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Compelling evidence supports the health benefits of physical exercise on the immune system, possibly through the molecules secreted by the skeletal muscles known as myokines. Herein, we assessed the impact of exercise interventions on plasma Heat shock protein 90 (Hsp90) levels in 27 patients with idiopathic inflammatory myopathies (IIM) compared with 23 IIM patients treated with standard-of-care immunosuppressive therapy only, and in 18 healthy subjects undergoing strenuous eccentric exercise, and their associations with the traditional serum markers of muscle damage and inflammation. In contrast to IIM patients treated with pharmacotherapy only, in whom we demonstrated a significant decrease in Hsp90 over 24 weeks, the 24-week exercise program resulted in a stabilization of Hsp90 levels. These changes in Hsp90 levels were associated with changes in several inflammatory cytokines/chemokines involved in the pathogenesis of IIM or muscle regeneration in general. Strenuous eccentric exercise in healthy volunteers induced a brief increase in Hsp90 levels with a subsequent return to baseline levels at 14 days after the exercise, with less pronounced correlations to systemic inflammation. In this study, we identified Hsp90 as a potential myokine and mediator for exercise-induced immune response and as a potential biomarker predicting improvement after physiotherapy in muscle endurance in IIM.

Background: The development of hand osteoarthritis (HOA) and its progression into the erosive subset are unclear, but inflammation is suspected to be the main source. To verify the involvement of inflammation in HOA pathogenesis, we evaluate serum inflammatory mediators and their association with HOA-related clinical features in patients., Methods: 153 participants (50 non-erosive HOA patients, 54 erosive HOA patients, and 49 healthy control subjects) were included in this study. All patients underwent clinical examination, which included assessment of tender and swollen small hand joints, ultrasound (US) examination, and self-reported measures (e.g., AUSCAN or algofunctional indexes). Serum inflammatory mediators were quantified using human cytokine 27-plex immunoassay. We employed linear modelling, correlation analysis, and resampling statistics to evaluate the association of these mediators to HOA., Results: We identified increased levels of nine inflammatory mediators (e.g., eotaxin, monocyte chemoattractant protein 1, interleukin-8, and tumour necrosis factor) in HOA patients compared to healthy controls. Increased mediators correlated with ultrasound findings as well as with clinically tender and swollen joint counts in patients with erosive HOA. However, none of the mediators distinguished between erosive and non-erosive HOA subtypes., Conclusion: Our findings support the hypothesis on the involvement of inflammation in HOA.

Objective: To evaluate circulating visfatin and its relationship with disease activity and serum lipids in patients with early, treatment-naïve rheumatoid arthritis (RA). Methods: Serum visfatin was measured in 40 patients with early RA before and after three months of treatment and in 30 age- and sex-matched healthy individuals. Disease activity was assessed using the Disease Activity Score for 28 joints (DAS28) at baseline and at three and 12 months. Multivariate linear regression analysis was performed to evaluate whether improved disease activity is related to serum visfatin or a change in visfatin level. Results: Serum visfatin was significantly elevated in early RA patients compared to healthy controls (1.92±1.17 vs. 1.36±0.93 ng/ml; p = 0.034) and significantly decreased after three months of treatment (to 0.99±0.67 ng/ml; p<0.001). Circulating visfatin and a change in visfatin level correlated with disease activity and improved disease activity over time, respectively. A decrease in visfatin after three months predicted a DAS28 improvement after 12 months. In addition, decreased serum visfatin was not associated with an improved atherogenic index but was associated with an increase in total cholesterol level. Conclusion: A short-term decrease in circulating visfatin may represent an independent predictor of long-term disease activity improvement in patients with early RA. [ABSTRACT FROM AUTHOR]

