Mitochondrial dysfunction and role of harakiri in the pathogenesis of myositis.

The etiology of myositis is unknown. Although attempts to identify viruses in myositis skeletal muscle have failed, several studies have identified the presence of a viral signature in myositis patients. Here we postulate that in individuals with susceptible genetic backgrounds, viral infection alters the epigenome to activate the pathological pathways leading to disease onset. To identify epigenetic changes, methylation profiling of Coxsackie B infected human myotubes and muscle biopsies from polymyositis (PM) and dermatomyositis (DM) patients were compared to changes in global transcript expression induced by in vitro Coxsackie B infection. Gene and protein expression analysis and live cell imaging were performed to examine the mechanisms. Analysis of methylation and gene expression changes identified that a mitochondria-localized activator of apoptosis - harakiri (HRK) - is upregulated in myositis skeletal muscle cells. Muscle cells with higher HRK expression have reduced mitochondrial potential and poor ability to repair from injury as compared to controls. In cells from myositis patient toll-like receptor 7 (TLR7) activates and sustains high HRK expression. Forced over expression of HRK in healthy muscle cells is sufficient to compromise their membrane repair ability. Endurance exercise that is associated with improved muscle and mitochondrial function in PM and DM patients decreased TLR7 and HRK expression identifying these as therapeutic targets. Increased HRK and TLR7 expression causes mitochondrial damage leading to poor myofiber repair, myofiber death and muscle weakness in myositis patients and exercise induced reduction of HRK and TLR7 expression in patients is associated with disease amelioration. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

New insights into the benefits of exercise for muscle health in patients with idiopathic inflammatory myositis.

With recommended treatment, a majority with idiopathic inflammatory myopathy (IIM) develop muscle impairment and poor health. Beneficial effects of exercise have been reported on muscle performance, aerobic capacity and health in chronic polymyositis and dermatomyositis and to some extent in active disease and inclusion body myositis (IBM). Importantly, randomized controlled trials (RCTs) indicate that improved health and decreased clinical disease activity could be mediated through increased aerobic capacity. Recently, reports seeking mechanisms underlying effects of exercise in skeletal muscle indicate increased aerobic capacity (i.e. increased mitochondrial capacity and capillary density, reduced lactate levels), activation of genes in aerobic phenotype and muscle growth programs, and down regulation in genes related to inflammation. Altogether, exercise contributes to both systemic and within-muscle adaptations demonstrating that exercise is fundamental to improve muscle performance and health in IIM. There is a need for RCTs to study effects of exercise in active disease and IBM.

Activated LTB4 pathway in muscle tissue of patients with polymyositis or dermatomyositis.

OBJECTIVE: To investigate the involvement of the leukotriene B4 (LTB4) pathway in polymyositis (PM) and dermatomyositis (DM) and the effect of immunosuppressive treatment on the LTB4 pathway. METHODS: 5-lipoxygenase (5-LO), 5-LO activating protein (FLAP) and LTB4 receptor-1 (BLT1) expression was analysed by immunohistochemistry in muscle tissue from patients with PM/DM before and after immunosuppressive treatment and from healthy individuals. In vivo LTB4 in thigh muscle was measured by microdialysis at rest and after acute exercise in another cohort of patients and healthy controls. RESULTS: The number of 5-LO-positive cells and BLT1-positive capillaries was higher in patients with PM/DM than in healthy individuals. The number of FLAP-expressing cells divided the patients into two groups (high/low expression). Treatment reduced the number of FLAP-positive cells in the group with initial high levels, however the expression remained high compared with healthy individuals. The number of BLT1-positive cells was also reduced while staining for 5-LO was unchanged. An inverse correlation was observed between the number of 5-LO or FLAP-positive cells in muscle tissue and muscle performance. LTB4 could be detected in dialysate of muscle tissue in vivo in both patients and healthy controls and was significantly increased after exercise in patients. CONCLUSION: The LTB4 pathway is upregulated in muscle tissue from patients with PM/DM and this upregulation correlated negatively to muscle performance, suggesting a role for LTB4 in myositis muscle weakness. The immunosuppressive treatment was insufficient on the LTB4 pathway and, for patients with high expression of FLAP, FLAP inhibitors may be considered as possible therapy.

