Extracorporeal Membrane Oxygenation for Acute Lung Injury in Idiopathic Inflammatory Myopathies-A Potential Lifesaving Intervention.

OBJECTIVES: Idiopathic inflammatory myopathies (IIM) can present with acute IIM-related lung injury and respiratory failure, leading to a high mortality risk in intensive care units (ICU). Extracorporeal membrane oxygenation (ECMO) in acute respiratory distress syndrome can be lifesaving. We aimed to report a case series of IIM patients that received ECMO. METHODS: Patients with IIM from tertiary care centers in Belgium, Canada, Denmark, United States, and Sweden who underwent ECMO were reviewed to describe clinical characteristics, disease outcomes and hospitalization course. Clinical characteristics at admission and during ICU stay including ECMO complications and mortality causes were summarized. RESULTS: The study included 22 patients (50% female, mean±SD age at admission 47 ± 12 years) with anti-MDA5 positive dermatomyositis (68%), anti-synthetase syndrome (14%), polymyositis (9%), overlap myositis (5%) and non-MDA5 dermatomyositis (5%). Patients had low comorbidity scores and 46% had received immunosuppression before their ICU admission. Eight (36%) patients died in the ICU, six (27%) were bridged to recovery and eight (36%) were bridged to transplant. When comparing patients bridged to recovery and those who died in the ICU, those who died were older (p= 0.03) and had higher median Charlson comorbidity index scores (p= 0.05). Both groups had similar frequencies of ECMO-related complications (33% vs 50%, p= 0.94). CONCLUSION: In the patients exposed to ECMO in this case series, 14 were successfully bridged to recovery or transplant, while 8 died in the ICU. Large studies are needed to collect data on clinical outcomes in patients with IIM-ILD exposed to ECMO to identify the best candidates for the intervention.

Effects of sporadic inclusion body myositis on skeletal muscle fibre type specific morphology and markers of regeneration and inflammation.

Sporadic inclusion body myositis (sIBM) is a subgroup of idiopathic inflammatory myopathies characterised by progressive muscle weakness and skeletal muscle inflammation. Quantitative data on the myofibre morphology in sIBM remains scarce. Further, no previous study has examined fibre type association of satellite cells (SC), myonuclei number, macrophages, capillaries, and myonuclear domain (MD) in sIBM patients. Muscle biopsies from sIBM patients (n = 18) obtained previously (NCT02317094) were included in the analysis for fibre type-specific myofibre cross-sectional area (mCSA), SCs, myonuclei and macrophages, myonuclear domain, and capillarisation. mCSA (p < 0.001), peripheral myonuclei (p < 0.001) and MD (p = 0.005) were higher in association with type 1 (slow-twitch) than type 2 (fast-twitch) fibres. Conversely, quiescent SCs (p < 0.001), centrally placed myonuclei (p = 0.03), M1 macrophages (p < 0.002), M2 macrophages (p = 0.013) and capillaries (p < 0.001) were higher at type 2 fibres compared to type 1 fibres. In contrast, proliferating (Pax7+/Ki67+) SCs (p = 0.68) were similarly associated with each fibre type. Type 2 myofibres of late-phase sIBM patients showed marked signs of muscle atrophy (i.e. reduced mCSA) accompanied by higher numbers of associated quiescent SCs, centrally placed myonuclei, macrophages and capillaries compared to type 1 fibres. In contrast, type 1 fibres were suffering from pathological enlargement with larger MDs as well as fewer nuclei and capillaries per area when compared with type 2 fibres. More research is needed to examine to which extent different therapeutic interventions including targeted exercise might alleviate these fibre type-specific characteristics and countermeasure their consequences in impaired functional performance.

High-intensity resistance training improves quality of life, muscle endurance and strength in patients with myositis: a randomised controlled trial.

