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
. 2024 Feb 9;2(2):CD003129.
doi: 10.1002/14651858.CD003129.pub2.

Methotrexate for juvenile idiopathic arthritis

Joachim Tan  1   2 , William D Renton  2   3   4 , Samuel L Whittle  2   5 , Tim Takken  6 , Renea V Johnston  2 , Georgina Tiller  2   3   4 , Jane Munro  2   3 , Rachelle Buchbinder  2
Affiliations

Methotrexate for juvenile idiopathic arthritis

Joachim Tan et al. Cochrane Database Syst Rev. .

Abstract

Background: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. Methotrexate has broad immunomodulatory properties and is the most commonly used disease-modifying antirheumatic drug (DMARD). This is an update of a 2001 Cochrane review. It supports a living guideline for children and young people with JIA.

Objectives: To assess the benefits and harms of methotrexate for children and young people with juvenile idiopathic arthritis.

Search methods: The Australian JIA Living Guideline Working Group created a registry of all randomised controlled trials (RCTs) of JIA by searching CENTRAL, MEDLINE, Embase, and trials registries. The date of the most recent search of online databases was 1 February 2023.

Selection criteria: We searched for RCTs that compared methotrexate with placebo, no treatment, or another DMARD (with or without concomitant therapies) in children and young people (aged up to 18 years) with JIA.

Data collection and analysis: We used standard Cochrane methods. The main comparison was methotrexate versus placebo. Our outcomes were treatment response, sustained clinically inactive disease, function, pain, participant global assessment of well-being, serious adverse events, and withdrawals due to adverse events. We used GRADE to assess the certainty of evidence for each outcome.

Main results: We identified three new trials in this update, bringing the total number of included RCTs to five (575 participants). Three trials evaluated oral methotrexate versus placebo, one evaluated methotrexate plus intra-articular glucocorticoid (IAGC) therapy versus IAGC therapy alone, and one evaluated methotrexate versus leflunomide. Doses of methotrexate ranged from 5 mg/m2/week to 15 mg/m2/week in four trials, and participants in the methotrexate group of the remaining trial received 0.5 mg/kg/week. Trial size varied from 31 to 226 participants. The average age of participants ranged from four to 10 years. Most participants were females and most had nonsystemic JIA. The study that evaluated methotrexate plus IAGC therapy versus IAGC therapy alone recruited children and young people with the oligoarticular disease subtype of JIA. Two placebo-controlled trials and the trial of methotrexate versus leflunomide were adequately randomised and blinded, and likely not susceptible to important biases. One placebo-controlled trial may have been susceptible to selection bias due to lack of adequate reporting of randomisation methods. The trial investigating the addition of methotrexate to IAGC therapy was susceptible to performance and detection biases. Methotrexate versus placebo Methotrexate compared with placebo may increase the number of children and young people who achieve treatment response up to six months (absolute difference of 163 more per 1000 people; risk ratio (RR) 1.67, 95% confidence interval (CI) 1.21 to 2.31; I2 = 0%; 3 trials, 328 participants; low-certainty evidence). However, methotrexate compared with placebo may have little or no effect on pain as measured on an increasing scale of 0 to 100 (mean difference (MD) -1.10 points, 95% CI -9.09 to 6.88; 1 trial, 114 participants), improvement in participant global assessment of well-being (absolute difference of 92 more per 1000 people; RR 1.23, 95% CI 0.88 to 1.72; 1 trial, 176 participants), occurrence of serious adverse events (absolute difference of 5 fewer per 1000 people; RR 0.63, 95% CI 0.04 to 8.97; 3 trials, 328 participants), and withdrawals due to adverse events (RR 3.46, 95% CI 0.60 to 19.79; 3 trials, 328 participants) up to six months. We could not estimate the absolute difference for withdrawals due to adverse events because there were no withdrawals in the placebo group. All outcomes were reported within six months of randomisation. We downgraded the certainty of the evidence to low for all outcomes due to indirectness (suboptimal dosing of methotrexate and diverse outcome measures) and imprecision (few participants and low event rates). No trials reported function or the number of participants with sustained clinically inactive disease. Serious adverse events included liver derangement, abdominal pain, and inadvertent overdose. Methotrexate plus intra-articular corticosteroid therapy versus intra-articular corticosteroid therapy alone Methotrexate plus IAGC therapy compared with IAGC therapy alone may have little or no effect on the probability of sustained clinically inactive disease or the rate of withdrawals due to adverse events up to 12 months in children and young people with the oligoarticular subtype of JIA (low-certainty evidence). We could not calculate the absolute difference in withdrawals due to adverse events because there were no withdrawals in the control group. We are uncertain if there is any difference between the interventions in the risk of severe adverse events, because none were reported. The study did not report treatment response, function, pain, or participant global assessment of well-being. Methotrexate versus an alternative disease-modifying antirheumatic drug Methotrexate compared with leflunomide may have little or no effect on the probability of treatment response or on function, participant global assessment of well-being, risk of serious adverse events, and rate of withdrawals due to adverse events up to four months. We downgraded the certainty of the evidence for all outcomes to low due to imprecision. The study did not report pain or sustained clinically inactive disease.

