Lengthening sleep reduces pain in childhood arthritis: a crossover randomised controlled trial.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a common chronic childhood disease and chronic pain is a debilitating feature. A strong link has been shown between poor sleep and pain in JIA. However, the causal direction is unknown. This study's aim was to determine if, in adolescents with JIA, a recommended healthful sleep duration leads to reductions in pain when compared with the restricted sleep (RS) duration that is commonly seen. METHODS: Patients with JIA (12-18 years old; pain score of ≥1 on a visual analogue scale) participated in a randomised, crossover sleep manipulation protocol. The 3-week protocol comprised a baseline week (BL), a week with healthy sleep duration (HSD; 9.5 hours in bed/night) and a RS week (RS; 6.5 hours in bed/night). After BL, participants were randomly assigned to either HSD or RS, and then crossed over to the other condition. Pain was self-assessed using the iCanCope with Pain app. We used Bayesian hierarchical models to estimate the effect of sleep duration on pain. RESULTS: Participants (n=31; mean age=15.0±1.8 years) averaged 1.4 (95% credible interval (CrI) 1.2-1.6) more hours of sleep per night during HSD relative to RS. Compared with RS, HSD resulted in a favourable effect on pain scores (OR 0.61, 95% CrI 0.39-0.95). CONCLUSION: It is possible to have adolescents with childhood arthritis get a healthier sleep duration, and this longer sleep results in reduced pain. These findings complement prior correlational studies and confirm a causal relationship between reduced sleep duration and increased pain. TRIAL REGISTRATION NUMBER: NCT04133662.

A decade of progress in juvenile idiopathic athritis treatments and outcomes in Canada: results from ReACCh-Out and the CAPRI registry.

OBJECTIVE: To assess changes in juvenile idiopathic arthritis (JIA) treatments and outcomes in Canada, comparing a 2005-2010 and a 2017-2021 inception cohorts. METHODS: Patients enrolled within three months of diagnosis in the Research in Arthritis in Canadian Children Emphasizing Outcomes (ReACCh-Out) and the Canadian Alliance of Pediatric Rheumatology Investigators Registry (CAPRI) cohorts were included. Cumulative incidences of drug starts and outcome attainment within 70 weeks of diagnosis were compared with Kaplan Meier survival analysis and multivariable Cox regression. RESULTS: The 2005-2010 and 2017-2021 cohorts included 1128 and 721 patients, respectively. JIA category distribution and baseline clinical juvenile idiopathic arthritis disease activity (cJADAS10) scores at enrolment were comparable. By 70 weeks, 6% of patients (95% CI 5, 7) in the 2005-2010 and 26% (23, 30) in the 2017-2021 cohort had started a biologic DMARD (bDMARD), and 43% (40, 47) and 60% (56, 64) had started a conventional DMARD (cDMARD), respectively. Outcome attainment was 64% (61, 67) and 83% (80, 86) for Inactive disease (Wallace criteria), 69% (66, 72) and 84% (81, 87) for minimally active disease (cJADAS10 criteria), 57% (54, 61) and 63% (59, 68) for pain control (<1/10), and 52% (47, 56) and 54% (48, 60) for a good health-related quality of life. CONCLUSION: Although baseline disease characteristics were comparable in the 2005-2010 and 2017-2021 cohorts, cDMARD and bDMARD use increased with a concurrent increase in minimally active and inactive disease. Improvements in parent and patient reported outcomes were smaller than improvements in disease activity.

Development of neoplasms in pediatric patients with rheumatic disease exposed to anti-tumor necrosis factor therapies: a single Centre retrospective study.