Myositis is associated with reduced quality of life, which is accompanied by significant impairments in muscle endurance and strength, altogether representing cardinal traits in patients with myositis. This randomised controlled trial aimed to investigate the effect of high-intensity resistance training on quality of life in patients with myositis. Thirty-two patients with established, stable myositis were randomised to 16 weeks of high-intensity resistance training (intervention group) or 16 weeks of usual care (control group). Primary outcome was quality of life assessed as the change in the physical component summary score (PCS) of the Short Form-36 health questionnaire from baseline to post-intervention. Secondary outcomes included functional capacity measures, such as functional index 3, and International Myositis Assessment and Clinical Studies Group (IMACS) disease activity and damage core set measures, including manual muscle testing 8 (MMT8). The primary outcome PCS showed an improvement in favour of high-intensity resistance training with a between-group difference of 5.33 (95% CI 0.61; 10.05) (p = 0.03). Additionally, functional index 3 showed a between-group difference indicating greater gains with high-intensity resistance training 11.49 (95% CI 3.37; 19.60) (p = 0.04), along with a between-group improvement in MMT8 1.30 (95% CI 0.09; 2.51) (p = 0.04). High-intensity resistance training for 16 weeks effectively improved quality of life in patients with myositis. Clinical measures of muscle endurance and muscle strength were also found to improve with high-intensity resistance training, while patients stayed in disease remission. Consequently, progressively adjusted high-intensity resistance training is feasible and causes no aggravation of the disease, while benefitting patients with myositis.Clinical trial registration: Clinicaltrials.gov ID: NCT04486261- https://clinicaltrials.gov/study/NCT04486261 .

Myositis-related autoantibody profile and clinical characteristics stratified by anti-cytosolic 5'-nucleotidase 1A status in connective tissue diseases.

INTRODUCTION/AIMS: Cytosolic 5'-nucleotidase 1A (cN-1A) autoantibodies have been recognized as myositis-related autoantibodies. However, their correlations with clinical characteristics and other myositis-specific and myositis-associated autoantibodies (MSAs/MAAs) are still unclear. We aimed to establish the prevalence and clinical and laboratory associations of cN-1A autoantibodies in a cohort of patients with connective tissue diseases. METHODS: A total of 567 participants (182 idiopathic inflammatory myopathies [IIM], 164 systemic lupus erythematosus [SLE], 121 systemic sclerosis [SSc], and 100 blood donors [BD]) were tested for the presence of cN-1A autoantibodies and other myositis-specific and myositis-associated autoantibodies (MSAs/MAAs). Clinical and laboratory characteristics were compared between anti-cN-1A positive and negative patients with sporadic inclusion body myositis (sIBM) and between anti-cN-1A positive and negative patients with non-IBM IIM. RESULTS: In the sIBM cohort, 30 patients (46.9%) were anti-cN-1A positive vs. 18 (15.2%) in the non-IBM IIM cohort, 17 (10%) were anti-cN-1A positive in the SLE cohort and none in the SSc or the BD cohorts. Anti-cN-1A positivity had an overall sensitivity of 46.9% and a specificity of 93.2% for sIBM. Dysphagia was more frequent in the anti-cN-1A positive vs. negative sIBM patients (p = .04). In the non-IBM IIM group, being anti-cN-1A antibody positive was associated with the diagnosis polymyositis (p = .04) and overlap-myositis (p = .04) and less disease damage evaluated by physician global damage score (p < .001). DISCUSSION: cN-1A autoantibodies were predominantly found in IIM patients and was associated with dysphagia in sIBM patients. Notably, anti-cN-1A appears to identify a distinct phenotype of anti-cN-1A positive non-IBM IIM patients with a milder disease course.

The EuroMyositis registry: an international collaborative tool to facilitate myositis research.

