Interleukin-35 (IL-35) is a newly described heterodimeric cytokine that belongs to the IL-12 family and consists of p35 (IL-12a) and EBI3 (IL-27b) subunits. IL-35 exerts immunomodulatory activities in several autoimmune inflammatory diseases.
Objectives
The aim of this study was to assess IL-35 expression in muscle tissue of patients with idiopathic inflammatory myopathies (IIM) and to compare serum levels of IL-35 in patients with IIM to healthy controls and asses potential association with activity of IIM.
Methods
The expression of IL-35 was studied in a series of 19 muscle biopsy samples of idiopathic inflammatory myopathies (9 dermatomyositis, 10 polymyositis) and 10 non-inflammatory control muscle biopsies from patients with myasthenia gravis.Serum levels of IL-35 were measured in 23 PM, 28 DM and 15 cancer associated myositis patients as well as in 40 healthy controls.Disease activity was evaluated by the Myositis Disease Activity Assessment Tool (MYOACT) and by serum muscle enzymes.
Results
Both IL-35 subunits were found in immune cells of the inflammatory infiltrates in IIM muscle biopsies, no immunoreactivity was observed in muscle tissue of control patients.IL-35 serum levels were increased in all IIM patients compared to healthy controls (p<0.001). There were no differences in IL-35 serum levels between myositis subgroups. Serum IL-35 levels correlated with the overall MYOACT score, with extramuscular and muscle domains of MYOACT, with physician9s global activity assessment and lactate dehydrogenase levels.
Conclusions
IL-35 subunits are overexpressed in inflammatory infiltrates in muscle tissue of IIM patients and elevated circulating IL-35 levels correlate with several disease activity parameters. These data suggest potential role of IL-35 in the pathogenesis of inflammatory myopathies.
Acknowledgement
Supported by MHCR support for conceptual development of a research organization (023728) and BTCure (115142–2).
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<0.001; p<0.05) in patients suffering from myositis when compared to controls. The expression regulation of the 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.
Systemic sclerosis (SSc) is characterized 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/tumor 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/m2, p<0.0001) and body fat % assessed by both iDXA (BF%: 37.2±6.6 vs. 32.6±8.2%, p=0.0014) and BIA (BF%: 31.1±6.4 vs. 24.6±7.8%, p<0.0001), and a trend to decreased visceral fat weight (0.9±0.9 vs. 0.5±0.5kg, p=0.0670). Compared to HC, SSc patients demonstrated significantly decreased lean body mass assessed by both iDXA (LBM: 46.6±7.5 vs. 40.9±6.8kg, p=0.0003) and BIA (LBM: 53.2±8.7 vs. 47.7±7.0kg, p=0.0017), and increased ECM/BCM ratio (extracellular mass/body cell mass: 1.03±0.1 vs. 1.29±0.4, p<0.0001), which reflects worse muscle predispositions for physical exercise, aerobic fitness/performance, and usually increases with deteriorating nutritional status. Compared to HC, SSc patients had significantly lower bone mineral density (BMD: 1.16±0.10 vs. 1.05±0.11g/cm2, p<0.0001), and were currently able to perform less energetically demanding physical activities according to HAP score (84.7±6.6 vs. 64.1±17.2, p<0.0001). Disease activity negatively correlated with BF% (r=-0.324, p=0.014), and physical activity (HAP) positively correlated with BMD (r=0.276, p=0.034) and negatively with ECM/BCM (r=-0.625, p<0.0001).
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.
