Design of the muscles in motion study: a randomized controlled trial to evaluate the efficacy and feasibility of an individually tailored home-based exercise training program for children and adolescents with juvenile dermatomyositis

BACKGROUND: Juvenile dermatomyositis (JDM) is a rare, often chronic, systemic autoimmune disease of childhood, characterized by inflammation of the microvasculature of the skeletal muscle and skin. Prominent clinical features include significant exercise intolerance, muscle weakness, and fatigue. Despite pharmacological improvements, these clinical features continue to affect patients with JDM, even when the disease is in remission. Exercise training is increasingly utilized as a non-pharmacological intervention in the clinical management of (adult) patients with chronic inflammatory conditions; however no randomized controlled trials (RCT) have been performed in JDM. In the current study, the efficacy and feasibility of an exercise training program in patients with JDM will be examined. METHODS/DESIGN: Subjects (n = 30) will include 8–18 year olds diagnosed with JDM. The intervention consists of an individually tailored 12-weeks home-based exercise training program in which interval training on a treadmill is alternated with strength training during each session. The program is based on previous literature and designed with a defined frequency, intensity, time, and type of exercise (FITT principles). Primary outcome measures include aerobic exercise capacity, isometric muscle strength, and perception of fatigue. The study methodology has been conceived according to the standards of the CONSORT guidelines. The current study will be a multi-center (4 Dutch University Medical Centers) RCT, with the control group also entering the training arm directly after completion of the initial protocol. Randomization is stratified according to age and gender. DISCUSSION: The current study will provide evidence on the efficacy and feasibility of an individually tailored 12-week home-based exercise training program in youth with JDM. TRIAL REGISTRATION: Medical Ethics Committee of the University Medical Center Utrecht, the Netherlands: 11–336; Netherlands Trial Register (NTR): NTR 3184

Endothelial and Inflammation Biomarker Profiles at Diagnosis Reflecting Clinical Heterogeneity and Serving as a Prognostic Tool For Treatment Response in Two Independent Cohorts of Patients With Juvenile Dermatomyositis

Objective: Juvenile dermatomyositis (DM) is a heterogeneous systemic immune-mediated vasculopathy. This study was undertaken to 1) identify inflammation/endothelial dysfunction–related biomarker profiles reflecting disease severity at diagnosis, and 2) establish whether such biomarker profiles could be used for predicting the response to treatment in patients with juvenile DM. Methods: In total, 39 biomarkers related to activation of endothelial

Elicitation of expert prior opinion: application to the MYPAN trial in childhood polyarteritis nodosa.

OBJECTIVES: Definitive sample sizes for clinical trials in rare diseases are usually infeasible. Bayesian methodology can be used to maximise what is learnt from clinical trials in these circumstances. We elicited expert prior opinion for a future Bayesian randomised controlled trial for a rare inflammatory paediatric disease, polyarteritis nodosa (MYPAN, Mycophenolate mofetil for polyarteritis nodosa). METHODS: A Bayesian prior elicitation meeting was convened. Opinion was sought on the probability that a patient in the MYPAN trial treated with cyclophosphamide would achieve disease remission within 6-months, and on the relative efficacies of mycophenolate mofetil and cyclophosphamide. Expert opinion was combined with previously unseen data from a recently completed randomised controlled trial in ANCA associated vasculitis. RESULTS: A pan-European group of fifteen experts participated in the elicitation meeting. Consensus expert prior opinion was that the most likely rates of disease remission within 6 months on cyclophosphamide or mycophenolate mofetil were 74% and 71%, respectively. This prior opinion will now be taken forward and will be modified to formulate a Bayesian posterior opinion once the MYPAN trial data from 40 patients randomised 1:1 to either CYC or MMF become available. CONCLUSIONS: We suggest that the methodological template we propose could be applied to trial design for other rare diseases

The development of offspring from mothers with systemic lupus erythematosus. A systematic review

Objective To analyze published data on the influence of maternal systemic lupus erythematosus (SLE) on different aspects of child development. Methods A systematic review was conducted using PubMed and Embase searches for SLE or SLE-related antibodies and physical, neurocognitive, psychiatric or motor development outcomes in children. Results In total 24 cohort and 4 case-control studies were included after initial screening of 1853 hits. Learning disorders (LD) were reported in 21.4–26% of SLE offspring, exceeding the prevalence in the general population. Four studies reported that dyslexia and reading problems were present in 14.3–21.6% of lupus offspring with a clear male predominance. Furthermore, a twofold increased rate of autism spectrum disorders (ASD) (n = 1 study) and a two- to threefold increased risk for speech disorders (n = 3 studies) were reported in lupus offspring compared to controls, although the latter was not statistically significant. More divergent results were found for attention deficit (n = 5 studies) and behavior disorders (n = 3 studies). In two large controlled studies attention disorders were more prevalent and a trend towards more behavior disorders was reported in 2 of 3 studies analyzing this subject. Finally, IQ and motor skills were not affected in respectively 7 and 5 studies. Cardiopulmonary functioning and mood disorders were scarcely investigated (both n = 1). Maternal anti-SSA antibodies were associated with LD in offspring in one study. Other SLE-related antibodies were rarely studied. Conclusion This systematic review suggests that maternal SLE is associated with LD (specifically dyslexia), ASD, attention deficit and probably speech problems in offspring. However, over half of the studies were assigned a low or moderate evidence level. Therefore, further research is necessary to substantiate the found evidence and expand the scope to lesser researched areas such as cardiopulmonary functioning

The development of offspring from mothers with systemic lupus erythematosus. A systematic review

