, with mean pain scores (visual analogue scale [VAS] 0 to 100, 0 no pain, minimal clinically important difference [MCID] = 15 mm) lower with TNFi (11 mm) compared to placebo (33 mm) (mean difference [MD] 22 mm, 95% CI 50 mm lower to 5.7 mm higher; 2 studies, 72 participants). Similarly, the effect of TNFi on function (Childhood Health Assessment Questionnaire [CHAQ], 0 to 3, 0 normal function) and quality of life (global assessment of well-being, VAS 0 to 100 mm, 0 no disease activity) is very uncertain. Mean function was 0.84 with TNFi and 1 with placebo (MD 0.16 lower, 95% CI 0.39 lower to 0.06 higher; 3 studies, 194 participants; very low-certainty evidence, downgraded for risk of bias and imprecision). The mean participant global assessment of well-being was 23 mm with TNFi and 34 mm with placebo (MD 11 mm lower, 95% CI 23 mm lower to 1 mm higher; 3 studies, 194 participants; very low-certainty evidence, downgraded for indirectness, imprecision, and risk of bias). No study reported data on remission. Harms at any time We are uncertain about the effect of TNFi on withdrawals due to adverse events (3%) compared to placebo (1%) (RR 3.41, 95% CI 0.73 to 15.9; 6 studies, 448 participants). We are also uncertain about the effect of TNFi on serious adverse events (7%) compared to placebo (6%) (RR 1.09, 95% CI 0.53 to 2.22; 6 studies, 448 participants). The certainty of evidence was very low, downgraded for risk of bias and imprecision. TNFi plus MTX versus MTX alone Benefits at 17 to 26 weeks We are uncertain about the effect of TNFi plus MTX on treatment response. Seventy per cent of participants receiving MTX and 90% receiving TNFi plus MTX achieved treatment response (RR 1.29, 95% CI 0.93 to 1.77; 1 study, 40 participants). We are also uncertain about the effect of TNFi plus MTX on remission. Five per cent of participants on MTX monotherapy and 40% on combination therapy were in remission (RR 8.00, 95% CI 1.10 to 58.19; 1 study, 40 participants). No study reported pain, function, or participant global assessment of well-being. Harms at any time We are uncertain about the effect of TNFi plus MTX on withdrawals due to adverse events and serious adverse events. Very low-certainty evidence from two studies shows that 2/53 participants (4%) receiving MTX alone and 3/55 (5%) receiving TNFi plus MTX withdrew due to adverse events (RR 1.31, 95% CI 0.18 to 9.82; 108 participants), and 5/53 (9%) receiving MTX alone and 0/55 receiving TNFi plus MTX reported serious adverse events (RR 0.16, 95% CI 0.02 to 1.32). Due to risk of bias and imprecision, the certainty of evidence was very low across all major outcomes for this comparison.

Authors' conclusions: In JIA, TNFi may result in a higher proportion of individuals achieving clinical improvement compared to placebo, but we are uncertain about the effect of TNFi on pain, function, and quality of life. We are also uncertain about the effect of TNFi combined with MTX versus MTX alone on clinical improvement and remission. Evidence for the safety of TNFi compared to placebo or MTX is very uncertain. There are no RCTs comparing TNFi to other treatments. More high-quality studies are warranted to assess the benefits and harms of TNFi in JIA.

PubMed Disclaimer

Conflict of interest statement

GC is the head of the Clinical Trial Unit at Skane University Hospital in Malmo, and therefore is involved as investigator in randomized controlled trials on adults with rheumatic diseases funded by different drug companies. His institution gets paid for this.

CBJ: none known.

FA: none known.

FW: ownership in investment fund Avanza Global, a feeder fund that invests in a global index fund.

MB has received research funding from ALF grant (nonprofit—Lund University) and Crafoord Foundation (nonprofit) for research projects not related to Cochrane.

IP received research funding (ALF funding) (Lund University) and FORTE (a national research council in Sweden) as well as reimbursement and fees for reviewing research grant proposals from the Norwegian Research Council, the Syskonen Lundgren Foundation, Malmo, the Kockska Foundation, Trelleborg, Sweden, and the National Research Council for the Swedish National Insurance Agency. He also receives reimbursement for a national project on national guidelines for musculoskeletal disorders through the Swedish National Board of Health and Welfare.

LD reports research grants from BMS and AbbVie and personal fees for lectures/consultation from Janssen, UCB, Galderma, MSD, and Eli Lilly, outside the submitted work

MC has received payment for one lecture in 2016 from AbbVie and payments from Sanofi for the conference fee at the 2019 ACR Annual meeting and writing of the congress report, not related to the present work.

