Clusterin is upregulated in serum and muscle tissue in idiopathic inflammatory myopathies and associates with clinical disease activity and cytokine profile.

OBJECTIVES: The aim of this cross-sectional study was to explore the circulating and skeletal muscle expression of clusterin (CLU) in inflammatory myopathies (IIM) and its potential implication in pathogenetic mechanisms of the disease. METHODS: A total of 85 IIM patients and 86 healthy controls (HC) were recruited. In addition, 20 IIM patients and 21 HC underwent a muscle biopsy. Circulating CLU was measured by ELISA. Serum cytokine profile of patients and HC was assessed by Cytokine 27-plex Assay. Immunohistochemical localisation of CLU was assessed in 10 IIM and 4 control muscle tissue specimens. The expression of CLU and myositis related cytokines in muscle was determined by qPCR. RESULTS: Serum levels of CLU were significantly increased in IIM patients compared to controls (86.2 (71.6-99.0) vs. 59.6 (52.6-68.4) µg/mL, p<0.0001) and positively correlated with myositis disease activity assessment (MYOACT) (r=0.337, p=0.008), myositis intention-to-treat activity index (MITAX) (r=0.357, p=0.004) and global disease assessment evaluated by physician (r=0.309, p=0.015). Moreover, serum CLU correlated with cytokines and chemokines involved in IIM and their combined effect on disease activity was revealed by multivariate redundancy analysis. In muscle tissue, CLU mRNA was increased in IIM patients compared to controls (p=0.032) and CLU accumulated in the cytoplasm of regenerating myofibres. CONCLUSIONS: We suggest that the up-regulation of clusterin in circulation and skeletal muscle of IIM patients may be an inflammation and atrophy induced response of the organism intended to limit the environment, favouring further muscle damage.

Alterations in activin A-myostatin-follistatin system associate with disease activity in inflammatory myopathies.

OBJECTIVES: The aim of this study was to investigate the systemic and skeletal muscle levels of atrophy-associated myokines in patients with idiopathic inflammatory myopathies (IIM) and their association with clinical characteristics of myositis. METHODS: A total of 94 IIM patients and 162 healthy controls were recruited. Of those, 20 IIM patients and 28 healthy controls underwent a muscle biopsy. Circulating concentrations of myostatin, follistatin, activin A and TGF-ß1 were assessed by ELISA. The expression of myokines and associated genes involved in the myostatin signalling pathway in muscle tissue was determined by real-time PCR. RESULTS: We report decreased levels of circulating myostatin (median 1817 vs 2659 pg/ml; P = 0.003) and increased follistatin (1319 vs 1055 pg/ml; P = 0.028) in IIM compared with healthy controls. Activin A levels were also higher in IIM (414 vs 309 pg/ml; P = 0.0005) compared with controls. Myostatin was negatively correlated to muscle disease activity assessed by physician on visual analogue scale (MDA) (r = -0.289, P = 0.015) and positively to manual muscle testing of eight muscles (r = 0.366, P = 0.002). On the other hand, follistatin correlated positively with MDA (r = 0.235, P = 0.047). Gene expression analysis showed higher follistatin (P = 0.003) and myostatin inhibitor follistatin-like 3 protein (FSTL3) (P = 0.008) and lower expression of activin receptor type 1B (ALK4) (P = 0.034), signal transducer SMAD3 (P = 0.023) and atrophy marker atrogin-1 (P = 0.0009) in IIM muscle tissue compared with controls. CONCLUSION: This study shows lower myostatin and higher follistatin levels in circulation and attenuated expression of myostatin pathway signalling components in skeletal muscle of patients with myositis, a newly emerging pattern of the activin A-myostatin-follistatin system in muscle wasting diseases.

The role of imaging in evaluating patients with idiopathic inflammatory myopathies.

OBJECTIVES: To describe imaging modalities for diagnosing and monitoring of patients with idiopathic inflammatory myopathies. METHODS: A detailed literature search summarising recent data documenting the contribution of different imaging techniques to current management of idiopathic inflammatory myopathies was performed. RESULTS: An overview of methods most frequently used for evaluation of inflammatory myopathies and the description of their role in the diagnostic and monitoring process is presented. CONCLUSIONS: MRI is currently the most useful method capable of demonstrating both inflammatory and post-inflammatory changes in the muscles and surrounding soft tissue. Several studies have documented potential usefulness of other imaging techniques, such as ultrasonography, positron emission tomography, scintigraphy, and dual-energy x-ray absorptiometry.

MRI scoring methods used in evaluation of muscle involvement in patients with idiopathic inflammatory myopathies.

PURPOSE OF REVIEW: MRI is a promising imaging method commonly used to assess muscle involvement in patients with idiopathic inflammatory myopathies (IIM). MRI enables evaluation of both activity and damage and is therefore an ideal noninvasive diagnostic and monitoring tool. Despite its widespread use, there is no universally accepted method for scoring and reporting of MRI findings. The aim of this review is to provide an overview of systems used in the evaluation of MR images in patients with IIM. RECENT FINDINGS: A number of semi-quantitative and quantitative methods have been used to evaluate and record the severity of myopathy on MRI. These scoring systems differ in the number and type of parameters assessed and in their complexity; furthermore, they were evaluated in different patient populations, all of which make comparisons between them difficult. SUMMARY: There is a need to create a standardized and validated protocol for evaluation of pathological changes in muscle MRI in IIM. The most appropriate number and distribution of muscle groups as well as evaluated pathological features need to be determined. Based on this literature search, the future scoring system should include assessment of muscle oedema, fatty infiltration, muscle atrophy and possibly the presence of fascial and subcutaneous inflammation. Whether the quantitative methods provide more reliable information regarding disease activity remains unclear.

