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ID PMID Title PublicationDate abstract
28138457 Interrelationships of Sex, Physician-Diagnosed Arthritis, Chronic Inflammation, and Physic 2015 Jan Objective: To examine whether serum concentrations of C-reactive protein (CRP) and fibrinogen were associated with total score on a validated 12-item physical functioning scale and whether the magnitude and direction of these associations differed according to sex and physician-diagnosed arthritis. Method: Secondary analyses of cross-sectional data from the Third National Health and Nutrition Examination Survey were conducted using a representative sample of 4,606 older adults, 60 years and older. Results: Linear models suggested that overall physical functioning was strongly and independently associated with CRP (adjusted β = +.68, 95% confidence interval [CI] = [+0.42, +0.94]) and fibrinogen (adjusted β = +1.66, 95% CI = [+0.89, +2.42]); these associations were modified by physician-diagnosed arthritis status, with strongest associations observed among individuals diagnosed with rheumatoid arthritis or no arthritis and weakest association observed among those diagnosed with osteoarthritis. Conclusion: CRP and fibrinogen may be associated with poorer physical functioning in older adults, especially among those having rheumatoid arthritis or no arthritis.
27663201 Is radiographic progression in modern rheumatoid arthritis trials still a robust outcome? 2016 Sep 23 BACKGROUND: The detection of statistically significant reductions in radiographic progression during clinical studies in patients with rheumatoid arthritis (RA) has become increasingly difficult over the past decade due to early-escape study designs and declining rates of progression in control-group patients. We investigated the impact of extremes of radiographic data (outliers) and baseline prognostic factors on detection of treatment effects, to provide guidance on future analysis of joint structural data in RA clinical trials. METHODS: Data were from two, phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib in adult patients with moderate to severe RA: ORAL Scan (NCT00847613) and ORAL Start (NCT01039688). These studies detected significant reductions in radiographic progression with tofacitinib 10 mg twice daily (BID) plus background methotrexate (ORAL Scan), and with tofacitinib 5 or 10 mg BID as monotherapy (ORAL Start). We evaluated mean changes from baseline in van der Heijde modified total Sharp score (mTSS) at month 6 and month 12, using analysis of covariance (ANCOVA). A trimmed analysis was used to deal with extremes of data. The impact of baseline prognostic factors on radiographic progression was evaluated using ANCOVA to analyze the mean change from baseline in mTSS for each factor in turn. RESULTS: The analysis included data from 720 patients from ORAL Scan and 880 patients from ORAL Start. Trimmed analyses were unbiased for the true mean estimate and enabled us to remove the effect of influential extreme observations in the data set. Almost all patients had at least one poor prognostic factor at baseline (e.g., high level of disease activity, or positive for rheumatoid factor). The strongest predictor of treatment effect was the severity of radiographic damage at baseline. CONCLUSIONS: A trimmed analysis can establish whether any significant inhibition of structural damage is being driven by extremes of data, and should be one of the sensitivity analyses of choice for structural data in RA clinical trials. Furthermore, analysis of radiographic data based on baseline prognostic factors may reveal increased treatment effects. Application of these methods to analysis of radiographic data from clinical trials in patients with RA, allows a more complete interpretation of data. TRIAL REGISTRATION: Clinicaltrials.gov NCT00847613 (registered 17 February 2009) and NCT01039688 (registered 23 December 2009).
27708970 Potential protein targets of the peptidylarginine deiminase 2 and peptidylarginine deimina 2016 Jun OBJECTIVE: The molecular mechanism of citrullination involves the calcium-dependent peptidylarginine deiminase (PAD) family of enzymes. These enzymes induce a stereochemical modification of normal proteins and transform them into autoantigens, which in rheumatoid arthritis trigger a complex cascade of joint inflammatory events followed by chronic synovitis, pannus formation, and finally, cartilage destruction. By hypothesizing that PAD2 and PAD4 enzymes produce autoantigens, we investigated five possible synovial protein targets of PAD enzymes. MATERIAL AND METHODS: We measured PAD2, PAD4, and citrullinated proteins in 10 rheumatoid and 10 osteoarthritis synovial biopsies and then assessed the post-translational modifications of fibrinogen, cytokeratin, tubulin, IgG, and vimentin proteins using a double-fluorescence assay with specific antibodies and an affinity-purified anti-citrullinated peptide (CCP) antibody. The degree of co-localization was analyzed, and statistical significance was determined by ANOVA, Fisher's exact test, and regression analysis. RESULTS: The principal results of this study demonstrated that citrullinated proteins, such as fibrinogen, IgG, and other probed proteins, were targets of PAD2 and PAD4 activity in rheumatoid synovial biopsies, whereas osteoarthritis biopsies were negative for this enzyme (p<0.0001). An analysis of citrullination sites using the UniProtKB/Swiss-Prot data bank predicts that the secondary structure of the analyzed proteins displays most of the sites for citrullination; a discussion regarding its possible meaning in terms of pathogenesis is made. CONCLUSION: Our results support the conclusion that the synovial citrullination of proteins is PAD2 and PAD4 dependent. Furthermore, there is a collection of candidate proteins that can be citrullinated.
