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ID PMID Title PublicationDate abstract
26056442 Effects of PVA coated nanoparticles on human immune cells. 2015 Nanotechnology provides new opportunities in human medicine, mainly for diagnostic and therapeutic purposes. The autoimmune disease rheumatoid arthritis (RA) is often diagnosed after irreversible joint structural damage has occurred. There is an urgent need for a very early diagnosis of RA, which can be achieved by more sensitive imaging methods. Superparamagnetic iron oxide nanoparticles (SPION) are already used in medicine and therefore represent a promising tool for early diagnosis of RA. The focus of our work was to investigate any potentially negative effects resulting from the interactions of newly developed amino-functionalized amino-polyvinyl alcohol coated (a-PVA) SPION (a-PVA-SPION), that are used for imaging, with human immune cells. We analyzed the influence of a-PVA-SPION with regard to cell survival and cell activation in human whole blood in general, and in human monocytes and macrophages representative of professional phagocytes, using flow cytometry, multiplex suspension array, and transmission electron microscopy. We found no effect of a-PVA-SPION on the viability of human immune cells, but cytokine secretion was affected. We further demonstrated that the percentage of viable macrophages increased on exposure to a-PVA-SPION. This effect was even stronger when a-PVA-SPION were added very early in the differentiation process. Additionally, transmission electron microscopy analysis revealed that both monocytes and macrophages are able to endocytose a-PVA-SPION. Our findings demonstrate an interaction between human immune cells and a-PVA-SPION which needs to be taken into account when considering the use of a-PVA-SPION in human medicine.
26048139 Carboxybetaine Modified Interface for Electrochemical Glycoprofiling of Antibodies Isolate 2015 Jun 30 Impedimetric lectin biosensors capable of recognizing two different carbohydrates (galactose and sialic acid) in glycans attached to antibodies isolated from human serum were prepared. The first step entailed the modification of a gold surface by a self-assembled monolayer (SAM) deposited from a solution containing a carboxybetaine-terminated thiol applied to the subsequent covalent immobilization of lectins and to resist nonspecific protein adsorption. In the next step, Sambucus nigra agglutinin (SNA) or Ricinus communis agglutinin (RCA) was covalently attached to the SAM, and the whole process of building a bioreceptive layer was optimized and characterized using a diverse range of techniques including electrochemical impedance spectroscopy, cyclic voltammetry, quartz crystal microbalance, contact angle measurements, zeta-potential assays, X-ray photoelectron spectroscopy, and atomic force microscopy. In addition, the application of the SNA-based lectin biosensor in the glycoprofiling of antibodies isolated from the human sera of healthy individuals and of patients suffering from rheumatoid arthritis (RA) was successfully validated using an SNA-based lectin microarray. The results showed that the SNA lectin, in particular, is capable of discriminating between the antibodies isolated from healthy individuals and those from RA patients based on changes in the amount of sialic acid present in the antibodies. In addition, the results obtained by the application of RCA and SNA biosensors indicate that the abundance of galactose and sialic acid in antibodies isolated from healthy individuals is age-related.
29119908 Comorbidity in Dupuytren disease. 2016 Sep In this report, a possible association between Dupuytren's disease (DD) and other health problems was investigated. The health problems included in this study are : cardiac ischemia, hypertension, hyper-lipidemia, diabetes mellitus, epilepsy, gout, rheumatoid arthritis, malignancy, asthma and COPD. The data of 725 patients with DD were collected from -Intego, a database including all morbidity presented to the General Practitioners (GPs) in Flanders. The control group of 2900 age and sex matched non-DD patients was selected from the same database. A possible influence of severity of DD was evaluated by comparing the data of 333 patients operated for DD with the group of Integopatients with DD. This study showed a significant association of every single studied health condition with DD. Comparison of the -operated group with the group from Intego with DD, demonstrated only some significant associations, a difference which may be explained by the difference in data collection.
25821796 Serum levels of anticyclic citrullinated peptide antibodies, interleukin-6, tumor necrosis 2015 The main cause of death in rheumatoid arthritis (RA) is cardiovascular events. We evaluated the relationship of anticyclic citrullinated peptide (anti-CCP) antibody levels with increased carotid intima-media thickness (cIMT) in RA patients. METHODS: Forty-five anti-CCP positive and 37 anti-CCP negative RA patients, and 62 healthy controls (HC) were studied. All groups were assessed for atherogenic index of plasma (AIP) and cIMT. Anti-CCP, C-reactive protein (CRP), and levels of tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The anti-CCP positive RA patients showed increased cIMT compared to HC and anti-CCP negative (P < 0.001). Anti-CCP positive versus anti-CCP negative RA patients, had increased AIP, TNFα and IL-6 (P < 0.01), and lower levels of high density lipoprotein cholesterol (HDL-c) (P = 0.02). The cIMT correlated with levels of anti-CCP (r = 0.513, P = 0.001), CRP (r = 0.799, P < 0.001), TNFα (r = 0.642, P = 0.001), and IL-6 (r = 0.751, P < 0.001). In multiple regression analysis, cIMT was associated with CRP (P < 0.001) and anti-CCP levels (P = 0.03). CONCLUSIONS: Levels of anti-CCP and CRP are associated with increased cIMT and cardiovascular risk supporting a clinical role of the measurement of cIMT in RA in predicting and preventing cardiovascular events.
