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

Lead Investigator: Joachim Tan, Monash University
Title of Proposal Research: Dose reduction and discontinuation of disease modifying anti-rheumatic drugs (DMARDs) for juvenile idiopathic arthritis
Vivli Data Request: 7427
Funding Source: The researchers performing this research are being funded by Cabrini Health Australia, a not-for-profit health service supporting health related research. The Monash-Cabrini Department of Musculoskeletal Health and Clinical Epidemiology performs high quality clinical research to answer clinically important questions and to promote the translation of clinical evidence into practice and policy change. Our current program of work concerns identifying and reducing low-value health care that arises from over-diagnosis and over-treatment, and identifying ways to improve the sustainability of the health care system. In 2018 we launched the National Health and Medical Research Council (NHMRC) Centre of Research Excellence for the Australia and New Zealand Musculoskeletal (ANZMUSC) Clinical Trial Network. We continue to manage the Australian Rheumatology Association Database and are an editorial base for Cochrane Musculoskeletal and Australasian Satellite of Cochrane Effective Practice and Organisation of Care (EPOC).
Potential Conflicts of Interest: None

Summary of the Proposed Research:

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 (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, leading to uncertainty for patients and unnecessary heterogeneity in practice.

This is a protocol for an intervention Cochrane Systematic Review, which will review and collate the data through meta-analysis of the currently available high quality evidence of a specified formulated question. A systematic review utilising Cochrane methodology will specifically extract and analyse data exclusively from randomised controlled trials. The review of existing research will be conducted using a well-established and clearly defined process to ensure accurate evaluation of the studies.

There are no existing Cochrane reviews exploring this topic. A recent systematic review has been undertaken but has not completely adhered to the Cochrane methodology. There are also several upcoming trials that will address this question and the topic could be suitable to adapt as a ‘Living Guideline’.

This will be a systematic review that will be conducted according to the guidelines recommended by the Cochrane Musculoskeletal Group Editorial Board. It will analyse relevant randomised controlled trials and collate results for meta-analysis.

Statistical Analysis Plan:

Meta-analysis will be conducted using Cochrane standards with a fixed effect metaanalysis using the inverse-variance method for dichotomous outcomes and calculation of the standardised mean difference for continuous outcomes.

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 will independently extract study characteristics from included studies. A third review author will spot-check study characteristics for accuracy against the trial report. We will extract the following study characteristics:
1. Methods: study design, total duration of study, details of any treatment ‘run-in’ period, number of study centres and location, study setting, withdrawals, and date of study.
2. Participants: Number (N), mean age, age range, sex, disease duration, JIA subtype, diagnostic criteria used, duration of inactive disease or remission, joint count, C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR), degree of uveitis activity (using Standardization of Uveitis Nomenclature (SUN) criteria if available), presence of systemic symptoms (fever, rash, serositis, splenomegaly, lymphadenopathy attributable to JIA), clinical Juvenile Arthritis Disease Activity Score (cJADAS) score, functional/participation outcomes (as defined by authors), physician global assessment of disease activity score, patient/parent global assessment of disease activity score, episodes of macrophage activation syndrome, trial inclusion criteria, and trial exclusion criteria.
3. Interventions: name of drug, dose, treatment duration, intervention category (fixed dose reduction, disease activity-guided dose reduction, therapeutic drug monitoring-guided dose reduction or discontinuation without prior dose reduction) and description of dose reduction strategy used (e.g., reduction in dose and time frame at reduced dose, or widening of interval between doses, or abrupt cessation of agent without prior dose reduction); co-intervention (name of drugs, dose, duration and frequency of co-intervention treatment); permitted concomitant medications include stable doses of certain analgesics, non-steroidal anti-inflammatory drugs and disease-modifying anti-rheumatic drugs.
4. Comparisons: name of drugs; dose, treatment duration, treatment frequency or intervals; co-intervention (name of drugs, dose, duration and frequency of co-intervention treatment); permitted concomitant medications.
5. Outcomes: primary and secondary outcomes specified and collected, and time points reported.
6. Characteristics of the design of the trial as outlined below in the ‘Assessment of risk of bias in included studies’ section.
7. Notes: funding for trial, and notable declarations of interest of trial authors; details of any correspondence with study authors.

At least two review authors 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. One review author will transfer data into Review Manager 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 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
• Proportion of patients with clinically inactive disease by cJADAS score
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

Assessment of risk of bias in included studies
At least two review authors will independently assess risk of bias for each study using version two of the Cochrane ‘Risk of bias’ tool (RoB2), outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We will resolve any disagreements by discussion or by involving another author. We will assess the risk of bias of a specific results of a trial according to the following domains:
1. bias arising from the randomisation process;
2. bias due to deviations from intended interventions;
3. bias due to missing outcome data;
4. bias in measurement of the outcome; and
5. bias in selection of the reported result.
We will assess the risk of bias for the outcomes of the included trials that will be included in our Summary of Findings table.
We are primarily interesting in assessing the effect of assignment to the interventions at baseline, regardless of whether the interventions are received as intended (the ‘intention-to-treat effect’).
We will use the signalling questions in the RoB2 tool and rate each domain as ‘low risk of bias’, ‘some concerns’ or ‘high risk of bias’. We will summarise the risk of bias judgements across different studies for each of the domains listed for each outcome. The overall risk of bias for the result is the least favourable assessment across the domains of bias.
When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.