AIMS: The EuroMyositis Registry facilitates collaboration across the idiopathic inflammatory myopathy (IIM) research community. This inaugural report examines pooled Registry data. METHODS: Cross-sectional analysis of IIM cases from 11 countries was performed. Associations between clinical subtypes, extramuscular involvement, environmental exposures and medications were investigated. RESULTS: Of 3067 IIM cases, 69% were female. The most common IIM subtype was dermatomyositis (DM) (31%). Smoking was more frequent in connective tissue disease overlap cases (45%, OR 1.44, 95% CI 1.09 to 1.90, p=0.012). Smoking was associated with interstitial lung disease (ILD) (OR 1.32, 95% CI 1.06 to 1.65, p=0.013), dysphagia (OR 1.43, 95% CI 1.16 to 1.77, p=0.001), malignancy ever (OR 1.78, 95% CI 1.36 to 2.33, p<0.001) and cardiac involvement (OR 2.40, 95% CI 1.60 to 3.60, p<0.001).Dysphagia occurred in 39% and cardiac involvement in 9%; either occurrence was associated with higher Health Assessment Questionnaire (HAQ) scores (adjusted OR 1.79, 95% CI 1.43 to 2.23, p<0.001). HAQ scores were also higher in inclusion body myositis cases (adjusted OR 3.85, 95% CI 2.52 to 5.90, p<0.001). Malignancy (ever) occurred in 13%, most commonly in DM (20%, OR 2.06, 95% CI 1.65 to 2.57, p<0.001).ILD occurred in 30%, most frequently in antisynthetase syndrome (71%, OR 10.7, 95% CI 8.6 to 13.4, p<0.001). Rash characteristics differed between adult-onset and juvenile-onset DM cases ('V' sign: 56% DM vs 16% juvenile-DM, OR 0.16, 95% CI 0.07 to 0.36, p<0.001). Glucocorticoids were used in 98% of cases, methotrexate in 71% and azathioprine in 51%. CONCLUSION: This large multicentre cohort demonstrates the importance of extramuscular involvement in patients with IIM, its association with smoking and its influence on disease severity. Our findings emphasise that IIM is a multisystem inflammatory disease and will help inform prognosis and clinical management of patients.

Cardiac abnormalities assessed by non-invasive techniques in patients with newly diagnosed idiopathic inflammatory myopathies.

OBJECTIVES: Knowledge of cardiac involvement in idiopathic inflammatory myopathies (IIM) is limited, especially in the early stage of disease. The objective of the present study was to perform a controlled evaluation of cardiac abnormalities in newly diagnosed, untreated patients with idiopathic inflammatory myopathies (IIM) by means of non-invasive techniques. METHODS: Fourteen patients with IIM (8 polymyositis, 4 dermatomyositis, 2 cancer-associated dermatomyositis) and 14 gender- and age- matched healthy control subjects were investigated. Participant assessments included a cardiac questionnaire, cardiac troponin-I (TnI), electrocardiogram (standard 12-lead and 48-h Holter monitoring), echocardiography with tissue Doppler measures, cardiac magnetic resonance (CMR) imaging with T2 mapping and semi-quantitative (99m)technetium pyrophosphate ((99m)Tc-PYP) scintigraphy. RESULTS: Dyspnoea was present in 8 (57%) of the patients compared to none of the controls (p<0.01). Median levels of TnI in patients and controls were 20 ng/L and 6 ng/L, respectively (p=0.06). QTc intervals were prolonged in the patient group (p=0.01). Two patients had systolic dysfunction, and one diastolic dysfunction. The myocardial (99m)Tc-PYP uptake and CMR results differed between patients and controls, albeit not with statistical significance. Overall, cardiac abnormalities were demonstrated in 9 (64%) of the patients versus 2 (14%) of the controls (p=0.02). CONCLUSIONS: Cardiac abnormalities assessed by TnI, ECG or imaging modalities were significantly more common in newly diagnosed, treatment naïve patients with IIM compared to healthy control subjects. These abnormalities, although subclinical, may indicate that myocardial involvement is common in patients and calls for larger controlled studies and further investigations of the prognostic implications of this finding.