Authors' conclusions: Oral methotrexate (5 mg/m2/week to 15 mg/m2/week) compared with placebo may increase the number of children and young people achieving treatment response but may have little or no effect on pain or participant global assessment of well-being. Oral methotrexate plus IAGC injections compared to IAGC injections alone may have little or no effect on the likelihood of sustained clinically inactive disease among children and young people with oligoarticular JIA. Similarly, methotrexate compared with leflunomide may have little or no effect on treatment response, function, and participant global assessment of well-being. Serious adverse events due to methotrexate appear to be rare. We will update this review as new evidence becomes available to inform the living guideline.

Trial registration: ClinicalTrials.gov NCT03728478.

PubMed Disclaimer

Conflict of interest statement

JT works as a Paediatric Rheumatologist; the intervention in question is widely used in his routine clinical practice. He declares personal payments from Pfizer Australia*: consultancy fees for participating in a Steering Committee for a rheumatology education meeting (EXcite) from 8 to 10 of September 2023, as well as travel and accommodation expenses for attending the meeting.

WR works as a Paediatric Rheumatologist at The Royal Children's Hospital in Melbourne and The Monash Children's Hospital in Melbourne. WR declares that he is a principal investigator for the ADJUST trial (NCT03816397), which is an ongoing study that is funded by the National Institute of Health (NIH); the investigational medicinal product is supplied by AbbVie. This is an unpaid position; however, WR has received support for travel and accommodation to attend an investigator meeting in San Francisco in 2019; paid to institution. WR also declares that he has published opinions on the topic (DOI 10.1186/s12969-019-0366-x; DOI 10.1093/rheumatology/kez441; and DOI 10.1136/archdischild-2018-315819).

SW is a Senior Consultant Rheumatologist at The Queen Elizabeth Hospital and the Vice President of the Australian Rheumatology Association, which has declared an opinion or position on the topic. SW is also a Cochrane Musculoskeletal Editor. He was not involved in the editorial process for this review. He is supported, in part, by an Australia and New Zealand Musculoskeletal (ANZMUSC) Clinical Trial Network Practitioner Fellowship.

TT declares that he has no conflicts of interest.

RJ is the Managing Editor for Cochrane Musculoskeletal. RJ was involved in selecting peer reviewers but was not otherwise involved in the editorial process for this review.

GT declares income from private practice.

JM declares income from private practice: she is the business owner of a private practice, the Victorian Children's Clinic, since 2012. JM also declares personal payments from AbbVie, for a one‐hour education panel on clinician well‐being in 2020 (one‐off fee), and from Pfizer Australia*, for giving a talk at the Excite meeting in September 2023.

Rachelle Buchbinder works as a Rheumatologist (adult) and is the Co‐ordinating Editor for Cochrane Musculoskeletal. She was not involved in the editorial process for this review. She is supported by an Australian National Health and Medical Research Council Investigator Fellowship.

*Review authors acquired these conflicts of interest after completion and submission of the review to the Central Editorial Service. Given the time points involved, the Research Integrity Team decided that these interests were not in breach of the Cochrane Conflict of Interest policy.

