Martin Klein

Objective: The objective of this work was to examine myomiR levels in plasma, skeletal muscle, and skeletal muscle cells of patients with idiopathic inflammatory myopathy (IIM), and their interrelations with the disease-related clinical phenotypes and with the effects of a disease-modifying 6-months-training intervention. Methods: Samples of vastus lateralis muscle (n = 12/13) and plasma (n = 21/20) were obtained from IIM patients and healthy controls, respectively. The muscle and plasma samples were obtained before and after a 6-months training intervention in 7 patients. MyomiRs miR-1, -206, -133a, and -133b were quantified using quantitative PCR (qPCR). The effects of pro-inflammatory (TNF) and metabolic (glucose, insulin) systemic factors and of immunosuppressive therapy (dexamethasone) on the myomiRs were examined in muscle cells in vitro. Results: MiR-133b was lower in the skeletal muscle of IIM patients than in that of healthy controls (P = 0.03). The levels of miR-133a, miR-1, and miR-206 were not regulated. Moreover, the plasma levels of miR-133b and miR-1 were reduced in patients with IIM compared with those in healthy controls (P <0.05). It was observed that exercise induced reciprocal regulation of specific myomiRs in the muscle and plasma of patients with IIM: it lowered miR-133b in muscle while increasing miR-133b and miR-206 in plasma. Treatment of myotubes with TNF, insulin, glucose and dexamethasone (individually) induced the downregulation of distinct myomiRs. Conclusion: Lower myomiR levels in the skeletal muscle of IIM patients might indicate reduced muscle regenerative potential in IIM, which could be linked to inflammation, metabolic dysfunction, and immunosuppressive therapy. Training-induced changes in muscle and plasma myomiRs indicate an increase in the release of myomiRs, which could contribute to the adaptive response underlying the positive systemic effects of exercise in IIM. Trial registration: ISRCTN register, https://www.isrctn.com/ ISRCTN35925199.

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).

To date, there is almost no information concerning the sexual health of patients with idiopathic inflammatory myopathies (IIM). This cross-sectional study aimed to compare sexual function in patients with IIM to age-/sex-matched healthy controls (HC) and determine the potential impact of clinical features on sexual function. In total, 122 women (61 with IIM, 61 age-matched HC) and 22 men (11 with IIM, 11 age-matched HC) aged 18–80 years completed gender specific selection of 11 well-established and validated questionnaires assessing sexual health and function (Female Sexual Function Index, Brief Index of Sexual Function for Women, Sexual Function Questionnaire, Sexual Quality of Life Questionnaire–Female, International Index of Erectile Function, Male Sexual Health Questionnaire, Sexual Quality of Life Questionnaire–Male). Results were compared between patients and HC and correlated with selected disease-related features. The prevalence of sexual dysfunction in IIM was 59% in women (vs 40% in HC), and 64% (vs 9% in HC) in men. Men and women with IIM reported significantly impaired sexual function compared with sex-/age-matched HC. Decreased sexual function was associated with muscle weakness, disability, physical inactivity, fatigue, depression, and decreased quality of life. Our results suggest that sexual dysfunction is common among IIM patients and more attention should be paid to this aspect of the disease.

Calprotectin may be a sensitive biomarker of rheumatoid arthritis (RA) disease activity. In the current study, we investigated whether calprotectin is a better biomarker than CRP for predicting clinical activity and ultrasound parameters in patients with RA. A total of 160 patients with RA underwent clinical (swollen joint count—SJC, tender joint count—TJC, Disease Activity Score—DAS28, Clinical Disease Activity Index—CDAI, and simplified Disease Activity Index—SDAI) and ultrasound (German US7) examination. Clinical and laboratory measures were correlated with ultrasound findings using Spearman´s correlation coefficient. Differences in serum calprotectin levels in patients with variable disease activity according to the DAS28-ESR and CDAI scores were assessed using ANOVA. Multivariate regression analysis was used to determine the predictive values of calprotectin, CRP and SJC for CDAI and PD US synovitis scores. Serum calprotectin was significantly associated with DAS28-ESR (r = 0.321, p<0.001), DAS28-CRP (r = 0.346, p<0.001), SDAI (r = 0.305, p<0.001), CDAI (r = 0.279, p<0.001) scores and CRP levels (r = 0.556, p<0.001). Moreover, calprotectin was significantly correlated with GS (r = 0.379, p<0.001) and PD synovitis scores (r = 0.419, p<0.001). The multivariate regression analysis showed that calprotectin is a better predictor of the CDAI score and PD US synovitis than CRP. The results of this study support an additional role of calprotectin in assessing inflammatory activity in patients with RA.