Multicentre investigation on the effect of decompressive surgery on Balance and physical ActiviTy Levels amongst patients with lumbar Spinal stenosis (B-ATLAS): protocol for a prospective cohort study.

INTRODUCTION: Patients with lumbar spinal stenosis may have poor balance, decreased physical function and problems maintaining physical activity levels due to radiculopathy. Decompressive surgery is often indicated if conservative management fails to achieve a satisfactory clinical outcome. While surgical management has proven effective at treating radiculopathy, and patients report increased physical function postoperatively, objective measures of postural control and physical activity remain sparse. This study aims to investigate the effects of decompressive surgery on postural control and activity levels of elderly patients with lumbar spinal stenosis using objective measurements. METHODS AND ANALYSIS: This is a 24-month, multicentre, prospective cohort study. Patients ≥65 years of age with MRI-verified symptomatic lumbar central canal stenosis will be recruited from two separate inclusion centres, and all participants will undergo decompressive surgery. Preoperative data are collected up to 3 months before surgery, with follow-up data collected at 3, 6, 12 and 24 months postoperatively. Postural control measurements are performed using the Wii Balance Board, mini Balance Evaluation Systems Test and Tandem test, and data concerning physical activity levels are collected using ActiGraph wGT3X-BT accelerometers. Patient-reported outcomes regarding quality-of-life and physical function are collected from the EuroQol-5D, 36-Item Short Form Health Survey and Zurich Claudication Questionnaire. Primary outcomes are the change in the sway area of centre of pressure and total activity counts per day from baseline to follow-up at 24 months. A sample size of 80 participants has been calculated. ETHICS AND DISSEMINATION: The study has been approved by the Regional Ethics Committee of Region Zealand (ID EMN-2022-08110) and the Danish Data Protection Agency (ID REG-100-2022). Written informed consent will be required from all participants before enrolment. All results from the study, whether positive, negative or inconclusive, will be published in international peer-reviewed journals and presented at national and international scientific meetings. Study findings will be further disseminated through national patient associations. TRIAL REGISTRATION NUMBERS: NCT06075862 and NCT06057428.

Effect modification of cancer on the association between dysphagia and mortality in early idiopathic inflammatory myopathies.

OBJECTIVE: The interplay between dysphagia, cancer, and mortality in idiopathic inflammatory myopathies (IIM) has not been carefully studied. The aim of this study was to investigate possible effect modification of cancer on the association between dysphagia and mortality in early IIM. METHODS: A multi-center cohort of 230 adult IIM patients with dysphagia assessment within 6 months of disease onset was assembled. Crude mortality rates in IIM patients exposed or not to dysphagia were estimated for the 5-year period following cohort entry. To explore possible effect modification of cancer on the association between dysphagia and mortality, adjusted Cox models stratified on cancer status were performed as well as an interaction model. RESULTS: Mortality rates per 100 person-years for IIM patients exposed to dysphagia were 2.3 (95 %CI 1.0 to 4.5) in those without cancer compared to 33.3 (95 %CI 16.6 to 59.5) in those with cancer. In stratified Cox models, the main effect of dysphagia was HR 0.5 (95 %CI 0.2 to 1.5) in non-cancer and 3.1 (95 %CI 1.0 to 10.2) in cancer patients. In the interaction model, the combination of dysphagia and cancer yielded a HR of 6.4 (1.2 to 35.1). CONCLUSION: In this IIM cohort, dysphagia in non-cancer patients was not associated with increased mortality, while it was in presence of cancer, supporting effect modification of cancer on the association between dysphagia and mortality. This suggests that IIM patients with and without cancer differ and separate analyses for the two groups should be conducted when the outcome of interest is mortality.

Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune Diseases.