26618631 Novel therapeutic compound tuftsin-phosphorylcholine attenuates collagen-induced arthritis 2016 Apr Treatment with helminthes and helminthes ova improved the clinical symptoms of several autoimmune diseases in patients and in animal models. Phosphorylcholine (PC) proved to be the immunomodulatory molecule. We aimed to decipher the tolerogenic potential of tuftsin-PC (TPC), a novel helminth-based compound in collagen-induced arthritis (CIA) a mouse model of rheumatoid arthritis (RA). CIA DBA/1 mice were treated with TPC subcutaneously (5 µg/0.1 ml) or orally (250 µg/0.1 ml), starting prior to disease induction. The control groups were treated with PBS. Collagen antibodies were tested by enzyme-linked immunosorbent assay (ELISA), cytokine protein levels by ELISA kits and regulatory T (Treg ) and regulatory B (Breg ) cell phenotypes by fluorescence-activated cell sorter (FACS). TPC-treated mice had a significantly lower arthritis score of 1.5 in comparison with control mice 11.8 (P < 0.0001) in both subcutaneous and orally treated groups at day 31. Moreover, histology analysis demonstrated highly inflamed joints in control mice, whereas TPC-treated mice maintained normal joint structure. Furthermore, TPC decreased the titres of circulating collagen II antibodies in mice sera (P < 0.0001), enhanced expression of IL-10 (P < 0.0001) and inhibited production of tumour necrosis factor (TNF)-α, interleukin (IL)-17 and IL-1β (P < 0.0001). TPC significantly expanded the CD4(+) CD25(+) forkhead box protein 3 (FoxP3(+) ) Treg cells and CD19(+) IL-10(+) CD5(high) CD1d(high) T cell immunoglobulin mucin-1 (TIM-1(+) ) Breg cell phenotypes (P < 0.0001) in treated mice. Our data indicate that treatment with TPC attenuates CIA in mice demonstrated by low arthritic score and normal joints histology. TPC treatment reduced proinflammatory cytokines and increased anti-inflammatory cytokine expression, as well as expansion of Treg and Breg cells. Our results may lead to a new approach for a natural therapy for early rheumatoid arthritis onset.
25799671 [Update in psoriatic arthritis treatment]. 2015 Jan 14 Psoriatic arthritis is a chronic inflammatory disease. It affects up to 40% of patients suffe- ring from skin psoriasis. Joint involvement is relatively heterogeneous. Some clinical manifestations are similar to those of rheumatoid arthritis, others are close to spondylarthritis manifestations and are therefore considered as part of this entity. Treatment depends on initial presentation (peripheral or axial) but often begins with non-steroidal anti-inflammatory drugs and methotrexate, followed by anti-TNFalpha if needed. New therapeutic op- tions are available or under evaluation, parti- cularly targeting cytokines involved in psoriatic arthritis (IL-12/IL-23 and IL-17).