Restoring normal physical functioning is a major therapeutic aim in the management of rheumatoid arthritis (RA). It is unknown, whether the extent of synovial inflammation quantified by musculoskeletal ultrasound (US) can predict current or future capacity for physical functioning. To answer this question we investigated the longitudinal relationship between physical function assessed by the health assessment questionnaire (HAQ) and the German 7-joint ultrasound score (US7S) in a prospective cohort of patients with RA. Patients with RA (n = 185 (46 with incident and 139 with prevalent disease) were followed for 30.9 ± 9.1 months. Baseline and annual assessments comprised the disease activity score in 28 joints (DAS28), HAQ and US7S. The US7S includes semiquantitative measurements of synovitis assessed by greyscale (GS) and power Doppler (PD) in seven joints of the clinically dominant hand and foot, which are then aggregated in PD and GS synovitis sum-scores (PDsynSS and GSsynSS). A linear mixed-effect model was used to assess the longitudinal relationship between GSsynSS, PDsynSS and HAQ. We used standard and time-lag models to explore the association between HAQ, and GSsynSS, PDsynSS and DAS28 measured at the same time or at the previous visit 12 months ago, respectively. When the standard model was applied, in univariate analyses HAQ score was positively associated with GSsynSS and PDsynSS with β coefficients significantly higher in incident than in prevalent disease. In multivariate analysis both synSSs were individually no longer significant predictors of HAQ score. When using the time-lag model, after adjustment for the previous DAS28 or HAQ score, both PDsynSS and GSsynSS were significantly and negatively associated with the current HAQ. US7 PD and GS synovitis sum-scores alone were positively associated with current functional status reflected by the HAQ in patients with RA, and this relationship was stronger in patients with early disease. When combined with the DAS28 or HAQ, US7 PD and GS synovitis sum-scores were predictive of the change in HAQ score over one year.

Clinical remission in some patients with rheumatoid arthritis (RA) may be associated with ongoing synovial inflammation that is not always detectable on clinical examination or reflected by laboratory tests but can be visualized by musculoskeletal ultrasound. The goal of our study was to determine the levels of serum calprotectin, a major leukocyte protein, in patients with RA in clinical remission and to investigate the ability of serum calprotectin levels to distinguish patients in ultrasound-defined remission from those with residual ultrasound subclinical inflammation. Seventy RA patients in clinical remission underwent clinical and ultrasound examination. Ultrasound examination was performed according to the German US7 score. Ultrasound remission was defined as grey scale (GS) range 0–1 and power Doppler (PD) range 0. The levels of serum calprotectin and C-reactive protein (CRP) were determined. The discriminatory capacity of calprotectin and CRP in detecting residual ultrasound inflammation was assessed using ROC curves. The total number of patients fulfilling the DAS28-ESR, DAS28-CRP, SDAI and CDAI remission criteria was 58, 67, 32 and 31, respectively. Residual synovial inflammation was found in 58–67% of the patients who fulfilled at least one set of clinical remission criteria. Calprotectin levels were significantly higher in patients with residual synovial inflammation than in those with ultrasound-defined remission (mean 2.5±1.3 vs. 1.7±0.8 μg/mL, p<0.005). Using ultrasound-defined remission criteria, calprotectin had an AUC of 0.692, p<0.05 using DAS28-ESR remission criteria and an AUC of 0.712, p<0.005 using DAS28-CRP remission criteria. Calprotectin correctly distinguished ultrasound remission from subclinical activity in 70% of patients. CRP (AUC DAS28-ESR = 0.494, p = NS; AUC DAS28-CRP = 0.498, p = NS) had lower and insignificant discriminatory capacity. The present study demonstrates the potential of calprotectin to distinguish RA patients in both clinical and ultrasound-defined remission from patients in clinical remission but with residual subclinical disease activity.