BACKGROUND: Anti-TNF (Tumor necrosis factor) therapy is effective in treating pediatric patients with refractory rheumatic disease. There is however a concern that anti-TNF usage may increase the risk of malignancy. Reports on specific types of malignancy in this patient population have been emerging over the past decade, but there is a need for additional malignancy reports, as these events are rare. Therefore, a retrospective chart review was performed on the biologic database of pediatric rheumatology patients at The Hospital for Sick Children (SickKids) from 1997 to 2013 for neoplasms, patient demographic information and rheumatologic treatment course. FINDINGS: 6/357 (1.68%) rheumatology patients treated with anti-TNF therapy between 1997 and 2013 developed neoplasms. One patient had two malignancies. One patient had a benign neoplasm. Cases were exposed to etanercept, infliximab or both. Neoplasms developed late after anti-TNF exposure (median 5.0 years) and infliximab treatment was associated with a shorter time to malignancy. The neoplasms identified were as follows: 2 renal clear cell carcinoma, 1 pilomatricoma, 1 nasopharyngeal carcinoma, 1 Ewing's sarcoma, 1 hepatic T-cell lymphoma, 1 lymphoproliferative disease. CONCLUSIONS: The malignancy rate at our centre is low, however more than half of the neoplasms identified were rare and unusual in the pediatric population. The 5-year malignancy-free probability for patients with juvenile idiopathic arthritis (JIA) treated with biologic therapy was 97% from our database. Long-term screening for rare neoplasms is important as part of the safety monitoring for any pediatric rheumatology patient receiving anti-TNF therapy.

Growth and weight gain in children with juvenile idiopathic arthritis: results from the ReACCh-Out cohort.

BACKGROUND: With modern treatments, the effect of juvenile idiopathic arthritis (JIA) on growth may be less than previously reported. Our objective was to describe height, weight and body mass index (BMI) development in a contemporary JIA inception cohort. METHODS: Canadian children newly-diagnosed with JIA 2005-2010 had weight and height measurements every 6 months for 2 years, then yearly up to 5 years. These measurements were used to calculate mean age- and sex-standardized Z-scores, and estimate prevalence and cumulative incidence of growth impairments, and the impact of disease activity and corticosteroids on growth. RESULTS: One thousand one hundred forty seven children were followed for median 35.5 months. Mean Z-scores, and the point prevalence of short stature (height < 2.5th percentile, 2.5% to 3.4%) and obesity (BMI > 95th percentile, 15.8% to 16.4%) remained unchanged in the whole cohort. Thirty-three children (2.9%) developed new-onset short stature, while 27 (2.4%) developed tall stature (>97.5th percentile). Children with systemic arthritis (n = 77) had an estimated 3-year cumulative incidence of 9.3% (95%CI: 4.3-19.7) for new-onset short stature and 34.4% (23-49.4) for obesity. Most children (81.7%) received no systemic corticosteroids, but 1 mg/Kg/day prednisone-equivalent maintained for 6 months corresponded to a drop of 0.64 height Z-scores (0.56-0.82) and an increase of 0.74 BMI Z-scores (0.56-0.92). An increase of 1 in the 10-cm physician global assessment of disease activity maintained for 6 months corresponded to a drop of 0.01 height Z-scores (0-0.02). CONCLUSIONS: Most children in this modern JIA cohort grew and gained weight as children in the general population. About 1 in 10 children who had systemic arthritis, uncontrolled disease and/or prolonged corticosteroid use, had increased risk of growth impairment.

The risk and nature of flares in juvenile idiopathic arthritis: results from the ReACCh-Out cohort.

OBJECTIVE: To describe probabilities and characteristics of disease flares in children with juvenile idiopathic arthritis (JIA) and to identify clinical features associated with an increased risk of flare. METHODS: We studied children in the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) prospective inception cohort. A flare was defined as a recurrence of disease manifestations after attaining inactive disease and was called significant if it required intensification of treatment. Probability of first flare was calculated with Kaplan-Meier methods, and associated features were identified using Cox regression. RESULTS: 1146 children were followed up a median of 24 months after attaining inactive disease. We observed 627 first flares (54.7% of patients) with median active joint count of 1, physician global assessment (PGA) of 12 mm and duration of 27 weeks. Within a year after attaining inactive disease, the probability of flare was 42.5% (95% CI 39% to 46%) for any flare and 26.6% (24% to 30%) for a significant flare. Within a year after stopping treatment, it was 31.7% (28% to 36%) and 25.0% (21% to 29%), respectively. A maximum PGA >30 mm, maximum active joint count >4, rheumatoid factor (RF)-positive polyarthritis, antinuclear antibodies (ANA) and receiving disease-modifying antirheumatic drugs (DMARDs) or biological agents before attaining inactive disease were associated with increased risk of flare. Systemic JIA was associated with the lowest risk of flare. CONCLUSIONS: In this real-practice JIA cohort, flares were frequent, usually involved a few swollen joints for an average of 6 months and 60% led to treatment intensification. Children with a severe disease course had an increased risk of flare.