27909436 Evaluation of Anti-inflammatory Effects of Steroids and Arthritis-Related Biotherapies in 2016 BACKGROUND: During rheumatoid arthritis (RA), steroids and biotherapies are used alone and combined. Efficacy has been established in clinical trials but their differential effects at the cellular level are less documented. The aim was to study these cellular effects using an in vitro model with synoviocytes interacting with peripheral blood mononuclear cells (PBMC) to reproduce the interactions in the RA synovium. METHODS: Activated-PBMC were cocultured with RA synoviocytes during 48 h. A dose-response of methylprednisolone (MP) was tested and different biotherapies (Infliximab, Etanercept, Adalimumab, Tocilizumab, Abatacept, and Rituximab) were added alone or in combination with MP. Cytokine production (IL-17, IL-6, IL-1β, IFN-γ and IL-10) was measured by ELISA. RESULTS: Addition of MP to cocultures inhibited the production of all cytokines. The response to the biotherapies alone was treatment-dependent. IL-17 production was inhibited only by Tocilizumab (p = 0.004), while IL-6 was decreased only by Infliximab (p ≤ 0.002). IL-1β level was affected in all conditions (p ≤ 0.03). IFN-γ production was mainly decreased by Infliximab (p = 0.004) and IL-10 by Infliximab and Tocilizumab (p ≤ 0.004). The combination MP and biotherapies did not induce an additional effect on pro-inflammatory cytokine inhibition. The combination MP and biotherapies induced a higher IL-10 secretion than MP alone, mainly with Rituximab. CONCLUSION: Steroids inhibited the secretion of all cytokines, and low doses were as potent. The anti-inflammatory effect of biotherapies was dependent on their mechanism of action. MP and biotherapy combination did not enhance the inhibitory effect on pro-inflammatory cytokines but could have a beneficial effect by increasing IL-10 production.
25935488 Anti-arthritis effect of a novel quinazoline derivative through inhibiting production of T 2015 Jul 10 TNF-α is a dominant inflammatory mediator in the pathogenesis of inflammatory diseases including rheumatoid arthritis. In our research, we discovered 2-chloro-N-(4-(2-morpholinoethoxy)phenyl)quinazolin-4-amine (9c) exhibited an outstanding anti-inflammatory activity on inhibiting TNF-α production with an IC50 of 8.86 μM in RAW264.7 cells. Interestingly, 9c had no effect on mRNA level of TNF-α but up-regulated the precursor of TNF-α (pro-TNF-α). Then, we studied TNF-α converting enzyme (TACE), which is the most important proteases responsible for the release of TNF-α from pro-TNF-α to soluble TNF-α. The results showed 9c reduced TACE both on the levels of mRNA and protein in a dose-dependent manner. In vivo study, collagen-induced arthritis (CIA) mice were treated by 9c orally. 9c exhibited significant anti-arthritis effect by ameliorating arthritic score, reducing inflammatory cell infiltration, protecting joints from destruction and decreasing the production of systemic TNF-α, IL-6, IL-1β. The underlying mechanism of 9c on CIA was coincided with the in vitro, which was mediated by TACE. In conclusion, we discovered a novel quinazoline derivative which ameliorates arthritis through inhibiting production of TNF-α mediated by TACE for the first time.
27446084 IL-17A and TNF-α Increase the Expression of the Antiapoptotic Adhesion Molecule Amigo-2 i 2016 Rheumatoid arthritis (RA) is a chronic inflammatory disorder, characterized by a persistent immune cell infiltrate in the synovium accompanied by high levels of inflammatory mediators and synovial hyperplasia. Despite significant therapeutic advances, RA remains an important unmet medical need. To discover potential new genes controlling inflammation and apoptosis in synoviocytes, genes induced by the two pro-inflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin 17A (IL-17A), were systematically searched. We identified Amphoterin-induced gene and ORF 2 (Amigo-2), a novel antiapoptotic adhesion molecule, as synergistically upregulated by the IL-17A/TNF combination specifically in RA synoviocytes. In addition, when RA synoviocytes were cocultured with immune cells, Amigo2 expression was significantly increased in both fibroblasts and immune cells. This induction persisted in RA synoviocytes even after the removal of the immune cells. Amigo2 induction was ERK-dependent and on the contrary, inhibited by JNK. Furthermore, Amigo2 expression levels correlated with apoptosis of the cells when exposed to the proapoptotic agent cadmium (Cd). Interestingly, exposure of the cells to HMGB1 in inflammatory conditions increased synergistically Amigo2 expression and significantly reduced Cd-mediated cellular toxicity. Our findings support a model whereby cell-cell contact with immune cells and exposure to the combination of both inflammatory cytokines and HMGB1 in the joints of RA patients increases Amigo2 expression in synoviocytes in an ERK-dependent manner which, in turn, enhances cellular adhesion and promotes cell survival and cellular proliferation.