Update of

  • doi: 10.1002/14651858.CD013715

References

References to studies included in this review

Alexeeva 2021 {published and unpublished data}
    1. Alexeeva E, Dvoryakovskaya T, Denisova R, Nikishina I, Zholobova E, Malievskiy V, et al. A randomised, double-blind, parallel study to compare rates of remission (inactive disease) in patients with JIA on MTX treatment alone versus a combination of MTX and etanercept. Annals of the Rheumatic Diseases 2018;77:486. [DOI: 10.1136/annrheumdis-2018-eular.2843] - DOI
    1. Alexeeva E, Dvoryakovskaya T, Denisova R, Zholobova E, Kriulin I, Horneff G, et al. Early combination therapy with etanercept and methotrexate in JIA patients shortens the time to reach an inactive disease state and remission: results of a double-blind placebo-controlled trial. Pediatric Rheumatology 2021;19(1):5. [DOI: 10.1186/s12969-020-00488-9] - DOI - PMC - PubMed
Brunner 2014 {published data only}
    1. Brunner H, Ruperto N, Tzaribachev N, Horneff G, Wouters C, Panaviene V, et al. A148: a multi-center, double-blind, randomized-withdrawal trial of subcutaneous golimumab in pediatric patients with active polyarticular course juvenile idiopathic arthritis despite methotrexate therapy: week 48 results. Arthritis & Rheumatology 2014;66:S191.
    1. Brunner HI, Ruperto N, Tzaribachev N, Horneff G, Chasnyk VG, Panaviene V, et al. Subcutaneous golimumab for children with active polyarticular-course juvenile idiopathic arthritis: results of a multicentre, double-blind, randomised-withdrawal trial. Annals of the Rheumatic Diseases 2018;77(1):21-9. - PMC - PubMed
    1. Brunner HI, Ruperto N, Tzaribachev N, Horneff G, Wouters C, Panaviene VV, et al. A multi-center, double-blind, randomized-withdrawal trial of subcutaneous golimumab in pediatric patients with active polyarticular course juvenile idiopathic arthritis despite methotrexate therapy: week 48 results. Arthritis & Rheumatology 2014;66(SUPPL. 10):S414-S415.
    1. EU/EEA Euctr Outside. A study of the safety and efficacy of CNTO 148 (golimumab) in children with juvenile idiopathic arthritis (JIA) and multiple joint involvement who have poor response to methotrexate (GO KIDS). https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2009-015019-42-Outs... 2012.
    1. Leu JH, Mendelsohn AM, Ford J, Davis HM, Xu Z. Body surface area-based dosing approach produced comparable golimumab exposure across different age ranges after subcutaneous administration of golimumab in pediatric patients with juvenile idiopathic arthritis. Arthritis and Rheumatism 2013;65(SUPPL. 10):S123.
Burgos‐Vargas 2015 {published data only}
    1. Burgos-Vargas R, Horneff G, Tse SM L, Quartier P, Unnebrink K, Anderson JK. Performance of disease activity measures in pediatric patients with enthesitis-related arthritis. Arthritis & Rheumatology 2017;69(Supplement 4):97-100.
    1. Burgos-Vargas R, Tse S, Horneff G, Pangan A, Unnebrink K, Anderson J. Efficacy and safety of adalimumab in pediatric patients with enthesitis related arthritis. Journal of Rheumatology 2014;41(7):1531-2.
    1. Burgos-Vargas R, Tse S, Horneff G, Pangan AL, Unnebrink K, Anderson JK. PReS-FINAL-2179: Efficacy and safety of adalimumab in pediatric patients with enthesitis related arthritis. In: Pediatric Rheumatology. Vol. 11. 2013. - PMC - PubMed
    1. Burgos-Vargas R, Tse SM L, Horneff G, Pangan AL, Unnebrink K, Anderson JK. Efficacy and safety of adalimumab in paediatric patients with enthesitis related arthritis. Rheumatology (United Kingdom) 2014;53(SUPPL. 1):i51-i52.
    1. Burgos-Vargas R, Tse SM L, Horneff G, Unnebrink K, Anderson JK. Long-term efficacy and safety of adalimumab in pediatric patients with enthesitis related arthritis. Arthritis & Rheumatology 2016;68(Supplement 10):491-2.
Burgos‐Vargas 2022 {published and unpublished data}
    1. Burgos-Vargas R, Loyola-Sanchez A, Ramiro S, Reding-Bernal A, Alvarez-Hernandez E, Heijde D, et al. A randomized, double-blind, placebo-controlled 12-week trial of infiximab in patients with juvenile-onset spondyloarthritis. Arthritis Research & Therapy 2022;24(1):187. [DOI: 10.1186/s13075-022-02877-9] [PMID: ] - DOI - PMC - PubMed
    1. NCT00591201. Efficacy, safety, and tolerability study of infliximab in juvenile spondyloarthropathies. https://clinicaltrials.gov/show/NCT00591201.
    1. Ramiro S, Casasola J, Van Der Heijde D, Landewe RB M, Burgos-Vargas R. Performance of disease activity measures in juvenile spondyloarthritis in a placebo controlled trial with infliximab. Arthritis & Rheumatology 2016;68:512-4. [DOI: 10.1002/art.39977] - DOI
    1. Ramiro S, Casasola-Vargas JC, Van Der Heijde D, Landewe R, Burgos-Vargas R. Performance of disease activity measures in juvenile spondyloarthritis in a placebo controlled trial with infliximab. Annals of the Rheumatic Diseases 2016;75:274-5. [DOI: 10.1136/annrheumdis-2016-eular.2580] - DOI
    1. Ramiro S, Casasola-Vargas JC, Van Der Heijde D, Landewe R, Burgos-Vargas R. Performance of disease activity measures in juvenile spondyloarthritis in a placebo controlled trial with infliximab. Pediatric Rheumatology 2017;15(Suppl 1):216. [DOI: 10.1186/s12969-017-0143-7] - DOI
Horneff 2013 {published data only}
    1. Horneff G, Foeldvari I, Minden K, Huppertz H-I, Klein A. Improvement of spinal inflammation induced by etanercept in enthesitis related arthritis JIA-patients. Data of the reminder-study. Arthritis & Rheumatology 2016;68(Supplement 10):4014-6.
    1. Horneff G, Foeldvari I, Minden K, Trauzeddel R, Kuemmerle-Deschner JB, Tenbrock K, et al. Induction and maintenance of remission by etanercept in enthesitis related arthritis jia-patients. Arthritis & Rheumatology 2015;67:SUPPL. 10. - PubMed
    1. Horneff G, Foeldvari I, Minden K, Trauzeddel R, Kummerle-Deschner JB, Tenbrock K, 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 & Rheumatology 2015;67(8):2240-9. - PubMed
    1. Horneff G, Schmalbach T, Kaul I. Remission induction by Etanercept in enthesitis-related arthritis JIA patients (juvenile undifferentiated spondylarthropathy)-REMINDER Study. Zeitschrift Fur Rheumatologie 2013;72(SUPPL. 1):S11.
Lovell 2000 {published data only}
    1. Lovell DJ, Giannini EH, Reiff A, Cawkwell GD, Silverman ED, Nocton JJ, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. New England Journal of Medicine 2000;342(11):763-9. [DOI: 10.1056/NEJM200003163421103] - DOI - PubMed
    1. Lovell DJ, Giannini EH, Reiff A, Jones OY, Schneider R, Olson JC, et al. Long-term efficacy and safety of etanercept in children with polyarticular-course juvenile rheumatoid arthritis: Interim results from an ongoing multicenter, open-label, extended-treatment trial. Arthritis and Rheumatism 2003;48(1):218-26. [DOI: 10.1002/art.10710] - DOI - PubMed
    1. Lovell DJ, Reiff A, Ilowite NT, Wallace CA, Chon Y, Lin SL, et al. Safety and efficacy of up to eight years of continuous etanercept therapy inpatients with juvenile rheumatoid arthritis. Arthritis and Rheumatism 2008;58(5):1496-504. [DOI: 10.1002/art.23427] - DOI - PubMed
    1. NCT03780959. Safety and efficacy of etanercept (recombinant human tumor necrosis factor receptor fusion protein [TNFR: fc]) in children with juvenile rheumatoid arthritis (JRA). https://clinicaltrials.gov/study/NCT03780959 (first received 18 December 2018).
Lovell 2008 {published data only}
    1. Lovell DJ, Brunner HI, Reiff AO, Jung L, Jarosova K, Nemcova D, et al. Long-term outcomes in patients with polyarticular juvenile idiopathic arthritis receiving adalimumab with or without methotrexate. RMD Open 2020;6(2):e001208. [DOI: 10.1136/rmdopen-2020-001208] [PMID: ] - DOI - PMC - PubMed
    1. Lovell DJ, Brunner HI, Reiff AO, Jung L, Jarosova K, Nemcova D, et al. Long-term outcomes in patients with polyarticular juvenile idiopathic arthritis receiving adalimumab with or without methotrexate. RMD Open 2020;6:e001208. [DOI: 10.1136/rmdopen-2020-001208] [PMID: ] - DOI - PMC - PubMed
    1. Lovell DJ, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K, et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. New England Journal of Medicine 2008;359(8):810-20. [DOI: 10.1056/NEJMoa0706290] - DOI - PubMed
    1. Lovell DJ, Ruperto N, Jarosova K, Nemcova D, Vargova V, Michels H, et al. The impact of adalimumab on growth in patients with juvenile idiopathic arthritis. Arthritis & Rheumatology 2014;66(A52):S77. [DOI: 10.1002/art.38468] - DOI
    1. Lovell DJ, Ruperto N, Jarosova K, Nemcova D, Vargova V, Michels H, et al. The impact of adalimumab on growth in patients with juvenile idiopathic arthritis. Arthritis and Rheumatism 2012;64(SUPPL. 10):S329-30.
Ruperto 2007 {published data only}
    1. NCT00036374. A study of the safety and effectiveness of infliximab (remicade) in patients with juvenile rheumatoid arthritis. https://clinicaltrials.gov/ct2/show/NCT00036374.
    1. Ruperto N, Lovell DJ, Cuttica R, Wilkinson N, Woo P, Espada G, et al. A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis and Rheumatism 2007;56(9):3096-106. - PubMed
    1. Visvanathan S, Wagner C, Marini JC, Lovell DJ, Martini A, Petty R, et al. The effect of infliximab plus methotrexate on the modulation of inflammatory disease markers in juvenile idiopathic arthritis: Analyses from a randomized, placebo-controlled trial. Pediatric Rheumatology 2010;8:24. [DOI: 10.1186/1546-0096-8-24] - DOI - PMC - PubMed
Tynjälä 2011 {published data only}
    1. NCT01015547. Aggressive combination drug therapy in very early polyarticular juvenile idiopathic arthritis. https://clinicaltrials.gov/ct2/show/NCT01015547. - PubMed
    1. Tarkiainen M, Tynjala P, Vahasalo P, Aalto K, Kroger L, Rebane K, et al. Economic evaluation of infiximab, synthetic triple therapy and methotrexate in the treatment of newly diagnosed juvenile idiopathic arthritis. Pediatric Rheumatology 2022;20:97. [DOI: 10.1186/s12969-022-00748-w] - DOI - PMC - PubMed
    1. Tarkiainen M, Tynjala P, Vahasalo P, Kroger L, Aalto K, Malin M, et al. Health-related quality of life in patients with newly diagnosed JIA with different treatment strategies (ACUTE-JIA study). Annals of the Rheumatic Diseases 2015;74(SUPPL. 2):387.
    1. Tarkiainen M, Tynjälä P, Vähäsalo P, Kröger L, Aalto K, Lahdenne P. Early aggressive treatment decreases pain in patients with juvenile idiopathic arthritis. Pediatric Rheumatology 2018;16(Supplement 2):no pagination. [DOI: 10.1186/s12969-018-0265-6] - DOI - PMC - PubMed
    1. Tarkiainen M, Tynjälä P, Vähäsalo P, Kröger L, Aalto K, Lahdenne P. Health-related quality of life during early aggressive treatment in patients with polyarticular juvenile idiopathic arthritis: results from randomized controlled trial. Pediatric Rheumatology Online Journal 2019;17(1):80. [DOI: 10.1186/s12969-019-0370-1] - DOI - PMC - PubMed