Later-onset rheumatoid factor negative polyarticular juvenile idiopathic arthritis (JIA): a unique patient group?

OBJECTIVES: To determine the two-year outcome of patients with later-onset polyarticular rheumatoid factor (RF) negative (-) juvenile idiopathic arthritis (JIA), and predictors of outcome. METHODS: All patients ages 10 to16 years diagnosed and followed in the Rheumatology Clinic at SickKids Hospital with the diagnosis of polyarticular RF- JIA were eligible for study. A retrospective chart analysis was performed and number of active joints, medications, laboratory information and childhood health assessment questionnaire scores were recorded at diagnosis, and 6, 12, and 24 months following diagnosis. RESULTS: As early as 6 months after diagnosis the mean number of active joints decreased from 16 to < 10, with 50% of the patients having < 5 active joints. The predominant joints affected were the wrist, knee, and small joints of the hand. The only predictor of active joint count at the 2-year follow-up was initial presenting active joint count as classified as mild, moderate, or severe. Sex, age, and laboratory results at presentation did not show any correlation with active joint count at 2 years. Majority of patients were treated with non-steroidal anti-inflammatory drugs (98%) and at least one disease-modifying anti-rheumatic drug (56%). CONCLUSIONS: The two-year outcome of patients with late-onset RF- polyarticular JIA was very good with the majority of patients having minimally active disease at last follow-up. Presence of significant polyarthritis at presentation was the only feature associated with long-term joint activity. Sex and lab results did not show any correlation with active joint in this cohort of RF-JIA patients.

Juvenile Psoriatic Arthritis (JPsA): juvenile arthritis with psoriasis?

BACKGROUND: Following the introduction of the ILAR criteria for juvenile idiopathic arthritis, juvenile psoriatic arthritis (JPsA) has become a better recognized category within the inflammatory arthritides of childhood. There are fewer reports describing the characteristics and long-term outcome of patients with JPsA than other subtypes of JIA.The aim of our study was to determine the long-term outcome and clinical course of patients with juvenile psoriatic arthritis (JPsA) and to define subgroups of JPsA. METHODS: Clinical records of all patients meeting criteria for JPsA were reviewed and divided into 4 groups depending on their clinical features and onset type. Patient characteristics and clinical features at onset and during follow-up were determined. RESULTS: The cohort consisted of 119 patients: 65 with oligoarticular-onset (55%; persistent 44 and extended 21), 34 (29%) with RF(-) and 4 (3%) RF(+) polyarticular and 16 (13%) enthesitis-related arthritis (ERA). At diagnosis patients with ERA were oldest and more commonly male (p=0.001 and =0.01 respectively). Patients with a polyarticular course had more involvement of small joints of the hands and wrist when compared to patients with persistent oligoarticular and ERA (p<0.001) while patients with ERA had more hip and sacroiliac arthritis (p<0.001 for both). Nail changes were seen in 66 patients (57%) and were associated with DIP involvement (p=0.0034). OUTCOME: Time to first inactive disease on, but not off, therapy was significantly longer among patients with polyarticular course when compared to oligoarticular and ERA (p=0.016 and p=0.48 respectively). Patients with polyarticular course more frequently had contractures during follow-up than other groups (p=0.01). CONCLUSION: The long-term outcome of with JPsA was generally good. Patients with JPsA did not appear to form distinct sub-group of patients but rather resembled JIA patients with onset types without psoriasis.

Sleep and fatigue and the relationship to pain, disease activity and quality of life in juvenile idiopathic arthritis and juvenile dermatomyositis.