27600785 [Immunomorphological characteristics of the synovial membrane in rheumatic diseases]. 2016 Jul The synovial membrane is frequently a target in rheumatic diseases. A search for diagnostic criteria and determination of changes in the pathological process necessitate standardized biopsy diagnostic techniques and quantification of morphological changes using digital imaging methods. The paper considers main methods for obtaining synovial membrane samples. It presents major morphological and immunohistochemical variations in synovitis in the presence of rheumatoid arthritis, ankylosing spondylitis, and osteoarthrosis. It shows different immunological and autoinflammatory mechanisms of these diseases. Synovial membrane inflammation in rheumatoid arthritis, ankylosing spondylitis, and osteoarthrosis is characterized by different components of morphogenesis, which is proven by the expression of different cell markers. Rheumatoid synovitis is an autoinflammatory process; synovitis in ankylosing spondylitis is characterized by autoinflammatory processes; biomechanical factors as joint inflammation triggers are leading in osteoarthrosis.
27752256 Understanding Immune Cells in Tertiary Lymphoid Organ Development: It Is All Starting to C 2016 Tertiary lymphoid organs (TLOs) are frequently observed in tissues affected by non-resolving inflammation as a result of infection, autoimmunity, cancer, and allograft rejection. These highly ordered structures resemble the cellular composition of lymphoid follicles typically associated with the spleen and lymph node compartments. Although TLOs within tissues show varying degrees of organization, they frequently display evidence of segregated T and B cell zones, follicular dendritic cell networks, a supporting stromal reticulum, and high endothelial venules. In this respect, they mimic the activities of germinal centers and contribute to the local control of adaptive immune responses. Studies in various disease settings have described how these structures contribute to either beneficial or deleterious outcomes. While the development and architectural organization of TLOs within inflamed tissues requires homeostatic chemokines, lymphoid and inflammatory cytokines, and adhesion molecules, our understanding of the cells responsible for triggering these events is still evolving. Over the past 10-15 years, novel immune cell subsets have been discovered that have more recently been implicated in the control of TLO development and function. In this review, we will discuss the contribution of these cell types and consider the potential to develop new therapeutic strategies that target TLOs.
26924005 Which is the best cutoff of body mass index to identify obesity in female patients with rh 2016 Feb 11 INTRODUCTION: Standard anthropometric measures used to diagnose obesity in the general population may not have the same performance in patients with rheumatoid arthritis. OBJECTIVE: To determine cutoff points for body mass index (BMI) and waist circumference (WC) for detecting obesity in women with rheumatoid arthritis (RA) by comparing these standard anthropometric measures to a dual-energy x-ray absorptiometry (DXA)-based obesity criterion. PATIENTS AND METHOD: Adult female patients with more than six months of diagnosis of RA underwent clinical evaluation, with anthropometric measures and body composition with DXA. RESULTS: Eighty two patients were included, mean age 55±10.7 years. The diagnosis of obesity in the sample was about 31.7% by BMI, 86.6% by WC and 59.8% by DXA. Considering DXA as golden standard, Cutoff points were identified for anthropometric measures to better approximate DXA estimates of percent body fat: for BMI value ≥ 25kg/m(2) was the best for definition of obesity in female patients with RA, with sensitivity of 80% and specificity of 60%. For WC, with 80% of sensitivity and 35% of specificity, the best value to detect obesity was 86cm. CONCLUSION: A large percentage of patients were obese. The traditional cutoff points used for obesity were not suitable for our sample. For this female population with established RA, BMI cutoff point of 25kg/m(2) and WC cutoff point of 86cm were the most appropriate to detect obesity.
27382497 An Autopsy Case of Fulminant Amebic Colitis in a Patient with a History of Rheumatoid Arth 2016 Generally, amebic colitis is localized around the mucosal membrane and often accompanied by diarrhea and abdominal pain. We describe a patient with a history of rheumatoid arthritis who had received prolonged steroid therapy. The patient complained of breathing difficulties because of rheumatoid lung disease. Although the patient was given antibacterial agent, the symptoms did not improve until death. We did an autopsy and found that he had fulminant amebic colitis, although the patient was not previously examined. Histochemical analysis revealed severe inflammation and full-thickness necrosis of the colon by ameba, suggesting the involvement of ameba in the progression of the overall condition.
