array(43) {
  ["project_title"]=>
  string(119) "Dose reduction and discontinuation of disease modifying anti-rheumatic drugs (DMARDs) for juvenile idiopathic arthritis"
  ["project_narrative_summary"]=>
  string(702) "Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood, affecting 1 in every 1000 children. It is a chronic condition mediated by the body's own immune system attacking joints of a young person, causing pain, stiffness, joint swelling, loss of function and loss of mobility.
There are many contemporary pharmacological treatments for JIA include glucocorticoids. The specific hypothesis being evaluated is whether withdrawal or dose reduction of Disease Modifying Anti-Rheumatic drugs in kids with JIA with clinically inactive disease after a period of time on treatment is a measure that can still lead to maintenance of disease inactivity and clinical remission." ["project_learn_source"]=> string(9) "colleague" ["project_learn_source_exp"]=> string(0) "" ["project_key_personnel"]=> array(9) { [0]=> array(6) { ["p_pers_f_name"]=> string(7) "Joachim" ["p_pers_l_name"]=> string(3) "Tan" ["p_pers_degree"]=> string(31) "MBBS MMed(Paed) BBiomedSc FRACP" ["p_pers_pr_affil"]=> string(17) "Monash University" ["p_pers_scop_id"]=> string(19) "0000-0003-1032-0457" ["requires_data_access"]=> string(0) "" } [1]=> array(6) { ["p_pers_f_name"]=> string(9) "Alexandra" ["p_pers_l_name"]=> string(7) "Gorelik" ["p_pers_degree"]=> string(76) "Bachelor of Arts (B.A.) Statistics Master of Science (MSc) Quality Assurance" ["p_pers_pr_affil"]=> string(17) "Monash University" ["p_pers_scop_id"]=> string(19) "0000-0002-5333-1781" ["requires_data_access"]=> string(0) "" } [2]=> array(6) { ["p_pers_f_name"]=> string(9) "Anneliese" ["p_pers_l_name"]=> string(4) "Arno" ["p_pers_degree"]=> string(236) "Bachelor's Degree in Biology (University of North Carolina) Bachelor's Degree in Economics (University of North Carolina) MSc (Global Health) - Trinity College, Dublin Doctor of Philosophy (Automation in Health Evidence Synthesis) - UCL" ["p_pers_pr_affil"]=> string(17) "Monash University" ["p_pers_scop_id"]=> string(19) "0000-0003-4845-9059" ["requires_data_access"]=> string(0) "" } [3]=> array(6) { ["p_pers_f_name"]=> string(8) "Georgina" ["p_pers_l_name"]=> string(6) "Tiller" ["p_pers_degree"]=> string(30) "MBBS (Monash University) FRACP" ["p_pers_pr_affil"]=> string(17) "Monash University" ["p_pers_scop_id"]=> string(19) "0000-0002-0597-0933" ["requires_data_access"]=> string(0) "" } [4]=> array(6) { ["p_pers_f_name"]=> string(4) "Jane" ["p_pers_l_name"]=> string(5) "Munro" ["p_pers_degree"]=> string(14) "MBBS FRACP MPH" ["p_pers_pr_affil"]=> string(17) "Monash University" ["p_pers_scop_id"]=> string(19) "0000-0001-7417-7691" ["requires_data_access"]=> string(0) "" } [5]=> array(6) { ["p_pers_f_name"]=> string(8) "Rachelle" ["p_pers_l_name"]=> string(10) "Buchbinder" ["p_pers_degree"]=> string(25) "MBBS (Hons) MSc FRACP PhD" ["p_pers_pr_affil"]=> string(17) "Monash University" ["p_pers_scop_id"]=> string(19) "0000-0002-9631-4455" ["requires_data_access"]=> string(0) "" } [6]=> array(6) { ["p_pers_f_name"]=> string(5) "Renea" ["p_pers_l_name"]=> string(8) "Johnston" ["p_pers_degree"]=> string(66) "BSc(Hons) - Monash University pHD (Physiology) - Monash University" ["p_pers_pr_affil"]=> string(17) "Monash University" ["p_pers_scop_id"]=> string(0) "" ["requires_data_access"]=> string(0) "" } [7]=> array(6) { ["p_pers_f_name"]=> string(6) "Samuel" ["p_pers_l_name"]=> string(7) "Whittle" ["p_pers_degree"]=> string(26) "MBBS (Hons) MClinEpi FRACP" ["p_pers_pr_affil"]=> string(17) "Monash University" ["p_pers_scop_id"]=> string(0) "" ["requires_data_access"]=> string(0) "" } [8]=> array(6) { ["p_pers_f_name"]=> string(7) "William" ["p_pers_l_name"]=> string(6) "Renton" ["p_pers_degree"]=> string(30) "MBBS (Monash University) FRACP" ["p_pers_pr_affil"]=> string(17) "Monash University" ["p_pers_scop_id"]=> string(0) "" ["requires_data_access"]=> string(0) "" } } ["project_ext_grants"]=> array(2) { ["value"]=> string(2) "no" ["label"]=> string(68) "No external grants or funds are being used to support this research." } ["project_funding_source"]=> string(206) "Grants funding this research is through Monash University (Monash-Cabrini Department of Musculoskeletal Health and Clinical Epidemiology). The researchers are also salaried through Cabrini Health Australia." ["project_assoc_trials"]=> array(1) { [0]=> object(WP_Post)#3704 (24) { ["ID"]=> int(1707) ["post_author"]=> string(4) "1363" ["post_date"]=> string(19) "2018-08-06 10:22:00" ["post_date_gmt"]=> string(19) "2018-08-06 10:22:00" ["post_content"]=> string(0) "" ["post_title"]=> string(205) "NCT01230827 - 