26774940 Effects of PVA-coated nanoparticles on human T helper cell activity. 2016 Mar 14 Superparamagnetic iron oxide nanoparticles (SPION) are used as high-sensitive enhancer for magnetic resonance imaging, where they represent a promising tool for early diagnosis of destructive diseases such as rheumatoid arthritis (RA). Since we could demonstrate that professional phagocytes are activated by amino-polyvinyl-alcohol-coated-SPION (a-PVA-SPION), the study here focuses on the influence of a-PVA-SPION on human T cells activity. Therefore, primary human CD4+ T cells from RA patients and healthy subjects were treated with varying doses of a-PVA-SPION for 20h or 72h. T cells were then analyzed for apoptosis, cellular energy, expression of the activation marker CD25 and cell proliferation. Although, we observed that T cells from RA patients are more susceptible to low-dose a-PVA-SPION-induced apoptosis than T cells from healthy subjects, in both groups a-PVA-SPION do not activate CD4+ T cells per se and do not influence mitogen-mediated T cells activation with regard to CD25 expression and cell proliferation. Nevertheless, our results demonstrate that CD4+ T cells from RA patients and healthy subjects differ in their response to mitogen stimulation and oxygen availability. We conclude from our data, that a-PVA-SPION do neither activate nor significantly influence mitogen-stimulated CD4+ T cells activation and have negligible influence on T cells apoptosis.
24297382 Identification of anticitrullinated protein antibody reactivities in a subset of anti-CCP- 2015 Mar INTRODUCTION: A hallmark of rheumatoid arthritis (RA) is the development of autoantibodies targeting proteins that contain citrulline. Anticitrullinated protein antibodies (ACPAs) are currently detected by the commercial cyclic citrullinated peptide (CCP) assay, which uses a mix of cyclised citrullinated peptides as an artificial mimic of the true antigen(s). To increase the sensitivity of ACPA detection and dissect ACPA specificities, we developed a multiplex assay that profiles ACPAs by measuring their reactivity to the citrullinated peptides and proteins derived from RA joint tissue. METHODS: We created a bead-based, citrullinated antigen array to profile ACPAs. This custom array contains 16 citrullinated peptides and proteins detected in RA synovial tissues. We used the array to profile ACPAs in sera from a cohort of patients with RA and other non-inflammatory arthritides, as well as sera from an independent cohort of RA patients for whom data were available on carriage of HLA-DRB1 'shared epitope' (SE) alleles and history of cigarette smoking. RESULTS: Our multiplex assay showed that at least 10% of RA patients who tested negative in the commercial CCP assay possessed ACPAs. Carriage of HLA-DRB1 SE alleles and a history of cigarette smoking were associated with an increase in ACPA reactivity-in anti-CCP(+) RA and in a subset of anti-CCP(-) RA. CONCLUSIONS: Our multiplex assay can identify ACPA-positive RA patients missed by the commercial CCP assay, thus enabling greater diagnostic sensitivity. Further, our findings suggest that cigarette smoking and possession of HLA-DRB1 SE alleles contribute to the development of ACPAs in anti-CCP(-) RA.
26818952 Power estimation and sample size determination for replication studies of genome-wide asso 2016 Jan 11 BACKGROUND: Replication study is a commonly used verification method to filter out false positives in genome-wide association studies (GWAS). If an association can be confirmed in a replication study, it will have a high confidence to be true positive. To design a replication study, traditional approaches calculate power by treating replication study as another independent primary study. These approaches do not use the information given by primary study. Besides, they need to specify a minimum detectable effect size, which may be subjective. One may think to replace the minimum effect size with the observed effect sizes in the power calculation. However, this approach will make the designed replication study underpowered since we are only interested in the positive associations from the primary study and the problem of the "winner's curse" will occur. RESULTS: An Empirical Bayes (EB) based method is proposed to estimate the power of replication study for each association. The corresponding credible interval is estimated in the proposed approach. Simulation experiments show that our method is better than other plug-in based estimators in terms of overcoming the winner's curse and providing higher estimation accuracy. The coverage probability of given credible interval is well-calibrated in the simulation experiments. Weighted average method is used to estimate the average power of all underlying true associations. This is used to determine the sample size of replication study. Sample sizes are estimated on 6 diseases from Wellcome Trust Case Control Consortium (WTCCC) using our method. They are higher than sample sizes estimated by plugging observed effect sizes in power calculation. CONCLUSIONS: Our new method can objectively determine replication study's sample size by using information extracted from primary study. Also the winner's curse is alleviated. Thus, it is a better choice when designing replication studies of GWAS. The R-package is available at: http://bioinformatics.ust.hk/RPower.html .
