Significant pain decrease in children with non-systemic Juvenile Idiopathic Arthritis treated to target: results over 24 months of follow up

Juvenile Idiopathic Arthritis (JIA) is the most common auto-immune disease in children, with an estimated prevalence of 33 per 100.000 children [1, 2]. Pain is a common and distressing symptom of JIA [3, 4]. It can cause sleep disturbances, disrupts school attendance and leads to a decline in quality of life that can persist into adulthood [5‐7]. Disease activity is a well-known contributor to pain severity, but not the only contributing factor [3, 8]. In recent years, introduction of (biologic) DMARDs earlier in the disease course has improved the outcome for JIA patients [9‐11]. However, this has not directly translated into better pain outcomes as some children experience pain during inactive disease despite adequate treatment and effective disease control [12‐14]. A possible explanation for persistent pain with low or no visible disease activity is a decreased pain threshold. Children with JIA were found to have a lower pain threshold than their healthy peers, even when they had no detectable joint inflammation after treatment [15], with longer disease duration as a possible predictor [16, 17]. It has been hypothesized that peripheral and central sensitization, causing prolonged hypersensitivity of pain circuits in the nerve system, contribute to a lower pain threshold [18]. This hypothesis suggests that pain, and the causes of pain should be treated as soon and adequately as possible to prevent sensitization.

In JIA, treatment to target (T2T) with clinical remission as a treatment goal has been widely recommended [19, 20]. Treating JIA to target makes drug-free inactive disease a feasible outcome for an increasing number of children with non-systemic JIA [11, 21]. However, improved patient reported outcomes, such as less fatigue and pain, have not yet been confirmed for treat to target therapy [22].

The aim of this subanalysis is to compare pain scores over two years in three treatment strategies in non-systemic JIA patients who were treated to target aimed at inactive disease [21]. Furthermore, we aim to determine the effect of inactive disease and time to inactive disease on pain in the Best for Kids cohort and to explore and identify baseline characteristics predicting unfavorable pain trajectories.

The BeSt for Kids is one of the first treat-to-target studies in newly diagnosed, DMARD naïve, non-systemic JIA patients investigating pain as outcome measure. In the current subanalysis, three frequently used initial treatment strategies were compared for effectiveness in treating pain [21, 32]. In the BeSt for Kids study, the treatment target was inactive disease. Pain was not a treatment target, and therefore treatment adjustments were, at least partly, independent of whether patients had residual pain. Nevertheless, our results show that targeted treatment can significantly reduce pain in children with JIA. After 24 months the mean(SD) VAS pain of JIA patients decreased from 55.3(SD 21.7) to 19.5(SD 25.3) mm, at a similar rate irrespective of initial treatment. Pain scores after two years are lower than in earlier studies assessing pain during non-targeted treatment with DMARDs [13, 33]. This suggests that treat-to-target is beneficial in achieving lower pain scores, although direct comparisons are lacking.

Although few studies have addressed pain over time as an outcome, we know from cross sectional data and reports from trials and prospective observational studies that pain scores can remain high after treatment. These high pain levels are reported after treatment according to clinical practice before the availability of biologic treatment [34, 35], but also in patients in whom disease activity has declined after successful treatment with abatacept and other biologicals [3, 13, 33]. Even in the biologic era, pain can remain present in the long term, and high pain perception affects quality of life [12, 14]. The decrease in pain seen in patients participating in our treat to target strategy is therefore promising.

Even though we saw a decrease of active disease and pain in the BeSt for kids study, still some of our patients who did achieve inactive disease continued to have pain. It is this group of patients that deserves additional attention [36, 37]. Central sensitization could be a factor involved in persistence of pain in chronic conditions like JIA [38]. Our analyses showed that longer time to inactive disease has a small, but significant association with more pain over time. Further research should focus on how to identify patients who are at risk for chronic pain even after the inflammation is abrogated. When we are able to recognize children with chronic pain in an early stage, they might benefit from education about the cause of their pain, relevant pain mechanisms, and the role of psychosocial and physical factors in precipitating and maintaining chronic pain [39, 40].

In addition to this, we could consider adding an extra patient reported outcome, to investigate whether the clinical improvement we find corresponds to what our patients regard as a satisfactory improvement in pain levels [37, 41, 42]. In adult RA it is recognized that clinicians may have another perspective on how a favorable outcome is defined than their patients, and research is increasingly directed towards more patient reported measures and a value based perception of health care [43, 44]. Recently, in adult rheumatology, the dual target strategy was proposed to enhance patient satisfaction, with one target representing control of inflammation (biological remission) and the other control of disease impact (symptom remission) [45].

We performed an exploratory analysis to identify baseline factors that predict pain over time. In univariable analyses we identified VAS pain, PGA, VAS patient/parent, number of active joints, PhS and PsS as significant predictors of pain over time. In a multivariable model including all previously tested variables, identified VAS pain, PGA, number of active joints, PhS and PsS remained predictive. This is in accordance with previous literature [31, 46‐48].

Counterintuitively and in contrast to previous studies, in our multivariable model, a lower PGA at baseline was associated with more pain during the two years follow up [8, 46]. This reversal of the effect compared to the results of our univariable analyses is related to the combination of predictors in our multivariable model. Due to the predictive nature of our model, this relationship with pain should not be interpreted causally.

Contrary to previous studies we did not find symptom duration as a significant baseline predictor for more pain over time. This could be due to lack of power, as these studies included more patients and the effect that was found was very small [8, 46].

In our previous publication [21], we reported intraarticular corticosteroid injections that were administered outside the study protocol. This happened rarely, but more frequently in arm 2 than in other treatment arms. Despite this difference in frequency, we do not see a difference in pain course over time, which could be attributed to the intraarticular injections.

There are some limitations to our study. The sample size of our study was limited, therefore more subtle differences might have been found in a larger study cohort. Second, pain is multifactorial in nature and affected by many psychosocial patient factors [39]. This study only looked at pain intensity and did not take a possible response shift during the study period into consideration [49]. Third, VAS pain scores were completed by patients or their parents. Parents were encouraged to obtain self-report by the child, but in young children this was not always possible. Patient-proxy reports are known to not always correspond, especially in children with a high disease burden [50]. Fourth, pain can be influenced by sensitization [18, 38]. This might have occurred prior to start of treatment. In our analyses, we have only looked at time to start of treatment, but other factors may have influenced sensitization and pain. And lastly, the prediction model was based upon a randomized cohort with strict inclusion criteria. To participate in the BeSt for kids study, symptom duration had to be less than 18 months. This and other inclusion criteria might limit the generalizability of the results.

We conclude that treat to target therapy is effective in reducing pain over time for DMARD-naïve non-systemic JIA patients, irrespective of initial treatment. On the other hand, some children still experience pain despite achieving clinically inactive disease. This emphasizes the necessity of addressing patient related outcomes in addition to targeted treatment to reduce disease activity. Several baseline predictors for pain over time were found, which could help to identify and support non-systemic JIA-patients with a high risk of pain in addition to a treat-to-target strategy treatment.