Background: Heat shock proteins (Hsps) are chaperones playing important roles in skeletal muscle physiology, adaptation to exercise or stress, and activation of inflammatory cells Objectives: The aim of our study was to assess Hsp90 expression in muscle biopsies and plasma of patients with idiopathic inflammatory myopathies (IIM) and to characterize 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; DM, 104/PM, 108/CADM, 31/IMNM, 25) and 157 healthy individuals (92 females, 65 males; mean age 47.0) were included in plasma analysis. Muscle biopsy samples (PM, DM, IMNM, myodystrophy, myasthenia gravis) were stained for Hsp90α (Thermo Fisher Scientific, USA) and Hsp90β (Abcam, UK). Plasma Hsp90 was measured by ELISA kit (eBioscience, Vienna, Austria). The cytokines/chemokines were analysed by using Bio-Plex Pro TM human Cytokine 27-plex Assay (BIO-RAD, California, USA.Data are presented as median(IQR). Results: In muscle biopsies, Hsp90 expression of both subunits (alpha and beta) was higher in IIM than in controls. Increased Hsp90 was detected in perifascicular degenerating and regenerating fibers, inflammatory cells (DM, PM), and necrotic and regenerating fibers (IMNM). Plasma Hsp90 levels were increased in IIM patients compared to healthy controls (55.9 (46.9 – 62.5)vs 9.76(7.5 – 13.8), p<0.0001), and in individual subgroups of IIM vs. healthy controls (DM-22.01(14.1 – 41.2), PM-19.7(14.3 – 42.2), CADM-18.9(11.7 – 29.7), IMNM-19.6(16.3 – 45.5), p<0.0001 for all). Hsp90 was higher in males compared to females (p=0.040) and in patients with ILD (p=0.003), cardiac involvement (p=0.004), dysphagia (p=0.018) and presence of anti-Ro52 (p=0.036). Hsp90 levels in all patients positively correlated with muscle enzymes (Tab.1). Hsp90 was associated with disease activity and skeletal muscle involvement (Tab.1). Out of all clinical parameters listed in above-mentioned univariate analysis, in multiple regression analysis Hsp90 levels in IIM patients were significantly affected by muscle enzymes only (p<0.0001, β=0.345). Furthermore, Hsp90 positively correlated with some crucial cytokines involved in pathogenesis of myositis (Tab. 1). Tab 1 Clinical parameters Spearman’s r p – value LDH; AST; ALT 0.554; 0.383; 0.181 < 0.0001; < 0.0001; 0.003 PtDGA; PhDGA; MITAX; MYOACT 0.223; 0.217; 0.175; 0.159 < 0.001; < 0.001; 0.004; 0.012 Pulmonary disease activity 0.201 0.001 Muscle disease activity 0.146 0.018 MMT8, total score; m. biceps brachii; m. gluteus maximus; m. iliopsoas -0.126; -0.125; -0.159; -0.143 0.042; 0.043; 0.011; 0.023 MDI – Myositis damage index – severity 0.150 0.041 Current Prednisone equivalent dose 0.183 0.006 Cytokines: IL-1b; IL-2; IL-4; IL-6; IFN-γ 0.188; 0.269; 0.190; 0.182; 0.229 0.002; < 0.0001; 0.002; 0.003; < 0.0001 Conclusion: We demonstrate increased Hsp90 expression in IIM muscle biopsy samples, specifically in inflammatory cells, degenerating, regenerating and/or necrotic fibers. 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. Acknowledgments: Supported by AZV-16-33542A, MHCR 023728 and SVV – 260373. Disclosure of Interests: Hana Štorkánová: None declared, Sabina Oreska: None declared, Maja Špiritović: None declared, Barbora Heřmánková: None declared, Olga Kryštůfková: None declared, Heřman Mann: None declared, Martin Komarc: None declared, Josef Zámečník: None declared, Karel Pavelka Consultant of: Abbvie, MSD, BMS, Egis, Roche, UCB, Medac, Pfizer, Biogen, Speakers bureau: Abbvie, MSD, BMS, Egis, Roche, UCB, Medac, Pfizer, Biogen, Jiří Vencovský: None declared, Ladislav Šenolt: None declared, Michal Tomcik: None declared
Calprotectin, a heterodimeric complex of S100A8/9 (MRP8/14), has been demonstrated as an important biomarker of clinical and laboratory disease activity and structural joint damage in rheumatoid arthritis (RA).1,2 Ultrasound is a sensitive and reliable tool for assessing synovial inflammation in RA.3
Objectives
To test the hypothesis that calprotectin is associated with clinical and ultrasound disease activity in patients with RA in a cross-sectional study and to investigate the contribution of various parameters to predict ultrasound findings.
