Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 28721628 | Disease activity, handgrip strengths, and hand dexterity in patients with rheumatoid arthr | 2017 Oct | Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the hand joints and leading to impairment in hand functions. Evaluation of functional impairment is necessary for assessing patient's quality of life, disease activity, and treatment outcome. To date, many scientific studies assessed the disease activity of patients with RA, but little attention has been carried out to assess these patients' hand functions and dexterity. The purposes of this study were to determine the clinical relevance of the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH), hand dexterity with the Purdue Pegboard Test (PPT), and handgrip strength and pinch strengths of RA patients and to look into their relation between each other. A prospective trial was performed in women with RA who were followed at the physical medicine and rehabilitation department of our university hospital. Eighty-two women between the ages of 18 and 70, with a diagnosis of RA according to the 2010 American College of Rheumatology/the European League Against Rheumatism (ACR/EULAR) criterion, were recruited to the study. The Disease Activity Scores were determined by using Disease Activity Score-28 (DAS-28). Handgrip strength was measured with a Jamar dynamometer, and lateral, palmar, and tip pinch strengths were measured by a pinchmeter. Hand functions were evaluated with the PPT, and functional outcomes were assessed with the QuickDASH questionnaire. The mean age of the study group was 49.27 ± 10.69 years. The average values of DAS-28 and the QuickDASH values were found to be 4.22 ± 1.28 and 38.33 ± 19.78, consecutively. High correlation was observed between DAS-28 and the QuickDASH values (p < 0.001). The mean grip strengths in both hands were significantly correlated with the QuickDASH values (p < 0.001), and also, DAS-28 values were very significantly correlated with the mean grip strength in the dominant hand (p < 0.001) and in the nondominant hand (p < 0.01). The mean lateral pinch strengths in both hands were correlated statistically significantly with DAS-28 and the QuickDASH scores (p < 0.001). The mean tip pinch strengths in both hands were correlated with DAS-28 scores, but correlation with the QuickDASH scores was seen just in the dominant hand (p < 0.05). There was no correlation between palmar pinch strengths in both hands with the DAS-28 and QuickDASH scores (p > 0.05). DAS-28 was correlated with PPT performance on the dominant hand (p < 0.05), but there was no correlation with the nondominant hand, both hands, and assembly (p > 0.05). The QuickDASH values were not correlated with all PPT performances (p > 0.05). Handgrip strengths of both hands were positively correlated with the PPT performances (p < 0.05). In conclusion, we determined that handgrip strengths were significantly related to disability and disease activity in the RA patients in our study. The QuickDASH is practical to use in clinical practice, and positively correlates with the disease activity. Dexterity measurements with PPT in the RA patient group were found practical and effective in our study. As a result, we can suggest using QuickDASH questionnaire for functional outcomes, handgrip strength measurements for assessment of hand disability and functional impairments, and also dexterity measurements even in patients with low disease activity. | |
| 28631779 | Recent advances in nanomedicines for the treatment of rheumatoid arthritis. | 2017 Jul 25 | Rheumatoid arthritis (RA) is a severe systemic inflammatory disease. It is often associated with serious cartilage destruction and massive inflammatory infiltration, which might ultimately cause disability, wide complications and reduced life quality. Current clinical treatments of RA show several drawbacks such as high doses, frequent administration and serious side effects. These limitations have motivated tremendous expansion of the research and application of nanomedicines in RA therapy. In this review, we summarize the cutting edge progress in nanomedicines for the treatment of RA and discuss the application of various targeting strategies. Additionally, we also discuss the pivotal challenges to be addressed, as well as future perspectives. | |
