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Objective To assess the role of the anti-TIF1γ auto-antibody (aAb) IgG2 isotype as a biomarker of cancer in anti-TIF1γ aAb-positive adult DM. Methods International multicentre retrospective study with the following inclusion criteria: (i) diagnosis of DM according to ENMC criteria; (ii) presence of anti-TIF1γ IgG aAb determined using an in-house addressable laser bead immunoassay (ALBIA) from cryopreserved serums sampled at time of DM diagnosis and (iii) available baseline characteristics and follow-up data until the occurrence of cancer and/or a minimum follow-up of 1 year for patients without known cancer at diagnosis. Detection and quantification of anti-TIF1γ IgG2 aAb was done using the in-house ALBIA. In addition, a recent ELISA commercial kit was used for anti-TIF1γ IgG aAb quantification. Results A total of 132 patients (mean age 55±15 years) of whom 72 (54.5%) had an associated cancer were analysed. The association between the presence of cancer and the presence of anti-TIF1γ IgG2 aAb was statistically significant (P = 0.026), with an OR of 2.26 (95% CI: 1.10, 4.76). Patients with cancer displayed significantly higher anti-TIF1γ IgG2 aAb ALBIA values with a median value of 1.15 AU/ml (IQR: 0.14–9.76) compared with 0.50 AU/ml (IQR: 0.14–1.46) for patients without cancer (P = 0.042). In addition, patients with cancer displayed significantly higher anti-TIF1γ IgG aAb ELISA values with a median value of 127.5 AU/ml (IQR: 81.5–139.6) compared with 93.0 AU/ml (IQR: 54.0–132.9) for patients without cancer (P = 0.004). Conclusion These results suggest considering anti-TIF1γ IgG2 ALBIA and IgG ELISA values as biomarkers of cancer in anti-TIF1 γ aAb-positive adult DM.

Objectives Many axial spondylarthritis (axSpA) patients receive a conventional synthetic DMARD (csDMARD) in combination with a TNF inhibitor (TNFi). However, the value of this co-therapy remains unclear. The objectives were to describe the characteristics of axSpA patients initiating a first TNFi as monotherapy compared with co-therapy with csDMARD, to compare one-year TNFi retention and remission rates, and to explore the impact of peripheral arthritis. Methods Data was collected from 13 European registries. One-year outcomes included TNFi retention and hazard ratios (HR) for discontinuation with 95% CIs. Logistic regression was performed with adjusted odds ratios (OR) of achieving remission (Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP Results Amongst 24 171 axSpA patients, 32% received csDMARD co-therapy (range across countries: 13.5% to 71.2%). The co-therapy group had more baseline peripheral arthritis and higher CRP than the monotherapy group. One-year TNFi-retention rates (95% CI): 79% (78, 79%) for TNFi monotherapy vs 82% (81, 83%) with co-therapy (P Conclusion This large European study of axial SpA patients showed similar one-year treatment outcomes for TNFi monotherapy and csDMARD co-therapy, although considerable heterogeneity across countries limited the identification of certain subgroups (e.g. peripheral arthritis) that may benefit from co-therapy.

Contains fulltext : 251829.pdf (Publisher’s version ) (Open Access) OBJECTIVE: There is a lack of real-life studies on interleukin-17 (IL-17) inhibition in psoriatic arthritis (PsA). We assessed real-life 6- and 12-month effectiveness (i.e., retention, remission, low disease activity [LDA], and response rates) of the IL-17 inhibitor secukinumab in PsA patients overall and across 1) number of prior biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), 2) years since diagnosis, and 3) European registries. METHODS: Thirteen quality registries in rheumatology participating in the European Spondyloarthritis Research Collaboration Network provided longitudinal, observational data collected as part of routine care for secondary use. Data were pooled and analyzed with Kaplan-Meier plots, log rank tests, Cox regression, and multiple linear and logistic regression analyses. RESULTS: A total of 2,017 PsA patients started treatment with secukinumab between 2015 and 2018. Overall secukinumab retention rates were 86% and 76% after 6 and 12 months, respectively. Crude (LUNDEX adjusted) 6-month remission/LDA (LDA including remission) rates for the 28-joint Disease Activity Index for Psoriatic Arthritis, the Disease Activity Score in 28 joints using the C-reactive protein level, and the Simplified Disease Activity Index (SDAI) were 13%/46% (11%/39%), 36%/55% (30%/46%), and 13%/56% (11%/47%), and 12-month rates were 11%/46% (7%/31%), 39%/56% (26%/38%), and 16%/62% (10%/41%), respectively. Clinical Disease Activity Index remission/LDA rates were similar to the SDAI rates. Six-month American College of Rheumatology 20%/50%/70% improvement criteria responses were 34%/19%/11% (29%/16%/9%); 12-month rates were 37%/21%/11% (24%/14%/7%). Secukinumab effectiveness was significantly better for b/tsDMARD-naive patients, similar across time since diagnosis (4 years), and varied significantly across the European registries. CONCLUSION: In this large real-world study on secukinumab treatment in PsA, 6- and 12-month effectiveness was comparable to that in previous observational studies of tumor necrosis factor inhibitors. Retention, remission, LDA, and response rates were significantly better for b/tsDMARD-naive patients, were independent of time since diagnosis, and varied significantly across the European countries.