OBJECTIVE: Systemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren disease (pSS), and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study was aimed at elucidating the genetics underlying these common features. METHODS: We performed targeted DNA sequencing of coding and regulatory regions from approximately 1,900 immune-related genes in a large cohort of 2,292 well-characterized Scandinavian patients with SIADs with SLE, pSS, and myositis as well as 1,252 controls. A gene-based functionally weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by in silico functional analyses and in vitro reporter experiments. RESULTS: Case-control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case-case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by antinuclear antibodies and anti-double-stranded DNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that dual-specificity phosphatase 1 (DUSP1) protective genetic variants lead to increased gene expression and potentially to anti-inflammatory effects on the SIAD-associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported down-regulation of the MAPK signaling-related gene DUSP1 in other skin disorders. CONCLUSION: Together, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks.

Right Ventricular Morphology and Function after Exercise Training in People with Systemic Sclerosis: A Randomized Controlled Pilot Study.

BACKGROUND: Vascular dysfunction and its concomitant multi-organ involvement, including cardiac involvement, affects prognosis in systemic sclerosis (SSc) patients. Regular exercise has demonstrated to be able to improve vascular function in SSc. However, the effects of an exercise program on the heart and specifically in right ventricular (RV) morphology and function in SSc have yet to be explored. The study aimed to examine whether a 3-month combined exercise program can affect RV morphology and function in SSc patients. METHODS: Twenty-eight SSc patients were randomly allocated to either the exercise training (ET) or the control (CON) group. Baseline and follow-up assessments consisted of a cardiopulmonary exercise test along with both a conventional and a two-dimensional speckle tracking echocardiography (2DSTE) focused on RV morphology and function. Following the baseline assessments, Group ET participated in a supervised combined exercise program for 12 weeks, while group CON received their usual care. RESULTS: The ET group demonstrated increases in peak oxygen consumption by 25.1% (p < 0.001), global RV free wall longitudinal systolic strain by 6.69% (p < 0.03), RV free wall longitudinal systolic strain of the basal segment by 13.5% (p < 0.001), and global RV four-chamber longitudinal systolic strain by 6.76% (p < 0.03) following the exercise program. No differences were observed in group CON. CONCLUSIONS: Combined exercise improved cardiorespiratory efficiency and indices of RV systolic function, as assessed by the 2DSTE, in SSc patients.

Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies.

BACKGROUND: In patients with idiopathic inflammatory myopathies (IIM), autoantibodies are associated with specific clinical phenotypes suggesting a pathogenic role of adaptive immunity. We explored if autoantibody profiles are associated with specific HLA genetic variants and clinical manifestations in IIM. METHODS: We included 1348 IIM patients and determined the occurrence of 14 myositis-specific or -associated autoantibodies. We used unsupervised cluster analysis to identify autoantibody-defined subgroups and logistic regression to estimate associations with clinical manifestations, HLA-DRB1, HLA-DQA1, HLA-DQB1 alleles, and amino acids imputed from genetic information of HLA class II and I molecules. FINDINGS: We identified eight subgroups with the following dominant autoantibodies: anti-Ro52, -U1RNP, -PM/Scl, -Mi2, -Jo1, -Jo1/Ro52, -TIF1γ or negative for all analysed autoantibodies. Associations with HLA-DRB1∗11, HLA-DRB1∗15, HLA-DQA1∗03, and HLA-DQB1∗03 were present in the anti-U1RNP-dominated subgroup. HLA-DRB1∗03, HLA-DQA1∗05, and HLA-DQB1∗02 alleles were overrepresented in the anti-PM/Scl and anti-Jo1/Ro52-dominated subgroups. HLA-DRB1∗16, HLA-DRB1∗07 alleles were most frequent in anti-Mi2 and HLA-DRB1∗01 and HLA-DRB1∗07 alleles in the anti-TIF1γ subgroup. The HLA-DRB1∗13, HLA-DQA1∗01 and HLA-DQB1∗06 alleles were overrepresented in the negative subgroup. Significant signals from variations in class I molecules were detected in the subgroups dominated by anti-Mi2, anti-Jo1/Ro52, anti-TIF1γ, and the negative subgroup. INTERPRETATION: Distinct HLA class II and I associations were observed for almost all autoantibody-defined subgroups. The associations support autoantibody profiles use for classifying IIM which would likely reflect underlying pathogenic mechanisms better than classifications based on clinical symptoms and/or histopathological features. FUNDING: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.