26415495 Diagnostic performance of measuring antibodies to the glycopeptidolipid core antigen speci 2015 Sep 28 INTRODUCTION: The aim of this study was to investigate the diagnostic performance of measuring antibodies to the glycopeptidolipid (GPL) core antigen specific to Mycobacterium avium complex (MAC) in patients with rheumatoid arthritis (RA). METHODS: We cross-sectionally investigated anti-GPL antibodies and radiographs of 396 patients with RA. A diagnosis of MAC pulmonary disease (MAC-PD) was made according to the criteria by the American Thoracic Society and the Infectious Diseases Society of America. Serum immunoglobulin A antibodies to MAC-specific GPL core antigen were measured by an enzyme immunoassay. All patients with RA with abnormal shadows on chest x-rays underwent chest computed tomography (CT). Bronchoscopy was performed on patients with negative cultures for MAC by expectorated sputum and positive CT findings compatible with MAC-PD. RESULTS: Ten patients were newly diagnosed with MAC-PD. Eight individuals who already had diagnoses of MAC-PD at the time of enrollment and nineteen who had negative expectorated sputum cultures for MAC and positive CT images compatible with MAC-PD and who refused bronchoscopy were excluded from the following analysis. Anti-GPL antibodies were detected in 12 of 369 patients. Eight of the ten patients with MAC-PD and 4 of 359 patients without MAC-PD tested positive for the anti-GPL antibodies. The specificity and sensitivity were 99 % and 80 %, respectively. Positive and negative predictive values were 67 %, and 97 %, respectively. When we analyzed diagnostic performance of the antibodies in 57 patients with RA who had abnormal shadows on chest x-rays, the positive and negative predictive values were 100 %, and 96 %, respectively. Twelve patients underwent bronchoscopy. Bronchoalveolar lavage fluid (BALF) samples from six patients were positive for MAC, and BALF samples from the remainder were negative. Anti-GPL antibodies were detected in the sera of all six patients with positive results for MAC by BALF sampling, whereas the antibodies were not detected in the sera from the remainder with negative results for MAC by BALF sampling. CONCLUSIONS: The measurement of anti-GPL antibodies is useful as a supplementary diagnostic tool for MAC-PD in patients with RA and may provide a new strategy, in combination with chest x-ray and CT, for differentiating MAC-PD from other pulmonary comorbidities in patients with RA.
27272171 Pharmacokinetics, Safety and Tolerability of ABT-494, a Novel Selective JAK 1 Inhibitor, i 2016 Dec BACKGROUND: ABT-494 is a potent and selective Janus kinase (JAK) 1 inhibitor being developed for the treatment of several autoimmune disorders, with potential for an improved safety profile compared with non-selective JAK inhibitors. This work characterized the pharmacokinetics, safety, and tolerability of ABT-494 following single and multiple dosing of the immediate-release formulation. METHODS: ABT-494 single (1-48 mg or placebo; n = 56) and multiple (3-24 mg or placebo twice daily for 14 days; n = 44) doses in healthy subjects, as well as multiple doses (3-24 mg or placebo twice daily for 27 days; n = 14) in subjects with rheumatoid arthritis (RA) on a background of methotrexate were evaluated. Pharmacokinetic samples were collected and safety and tolerability were assessed. RESULTS: ABT-494 followed bi-exponential disposition, with a terminal elimination half-life of 6-16 h and a functional half-life, calculated from maximum observed plasma concentration (C (max)) to trough plasma concentration (C (trough)) ratio at steady state, of 3-4 h. ABT-494 exposure was approximately dose proportional over the 3-36 mg dose range, with no significant accumulation with repeated dosing. In subjects with RA, no pharmacokinetic interaction between ABT-494 and methotrexate was observed. The fraction of ABT-494 dose eliminated in urine as unchanged ABT-494 was 14-25 %. All treatment-emergent adverse events (TEAEs) were mild or moderate in severity, with headache being the most frequently observed TEAE (15.6 % for ABT-494 vs. 16.7 % for placebo) after multiple twice-daily administration to healthy subjects. No clinically significant changes in laboratory parameters, vital signs, or electrocardiogram findings in healthy or RA subjects were observed. CONCLUSIONS: The favorable pharmacokinetics, safety, and tolerability results from these studies supported further evaluations of ABT-494 in phase IIb dose-ranging trials in RA and Crohn's disease. TRIAL REGISTRATION: ClinicalTrials.gov ( https://clinicaltrials.gov/ ) identifier: NCT01741493.