Objective To investigate TNF inhibitor (TNFi) retention and response rates in European biologic-naïve patients with PsA. Methods Prospectively collected data on PsA patients in routine care from 12 European registries were pooled. Heterogeneity in baseline characteristics between registries were explored (analysis of variance and pairwise comparison). Retention rates (Kaplan–Meier), clinical remission [28-joint count DAS (DAS28) Results Overall, 14 261 patients with PsA initiated a first TNFi. Considerable heterogeneity of baseline characteristics between registries was observed. The median 12-month retention rate (95% CI) was 77% (76, 78%), ranging from 68 to 90% across registries. Overall, DAS28/28 joint Disease Activity index for Psoriatic Arthritis remission rates at 6 months were 56%/27% (LUNDEX: 45%/22%). Six-month ACR20/50/70 responses were 53%/38%/22%, respectively. In patients initiating a first TNFi after 2009 with registered fulfilment of ClASsification for Psoriatic ARthritis (CASPAR) criteria (n = 1980) or registered one or more swollen joint at baseline (n = 5803), the retention rates and response rates were similar to those found overall. Conclusion Approximately half of >14 000 patients with PsA who initiated first TNFi treatment in routine care were in DAS28 remission after 6 months, and three-quarters were still on the drug after 1 year. Considerable heterogeneity in baseline characteristics and outcomes across registries was observed. The feasibility of creating a large European database of PsA patients treated in routine care was demonstrated, offering unique opportunities for research with real-world data.

Objective.To evaluate the efficacy, safety, pharmacokinetics, and immunogenicity of CNTO6785, a fully human monoclonal antibody that binds to human interleukin 17A, in patients with active rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX) therapy.Methods.This randomized, double-blind, placebo-controlled, dose-ranging study enrolled patients aged 18 to 80 years (inclusive) with active RA (≥ 6/66 swollen and ≥ 6/68 tender joints) who were refractory to MTX treatment (7.5–25 mg weekly, inclusive). The study duration was 38 weeks, containing a 10-week safety followup. Patients were randomized 1:1:1:1:1 to receive CNTO6785 15, 50, 100, or 200 mg every 4 weeks + MTX or placebo + MTX. The primary endpoint was American College of Rheumatology 20 (ACR20) response at Week 16.Results.There were no significant differences from placebo in the proportion of patients treated with CNTO6785 in the primary endpoint of ACR20 response at Week 16. There were no significant findings in any additional efficacy variables through Week 32. No dose-response relationships or specific patterns were observed in adverse event profiles among CNTO6785 treatment groups. Infections occurred with similar frequency across all groups, and injection site reactions were mild or moderate and did not demonstrate a dose-response relationship. Median serum CNTO6785 concentration increases through Week 38 were about dose-proportional; the incidence of neutralizing antidrug antibodies was 19.4% and was not associated with study drug dose level.Conclusion.CNTO6785 was well tolerated, but did not demonstrate clinical efficacy in patients with active RA with inadequate response to MTX.

ObjectivesTo study the effects of abatacept on disease activity and on muscle biopsy features of adult patients with dermatomyositis (DM) or polymyositis (PM).MethodsTwenty patients with DM (n=9) or PM (n=11) with refractory disease were enrolled in a randomised treatment delayed-start trial to receive either immediate active treatment with intravenous abatacept or a 3 month delayed-start. The primary endpoint was number of responders, defined by the International Myositis Assessment and Clinical Studies Group definition of improvement (DOI), after 6 months of treatment. Secondary endpoints included number of responders in the early treatment arm compared with the delayed treatment arm at 3 months. Repeated muscle biopsies were investigated for cellular markers and cytokines.Results8/19 patients included in the analyses achieved the DOI at 6 months. At 3 months of study, five (50%) patients were responders after active treatment but only one (11%) patient in the delayed treatment arm. Eight adverse events (AEs) were regarded as related to the drug, four mild and four moderate, and three serious AEs, none related to the drug. There was a significant increase in regulatory T cells (Tregs), whereas other markers were unchanged in repeated muscle biopsies.ConclusionsIn this pilot study, treatment of patients with DM and PM with abatacept resulted in lower disease activity in nearly half of the patients. In patients with repeat muscle biopsies, an increased frequency of Foxp3+ Tregs suggests a positive effect of treatment in muscle tissue.

© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved., Objectives: To assess the impact of 'patient's minus evaluator's global assessment of disease activity' (ΔPEG) at treatment initiation on retention and remission rates of TNF inhibitors (TNFi) in psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) patients across Europe. Methods: Real-life data from PsA and axSpA patients starting their first TNFi from 11 countries in the European Spondyloarthritis Research Collaboration Network were pooled. Retention rates were compared by Kaplan-Meier analyses with log-rank test and by Cox regression, and remission rates by χ2 test and by logistic regression across quartiles of baseline ΔPEG, separately in female and male PsA and axSpA patients. Results: We included 14 868 spondyloarthritis (5855 PsA, 9013 axSpA) patients. Baseline ΔPEG was negatively associated with 6/12/24-months' TNFi retention rates in female and male PsA and axSpA patients (P

To describe imaging modalities for diagnosing and monitoring of patients with idiopathic inflammatory myopathies.A detailed literature search summarising recent data documenting the contribution of different imaging techniques to current management of idiopathic inflammatory myopathies was performed.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.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.

Approximately half of patients with rheumatoid arthritis (RA) have normal C-reactive protein (CRP) levels. Calprotectin is a promising and likely more specific biomarker of disease activity than conventionally used acute phase reactants. We aimed to analyse the levels of serum calprotectin in RA patients with clinically active disease and with normal/low CRP. A total of 160 RA patients underwent clinical examination (DAS28-ESR and CDAI). The levels of calprotectin were analysed in patients with moderate to high disease activity with normal/low CRP levels and in 32 healthy subjects. The discriminatory capacity of calprotectin to identify clinically active patients in spite of normal/low CRP was assessed using ROC curves. Out of all RA patients, 74/160 (46.3%) were in remission or had low disease activity according to DAS28 and had normal/low CRP levels. However, 51/160 (32%) had normal/low CRP levels despite having moderate to high disease activity. In these patients, calprotectin levels were significantly higher than those in patients who had normal/low CRP and were in remission or showed low disease activity (2.7 ± 1.5 vs. 2.1 ± 1.2 μg/mL, p = 0.043), which differed from those in healthy subjects (2.7 ± 1.5 vs. 1.9 ± 1.2 μg/mL, p = 0.011). The discriminatory capacity for calprotectin to distinguish clinically active vs. inactive disease despite normal/low CRP using AUC of the DAS28 was 0.607 (95% CI 0.503 to 0.711, p = 0.043). The present study demonstrates that calprotectin may reflect inflammatory activity in RA patients where CRP fails to do so.

Objective: Understanding the extent to which treat-to-target (T2T) recommendations are applied by rheumatologists in patients with rheumatoid arthritis (RA) may identify gaps or issues in disease management. This study evaluated application of key T2T principles in routine management of RA patients in selected Central-Eastern European countries. Methods: This prospective, single-arm, observational study was conducted in seven countries. Patients with early RA (

Background Idiopathic inflammatory myopathies (IIM) are characterised by inflammation and atrophy of skeletal muscles, pulmonary and articular involvement, which limit the mobility/self-sufficiency of patients, and can have a negative impact on body composition. Objectives To assess body composition and physical activity of IIM patients and healthy controls (HC). Methods 54 patients with IIM (45 females/9 males; mean age 57.3; disease duration 5.8 years; polymyositis (PM,22)/dermatomyositis (DM,25)/necrotizing myopathy (IMNM,7)) and 30 age-/sex-matched HC (25 females/5 males, mean age 54.9) without rheumatic/tumour diseases or manifest cardiovascular event were included. PM/DM patients fulfilled Bohan/Peter criteria for PM/DM. Anthropometric parameters and body composition were assessed (by densitometry-iDXA Lunar, and by bioelectric impedance-BIA2000-M), and physical activity was evaluated using Human Activity Profile (HAP) questionnaire. Routine biochemistry analysis was performed after 8 hours of fasting. Muscle involvement was evaluated by manual muscle test (MMT)−8. Data are presented as mean±SD. Results Compared to HC, patients with IIM had significantly increased body fat% as assessed by iDXA (BF%: 38.7±6.7 vs. 42.5%±7.1%, p=0.015), but decreased lean body mass as assessed both by iDXA (LBM: 45.7±6.6 vs. 40.3±7.0 kg, p=0.0005) and BIA (LBM: 53.2±8.5 vs. 48.7±9.0 kg, p=0.0295), and increased ECM/BCM ratio (extracellular mass/body cell mass: 1.00±0.12 vs. 1.43±0.42, p Conclusions Compared to healthy age-/sex-matched individuals we found significant negative changes in body composition of our IIM patients, which are associated with their disease duration, inflammatory status, skeletal muscle involvement, and physical activity, and could reflect their impaired nutritional status and predispositions for physical exercise, aerobic fitness and performance. Acknowledgement Supported by AZV-16–33574A.