OBJECTIVES: To determine and compare the prevalence of disturbed sleep in JIA and JDM and the relationship of sleep disturbance to pain, function, disease activity and medications. METHODS: One hundred fifty-five patients (115 JIA, 40 JDM) were randomly sampled and were mailed questionnaires. Sleep disturbance was assessed by the sleep self-report (SSR) and the children's sleep habits questionnaire (CSHQ). Fatigue, pain and function were assessed by the paediatric quality of life inventory (PedsQL) and disease activity by visual analogue scales (VASs). Joint counts were self-reported. RESULTS: Eighty-one per cent responded, of whom 44% reported disturbed sleep (CSHQ > 41); there were no differences between disease groups. Poor reported sleep (SSR) was highly correlated with PedsQL fatigue (r = 0.56, P < 0.0001). Fatigue was highly negatively correlated with quality of life (r = -0.77, P < 0.0001). The worst pain intensity in the last week was correlated to sleep disturbance (r = 0.32, P = 0.0005). Fatigue was associated with prednisone and DMARD use. CONCLUSIONS: Sleep disturbance and fatigue are prevalent among children with different rheumatic diseases. Sleep disturbance and fatigue are strongly associated with increased pain and decreased quality of life. Strategies aimed at improving sleep and reducing fatigue should be studied as possible ways of improving quality of life for children with rheumatic illness.

Early outcomes and improvement of patients with juvenile idiopathic arthritis enrolled in a Canadian multicenter inception cohort.

OBJECTIVE: To determine early outcomes and early improvements in a prospective inception cohort of children with juvenile idiopathic arthritis (JIA) treated with current standard therapies. METHODS: Patients selected were enrolled in an inception cohort of JIA, the Research in Arthritis in Canadian Children Emphasizing Outcomes Study. The juvenile rheumatoid arthritis core criteria set measures were completed at enrollment and 6 months later. Frequencies of normal values for each of the core set measures and the American College of Rheumatology (ACR) Pediatric 30, 50, and 70 (Pedi 70) criteria response rates achieved at 6 months after enrollment were calculated for each JIA-onset subtype group. RESULTS: Among 354 patients in the study, the median interval between diagnosis and enrollment was 0.7 months. At 6 months after enrollment, median values of active joint counts were highest in patients with rheumatoid factor (RF)-positive polyarthritis (4) and RF-negative polyarthritis (2), but were 0 or 1 for other subtypes. Fifty percent or more of patients with oligoarthritis, systemic arthritis, enthesitis-related arthritis, and undifferentiated arthritis had no active joints, and the ACR Pedi 70 criteria response rate was 48% or more in those with oligoarthritis, RF-negative polyarthritis, and systemic arthritis. CONCLUSION: With current management strategies in clinical practice, improvement in disease activity was noted in considerable proportions of patients in all of the JIA subtype groups, but low levels of disease activity persisted in many. We expect that these early outcomes will prove to be significant predictors of long-term outcomes.

Comparison of patients with juvenile psoriatic arthritis and nonpsoriatic juvenile idiopathic arthritis: how different are they?

OBJECTIVE: To compare the clinical features and outcome between patients with juvenile psoriatic arthritis (JPsA) and non-JPsA juvenile idiopathic arthritis (JIA). METHODS: Fifty-three children with JPsA, 32 with < 5 joints in the first 6 months of disease (oligo-JPsA) and 21 (> or = 5 joints) polyarticular-onset (poly-JPsA) were compared to 53 patients with JIA who were matched by sex, age, date of diagnosis, and articular onset pattern. RESULTS: There was no difference in the percentage of patients between the oligoarticular groups who developed extended oligoarthritis or in the percentage of patients who were positive for antinuclear antibodies. The only differences were that 25% of patients with oligo-JPsA had dactylitis compared to 0% of patients with oligo-JIA (p < 0.01) and 50% had nail pitting as compared to 18.7% (p < 0.05). In polyarticular patients the percentages with dactylitis were similar (19% vs 38%; p = 0.25). The frequency of uveitis was identical in the oligoarticular patients but a higher rate was seen in poly-JPsA compared to poly-JIA (23.8% vs 0%; p = 0.02), while contractures were more frequent in poly-JIA compared to poly-JPsA during the course of the illness (47.6% vs 14.3%; p = 0.03) but not at last followup (14.3% vs 4.7%; p = 0.6). At last followup the mean Childhood Health Assessment Questionnaire scores were similar in both the polyarticular and oligoarticular groups. CONCLUSION: There were only a few differences between patients with JPsA and JIA regarding disease onset, disease course, and outcome. We suggest that large, longterm prospective studies are required to accurately determine whether subdividing JIA according to psoriasis is worthwhile.