Myositis is a heterogeneous group of autoimmune diseases, with different pathogenic mechanisms contributing to the different subsets of disease. The aim of this study was to test whether the autoantibody profile in patients with myositis is associated with a type I interferon (IFN) signature, as in patients with systemic lupus erythematous (SLE). Patients with myositis were prospectively enrolled in the study and compared to healthy controls and to patients with SLE. Autoantibody status was analysed using an immunoassay system and immunoprecipitation. Type I IFN activity in whole blood was determined using direct gene expression analysis. Serum IFN‐inducing activity was tested using peripheral blood cells from healthy donors. Blocking experiments were performed by neutralizing anti‐IFNAR or anti‐IFN‐α antibodies. Patients were categorized into IFN high and IFN low based on an IFN score. Patients with autoantibodies against RNA‐binding proteins had a higher IFN score compared to patients without these antibodies, and the IFN score was related to autoantibody multispecificity. Patients with dermatomyositis (DM) and inclusion body myositis (IBM) had a higher IFN score compared to the other subgroups. Serum type I IFN bioactivity was blocked by neutralizing anti‐IFNAR or anti‐IFN‐α antibodies. To conclude, a high IFN score was not only associated with DM, as previously reported, and IBM, but also with autoantibody monospecificity against several RNA‐binding proteins and with autoantibody multispecificity. These studies identify IFN‐α in sera as a trigger for activation of the type I IFN pathway in peripheral blood and support IFN‐α as a possible target for therapy in these patients.

Objectives To estimate the time to reach reliable results in a larger group of rheumatologists at onset of their musculoskeletal ultrasound (MSUS) training in modified 7-joints scoring system (US7). Methods US7 has been shown a useful tool to estimate activity of rheumatoid arthritis (RA) in daily clinical practice. The system has been extensively described including an atlas. Targets of the US7 include synovitis (in B-mode and Power Doppler (BM+PD)), tenosynovitis (BM+PD) and erosive changes of 7 joints (wrist, MCP II+III, PIP II+III, MTP II+V) on the dominant site. We used a modification of the original US7 published, assessing both palmar and dorsal view of MCP and PIP joints. 9 rheumatologists with basic/intermed. level of MSUS underwent a training in general MSUS+US7. At month 1, reliability testing in scoring of static pictures was performed. At months 3 and 12, two reliability-testing sessions were organized. 4 patients with various stages of activity and disease progression of RA were repeatedly scanned, in 2 rounds per session. Sonographers were blind to all patients' data. 2 US machines were used for each session and the setting was fixed before the start. Smoking or drinking alcohol was not allowed. Each patient was investigated by the same US machine in the same daytime in each round of a testing session. Inter-/intra-observer agreement was calculated for each modality of US7 (synovitis score in BM+PD, tenosynovitis score in BM+PD, erosion score) by using non-weighted Cohen kappa (intra-observer agreement) and Light's kappa (inter-observer agreement). Results At month 1, mean intra- and inter-observer agreement in scoring of static images was reached; κ=0,61 and 0,60 respectively (good). At month 3, mean inter-observer reliability was low (κConclusions Ultrasound is an operator dependent technique. The level of experience necessary to obtain reliable results in modified US7 (as an example of easy and well determined US method) was achieved after 12 months of low intensity training with direct supervision of a specialist on demand. Low intensity training is in the authors' experience the most frequently used method among beginners in MSUS. Scoring of static images was reliable already after 1 month. Although the probe positions in US7 are well defined, the inter-/intra-observer reliability in scoring of self-obtained images was none in month 3 and the difference leading to good results in month 12 must have been achieved in this later period of training. The difference between higher intra-observer and none inter-observer agreement in month 3 suggests that direct supervision of a specialist in MSUS in this stage of education would lead to quicker progress and better results in achieving reliability among the group members. Acknowledgement Supported by the project for conceptual development of research organization 023728 and by project no. NT12437. Disclosure of Interest None declared