Background Involvement of skin and musculoskeletal system in systemic sclerosis (SSc) leads to loss of function, disability and reduced quality of life. Data on efficacy of non-pharmacologic care in SSc is very limited due to variety in studied interventions/outcomes. Objectives and methods To address the limitations of existing studies, and evaluate the effect of a controlled, long-term (24-week intervention, 24-week follow-up), intensive (1 hour physiotherapy +0.5 hour occupational therapy twice weekly, and home-exercise for 0.5 hour 5x weekly), tailored physiotherapy program on function/impairment of hands/face, and quality of life/disability in cohorts with a substantial number of SSc patients. All patients fulfilled ACR/EULAR 2013 criteria, had skin involvement of hands/mouth, and were consecutively recruited between 2014–2016. At months 0,3,6,12 all patients were assessed by a physician (physical history, mRSS, EUSTAR SSc activity score, Medsger severity score), and a physiotherapist blinded to intervention [validated measurements (dFTP-delta finger to palm, inter-incisor/inter-lip distance, grip strength using Baseline dynamometer ); tests (HAMIS-Hand Mobility In Scleroderma)], patients filled out PRO questionnaires (CHFS-Cochin Hand Function Scale, MHISS-Mouth Handicap In SSc Scale, HAQ, SHAQ, SF-36) and provided blood for routine laboratory analysis and biobanking. Normality of data was tested and inter-group analysis performed with 2-way ANOVA and intra-group analysis by Friedmann’s test with Dunn’s post hoc test. Results 25 SSc patients (22 female/3 male, 14 lcSSc/11dcSSc, median of age 54.0 and disease duration 7.0 years, mRSS 12) were recruited into the intervention group (IG) and 29 patients into CG (25 female/4 male, 16 lcSSc/13 dcSSc, median of age 49.0 and disease duration 5.0 years, mRSS 11). Compared to observed statistically significant deterioration in CG over the period of m0-m6, we found statistically significant improvement in dFTP, grip strength, HAMIS, inter-incisor and inter-lip distance. Only numerical improvement in IG compared to numerical deterioration in CG, which have not reached statistical significance, were observed in patient reported outcomes (CHFS, MHISS, HAQ, SHAQ, SF-36). Conclusions Our physiotherapy program not only prevented the natural course of progressive deterioration of function of hands/mouth (observed in CG), but led to a significant improvement in monitored parameters, which was clinically meaningful in a substantial proportion of patients. Acknowledgement Supported by AZV-16–33574A.

Background Heat shock proteins (Hsps) are chaperones playing important roles in skeletal muscle physiology, adaptation to exercise or stress, and activation of inflammatory cells. The aim of our study was to assess Hsp90 expression in muscle biopsies and plasma of patients with idiopathic inflammatory myopathies (IIM) and to characterise its association with IIM-related features. Methods Total of 277 patients with IIM (198 females, 79 males; mean age 54.8; disease duration 4.1 years; dermatomyositis (DM, 104)/polymyositis (PM, 104)/cancer associated myositis (CAM, 42)/necrotizing myopathy (IMNM, 27)) and 100 age-/sex-matched healthy individuals were included in plasma analysis and 50 muscle biopsy samples were stained for Hsp90 (in PM, DM, IMNM, myodystrophy, myasthenia gravis, 10 each). Plasma Hsp90 was measured by ELISA (eBioscience, Vienna). CK, LD, ALT, AST and CRP were analysed by routine techniques and IIM-specific autoantibodies by in-line blot/immunoprecipitation. Data are presented as median. Results In muscle biopsies Hsp90 expression was higher in IIM than in myodystrophy (myasthenia gravis used as another control was negative). Increased Hsp90 was detected in perifascicular degenerating and/or regenerating fibres, inflammatory cells (DM, PM), and necrotic and regenerating fibres (IMNM). Plasma Hsp90 levels were increased in IIM patients compared to healthy controls (20.2 vs. 9.2 ng/ml, p Conclusions We demonstrate increased Hsp90 expression in IIM muscle biopsy samples, specifically in inflammatory cells, degenerating, regenerating and/or necrotic fibres. Increased Hsp90 plasma levels in IIM patients are associated with disease activity and damage, and with the involvement of proximal skeletal muscles, heart and lungs. Acknowledgement Supported by AZV-16–33542A.