Objective To analyze published data on the influence of maternal systemic lupus erythematosus (SLE) on different aspects of child development. Methods A systematic review was conducted using PubMed and Embase searches for SLE or SLE-related antibodies and physical, neurocognitive, psychiatric or motor development outcomes in children. Results In total 24 cohort and 4 case-control studies were included after initial screening of 1853 hits. Learning disorders (LD) were reported in 21.4–26% of SLE offspring, exceeding the prevalence in the general population. Four studies reported that dyslexia and reading problems were present in 14.3–21.6% of lupus offspring with a clear male predominance. Furthermore, a twofold increased rate of autism spectrum disorders (ASD) (n = 1 study) and a two- to threefold increased risk for speech disorders (n = 3 studies) were reported in lupus offspring compared to controls, although the latter was not statistically significant. More divergent results were found for attention deficit (n = 5 studies) and behavior disorders (n = 3 studies). In two large controlled studies attention disorders were more prevalent and a trend towards more behavior disorders was reported in 2 of 3 studies analyzing this subject. Finally, IQ and motor skills were not affected in respectively 7 and 5 studies. Cardiopulmonary functioning and mood disorders were scarcely investigated (both n = 1). Maternal anti-SSA antibodies were associated with LD in offspring in one study. Other SLE-related antibodies were rarely studied. Conclusion This systematic review suggests that maternal SLE is associated with LD (specifically dyslexia), ASD, attention deficit and probably speech problems in offspring. However, over half of the studies were assigned a low or moderate evidence level. Therefore, further research is necessary to substantiate the found evidence and expand the scope to lesser researched areas such as cardiopulmonary functioning

Muscle Metabolic Responses During Dynamic In-Magnet Exercise Testing:A Pilot Study in Children with an Idiopathic Inflammatory Myopathy

Rationale and Objectives: The clinical utility of supine in-magnet bicycling in combination with phosphorus magnetic resonance spectroscopy (P-31 MRS) to evaluate quadriceps muscle metabolism was examined in four children with juvenile dermatomyositis (JDM) in remission and healthy age- and gender-matched controls. Materials and Methods: Two identical maximal supine bicycling tests were performed using a magnetic resonance-compatible ergometer. During the first test, cardiopulmonary performance was established in the exercise laboratory. During the second test, quadriceps energy balance and acid/base balance during incremental exercise and phosphocreatine recovery were determined using P-31 MRS. Results: During the first test, no significant differences were found between patients with JDM and their healthy peers regarding cardiopulmonary performance. The outcomes of the first test indicate that both groups attained maximal performance. During the second test, quadriceps phosphocreatine and pH time courses were similar in all but one patient experiencing idiopathic postexercise pain. This patient demonstrated faster phosphocreatine depletion and acidification during exercise, yet postexercise mitochondrial adenosine triphosphate synthesis rate measured by phosphocreatine recovery kinetics was approximately twofold faster than control (time constant 23 seconds vs 43 +/- 7 seconds, respectively). Conclusions: These results highlight the utility of in-magnet cycle ergometry in combination with P-31 MRS to assess and monitor muscle energetic patterns in pediatric patients with inflammatory myopathies

QUANTITATIVE MUSCLE ULTRASONOGRAPHY IN THE FOLLOW-UP OF JUVENILE DERMATOMYOSITIS

Introduction: We explored the use of quantitative muscle ultrasonography (QMUS) for follow-up of juvenile dermatomyositis (JDM). Methods: Seven JDM patients were evaluated at diagnosis and 1, 3, 6, 12, and 24 months using the Childhood Myositis Assessment Scale (CMAS) and QMUS. Muscle thickness (MT) and quantitative muscle echo intensity (EI) were assessed with QMUS in 4 muscles. Results: Six patients experienced a monocyclic course. At diagnosis EI was slightly increased, and MT was relatively normal. After start of treatment MT first decreased and EI increased, with normalization of EI within 6-12 months (n = 4). One patient had higher EIs at diagnosis and slower normalization, indicating fibrosis, despite early normalization of CMAS. One patient experienced a chronic course, with high EIs and atrophy during follow-up. Conclusions: QMUS can provide additional information for follow-up of JDM regarding disease severity and residual muscle damage, particularly after normalization of CMAS

2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Juvenile Dermatomyositis : An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative

Objective: To develop response criteria for juvenile dermatomyositis (DM). Methods: We analyzed the performance of 312 definitions that used core set measures from either the International Myositis Assessment and Clinical Studies Group (IMACS) or the Paediatric Rheumatology International Trials Organisation (PRINTO) and were derived from natural history data and a conjoint analysis survey. They were further validated using data from the PRINTO trial of prednisone alone compared to prednisone with methotrexate or cyclosporine and the Rituximab in Myositis (RIM) trial. At a consensus conference, experts considered 14 top candidate criteria based on their performance characteristics and clinical face validity, using nominal group technique. Results: Consensus was reached for a conjoint analysis–based continuous model with a total improvement score of 0–100, using absolute percent change in core set measures of minimal (≥30), moderate (≥45), and major (≥70) improvement. The same criteria were chosen for adult DM/polymyositis, with differing thresholds for improvement. The sensitivity and specificity were 89% and 91–98% for minimal improvement, 92–94% and 94–99% for moderate improvement, and 91–98% and 85–86% for major improvement, respectively, in juvenile DM patient cohorts using the IMACS and PRINTO core set measures. These criteria were validated in the PRINTO trial for differentiating between treatment arms for minimal and moderate improvement (P = 0.009–0.057) and in the RIM trial for significantly differentiating the physician's rating for improvement (P < 0.006). Conclusion: The response criteria for juvenile DM consisted of a conjoint analysis–based model using a continuous improvement score based on absolute percent change in core set measures, with thresholds for minimal, moderate, and major improvement