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)" ["post_excerpt"]=> string(0) "" ["post_status"]=> string(7) "publish" ["comment_status"]=> string(4) "open" ["ping_status"]=> string(4) "open" ["post_password"]=> string(0) "" ["post_name"]=> string(192) "nct01230827-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" ["to_ping"]=> string(0) "" ["pinged"]=> string(0) "" ["post_modified"]=> string(19) "2024-03-25 17:21:28" ["post_modified_gmt"]=> string(19) "2024-03-25 21:21:28" ["post_content_filtered"]=> string(0) "" ["post_parent"]=> int(0) ["guid"]=> string(241) "https://dev-yoda.pantheonsite.io/clinical-trial/nct01230827-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/" ["menu_order"]=> int(0) ["post_type"]=> string(14) "clinical_trial" ["post_mime_type"]=> string(0) "" ["comment_count"]=> string(1) "0" ["filter"]=> string(3) "raw" } } ["project_date_type"]=> string(18) "full_crs_supp_docs" ["property_scientific_abstract"]=> string(1866) "Background:
Juvenile Idiopathic Arthritis (JIA) is the most common rheumatic disease in childhood. Patients with JIA may be able to achieve a state of clinically inactive disease with contemporary treatment measures. Many patients are able to sustain a state of remission after ceasing medication. For this reason, it is appropriate to consider medication dose reduction or discontinuation in some patients, but we do not yet know the best strategies for medication dose reduction or discontinuation.
Objective:
To assess the benefits and harms of DMARD dose reduction or discontinuation in children and young people with JIA and clinically inactive disease.
Study Design:
This systematic review will be a meta-analysis of randomised controlled trials (RCTs) studying the impact of drug withdrawal or discontinuation in patients with JIA.
Participants:
RCTs studying sample populations of children and young people with JIA and clinically inactive disease that are undergoing withdrawal of treatment will be included.
Main Outcome Measure(s):
Major and minor outcome measures will be studied to assess scores of disease inactivity. A composite summary of adverse events will also be reported.
Statistical Analysis:
We will present two main comparisons - dose reduction compared with continuation; and abrupt discontinuation (without prior dose reduction) compared with continuation to provide estimates of benefit and harm. We plan to synthesise effect estimates using a random-effects meta-analysis model based on the assumption that clinical diversity is likely to exist, and that different studies are estimating different intervention effects.
Where we cannot pool data, we plan to present effect estimates and 95% CIs of each trial in tables, and summarise the results in text." ["project_brief_bg"]=> string(3179) "Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. JIA is an umbrella term for a heterogeneous group of disorders that manifest as early onset arthritis. The International League Against Rheumatism (ILAR) classification criteria define JIA as arthritis that begins before a patient is aged 16 years, persists for more than 6 weeks and is of unknown origin. These criteria define the following mutually exclusive subtypes on the basis of clinical and laboratory features: systemic arthritis, oligoarthritis, polyarthritis (rheumatoid factor negative), polyarthritis (rheumatoid factor positive), psoriatic arthritis, enthesitis-related arthritis and undifferentiated arthritis (Petty 2004).
JIA typically manifests with arthritis, although extra-articular symptoms such as fever, constitutional symptoms and ocular inflammation can also occur. It affects approximately 1-4 per 1,000 children under the age of 16. Girls are more commonly affected than boys in an overall ratio of approximately 3:2 but the ratio varies significantly between JIA subtypes (Thierry 2014). It is a heterogeneous condition with varied long-term outcomes. Complications including permanent disability were common before effective treatments were introduced (Colver 1937). Fortunately, innovations over the last few decades have led to exponential growth in the number of therapeutic options and have drastically improved outcomes for the vast majority of patients who can access them (Hinze 2015).
The cause of JIA is not completely understood but is probably due to a combination of genetic and environmental factors. Systemic onset juvenile idiopathic arthritis (SoJIA) is well recognised as being genetically and pathophysiologically distinct from the other subtypes of JIA (also referred to as "non-systemic" JIA) (Ombrello 2017). Treatment strategies and long term outcomes also differ between SoJIA and non-systemic JIA. Macrophage activation syndrome is a serious and potentially fatal complication of JIA and is almost exclusively observed in patients with SoJIA.
