Abstract
Objective Despite treatment advances, pain remains a serious problem for many children with juvenile idiopathic arthritis (JIA). To better understand pain in children with JIA and identify potentially modifiable factors, this study evaluated Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Pain Interference (PI) and its relationships with other pain measures and demographic, clinical, psychosocial, and functional variables.
Methods This cross-sectional, observational, multicenter study used descriptive statistics and a mix of bivariate and multivariable analyses to describe PI and characterize relationships with other measures and variables.
Results Among 355 children with JIA, 27% reported moderate or severe PI and 13.3% reported daily pain. PI correlated with other pain measures. Increasing age, decreasing disease duration, and increasing number of active joints, as well as presence of active disease, steroid treatment, and biologic treatment, were associated with greater PI. All PROMIS psychosocial and functional measures were associated with PI in the expected direction except for PROMIS Pediatric Physical Activity, which showed no association. In multivariable analyses, only PROMIS Fatigue, PROMIS Mobility, and the exploratory interaction of PROMIS Anxiety and disease-modifying antirheumatic drug treatment were significant.
Conclusion Moderate and severe PI was prevalent in this sample of children with JIA. PI increased with age and indicators of disease activity, but was more strongly associated with increasing fatigue and decreasing mobility. Findings support the use of PI as a short, easily administered multidimensional pain measure as part of routine clinical care. Fatigue, mobility, and disease activity should be assessed further when PI is high.
Juvenile idiopathic arthritis (JIA) affects 50 per 100,000 children in the United States and is the leading cause of arthritis in children.1 Active JIA causes joint pain, swelling, and stiffness, and can lead to functional limitations and disability. Despite major therapeutic advances, pain often persists, reducing physical and social functioning and decreasing quality of life (QOL).2,3 Identifying modifiable factors that contribute to pain in children with JIA represents an unmet need.
Pain is complex and challenging to interpret, measure, and study. Pain often changes rapidly within an individual, so a single measure of pain intensity may not fully represent fluctuating symptoms nor the enduring effect of pain on several QOL dimensions. Individual-level factors have been reported in association with pain in JIA, including disease activity, JIA category, anxiety, stress, mood, and coping skills,4-6 although studies are difficult to compare because of varying measures and methods. Diverging pain trajectories over time,7 lowered pain thresholds,8 and pain hypersensitivity9 add additional complexity. Environmental factors, including family dynamics,10 parental distress,11 and parental personal history of pain,12 have also been reported to influence child-reported pain in JIA. Thus, pain in children with JIA is complex, multidimensional, and challenging to study.
Pain interference (PI), or the extent to which pain hinders engagement with social, cognitive, emotional, physical, and recreational activities, may better capture the complex, multidimensional nature of pain in JIA across clinical and research settings.13,14 This study sought to evaluate PI against other pain measures and identify associations between PI and demographic, clinical, psychosocial, and functional variables. Findings will increase understanding of pain and help target strategies to reduce PI, ultimately improving QOL for children with JIA.
METHODS
Ethics. The study was reviewed and approved by the Institutional Review Board (IRB) at Duke University (#Pro00085709 and #Pro00054616) and individual site IRBs as required. Written parental consent and child assent were obtained prior to participation.
Design and sample. This was a cross-sectional analysis from a multicenter cohort study of children with chronic diseases (Pediatric Patient Reported Outcomes in Chronic Diseases [PEPR] Consortium).15 PEPR recruited participants with JIA from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, the largest registry of pediatric-onset rheumatic diseases in North America, aged 8 to 17 years at enrollment and meeting International League of Associations for Rheumatology (ILAR) criteria. Full inclusion/exclusion criteria and methods are previously reported.16 Measures were collected at study visits, which, by design, aligned with standard-of-care clinic and CARRA Registry visits.