| 28679993 | [Iatrogenic immunodeficiency-associated Epstein-Barr virus (EBV) -negative natural killer | 2017 | Here we present a patient with rheumatoid arthritis (RA), who was suspected to have developed malignant lymphoma during immunosuppressive therapy 5 years earlier. She temporarily achieved remission after discontinuing therapy; however, her disease worsened with remittent fever and splenomegaly. Splenic biopsy demonstrated infiltration by abnormal cells, which were positive for CD56 and T cell intracytoplasmic antigen, but negative for CD3 and Epstein-Barr virus (EBV) -encoded RNA. Cytogenetic analysis of bone marrow and lumbar spine tumor revealed common complex karyotype abnormalities. Thus, she was diagnosed with chronic natural killer cell lymphoproliferative disorder (NK-LPD) and finally died of disease progression. The most common type of LPD in methotrexate-related patients with RA is B-lymphoid LPD, whereas NK-LPD is extremely rare. Furthermore, almost all cases of NK-LPD have been reported to be positive for EBV. This is the first case report on a patient with EBV-negative NK-LPD developed during immunosuppressive therapy for RA. | |
| 27908300 | Serum complement C3 strongly correlates with whole-body insulin sensitivity in rheumatoid | 2017 Jan | OBJECTIVES: Rheumatoid arthritis (RA) is characterised by an excess of cardiovascular diseases (CVD) risk, attributable to a synergy between under-diagnosed traditional risk factors (i.e. insulin resistance) and inflammatory disease activity. The aim of the present study was to evaluate the correlation between inflammatory measures and insulin sensitivity in RA patients. METHODS: Forty non-diabetic RA patients (19 males) were recruited. All patients underwent anthropometric measurements, laboratory evaluation and oral glucose tolerance test (OGTT). Insulin sensitivity index (ISI) was calculated with the equation proposed by Matsuda et al., from dynamic values of glucose and insulin obtained during OGTT. RESULTS: In the univariate analysis, lnISI correlated inversely with age, BMI, waist circumference, sBP, ESR, lnCRP and complement C3, but not with disease duration, dBP or complement C4. In non-obese patients (BMI <30 kg/m2, n=28), only age, BMI, lnCRP and C3 maintained their correlation with lnISI. In a stepwise multiple regression using lnISI as the dependent variable and BMI, age, lnCRP and complement C3 as predictors, only BMI and C3 entered the equation and accounted for 38.2% of the variance in lnISI. In non-obese patients, only C3 entered the regression equation, accounting for 32.2% of the variance in lnISI. Using a ROC curve, we identified the best cut-off for complement C3 of 1.22 g/L that yielded a sensitivity of 67% and a specificity of 79% for classification of insulin resistant patients. CONCLUSIONS: In RA patients, complement C3 correlates strongly with insulin sensitivity, in both obese and non-obese individuals. | |
| 28619676 | Peroxynitrite-modified histone as a pathophysiological biomarker in autoimmune diseases. | 2017 Sep | Under physiological conditions, reactive nitrogen and oxygen species are produced continuously. However, excess of these radicals may damage biomolecules like lipids, proteins and nucleic acids. These reactive species have been implicated in many disease conditions including acute/chronic inflammation, rheumatoid arthritis (RA), neurodegenerative diseases and systemic lupus erythematosus (SLE). Peroxynitrite, an oxidant and nitrating molecule, formed in in vivo, when nitric oxide reacts with superoxide radical. The abnormal levels of nitrotyrosine detected in tissues affected by autoimmune diseases have been attributed to peroxynitrite-mediated enhanced nitration of tyrosine residues in proteins. The chromosomal histone proteins are conserved and weak immunogens. However, they exhibit strong immunogenicity after nitration. Rabbits challenged with peroxynitrite-modified histone induce high titre antibodies, indicating that peroxynitrite modification generated immunogenic epitopes. The preferential binding of peroxynitrite-modified histones by autoantibodies derived from SLE and RA sera shows oxidatively and nitrated modified histones involve in the initiation and progression of autoimmune diseases. This review article presents the literature review of the physicochemical and immunological studies on histone proteins modified with peroxynitrite with an objective of the possible role of oxidatively nitrated histones in the initiation/progression of autoimmune inflammatory diseases. | |
| 28666971 | Postmenopausal osteoporosis in rheumatoid arthritis: The estrogen deficiency-immune mechan | 2017 Oct | Rheumatoid arthritis (RA) is characterized, among other factors, by systemic bone loss, reaching ~50% prevalence of osteoporosis in postmenopausal women. This is roughly a doubled prevalence in comparison with age-matched non-RA women. Postmenopausal RA women are more likely to be sero-positive for the anti-citrullinated peptide antibody (ACPA). Our extensive review of recent scientific literature enabled us to propose several mechanisms as responsible for the accelerated bone loss in ACPA(+) RA postmenopausal women. Menopause-associated estrogen deficiency plays a major role in these pathological mechanisms, as follows. | |