Contemporary pharmacological treatments for JIA include glucocorticoids (systemic and intra-articular), non-steroidal anti-inflammatory drugs (NSAIDs) and disease modifying anti-rheumatic drugs (DMARDS) including conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs).
Due largely to these treatments, disease remission is now a realistic target for many patients.
Many patients with JIA are able to achieve clinical remission off medication (Guzman 2015; Tiller 2018; Wallace 2004). For this reason, it is appropriate to consider medication dose reduction or discontinuation for some patients. There is no consensus on the optimal strategy for dose reduction or discontinuation of medications in patients with JIA and clinically inactive disease. This topic has not been addressed in major international guidelines given the paucity of evidence (Davies 2010; Munro 2014; Ravelli 2018; Ringold 2019), leading to uncertainty for patients and unnecessary heterogeneity in practice (Horton 2017; Shenoi 2019)." ["project_specific_aims"]=> string(540) "This is a protocol for a Cochrane Systematic Review (intervention). The objectives are as follows:
To assess the benefits and harms of DMARD dose reduction or discontinuation in children and young people with JIA and clinically inactive disease.
The specific hypothesis being evaluated is whether withdrawal or dose reduction of DMARD therapy in children with JIA with clinically inactive disease after a period of time on treatment is a measure that can still lead to maintenance of disease inactivity and clinical remission." ["project_study_design"]=> string(0) "" ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(0) { } ["project_purposes_exp"]=> string(0) "" ["project_software_used"]=> array(2) { ["value"]=> string(11) "open_office" ["label"]=> string(11) "Open Office" } ["project_software_used_exp"]=> string(39) "We will be utilising the Vivli platform" ["project_research_methods"]=> string(1101) "Data will be sourced from Vivli and YODA. Where data is relevant, it may also be extracted directly from published manuscripts.
This will be a systematic review designed as a meta-analysis of relevant randomised controlled trials (RCTs) and controlled clinical trials that use quasi randomised methods to assess the benefits and harms of DMARD dose reduction or discontinuation in children and young people with JIA and clinically inactive disease.
We will include children and young people under 21 years of age, with a diagnosis of juvenile idiopathic arthritis (JIA) and clinically inactive disease. The JIA should have been diagnosed using the International League Against Rheumatism (ILAR) criteria (Petty 2004), or earlier equivalents, including criteria from the European League Against Rheumatism (EULAR (Fantini 1977)), or American College of Rheumatology (ACR (Cassidy 1989)).
We will include trials comparing disease-modifying anti-rheumatic drug (DMARD) dose reduction or discontinuation with a continuing, static dose of DMARDs (no dose reduction or discontinuation)." ["project_main_outcome_measure"]=> string(1164) "Major outcomes
1. Proportion with sustained clinically inactive disease
2. Proportion with sustained remission off medication defined as per the Wallace criteria (Wallace 2004; Wallace 2011).
3. Proportion with a flare of articular disease (as defined by the Wallace criteria (Wallace 2004; Wallace 2011) or as defined by the authors).
4. Proportion with flare of ocular disease (as defined by the Wallace criteria (Wallace 2004; Wallace 2011) or as defined by the authors).
5. Proportion with flare of systemic disease (as defined by the Wallace criteria (Wallace 2004; Wallace 2011) or as defined by the authors).
6. Serious adverse events.
7. Study withdrawal due to adverse events.
Minor outcomes
1. Proportion with the need to recommence or increase dose of DMARD treatments.
2. cJADAS score (Consolaro 2014).
3. Proportion needing to start or increase glucocorticoid treatment (systemic or intra-articular).
4. Functional assessment and assessment of participation (as defined by authors).
5. Total adverse events
6. Episodes of macrophage activaiton syndrome." ["project_main_predictor_indep"]=> string(955) "We will include trials comparing disease-modifying anti-rheumatic drug (DMARD) dose reduction or discontinuation with a continuing, static dose of DMARDs (no dose reduction or discontinuation).
The dose reduction or discontinuation strategies to be included in this review are:
Dose reduction by:
-Down-titration to a lower dose (e.g. 40 mg adalimumab once every two weeks, reduced to 20 mg once every two weeks); or