Measures. PI was measured using the Patient Reported Outcomes Measurement Information System (PROMIS) Pediatric PI v2.0 (freely available at https://www.healthmeasures.net). PROMIS PI t-scores are standardized to a mean of 50 (SD 10), with higher t-scores reflecting more PI. The median PROMIS PI t-score in the US general pediatric population is 36, with cutpoints estimated at < 49 (mild), 49-58 (moderate), and > 58 (severe).17 Other pain measures were current pain intensity (range 0-10 at time of visit, with higher scores indicating greater pain intensity, from PROMIS Pediatric Numeric Rating Scale Pain Intensity v1.0), maximum pain intensity in past 7 days (range 0-10, with higher scores indicating higher pain intensity, from PROMIS Pain Intensity v2.0), and number of days with pain in the past 2 weeks (range 0-14 days). Demographic variables were age, sex, self-reported race and ethnicity, parent highest education level, and insurance status. Clinical variables were JIA category by ILAR criteria (with enthesitis-related arthritis, psoriatic arthritis, and juvenile ankylosing spondylitis combined into “spondyloarthritis”), disease duration, number of active joints, active disease (defined as physician global assessment ≥ 1 and/or number of active joints > 0), and current treatment with disease-modifying antirheumatic drugs (DMARDs), biologics, systemic corticosteroids (CS), and/or nonsteroidal antiinflammatory medications (NSAIDs). Psychosocial variables were PROMIS Pediatric measures of Depressive Symptoms v1.0, Anxiety v2.0, Psychological Stress v1.0, Family Relationships v1.0, and Peer Relationships v2.0. Functional variables were PROMIS Pediatric measures of Fatigue v2.0, Mobility v2.0, and Physical Activity v1.0. All PROMIS measures were administered by computerized adaptive testing. Both parent proxy and child measures were collected; only child measures were used for analysis.
Statistical analysis. Descriptive statistics were used to report PI, other pain measures, and demographic, clinical, psychosocial, and functional variables, with percentages for categorical variables and means with SDs for continuous variables. Associations were evaluated with Spearman correlation, and relationships between PI and variables were examined using simple linear regression, t test, or 1-way ANOVA. Variables that demonstrated a statistically significant relationship in bivariate analyses were included in multivariable linear regression modeling. Interactions (PROMIS Anxiety and DMARD treatment, PROMIS Anxiety and biologic treatment, PROMIS Depressive Symptoms and PROMIS Fatigue, PROMIS Family Relationships and active disease) were explored in the final model. Collinearity was evaluated with variance inflation factor (VIF). The final model was evaluated with goodness-of-fit and residual plots. In the event of missing disease duration data, time from diagnosis (in years) was substituted. Participants were excluded from analysis in the event of missing data for disease category, active disease, or switching DMARDs and/or biologic treatment within 3 months of the study inclusion date. Otherwise, participants with missing or incomplete data were included in analysis.
RESULTS
A total of 355 children with JIA were included for analysis. As shown in Table 1, the majority were female (69.5%), mean age was 13.5 years, self-reported race was mostly White (81.1%), and self-reported ethnicity was non-Hispanic (92.1%) for almost all children in the sample. Most had private insurance (85.6%), and more than half had parent education levels reported as college degree or higher. Disease duration ranged from 2.5 months to 16.7 years. About a third had polyarticular or oligoarticular disease (36.6% and 33.8%, respectively), whereas spondyloarthritis or systemic disease were less frequent (25.1% and 4.5%, respectively). About one-third (34.4%) had active disease, although the majority had 1 or no active joint. At the time, most were being treated with nonbiologic DMARDs (86.5%) and/or biologics (73.2%) and/or NSAIDs (58.6%). Few were being treated with systemic CS (3.7%).
Demographics and clinical characteristics of 355 children with juvenile idiopathic arthritis.
PROMIS PI t-score mean was 43.8 (SD 8.4, range 34.6-68.7; Table 2). Most (n = 259, 73%) reported no/mild PI, 67 (18.8%) reported moderate PI, and 29 (8.2%) reported severe PI. Descriptive statistics for other PROMIS scores are shown in Table 2. Missingness was low, with only 1 to 2 participants missing any PROMIS score.
PROMIS Pediatric measure t-scores in children with juvenile idiopathic arthritis and PROMIS established reference cutpoints.
Means of other pain measures were 1.2 (SD 1.9, range 0-9, n = 240) for current pain intensity, 2.1 (SD 2.2, range 0-10, n = 240) for maximum pain intensity in past 7 days, and 4.6 (SD 4.8, range 0-14, n = 226) for number of days with pain in past 2 weeks. Pain measure distributions were skewed toward mild/no pain; however, 30 of the 226 (13.3%) children reporting on number of days with pain reported pain every day for the past 2 weeks. Moderate correlations between PI scores and other pain measures were found, including current pain intensity (r 0.44, P < 0.01), maximum pain intensity in past 7 days (r 0.45, P < 0.01), and number of days with pain in the past 2 weeks (r 0.50, P < 0.01). The following pain measures showed strong correlations with each other: current pain intensity and maximum pain intensity in past 7 days (r 0.78, P < 0.01), current pain intensity and number of days with pain in the past 2 weeks (r 0.75, P < 0.01), and maximum pain intensity in past 7 days and number of days with pain in past 2 weeks (r 0.85, P < 0.01).