26713842 Histone Methylation and STAT-3 Differentially Regulate Interleukin-6-Induced Matrix Metall 2016 May OBJECTIVE: Synovial fibroblasts (SFs) produce matrix-degrading enzymes that cause joint destruction in rheumatoid arthritis (RA). Epigenetic mechanisms play a pivotal role in autoimmune diseases. This study was undertaken to elucidate the epigenetic mechanism that regulates the transcription of matrix metalloproteinases (MMPs) in RASFs. METHODS: MMP gene expression and histone methylation profiles in the MMP promoters were examined in RASFs. The effect of WD repeat domain 5 (WDR5) silencing on histone methylation and MMP gene expression in RASFs was analyzed. MMP gene expression, surface expression of the interleukin-6 (IL-6) receptor, phosphorylation of STAT-3, and binding of STAT-3 in the MMP promoters were investigated in RASFs stimulated with IL-6. RESULTS: The MMP-1, MMP-3, MMP-9, and MMP-13 genes were actively transcribed in RASFs. Correspondingly, the level of histone H3 trimethylated at lysine 4 (H3K4me3) was elevated, whereas that of H3K27me3 was suppressed in the MMP promoters in RASFs. The decrease in H3K4me3 via WDR5 small interfering RNA reduced the levels of messenger RNA for MMP-1, MMP-3, MMP-9, and MMP-13 in RASFs. Interestingly, IL-6 signaling significantly increased the expression of MMP-1, MMP-3, and MMP-13, but not MMP-9, in RASFs. Although the IL-6 signaling pathway was similarly active in RASFs and osteoarthritis SFs, STAT-3 bound to the MMP-1, MMP-3, and MMP-13 promoters, but not the MMP-9 promoter, after IL-6 stimulation in RASFs. CONCLUSION: Our findings indicate that histone methylation and STAT-3 regulate spontaneous and IL-6-induced MMP gene activation in RASFs. The combination of chromatin structure and transcription factors may regulate distinct arthritogenic properties of RASFs.
27824863 Demethylation of MicroRNA-124a Genes Attenuated Proliferation of Rheumatoid Arthritis Deri 2016 OBJECTIVE: To examine the impact of 5-Aza-2'-deoxycytidine (5-AzadC) on methylation status of miR-124a genes in rheumatoid arthritis (RA) associated fibroblast-like synoviocytes (FLS) and its effect on RA-FLS proliferation and TNF-α expression. MATERIALS AND METHODS: FLS were isolated from seven RA-derived synovial tissues and cultured in vitro. The expression of miR-124a was measured by real time quantitative polymerase chain reaction (PCR) in FLS with or without 5-AzadC treatment. MiR-124a gene methylation was detected by methylation-specific PCR. FLS were divided into three groups as control, IL-1β and IL-1β/5-AzadC, respectively. The cells in the IL-1β group were treated with 5 μg/L of IL-1β for 24 hours, whereas the cells in the IL-1β/5-AzadC group were first treated with IL-1β exactly as those in the IL-1β group for 24 h but further treated with 1μM 5-AzadC for additional 3 days. The cell growth was estimated based on absorbance at UV450nm. Secreted TNF-α from the cells was evaluated by enzyme-linked immunosorbent assay. After that, RA-FLS treated with IL-1β plus 5-AzadC were further transfected with miR-124a inhibitor or scrambled control. After culturing for 3 days, cell growth and TNF-α concentrations were measured. RESULTS: After 5-AzadC treatment, the expression of miR-124a was significantly increased compared with the control group (1.545 ± 0.189 vs 0.836 ± 0.166, p = 0.001). On the other hand, 5-AzadC significantly reduced IL-1β-mediated cell proliferation by nearly 2.5 fold (p = 0.006). Also, the level of TNF-α secreted from the cells treated with IL-1β plus 5-AzadC was considerably less than that from the cells treated with IL-1β alone (324.99 ± 22.73 ng/L vs 387.91 ± 58.51 ng/L, p = 0.022). After transfection with miR-124a inhibitor in RA-FLS treated with IL-1β plus 5-AzadC, the cell proliferation was increased by 18.2% and the TNF-α expression was increased by 19.0% (p = 0.001 and 0.011, respectively). CONCLUSION: Methylation of miR-124a genes contributed to IL-1β-mediated RA-FLS proliferation and TNF-α expression.