-Increasing the interval between doses (e.g. 40 mg adalimumab once every two weeks, reduced to 40 mg once every three weeks); or
-Relative down-titration, by leaving a fixed dose rather than adjusting for anthropometric changes (e.g. allowing the young person to 'grow out of a dose', by leaving a fixed dose at 10 mg methotrexate once every week, rather than targeting a dose relative to body surface area that will increase throughout childhood).
-Discontinuation (without prior dose reduction)" ["project_other_variables_interest"]=> string(1107) "All disease modifying treatments for JIA will be eligible for inclusion. This will include, but not be limited to, the following treatments:
? Conventional synthetic DMARDs (csDMARDs), such as methotrexate, leflunomide, sulfasalazine and hydroxychloroquine, that do not target a specific molecular structure; or
? Biologic DMARDs (bDMARDs), such as infliximab, etanercept, adalimumab, certolizumab, golimumab, tocilizumab, sarilumab, anakinra, rilonacept, canakinumab, abatacept and rituximab that are derived biologically and are designed to target specific cells or proteins involved in the inflammatory response present in JIA. Given these are biologically derived proteins, it is impossible to exactly reproduce their complex structure. Therefore, biologic DMARDs can be further classified into bio-originator and biosimilar DMARDs, to specify whether they were made by the first or subsequent manufacturers; or
? Targeted synthetic DMARDs (tsDMARDs), such as tofacitinib, baricitinib, and upadacitinib that, similarly to bDMARDs, are designed to act on a specific molecular target." ["project_stat_analysis_plan"]=> string(2467) "We will use a standard data collection form to extract study characteristics and outcome data. We will pilot the form on at least one study in the review. At least two review authors (WR, JT, JA, RJ) will independently extract study characteristics from included studies. A third review author (JM) will spot-check study characteristics for accuracy against the trial report.
At least two review authors (WR, JT, JA, RJ) will independently extract outcome data from included studies. We will extract the number of events and number of participants per treatment group for dichotomous outcomes, and means and standard deviations and number of participants per treatment group for continuous outcomes. We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way and when data were transformed or estimated from a graph. We will resolve disagreements by consensus or by involving a third person (JM). One review author (WR, JT, JA, RJ) will transfer data into Review Manager (RevMan 2020) file. We will double-check that data are entered correctly by comparing the data presented in the systematic review with the study reports.
We will use freely available software (e.g. DigitizeIt: digitizeit.de/) to extract data from graphs or figures if means and measures of variance are not reported in the text of included studies. These data will also be extracted in duplicate.
As these diseases have heterogeneous presentations, monitoring often includes a broad variety of assessments. If more than one measure is provide for an outcome we will use the following pre-specified hierarchy for remission:
? Proportion of patients with clinical remission by Wallace criteria (Wallace 2004, Wallace 2011)
? Proportion of patients with clinically inactive disease by cJADAS score (Consolaro 2014)
We will apply the following decision rules in the event of multiple outcome reporting:
? if both final values and change from baseline values are reported for the same outcome, we will extract final values
? if both unadjusted and adjusted values for the same outcome are reported, we will extract adjusted values
? if data are analysed based on an intention-to-treat (ITT) sample and another sample (e.g. per-protocol, as-treated), we will extract ITT data
? If multiple time points are reported we will extract the data at the time point of longest duration" ["project_timeline"]=> string(208) "Anticipated start date: 1 April 2022
Analysis completion date: 1 April, 2023
Manuscript drafted & submitted for publication: Dec 1, 2023
Results reported back to YODA project: Dec 1, 2023" ["project_dissemination_plan"]=> string(485) "We will publish our results in a peer-reviewed journal and findings presented at academic conferences.
A poster will be registered at the American College of Rheumatology (ACR) Convergence and at the congress for the Paediatric Rheumatology European Society (PReS).
We intend to submit the manuscript/s to Pediatric Rheumatology, which is an open-access, peer-reviewed online journal widely considered to have one of the highest impact factors in Paediatric Rheumatology." ["project_bibliography"]=> string(13121) "