References to studies excluded from this review

Acharya 2020 {published data only}
    1. Acharya NR, Ebert CD, Kelly NK, Porco TC, Ramanan AV, Arnold BF, the ADJUST Research Group. Discontinuing adalimumab in patients with controlled juvenile idiopathic arthritis-associated uveitis (ADJUST-Adalimumab in Juvenile Idiopathic Arthritis-associated Uveitis Stopping Trial): study protocol for a randomised controlled trial. Trials 2020;21:887. [DOI: 10.1186/s13063-020-04796-z] - DOI - PMC - PubMed
    1. NCT03816397. Adalimumab in JIA-associated uveitis stopping trial (ADJUST). https://clinicaltrials.gov/ct2/show/study/NCT03816397.
Alexeeva 2020 {published data only}
    1. Alexeeva E, Dvoryakovskaya T, Denisova R, Sleptsova T, Isaeva K, Chomahidze A, et al. Efficacy and safety of adalimumab as the first- and second-line biologic therapy for children with juvenile idiopathic arthritis under four years of age. Egyptian Rheumatologist 2020;42(3):231-6. [DOI: 10.1016/j.ejr.2020.02.011] - DOI
Baranov 2015 {published data only}
    1. Baranov AA, Alexeeva EI, Bzarova TM, Valieva SI, Isaeva KB, Chistyakova EG, et al. Long term follow-up on effectiveness and safety of etanercept in juvenile idiopathic arthritis without systemic manifestations. Voprosy Sovremennoi Pediatrii - Current Pediatrics 2015;14(2):224-235. [DOI: 10.15690/vsp.v14i2.1291] - DOI
Burgos‐Vargas 2018 {published data only}
    1. Burgos-Vargas R, Tse SML, Minden K, Quartier P, Anderson JK, Unnebrink K, et al. The impact of adalimumab on growth in patients with pediatric enthesitis-related arthritis. Arthritis & Rheumatology 2018;70:2652.
Calvo 2002 {published data only}
    1. Calvo I, Soriano J, Andreu E. Results of treatment with etanercept in juvenile idiopathic arthritis and compared with methotrexate. Anales Espanoles de Pediatria 2002;56(4):382.
Emmrich 2000 {published data only}
    1. Emmrich P, Kruse K. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Monatsschrift fur Kinderheilkunde 2000;148(8):785. [DOI: 10.1007/s001120050641] - DOI
EU/EEA 2009 {published data only}
    1. NCT00775437. Compassionate use study of adalimumab in children 2 to < 4 years old or age 4 and above weighing less than 15 kg with active juvenile idiopathic arthritis (JIA). https://clinicaltrials.gov/ct2/show/NCT00775437 (first received 17 October 2008).
EUCTR 2009 {published data only}
    1. Euctr 2009. Study evaluating etanercept in 3 subtypes of childhood arthritis. https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-012520-84/re....
EUCTR 2019 {published data only}
    1. EUCTR2019-000119-10-FR. A study of Baricitinib in children and young adults with JIA associated eye inflammation. https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2019-000119-10-FR.
Gaidar 2017 {published data only}
    1. Gaidar E, Kostik M, Dubko M, Masalova V, Serogodskaya E, Snegireva L, et al. The evaluation of efficacy of adalimumab in juvenile idiopathic arthritis-associated uveitis and chronic anterior uveitis. Pediatric Rheumatology 2017;15(Supplement 1):447.
Gerbaux 2017 {published data only}
    1. Gerbaux M, Le PQ, Goffin L, Badot V, La C, Caspers L, et al. Long-term efficacy and safety of biologic therapy in children with juvenile idiopathic arthritis or non-infectious uveitis. Pediatric Rheumatology 2017;15(Supplement 1):330.
Hissink Muller 2012 {published data only}
    1. Hissink Muller P, Yildiz B, Allaart CF, Brinkman DM, Van Rossum MA, Van Den Berg JM, et al. Randomized clinical trial in pediatric rheumatology: Are parents and patients in equipoise? Arthritis and Rheumatism 2012;64(SUPPL. 10):S849. [DOI: 10.1002/art.37735] - DOI
Hissink Muller 2017 {published data only}
    1. Hissink Muller P, Brinkman D, Schonenberg-Meinema D, Van Den Bosch W, Koopman-Keemink Y, Brederije I, et al. Treatment strategy study in new onset DMARD naive juvenile idiopathic arthritis first results on 24 months clinical outcome. Annals of the Rheumatic Diseases 2018;77:478. [DOI: 10.1136/annrheumdis-2018-eular.2623] - DOI - PubMed
    1. Hissink Muller P, Brinkman DM, Schonenberg D, Koopman-Keemink Y, Van Den Berg JM, Bekkering P, et al. Three treatment strategies in recent onset DMARD naive juvenile idiopathic arthritis: initial results of the best for kids-study. Annals of the Rheumatic Diseases 2015;74(SUPPL. 2):94. [DOI: 10.1136/annrheumdis-2015-eular.2048] - DOI
    1. Hissink Muller PC E, Van Braak WG, Schreurs D, Nusman CM, Bergstra SA, Hemke R, et al. No radiographic wrist damage after treatment to target in recent-onset juvenile idiopathic arthritis. Pediatric Rheumatology 2019;17(1):62. [DOI: 10.1186/s12969-019-0362-1] [PMID: ] - DOI - PMC - PubMed
    1. Hissink Muller PC, Brinkman DM, Schonenberg D, Koopman-Keemink Y, Brederije IC, Bekkering WP, et al. A comparison of three treatment strategies in recent onset non-systemic Juvenile Idiopathic Arthritis: initial 3-months results of the BeSt for Kids-study. Pediatric Rheumatology Online Journal 2017;15(1):11. [DOI: 10.1186/s12969-017-0138-4] [PMID: ] - DOI - PMC - PubMed
    1. Muller PH, Brinkman D, Schonenberg D, Van Den Bosch W, Koopman-Keemink Y, Brederije I, et al. Three treatment strategies in recent onset DMARD naive juvenile idiopathic arthritis: first results of clinical outcome after 24 months. Pediatric Rheumatology 2017;15(Supplement 2):9. [DOI: 10.1186/s12969-017-0185-x] - DOI - PMC - PubMed
Horton 2019 {published data only}
    1. Horton S, Jones AP, Guly CM, Hardwick B, Beresford MW, Lee RW, et al. Adalimumab in juvenile idiopathic arthritis-associated uveitis: 5-year follow-up of the bristol participants of the SYCAMORE trial. American Journal of Ophthalmology 2019;207:170-4. [DOI: 10.1016/j.ajo.2019.06.007] - DOI - PubMed
Kingsbury 2013 {published data only}
    1. Kingsbury D, Quartier P, Arora V, Kalabic J, Kupper H, Mozaffarian N. Safety and effectiveness of adalimumab in children with polyarticular juvenile idiopathic arthritis aged 2 to >4 years or >4 years weighing <15 kg. Pediatric Rheumatology 2013;11(SUPPL. 2):P173.
    1. Kingsbury D, Quartier P, Arora V, Kalabic J, Kupper H, Mozaffarian N. Safety and effectiveness of adalimumab in children with polyarticular juvenile idiopathic arthritis aged 2 to <4 years or >4 years weighing <15 kg. Annals of the Rheumatic Diseases 2013;72(SUPPL. 3):729.
    1. Kingsbury D, Quartier P, Arora V, Kalabic J, Kupper H, Mozaffarian N. Safety and effectiveness of adalimumab in children with polyarticular juvenile idiopathic arthritis aged 2 to <4 years or >=4 years weighing <15 kg. Rheumatology (United Kingdom) 2014;53(SUPPL. 1):i164-5. - PMC - PubMed
    1. Kingsbury DJ, Quartier P, Arora V, Kalabic J, Kupper H, Mozaffarian N. Safety and effectiveness of adalimumab in children with polyarticular juvenile idiopathic arthritis aged 2 to >4 years or >4 years weighing <15 kg. Arthritis and Rheumatism 2013;65(SUPPL. 10):S117.
Leu 2013 {published data only}
    1. Leu JH, Mendelsohn AM, Ford J, Davis HM, Xu Z. Body surface area-based dosing approach produced comparable golimumab exposure across different age ranges after subcutaneous administration of golimumab in pediatric patients with juvenile idiopathic arthritis. Arthritis and Rheumatism 2013;65(10):S123. [DOI: 10.1002/art.38216] - DOI