| 28132102 | Comparative effectiveness of treatment options after conventional DMARDs failure in rheuma | 2017 Jun | OBJECTIVE: To compare the clinical effectiveness of two treatment strategies for active rheumatoid arthritis (RA) refractory to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs): starting TNF inhibitors (TNFIs) or changing csDMARDs. METHODS: We used two nationwide Korean RA registries for patient selection. TNFI users were selected from the BIOPSY, which is an inception cohort of RA patients starting biologic DMARDs. As a control group, we selected RA patients with moderate or high disease activity from the KORONA database whose treatment was changed to other csDMARDs. After comparing baseline characteristics between the two groups in either unmatched or propensity score matched cohorts, we compared potential differences in the 1-year remission rate as a primary outcome and changes in HAQ-DI and EQ-5D scores as secondary outcomes. RESULTS: A total of 356 TNFI starters and 586 csDMARD changers were identified from each registry as unmatched cohorts, and 294 patients were included in the propensity score matched cohort. In the intention-to-treat analysis, TNFI starters had higher 1-year remission rates than csDMARD changers in both unmatched (19.1 vs. 18.4%, p < 0.01) and matched cohorts (19.7 vs. 15.0%, p < 0.01). In per protocol analysis, TNFI starters had much higher remission rates in unmatched (37.2 vs. 28.0%, p = 0.04) and matched cohorts (35.4 vs. 19.1%, p = 0.04). However, in matched cohorts, no significant differences were observed between two groups in HAQ-DI and EQ-5D scores. CONCLUSIONS: We compared the clinical effectiveness of the two treatment strategies for active RA refractory to csDMARDs. TNFI starters showed higher 1-year remission rates than csDMARD changers. | |
| 28456616 | Actions of SPM in regulating host responses in arthritis. | 2017 Dec | The discovery and identification of omega-3 fatty acid derived specialized pro-resolving mediators (SPM) provides a molecular mechanism for the beneficial effects of fish oil supplementation in patients suffering from arthritis. Here we review the plethora of bioactions of SPM in the context of joint diseases, focusing on both cellular targets and molecular mechanisms. Whenever possible, a parallel to clinical and preclinical data produced with fish oil supplementation is made to strengthen the mechanistic link between omega-3 fatty acids and SPM biosynthesis. SPM can modulate the reactivity of many cells that are pivotal to the development and/or maintenance of joint disease. Whereas work has so far focused on the actions of SPM on immune cells and therefore, within this context, macrophages, neutrophils, mast cells and T cells, we reason that more work needs to focus on the effects that these bioactive lipid mediators may have on the structural cell component of the joint, this encompassing synovial fibroblasts, chondrocytes, osteoclasts and osteoblasts. Full definition of the properties that SPM may exert on these cells can help in unveiling their ability to promote tissue restoration and regeneration, a prerequisite to repair joint damage, and as such promote the development of innovative therapeutic strategies based on the science of SPM and resolution. | |
| 28339738 | A multi-biomarker score measuring disease activity in rheumatoid arthritis patients taperi | 2017 Jun 1 | OBJECTIVE: The aim was to evaluate the predictive value of the baseline multi-biomarker disease activity (MBDA) score in long-standing RA patients with low disease activity tapering TNF inhibitors (TNFi) for successful tapering or discontinuation, occurrence of flare and major flare, and radiographic progression. METHODS: Dose REduction Strategies of Subcutaneous TNF inhibitors (Dutch Trial Register, NTR 3216) is an 18-month non-inferiority randomized controlled trial comparing tapering of TNFi until discontinuation or flaring with usual care (UC) in long-standing RA patients with stable low disease activity. Flare was defined as DAS28-CRP increase >1.2 or >0.6 if current DAS ⩾3.2; major flare was a flare lasting >3 months, despite treatment intervention. MBDA scores were measured at baseline. Radiographs were scored at baseline and 18 months using the Sharp-van der Heijde score. The area under the receiver operating characteristic (AUROC) curve was used to analyse the capability of baseline MBDA score to predict the above-mentioned outcomes. RESULTS: Serum samples and outcomes were available for 171 of 180 patients from Dose REduction Strategies of Subcutaneous TNF inhibitors (115 tapering; 56 UC). AUROC analyses showed that baseline MBDA score was not predictive for the above-mentioned clinical outcomes in the taper group, but did predict major flare in the UC group (AUROC = 0.72, 95% CI: 0.56, 0.88). Radiographic progression was minimal and was not predicted by MDBA score. CONCLUSION: In this disease activity-guided strategy study of TNFi tapering in RA patients with low disease activity, baseline MBDA score was not predictive for successful tapering, discontinuation, flare, major flare or radiographic progression in patients who tapered TNFi. | |