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Ravelli A , Consolaro A , Horneff G , Laxer R M , Lovell D J , Wulffraat N M , Akikusa J D , Al-Mayouf S M , Anton J , Avcin T , Berard R A , Beresford M W , Burgos-Vargas R , Cimaz R , De Benedetti F , Demirkaya E , Foell D , Itoh Y , Lahdenne P , Morgan E M , Quartier P , Ruperto N , Russo R , Saad-Magalhaes C , Sawhney S , Scott C , Shenoi S , Swart J F , Uziel Y , Vastert S J , Smolen J S . Treating juvenile idiopathic arthritis to target: recommendations of an international task force. Ann Rheum Dis 2018;77(6):819-828.
Remesal 2010
Remesal A , J D E Inocencio, Merino R , Garcia-Consuegra J . Discontinuation of etanercept after successful treatment in patients with juvenile idiopathic arthritis. J Rheumatol 2010;37(9):1970-1.
Ringold 2019
Ringold S , Angeles-Han S T , Beukelman T , Lovell D , Cuello C A , Becker M L , Colbert R A , Feldman B M , Ferguson P J , Gewanter H , Guzman J , Horonjeff J , Nigrovic P A , Ombrello M J , Passo M H , Stoll M L , Rabinovich C E , Schneider R , Halyabar O , Hays K , Shah A A , Sullivan N , Szymanski A M , Turgunbaev M , Turner A , Reston J . 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Non-Systemic Polyarthritis, Sacroiliitis, and Enthesitis. Arthritis Rheumatol 2019;71(6):846-863.
Schnemann 2019
Schnemann 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 MS, Li T, Page MJ, et al, editor(s), Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated October 2019). The Cochrane Collaboration, 2019. Available from www.training.cochrane.org/handbook.
Sengler 2015
Sengler C , Klotsche J , Niewerth M , Liedmann I , Foll D , Heiligenhaus A , Ganser G , Horneff G , Haas J P , Minden K . The majority of newly diagnosed patients with juvenile idiopathic arthritis reach an inactive disease state within the first year of specialised care: data from a German inception cohort. RMD Open 2015;1