    1. Leu JH, Mendelsohn AM, Ford J, Davis HM, Zhou H, Xu Z. Long-term pharmacokinetics of body surface area-adjusted doses of golimumab following repeated subcutaneous administrations in pediatric patients with polyarticular juvenile idiopathic arthritis. Arthritis & Rheumatology 2014;66(SUPPL. 10):S125-S126. [URL: acrabstracts.org/abstract/long-term-pharmacokinetics-of-body-surface-are...
NCT00029042 {published data only}
    1. NCT00029042. Infliximab to treat children with juvenile rheumatoid arthritis. https://clinicaltrials.gov/show/NCT00029042.
News for the practitioner 2000 {published data only}
    1. Unknown. Efficacy of etanercept in the treatment of children with polyarticular juvenile rheumatoid arthritis. European Journal of Pediatrics 2000;159(10):785. [DOI: 10.1007/s004310000529] - DOI
Quartier 2016 {published data only}
    1. NCT01385826. Effect of adalimumab for the treatment of uveitis in juvenile idiopathic arthritis. https://www.clinicaltrials.gov/ct2/show/NCT01385826.
    1. Quartier P, Baptiste A, Despert V, Allain-Launay E, Kone-Paut I, Belot A, et al. ADJUVITE: a double-blind, randomised, placebo-controlled trial of adalimumab in early onset, chronic, juvenile idiopathic arthritis-associated anterior uveitis. Annals of the Rheumatic Diseases 2018;77(7):1003-11. [DOI: 10.1136/annrheumdis-2017-212089] [PMID: ] - DOI - PubMed
    1. Quartier P, Despert V, Poignant S, Baptiste A, Elie C, Kone-Paut I, et al. Adjuvite: a double-blind, randomized, placebo-controlled trial of Adalimumab in juvenile idiopathic arthritis associated uveitis. Pediatric Rheumatology 2017;15:(Supplement 1). [DOI: 10.1186/s12969-017-0143-7] - DOI
    1. Quartier P, Despert V, Poignant S, Elie C, Kone-Paut I, Belot A, et al. Adjuvite: a double-blind, randomized, placebo-controlled trial of adalimumab in juvenile idiopathic arthritis associated uveitis. Annals of the Rheumatic Diseases 2016;75:273. [DOI: 10.1136/annrheumdis-2016-eular.2362] - DOI - PubMed
Ramanan 2014 {published data only}
    1. Hughes DA, Culeddu G, Plumpton CO, Wood E, Dick AD, Jones AP, et al. Cost-effectiveness analysis of adalimumab for the treatment of uveitis associated with juvenile idiopathic arthritis. Ophthalmology 2018;126:415-24. [DOI: 10.1016/j.ophtha.2018.09.043] - DOI - PubMed
    1. Hughes DA, Culeddu G, Plumpton CO, Wood E, Dick AD, Jones AP, et al. Cost-effectiveness analysis of adalimumab for the treatment of uveitis associated with juvenile idiopathic arthritis. Ophthalmology 2019;126(3):415-24. [DOI: 10.1016/j.ophtha.2018.09.043] - DOI - PubMed
    1. Ramanan AV, Dick AD, Benton D, Compeyrot-Lacassagne S, Dawoud D, Hardwick B, et al. A randomised controlled trial of the clinical effectiveness, safety and cost-effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis (SYCAMORE Trial). Trials 2014;15:14. [DOI: 10.1186/1745-6215-15-14] - DOI - PMC - PubMed
    1. Ramanan AV, Dick AD, Benton D, Compeyrot-Lacassagne S, Dawoud D, Hardwick B, et al. A randomised controlled trial of the clinical effectiveness, safety and cost-effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis (SYCAMORE Trial). Trials 2014;15:Article no. 14. [DOI: 10.1186/1745-6215-15-14] - DOI - PMC - PubMed
    1. Ramanan AV, Dick AD, Jones AP, Hughes DA, McKay A, Rosala-Hallas A, et al. Adalimumab in combination with methotrexate for refractory uveitis associated with juvenile idiopathic arthritis: a RCT. Health Technology Assessment 2019;23(15):1-139. [DOI: 10.3310/hta23150] - DOI - PMC - PubMed
Ramanan 2021 {published data only}
    1. NCT04088409. A study of baricitinib (LY3009104) in participants from 2 years to less than 18 years old with active JIA-associated uveitis or chronic anterior antinuclear antibody-positive uveitis. https://clinicaltrials.gov/show/NCT04088409.
    1. Ramanan AV, Guly CM, Keller SY, Schlichting DE, Bono S, Liao R, et al. Clinical effectiveness and safety of baricitinib for the treatment of juvenile idiopathic arthritis-associated uveitis or chronic anterior antinuclear antibody-positive uveitis: study protocol for an open-label, adalimumab active-controlled phase 3 clinic. Trials 2021;22(1):689. [DOI: 10.1186/s13063-021-05651-5] - DOI - PMC - PubMed
Romero 2017 {published data only}
    1. Romero ER, Galan RA, Almagro RM, Munoz A, Povedano J. Treatment of non-infectious uveitis: a comparative long-term study between biologic therapy with adalimumab and two conventional disease-modifying antirheumatic drugs. Arthritis & Rheumatology 2017;69:Supplement 10. [ABSTRACT NUMBER: 1158] [URL: acrabstracts.org/abstract/treatment-of-non-infectious-uveitis-a-comparat...
Ruperto 2008 {published data only}
    1. Ruperto N, Lovell DJ, Quartier P, Paz E, Rubio-Perez N, Silva CA, et al. Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet 2008;372(9636):383‐91. [DOI: 10.1016/S0140-6736(08)60998-8] - DOI - PubMed
    1. Ruperto N, Lovell DJ, Quartier P, Paz E, Rubio-Perez N, Silva CA, et al. Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis. Arthritis and Rheumatism 2010;62(6):1792-802. [DOI: 10.1002/art.27431] - DOI - PubMed
Ruperto 2013 {published data only}
    1. Ruperto N, Lovell DJ, Jarosova K, Nemcova D, Vargova V, Michels H, et al. The impact of adalimumab on growth in patients with juvenile idiopathic arthritis. Pediatric Rheumatology 2013;11(SUPPL. 2):383-91. [DOI: 10.1186/1546-0096-11-S2-O4] - DOI
Ruperto 2021 {published data only}
    1. Ruperto N, Brunner HI, Pacheco-Tena C, Louw I, Vega-Cornejo G, Spindler AJ, et al. Open-label phase 3 study of intravenous golimumab in patients with polyarticular juvenile idiopathic arthritis. Rheumatology (Oxford, England) 2021;60(10):4495-507. [DOI: 10.1093/rheumatology/keab021] [PMID: ] - DOI - PMC - PubMed
Sharma 2007 {published data only}
    1. Sharma SM, Ramanan AV, Riley P, Dick AD. Use of infliximab in juvenile onset rheumatological disease-associated refractory uveitis: efficacy in joint and ocular disease. Annals of the Rheumatic Diseases 2007;66(6):840-1. [DOI: 10.1136/ard.2006.06544] - DOI - PMC - PubMed
Smith 2005 {published data only}
    1. NCT00001862. TNRF: fc to treat eye inflammation in juvenile rheumatoid arthritis. https://clinicaltrials.gov/ct2/show/NCT00001862.
    1. Smith JA, Thompson DJ, Whitcup SM, Suhler E, Clarke G, Smith S, et al. A randomized, placebo-controlled, double-masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis. Arthritis and Rheumatism 2005;53(1):18-23. - PubMed
Thapa 2012 {published data only}
    1. NCT00443430. Trial of early aggressive drug therapy in juvenile idiopathic arthritis. https://clinicaltrials.gov/show/NCT00443430. - PMC - PubMed
    1. Thapa M, Spalding SJ, Hashkes PJ, Ringold S, Zeft AS, Sundel RP, et al. MRI findings from the trial of early aggressive therapy (TREAT) study. Pediatric Rheumatology 2012;10(SUPPL. 1):A36. [DOI: 10.1186/1546-0096-10-S1-A36] - DOI
Tzaribachev 2013 {published data only}
    1. Tzaribachev N, Tzaribachev C, Koos B. Go-kids imaging substudy: MRI treatment response to 30 mg/m2 4-weekly subcutaneous injections of golimumab in children with polyarticular jia—preliminary results of the open label portion. Arthritis and Rheumatism 2013;65:S118. [DOI: 10.1002/art.38216] - DOI
    1. Tzaribachev N, Tzaribachev C, Mehrwald M, Koos B. A62: GO-KIDS imaging substudy: MRI treatment response to 30 mg/m2 Q4W subcutaneous (SC) injections of golimumab (GLM) and placebo in children with polyarticular JIA (pjia)—preliminary results of the placebo controlled portion (week 48). Arthritis & Rheumatology 2014;66:S91-2. [DOI: 10.1002/art.38478] - DOI