Background Systemic sclerosis (SSc) is characterised by fibrosis of the skin and visceral organs, especially digestive tract, and musculoskeletal involvement, which limit mobility/self-sufficiency of patients, and can have a negative impact on body composition. Objectives To assess body composition and physical activity of SSc patients and healthy controls (HC). Methods 59 patients with SSc (50 females, 9 males; mean age 52.1; disease duration 6.7 years; limited cutaneous (lcSSc,36)/diffuse cutaneous (dcSSc,23)) and 36 age-/sex-matched HC (30 females, 6 males, mean age 51.4) without rheumatic/tumour diseases or manifest cardiovascular event were included. SSc patients fulfilled EULAR/ACR 2013 criteria. Anthropometric parameters and body composition were assessed (by densitometry-iDXA Lunar, and by bioelectric impedance-BIA-2000-M), and physical activity was evaluated using Human Activity Profile (HAP) questionnaire. Routine biochemistry analysis was performed after 8 hours of fasting. Disease activity was evaluated by EUSTAR SSc activity score. Data are presented as mean±SD. Results Compared to HC, patients with SSc had significantly lower body-mass index (BMI: 26.4±3.3 vs. 22.4±4.3 kg/m 2 , p 2 , p Conclusions Compared to healthy age-/sex-matched individuals we found significant negative changes in body composition of our SSc patients, which are associated with their disease activity and physical activity, and could reflect their nutritional status, and gastrointestinal and musculoskeletal involvement. Acknowledgement Supported by AZV-16–33574A.

Background MicroRNAs (miRNAs) are small RNAs that regulate gene expression by targeting mRNA. It was proved that some miRNAs are significantly deregulated in rheumatoid arthritis (RA). MicroRNA-125b negatively regulates expression of TNF-α, which plays a crucial role in RA pathogenesis. The aim of this study was to determine the treatment outcome of patients with early RA based on the expression of circulating and cellular miR-125b. Methods Total RNA was isolated from the plasma and peripheral blood mononuclear cells (PBMCs) of 58 patients with early RA before and three months after treatment initiation and of 54 age- and sex-matched healthy controls (HC). The expression of miR-125b was measured by TaqMan quantitative PCR. The treatment responders were defined as patients achieving remission or low disease activity (28-joint count disease activity score (DAS28)

We aimed to evaluate in vivo effects of abatacept on phenotypes of T and B cells in the circulation of myositis patients in a sub-study of the ARTEMIS trial. Twelve patients with paired frozen PBMCs before and after 6-month abatacept treatment were included in this sub-study where mass cytometry (CyTOF) was chosen as a technology to be tested for its utility in a real-life clinical immune monitoring setting. Using CyTOF, the peripheral T cell phenotypes demonstrated considerable variation over time and between individuals precluding the identification of treatment-specific changes. We therefore conclude that studies of patient cohorts displaying wide clinical heterogeneity using mass cytometry must be relatively large in order to be suited for discovery research and immune monitoring. Still, we did find some correlations with functional muscle outcome, namely positive correlations between the ratio of CD4+ T cells and CD8+ T cells (CD4/CD8) in peripheral blood samples both at baseline and after treatment with muscle endurance improvement as assessed by the functional index-2 (FI-2) test. Our data suggest that the CD4/CD8 ratio in circulation at time of active disease may be a predictor of treatment efficacy in myositis patients.

Microparticles are recently recognized players of intercellular communication. They are involved in signal transduction, cell activation and apoptosis. Their importance is also suggested in autoimmune diseases such as rheumatoid arthritis and systemic sclerosis. We investigated the role of microparticles in polymyositis/dermatomyositis, a group of rare autoimmune diseases, characterized by specific skin lesions and muscle weakness. The plasma concentration of monocyte and lymphocyte derived microparticles of 20 patients with polymyositis/dermatomyositis and 20 healthy controls were determined by flow cytometry. The structure of microparticles was visualized by electron microscopy. Significantly elevated numbers of monocyte (CD14 positive), T-lymphocyte (CD3 positive) and B-lymphocyte (CD19 positive) derived microparticles were found in the plasma samples of polymyositis/dermatomyositis patients, compared to healthy controls (p=0.001, 0.01 and 0.006, respectively). Furthermore, the plasma levels of monocyte and B-lymphocyte derived microparticles correlated with the manual muscle strength test (r=0.497, p=0.027; r=0.508, p=0.023; respectively). Patients with anti-Jo-1 antibody and lung involvement had significantly higher numbers of T- and B-lymphocyte and monocyte derived MPs (p=0.006, 0.012 and 0.007, respectively, for anti-Jo-1; p=0.013, 0.016 and 0.025, respectively, for lung involvement). After ultracentrifugation, CK activity could be detected only in traces in the resuspended pellet containing microparticles of healthy and diseased individuals. The electron microscopy revealed slightly different microparticles in the samples of patients with polymyositis/dermatomyositis. These results suggest that immune cell derived microparticles may contribute to the inflammatory process in polymyositis/dermatomyositis, however, CK-positive, possibly muscle derived microparticles do not seem to be present in the blood of patients with polymyositis/dermatomyositis.