Among demographic variables, PI scores increased with increasing age (R2 0.046, P < 0.01). Parent highest education level of less than college degree showed generally higher PI scores than college degree or higher; however, more than a third of the sample had missing data or declined to answer. Otherwise, no significant differences in PI scores by sex, race and ethnicity, or insurance status were observed.
Among clinical variables, mean PI scores were higher among children with active vs inactive disease (47.7 [SD 8.6] vs 41.8 [SD 7.6], P < 0.01) and those currently treated with CS vs no CS (55.3 [SD 6.7] vs 43.4 [SD 8.2], P < 0.01) and biologics vs nonbiologic DMARDs (44.4 [SD 8.5] vs 42.3 [SD 8.2], P = 0.04). PI scores increased with increasing number of active joints (R2 0.09, P < 0.01), and slightly decreased with increasing disease duration (R2 −0.02, P = 0.02). There were no significant differences in PI scores by JIA category, DMARDs, or NSAIDs.
All psychosocial and functional variables showed significant linear correlations in the expected directions with PI, except PROMIS Physical Activity, which showed no association. Coefficient of determination (R2) values for PROMIS Pediatric measures were as follows: 0.21 (P < 0.01) for PROMIS Depressive Symptoms, 0.15 (P < 0.01) for PROMIS Anxiety, 0.22 (P < 0.01) for PROMIS Psychological Stress, 0.46 (P < 0.01) for PROMIS Fatigue, −0.49 (P < 0.01) for PROMIS Mobility, −0.06 (P < 0.01) for PROMIS Family Relationships, −0.12 (P < 0.01) for PROMIS Peer Relationships, and 0.00 (P = 0.76) for PROMIS Physical Activity.
Multivariable linear regression results are reported in Table 3. The final model accounted for a majority of the variance observed in PI (R2 0.63, F 30.9, P < 0.01), but only PROMIS Fatigue and Mobility were statistically significant, plus the exploratory interaction between PROMIS Anxiety and DMARDs. PROMIS Fatigue was positively associated with PI, whereas PROMIS Mobility was negatively associated with PI. Modeling was repeated substituting number of active joints for active disease with nearly identical results. Examination of goodness-of-fit and residual plots for the final model showed no unexpected patterns and VIFs were < 10.
Multivariable linear regression analysis of PROMIS Pediatric Pain Interference t-scores in children with juvenile idiopathic arthritis.
DISCUSSION
We found that approximately 1 in 4 children with JIA had moderate to severe PI and 13.3% reported daily pain. These findings underscore the pressing need to understand and reduce pain. Our findings support the use of PROMIS Pediatric PI as a multidimensional pain measure that is short and easily administered as part of routine clinical care. PI scores showed expected moderate correlations between PI and other pain measures. PI scores were also higher, as expected, among children with active disease and with increasing numbers of active joints. In addition, PI scores showed, as expected, at least weak to moderate associations between PI and several psychosocial and functional variables. Collectively, these findings add to the body of literature supporting the use of PI as a multidimensional pain measure in pediatric chronic diseases including JIA.13,15,18,19 Compared to other regularly used pain measures, such as pain intensity at time of clinical care and number of days with pain, PI may more fully reflect the actual lived experience of pain.
Among demographic factors, increasing age appeared to correspond with higher PI scores, although the overall effect was small. In an earlier analysis of CARRA Registry data, older age was also associated with higher scores for pain intensity.5 Higher PI with increasing age in this study may be explained by the generally older ages and increased pain reporting among children with JIA in the enthesitis-related category. Although no differences in PI scores were observed across JIA categories in the current study, the number of children included in this sample with JIA in the enthesitis-related category was notably smaller than in the separate analysis. An important consideration is that pain may be underreported in younger patients, though this study included only children aged 8 to 17 years. Indicators of greater disease activity also corresponded with higher PI scores. This association was previously reported in a convenience sample of 44 children with JIA14 and a larger PROMIS validation study of 265 children with JIA.13 More intensive treatment (ie, systemic CS and biologics) was also associated with higher PI scores in this study. This finding is likely related to disease activity, but it has not been consistently reported in other studies.2,5,20 Overall, the magnitude of relationships between PI and demographic and clinical variables was small, and findings lost statistical significance when combined in multivariable analysis.