26800284 Salivary and serum procalcitonin and C-reactive protein as biomarkers of periodontitis in 2016 Serum procalcitonin (ProCT) is elevated in response to bacterial infections, whereas high sensitivity C-reactive protein (hsCRP) is a nonspecific inflammatory marker that is increased by excess adipose tissue. We examined the efficacy of ProCT and hsCRP as biomarkers of periodontitis in the saliva and serum of patients with arthritis, which is characterized by variable levels of systemic inflammation that potentially can confound the interpretation of inflammatory biomarkers. Blood and unstimulated whole saliva were collected from 33 patients with rheumatoid arthritis (RA) and 50 with osteoarthritis (OA). Periodontal status was assessed by full mouth examination and patients were categorized as having no/mild, moderate or severe periodontitis by standard parameters. Salivary and serum ProCT and hsCRP concentrations were compared. BMI, diabetes, anti-inflammatory medications and smoking status were ascertained from the patient records. Differences between OA and RA in proportionate numbers of patients were compared for race, gender, diabetes, adiposity and smoking status. Serum ProCT was significantly higher in arthritis patients with moderate to severe and severe periodontitis compared with no/mild periodontitis patients. There were no significant differences in salivary ProCT or salivary or serum hsCRP in RA patients related to periodontitis category. Most of the OA and RA patients were middle aged or older, 28.9% were diabetic, 78.3% were overweight or obese, and slightly more than half were either current or past smokers. The OA and RA groups differed by race, but not gender; blacks and males were predominant in both groups. The OA and RA groups did not differ in terms of controlled or uncontrolled diabetes, smoking status or BMI. The RA patients had been prescribed more anti-inflammatory medication than the OA patients. Our results demonstrate that circulating ProCT is a more discriminative biomarker for periodontitis than serum hsCRP in patients with underlying arthritis. Any elevation in salivary and serum hsCRP due to periodontitis apparently was overshadowed by differences among these patients in factors that influence CRP, such as the extent of inflammation between RA and OA, the extent of adipose tissue, the use of anti- inflammatory medications and smoking status. Although our study showed no differences in salivary ProCT related to severity of periodontitis, this biomarker also may be useful with further refinement.
27212598 [Dynamic analysis of immune inflammation and bone destruction by intravital imaging]. 2016 Rapid development of fluorescent imaging techniques enables us to understand cellular dynamics in vivo. We have originally established an advanced imaging system for visualizing living bone tissues with intravital two-photon microscopy. By means of the system, we have recently succeeded in visualization of the in vivo behavior of living mature osteoclasts on the bone surface, and identified different functional subsets of osteoclasts in terms of their motility and function, i.e., 'static - bone resorptive' and 'moving - non resorptive'. Pathological conditions changed the composition of these populations as well as the total number of mature osteoclasts. We also found that RANKL-bearing Th17 cells could control bone resorption of mature osteoclasts, demonstrating novel actions of Th17. Furthermore, we have also developed the imaging system to visualize bone destruction by osteoclasts in arthritic joints using intravital two-photon microscopy. In this review, we summarize the latest data of intravital imaging of osteoclast dynamics, and also discuss its further application.
26148347 Relationship of abdominal adiposity and body composition with endothelial dysfunction in p 2015 Jul OBJECTIVES: We aimed to investigate whether the abnormalities in body composition and abdominal fat that occur in rheumatoid arthritis (RA) are associated with the presence of endothelial dysfunction. METHODS: Cross-sectional study that encompassed 197 women (100 RA patients and 97 age-matched controls). Patients and controls were evaluated to establish endothelial function by brachial artery flow-mediated dilatation (FMD). Dual-x-ray-absorptiometry-derived body composition and abdominal adiposity by magnetic resonance imaging were assessed. Multiple regression analysis was performed to study the relationship between body composition and endothelial function. RESULTS: FMD was higher in controls compared to RA patients (8.5 [4.5-15.6] % vs. 5.3 [0.0-9.2] %, p=0.00). Appendicular-to-total lean mass ratio (0.42 ± 0.02 vs. 0.40 ± 0.03, p=0.00) and appendicular-to-trunk lean mass (0.82 ± 0.08 vs. 0.78 ± 0.08, p=0.00) were lower in RA patients. Visceral and subcutaneous abdominal fat tissues did not differ between patients and controls. Body mass index over 30 kg/m2 was common in patients and controls (44 and 32%). High sarcopenia tended to be more elevated in RA after multivariate adjustment (13% vs. 7%, p=0.06). Fat mass index showed a negative association (per standard deviation-SD-), after adjusting for comorbidity, with FMD in controls (beta coef. -0.45[-1.05-0.05], p=0.03) but not in patients. Overfat definition (beta coef. -0.81[-1.73-0.00], p=0.05) and visceral fat (per SD beta coef. -0.60 [-1.18-0.02], p=0.04) were associated with a lower FMD values in controls but not in RA patients. Trend analysis revealed that sarcopenia was related to increased endothelial dysfunction in both patients and controls. CONCLUSIONS: Our findings suggest that fat accumulation is not associated with endothelial dysfunction in RA patients. However, RA patients with sarcopenia are more likely to suffer endothelial dysfunction possibly being at higher cardiovascular risk.