The paper discusses the development of a first course in control engineering and its support using the simulation package Dynast. The work, which has several partners, was supported by the Leonardo Agency in a more extensive project DynLAB on web based education. Examples and virtual reality experiments in Dynast support the learning of the control analysis and design methods.

Background Calprotectin may be a sensitive biomarker of rheumatoid arthritis (RA) disease activity. Objectives 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. Methods 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. Results Serum calprotectin was significantly associated with DAS28-ESR (r = 0.321, p

Statins are well-established lipid-lowering drugs that reduce morbidity and mortality due to cardiovascular disease and cause adverse effects relatively rarely. It is still unclear whether statins are capable of inducing an immune-mediated response directed against skeletal muscle. Here, we present the cases of three patients who developed inflammatory myopathy in the course of statin treatment. Moreover, multiple mitochondrial DNA deletions were found in two of them. The ability of statins to induce an immune-mediated response and their interactions with mitochondrial metabolism pathways are discussed.

Objective 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. Methods 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. Results 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

The risk of activation of latent tuberculosis infection (LTBI) is increased in patients treated with anti-TNF-α drugs. Tuberculin skin test (TST) and Quantiferon-TB Gold test (QFT) are used to detect LTBI before and during anti-TNF-α treatment. We describe here a relation of these tests at various timepoints and also longitudinal QFT data.Study group consisted of 305 patients with several rheumatic inflammatory diseases treated and/or scheduled for anti-TNF-α drugs. The QFT was performed in 303 patients during therapy and in 177 patients also during screening. The TST was used in 284 patients. Both tests simultaneously were utilised in 360 instances.Twenty-two patients were QFT positive; 3.9% before and 5.9% during anti-TNF-α treatment. Two patients who became QFT positive developed active tuberculosis. The TST was positive in 42% and 38% of patients before and during treatment, respectively. There was poor agreement between the two tests. Patients on glucocorticoids had a negative TST more frequently. The IFN-γ response to mycobacterial antigens significantly increased after application of tuberculin, but never reached the positive threshold. There was a significant increase in mitogen-induced IFN-γ production after initiation of anti-TNF-α therapy.Poor correlation between the QFT and TST renders the TST non-specific for LTBI. QFT is more specific to detect LTBI and conversion to a positive result may predict active TB. An increase in IFN-γ production in response to mycobacterial antigens is seen when the TST is performed before the QFT. Mitogen-induced IFN-γ production increases after initiation of anti-TNF-α therapy.

ObjectiveThe first 3 months after symptom onset represent an important therapeutic window for rheumatoid arthritis (RA). This study investigates the extent and causes of delay in assessment of patients with RA in eight European countries.MethodData on the following levels of delay were collected from 10 centres (Berlin, Birmingham, Heraklion, Lund, Prague, Stockholm, Umeå, Vienna, Warsaw and Zurich): (1) from onset of RA symptoms to request to see healthcare professional (HCP); (2) from request to see HCP to assessment by that HCP; (3) from initial assessment by HCP to referral to rheumatologist; and (4) from referral to rheumatologist to assessment by that rheumatologist.ResultsData were collected from 482 patients with RA. The median delay across the 10 centres from symptom onset to assessment by the rheumatologist was 24 weeks, with the percentage of patients seen within 12 weeks of symptom onset ranging from 8% to 42%. There were important differences in the levels underlying the total delays at individual centres.ConclusionsThis research highlights the contribution of patients, professionals and health systems to treatment delay for patients with RA in Europe. Although some centres have strengths in minimising certain types of delay, interventions are required in all centres to ensure timely treatment for patients.

When confronted with a dermatomyositis or polymyositis patient not responding to immunosuppressive treatment, physicians must first ask whether the original diagnosis was correct. In this review, we provide a guide to the clinical features and ancillary tests, which might be helpful in the differential diagnosis of myositis. Particular attention is paid to the role of autoantibody detection, as some of them are not only relatively specific for the disease but also associated with unique clinical features including resistance to treatment. Subsequently, other possible explanations of treatment resistance are listed and a short overview of treatment options for resistant myositis patients is given.