Measures of treatment effect
We will analyse dichotomous data as risk ratios or Peto odds ratios when the outcome is a rare event (approximately less than 10%), and use 95% confidence intervals (CIs). Continuous data will be analysed as mean difference (MD) or standardised mean difference (SMD), depending on whether the same scale is used to measure an outcome, and 95% CIs. We will enter data presented as a scale with a consistent direction of effect across studies.
When different scales are used to measure the same conceptual outcome (e.g. disability), SMDs will be calculated instead, by multiplying the SMD by a typical among-person standard deviation (e.g. the standard deviation of the control group at baseline from the most representative trial).
We will analyse time-to-event data as hazard ratios. Rate data will be analysed using Poisson methods.
For dichotomous outcomes, the number needed-to-treat for an additional beneficial outcome (NNTB), or the number needed to treat for an additional harmful outcome (NNTH) will be calculated from the control group event rate and the relative risk using the Visual Treatment Number-Needed to Treat (Rx NNT) calculator (Cates 2008). The NNTB or NNTH for continuous measures will be calculated using the Wells calculator. The minimal clinical important difference (MCID) will be used in the calculation of NNTB or NNTH.
The MCID has not formally been defined or validated for the cJADAS however an MCID of +1.7 has been determined for worsening using the JADAS-27 (a similar scale that also includes a normalised erythrocyte sedimentation rate (ESR) value in calculating an overall score). For the purpose of this study an MCID for +1.7 for worsening will be used for the cJADAS given that the addition of ESR is unlikely to have a clinically meaningful effect in a cohort of patients with clinically inactive disease at baseline. An MCID of 10% will be used for other measures including proportion of patients with sustained remission.
For dichotomous outcomes, the absolute percent change will be calculated from the difference in the risks between the intervention and control group and expressed as a percentage. The relative percent change will be calculated as the Risk Ratio – 1 and expressed as a percentage.
For continuous outcomes, we will calculate the absolute percent change by dividing the mean difference by the scale of the measure and expressed as a percentage. The relative difference wil be calculated as the absolute benefit (mean difference) divided by the baseline mean of the control group, and expressed as a percentage.
In the ‘Effects of interventions’ results section and the ‘What happens’ column of the ‘Summary of findings’ table, we will provide the absolute percent change, the relative per cent change from baseline, and the NNTB or NNTH (the NNTB or NNTH will be provided only when the outcome shows a clinically significant difference).

Dealing with missing data
We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as abstract only). Where possible, we will use the Revman calculator to calculate missing standard deviations using other data from the trial, such as confidence intervals, based on methods outlined in The Cochrane Handbook. Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis.
For dichotomous outcomes (e.g. number of withdrawals due to adverse events), the withdrawal rate will be calculated using the number of participants randomised in the group as the denominator. For continuous outcomes (e.g. mean change in pain score), we will calculate the MD or SMD based on the number of participants analysed at that time point. If the number of patients analysed is not presented for each time point, the number of randomised patients in each group at baseline will be used.

Requested Studies:

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Efficacy, and Pharmacokinetics of the Human Anti-TNF Monoclonal Antibody Adalimumab in Children With Polyarticular Juvenile Idiopathic Arthritis
Data Contributor: AbbVie
Study ID: NCT00048542
Sponsor ID: DE038

A Multicenter, Double-Blind, Randomized-Withdrawal Trial of Subcutaneous Golimumab, a Humanized Anti-TNFa Antibody, in Subjects With Active Polyarticular Juvenile Idiopathic Arthritis (JIA) Despite Standard Therapy
Data Contributor: Johnson & Johnson
Study ID: NCT01230827
Sponsor ID: CR017089

A 24 Week Randomized, Double-blind, Placebo-controlled Withdrawal Trial With a 16 Week Open-label lead-in Phase, and 64 Week Open-label Follow-up, to Evaluate the Effect on Clinical Response and the Safety of Tocilizumab in Patients With Active Polyarticular-course Juvenile Idiopathic Arthritis
Data Contributor: Roche
Study ID: NCT00988221
Sponsor ID: WA19977

Summary of results:

We were not able to use the data from the studies. The key learnings we learned from this proposal was that the studies provided would not feasibly provide sub analysis data that would adequately fit within the inclusion criteria for our systematic review.