References to studies awaiting assessment

NCT00078806 {published data only}
    1. NCT00078806. Safety and efficacy study of etanercept (Enbrel®) in children with systemic onset juvenile rheumatoid arthritis. https://clinicaltrials.gov/show/NCT00078806.
NCT03728478 {unpublished data only}
    1. Burrone M, Mazzoni M, Naddei R, Pistorio A, Spelta M, Scala S, et al, Paediatric Rheumatology International Trials Organisation (PRINTO). Looking for the best strategy to treat children with new onset juvenile idiopathic arthritis: presentation of the "comparison of STep-up and step-down therapeutic strategies in childhood ARthritiS" (STARS) trial. Pediatric Rheumatology Online Journal 2022;20(1):80. - PMC - PubMed
    1. NCT03728478. Step-up and step-down therapeutic strategies in childhood arthritis (STARS). https://clinicaltrials.gov/show/NCT03728478.
NCT03781375 {unpublished data only}
    1. NCT03781375. Etanercept plus methotrexate versus methotrexate alone in children with polyarticular course juvenile rheumatoid arthritis. https://clinicaltrials.gov/show/NCT03781375.
Zeng ADA 2016 {published and unpublished data}
    1. Zeng H, Tang Y. A randomized double-blind controlled trial of adalimumab in juvenile idiopathic arthritis. International Journal of Rheumatic Diseases 2016;19 (Supplement 2):161. [DOI: 10.1111/1756-185X.12962] - DOI
Zeng ETN 2013 {published and unpublished data}
    1. Zeng H, Ping Z. A randomized double-blind controlled clinical trial to evaluate the efficacy of recombinant human tnf-alpha receptor II fusion protein in juvenile idiopathic arthritis. International Journal of Rheumatic Diseases 2016;19(Supplement 2):149. [DOI: 10.1111/1756-185X.12962] - DOI
    1. Zeng H, Zeng P, Xie Y, Tang Y, Li F. A randomized controlled clinical trial to evaluate the efficacy of recombinant human tumor necrosis factor-a receptor type II fusion protein antibody in juvenile idiopathic arthritis. Allergy 2013;68(SUPPL. 98):11. [DOI: 10.1111/all.12282] - DOI
    1. Zeng H, Zeng P, Xie Y, Tang Y, Li F. A randomized controlled clinical trial to evaluate the efficacy of recombinant human tumor necrosis factor-alpha receptor ii fusion protein in juvenile idiopathic arthritis. Annals of the Rheumatic Diseases June 2014;73(SUPPL. 2):933-4. [DOI: 10.1136/annrheumdis-2014-eular.5459] - DOI
Zeng IFX 2016 {published data only}
    1. Xie Y, Zeng H. Efficacy and safety of infliximab in juvenile idiopathic arthritis and juvenile ankylosing spondylitis: a randomised, double-blind, controlled study. In: 13th Congress of Asian Society for Pediatric Research; Hong Kong. 23. 2018:44-5.
    1. Zeng H, Ping Z. Efficacy and safety of infliximab in juvenile idiopathic arthritis and juvenile ankylosing spondylitis: a randomized, double-blind, controlled study. International Journal of Rheumatic Diseases 2016;19(Supplement 2):9. [DOI: 10.1111/1756-185X.12961] - DOI
    1. Zeng H, Zeng P, Tang Y, Wang M. Efficacy and safety of infliximab in juvenile idiopathic arthritis and juvenile ankylosing spondylitis. Conference: Annual European Congress of Rheumatology of the European League Against Rheumatism, EULAR. Annals of the Rheumatic Diseases 2014;73(SUPPL. 2):239. [DOI: 10.1136/annrheumdis-2014-eular.5363] - DOI

References to ongoing studies

NCT04527380 {published data only}
    1. EUCTR2018-000681-10-BE. An Ixekizumab study with Adalimumab reference arm in children and young adults with Juvenile Idiopathic Arthritis Subtypes of Enthesitis-related Arthritis. https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2018-000681-10-BE .
    1. NCT04527380. A study of ixekizumab (LY2439821) in children with juvenile idiopathic arthritis categories of enthesitis-related arthritis (including juvenile onset ankylosing spondylitis) and juvenile psoriatic arthritis. https://clinicaltrials.gov/show/NCT04527380.