Background and objectives Genes within the major histocompatibility complex (MHC) region has a strong genetic relevance in autoimmunity development. The involvement of the class I and class II genes, as well as class III (non-Class I/II MHC) genes has been proposed. For the myositis development, the HLA-DRB1*03 is a known risk factor in Caucasian population. However, there are another genes appearing to be significant players in the ethiology of myositis located near the HLA-DRB1 locus. In the present study the authors have focused on one of these risk factors – the regulation of MHC-linked inducible HSP70 genes expression and their relation to the known immunogenetic risk factor located within the MHC (HLA-DRB1*03). Materials and methods The authors have investigated the gene specific HSP70 expression in 20 patients with dermatopolymyositis and 15 healthy people matching in age as control samples. Expression levels of the two inducible HSP70 genes ( HSPA1A , HSPA1B ) were analysed both in patients and controls. Both of the groups were additionally genotyped for HLA-DRB1 locus. Myositis-specific and associated autoantibodies were also identified in patients. Results The expression of both, the HSPA1A and HSPA1B genes was significantly upregulated (p HSPA1A was found to be associated with the presence of the HLA-DRB1*03 risk allele in patients. However, this was not observed for the HSPA1B gene. In contrast, the authors found a positive correlation between the expression regulation of the HSPA1B gene and the presence of disease specific autoantibodies in myositis patients. Additionally, positive correlation between the presence of disease specific autoantibodies and the HLA-DRB1*03 risk allele was found. None of these observations were found in healthy controls. Conclusions The results suggest that the two MHC-linked inducible genes are differentially expressed in dependence on the autoantibody or HLA risk allele presence. The differential gene expression regulation shows that the HSPA1B is an – on HLA-DRB1 – independent molecular marker for myositis development.

Background and Objectives Classical (CM), non-classical (NCM) and intermediate populations of human monocytes are characterised by differential expression of CD14 and CD16. NCM and IM are potent antigen presenting cells and producers of pro-inflammatory cytokines. They are enriched in patients with established rheumatoid arthritis (RA) and their numbers correlate with disease activity and response to therapy with methotrexate (MTX) and glucocorticoids (GCS). CD11c plays a role in antigen presentation and production of pro-inflammatory cytokines. Increased expression of CD11c on mononuclear blood cells and a predictive role of higher CD11c mRNA expression for response to TNFα blocking treatment in RA were described. We evaluated the expression of CD11c on monocyte subpopulations in patients with early rheumatoid arthritis (ERA) and its changes after three months of treatment with GCS and non-biological disease modifying drugs. Materials and Methods 29 patients with ERA and 10 gender and age-matched healthy controls (HC) were included in this study. ERA patients had symptom duration for + CD16 - , NCM:CD14 dim CD16 ++ ) using multicolour flow cytometry. Based on isotype and FMO controls for CD14 and CD16; two intermediate (IM) populations were evaluated (CD14 + CD16 dim and CD14 + CD16 ++ ). CD11c expression was analysed by median fluorescence intensity. Results Expansion of both intermediate populations (IM-CD16 dim , p ++ , p = 0.02) and reduction of CM (p + or ++ and NCM: rs = -0.64, -0.55 or -0.50 and -0.40; p = 0.004, 0.08 or 0.02 and 0.09) at month three. No associations with disease activity or with MTX dosage were found. Conclusions The expansion of intermediate monocyte subpopulations in ERA patients and enhancement of CD11c expression with reduction after three months of treatment with GCS suggest their possible role in the pathogenesis of RA at early stages of the disease. Acknowledgement Institutional support MZCR0002372801

Background and Objectives MicroRNAs can regulate the gene expression and cellular functions such as cell cycle, differentiation, or apoptosis. Emerging evidence has demonstrated that miRNAs play a vital role also in the regulation of immunological functions, including the development of autoimmunity. Like in most of other autoimmune diseases, the etiopathogenesis of Idiopathic inflammatory myopathy (IIM) is also believed to be triggered by environmental factors in combination with susceptible genetic background. Beside a genetic risk located within the MHC complex, the role of epigenetic regulations including changes in miRNAs expression profiles in autoimmunity development have recently also been implicated. The aim of this study was to look for specific miRNA expression patterns in the serum, peripheral blood mononuclear cells (PBMCs) and muscle biopsies of patients suffering from idiopathic inflammatory myopathy. Materials and Methods RNA was isolated from serum, PBMCs and muscle biopsy samples of patients suffering from IIM using modified Trizol-chloroform method. The expression profile of miRNAs was determined by 60K high density microarray from Agilent Company. Results In total, 87 miRNAs were found to be differentially expressed at a significant level (p Conclusions This is the first study providing information about complete expression profile of miRNA molecules found in the serum, PBMCs and muscle biopsy samples of patients with IIM. We have found that a number of miRNAs were differentially expressed in diverse tissue samples indicating tissue specific expression of miRNAs. The “missregulated” miRNAs might potentially act as biomarkers of initiated systemic inflammatory response, or functional molecules related to muscle tissue injury, or molecules involved in regulation of immune response. Acknowledgement This study was supported by the Internal Grant Agency of the Ministry of Health in the Czech Republic [MZCR NT 12452-4], Institutional support of MHCR VZ (00023728) and The Charles University Grant Agency (No.621812).