Lack of muscle stem cell proliferation and myocellular hypertrophy in sIBM patients following blood-flow restricted resistance training.

Sporadic inclusion body myositis (sIBM) is characterised by skeletal muscle inflammation, progressive muscle loss and weakness, which is largely refractory to immunosuppressive treatment. Low-load blood-flow restricted (BFR) training has been shown to evoke gains in myofibre cross sectional area (mCSA) in healthy adults. This could partially be due to the activation and integration of muscle satellite cells (SC) resulting in myonuclei addition. Consequently, this study investigated the effect of 12-weeks lower limb low-load BFR resistance training in sIBM patients on SC and myonuclei content, myofibre size and capillarization. Muscle biopsies from sIBM patients randomised to 12-weeks of low-load BFR resistance training (n = 11) or non-exercising controls (CON) (n = 9) were analysed for SC and myonuclei content, myofibre size and capillarization using three-colour immunofluorescence microscopy and computerised quantification procedures. No between-group differences (time-by-group interactions) or within-groups changes were observed for resident SCs (Pax7+/Six1+), proliferating SCs (Pax7+/ Ki67+), myonuclei (Six1+), type 1 mCSA or capillary number (CD31+). However, a time-by-group interaction for type 2 mCSA was observed (p = 0.04). Satellite cell content, myonuclei number, mCSA and capillary density remained unaffected following 12-weeks low-load BFR resistance training, indicating limited myogenic capacity and satellite cell plasticity in long-term sIBM patients.

Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases.

OBJECTIVE: Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjögren's syndrome (SS), or myositis. METHODS: Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterized Scandinavian patients with SLE, primary SS, or myositis and 1,251 healthy controls. RESULTS: A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2-33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 1.7-5.5]). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals' capacity to deposit C4b on immune complexes. CONCLUSION: We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account.

High-intensity strength training in patients with idiopathic inflammatory myopathies: a randomised controlled trial protocol.

INTRODUCTION: Idiopathic inflammatory myopathies (IIMs) are rare diseases characterised by non-suppurative inflammation of skeletal muscles and muscle weakness. Additionally, IIM is associated with a reduced quality of life. Strength training is known to promote muscle hypertrophy and increase muscle strength and physical performance in healthy young and old adults. In contrast, only a few studies have examined the effects of high intensity strength training in patients with IIM and none using a randomised controlled trial (RCT) set-up. Thus, the purpose of this study is to investigate the effects of high-intensity strength training in patients affected by the IIM subsets polymyositis (PM), dermatomyositis (DM) and immune-mediated necrotising myopathy (IMNM) using an RCT study design. METHODS AND ANALYSIS: 60 patients with PM, DM or IMNM will be included and randomised into (1) high-intensity strength training or (2) Care-as-Usual. The intervention period is 16 weeks comprising two whole-body strength exercise sessions per week. The primary outcome parameter will be the changes from pre training to post training in the Physical Component Summary measure in the Short Form-36 health questionnaire. Secondary outcome measures will include maximal lower limb muscle strength, skeletal muscle mass, functional capacity, disease status (International Myositis Assessment and Clinical Studies Group core set measures) and questionnaires assessing physical activity levels and cardiovascular comorbidities. Furthermore, blood samples and muscle biopsies will be collected for subsequent analyses. ETHICS AND DISSEMINATION: The study complies with the Helsinki Declaration II and is approved by The Danish Data Protection Agency (P-2020-553). The study is approved by The Danish National Committee on Health Research Ethics (H-20030409). The findings of this trial will be submitted to relevant peer-reviewed journals. Abstracts will be submitted to international conferences. TRIAL REGISTRATION NUMBER: NCT04486261.