27623446 Cell-contact-dependent activation of CD4(+) T cells by adhesion molecules on synovial fibr 2017 May OBJECTIVE: To determine how cell-cell contact with synovial fibroblasts (SF) influence on the proliferation and cytokine production of CD4(+ )T cells. METHODS: Naïve CD4(+ )T cells were cultured with SF from rheumatoid arthritis patients, stimulated by anti-CD3/28 antibody, and CD4(+ )T cell proliferation and IFN-γ/IL-17 production were analyzed. To study the role of adhesion molecules, cell contact was blocked by transwell plate or anti-intracellular adhesion molecule-1 (ICAM-1)/vascular cell adhesion molecule-1(VCAM-1) antibody. To study the direct role of adhesion molecules for CD4(+ )T cells, CD161(+ )or CD161(-) naïve CD4(+ )T cells were stimulated on plastic plates coated by recombinant ICAM-1 or VCAM-1, and the source of IFN-γ/IL-17 were analyzed. RESULTS: SF enhanced naïve CD4(+ )T cell proliferation and IFN-γ/IL-17 production in cell-contact and in part ICAM-1-/VCAM-1-dependent manner. Plate-coated ICAM-1 and VCAM-1 enhanced naïve CD4(+ )T cell proliferation and IFN-γ production, while VCAM-1 efficiently promoting IL-17 production. CD161(+ )naïve T cells upregulating LFA-1 and VLA-4 were the major source of IFN-γ/IL-17 upon interaction with ICAM-1/VCAM-1. CONCLUSION: CD4(+ )T cells rapidly expand and secrete IFN-γ/IL-17 upon cell-contact with SF via adhesion molecules. Interfering with ICAM-1-/VCAM-1 may be beneficial for inhibiting RA synovitis.
27181239 [Misfolded proteins complexed with MHC class II molecules are targets for autoantibodies]. 2016 Major histocompatibility complex (MHC) molecule is important for immune system through its function of presentation of peptide antigens. MHC is the gene most strongly associated with susceptibility to many autoimmune diseases. We recently found a novel function of MHC class II molecules to transport cellular misfolded proteins to the cell surface without processing to peptides. Interestingly, misfolded proteins transported to the cell surface by MHC class II molecules were found to be a specific targets for autoantibodies produced in patients with autoimmune diseases such as rheumatoid arthritis and antiphospholipid syndrome. Furthermore, autoantibody binding to misfolded proteins complexed with MHC class II molecules is strongly associated with the susceptibility to autoimmune diseases conferred by each MHC class II allele. Therefore, misfolded proteins associated with MHC class II molecules might be involved in the pathogenesis of autoimmune diseases.
27344240 Analysis of the cell populations composing the mononuclear cell infiltrates in the labial 2016 Sep OBJECTIVES: Sicca symptoms occur in around 30% of rheumatoid arthritis (RA) patients. Herein, we examined the characteristics of RA patients bearing sicca symptomatology (RA-sicca) with a special focus on the immunohistopathological features of their labial minor salivary gland (LMSG) biopsies. METHODS: Our cohort included 100 consecutive RA patients which were interrogated using a sicca symptoms questionnaire. Positive responders were evaluated for ocular and oral dryness and underwent an LMSG biopsy. All samples were immunohistochemically evaluated for the presence and distribution of specific leukocyte subsets using appropriate markers and for the expression of certain immunoregulatory molecules by salivary gland epithelial cells. Positively stained and total mononuclear cells (MNC) were counted in the entire section. Counts were expressed as cell frequency (percentage of cell type number/total infiltrating MNC number). RESULTS: In the majority (86.1%) of the 44 RA-sicca cases, periductal infiltrates were observed in LMSG biopsies. The frequencies of infiltrating cell subtypes and their correlation with lesion severity were different from that previously described in primary Sjögren's syndrome (pSS). Moreover, DCs and ΜΦs frequencies were increased in RA-sicca patients who had a biopsy focus score <1 and absence of anti-Ro/anti-La autoantibodies, in contrast to what was observed for B cells. In about half of the biopsies, salivary gland epithelial cells expressed CD80/B7.1 molecules, most commonly in patients with a positive biopsy or anti-Ro/anti-La autoantibodies. CONCLUSION: LMSG infiltrates composition in RA-sicca patients is distinct from that described in pSS. These differences, further attest to diverse pathophysiologic processes operating in these two entities.