| 28190118 | Receptor activator of nuclear factor kappa-B ligand (RANKL) but not sclerostin or gene pol | 2017 May | The aim of this study was to analyze relationships between receptor activator of nuclear factor kappa-B (RANKL), sclerostin and their gene polymorphisms with radiological progression in patients with early rheumatoid arthritis (RA). Patients with early RA (n = 407, symptomatic <1 year) (ARA criteria) examined radiologically at inclusion and after 24 months were consecutively included. Disease activity score and C-reactive protein were regularly recorded. Sclerostin, RANKL, and anti-CCP2 antibodies were analyzed in plasma at baseline using ELISAs. Data on gene polymorphism for sclerostin and RANKL were extracted from Immunochip analysis. Sex- and age-matched controls (n = 71) were identified from the Medical Biobank of Northern Sweden. The concentration of RANKL was significantly higher in patients compared with controls, median (IQR) 0.56 (0.9) nmol/L and 0.20 (0.25) nmol/L (p < 0.001), and in anti-CCP2-positive patients compared with sero-negative individuals. Sclerostin was significantly increased in female patients 0.59 (0.47-0.65) ng/mL compared with female controls 0.49 (0.4-0.65) ng/mL (p < 0.02). RANKL concentration was related to the Larsen score at baseline (p < 0.01), after 24 months (p < 0.001), and to radiological progression at 24 months (p < 0.001). Positivity of RANKL and anti-CCP2 yielded significant risk for progression with negativity for both as reference. No single nucleotide polymorphism encoding TNFSF11 or SOST was associated with increased concentrations of the factors. The concentration of RANKL was related to the Larsen score at baseline, at 24 months, and radiological progression at 24 months particularly in anti-CCP2-positive patients, while the concentration of sclerostin was unrelated to radiological findings. | |
| 29442463 | Knowledge and selected variables as determinants of the quality of life and general health | 2017 Dec | BACKGROUND: Rheumatoid arthritis (RA) is an incurable disease resulting in progressive disability, which is associated with the loss of productivity and the inability to earn money, which might lead to a financial burden on the patient's family. Undoubtedly, the clinical picture of the disease and its consequences lead to the reduction of the quality of life. OBJECTIVES: The aim of this study is to evaluate the influence of selected factors on the subjective assessment of the quality of life and general health of patients with RA. MATERIAL AND METHODS: The study was conducted among 270 patients with RA treated at the Department of Rheumatology and Internal Medicine. The quality of life and general health were assessed with the use of the SF-36 and the GHQ-30 questionnaires. RESULTS: In the study group, a statistically significant correlation between the results of the SF-36 and the GHQ-30 questionnaires was observed. It has been shown that the level of role limitations due to physical health problems (RP) is mostly affected by interpersonal relationships based on GHQ-30 questionnaire (p = 0.002), general health (GHQ-30) (p = 0.001) and subjective health condition (SF-36) (p < 0.001). In contrast, general health (GHQ-30) is positively affected by education (p = 0.003) and professional activity (p = 0.001), and negatively affected by a positive family history of RA (p = 0.002), frequent hospitalization (p = 0.008) and poor subjective health condition (p < 0.001). CONCLUSIONS: People with poor subjective health condition are characterized by more limited activity due to physical health and lower general health condition. General health (GHQ-30) in patients with rheumatoid arthritis is influenced by education, place of residence, professional work, family history of RA and subjective health status. | |