Objectives. The S100A4 protein is known as a metastasis promoting factor; however, its involvement in non-malignant diseases such as RA and psoriasis has been recently described. The aim of this study was to investigate the expression and possible role of S100A4 in idiopathic inflammatory myopathies.Methods. S100A4 protein expression was detected by immunohistochemistry in muscle tissue from control individuals (n = 11) and patients with PM and DM (n = 8/6). IF staining was used to co-localize S100A4 with selected cells. Cytokine expression and protein synthesis in S100A4-treated cells were analysed by RT-PCR and ELISA.Results. S100A4 protein was significantly up-regulated in muscle tissue of patients with inflammatory myopathies compared with control individuals and was associated particularly with the presence of mononuclear infiltrates. Only few regenerating muscle fibres in PM/DM expressed S100A4. Then we analysed the effect of S100A4 on human myocytes and peripheral blood mononuclear cells (PBMCs). Although S100A4 did not affect myocytes, stimulation of PBMCs with S100A4 significantly induced the expression and synthesis of TNF-α, IL-1β and IL-6, but not of IFN-α. We showed that S100A4 is not directly involved in perforin/granzyme B-induced apoptosis and that it does not modulate the expression of Bax and Bcl2 mRNA in myocytes and PBMCs.Conclusion. Increased expression of S100A4 in inflamed muscle tissue highlights its potential role in the pathogenesis of inflammatory myopathies. S100A4 may act as a cytokine-like factor indirectly promoting muscle fibre damage by stimulating mononuclear cells to increase the synthesis of pro-inflammatory cytokines. [ABSTRACT FROM PUBLISHER]

Highlights • S100A11 accumulates in regenerating and necrotizing muscle fibres of myositis patients. • S100A11 is elevated in plasma of patients with DM and CAM. • Increased S100A11 reflects disease activity and extramuscular manifestations in DM. Abstract Background S100A11 (calgizzarin), a member of the S100 family, is associated with oncogenesis, inflammation and myocardial damage. Our aim was to analyse S100A11 in idiopathic inflammatory myopathies (IIMs) and its association with disease activity features and cancer development. Methods S100A11 in muscle was determined by immunohistochemistry in polymyositis (PM), dermatomyositis (DM), myasthenia gravis (MG) and in subjects without autoimmune inflammatory disease (HC). S100A11 in plasma was measured in 110 patients with IIMs (PM, DM, and cancer associated myositis (CAM) patients) and in 42 HC. Disease activity was assessed by myositis disease activity assessment (MYOACT), muscle enzymes and C-reactive protein (CRP) were measured by routine laboratory techniques; autoantibodies by immunoprecipitation or by immunoblot. Results We observed an accumulation of S100A11 in the cytoplasm of regenerating and necrotizing muscle fibres of PM and DM patients. S100A11 was increased in plasma of all myositis patients compared to HC (3.8 (1.5–16.8) vs 2.8 (1.7–11.2) ng/ml, p = 0.011) and in DM and CAM patients compared to HC (4.0 (2.2–14.9) and 4.5 (1.5–9.1) vs 2.8 (1.7–11.2) ng/ml, p < 0.001 and p = 0.022, respectively). In all myositis patients, S100A11 correlated with the levels of lactate dehydrogenase (r = 0.256, p = 0.011), aspartate aminotransferase (AST) (r = 0.312, p = 0.002), CRP (r = 0.254, p = 0.022) and MYOACT (r = 0.245, p = 0.022). S100A11 was associated with MYOACT (r = 0.377, p = 0.030) and pulmonary and cutaneous disease activity in DM patients (r = 0.408, p = 0.017 and r = 0.417, p = 0.01, respectively). S100A11 was related to the levels of AST (r = 0.412, p = 0.027) in PM and to the levels of creatine phosphokinase (r = 0.432, p = 0.028) in CAM patients. Conclusions We show for a first time a potential implication of S100A11 in the local inflammatory and tissue remodelling processes in myositis and an association of circulating S100A11 with disease activity and extra muscular manifestations in DM. [ABSTRACT FROM AUTHOR]

Background Interleukin (IL)-20 is a pro-inflammatory cytokine that may be implicated in the pathogenesis of rheumatoid arthritis (RA). This study aimed to determine the association between IL-20 and disease activity in patients with RA. Methods The levels of serum and synovial fluid IL-20 were measured in patients with RA and OA. The disease activity was assessed based on the Disease Activity Score of 28 joints (DAS28). The expression of IL-20 in synovial tissue samples from patients with RA and OA were determined by immunohistochemistry. Immunofluorescence staining was used to co-localize IL-20 with selected cells. The secretion of IL-20 was analysed in human peripheral blood mononuclear cells (PBMCs) of patients with RA. Results Synovial fluid and synovial tissue IL-20 were significantly increased in patients with RA compared with patients with OA. The expression of IL-20 in RA synovial tissue was particularly associated with macrophages and neutrophil granulocytes, but also with synovial fibroblasts and lymphocytes. The IL-20 levels in synovial fluid correlated with DAS28 (r = 0.434; p = 0.015) and were significantly elevated in anti-CCP positive RA compared with anti-CCP negative RA (122.3 ± 104.1 pg/ml and 45.9 ± 35.8 pg/ml; p = 0.008). IL-20 production from PBMCs was induced by Poly I:C and LPS but not with pro-inflammatory cytokines, such as TNF-α or IL-1. Conclusion Our data showed that IL-20 is independently associated with RA disease activity and may be triggered by TLR ligands at local sites of inflammation. [ABSTRACT FROM AUTHOR]