Additional references

Amarilyo 2016
    1. Amarilyo G, Tarp S, Foeldvari I, Cohen N, Pope TD, Woo JM, et al. Biological agents in polyarticular juvenile idiopathic arthritis: A meta-analysis of randomized withdrawal trials. Seminars in Arthritis and Rheumatism 2016;46(3):312-8. [DOI: 10.1016/j.semarthrit.2016.07.001] [PMID: ] - DOI - PubMed
Amine 2009
    1. Amine B, Rostom S, Benbouazza K, Abouqal R, Hajjaj-Hassouni N. Health related quality of life survey about children and adolescents with juvenile idiopathic arthritis. Rheumatology International 2009;29(3):275-9. - PubMed
Beukelman 2011
    1. Beukelman T, Patkar NM, Saag KG, Tolleson-Rinehart S, Cron RQ, DeWitt EM, et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care & Research 2011;63(4):465-82. - PMC - PubMed
Breedveld 2006
    1. Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, Vollenhoven R, et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis and Rheumatism 2006;54(1):26-37. - PubMed
Brewer 1977
    1. Brewer EJ Jr, Bass J, Baum J, Cassidy JT, Fink C, Jacobs J, et al. Current proposed revision of JRA criteria. JRA criteria subcommittee of the diagnostic and therapeutic criteria committee of the American Rheumatism Section of the Arthritis Foundation. Arthritis and Rheumatism 1977;20(2 Suppl):195-9. - PubMed
Brunner 2005
    1. Brunner HI, Klein-Gitelman MS, Miller MJ, Barron A, Baldwin N, Trombley M, et al. Minimal clinically important differences of the childhood health assessment questionnaire. Journal of Rheumatology 2005;32(1):150-61. [PMID: ] - PubMed
Brunner 2015
    1. Brunner HI, Ruperto N, Zuber Z, Keane C, Harari O, Kenwright A, et al, Paediatric Rheumatology International Trials Organisation PRINTO, Pediatric Rheumatology Collaborative Study Group (PRCSG). Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial. Annals of the Rheumatic Diseases 2015;74(6):1110-7. [CENTRAL: 4431348] [DOI: 10.1136/annrheumdis-2014-205351] [PMID: ] - DOI - PMC - PubMed
Brunner 2018
    1. Brunner HI, Ruperto N, Tzaribachev N, Horneff G, Chasnyk VG, et al. Subcutaneous golimumab for children with active polyarticular-course juvenile idiopathic arthritis: results of a multicentre, double-blind, randomised-withdrawal trial. Annals of the Rheumatic Diseases 2018;77(1):21-9. [DOI: 10.1136/annrheumdis-2016-210456] - DOI - PMC - PubMed
Cabrera 2020
    1. Cabrera N, Avila-Pedretti G, Belot A, Larbre JP, Mainbourg S, Duquesne A, et al. The benefit-risk balance for biological agents in juvenile idiopathic arthritis: a meta-analysis of randomized clinical trials. Rheumatology 2020;59(9):2226-36. [DOI: 10.1093/rheumatology/keaa170] - DOI - PubMed
Campbell 2020
    1. Campbell M, McKenzie JE, Sowden A, Katikireddi SV, Brennan SE, Ellis S, et al. Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline. BMJ (Clinical Research Ed.) 2020;368:l6890. [DOI: 10.1136/bmj.l6890] - DOI - PMC - PubMed
Cassidy 1986
    1. Cassidy JT, Levinson JE, Bass JC, Baum J, Brewer EJ Jr, Fink CW, et al. A study of classification criteria for a diagnosis of juvenile rheumatoid arthritis. Arthritis and Rheumatism 1986;29(2):274-81. - PubMed
Consolaro 2012
    1. Consolaro A, Bracciolini G, Ruperto N, Pistorio A, Magni-Manzoni S, Malattia C, et al. Remission, minimal disease activity, and acceptable symptom state in juvenile idiopathic arthritis: defining criteria based on the Juvenile Arthritis Disease Activity Score. Arthritis and Rheumatism 2012;64:2366-74. - PubMed
Consolaro 2014
    1. Consolaro A, Negro G, Gallo MC, Bracciolini G, Ferrari C, Schiappapietra B, et al. Defining criteria for disease activity states in nonsystemic juvenile idiopathic arthritis based on a three-variable juvenile arthritis disease activity score. Arthritis Care & Research (Hoboken) 2014;66(11):1703-9. - PubMed
Covidence [Computer program]
    1. Covidence. Version accessed 17 July 2021. Melbourne, Australia: Veritas Health Innovation, 2021. Available at www.covidence.org.
Davies 2017
    1. Davies R, Gaynor D, Hyrich KL, Pain CE. Efficacy of biologic therapy across individual juvenile idiopathic arthritis subtypes: A systematic review. Seminars in Arthritis and Rheumatism 2017;46(5):584-93. [DOI: 10.1016/j.semarthrit.2016.10.008] - DOI - PubMed
Deeks 2019
    1. Deeks JJ, Higgins JP, Altman DG (editors). Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019. Available from training.cochrane.org/handbook/archive/v6.
Dewitt 2012
    1. DeWitt EM, Kimura Y, Beukelman T, Nigrovic PA, Onel K, Prahalad S, et al, Juvenile Idiopathic Arthritis Disease Specific Research Committee of the Children's Arthritis and Rheumatology Research Alliance. Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis. Arthritis Care & Research 2012;64(7):1001-10. [DOI: 10.1002/acr.21625] - DOI - PMC - PubMed
Diener 2019
    1. Diener C, Horneff G. Comparison of adverse events of biologicals for treatment of juvenile idiopathic arthritis: a systematic review. Expert Opinion on Drug Safety 2019;18(8):719-32. [DOI: 10.1080/14740338.2019.1632288] [PMID: ] - DOI - PubMed
FDA 2014
    1. US Food and Drug Administration. What is a serious adverse event? www.fda.gov/safety/medwatch/howtoreport/ucm053087.htm (accessed 23 January 2019).
Ferrara 2018
    1. Ferrara G, Mastrangelo G, Barone P, La Torre F, Martino S, Pappagallo G, et al, Rheumatology Italian Study Group. Methotrexate in juvenile idiopathic arthritis: advice and recommendations from the MARAJIA expert consensus meeting. Pediatric Rheumatology Online Journal 2018;16(1):46. [DOI: 10.1186/s12969-018-0255-8] - DOI - PMC - PubMed
Filocamo 2007
    1. Filocamo G, Sztajnbok F, Cespedes-Cruz A, Magni-Manzoni S, Pistorio A, Viola S. Development and validation of a new short and simple measure of physical function for juvenile idiopathic arthritis. Arthritis and Rheumatism 2007;57(6):913-20. - PubMed
Foeldvari 2019
    1. Foeldvari I, Baer J. Secukinumab Is a promising treatment for patients with juvenile enthesitis related arthritis nonresponsive to anti-TNF treatment according the Juvenile Spondyloarthritis Disease Activity Index. In: 2019 ACR/ARP Annual Meeting. 2019. [URL: acrabstracts.org/abstract/secukinumab-is-a-promising-treatment-for-patie... - PubMed
Gartlehner 2008
    1. Gartlehner G, Hansen RA, Jonas BL, Thieda P, Lohr KN. Biologics for the treatment of juvenile idiopathic arthritis: a systematic review and critical analysis of the evidence. Clinical Rheumatology 2008;27(1):67-76. [DOI: 10.1007/s10067-007-0654-6] [PMID: ] - DOI - PubMed
Giancane 2016
    1. Giancane G, Minoia F, Davì S, Bracciolini G, Consolaro A, Ravelli A. IL-1 inhibition in systemic juvenile idiopathic arthritis. Frontiers in Pharmacology 2016;6(7):467. [CENTRAL: 5138234] [DOI: 10.3389/fphar.2016.00467] [PMID: ] - DOI - PMC - PubMed
Giannini 1992
    1. Giannini EH, Brewer EJ, Kuzmina N, Shaikov A, Maximov A, Vorontsov I, et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A. -U.S.S.R. double-blind, placebo-controlled trial. The pediatric rheumatology collaborative study group and the cooperative children's study group. New England Journal of Medicine 1992;326(16):1043-9. - PubMed
Giannini 1997
    1. Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis and Rheumatism 1997;40(7):1202-9. - PubMed
GRADEpro GDT [Computer program]
    1. GRADEpro GDT. Version accessed 25 October 2021. Hamilton (ON): McMaster University (developed by Evidence Prime), 2021. Available from gradepro.org.
Grom 1996