The influence of experimentally induced pain on shoulder muscle activity.

Muscle function is altered in painful shoulder conditions. However, the influence of shoulder pain on muscle coordination of the shoulder has not been fully clarified. The aim of the present study was to examine the effect of experimentally induced shoulder pain on shoulder muscle function. Eleven healthy men (range 22-27 years), with no history of shoulder or cervical problems, were included in the study. Pain was induced by 5% hypertonic saline injections into the supraspinatus muscle or subacromially. Seated in a shoulder machine, subjects performed standardized concentric abduction (0 degrees -105 degrees) at a speed of approximately 120 degrees/s, controlled by a metronome. During abduction, electromyographic (EMG) activity was recorded by intramuscular wire electrodes inserted in two deeply located shoulder muscles and by surface-electrodes over six superficially located shoulder muscles. EMG was recorded before pain, during pain and after pain had subsided and pain intensity was continuously scored on a visual analog scale (VAS). During abduction, experimentally induced pain in the supraspinatus muscle caused a significant decrease in activity of the anterior deltoid, upper trapezius and the infraspinatus and an increase in activity of lower trapezius and latissimus dorsi muscles. Following subacromial injection a significantly increased muscle activity was seen in the lower trapezius, the serratus anterior and the latissimus dorsi muscles. In conclusion, this study shows that acute pain both subacromially and in the supraspinatus muscle modulates coordination of the shoulder muscles during voluntary movements. During painful conditions, an increased activity was detected in the antagonist (latissimus), which support the idea that localized pain affects muscle activation in a way that protects the painful structure. Further, the changes in muscle activity following subacromial pain induction tend to expand the subacromial space and thereby decrease the load on the painful structures.

The immune system in sporadic inclusion body myositis patients is not compromised by blood-flow restricted exercise training.

BACKGROUND: Sporadic inclusion body myositis (sIBM) is clinically characterised by progressive proximal and distal muscle weakness and impaired physical function while skeletal muscle tissue displays abnormal cellular infiltration of T cells, macrophages, and dendritic cells. Only limited knowledge exists about the effects of low-load blood flow restriction exercise in sIBM patients, and its effect on the immunological responses at the myocellular level remains unknown. The present study is the first to investigate the longitudinal effects of low-load blood flow restriction exercise on innate and adaptive immune markers in skeletal muscle from sIBM patients. METHODS: Twenty-two biopsy-validated sIBM patients were randomised into either 12 weeks of low-load blood flow restriction exercise (BFRE) or no exercise (CON). Five patients from the control group completed 12 weeks of BFRE immediately following participation in the 12-week control period leading to an intervention group of 16 patients. Muscle biopsies were obtained from either the m. tibialis anterior or the m. vastus lateralis for evaluation of CD3-, CD8-, CD68-, CD206-, CD244- and FOXP3-positive cells by three-colour immunofluorescence microscopy and Visiopharm-based image analysis quantification. A linear mixed model was used for the statistical analysis. RESULTS: Myocellular infiltration of CD3-/CD8+ expressing natural killer cells increased following BFRE (P < 0.05) with no changes in CON. No changes were observed for CD3+/CD8- or CD3+/CD8+ T cells in BFRE or CON. CD3+/CD244+ T cells decreased in CON, while no changes were observed in BFRE. Pronounced infiltration of M1 pro-inflammatory (CD68+/CD206-) and M2 anti-inflammatory (CD68+/CD206+) macrophages were observed at baseline; however, no longitudinal changes in macrophage content were observed for both groups. CONCLUSIONS: Low-load blood flow restriction exercise elicited an upregulation in CD3-/CD8+ expressing natural killer cell content, which suggests that 12 weeks of BFRE training evokes an amplified immune response in sIBM muscle. However, the observation of no changes in macrophage or T cell infiltration in the BFRE-trained patients indicates that patients with sIBM may engage in this type of exercise with no risk of intensified inflammatory activity.