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2022-4888

General Information

How did you learn about the YODA Project?: Colleague

Conflict of Interest

Request Clinical Trials

Associated Trial(s):
  1. NCT01230827 - 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)
What type of data are you looking for?: Individual Participant-Level Data, which includes Full CSR and all supporting documentation

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Data Request Status

Status: Concluded

Research Proposal

Project Title: Dose reduction and discontinuation of disease modifying anti-rheumatic drugs (DMARDs) for juvenile idiopathic arthritis

Scientific Abstract: Background:
Juvenile Idiopathic Arthritis (JIA) is the most common rheumatic disease in childhood. Patients with JIA may be able to achieve a state of clinically inactive disease with contemporary treatment measures. Many patients are able to sustain a state of remission after ceasing medication. For this reason, it is appropriate to consider medication dose reduction or discontinuation in some patients, but we do not yet know the best strategies for medication dose reduction or discontinuation.
Objective:
To assess the benefits and harms of DMARD dose reduction or discontinuation in children and young people with JIA and clinically inactive disease.
Study Design:
This systematic review will be a meta-analysis of randomised controlled trials (RCTs) studying the impact of drug withdrawal or discontinuation in patients with JIA.
Participants:
RCTs studying sample populations of children and young people with JIA and clinically inactive disease that are undergoing withdrawal of treatment will be included.
Main Outcome Measure(s):
Major and minor outcome measures will be studied to assess scores of disease inactivity. A composite summary of adverse events will also be reported.
Statistical Analysis:
We will present two main comparisons - dose reduction compared with continuation; and abrupt discontinuation (without prior dose reduction) compared with continuation to provide estimates of benefit and harm. We plan to synthesise effect estimates using a random-effects meta-analysis model based on the assumption that clinical diversity is likely to exist, and that different studies are estimating different intervention effects.
Where we cannot pool data, we plan to present effect estimates and 95% CIs of each trial in tables, and summarise the results in text.

Brief Project Background and Statement of Project Significance: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. JIA is an umbrella term for a heterogeneous group of disorders that manifest as early onset arthritis. The International League Against Rheumatism (ILAR) classification criteria define JIA as arthritis that begins before a patient is aged 16 years, persists for more than 6 weeks and is of unknown origin. These criteria define the following mutually exclusive subtypes on the basis of clinical and laboratory features: systemic arthritis, oligoarthritis, polyarthritis (rheumatoid factor negative), polyarthritis (rheumatoid factor positive), psoriatic arthritis, enthesitis-related arthritis and undifferentiated arthritis (Petty 2004).
JIA typically manifests with arthritis, although extra-articular symptoms such as fever, constitutional symptoms and ocular inflammation can also occur. It affects approximately 1-4 per 1,000 children under the age of 16. Girls are more commonly affected than boys in an overall ratio of approximately 3:2 but the ratio varies significantly between JIA subtypes (Thierry 2014). It is a heterogeneous condition with varied long-term outcomes. Complications including permanent disability were common before effective treatments were introduced (Colver 1937). Fortunately, innovations over the last few decades have led to exponential growth in the number of therapeutic options and have drastically improved outcomes for the vast majority of patients who can access them (Hinze 2015).
The cause of JIA is not completely understood but is probably due to a combination of genetic and environmental factors. Systemic onset juvenile idiopathic arthritis (SoJIA) is well recognised as being genetically and pathophysiologically distinct from the other subtypes of JIA (also referred to as "non-systemic" JIA) (Ombrello 2017). Treatment strategies and long term outcomes also differ between SoJIA and non-systemic JIA. Macrophage activation syndrome is a serious and potentially fatal complication of JIA and is almost exclusively observed in patients with SoJIA.
Contemporary pharmacological treatments for JIA include glucocorticoids (systemic and intra-articular), non-steroidal anti-inflammatory drugs (NSAIDs) and disease modifying anti-rheumatic drugs (DMARDS) including conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs).
Due largely to these treatments, disease remission is now a realistic target for many patients.
Many patients with JIA are able to achieve clinical remission off medication (Guzman 2015; Tiller 2018; Wallace 2004). For this reason, it is appropriate to consider medication dose reduction or discontinuation for some patients. There is no consensus on the optimal strategy for dose reduction or discontinuation of medications in patients with JIA and clinically inactive disease. This topic has not been addressed in major international guidelines given the paucity of evidence (Davies 2010; Munro 2014; Ravelli 2018; Ringold 2019), leading to uncertainty for patients and unnecessary heterogeneity in practice (Horton 2017; Shenoi 2019).