Application of the DETECT algorithm for detection of risk of pulmonary arterial hypertension in systemic sclerosis: data from a Czech tertiary centre.

OBJECTIVE: The early, simple and reliable detection of pulmonary arterial hypertension (PAH) in SSc (DETECT) study described a new algorithm for early detection of PAH in patients with SSc. The aim of this retrospective, single-centre, cross-sectional study was to apply a modified DETECT calculator in patients with SSc in the East Bohemian region, Czech Republic, to assess the risk of PAH and to compare these results with PAH screening based on the European Society of Cardiology/European Respiratory Society (ESC/ERS) 2009 guidelines. METHODS: Sixty patients were recruited with a diagnosis of SSc (according to ACR criteria), aged 27-78 years. A modified DETECT algorithm using the modified parameter of (1.4 × right ventricle diameter)(2) in place of right atrium area was applied to all patients. Right heart catheterization (RHC) was performed in all patients with an estimated (by echocardiography) increased systolic pulmonary artery pressure ≥50 mm Hg in accordance with the ESC/ERS guidelines; however, RHC was not performed in patients solely recommended for RHC using the modified DETECT algorithm. RESULTS: Using the modified DETECT calculator, 24/58 (41.4%) patients were recommended for RHC, compared with 14/58 (24.1%) when applying the ESC/ERS 2009 guidelines. PAH was diagnosed in 7/58 (12.1%) patients. During follow-up, PAH was diagnosed in six patients. Of these, four were modified DETECT score-positive for 2 years and all for 1 year before PAH diagnosis. CONCLUSION: The modified DETECT algorithm detects all patients with PAH diagnosed according to ECS/ERS 2009 guidelines and RHC. Data of the 2-year follow-up indicate a possible positive predictive role for the modified DETECT calculator.

255th ENMC workshop: Muscle imaging in idiopathic inflammatory myopathies. 15th January, 16th January and 22nd January 2021 - virtual meeting and hybrid meeting on 9th and 19th September 2022 in Hoofddorp, The Netherlands.

The 255th ENMC workshop on Muscle Imaging in Idiopathic Inflammatory myopathies (IIM) aimed at defining recommendations concerning the applicability of muscle imaging in IIM. The workshop comprised of clinicians, researchers and people living with myositis. We aimed to achieve consensus on the following topics: a standardized protocol for the evaluation of muscle images in various types of IIMs; the exact parameters, anatomical localizations and magnetic resonance imaging (MRI) techniques; ultrasound as assessment tool in IIM; assessment methods; the pattern of muscle involvement in IIM subtypes; the application of MRI as biomarker in follow-up studies and clinical trials, and the place of MRI in the evaluation of swallowing difficulty and cardiac manifestations. The following recommendations were formulated: In patients with suspected IIM, muscle imaging is highly recommended to be part of the initial diagnostic workup and baseline assessment. MRI is the preferred imaging modality due to its sensitivity to both oedema and fat accumulation. Ultrasound may be used for suspected IBM. Repeat imaging should be considered if patients do not respond to treatment, if there is ongoing diagnostic uncertainty or there is clinical or laboratory evidence of disease relapse. Quantitative MRI is established as a sensitive biomarker in IBM and could be included as a primary or secondary outcome measure in early phase clinical trials, or as a secondary outcome measure in late phase clinical trials. Finally, a research agenda was drawn up.

The effect of a 24-week training focused on activities of daily living, muscle strengthening, and stability in idiopathic inflammatory myopathies: a monocentric controlled study with follow-up.

BACKGROUND: The structural and functional changes of the skeletal muscles in idiopathic inflammatory myopathies (IIM) caused by inflammation and immune changes can be severely disabling. The objective of this study was to assess the effect of a 24-week program combining a supervised training of activities of daily living (ADL), resistance, and stability with home exercise for improving muscle function, compared to a daily home-based exercise representing the regular outpatient care. METHODS: Fifty-seven patients with IIM were consecutively and non-selectively enrolled in an intervention (IG, n = 30) or control (CG, n = 27) group. Both groups were provided a standard-of-care pharmacological treatment and follow-up. Only the IG underwent the supervised intervention twice a week for 1 h per session. At baseline, 12, 24, and 48 weeks, all patients were assessed by an assessor blinded to the intervention for primary outcomes: muscle strength (Manual Muscle Testing of eight muscle groups [MMT-8]) and endurance (Functional Index-2 [FI-2]), and secondary outcomes: stability and body composition. Secondary outcomes also included questionnaires evaluating disability (Health Assessment Questionnaire [HAQ]), quality of life (Short Form 36 [SF-36]), depression (Beck's Depression Inventory-II [BDI-II]), and fatigue (Fatigue Impact Scale [FIS]), and analysis of the systemic and local inflammatory response and perceived exertion to assess the safety of the intervention. RESULTS: Twenty-seven patients in the IG and 23 in the CG completed the entire program and follow-up. At week 24, compared to deterioration in the CG, we found a significant improvement in the IG in muscle strength (mean % improvement compared to baseline by 26%), endurance (135%), disability (39%), depression (26%), stability (11%), and basal metabolism (2%) and a stabilization of fitness for physical exercise. The improvement was clinically meaningful (a 24-week change by >20%) in most outcomes in a substantial proportion of patients. Although the improvement was still present at 48 weeks, the effect was not sustained during follow-up. No significant increase in the systemic or local expression of inflammatory markers was found throughout the intervention. CONCLUSIONS: This 24-week supervised intervention focused on ADL training proved to be safe and effective. It not only prevented the progressive deterioration, but also resulted in a significant improvement in muscle strength, endurance, stability, and disability, which was clinically meaningful in a substantial proportion of patients. TRIAL REGISTRATION: ISRCTN35925199 (retrospectively registered on 22 May 2020).