Figures

1
1
PRISMA study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Methotrexate versus placebo, Outcome 1: Treatment response
1.2
1.2. Analysis
Comparison 1: Methotrexate versus placebo, Outcome 2: Sustained clinically inactive disease (Wallace criteria or as defined by study authors)
1.3
1.3. Analysis
Comparison 1: Methotrexate versus placebo, Outcome 3: Function (Childhood Health Assessment Questionnaire or equivalent)
1.4
1.4. Analysis
Comparison 1: Methotrexate versus placebo, Outcome 4: Pain (visual analogue scale)
1.5
1.5. Analysis
Comparison 1: Methotrexate versus placebo, Outcome 5: Participant global assessment of well‐being
1.6
1.6. Analysis
Comparison 1: Methotrexate versus placebo, Outcome 6: Serious adverse events
1.7
1.7. Analysis
Comparison 1: Methotrexate versus placebo, Outcome 7: Withdrawals due to adverse events
2.1
2.1. Analysis
Comparison 2: Methotrexate (MTX) plus intra‐articular glucocorticoid (IAGC) versus IAGC alone, Outcome 1: Treatment response (American College of Rheumatology criteria or as defined by study authors)
2.2
2.2. Analysis
Comparison 2: Methotrexate (MTX) plus intra‐articular glucocorticoid (IAGC) versus IAGC alone, Outcome 2: Sustained clinically inactive disease (Wallace criteria or as defined by study authors)
2.3
2.3. Analysis
Comparison 2: Methotrexate (MTX) plus intra‐articular glucocorticoid (IAGC) versus IAGC alone, Outcome 3: Function (Childhood Health Assessment Questionnaire or equivalent)
2.4
2.4. Analysis
Comparison 2: Methotrexate (MTX) plus intra‐articular glucocorticoid (IAGC) versus IAGC alone, Outcome 4: Pain (visual analogue scale or equivalent)
2.5
2.5. Analysis
Comparison 2: Methotrexate (MTX) plus intra‐articular glucocorticoid (IAGC) versus IAGC alone, Outcome 5: Participant global assessment of well‐being
2.6
2.6. Analysis
Comparison 2: Methotrexate (MTX) plus intra‐articular glucocorticoid (IAGC) versus IAGC alone, Outcome 6: Serious adverse events
2.7
2.7. Analysis
Comparison 2: Methotrexate (MTX) plus intra‐articular glucocorticoid (IAGC) versus IAGC alone, Outcome 7: Withdrawals due to adverse events
3.1
3.1. Analysis
Comparison 3: Methotrexate versus alternative disease‐modifying antirheumatic drug (DMARD), Outcome 1: Treatment response (American College of Rheumatology criteria or as defined by study authors)
3.2
3.2. Analysis
Comparison 3: Methotrexate versus alternative disease‐modifying antirheumatic drug (DMARD), Outcome 2: Sustained clinically inactive disease (Wallace criteria or as defined by study authors)
3.3
3.3. Analysis
Comparison 3: Methotrexate versus alternative disease‐modifying antirheumatic drug (DMARD), Outcome 3: Function (Childhood Health Assessment Questionnaire or equivalent)
3.4
3.4. Analysis
Comparison 3: Methotrexate versus alternative disease‐modifying antirheumatic drug (DMARD), Outcome 4: Pain (visual analogue scale or equivalent)
3.5
3.5. Analysis
Comparison 3: Methotrexate versus alternative disease‐modifying antirheumatic drug (DMARD), Outcome 5: Participant global assessment of well‐being
3.6
3.6. Analysis
Comparison 3: Methotrexate versus alternative disease‐modifying antirheumatic drug (DMARD), Outcome 6: Serious adverse events
3.7
3.7. Analysis
Comparison 3: Methotrexate versus alternative disease‐modifying antirheumatic drug (DMARD), Outcome 7: Withdrawals due to adverse events
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Bharadwaj 2003 {published data only}
    1. Bharadwaj A, Aggarwal A, Misra R. Methotrexate in juvenile rheumatoid arthritis: randomized, placebo controlled trial. Journal of Indian Rheumatology Association 2003;11:30-4. [ISSN: 0971-5045]
Giannini 1992 {published data only}
    1. Giannini EH, Brewer EJ, Kuzmina N, Shaikov A, Maximov A, Vorontsov I, et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the USA-USSR double-blind, placebo-controlled trial. New England Journal of Medicine 1992;326(16):1043-9. [DOI: 10.1056/NEJM199204163261602] [PMID: ] - DOI - PubMed
Ravelli 2017 {published data only}
    1. Ravelli A, Davì S, Bracciolini G, Pistorio A, Consolaro A, Dijkhuizen EH, et al. Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial. Lancet 2017;389(10072):909-16. [DOI: 10.1016/S0140-6736(17)30065-X] [PMID: ] - DOI - PubMed
Silverman 2005 {published data only}
    1. Silverman E, Mouy R, Spiegel L, Jung LK, Saurenmann RK, Lahdenne P, et al. Leflunomide or methotrexate for juvenile rheumatoid arthritis. New England Journal of Medicine 2005;352(16):1655-66. [DOI: 10.1056/NEJMoa041810] [PMID: ] - DOI - PubMed
Woo 2000 {published data only}
    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 Rheumatology 2000;43(8):1849-57. [DOI: 10.1002/1529-0131(200008)43:8<1849::AID-ANR22>3.0.CO;2-F] [PMID: ] - DOI - PubMed