    1. Grom AA, Murray KJ, Luyrink L, Emery H, Passo MH, Glass DN, et al. Patterns of expression of tumor necrosis factor alpha, tumor necrosis factor beta, and their receptors in synovia of patients with juvenile rheumatoid arthritis and juvenile spondylarthropathy. Arthritis and Rheumatism 1996;39(10):1703-10. - PubMed
Gutierrez‐Suarez 2007
    1. Gutierrez-Suarez R, Pistorio A, Cespedes Cruz A, Norambuena X, Flato B, et al, Pediatric Rheumatology International Trials Organisation. Health-related quality of life of patients with juvenile idiopathic arthritis coming from 3 different geographic areas. The PRINTO multinational quality of life cohort study. Rheumatology (Oxford, England) 2007;46(2):314-20. - PubMed
Gutierrez‐Suarez 2010
    1. Gutierrez-Suarez R, Burgos-Vargas R. The use of methotrexate in children with rheumatic diseases. Clinical and Experimental Rheumatology 2010;28(5 Suppl 61):S122-7. - PubMed
Haverman 2012
    1. Haverman L, Grootenhuis MA, den Berg JM, Veenendaal M, Dolman KM, Swart JF, et al. Predictors of health-related quality of life in children and adolescents with juvenile idiopathic arthritis: results from a Web-based survey. Arthritis Care & Research 2012;64(5):694-703. - PubMed
Higgins 2017
    1. Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Churchill R, Chandler J, Cumpston MS (editors). Cochrane Handbook for Systematic Reviews of Interventions version 5.2.0 (updated June 2017). Cochrane, 2017. Available from training.cochrane.org/handbook/archive/v5.2.
Higgins 2023
    1. Higgins JPT, Li T, Deeks JJ (editors). Chapter 6: Choosing effect measures and computing estimates of effect. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.4 (updated August 2023). Cochrane, 2023. Available from training.cochrane.org/handbook/archive/v6.4.
Horneff 2023
    1. Horneff G, Minden K, Rolland C, Hernandez Daly AC, Borlenghi C, Ruperto N. Efficacy and safety of TNF inhibitors in the treatment of juvenile idiopathic arthritis: a systematic literature review. Pediatric Rheumatology Online Journal 2023;21:20. - PMC - PubMed
Howe 1991
    1. Howe S, Levinson J, Shear E, Hartner S, McGirr S, Schulte M, et al. Development of a disability measurement tool for juvenile rheumatoid arthritis: the Juvenile Arthritis Functional Assessment Report. Arthritis and Rheumatism 1991;34(7):873-80. - PubMed
Kay 2008
    1. Kay J, Matteson EL, Dasgupta B, Nash P, Durez P, Hall S, et al. Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study. Arthritis and Rheumatism 2008;58(4):964-75. - PubMed
Kearsley‐Fleet 2019
    1. Kearsley-Fleet L, Sampath S, McCann LJ, Baildam E, Beresford MW, Davies R, et al. Use and effectiveness of rituximab in children and young people with juvenile idiopathic arthritis in a cohort study in the United Kingdom. Rheumatology (Oxford, England) 2019;58(2):331-5. [CENTRAL: 6343463] [DOI: 10.1093/rheumatology/key306] [PMID: ] - DOI - PMC - PubMed
Kemper 2012
    1. Kemper AR, Van Mater HA, Coeytaux RR, Williams JW Jr, Sanders GD. Systematic review of disease-modifying antirheumatic drugs for juvenile idiopathic arthritis. BMC Pediatrics 2012;15(12):29. [CENTRAL: PMC3340294] [DOI: 10.1186/1471-2431-12-29] [PMID: ] - DOI - PMC - PubMed
Koike 2014
    1. Koike T, Harigai M, Ishiguro N, Inokuma S, Takei S, Takeuchi T, et al. Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients: postmarketing surveillance report of 7740 patients. Modern Rheumatology 2014;24(3):390-8. - PubMed
Kutukculer 1998
    1. Kutukculer N, Caglayan S, Aydogdu F. Study of pro-inflammatory (TNF-alpha, IL-1alpha, IL-6) and T-cell-derived (IL-2, IL-4) cytokines in plasma and synovial fluid of patients with juvenile chronic arthritis: correlations with clinical and laboratory parameters. Clinical Rheumatology 1998;17(4):288-92. - PubMed
Lepore 1994
    1. Lepore L, Pennesi M, Saletta S, Perticarari S, Presani G, Prodan M. Study of IL-2, IL-6, TNF alpha, IFN gamma and beta in the serum and synovial fluid of patients with juvenile chronic arthritis. Clinical and Experimental Rheumatology 1994;12(5):561-5. - PubMed
Li 2019
    1. Li T, Higgins JPT, Deeks JJ (editors). Chapter 5: Collecting data. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019. Available from training.cochrane.org/handbook/archive/v6.
Li 2021
    1. Li Y, Mao X, Tang X, Mao H. Efficacy and safety of anti-tnf alpha therapy for uveitis associated with juvenile idiopathic arthritis: a systematic review and meta-analysis. Rheumatology and Therapy 2021;8(2):711-27. [DOI: 10.1007/s40744-021-00296-x] [PMID: ] - DOI - PMC - PubMed
Lovell 1989
    1. Lovell DJ, Howe S, Shear E, Hartner S, McGirr G, Schulte M, et al. Development of a disability measurement tool for juvenile rheumatoid arthritis. The Juvenile Arthritis Functional Assessment Scale. Arthritis and Rheumatism 1989;32(11):1390-5. - PubMed
Lovell 2000
    1. Lovell DJ, Giannini EH, Reiff A, Cawkwell GD, Silverman ED, Nocton JJ, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. New England Journal of Medicine 2000;342(11):763-9. - PubMed
Lovell 2008
    1. Lovell DJ, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K, et al, Pediatric Rheumatology Collaborative Study Group, Pediatric Rheumatology International Trials Organisation. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. New England Journal of Medicine 2008;359(8):810-20. - PubMed
Lovell 2015
    1. Lovell DJ, Ruperto N, Mouy R, Paz E, Rubio-Pérez N, Silva CA, et al, Pediatric Rheumatology Collaborative Study Group and the Paediatric Rheumatology International Trials Organisation. Long-term safety, efficacy, and quality of life in patients with juvenile idiopathic arthritis treated with intravenous abatacept for up to seven years. Arthritis and Rheumatology (Hoboken, NJ) 2015;67(10):2759-70. [CENTRAL: 5054936] [DOI: 10.1002/art.39234] [PMID: ] - DOI - PMC - PubMed
Mangge 1995
    1. Mangge H, Kenzian H, Gallistl S, Neuwirth G, Liebmann P, Kaulfersch W, et al. Serum cytokines in juvenile rheumatoid arthritis: correlation with conventional inflammation parameters and clinical subtypes. Arthritis and Rheumatism 1995;38(2):211-20. - PubMed
Morgan 2019
    1. Morgan EM, Munro JE, Horonjeff J, Horgan B, Shea B, Feldman BM, et al. Establishing an updated core domain set for studies in juvenile idiopathic arthritis: a report from the OMERACT 2018 JIA Workshop. Journal of Rheumatology 2019;46(8):1006-13. [DOI: 10.3899/jrheum.181088] - DOI - PubMed
NCT02592434
    1. NCT02592434. Efficacy study of tofacitinib in pediatric JIA population [Efficacy, safety and tolerability of Tofacitinib for treatment of polyarticular course Juvenile Idiopathic Arthritis (JIA) in children and adolescent subjects]. clinicaltrials.gov/ct2/show/NCT02592434 (first received 30 October 2015).
NCT03725007
    1. NCT03725007. A study to evaluate the pharmacokinetics, safety, and tolerability of upadacitinib in pediatric subjects with polyarticular course juvenile idiopathic arthritis [An open-label multiple-dose study to evaluate the pharmacokinetics, safety, and tolerability of upadacitinib in pediatric subjects with polyarticular course juvenile idiopathic arthritis]. clinicaltrials.gov/ct2/show/NCT03725007 (first received 30 October 2018).
NCT03773978
    1. NCT03773978. A study of baricitinib in participants from 2 years to less than 18 years old with juvenile idiopathic arthritis (JUVE-BASIS) [A randomized, double-blind, placebo-controlled, withdrawal, safety and efficacy study of oral baricitinib in patients from 2 years to less than 18 years old with juvenile idiopathic arthritis (JIA)]. clinicaltrials.gov/ct2/show/NCT03773978 (first received 12 December 2018).