Objective Interleukin-35 (IL-35) is a heterodimeric member of the IL-12 family consisting of p35/IL-12a and EBI3/IL-27b subunits. Expressed in murine Treg cells, IL-35 controls inflammatory diseases in mouse models. However, human IL-35 is expressed in Teff cells rather than in Treg cells and is shown to be upregulated under inflammatory conditions. Our aim was to examine the involvement of IL-35 in the pathogenesis of rheumatoid arthritis (RA). Methods Immunohistochemical and immunofluorescence analysis was used to determine the expression and localization of IL-35 and its subunits (p35/EBI3) and IL-35 receptor (IL12Rβ2/gp130) in RA, osteoarthritis (OA) and psoriatic arthritis (PsA) synovial tissues. Expression of p35/EBI3 subunits and release of inflammatory cytokines upon stimulation with IL-35 were assessed in RA synovial fibroblasts (SFs) and peripheral blood mononuclear cells (PBMCs). Results Both IL-35 and its subunits were upregulated in RA in comparison with OA or PsA synovium. Using cell-specific markers, p35 and EBI3 were identified in macrophages, dendritic cells, SFs, and T as well as B cells in RA synovium. Both p35 and EBI3 were induced by TNFα in RASFs and PBMCs. IL-35 dose-dependently upregulated release of pro-inflammatory mediators IL-1β, IL-6 and MCP-1 in PBMCs. While gp130 receptor subunit was upregulated in RA synovium and was expressed in RASFs and PBMCs, there was no difference in IL12Rβ2 expression subunit among tissues and its presence in RASFs was lacking. Conclusion Upregulation of IL-35 at sites of inflammation in RA and its pro-inflammatory potential suggests that IL-35 might play an important role in RA pathogenesis. [ABSTRACT FROM AUTHOR]

Highlights: [•] FABP4 are significantly higher in serum and synovial fluid of patients with RA. [•] FABP4 is correlated with total and LDL cholesterol in patients with RA. [•] FABP4 may represent a link between RA and the risk of atherosclerotic changes. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Adiponectin was initially described as a regulator of metabolic homeostases. Further studies demonstrated its involvement in the regulation of inflammatory diseases, particularly rheumatic and vascular diseases and some fibrotic processes. The aim of this study was to evaluate adiponectin in the circulation of patients with systemic sclerosis (SSc) and characterise its potential association with skin changes and SSc-related features. Methods: Serum levels of adiponectin, interleukin-6 and soluble receptor for interleukin-2 (by ELISA), lipid levels, CRP (by turbidimetry), ANA (by immunofluorescence), autoantibodies of the ENA complex (by immunoblot) and urine levels of pyridinoline and deoxypyridinoline (by HPLC) were measured in 39 patients with SSc, and adiponectin levels were determined in 30 healthy controls matched by age, sex, and body mass index (BMI). Organ manifestations were recorded and skin changes were assessed using the modified Rodnan skin score. Results: Adiponectin serum levels were similar between patients with SSc and healthy controls (median (IQR), 6.9 (5.9–9.1) vs. 7.8 (6.2–9.5)μg/ml, p =0.670). Levels of serum (ln) adiponectin were negatively correlated with the skin score (r =−0.379, p =0.017). Regression analysis of the relationship between adiponectin and markers of interest provided two statistically significant models: A- with explanatory variables HDL–cholesterol, skin score, disease duration, age (R 2 =0.580); and B- with CRP, skin score, age (R 2 =0.550); in order of a decreasing influence. Conclusion: Based on the results of this study, it might be speculated that adiponectin plays a protective role in skin- and atherosclerosis-related changes during SSc. [Copyright &y& Elsevier]