References to studies excluded from this review

Dupuis 1995 {published data only}
    1. Dupuis LL, Koren G, Silverman ED, Laxer RM. Influence of food on the bioavailability of oral methotrexate in children. Journal of Rheumatology 1995;22(8):1570-3. [PMID: ] - PubMed
EUDRACT 2018‐001571‐21 {published data only}
    1. EUDRACT 2018-001571-21. Training immune functions through pharmacotherapeutic conditioning in juvenile idiopathic arthritis. www.clinicaltrialsregister.eu/ctr-search/search?query=2018-001571-21 (first received 23 May 2018).
Foell 2010 {published data only}
    1. Foell D, Wulffraat N, Wedderburn LR, Wittkowski H, Frosch M, Gerss J, et al. Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial. Journal of the American Medical Association 2010;303(13):1266-73. [DOI: 10.1001/jama.2010.375. Erratum in: JAMA. 2010 May 26;303(20):2034] [PMID: ] - PubMed
Forster 2000 {published data only}
    1. Forster J. Arbeitsgemeinschaft für Kinder und Jugendrheumatologie (German/Swiss/Austrian working group on juvenile rheumatic diseases) presents a design of a prospective controlled trial in children with oligoarthritis type I [Prospektive Studie zur JCR-Oligo I der Arbeitsgemeinschaft Kinder- und Jugendrheumatologie [German]]. Zeitschrift für Rheumatologie 2000;59(2)(2):122-3. [DOI: 10.1007/s003930050216] - DOI - PubMed
Gao 2003 {published data only}
    1. Gao JS, Wu H, Tian J. Treatment of patients with juvenile rheumatoid arthritis with combination of leflunomide and methotrexate. Chinese Journal of Pediatrics 2003;41(6):435-8. [PMID: ] - PubMed
Hissink 2019 {published data only}
    1. Hissink Muller P, Brinkman DM, Schonenberg-Meinema D, den Bosch WB, Koopman-Keemink Y, Brederije IC, et al. Treat to target (drug-free) inactive disease in DMARD-naive juvenile idiopathic arthritis: 24-month clinical outcomes of a three-armed randomised trial. Annals of Rheumatic Diseases 2019;78(1):51-9. [DOI: 10.1136/annrheumdis-2018-213902. Epub 2018 Oct 11] [PMID: ] - PubMed
Kvien 1985 {published data only}
    1. Kvien TK, Høyeraal HM, Sandstad B. Slow acting antirheumatic drugs in patients with juvenile rheumatoid arthritis--evaluated in a randomized, parallel 50-week clinical trial. Journal of Rheumatology 1985;12(3):533-9. [PMID: ] - PubMed
NCT04614311 {published data only}
    1. NCT04614311. Strategies towards personalised treatment in Juvenile Idiopathic Arthritis (JIA). (MyJIA). clinicaltrials.gov/ct2/show/NCT04614311 (first received 3 November 2020).
NL5742 {published data only}
    1. Children with arthritis: monotherapy or polytherapy?; June 2016 (updated August 2022). www.onderzoekmetmensen.nl/en/trial/29408.
Rezaieyazdi 2023 {published data only}
    1. Rezaieyazdi Z, Ravanshad S, Khodashahi M, Bokaeian M, Mehrad Majd H, Salari M. Comparison of the efficacy and safety of methotrexate alone or in combination with leflunomide in the treatment of juvenile idiopathic arthritis: a double-blind, placebo-controlled, randomized trial. Reumatologia 2023;61(1):4-12. [CENTRAL: PMC10044028] [DOI: 10.5114/reum/161317. Epub 2023 Mar 8] [PMID: ] - 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. In: Arthritis & Rheumatology. Vol. 69. 2017. [ABSTRACT NUMBER: 1158] [URL: acrabstracts.org/abstract/treatment-of-non-infectious-uveitis-a-comparat...
Ruperto 2004 {published data only}
    1. Ruperto N, Murray KJ, Gerloni V, Wulffraat N, Oliveira SK, Falcini F, et al. 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 & Rheumatism 2004;50(7):2191-201. [DOI: 10.1002/art.20288] [PMID: ] - DOI - PubMed
Tynjälä 2011 {published data only}
    1. Tynjälä P, Vähäsalo P, Tarkiainen M, Kröger L, Aalto K, Malin M, et al. Aggressive combination drug therapy in very early polyarticular juvenile idiopathic arthritis (ACUTE-JIA): a multicentre randomised open-label clinical trial. Annals of Rheumatic Diseases 2011;70(9):1605-12. [DOI: 10.1136/ard.2010.143347. Epub 2011 May 28] [PMID: ] - PubMed
Verkaaik 2011 {published data only}
    1. Verkaaik M, Bulatović M, Sinnema G, Rademaker C, Wulffraat NM. Treatment of methotrexate (MTX) intolerance: behavioural therapy, versus switch to parenteral MTX versus oral MTX. Pediatric Rheumatology 2011;9(Suppl 1):O23. [CENTRAL: PMC3194418] [DOI: 10.1186/1546-0096-9-S1-O23] - DOI
Wallace 2012 {published data only}
    1. Wallace CA, Giannini EH, Spalding SJ, Hashkes PJ, O'Neil KM, Zeft AS, et al. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis & Rheumatism 2012;64(6):2012-21. [DOI: 10.1002/art.34343. Epub 2011 Dec 19.] [PMID: ] - PMC - PubMed