NCT06222034
    1. NCT06222034. Study to Measure Filgotinib in the Blood of Children and Teenagers With Arthritis Taking Filgotinib (SCALESIA) [An Open-label, Multiple Dose, Multicenter Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Filgotinib in Children and Adolescents From 8 to Less Than 18 Years of Age With Juvenile Idiopathic Arthritis]. clinicaltrials.gov/ct2/show/NCT06222034 (first received 4 January 2024).
Oberle 2014
    1. Oberle EJ, Harris JG, Verbsky JW. Polyarticular juvenile idiopathic arthritis—epidemiology and management approaches. Journal of Clinical Epidemiology 2014;6:379-93. - PMC - PubMed
Otten 2013
    1. Otten MH, Anink J, Spronk S, Suijlekom-Smit LW. Efficacy of biological agents in juvenile idiopathic arthritis: a systematic review using indirect comparisons. Annals of the Rheumatic Diseases 2013;72(11):1806-12. [DOI: 10.1136/annrheumdis-2012-201991] [PMID: ] - DOI - PubMed
Petty 2004
    1. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al, International League of Associations for Rheumatology. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. Journal of Rheumatology 2004;31(2):390-2. - PubMed
Plot Digitizer [Computer program]
    1. Plot Digitizer. Huwaldt JA. SourceForge, 2001. Available at plotdigitizer.sourceforge.net.
PRISMA Group 2009
    1. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ (Clinical Research Ed.) 2009;339:b2535. [DOI: 10.1136/bmj.b2535] - DOI - PMC - PubMed
Ramanan 2023
    1. Ramanan AV, Quartier P, Okamoto N, Foeldvari I, Spindler A, Fingerhutova S, et al. Baricitinib in juvenile idiopathic arthritis: an international, phase 3, randomised, double-blind, placebo-controlled, withdrawal, efficacy, and safety trial. Lancet 2023;402(10401):555-70. [DOI: 10.1016/S0140-6736(23)00921-2] - DOI - PubMed
Review Manager 2020 [Computer program]
    1. Review Manager 5 (RevMan 5). Version 5.4. Copenhagen: The Cochrane Collaboration, 2020.
RevMan 2025 [Computer program]
    1. Review Manager (RevMan). Version 8.14.0. The Cochrane Collaboration, 2025. Available at revman.cochrane.org.
Ringold 2014
    1. Ringold S, Weiss PF, Colbert RA, DeWitt EM, Lee T, Onel K, et al, Juvenile Idiopathic Arthritis Research Committee of the Children's Arthritis and Rheumatology Research Alliance (CARRA). Childhood Arthritis and Rheumatology Research Alliance consensus treatment plans for new onset polyarticular juvenile idiopathic arthritis. Arthritis Care & Research 2014;66(7):1063-72. [DOI: 10.1002/acr.22259] - DOI - PMC - PubMed
Ruperto 2004
    1. Ruperto N, Murray KJ, Gerloni V, Wulffraat N, Oliveira SK, Falcini F, et al, Pediatric Rheumatology International Trials Organization. A randomized trial of parenteral methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate. Arthritis and Rheumatism 2004;50(7):2191-201. - PubMed
Ruperto 2007
    1. Ruperto N, Lovell DJ, Cuttica R, Wilkinson N, Woo P, Espada G, et al, Paediatric Rheumatology International Trials Organisation, Pediatric Rheumatology Collaborative Study Group. A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis & Rheumatology 2007;56(9):3096-106. - PubMed
Ruperto 2021
    1. Ruperto N, Brunner HI, Synoverska O, Ting TV, Mendoza CA, Spindler A, et al. Tofacitinib in juvenile idiopathic arthritis: a double-blind, placebo-controlled, withdrawal phase 3 randomised trial. Lancet 2021;398(10315):1984-96. [DOI: 10.1016/S0140-6736(21)01255-1] [PMID: ] - DOI - PubMed
Schünemann 2017a
    1. Schünemann HJ, Oxman AD, Higgins JPT, Vist GE, Glasziou P, Akl E, et al (editors). Chapter 11: Completing ‘Summary of findings' tables and grading the confidence in or quality of the evidence. In: Higgins JPT, Churchill R, Chandler J, Cumpston MS (editors). Cochrane Handbook for Systematic Reviews of Interventions version 5.2.0 (updated June 2017). Cochrane, 2017. Available from training.cochrane.org/handbook/archive/v5.2.
Schünemann 2017b
    1. Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, et al (editors). Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Churchill R, Chandler J, Cumpston MS (editors). Cochrane Handbook for Systematic Reviews of Interventions version 5.2.0 (updated June 2017). Cochrane, 2017. Available from training.cochrane.org/handbook/archive/v5.2.
Shepherd 2016
    1. Shepherd J, Cooper K, Harris P, Picot J, Rose M. The clinical effectiveness and cost-effectiveness of abatacept, adalimumab, etanercept and tocilizumab for treating juvenile idiopathic arthritis: a systematic review and economic evaluation. Health Technology Assessment (Winchester, England) 2016;20(34):1-222. [CENTRAL: PMC4867422] [DOI: 10.3310/hta20340] [PMID: ] - DOI - PMC - PubMed
Simonini 2013
    1. Simonini G, Paudyal P, Jones GT, Cimaz R, Macfarlane GJ. Current evidence of methotrexate efficacy in childhood chronic uveitis: a systematic review and meta-analysis approach. Rheumatology 2013;52(5):825-31. - PubMed
Singh 1994
    1. Singh G, Athreya B, Fries JF, Goldsmith DP. Measurement of health status in children with juvenile rheumatoid arthritis. Arthritis and Rheumatism 1994;37(12):1761-9. [DOI: 10.1002/art.1780371209] [PMID: ] - DOI - PubMed
Sterne 2017
    1. Sterne JAC, Egger M, Moher D, Boutron I (editors). Chapter 10: Addressing reporting biases. In: Higgins JPT, Churchill R, Chandler J, Cumpston MS (editors). Cochrane Handbook for Systematic Reviews of Interventions version 5.2.0 (updated June 2017). Cochrane, 2017. Available from training.cochrane.org/handbook/archive/v5.2.
Thierry 2014
    1. Thierry S, Fautrel B, Lemelle I, Guillemin F. Prevalence and incidence of juvenile idiopathic arthritis: a systematic review. Joint, Bone, Spine 2014;81(2):112-7. - PubMed
Ungar 2013
    1. Ungar WJ, Costa V, Burnett HF, Feldman BM, Laxer RM. The use of biologic response modifiers in polyarticular-course juvenile idiopathic arthritis: a systematic review. Seminars in Arthritis and Rheumatism 2013;42(6):597-618. [DOI: 10.1016/j.semarthrit.2012.10.006] [PMID: ] - DOI - PubMed
van Rossum 1998
    1. Rossum MA, Fiselier TJ, Franssen MJ, Zwinderman AH, Ten Cate R, Suijlekom-Smit LW, et al. Sulfasalazine in the treatment of juvenile chronic arthritis: a randomized, double-blind, placebo-controlled, multicenter study. Dutch Juvenile Chronic Arthritis Study Group. Arthritis and Rheumatism 1998;41(5):808-16. - PubMed
Wallace 2004
    1. Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. Journal of Rheumatology 2004;31(11):2290-4. - PubMed
Wallace 2011
    1. Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care & Research 2011;63:929-36. - PubMed
Wallace 2017
    1. Wallace BC, Noel-Storr A, Marshall IJ, Cohen AM, Smalheiser NR, Thomas J. Identifying reports of randomized controlled trials (RCTs) via a hybrid machine learning and crowdsourcing approach. Journal of the American Medical Informatics Association 2017;24(6):1165-8. - PMC - PubMed
Woo 2000
    1. Woo P, Southwood TR, Prieur AM, Dore CJ, Grainger J, David J, et al. Randomized, placebo-controlled, crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis. Arthritis and Rheumatism 2000;43(8):1849-57. - PubMed
Wright 1994
    1. Wright FV, Law M, Crombie V, Goldsmith CH, Dent P. Development of a self-report functional status index for juvenile rheumatoid arthritis. Journal of Rheumatology 1994;21(3):536-44. - PubMed
Żuber 2015
    1. Zuber Z, Turowska-Heydel D, Sobczyk M, Chudek J. Prevalence of HLA-B27 antigen in patients with juvenile idiopathic arthritis. Reumatologia 2015;53(3):125-30. [DOI: 10.5114/reum.2015.53133] - DOI - PMC - PubMed

MeSH terms

LinkOut - more resources