Abstract: Objective: Visfatin, also known as pre-B cell colony-enhancing factor, was recently characterized as a potent pro-inflammatory mediator in rheumatoid arthritis (RA). The aim of this study was to determine the effect of B cell depletion with rituximab on serum visfatin levels in patients with active RA. Methods: We evaluated 31 patients with RA starting rituximab therapy at baseline and after 16 and 24weeks using disease activity score (DAS28). The control group consisted of 33 gender and age-matched healthy individuals. CD19+ B cells were assessed by flow cytometry and serum levels of visfatin and B cell-activating factor of the TNF family (BAFF) were measured by ELISA at baseline and week 16. Results: Total number of B cells correlated positively with serum visfatin levels (rs=0.417, P =0.025) and negatively with serum BAFF levels (rs=−0.486, P =0.008) at baseline. Serum visfatin levels were significantly higher in patients with RA compared with healthy controls (P =0.026), and significantly decreased (P =0.010), while BAFF increased (P <0.001), and both proteins became negatively correlated following treatment with rituximab (rs=−0.438, P =0.017). Visfatin levels did not correlate with the disease activity, but lack of change in the serum visfatin levels between baseline and week 16 predicted worsening disease activity between weeks 16 and 24 (rs=0.452, P =0.014). Conclusion: In patients with active RA, serum visfatin levels are related to the number of B cells rather than to disease activity and decrease in response to treatment with rituximab. Further studies are necessary to show if visfatin is a marker with predictive value for deterioration of RA. [Copyright &y& Elsevier]

• IL-35 subunits are expressed in the inflammatory infiltrates in muscle biopsies of patients with myositis. • Serum IL-35 levels are elevated in myositis patients compared to healthy controls. • Serum IL-35 levels correlate with disease activity. Interleukin-35 (IL-35) is a recently described heterodimeric cytokine that belongs to the IL-12 family and consists of p35 (IL-12a) and EBI3 (IL-27b) subunits. The expression of IL-35 in humans is inducible in response to inflammatory stimuli. Increased IL-35 levels were documented in several autoimmune inflammatory diseases, suggesting a possible immunomodulatory role in their pathogenesis. The aim of this study was to explore a potential role of IL-35 in the pathogenesis of idiopathic inflammatory myopathies (IIM) by studying the expression of IL-35 subunits in muscle biopsy samples and by evaluating serum levels of IL-35 and their association with disease activity in IIM patients. The expression of IL-35 subunits was studied in serial sections of 9 muscle biopsy samples [4 polymyositis (PM), 5 dermatomyositis (DM)] and in 7 non-inflammatory control muscle biopsies. Serum levels of IL-35 were measured in 23 PM, 28 DM and 15 cancer associated myositis (CAM) patients as well as in 40 healthy controls. Disease activity was evaluated using the Myositis Disease Activity Assessment Tool (MDAAT) and by serum muscle enzymes. Expression of both IL-35 subunits was evident in the inflammatory infiltrates in IIM muscle biopsies, while no IL-35 expression was observed in control muscle samples. IL-35 serum levels were increased in all IIM patients compared to healthy controls [median 119.5 (range 32.1–1074.5) vs 36.2 (range 1.5–86.5) pg/ml, P < 0.001]. There were no differences in IL-35 serum levels between myositis subgroups (DM, PM or CAM). Serum IL-35 levels correlated significantly with physician's assessment of global (r = 0.29, p = 0.021), muscle (r = 0.30, p = 0.017) and extramuscular (r = 0.30, p = 0.016) disease activity as well as creatine kinase (r = 0.26, p = 0.044) and lactate dehydrogenase (r = 0.40, p = 0.003) levels. There was a significant correlation with pulmonary activity in patients with interstitial lung disease (r = 0.39, p = 0.037). Serum IL-35 correlated negatively with duration of treatment (r = −34, p = 0.009). IL-35 is overexpressed in inflammatory infiltrates in muscle tissue and serum in IIM patients and there is correlation with several disease activity parameters. These data suggest potential role of locally produced IL-35 in the pathogenesis of inflammatory myopathies. [ABSTRACT FROM AUTHOR]