References to studies awaiting assessment

Burrone 2022 {published data only}
    1. Burrone M, Mazzoni M, Naddei R, Pistorio A, Spelta M, Scala S, et al. 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 2022;20(1):80. [CENTRAL: PMC9450438] [DOI: 10.1186/s12969-022-00739-x] [PMID: ] - DOI - PMC - PubMed

Additional references

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 and Research 2011;63(4):465-82. [DOI: 10.1002/acr.20460] [PMID: ] - DOI - PMC - PubMed
Braun 2009
    1. Braun J, Rau R. An update on methotrexate. Current Opinion in Rheumatology 2009;21(3):216-23. [DOI: 10.1097/BOR.0b013e328329c79d] [PMID: ] - DOI - 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 & Rheumatology 1977;20(Suppl 2):195-9. [PMID: ] - PubMed
Brooker 2019
    1. Guidance for the production and publication of Cochrane living systematic reviews: Cochrane Reviews in living mode; December 2019. Available at community.cochrane.org/sites/default/files/uploads/inline-files/Transfor... (accessed 17 December 2020).
Bulatović 2011
    1. Bulatović M, Heijstek MW, Verkaaik M, Dijkhuizen EH, Armbrust W, Hoppenreijs EP, et al. High prevalence of methotrexate intolerance in juvenile idiopathic arthritis: development and validation of a methotrexate intolerance severity score. Arthritis & Rheumatology 2011;63(7):2007-13. [DOI: 10.1002/art.30367] [PMID: ] - DOI - PubMed
Cassidy 1989
    1. Cassidy JT, Levinson JE, Brewer EJ. The development of classification criteria for children with juvenile rheumatoid arthritis. Bulletin on the Rheumatic Diseases 1989;38(6):1-7. - PubMed
Cochrane Crowd 2019
    1. Cochrane Crowd. crowd.cochrane.org (accessed 1 December 2019).
Consolaro 2014
    1. Consolaro A, Negro G, Chiara Gallo M, 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 2014;66(11):1703-9. [DOI: 10.1002/acr.22393] [PMID: ] - DOI - PubMed
Consolaro 2016
    1. Consolaro A, Giancane G, Schiappapietra B, Davi S, Calandra S, Lanni S, et al. Clinical outcome measures in juvenile idiopathic arthritis. Pediatric Rheumatology 2016;14(1):23. [DOI: 10.1186/s12969-016-0085-5] - DOI - PMC - PubMed
Covidence [Computer program]
    1. Covidence. Version accessed 1 February 2023. Melbourne, Australia: Veritas Health Innovation. Available at www.covidence.org.
Cronstein 2020
    1. Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nature Reviews Rheumatology 2020;16(3):145-54. - PubMed
CRS Web
    1. Cochrane. Cochrane Register of Studies (CRS). community.cochrane.org/help/tools-and-software/crs-cochrane-register-stu... (accessed 30 January 2019).
Deeks 2021
    1. Deeks JJ, Higgins JP, Altman DG, editor(s). Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook/archive/v6.2.
Endnote Version 20.4 [Computer program]
    1. Endnote. Version 20.4. Clarivate, 2020.
Fantini 1977
    1. Fantini F. Rheumatoid arthritis in children and related forms. Updating of nomenclature, nosography, clinical manifestations and therapy, with reference to the EULAR/WHO workshop on the care of rheumatic children, Oslo, March 1977. Reumatismo 1977;29(1):7-32. [PMID: ] - PubMed
Ferrara 2018
    1. Ferrara G, Mastrangelo G, Barone P, La Torre F, Martino S, Pappagallo G, et al. Methotrexate in juvenile idiopathic arthritis: advice and recommendations from the MARAJIA expert consensus meeting. Pediatric Rheumatology 2018;16(1):46. [DOI: 10.1186/s12969-018-0255-8] [PMID: ] - DOI - PMC - PubMed
Filocamo 2010