Functional and psychosocial factors seem strongly related to PI. We found strong associations between PI and PROMIS Pediatric measures of Fatigue and Mobility, and to a lesser extent, PROMIS Depressive Symptoms and Psychological Stress. These areas should be assessed if PI is high. Assessment may lead to clinical actions, for example, asking about sleep habits and counseling on sleep hygiene to mitigate fatigue, or inquiring about the need for mobility-related accommodations (eg, using a rolling backpack or elevator at school). If not already routinely incorporated into clinical practice, screening for mental health comorbidities and providing support and referrals may be especially important in children with high PI. Although causality cannot be inferred from this cross-sectional analysis, future efforts could evaluate the effect of these interventions on PI. A related concept not directly assessed in this study is coping, which was previously reported to account for a significant amount of variance in JIA pain and may be a modifiable factor for future investigation.6,21
Surprisingly, we found no relationship between PI and PROMIS Physical Activity. Findings could represent true lack of association, as prior studies have not consistently shown reduced physical activity in children with JIA.22-24 However, findings could also reflect limitations in the Physical Activity questionnaire itself, as it has not been as widely evaluated compared to other measures.25 It includes several items related to exertion (eg, “How many days did you exercise or play so hard that your body got tired?”), which is a target that could vary greatly depending on individualized pain thresholds and tolerance. The relationship between pain measures and PROMIS Physical Activity scores requires further study. In addition, the exploratory interaction between PROMIS Anxiety and DMARDs could suggest that children with JIA and anxiety undergoing DMARD treatment have lower PI compared to those undergoing other treatments. Individualized effects of treatments on pain response in subgroups of children with JIA is an intriguing area for future investigation.
An important limitation of the study is the cross-sectional design, which may actually underestimate pain in JIA if painful events occur between clinical encounters. Pain in children with JIA changes over time,7 suggesting a need for additional, longitudinal studies. Causality cannot be inferred from the study design, so the observed relationships, especially between PI and fatigue and mobility, should be investigated in future, prospective, and/or interventional studies. Although missingness was extremely low for PROMIS measures, there were missing data in other variables that might have resulted in a failure to capture significant relationships, overestimation of other relationships, or in some cases, preclude analysis (eg, parental education level). As with all observational studies, unmeasured factors may also influence findings, though a strength of this study was inclusion of variables spanning several dimensions of health. Statistically significant findings from our analysis should be repeated in another sample for confirmation. Finally, the external generalizability of the findings is limited by the lack of racial and ethnic diversity in the sample. Future studies in more diverse populations are needed.
Overall, pain and PI are highly prevalent in this large sample of children with JIA. Findings support the use of PROMIS Pediatric PI as a multidimensional pain measure and show the importance of fatigue and mobility on PI. Future, longitudinal studies should include evaluation of fatigue and mobility, in addition to disease activity, to help develop strategies to reduce PI and improve QOL in children with JIA.
ACKNOWLEDGMENT
We thank Sarah Ringold and Antonia Bennett for contributing to the concept and interpretation of study results.
Footnotes
RLR receives support from the National Institutes of Health (NIH) and Lupus Foundation of America, and was supported by the National Institute of General Medical Sciences and the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the NIH under award no. T32GM086330/5T32HD104576 while working on this project. LES, BBR, ERW, EvS, CMM, and CKZ have received support from Pediatric Patient Reported Outcomes in Chronic Diseases (PEPR), which was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH under award no. U19AR069522.
RLR’s spouse has financial relationships with Merck and Biogen. CKZ has received research funds from CARRA, NIH, and FDA. EVS served as president for CARRA and has received research funding from PCORI. LES is supported by PCORI under award no. PaCr-2017C2-8177 and CARRA. LES has received research funds from BMS and CARRA; serves on the data and safety monitoring board for Sanofi (sarilumab) and UCB (certolizumab); and is a former president, board member, and is currently Senior Advisor for CARRA Registry and Partnership Development. The remaining authors declare no conflicts of interest relevant to this article.
- Accepted for publication July 24, 2024.
- Copyright © 2024 by the Journal of Rheumatology