Methods
A total of 37 patients with RA (24 females, median disease duration 18 months) underwent clinical examination (DAS28) and 7-joint ultrasound score (US-7) of clinically dominant wrist, second and third metacarpophalangeal and proximal interphalangeal, and second and fifth metatarsophalangeal joints to assess synovitis and tenosynovitis by gray-scale (GS) and power Doppler (PD) ultrasound using semiquantitative grading 0-3. The levels of serum calprotectin and C-reactive protein were measured at the time of ultrasound assessment. Clinical and laboratory measures were correlated with ultrasound findings. Multiple regression analysis was used to determine the predictive value of calprotectin, CRP and DAS28 to determine PD synovitis.
Results
We found that DAS28 (r=0.605, p<0.001; r=0.605, p<0.001, resp.) and CRP levels (r=0.451, p=0.006; r=0.463, p=0.004, resp.) correlate significantly with GS and PD synovitis. In addition, calprotectin correlated significantly with PD synovitis (r=0.497, p<0.005). Furthermore, serum calprotectin significantly correlated with CRP (r=0.629, p<0.001) and DAS28 (r=0.385, p<0.019). In addition to DAS28 (p=0.001), calprotectin (p<0.001) was a strong predictor of active PD synovitis (adjusted R2=0.811).
Conclusions
This study confirms tight association between clinical, laboratory and ultrasound assessment and support circulating calprotectin as an important biomarker for monitoring synovial inflammation in RA.
References
Andrés Cerezo L, Mann H, Pecha O, et al. Decreases in serum levels of S100A8/9 (calprotectin) correlate with improvements in total swollen joint count in patients with recent-onset rheumatoid arthritis. Arthritis Res Ther. 2011;13(4):R122. Hammer HB, Fagerhol MK, Wien TN, Kvien TK. The soluble biomarker calprotectin (an S100 protein) is associated to ultrasonographic synovitis scores and is sensitive to change in patients with rheumatoid arthritis treated with adalimumab. Arthritis Res Ther. 2011;13(5):R178. Backhaus TM, et al. The US7 score is sensitive to change in a large cohort of patients with rheumatoid arthritis over 12 months of therapy. Ann Rheum Dis. 2013 Jul;72(7):1163-9.
Acknowledgements
This work was supported by project of MHCR for conceptual development of research organization 023728, IGA grant No. NT12437 and GAUK grant No. 1010213.
Systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM) are very rare rheumatic diseases burdened by a high prevalence of sexual dysfunctions. However, no specific treatment has been proposed to date. To our knowledge, this is the first (pilot) study aiming to investigate the effect of an 8-week tailored physiotherapy program on the sexual health of women with SSc and IIM.In total, 12 women with SSc and 4 women with IIM were enrolled in the study. Based on the patients' capability to participate in the program, they were divided into an intervention group (IG) (mean ± SD age 46.8 ± 8.6 years) and a control group (CG) (mean ± SD age 46.3 ± 8.5 years). IG underwent the 8-week program (1 h of supervised physiotherapy twice weekly), whereas CG received no physiotherapy. At weeks 0 and 8, all patients filled in questionnaires assessing sexual function (Female Sexual Function Index [FSFI], Brief Index of Sexual Functioning for Women [BISF-W]), sexual quality of life (Sexual Quality of Life-Female [SQoL-F]), functional ability (Health Assessment Questionnaire [HAQ]), quality of life (Medical Outcomes Short Form-36 [SF-36]), and depression (Beck's Depression Inventory-II [BDI-II]). The changes were analyzed with two-way ANOVA and Friedmann's test.Compared to the statistically significant deterioration in CG over weeks 0-8, we found statistically significant improvements in the total scores of FSFI and BISF-W, and some of their domains, functional status, and the physical component of quality of life.Our 8-week physiotherapy program not only prevented the natural course of progressive deterioration of functional ability but also led to a significant improvement in sexual function and quality of life in women with SSc and IIM. However, due to the lack of randomization and a relatively small sample size resulting from the strict inclusion criteria, further validation of our results is needed.ISRCTN91200867 (prospectively registered).
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