    1. Filocamo G, Davì S, Pistorio A, Bertamino M, Ruperto N, Lattanzi B, et al. Evaluation of 21-numbered circle and 10-centimeter horizontal line visual analog scales for physician and parent subjective ratings in juvenile idiopathic arthritis. Journal of Rheumatology 2010;37(7):1534-41. [EMBASE: 10.3899/jrheum.091474 Epub 2010 Jun 15] [PMID: ] - PubMed
Friedman 2019
    1. Friedman B, Cronstein B. Methotrexate mechanism in treatment of rheumatoid arthritis. Joint Bone Spine 2019;86(3):301-7. [CENTRAL: PMC6360124] [DOI: 10.1016/j.jbspin.2018.07.004. Epub 2018 Aug 3] [PMID: ] - PMC - PubMed
Giannini 1997
    1. Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis & Rheumatology 1997;40(7):1202-9. [DOI: 10.1002/1529-0131(199707)40:7<1202::AID-ART3>3.0.CO;2-R] [PMID: ] - DOI - PubMed
Graham 1992
    1. Graham LD, Myones BL, Rivas-Chacon RF, Pachman LM. Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis. Journal of Pediatrics 1992;120(3):468-73. [DOI: 10.1016/s0022-3476(05)80923-0] [PMID: ] - DOI - PubMed
Hazlewood 2016
    1. Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe DJ, Bombardier C. Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying anti‐rheumatic drugs for rheumatoid arthritis: A network meta‐analysis. Cochrane Database of Systematic Reviews 2016, Issue 8. Art. No: CD010227. [ART. NO.: ] [DOI: 10.1002/14651858.CD010227.pub2] - DOI - PMC - PubMed
Hazlewood 2020
    1. Hazlewood GS, Whittle SL, Kamso MM, Akl EA, Wells GA, Tugwell P, et al. Disease‐modifying anti‐rheumatic drugs for rheumatoid arthritis: a systematic review and network meta‐analysis. Cochrane Database of Systematic Reviews 2020, Issue 3. Art. No: CD013562. [DOI: 10.1002/14651858.CD013562] - DOI
Higgins 2021
    1. Higgins JP, Li T, Deeks JJ, editor(s). Chapter 6: Choosing effect measures and computing estimates of effect. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook/archive/v6.2.
Hinze 2015
    1. Hinze C, Gohar F, Foell D. Management of juvenile idiopathic arthritis: hitting the target. Nature Reviews Rheumatology 2015;11(5):290-300. [DOI: 10.1038/nrrheum.2014.212. Epub 2015 Jan 6] [PMID: ] - PubMed
JIA Living Guidelines
    1. Renton W. An Australian Living Guideline for the Management of Juvenile Idiopathic Arthritis. files.magicapp.org/guideline/1d74e8af-0ac3-42c5-a9fb-94fc67294150/publis... (accessed 15 May 2023).
Joos 1991
    1. Joos E, Peretz A, Beguin S, Famaey JP. Reliability and reproducibility of visual analogue scale and numeric rating scale for therapeutic evaluation of pain in rheumatic patients. Journal of Rheumatology 1991;18(8):1269-70. [PMID: ] - PubMed
Jundt 1993
    1. Jundt JW, Browne BA, Fiocco GP, Steele AD, Mock D. A comparison of low dose methotrexate bioavailability: oral solution, oral tablet, subcutaneous and intramuscular dosing. Journal of Rheumatology 1993;20(11):1845-9. [PMID: ] - PubMed
Klein 2012
    1. Klein A, Kaul I, Foeldvari I, Ganser G, Urban A, Horneff G. Efficacy and safety of oral and parenteral methotrexate therapy in children with juvenile idiopathic arthritis: an observational study with patients from the German Methotrexate Registry. Arthritis Care & Research 2012;64(9):1349-56. [DOI: 10.1002/acr.21697] [PMID: ] - DOI - PubMed
Korell 2014
    1. Korell J, Duffull SB, Dalrymple JM, Drake J, Zhang M, Barclay ML, et al. Comparison of intracellular methotrexate kinetics in red blood cells with the kinetics in other cell types. British Journal of Clinical Pharmacology 2014;77(3):493-7. [CENTRAL: PMC3952723] [DOI: 10.1111/bcp.12209] [PMID: ] - DOI - PMC - PubMed
Lopez‐Olivo 2014