Predictors of early inactive disease in a juvenile idiopathic arthritis cohort: results of a Canadian multicenter, prospective inception cohort study.

OBJECTIVE: To determine early predictors of 6-month outcomes in a prospective cohort of patients with juvenile idiopathic arthritis (JIA). METHODS: Patients selected were those enrolled in an inception cohort study of JIA, the Research in Arthritis in Canadian Children Emphasizing Outcomes Study, within 6 months after diagnosis. The juvenile rheumatoid arthritis core criteria set and quality of life measures were collected at enrollment and 6 months later. Outcomes evaluated included inactive disease, Juvenile Arthritis Quality of Life Questionnaire (JAQQ) scores, and Childhood Health Assessment Questionnaire (C-HAQ) scores at 6 months. RESULTS: Thirty-three percent of patients had inactive disease at 6 months. Onset subtype and most baseline core criteria set measures correlated with all 3 outcomes. Relative to oligoarticular JIA, the risks of inactive disease were lower for enthesitis-related arthritis, polyarthritis rheumatoid factor (RF)-negative JIA, and polyarthritis RF-positive JIA, and were similar for psoriatic arthritis. In multiple regression analyses, the baseline JAQQ score was an independent predictor of all 3 outcomes. Other independent baseline predictors included polyarthritis RF-negative and systemic JIA for inactive disease; C-HAQ score and polyarthritis RF-positive JIA for the 6-month C-HAQ score; and active joint count, pain, and time to diagnosis for the 6-month JAQQ score. CONCLUSION: Clinical measures soon after diagnosis predict short-term outcomes for patients with JIA. The JAQQ is a predictor of multiple outcomes. Time to diagnosis affects quality of life in the short term.

Feasibility and effectiveness of an aerobic exercise program in children with fibromyalgia: results of a randomized controlled pilot trial.

OBJECTIVE: To determine the feasibility of conducting a randomized controlled trial of a 12-week exercise intervention in children with fibromyalgia (FM) and to explore the effectiveness of aerobic exercise on physical fitness, function, pain, FM symptoms, and quality of life (QOL). METHODS: FM patients ages 8-18 years were randomized to a 12-week exercise intervention of either aerobics or qigong. Both groups participated in 3 weekly training sessions. Program adherence and safety were monitored at each session. Data were collected at 3 testing sessions, 2 prior to and 1 after the intervention, and included FM symptoms, function, pain, QOL, and fitness measures. RESULTS: Thirty patients participated in the trial. Twenty-four patients completed the program; 4 patients dropped out prior to training and 2 dropped out of the aerobics program. Better adherence was reported in the aerobics group than in the qigong group (67% versus 61%). Significant improvements in physical function, functional capacity, QOL, and fatigue were observed in the aerobics group. Anaerobic function, tender point count, pain, and symptom severity improved similarly in both groups. CONCLUSION: It is feasible to conduct an exercise intervention trial in children with FM. Children with FM tolerate moderate-intensity exercise without exacerbation of their disease. Significant improvements in physical function, FM symptoms, QOL, and pain were demonstrated in both exercise groups; the aerobics group performed better in several measures compared with the qigong group. Future studies may need larger sample sizes to confirm clinical improvement and to detect differences in fitness in childhood FM.

Reliability of exercise testing and functional activity questionnaires in children with juvenile arthritis.

