Physical exercise as a targeted therapy in idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies are comprised of polymyositis (PM) and dermatomyositis (DM) with muscle impairment being the primary clinical feature. With the currently recommended treatment regimen, a majority of patients develop sustained impaired muscle performance and poor health for undetermined reasons. The overall aim was to test the hypothesis that sustained muscle impairment and poor health in patients with established PM/DM are consequences of low aerobic capacity and that the use of endurance exercise, as the targeted intervention, will contribute to beneficial systemic and muscle adaptations and to clinical improvement. A further aim was to evaluate the individual priorities (e.g., patient preferences) of patients with established PM/DM. The effect of a 12-week endurance exercise intervention was evaluated in a multi- center, randomized control trial in patients with established PM/DM (Papers II-IV). Exercise performance, aerobic capacity (maximal oxygen uptake (VO2 max)), and lactate levels in skeletal muscle were compared between patients (n = 23) and healthy controls (HC) (n = 12). Patients (n = 21) were randomized into an endurance exercise program or a nonexercise control group. Clinical assessments were performed at 0 and 12 weeks and consisted of: VO2 max, health (SF-36), muscle performance and disease activity (International Myositis Assessment and Clinical Studies Group criteria). Disability assessments were repeated at 52 weeks in an open extension. Associations between changes in clinical outcome measures and muscle properties were studied in vastus lateralis muscles by measuring extracellular lactate levels with microdialysis and by analyzing muscle biopsies for: mitochondrial enzyme activities (citrate synthase and β-hydroxyacyl-CoA dehydrogenase); mRNA expression profile; target protein validation by western blot analysis and by immuno-histochemistry (capillary density and inflammatory markers). In Paper I, we describe the patient preference in patients with PM/DM (n = 28) using the MacMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR). Exercise performance and VO2 max were lower in the patients than in the HCs, whereas their lactate levels at exhaustion were similar. 12 weeks of endurance exercise added to the recommended pharmacological treatment in patients with established PM/DM increased capillary density and mitochondrial capacity in skeletal muscle, which could have contributed to the markedly improved muscle performance through increased aerobic capacity. Lactate levels at exhaustion decreased. The improved health and decreased clinical disease activity could potentially be mediated through the demonstrated improved VO2 max from the endurance exercise. 12 weeks of endurance exercise only had a long-term beneficial effect on muscle strength. Changes in gene expression following the endurance exercise program indicate activation of the aerobic phenotype and muscle growth pathways, which overwrites the muscle atrophy process and simultaneously suppresses the inflammatory response. However, other mechanisms, such as muscle weakness, also seem to contribute to impaired muscle performance in patients. The MACTAR revealed disease consequences important to individual patients that were not assessed in the recommended PM/DM outcome measures. Altogether the results of this thesis indicate that endurance exercise is essential to improve aerobic capacity, muscle performance, and health in these patients

Patient Preference Assessment Reveals Disease Aspects Not Covered by Recommended Outcomes in Polymyositis and Dermatomyositis

Objectives. Polymyositis (PM) and dermatomyositis (DM) are characterized by impaired muscle function with a majority of patients developing sustained disability. The aim of this study was to evaluate the patient's individual priorities (patient preference) of disabilities most important to improve in PM/DM using the MacMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR), to correlate the MACTAR to myositis outcomes and to evaluate its test-retest reliability. Methods. Twenty-eight patients with PM/DM performed recommended outcomes as well as the MACTAR, which was performed twice with one week apart. Results. Sexual activity, walking, biking, social activities, and sleep constituted the predominating disabilities. Seventy-two and 33% of the identified disabilities were not covered by items of the Health Assessment Questionnaire and the Myositis Activities Profile. Correlations between the MACTAR and health-related quality of life measures were rs = −0.67–0.73, correlations with measures of activities of daily living and participation in society were rs = 0.51–0.60 with lower correlations for other outcomes. Intraclass correlation (ICC) and weighted Kappa (Kw) coefficients were 0.83 and 0.68, respectively, for test-retest reliability of the MACTAR. Conclusions. The MACTAR interview had promising measurement properties and identified patient preference disabilities in PM/DM that were not covered by recommended outcomes