Muscle Strength and Muscle Endurance During the First Year of Treatment of Polymyositis and Dermatomyositis: A Prospective Study.

OBJECTIVE: To investigate muscle impairment (isometric and dynamic) and disease activity during the first year after diagnosis of polymyositis (PM) and dermatomyositis (DM), and to study the relationship between muscle impairment, patient-reported health, and disease activity. METHODS: Seventy-two patients enrolled in the Swedish Myositis Register, 2003-2010, were followed prospectively. The Manual Muscle test (MMT-8; isometric muscle strength), the Functional Index of myositis test (FI-2; dynamic, repetitive muscle function), and disease activity (6-item core set) were retrieved at the time of diagnosis, and after 6 and 12 months. Self-reported health (Medical Outcomes Study Short Form-36; SF-36) was retrieved at 12 months. RESULTS: At the time of diagnosis, median (Q1-Q3) for the FI-2 was 27.2% (7.9-60.5%) of maximal score compared to 93.8% (92.5-98.8%) of maximal MMT-8. At 12 months, the FI-2 and the MMT-8 improved to 29.4% (16.5-60.7%; p < 0.05) and 96.1% (88.1-99.4%), respectively (p < 0.01). At 12 months, 45% of patients improved ≥ 20%, and 27% worsened ≥ 20% in FI-2 score, while 10% improved ≥ 20% in MMT-8. Physician's global visual analog scale (VAS), Health Assessment Questionnaire, and creatine phosphokinase levels improved significantly at 12 months (p < 0.05-0.001) while patient's global and extramuscular VAS remained unchanged. The SF-36 physical function correlated strongly with the FI-2 (rs = 0.74; CI 0.55-0.85) and moderately with the MMT (rs = 0.54; CI 0.27-0.73), with lower correlations between muscle function and other SF-36 domains. CONCLUSION: Patients with PM/DM were characterized by impaired dynamic repetitive muscle function (DRMF) that correlated well with patient-reported physical function. Assessment of DRMF adds information regarding muscle impairment in these patients.

Development of a method to maximize the transcutaneous electrical nerve stimulation intensity in women with fibromyalgia.

Introduction: Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacological intervention clinically used for pain relief. The importance of utilizing the adequate stimulation intensity is well documented; however, clinical methods to achieve the highest possible intensity are not established. Objectives: Our primary aim was to determine if exposure to the full range of clinical levels of stimulation, from sensory threshold to noxious, would result in higher final stimulation intensities. A secondary aim explored the association of pain, disease severity, and psychological variables with the ability to achieve higher final stimulation intensity. Methods: Women with fibromyalgia (N=143) were recruited for a dual-site randomized controlled trial - Fibromyalgia Activity Study with TENS (FAST). TENS electrodes and stimulation were applied to the lumbar area, and intensity was increased to sensory threshold (ST), then to "strong but comfortable" (SC1), then to "noxious" (N). This was followed by a reduction to the final stimulation intensity of "strong but comfortable" (SC2). We called this the Setting of Intensity of TENS (SIT) test. Results: There was a significant increase from SC1 (37.5 mA IQR: 35.6-39.0) to SC2 (39.2 mA IQR: 37.1-45.3) (p<0.0001) with a mean increase of 1.7 mA (95% CI: 1.5, 2.2). Linear regression analysis showed that those with the largest increase between SC1 and N had the largest increase in SC2-SC1. Further, those with older age and higher anxiety were able to achieve greater increases in intensity (SC2-SC1) using the SIT test. Conclusion: The SC2-SC1 increase was significantly associated with age and anxiety, with greater mean increases associated with older age and higher anxiety. Thus, although all patients may benefit from this protocol, older women and women with elevated anxiety receive the greatest benefit.

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 NCT01184625.

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.

Disabilities of importance for patients to improve--using a patient preference tool in rheumatoid arthritis.