25862243 Balneotherapy (or spa therapy) for rheumatoid arthritis. 2015 Apr 11 BACKGROUND: No cure for rheumatoid arthritis (RA) is known at present, so treatment often focuses on management of symptoms such as pain, stiffness and mobility. Treatment options include pharmacological interventions, physical therapy treatments and balneotherapy. Balneotherapy is defined as bathing in natural mineral or thermal waters (e.g. mineral baths, sulphur baths, Dead Sea baths), using mudpacks or doing both. Despite its popularity, reported scientific evidence for the effectiveness or efficacy of balneotherapy is sparse. This review, which evaluates the effects of balneotherapy in patients with RA, is an update of a Cochrane review first published in 2003 and updated in 2008. OBJECTIVES: To perform a systematic review on the benefits and harms of balneotherapy in patients with RA in terms of pain, improvement, disability, tender joints, swollen joints and adverse events. SEARCH METHODS: We searched the Cochrane 'Rehabilitation and Related Therapies' Field Register (to December 2014), the Cochrane Central Register of Controlled Trials (2014, Issue 1), MEDLIINE (1950 to December 2014), EMBASE (1988 to December 2014), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to December 2014), the Allied and Complementary Medicine Database (AMED) (1985 to December 2014), PsycINFO (1806 to December 2014) and the Physiotherapy Evidence Database (PEDro). We applied no language restrictions; however, studies not reported in English, Dutch, Danish, Swedish, Norwegian, German or French are awaiting assessment. We also searched the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing and recently completed trials. SELECTION CRITERIA: Studies were eligible if they were randomised controlled trials (RCTs) consisting of participants with definitive or classical RA as defined by the American Rheumatism Association (ARA) criteria of 1958, the ARA/American College of Rheumatology (ACR) criteria of 1988 or the ACR/European League Against Rheumatism (EULAR) criteria of 2010, or by studies using the criteria of Steinbrocker.Balneotherapy had to be the intervention under study, and had to be compared with another intervention or with no intervention.The World Health Organization (WHO) and the International League Against Rheumatism (ILAR) determined in 1992 a core set of eight endpoints in clinical trials concerning patients with RA. We considered pain, improvement, disability, tender joints, swollen joints and adverse events among the main outcome measures. We excluded studies when only laboratory variables were reported as outcome measures. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, performed data extraction and assessed risk of bias. We resolved disagreements by consensus and, if necessary, by third party adjudication. MAIN RESULTS: This review includes two new studies and a total of nine studies involving 579 participants. Unfortunately, most studies showed an unclear risk of bias in most domains. Four out of nine studies did not contribute to the analysis, as they presented no data.One study involving 45 participants with hand RA compared mudpacks versus placebo. We found no statistically significant differences in terms of pain on a 0 to 100-mm visual analogue scale (VAS) (mean difference (MD) 0.50, 95% confidence interval (CI) -0.84 to 1.84), improvement (risk ratio (RR) 0.96, 95% CI 0.54 to 1.70) or number of swollen joints on a scale from 0 to 28 (MD 0.60, 95% CI -0.90 to 2.10) (very low level of evidence). We found a very low level of evidence of reduction in the number of tender joints on a scale from 0 to 28 (MD -4.60, 95% CI -8.72 to -0.48; 16% absolute difference). We reported no physical disability and presented no data on withdrawals due to adverse events or on serious adverse events.Two studies involving 194 participants with RA evaluated the effectiveness of additional radon in carbon dioxide baths. We found no statistically significant differences between groups for all outcomes at three-month follow-up (low to moderate level of evidence). We noted some benefit of additional radon at six months in terms of pain frequency (RR 0.6, 95% CI 0.4 to 0.9; 31% reduction; improvement in one or more points (categories) on a 4-point scale; moderate level of evidence) and 9.6% reduction in pain intensity on a 0 to 100-mm VAS (MD 9.6 mm, 95% CI 1.6 to 17.6; moderate level of evidence). We also observed some benefit in one study including 60 participants in terms of improvement in one or more categories based on a 4-point scale (RR 2.3, 95% CI 1.1 to 4.7; 30% absolute difference; low level of evidence). Study authors did not report physical disability, tender joints, swollen joints, withdrawals due to adverse events or serious adverse events.One study