Specific Aims of the Project: This is a protocol for a Cochrane Systematic Review (intervention). The objectives are as follows:
To assess the benefits and harms of DMARD dose reduction or discontinuation in children and young people with JIA and clinically inactive disease.
The specific hypothesis being evaluated is whether withdrawal or dose reduction of DMARD therapy in children with JIA with clinically inactive disease after a period of time on treatment is a measure that can still lead to maintenance of disease inactivity and clinical remission.

Study Design:

What is the purpose of the analysis being proposed? Please select all that apply.:

Software Used: Open Office

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: Data will be sourced from Vivli and YODA. Where data is relevant, it may also be extracted directly from published manuscripts.
This will be a systematic review designed as a meta-analysis of relevant randomised controlled trials (RCTs) and controlled clinical trials that use quasi randomised methods to assess the benefits and harms of DMARD dose reduction or discontinuation in children and young people with JIA and clinically inactive disease.
We will include children and young people under 21 years of age, with a diagnosis of juvenile idiopathic arthritis (JIA) and clinically inactive disease. The JIA should have been diagnosed using the International League Against Rheumatism (ILAR) criteria (Petty 2004), or earlier equivalents, including criteria from the European League Against Rheumatism (EULAR (Fantini 1977)), or American College of Rheumatology (ACR (Cassidy 1989)).
We will include trials comparing disease-modifying anti-rheumatic drug (DMARD) dose reduction or discontinuation with a continuing, static dose of DMARDs (no dose reduction or discontinuation).

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: Major outcomes
1. Proportion with sustained clinically inactive disease
2. Proportion with sustained remission off medication defined as per the Wallace criteria (Wallace 2004; Wallace 2011).
3. Proportion with a flare of articular disease (as defined by the Wallace criteria (Wallace 2004; Wallace 2011) or as defined by the authors).
4. Proportion with flare of ocular disease (as defined by the Wallace criteria (Wallace 2004; Wallace 2011) or as defined by the authors).
5. Proportion with flare of systemic disease (as defined by the Wallace criteria (Wallace 2004; Wallace 2011) or as defined by the authors).
6. Serious adverse events.
7. Study withdrawal due to adverse events.
Minor outcomes
1. Proportion with the need to recommence or increase dose of DMARD treatments.
2. cJADAS score (Consolaro 2014).
3. Proportion needing to start or increase glucocorticoid treatment (systemic or intra-articular).
4. Functional assessment and assessment of participation (as defined by authors).
5. Total adverse events
6. Episodes of macrophage activaiton syndrome.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: We will include trials comparing disease-modifying anti-rheumatic drug (DMARD) dose reduction or discontinuation with a continuing, static dose of DMARDs (no dose reduction or discontinuation).
The dose reduction or discontinuation strategies to be included in this review are:
Dose reduction by:
-Down-titration to a lower dose (e.g. 40 mg adalimumab once every two weeks, reduced to 20 mg once every two weeks); or
-Increasing the interval between doses (e.g. 40 mg adalimumab once every two weeks, reduced to 40 mg once every three weeks); or
-Relative down-titration, by leaving a fixed dose rather than adjusting for anthropometric changes (e.g. allowing the young person to 'grow out of a dose', by leaving a fixed dose at 10 mg methotrexate once every week, rather than targeting a dose relative to body surface area that will increase throughout childhood).
-Discontinuation (without prior dose reduction)

