Rationale
The panel reviewed the current evidence regarding dose reduction or discontinuation of b/tsDMARDs in children and young people with JIA. While evidence was available from thirteen RCTs of b/tsDMARD discontinuation, the majority of these trials were designed to demonstrate efficacy and, as such, exposure to b/tsDMARDs was relatively brief, and many of the participants had not achieved the prolonged clinically-inactive disease that would typically prompt a discussion of treatment reduction in clinical practice. Furthermore, there were no clinical trials of b/tsDMARD dose reduction in JIA. Therefore, the panel had little direct evidence regarding the relative benefits and harms of dose reduction or discontinuation in children and young people with JIA who have achieved excellent disease control with b/tsDMARDs, or on the predictors of successful dose reduction.
Further, while the current evidence base (including data from both RCTs and observational studies) indicates that withdrawal of therapy is likely to be associated with a risk of disease flare, the panel recognised that many young people with JIA (and their families) desire a life free from medications and may wish to explore a trial of dose reduction or discontinuation despite the risk of flare.
Indeed, while there are currently no international guideline recommendations on this topic in non-systemic JIA, tapering and discontinuation of DMARDs in patients with JIA who have responded well to treatment is the highest priority guideline question among Australian and New Zealand paediatric rheumatologists and healthcare professionals 86. Panellists reported that in their clinical and lived experience, DMARD dose reduction and discontinuation is a question of interest to children and young people with JIA, their families, and their healthcare team, and that there is likely to be variation in current clinical practice. In light of this, the panel elected to develop a recommendation despite the paucity of evidence.
Given the uncertainty, and the risk of disease flare (particularly in the population of people with JIA who have required advanced therapies to achieve disease control), the panel acknowledged that continuation of b/tsDMARDs may be the preferred choice for many children and young people with JIA, especially those who have tolerated treatment well. However, it was the view of the panel that a conditional recommendation in favour of a trial of treatment withdrawal may permit exploration of the possibility of remission off medication, which remains a realistic possibility for a substantial proportion of children and young people with JIA who have achieved sustained disease control with DMARDs.
As a conditional recommendation, it is highly dependent on individual values, preferences, goals, experiences and context. The panel reiterated the importance of a shared decision based on consideration of all relevant factors, including the subtype of JIA, prior clinical features and severity (including prior joint damage and extra-articular disease manifestations, particularly uveitis), the duration of clinically inactive disease, age, responsiveness of the disease to treatment, comorbidity, and individual life circumstances.
The panel noted that a history of uveitis, in particular, is an important consideration due to the risk and potential impact of a flare, and highlighted the importance of close follow-up in this group. The panel discussed the results of the ADJUST trial 168, which showed an increased risk of articular and ocular flare in people with JIA-associated uveitis who discontinued adalimumab after at least one year of controlled disease, although all who flared recaptured disease control by the end of the study period.
The panel also noted that children and young people with systemic-onset JIA who have achieved a sustained remission with treatment may be more likely to successfully withdraw from therapy than those with non-systemic JIA, although the same caveats apply, including consideration of individual contextual factors, the need for explicit planning in a shared decision-making framework, close follow-up, and a clear plan for intervention in the case of disease flare.
This conditional recommendation, and the relevant individual considerations, is very similar to our recommendation on dose reduction or discontinuation of csDMARDs. For the current recommendation, the panel considered that the risks or consequences of disease flare may be higher in the population of people with JIA who have required b/tsDMARDs, and therefore suggested a slightly more stringent description of the target disease state (“a sustained period of inactive disease”) to reflect the clinical impression that a prolonged period of inactive disease probably represents the optimal conditions under which to undertake a trial of treatment reduction.
This recommendation applies equally to children and young people with JIA who have achieved a state of inactive disease with b/tsDMARDs either alone or in combination with csDMARDs. It does not address which DMARD to discontinue first in those who are using a combination of csDMARDs and b/tsDMARDs. This will be the subject of a future recommendation.
The recommendation does not favour either dose reduction or discontinuation as the preferred method of dose adjustment. This decision is also highly conditional and depends on a number of considerations within the individual context. While gradual dose reduction may, in theory, reduce the risk of flare and permit exploration of the lowest effective dose, there are concerns that dose reduction may increase the risk of immunogenicity to the bDMARD and therefore risk loss of efficacy in the event of a disease flare 177178. This may be a particularly important consideration in some settings, such as uveitis, in which there are few effective therapies.
The importance of this question and the current lack of evidence highlights the importance and urgency of RCTs that directly address this topic. This living recommendation will continue to be updated as soon as relevant new information becomes available.