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ABSTRACT. Objective. Currently there are no evidence-based recommendations regarding fitness and strength tests for patients with childhood or adult idiopathic inflammatory myopathies (IIM). This hinders clinicians and researchers in choosing the appropriate fitness-or muscle strength-related outcome measures for these patients. Through a Delphi survey, we aimed to identify a candidate core set of fitness and strength tests for children and adults with IIM. Methods. Fifteen experts participated in a Delphi survey that consisted of 5 stages to achieve a consensus. Using an extensive search of published literature and through the work of experts, a candidate core set based on expert opinion and clinimetrics properties was developed. Members of the International Myositis Assessment and Clinical Studies Group were invited to review this candidate core set during the final stage, which led to a final candidate core set. Results. A core set of fitness-and strength-related outcome measures was identified for children and adults with IIM. For both children and adults, different tests were identified and selected for maximal aerobic fitness, submaximal aerobic fitness, anaerobic fitness, muscle strength tests, and muscle function tests. Conclusion. The core set of fitness-and strength-related outcome measures provided by this expert consensus process will assist practitioners and researchers in deciding which tests to use in patients with IIM. This will improve the uniformity of fitness and strength tests across studies, thereby facilitating the comparison of study results and therapeutic exercise program outcomes among patients wit

Improved exercise performance and increased aerobic capacity after endurance training of patients with stable polymyositis and dermatomyositis

Introduction: This randomized, controlled study on patients with polymyositis or dermatomyositis was based on three hypotheses: patients display impaired endurance due to reduced aerobic capacity and muscle weakness, endurance training improves their exercise performance by increasing the aerobic capacity, and endurance training has general beneficial effects on their health status. Methods: In the first part of this study, we compared 23 patients with polymyositis or dermatomyositis with 12 age-and gender-matched healthy controls. A subgroup of patients were randomized to perform a 12-week endurance training program (exercise group, n = 9) or to a non-exercising control group (n = 6). We measured maximal oxygen uptake (VO2 max) and the associated power output during a progressive cycling test. Endurance was assessed as the cycling time to exhaustion at 65% of VO2 max. Lactate levels in the vastus lateralis muscle were measured with microdialysis. Mitochondrial function was assessed by measuring citrate synthase (CS) and beta-hydroxyacyl-CoA dehydrogenase (beta-HAD) activities in muscle biopsies. Clinical improvement was assessed according to the International Myositis Assessment and Clinical Studies Group (IMACS) improvement criteria. All assessors were blinded to the type of intervention (that is, training or control). Results: Exercise performance and aerobic capacity were lower in patients than in healthy controls, whereas lactate levels at exhaustion were similar. Patients in the exercise group increased their cycling time, aerobic capacity and CS and beta-HAD activities, whereas lactate levels at exhaustion decreased. Six of nine patients in the exercise group met the IMACS improvement criteria. Patients in the control group did not show any consistent changes during the 12-week study. Conclusions: Polymyositis and dermatomyositis patients have impaired endurance, which could be improved by 12 weeks of endurance training. The clinical improvement corresponds to increases in aerobic capacity and muscle mitochondrial enzyme activities. The results emphasize the importance of endurance exercise in addition to immunosuppressive treatment of patients with polymyositis or dermatomyositis

Effect of endurance exercise on microRNAs in myositis skeletal muscle-A randomized controlled study.