    1. Lopez‐Olivo MA, Siddhanamatha HR, Shea B, Tugwell P, Wells GA, Suarez‐Almazor ME. Methotrexate for treating rheumatoid arthritis. Cochrane Database of Systematic Reviews 2014, Issue 6. Art. No: CD000957. [DOI: 10.1002/14651858.CD000957.pub2] - DOI - PMC - 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. [DOI: 10.1056/NEJM200003163421103] [PMID: ] - DOI - PubMed
MagicApp [Computer program]
    1. MagicApp. Version accessed 01 December 2023. MagicApp. app.magicapp.org/.
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. [PMID: 10.3899/jrheum.181088] [PMID: ] - DOI - PubMed
Page 2021
    1. Page MJ, Higgins JP, Sterne JA. Chapter 13: Assessing risk of bias due to missing results in a synthesis. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook/archive/v6.2.
Patil 2014
    1. Patil P, Parker RA, Rawcliffe C, Olaleye A, Moore S, Daly N, et al. Methotrexate-induced nausea and vomiting in adolescent and young adult patients. Clinical Rheumatology 2014;33(3):403-7. [CENTRAL: PMC3937539] [DOI: 10.1007/s10067-013-2389-x] [PMID: ] - DOI - PMC - PubMed
Petty 1998
    1. Petty RE, Southwood TR, Baum J, Bhettay E, Glass DN, Manners P, et al. Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. Journal of Rheumatology 1998;25(10):1991-4. [PMID: ] - PubMed
Petty 2004
    1. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology Classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. Journal of Rheumatology 2004;31(2):390-2. [PMID: ] - PubMed
PRISMA Statement 2020
    1. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. [CENTRAL: PMC8005924] [DOI: 10.1136/bmj.n71] [PMID: ] - DOI - PMC - PubMed
Ravelli 2018
    1. Ravelli A, Consolaro A, Horneff G, Laxer RM, Lovell DJ, Wulffraat NM, et al. Treating juvenile idiopathic arthritis to target: recommendations of an international task force. Annals of Rheumatic Diseases 2018;77(6):819-28. [DOI: 10.1136/annrheumdis-2018-213030] [PMID: ] - DOI - PubMed
Review Manager 2020 [Computer program]
    1. Review Manager 5 (RevMan 5). Version 5.4.1. Copenhagen: The Cochrane Collaboration, 2020.
Rose 1990
    1. Rose CD, Singsen BH, Eichenfield AH, Goldsmith DP, Athreya BH. Safety and efficacy of methotrexate therapy for juvenile rheumatoid arthritis. Journal of Pediatrics 1990;117(4):653-9. [DOI: 10.1016/s0022-3476(05)80709-7] [PMID: ] - DOI - PubMed
Ruperto 2001
    1. Ruperto N, Ravelli A, Pistorio A, Malattia C, Cavuto S, Gado-West L, et al. Cross-cultural adaptation and psychometric evaluation of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ) in 32 countries. Review of the general methodology. Clinical and Experimental Rheumatology 2001;19(4 Suppl 23):S1-9. [PMID: ] - PubMed
Ruperto 2004
    1. Ruperto N, Murray KJ, Gerloni V, Wulffraat N, Oliveira SK, Falcini F, et al. 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 & Rheumatology 2004;50(7):2191-201. [DOI: 10.1002/art.20288] [PMID: ] - DOI - PubMed
Saurenmann 2007
    1. Saurenmann RK, Rose JB, Tyrrell P, Feldman BM, Laxer RM, Schneider R, et al. Epidemiology of juvenile idiopathic arthritis in a multiethnic cohort: ethnicity as a risk factor. Arthritis & Rheumatology 2007;56(6):1974-84. [DOI: 10.1002/art.22709] [PMID: ] - DOI - PubMed
Schünemann 2021a
    1. Schünemann HJ, Higgins JP, Vist GE, Glasziou P, Akl EA, Skoetz N, et al. Chapter 14: Completing 'Summary of findings' tables and grading the certainty of the evidence. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editor(s). Cochrane Handbook for Systematic Reviews of InterventionsVersion 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook/archive/v6.2.