| 28967792 | Abatacept and granulocyte-colony stimulating factor in a patient with rheumatoid arthritis | 2017 Oct | Neutropenia in patients with inflammatory diseases increases the risk of infection due to the disease itself and the related immunosuppressive treatments. We report the case of a 54-year-old female with rheumatoid arthritis and following development of chronic neutropenia. All investigations excluded pathogenic relations with drugs and/or other clinical situations; the gravity of neutropenia required a treatment with G-CSF and the increased articular inflammatory activity justified a biologic-therapy, abatacept (CTLA4 inhibitors). The juxtaposition of immunostimulants and immunosuppressors led to great effectiveness for both hematological and rheumatic issues. To date, while some biologic drugs (TNF, IL6R and CD20 inhibitors) have reported relations with neutropenia, no such relevance subsists for Abatacept. Our case reports the experience of the safe effective use of abatacept and G-CSF for 8 years. | |
| 28594252 | Not all TNF inhibitors in rheumatoid arthritis are created equal: important clinical diffe | 2017 Aug | Anti-TNF therapy has dramatically changed how we manage rheumatoid arthritis. There are many similarities among the five approved agents but also some important differences. Rheumatologists have 5 different options to choose from when they are ready to commence anti-TNF therapy. Although all block the TNF cytokine, there are important critical differences among them that affect their safety profile and clinical utility in certain scenarios. Unfortunately, there are no head to head trials to compare the different anti-TNF agents and none appear to be in the horizon. Areas covered: This article reviews the various clinical situations where it may be important to use a particular anti-TNF agent. The authors also give their expert opinion and future perspectives on the area. Expert opinion: Although there are many similarities among the five different TNFi that are clinically available, there are important clinical niches, where the limited data that are available, that clearly support the preferential use of a particular agent or class of agents. Assays or tests that allow us to find the 'sweet spot' of TNF inhibition at the level of each patient are long overdue. | |
| 28306596 | Biosimilars: implications for rheumatoid arthritis therapy. | 2017 May | PURPOSE OF REVIEW: Abbreviated pathways for the approval of biosimilars have been established in the European Union (EU), the United States, and other countries. Biosimilar TNF inhibitors have been available in South Korea and the EU since 2012 and 2013, respectively, and the first biosimilar infliximab was introduced to the clinic in the United States in November 2016. Five TNF inhibitor biosimilars have now been approved, and many other biosimilars to treat rheumatoid arthritis and other inflammatory diseases are in development. RECENT FINDINGS: Over the last 18 months, published results of randomized clinical trials (RCTs) have shown equivalent efficacy and comparable safety and immunogenicity of biosimilars with their reference products. 'Real world' experience with biosimilars in the EU continues to increase and provides evidence regarding the efficacy and safety of using biosimilars in the clinic and of switching from bio-originators to their biosimilars. SUMMARY: Cost implications of using biosimilars and extrapolation of their use to treat diseases in which they were not tested in RCTs are of great interest. We review the results of RCTs and available experience with biosimilars in the clinic. | |
| 28579757 | Profile of sarilumab and its potential in the treatment of rheumatoid arthritis. | 2017 | In recent years the use of biotechnological agents has drastically revolutionized the therapeutic approach and the progression of rheumatoid arthritis (RA). In particular, interleukin-6 (IL-6) has been demonstrated as a pivotal cytokine in the pathogenesis of the disease by contributing to both the innate and the adaptive immune system perturbation, and to the production of acute-phase proteins involved in the systemic expression of the disorder. The first marketed IL-6 blocker was tocilizumab, a humanized anti-IL-6 receptor (anti-IL-6R) monoclonal antibody. The successful use of tocilizumab in RA has encouraged the development of other biologic agents specifically targeting the IL-6 pathway, either directed against IL-6 cytokine (sirukumab, olokizumab, and clazakizumab) or IL-6 receptor (sarilumab). One Phase II and six Phase III randomized controlled trials demonstrated a broad efficacy of sarilumab across all RA patient subtypes, ranging from methotrexate (MTX) to tumor necrosis factor inhibitor insufficient responders. In particular, sarilumab as monotherapy demonstrated a clear head-to-head superiority over adalimumab in MTX-intolerant subjects. In addition, compared with tocilizumab, sarilumab showed a similar safety profile with significantly higher affinity and longer half-life, responsible for a reduction of the frequency of administration (every other week instead weekly). All these aspects may be important in defining the strategy for positioning sarilumab in the treatment algorithm of RA. Indeed, observational data coming from post-marketing real-life studies may provide crucial additional information for better understanding the role of sarilumab in the management of the disease. This review summarizes both the biological role of IL-6 in RA and the clinical data available on sarilumab as an alternative therapeutic option in RA patients. | |