Objective To identify changes in skeletal muscle microRNA expression after endurance exercise and associate the identified microRNAs with mRNA and protein expression to disease-specific pathways in polymyositis (PM) and dermatomyositis (DM) patients. Methods Following a parallel clinical trial design, patients with probable PM or DM, exercising less than once a week, and on stable medication for at least one month were randomized into two groups at Karolinska University Hospital: a 12-week endurance exercise group (n = 12) or a non-exercised control group (n = 11). Using an Affymetrix microarray, microRNA expression was determined in paired muscle biopsies taken before and after the exercise intervention from 3 patients in each group. Ingenuity pathway analysis with a microRNA target filter was used to identify microRNA transcript targets. These targets were investigated at the mRNA (microarray) and protein (mass spectrometry) levels in patients. Results Endurance exercise altered 39 microRNAs. The microRNAs with increased expression were predicted to target transcripts involved in inflammatory processes, metabolism, and muscle atrophy. Further, these target transcripts had an associated decrease in mRNA expression in exercised patients. In particular, a decrease in the NF-κB regulator IKBKB was associated with an increase in its target microRNA (miR-196b). At the protein level, there was an increase in mitochondrial proteins (AK3, HIBADH), which were associated with a decrease in microRNAs that were predicted to regulate their expression. Conclusion Improvement in disease phenotype after exercise is associated with increasing microRNAs that target and downregulate immune processes at the transcript level, as well as decreasing microRNAs that target and upregulate mitochondrial content at the protein level. Therefore, microRNAs may improve disease by decreasing immune responses and increasing mitochondrial biogenesis. Trial registration ClinicalTrials.gov NCT0118462

Proposal for a Candidate Core Set of Fitness and Strength Tests for Patients with Childhood or Adult Idiopathic Inflammatory Myopathies

OBJECTIVE: Currently there are no evidence-based recommendations regarding fitness and strength tests for patients with childhood or adult idiopathic inflammatory myopathies (IIM). This hinders clinicians and researchers in choosing the appropriate fitness- or muscle strength-related outcome measures for these patients. Through a Delphi survey, we aimed to identify a candidate core set of fitness and strength tests for children and adults with IIM. METHODS: Fifteen experts participated in a Delphi survey that consisted of 5 stages to achieve a consensus. Using an extensive search of published literature and through the work of experts, a candidate core set based on expert opinion and clinimetrics properties was developed. Members of the International Myositis Assessment and Clinical Studies Group were invited to review this candidate core set during the final stage, which led to a final candidate core set. RESULTS: A core set of fitness- and strength-related outcome measures was identified for children and adults with IIM. For both children and adults, different tests were identified and selected for maximal aerobic fitness, submaximal aerobic fitness, anaerobic fitness, muscle strength tests, and muscle function tests. CONCLUSION: The core set of fitness- and strength-related outcome measures provided by this expert consensus process will assist practitioners and researchers in deciding which tests to use in patients with IIM. This will improve the uniformity of fitness and strength tests across studies, thereby facilitating the comparison of study results and therapeutic exercise program outcomes among patients with IIM

Proposal for a Candidate Core Set of Fitness and Strength Tests for Patients with Childhood or Adult Idiopathic Inflammatory Myopathies

OBJECTIVE: Currently there are no evidence-based recommendations regarding fitness and strength tests for patients with childhood or adult idiopathic inflammatory myopathies (IIM). This hinders clinicians and researchers in choosing the appropriate fitness- or muscle strength-related outcome measures for these patients. Through a Delphi survey, we aimed to identify a candidate core set of fitness and strength tests for children and adults with IIM. METHODS: Fifteen experts participated in a Delphi survey that consisted of 5 stages to achieve a consensus. Using an extensive search of published literature and through the work of experts, a candidate core set based on expert opinion and clinimetrics properties was developed. Members of the International Myositis Assessment and Clinical Studies Group were invited to review this candidate core set during the final stage, which led to a final candidate core set. RESULTS: A core set of fitness- and strength-related outcome measures was identified for children and adults with IIM. For both children and adults, different tests were identified and selected for maximal aerobic fitness, submaximal aerobic fitness, anaerobic fitness, muscle strength tests, and muscle function tests. CONCLUSION: The core set of fitness- and strength-related outcome measures provided by this expert consensus process will assist practitioners and researchers in deciding which tests to use in patients with IIM. This will improve the uniformity of fitness and strength tests across studies, thereby facilitating the comparison of study results and therapeutic exercise program outcomes among patients with IIM