PURPOSE: To investigate, using the McMaster Toronto Arthritis patient preference disability questionnaire (MACTAR), disabilities most important to improve in Swedish patients with rheumatoid arthritis (RA) and to compare these with the pre-defined activities in the International Classification of Functioning (ICF) comprehensive core set for RA and the Stanford Health Assessment Questionnaire (HAQ). Also to categorize patient preference selected disabilities using the ICF, to correlate the MACTAR score to RA core set measures and to evaluate the MACTAR's test-retest reliability. METHODS: 45 patients with RA (median (md) age 59 years, diagnosis duration md 10 years) were included. Assessments included disease activity score (DAS28), timed-stands test (TST), shoulder function assessment (SFA), visual analogue scale for pain (VAS), HAQ, patients' global assessment of well-being (PGA) and the MACTAR. RESULTS: 58 disabilities were identified of which 17 were identified by at least 5 patients. 47% of them were represented in the Comprehensive ICF RA core set and 53% in the HAQ. 16/17 were categorized in the ICF activities and participation component. Correlations between the MACTAR and other measures were: DAS28 (rs -0.65), TST (rs -0.19), SFA (rs 0.38), VAS (rs -0.61), HAQ (rs -0.51) and PGA (rs -0.61). Weighted κ was 0.59. CONCLUSIONS: Half of the disabilities patients with RA identified by use of the MACTAR are not evaluated in the Comprehensive ICF core set for RA or the HAQ. MACTAR has moderate test-retest reliability. MACTAR can be considered to be used in addition to traditional RA outcomes and may potentially improve clinical assessment of patients with RA. IMPLICATIONS FOR REHABILITATION: RA has an impact on personal life areas. The MACTAR helps identify individual disease-related disabilities of importance to improve. The MACTAR provides an opportunity for individualized goal-setting in rehabilitation and can thus promote adherence in rehabilitation. MACTAR may potentially improve clinical assessment for patients with RA.

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 ß-hydroxyacyl-CoA dehydrogenase (ß-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 ß-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. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01184625.

Improvement in health and possible reduction in disease activity using endurance exercise in patients with established polymyositis and dermatomyositis: a multicenter randomized controlled trial with a 1-year open extension followup.

OBJECTIVE: To determine the effects of a 12-week endurance exercise program on health, disability, VO2 max, and disease activity in a multicenter randomized controlled trial in patients with established polymyositis (PM) and dermatomyositis (DM), and to evaluate health and disability in a 1-year open extension study. METHODS: Patients were randomized into a 12-week endurance exercise program group (EG; n = 11) or a control group (CG; n = 10). Assessments of health (Short Form 36 [SF-36]), muscle performance (5 voluntary repetition maximum [5 VRM]), activities of daily living (ADL), patient preference (McMaster Toronto Arthritis Patient Preference Disability Questionnaire), VO2 max, and disease activity (International Myositis Assessment and Clinical Studies criteria of improvement of the 6-item core set) were performed at 0 and 12 weeks. Disability assessments were performed again at 52 weeks in an open extension period. All assessments were performed by blinded observers. RESULTS: The EG improved compared to the CG in SF-36 physical function and vitality (P = 0.010 and P = 0.046, respectively), ADL score (P = 0.035), 5 VRM (P = 0.026), and VO2 max (P = 0.010). More patients in the EG (7 of 11) were responders with reduced disease activity compared to none in the CG (P = 0.002). Correlations between VO2 max and SF-36 physical function were 0.90 and 0.91 at 0 and 12 weeks, respectively (P < 0.05). The EG improvement in 5 VRM was sustained up to 52 weeks compared to baseline (5.7 kg; P < 0.001), but not in ADL score or SF-36. CONCLUSIONS: Endurance exercise improves health and may reduce disease activity in patients with established PM/DM. This potentially could be mediated through improved aerobic fitness. The results also indicate sustained muscle strength up to 1 year after a supervised program.

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 r(s) = -0.67-0.73, correlations with measures of activities of daily living and participation in society were r(s) = 0.51-0.60 with lower correlations for other outcomes. Intraclass correlation (ICC) and weighted Kappa (K(w)) 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.