The effect of handedness on electromyographic activity of human shoulder muscles during movement.

The aim of the study was to investigate whether there was a difference in the electromyographic (EMG) activity of human shoulder muscles between the dominant and nondominant side during movement and to explore whether a possible side-difference depends on the specific task. We compared the EMG activity with surface and intramuscular electrodes in eight muscles of both shoulders in 20 healthy subjects whose hand preference was evaluated using a standard questionnaire. EMG signals were recorded during abduction and external rotation. During abduction, the normalized EMG activity was significantly smaller on the dominant side compared to the nondominant side for all the muscles except for infraspinatus and lower trapezius (P

Quantitative 3D scintigraphy shows increased muscular uptake of pyrophosphate in idiopathic inflammatory myopathy.

BACKGROUND: Nuclear imaging is increasingly being used in the diagnostic work-up of idiopathic inflammatory myopathy (IIM). Increased muscular uptake of technetium-99m-pyrophosphate (99mTc-PYP) has hitherto been assessed qualitatively by planar scintigraphy. We set out to perform quantitative tomographic scintigraphy in IIM. RESULTS: Ninety IIM patients and 48 control subjects underwent 99mTc-PYP single-photon emission computed tomography (SPECT)/CT of the upper and lower body. Scans were evaluated visually by an intensity score (1-4) and quantitatively by the mean standardized uptake value (SUVmean) in thigh muscles after semi-automated segmentation of these. Furthermore, a SUVmean gradient down along the thighs was determined by linear regression of the slice-by-slice activity. Interobserver analyses were performed on qualitative evaluations. Compared to controls, patients more often had a high intensity score (p < 0.0001), but interobserver analyses revealed only moderate agreement. The thigh muscular 99mTc-PYP activity (SUVmean) was 60% higher in patients than in controls, p < 0.0001, albeit with a wide range. There was an activity gradient down the thigh muscle, the proximal tracer uptake being highest, and this gradient was steeper in patients than in controls; the activity decreased by 0.00024 and 0.00010 SUVmean mm-1, respectively, along the thighs. CONCLUSIONS: The muscular uptake of 99mTc-PYP was significantly higher in patients than in healthy controls by qualitative and quantitative assessment. The tracer uptake was higher in the proximal than in the distal part of the thigh muscle, and SUVmean gradients differed between groups. Hence, tomographic nuclear imaging allowing for quantification of the 99mTc-PYP uptake might contribute to the diagnosis of IIM, and SPECT/CT of the lower body might suffice.

Cardiac involvement in adult and juvenile idiopathic inflammatory myopathies.

Idiopathic inflammatory myopathies (IIM) include the main subgroups polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM) and juvenile DM (JDM). The mentioned subgroups are characterised by inflammation of skeletal muscles leading to muscle weakness and other organs can also be affected as well. Even though clinically significant heart involvement is uncommon, heart disease is one of the major causes of death in IIM. Recent studies show an increased prevalence of traditional cardiovascular risk factors in JDM and DM/PM, which need attention. The risk of developing atherosclerotic coronary artery disease is increased twofold to fourfold in DM/PM. New and improved diagnostic methods have in recent studies in PM/DM and JDM demonstrated a high prevalence of subclinical cardiac involvement, especially diastolic dysfunction. Interactions between proinflammatory cytokines and traditional risk factors might contribute to the pathogenesis of cardiac dysfunction. Heart involvement could also be related to myocarditis and/or myocardial fibrosis, leading to arrhythmias and congestive heart failure, demonstrated both in adult and juvenile IIM. Also, reduced heart rate variability (a known risk factor for cardiac morbidity and mortality) has been shown in long-standing JDM. Until more information is available, patients with IIM should follow the same recommendations for cardiovascular risk stratification and prevention as for the corresponding general population, but be aware that statins might worsen muscle symptoms mimicking myositis relapse. On the basis of recent studies, we recommend a low threshold for cardiac workup and follow-up in patients with IIM.