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: All disease modifying treatments for JIA will be eligible for inclusion. This will include, but not be limited to, the following treatments:
? Conventional synthetic DMARDs (csDMARDs), such as methotrexate, leflunomide, sulfasalazine and hydroxychloroquine, that do not target a specific molecular structure; or
? Biologic DMARDs (bDMARDs), such as infliximab, etanercept, adalimumab, certolizumab, golimumab, tocilizumab, sarilumab, anakinra, rilonacept, canakinumab, abatacept and rituximab that are derived biologically and are designed to target specific cells or proteins involved in the inflammatory response present in JIA. Given these are biologically derived proteins, it is impossible to exactly reproduce their complex structure. Therefore, biologic DMARDs can be further classified into bio-originator and biosimilar DMARDs, to specify whether they were made by the first or subsequent manufacturers; or
? Targeted synthetic DMARDs (tsDMARDs), such as tofacitinib, baricitinib, and upadacitinib that, similarly to bDMARDs, are designed to act on a specific molecular target.

Statistical Analysis Plan: We will use a standard data collection form to extract study characteristics and outcome data. We will pilot the form on at least one study in the review. At least two review authors (WR, JT, JA, RJ) will independently extract study characteristics from included studies. A third review author (JM) will spot-check study characteristics for accuracy against the trial report.
At least two review authors (WR, JT, JA, RJ) will independently extract outcome data from included studies. We will extract the number of events and number of participants per treatment group for dichotomous outcomes, and means and standard deviations and number of participants per treatment group for continuous outcomes. We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way and when data were transformed or estimated from a graph. We will resolve disagreements by consensus or by involving a third person (JM). One review author (WR, JT, JA, RJ) will transfer data into Review Manager (RevMan 2020) file. We will double-check that data are entered correctly by comparing the data presented in the systematic review with the study reports.
We will use freely available software (e.g. DigitizeIt: digitizeit.de/) to extract data from graphs or figures if means and measures of variance are not reported in the text of included studies. These data will also be extracted in duplicate.
As these diseases have heterogeneous presentations, monitoring often includes a broad variety of assessments. If more than one measure is provide for an outcome we will use the following pre-specified hierarchy for remission:
? Proportion of patients with clinical remission by Wallace criteria (Wallace 2004, Wallace 2011)
? Proportion of patients with clinically inactive disease by cJADAS score (Consolaro 2014)
We will apply the following decision rules in the event of multiple outcome reporting:
? if both final values and change from baseline values are reported for the same outcome, we will extract final values
? if both unadjusted and adjusted values for the same outcome are reported, we will extract adjusted values
? if data are analysed based on an intention-to-treat (ITT) sample and another sample (e.g. per-protocol, as-treated), we will extract ITT data
? If multiple time points are reported we will extract the data at the time point of longest duration

Narrative Summary: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood, affecting 1 in every 1000 children. It is a chronic condition mediated by the body's own immune system attacking joints of a young person, causing pain, stiffness, joint swelling, loss of function and loss of mobility.
There are many contemporary pharmacological treatments for JIA include glucocorticoids. The specific hypothesis being evaluated is whether withdrawal or dose reduction of Disease Modifying Anti-Rheumatic drugs in kids with JIA with clinically inactive disease after a period of time on treatment is a measure that can still lead to maintenance of disease inactivity and clinical remission.

Project Timeline: Anticipated start date: 1 April 2022
Analysis completion date: 1 April, 2023
Manuscript drafted & submitted for publication: Dec 1, 2023
Results reported back to YODA project: Dec 1, 2023

Dissemination Plan: We will publish our results in a peer-reviewed journal and findings presented at academic conferences.
A poster will be registered at the American College of Rheumatology (ACR) Convergence and at the congress for the Paediatric Rheumatology European Society (PReS).
We intend to submit the manuscript/s to Pediatric Rheumatology, which is an open-access, peer-reviewed online journal widely considered to have one of the highest impact factors in Paediatric Rheumatology.

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