| 28182854 | Anti-Citrullinated Protein Antibodies Are Associated With Neutrophil Extracellular Traps i | 2017 Jun | OBJECTIVE: Studies suggest that rheumatoid arthritis (RA)-related autoimmunity is initiated at a mucosal site. However, the factors associated with the mucosal generation of this autoimmunity are unknown, especially in individuals who are at risk of future RA. Therefore, we tested anti-cyclic citrullinated peptide (anti-CCP) antibodies in the sputum of RA-free first-degree relatives (FDRs) of RA patients and patients with classifiable RA. METHODS: We evaluated induced sputum and serum samples from 67 FDRs and 20 RA patients for IgA anti-CCP and IgG anti-CCP, with cutoff levels for positivity determined in a control population. Sputum was also evaluated for cell counts, neutrophil extracellular traps (NETs) using sandwich enzyme-linked immunosorbent assays for protein/nucleic acid complexes, and total citrulline. RESULTS: Sputum was positive for IgA and/or IgG anti-CCP in 14 of 20 RA patients (70%) and 17 of 67 FDRs (25%), including a portion of FDRs who were serum anti-CCP negative. In the FDRs, elevations of sputum IgA and IgG anti-CCP were associated with elevated sputum cell counts and NET levels. IgA anti-CCP was associated with ever smoking and with elevated sputum citrulline levels. CONCLUSION: Anti-CCP is elevated in the sputum of FDRs, including seronegative FDRs, suggesting that the lung may be a site of anti-CCP generation in this population. The association of anti-CCP with elevated cell counts and NET levels in FDRs supports a hypothesis that local airway inflammation and NET formation may drive anti-CCP production in the lung and may promote the early stages of RA development. Longitudinal studies are needed to follow the evolution of these processes relative to the development of systemic autoimmunity and articular RA. | |
| 27695991 | The functional variants of endothelial nitric oxide synthase gene associated with rheumato | 2017 Mar | This study aimed to investigate whether functional variants of endothelial nitric oxide synthase (eNOS) gene play any role in rheumatoid arthritis (RA) ethiopathogenesis and treatment in the Turkish population. Because, eNOS variants are responsible for alteration of the NO level in plasma, by reducing/increasing the endothelial NO synthesis. In the study, two eNOS gene variants (G894T and intron 4 VNTR A/B) were examined at extracted DNAs from 65 peripheral blood cell of RA patients. For the control, blood samples obtained from 70 healthy persons were studied. Genotyping of molecular variants was performed by PCR-RFLP and/or PCR technique. The data obtained was compared in itself and response to therapy. We found that "TT genotypic frequency" for the G894T variant was significantly associated with RA with an overall risk of 8.3-fold (p 0.029). No association was identified between intron 4 VNTR A/B variant and RA. At the 6Â months, the mean visual analog scale (VAS), health assessment questionnaire (HAQ), and disease activity score for 28 joints (DAS 28) improvement was not significant among groups. Improvement in DAS was significantly better in anti-TNF treatment than disease-modifying antirheumatic drugs (DMARD) treatment treated subgroup. We report for the first time that variants in the eNOS "TT" genotype might be contributed to the increased risk of RA in the Turkish population. These results imply that functional variants of eNOS gene might have an effect on RA patients and response to anti-TNF treatment. In addition, the results suggest that eNOS variants might be associated and affect host susceptibility and/or response to treatment in Turkish RA patients. | |