involving 148 participants with RA compared balneotherapy (seated immersion) versus hydrotherapy (exercises in water), land exercises or relaxation therapy. We found no statistically significant differences in pain on the McGill Questionnaire or in physical disability (very low level of evidence) between balneotherapy and the other interventions. No data on improvement, tender joints, swollen joints, withdrawals due to adverse events or serious adverse events were presented.One study involving 57 participants with RA evaluated the effectiveness of mineral baths (balneotherapy) versus Cyclosporin A. We found no statistically significant differences in pain intensity on a 0 to 100-mm VAS (MD 9.64, 95% CI -1.66 to 20.94; low level of evidence) at 8 weeks (absolute difference 10%). We found some benefit of balneotherapy in overall improvement on a 5-point scale at eight weeks of 54% (RR 2.35, 95% CI 1.44 to 3.83). We found no statistically significant differences (low level of evidence) in the number of swollen joints, but some benefit of Cyclosporin A in the number of tender joints (MD 8.9, 95% CI 3.8 to 14; very low level of evidence). Physical disability, withdrawals due to adverse events and serious adverse events were not reported. AUTHORS' CONCLUSIONS: Overall evidence is insufficient to show that balneotherapy is more effective than no treatment, that one type of bath is more effective than another or that one type of bath is more effective than mudpacks, exercise or relaxation therapy.
25837280 Salvia plebeia extract inhibits the inflammatory response in human rheumatoid synovial fib 2015 Mar 15 Salvia plebeia R. Br. has been used to treat a variety of inflammatory diseases and as an antioxidant in many countries, including Korea and China. In this study, we investigated the effects of S. plebeia extract (SPE) on inflammatory arthritis and the underlying mechanisms of action. We used a collagen-induced arthritis (CIA) mouse model. TNF-α-stimulated rheumatoid arthritis (RA) synovial fibroblasts were used to elucidate the underlying mechanisms of action. Oral administration of SPE improved the clinical arthritis score, footpad thickness, and histologic changes, as well as serum IgG1 and IgG2a levels. SPE administration inhibited Th1/Th2/Th17 phenotype CD4(+) T lymphocyte expansion in inguinal lymph node and expression of inflammatory mediators such as cytokines, MMP-1, and MMP-3 in the ankle joint tissue. SPE significantly suppressed the expression of cytokines and MMP-1 by down-regulating NF-κB, Akt, and mitogen-activated protein kinases in RA synovial fibroblasts. Taken together, these results indicate that SPE is therapeutically efficacious against chronic inflammatory arthritis, suggesting that SPE is a candidate for treating RA.
27856432 Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatme 2017 May OBJECTIVES: To compare efficacy and safety of sarilumab monotherapy with adalimumab monotherapy in patients with active rheumatoid arthritis (RA) who should not continue treatment with methotrexate (MTX) due to intolerance or inadequate response. METHODS: MONARCH was a randomised, active-controlled, double-blind, double-dummy, phase III superiority trial. Patients received sarilumab (200 mg every 2 weeks (q2w)) or adalimumab (40 mg q2w) monotherapy for 24 weeks. The primary end point was change from baseline in 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) at week 24. RESULTS: Sarilumab was superior to adalimumab in the primary end point of change from baseline in DAS28-ESR (-3.28 vs -2.20; p<0.0001). Sarilumab-treated patients achieved significantly higher American College of Rheumatology 20/50/70 response rates (sarilumab: 71.7%/45.7%/23.4%; adalimumab: 58.4%/29.7%/11.9%; all p≤0.0074) and had significantly greater improvement in Health Assessment Questionnaire-Disability Index (p=0.0037). Importantly, at week 24, more patients receiving sarilumab compared with adalimumab achieved Clinical Disease Activity Index remission (7.1% vs 2.7%; nominal p=0.0468) and low disease activity (41.8% vs 24.9%; nominal p=0.0005, supplemental analysis). Adverse events occurred in 63.6% (adalimumab) and 64.1% (sarilumab) of patients, the most common being neutropenia and injection site reactions (sarilumab) and headache and worsening RA (adalimumab). Incidences of infections (sarilumab: 28.8%; adalimumab: 27.7%) and serious infections (1.1%, both groups) were similar, despite neutropenia differences. CONCLUSIONS: Sarilumab monotherapy demonstrated superiority to adalimumab monotherapy by improving the signs and symptoms and physical functions in patients with RA who were unable to continue MTX treatment. The safety profiles of both therapies were consistent with anticipated class effects. TRIAL REGISTRATION NUMBER: NCT02332590.