OBJECTIVE: To determine the reliability of formal exercise testing and the reliability of functional and activity questionnaires in children with juvenile idiopathic arthritis (JIA). METHODS: Children with JIA of any subtype ages 8-16 years who were recruited to a randomized trial comparing different exercise therapies participated in 2 preintervention sessions of exercise testing 2-6 weeks apart. Exercise testing included 1) submaximal oxygen uptake (VO(2submax)), 2) peak VO(2) (VO(2peak)), and 3) anaerobic power using modified Wingate tests (W(ant)). Two physical function questionnaires (the Childhood Health Assessment Questionnaire [C-HAQ] and Revised Activity Scale for Kids [ASK]) and 1 daily physical activity questionnaire (the Habitual Activity Estimation Scale [HAES]) were also completed at these times. Test-retest reliability was assessed using type 3, intrarater intraclass correlation coefficient (ICC(3,1)) and Bland and Altman plots were used to determine limits of agreement. RESULTS: Data were available for 74 patients (58 girls). VO(2submax), VO(2peak), and W(ant) demonstrated high reliability (ICC(3,1) 0.82, 0.91, and 0.94, respectively). C-HAQ and ASK questionnaires also had very high reliability (ICC(3,1) 0.82 and 0.91, respectively). The HAES demonstrated low reliability for total activity score (ICC(3,1) 0.15) and moderate reliability when the number of very active hours was analyzed separately (ICC(3,1) 0.59). CONCLUSION: Results of this investigation suggest that exercise testing and functional questionnaires in children with JIA are consistent and reliable. Reliability of the HAES total score was poor, but moderate when the very active hours subscale score was used.

The effects of vigorous exercise training on physical function in children with arthritis: a randomized, controlled, single-blinded trial.

OBJECTIVE: To examine the effectiveness of high-intensity aerobic training compared with low-intensity training in terms of energy cost of locomotion, peak oxygen uptake, peak power, and self-reported physical function in children with juvenile idiopathic arthritis (JIA). METHODS: Eighty children with JIA, ages 8-16 years, were enrolled in a randomized, single-blind controlled trial. Both groups participated in a 12-week, 3-times-weekly training program consisting of high-intensity aerobics in the experimental group and qigong in the control group. Subjects underwent exercise testing measuring submaximal oxygen uptake at 3 km/hour (VO(2submax)) as the primary outcome, maximal oxygen uptake, and peak power at the beginning and end of the program. Physical function was measured using the Child Health Assessment Questionnaire (C-HAQ). RESULTS: The exercise program was well tolerated in both groups. There was no difference in VO(2submax) or any other exercise testing measures between the groups through the study period and no indication of improvement. Both groups showed significant improvements in C-HAQ with no difference between the groups. Adherence was higher in the control group than the experimental group. CONCLUSION: Our findings suggest that activity programs with or without an aerobic training component are safe and may result in an important improvement in physical function. The intensity of aerobic training did not seem to provide any additional benefits, but higher adherence in the qigong program may suggest that less intensive regimens are easier for children with JIA to comply with, and provide a degree of benefit equivalent to more intensive programs.

Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer.

Early detection remains the most promising approach to improve long-term survival of patients with ovarian cancer. In a five-center case-control study, serum proteomic expressions were analyzed on 153 patients with invasive epithelial ovarian cancer, 42 with other ovarian cancers, 166 with benign pelvic masses, and 142 healthy women. Data from patients with early stage ovarian cancer and healthy women at two centers were analyzed independently and the results cross-validated to discover potential biomarkers. The results were validated using the samples from two of the remaining centers. After protein identification, biomarkers for which an immunoassay was available were tested on samples from the fifth center, which included 41 healthy women, 41 patients with ovarian cancer, and 20 each with breast, colon, and prostate cancers. Three biomarkers were identified as follows: (a) apolipoprotein A1 (down-regulated in cancer); (b) a truncated form of transthyretin (down-regulated); and (c) a cleavage fragment of inter-alpha-trypsin inhibitor heavy chain H4 (up-regulated). In independent validation to detect early stage invasive epithelial ovarian cancer from healthy controls, the sensitivity of a multivariate model combining the three biomarkers and CA125 [74% (95% CI, 52-90%)] was higher than that of CA125 alone [65% (95% CI, 43-84%)] at a matched specificity of 97% (95% CI, 89-100%). When compared at a fixed sensitivity of 83% (95% CI, 61-95%), the specificity of the model [94% (95% CI, 85-98%)] was significantly better than that of CA125 alone [52% (95% CI, 39-65%)]. These biomarkers demonstrated the potential to improve the detection of early stage ovarian cancer.