| 28603283 | TXNDC5 synergizes with HSC70 to exacerbate the inflammatory phenotype of synovial fibrobla | 2018 Jul | The upregulated expression of thioredoxin domain-containing protein 5 (TXNDC5) is associated with rheumatoid arthritis in patients and model mice. However, the underlying mechanism by which TXNDC5 influences the pathological activation of rheumatoid arthritis synovial fibroblasts (RASFs) remains unknown. In this study, we show that TXNDC5 expression in RASFs and their cytokine production are significantly upregulated in response to LPS, TNF-α and IL-6, but suppressed by transfection with TXNDC5-siRNA. TXNDC5 is further validated as the direct target of NF-κB signaling. Mechanistically, TXNDC5 directly interacts with heat shock cognate 70 protein (HSC70) to sequester it in the cytoplasm, and HSC70 silencing exerts the same effects as TXNDC5 on the biological activity of RASFs (for example, decreased cell viability, invasion and cytokine production). Furthermore, HSC70 activates NF-κB signaling by destabilizing IκBβ protein in the absence of LPS or facilitating its nuclear translocation in the presence of LPS. Importantly, TXNDC5 can also regulate the activity of NF-κB signaling in a HSC70-IκBβ-dependent manner. Taken together, by linking HSC70 and NF-κB signaling, TXNDC5 plays a pro-inflammatory role in RASFs, highlighting a potential approach to treat RA by blocking the TXNDC5/HSC70 interaction. | |
| 28261963 | Phosphoproteome analysis of synoviocytes from patients with rheumatoid arthritis. | 2017 Jun | AIM: To explore disease-associated molecules in rheumatoid arthritis (RA), we comprehensively analyzed phosphoproteins purified from RA synoviocytes. METHOD: Synoviocytes were obtained from three patients with RA and three patients with osteoarthritis (OA). Profiles of phosphoproteins purified from the synoviocytes were compared by two-dimensional differential gel electrophoresis (2D-DIGE) between the RA and OA groups. Protein spots with significantly different phosphorylation levels were identified by mass spectrometry. Recombinant protein of annexin A4 (ANXA4), one of the identified phosphoproteins, was transfected into synoviocytes from an OA patient to mimic RA synoviocytes and humoral factor secretion was compared between rANXA4-transfected and non-transfected synoviocytes under a tumor necrosis factor-α (TNFα)-stimulated condition. RESULTS: In 2D-DIGE, 318 phosphoprotein spots were detected, of which 94 spots showed significantly different intensities between the two groups (P < 0.05). Among the 94 spots, 22 spots showed two-fold or higher intensity and one spot showed less than 1/2-fold intensity in the RA group compared to the OA group. From the 22 spots, 11 phosphoproteins were identified, which included kinases, carrier and chaperone proteins, cytoskeletal proteins, proteases and calcium-binding proteins. One of the identified calcium-binding proteins was ANXA4, an exocytosis-regulating protein. The transfected rANXA4 was found to be phosphorylated intracellularly, and secretion of chemokine (C-X-C motif) ligand 1 and interleukin-8 induced by TNFα stimulation was significantly suppressed by the transfection (P < 0.01). CONCLUSION: The phosphoprotein profile of RA synoviocytes was different from that of OA synoviocytes. This difference would reflect the different pathophysiologies of the diseases. ANXA4 may be one of therapeutic targets in RA. | |
| 28110385 | The prevalence of anticitrullinated protein antibodies increases with age in healthy indiv | 2017 Mar | Transition from genetic risk to the development of systemic autoimmunity associated with rheumatoid arthritis (RA) is considered a key step for the development of RA and often referred to as the immune onset of the disease. The aim of this study is to identify predictors for the presence of anticitrullinated protein antibodies (ACPA) as a marker of systemic autoimmunity associated with RA in a high-risk population, an ongoing cohort of first-degree relatives of patients with RA. We assessed the presence of ACPA in individuals without clinical evidence of RA. We examined characteristics associated with ACPA positivity using general estimation equations to account for multiple observations per individual. A total of 1159 serum samples from 1025 subjects were analyzed, 69 samples (6%) were ACPA-positive, and 227 (20%) positive for rheumatoid factor. Participants had a median age of 45 years (interquartile range (IQR): 33-55) at baseline and 76% were women. Overall, ACPA positivity increased with age (p < 0.001). Among women, ACPA positivity was particularly associated with the age group 45 to 55 years (p = 0.003), but not among men (p = 0.7). In multivariable adjusted analyses, age older than 45, female sex and tobacco smoking were independently associated with ACPA positivity. In our cohort, the presence of ACPA was associated with older age and peaked in women around age 45 to 55 years, the perimenopausal period, suggesting that the development of ACPA may be favored by the decline in ovarian function. |