Schünemann 2021b
    1. Schünemann HJ, Vist GE, Higgins JP, Santesso N, Deeks JJ, Glasziou P, et al. Chapter 15: Interpreting results and drawing conclusions. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook/archive/v6.2.
Smith 2017
    1. Smith C. Efficacy and Safety of Pharmacological and Non-Pharmacological Interventions in Juvenile Idiopathic Arthritis: A Series of Systematic Reviews and Network Meta-Analyses [Masters thesis]. Ottawa (CA): University of Ottawa, 2017. [DOI: 10.20381/ruor-701] - DOI
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. [DOI: 10.1016/j.jbspin.2013.09.003. Epub 2013 Nov 6] [PMID: ] - PubMed
Tian 2007
    1. Tian H, Cronstein BN. Understanding the mechanisms of action of methotrexate: implications for the treatment of rheumatoid arthritis. Bulletin of the NYU Hospital for Joint Diseases 2007;65(3):168-73. [PMID: ] - PubMed
Tiller 2018
    1. Tiller G, Buckle J, Allen R, Munro J, Gowdie P, Cox A, et al. Juvenile idiopathic arthritis managed in the new millennium: one year outcomes of an inception cohort of Australian children. Pediatrioc Rheumatology 2018;16(1):69. [CENTRAL: PMC6230231] [DOI: 10.1186/s12969-018-0288-z] [PMID: ] - DOI - PMC - PubMed
van Dijkhuizen 2015
    1. Dijkhuizen EH, Bulatović Ćalasan M, Pluijm SM, Rotte MC, Vastert SJ, Kamphuis S, et al. Prediction of methotrexate intolerance in juvenile idiopathic arthritis: a prospective, observational cohort study. Pediatric Rheumatology 2015;13:5. [CENTRAL: PMC4349799] [DOI: 10.1186/s12969-015-0002-3] [PMID: ] - DOI - PMC - PubMed
Wallace 2004
    1. Wallace CA, Ruperto N, Giannini E, Childhood Arthritis and Rheumatology Research Alliance, Pediatric Rheumatology International Trials Organization, Pediatric Rheumatology Collaborative Study Group. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. Journal of Rheumatology 2004;31(11):2290-4. [PMID: ] - PubMed
Wallace 2011
    1. Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N, Childhood Arthritis Rheumatology Research Alliance, et al. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care & Research 2011;63(7):929-36. [PMID: ] - PubMed
Wallace 2012
    1. Wallace CA, Giannini EH, Spalding SJ, Hashkes PJ, O’Neil KM, Zeft AS, et al. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis Rheumatism 2012;64(6):2012-21. [DOI: 10.1002/art.34343] [PMCID: PMC3319524] [PMID: ] - DOI - PMC - 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. [CENTRAL: PMC5975623] [DOI: 10.1093/jamia/ocx053] [PMID: ] - DOI - PMC - PubMed
Wilsdon 2019
    1. Wilsdon TD, Whittle SL, Thynne TRJ, Mangoni AA. Methotrexate for psoriatic arthritis. Cochrane Database of Systematic Reviews 2019, Issue 1. Art. No: CD012722. [DOI: 10.1002/14651858.CD012722.pub2] - DOI - PMC - PubMed
Zulian 2004
    1. Zulian F, Martini G, Gobber D, Plebani M, Zacchello F, Manners P. Triamcinolone acetonide and hexacetonide intra-articular treatment of symmetrical joints in juvenile idiopathic arthritis: a double-blind trial. Rheumatology 2004;43(10):1288-91. [DOI: 10.1093/rheumatology/keh313. Epub 2004 Jul 13] [PMID: ] - PubMed

References to other published versions of this review

Takken 2001
    1. Takken T, Net JJ, Helders PP. Methotrexate for treating juvenile idiopathic arthritis. Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No: CD003129. [DOI: 10.1002/14651858.CD003129] - DOI - PubMed

Publication types

Associated data