Background Interleukin-35 (IL-35) is a newly described hetero-dimeric cytokine of the IL-12 family. Studies of immunopathogenesis in idiopathic inflammatory myopathies (IIM) are of interest for future biological therapies. Objective To analyze expression of IL-35 in muscle biopsies and to study its effects on peripheral blood mononuclear cells (PBMC) in vitro to assess its pathogenetic and diagnostic value. Materials and methods Immunoexpression of IL-35 subunits (p35, EBI3) was studied immunohistochemically in 23 muscle biopsies of IIM (12 dermatomyositis, 11 polymyositis), 10 noninflammatory myopathies and 10 controls. PBMCs were stimulated with human recombinant IL-35 protein or TNF-α in vitro. Taq-Man RT-PCR was performed to analyze gene expression after 6hours and ELISA assays were used to confirm the protein secretion after 24 hours of stimulation. Results We showed localization of both IL-35 subunits in B-cells, T-cells and macrophages of the inflammatory infiltrates in IIM. No immunoreactivity was observed in controls. We found that gene expression of both IL-35 subunits were dose- and time-dependently induced by TNF-α in PBMCs. Conclusion Our data suggest pro-inflammatory properties of IL-35 and its potential role in the pathogenesis of IIM. The immunohistochemical expression of IL-35 might be also of diagnostic help in muscle biopsy.

Background Specific or associated autoantibodes are present in a majority of patients with idiopathic inflammatory myopathies (IIM). The most frequent myositis associated autoautoantibodies are directed to Ro52-kd protein (present in 12–26%). Antibodies towards the immunodominant epitope (p200) of Ro52 are associated with neonatal heart block (CHB) in SLE and Sjogren9s syndrome (SjS) with the increasing evidence for their pathogenic role. Less is known about possible pathogenic involvement of anti-Ro52 in IIM. Presence of anti-Ro52 in patients with anti-Jo-1 autoantibody is associated with interstitial lung disease (ILD) and suggested decreased survival rate. Objective To investigate possible associations of reactivity to Ro52 epitopes with disease manifestations, autoantibody profile and HLA-DRB1 alleles in myositis. In order to confirm the hypothesis of ongoing epitope spreading with time, the association of disease duration with polyreactivity was evaluated. Methods Serum samples from 468 myositis patients were collected in three countries: Czech (n=133); Hungary (n=202), Sweden (n=133). Antibody specificity against recombinant full length (FL) Ro52 antigen, its four deletion fragments (Ro52-3, -4, -5 and -6) and 7 overlapping synthetic peptides (p136–200) covering the major immunodominant region (Ro52-3) was measured by ELISA. Myositis specific and associated autoantibodies (Jo-1, PL-7, PL-12, EJ, OJ, SRP, PM-Scl, Ku, Mi-2β, U1-RNP) were detected by line-blot immunoassay. 417 patients were genotyped for HLA-DRB1. Results One hundred and eighty-four patients with dermatomyositis (DM), 250 polymyositis (PM), 11 inclusion body myositis, 20 juvenile DM/PM and three with mixed connective tissue disease were included in the analysis. Overlap with other systemic disease (OM) was present in 67 (14%) and ILD in 132 (29%) of patients. Median disease duration was 4.7 (0–41.5) years. Reactivity to Ro52-FL was present in 97 (21%) samples. Of these, 87 (90%) patients showed specificity to Ro52-3. Within these anti-p176 dominated (66; 76%) compared to anti-p200 in 44 (51%) patients. Anti-Ro52FL positivity was associated with presence of ILD (OR 3.8; p Conclusion Our results confirm the association between anti-Ro52 autoantibody positivity with lung involvement, anti-Jo-1 autoantibodies and HLA-DRB1*03 allele in myositis. The predominance of reactivity to epitope p176 in myositis patients is different from that which has been reported in patients with SLE and SjS, but the clinical significance is not clear. There was no evidence of epitope spreading in anti-Ro52 response. Acknowledgement Supported by European Union 6.FP integrated project AutoCure LSHB CT-2006-018661; by MSM 0021620812 from Ministry of Education, Youth and Sports in the Czech Republic and by Grant NT 12438 of IGA Ministry of Health in the Czech Republic.

Background 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. Methods 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. Results 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. Conclusions 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. Electronic supplementary material The online version of this article (doi:10.1186/s13075-016-1208-6) contains supplementary material, which is available to authorized users.