27422713 Autoimmunity in 2015. 2016 Aug Compared to the clear trend observed in previous years, the number of peer-reviewed articles published during 2015 and retrieved using the "autoimmunity" key word declined by 4 %, while remaining 5 % of immunology articles. On the other hand, a more detailed analysis of the published articles in leading immunology and autoimmunity journals revealed exciting scenarios, with fascinating lines of evidence being supported by convincing data and likely followed by rapid translational or clinical developments. As examples, the study of the microbiome, the development of new serum or other tissue biomarkers, and a more solid understanding of disease pathogenesis and tolerance breakdown mechanisms have been central issues in the past year. Furthermore and similar to the oncology field, progress in the understanding of single autoimmune condition is becoming most specific with psoriatic and rheumatoid arthritis being ideal paradigms with treatment options diverging after decades of common therapies, as illustrated by IL17-targeting approaches. The ultimate result of these advances is towards personalized medicine with an ideal approach being tailored on a single patient, based on a finely tuned definition of the immunogenetics, epigenetics, microbiome, and biomarkers. Finally, experimental reports suggest that cancer-associated immune mechanisms or the role of T and B cell subpopulations should be better understood in autoimmune diseases. While we hailed the 2014 literature in the autoimmunity world as part of an annus mirabilis, we should not be mistaken in the strong stimulus of research in autoimmunity represented by the 2015 articles that will be summarized in this article.
27014713 Pixel-based approach to assess contrast-enhanced ultrasound kinetics parameters for differ 2015 Jul Inflammatory rheumatic diseases are the leading causes of disability and constitute a frequent medical disorder, leading to inability to work, high comorbidity, and increased mortality. The standard for diagnosing and differentiating arthritis is based on clinical examination, laboratory exams, and imaging findings, such as synovitis, bone edema, or joint erosions. Contrast-enhanced ultrasound (CEUS) examination of the small joints is emerging as a sensitive tool for assessing vascularization and disease activity. Quantitative assessment is mostly performed at the region of interest level, where the mean intensity curve is fitted with an exponential function. We showed that using a more physiologically motivated perfusion curve, and by estimating the kinetic parameters separately pixel by pixel, the quantitative information gathered is able to more effectively characterize the different perfusion patterns. In particular, we demonstrated that a random forest classifier based on pixelwise quantification of the kinetic contrast agent perfusion features can discriminate rheumatoid arthritis from different arthritis forms (psoriatic arthritis, spondyloarthritis, and arthritis in connective tissue disease) with an average accuracy of 97%. On the contrary, clinical evaluation (DAS28), semiquantitative CEUS assessment, serological markers, or region-based parameters do not allow such a high diagnostic accuracy.
27843577 Age affects joint space narrowing in patients with early active rheumatoid arthritis. 2016 BACKGROUND: Joint space narrowing (JSN) in rheumatoid arthritis (RA) may be a manifestation of (primary) osteoarthritis becoming more prominent with age. We investigated the severity and predictors of JSN progression among different age groups. METHODS: 10-year follow-up data of the BeSt study, a randomised controlled treat-to-target trial in early RA were used. Annual X-rays of hands and feet were scored using the Sharp/van der Heijde score (SHS). Subgroups were defined by age at baseline: ≥55, ≥40<55 and <40 years. JSN progression predictors were assessed by Poisson regression. RESULTS: Baseline JSN scores (median (IQR)) were higher in patients ≥55 (2.0 (0.0-6.0)) compared with the other age groups: 1.0 (0.0-3.0) ≥40<55 and 0.3 (0.0-3.0) <40, p<0.001. After 10 years, total JSN and SHS were similar in all age groups. In patients ≥55 the mean erythrocyte sedimentation rate (ESR) over time (relative risk 1.02 (95% CI 1.00 to 1.03)) and the combined presence of rheumatoid factor and anticitrullinated protein antibodies (RF+/ACPA+) (3.27 (1.25-8.53)) were significantly correlated with JSN progression. In patients <40 the baseline swollen joint count (SJC; 1.09 (1.01-1.18)) and ESR over time (1.04 (1.02-1.06)) were significantly associated. CONCLUSIONS: At baseline, patients with RA ≥55 years had more JSN than younger patients but after 10 years JSN scores were similar between age groups. Independent risk factors for JSN progression were baseline SJC and ESR over time in patients <40, RF+/ACPA+ and ESR over time in patients ≥55 years. This suggests that mechanisms leading to JSN progression are related to (residual) rheumatoid inflammation and vary between age groups. These mechanisms remain to be elucidated. TRIAL REGISTRATION NUMBERS: NTR262, NTR265.
26434922 Pregnancy Outcomes in Women With Rare Autoimmune Diseases. 2015 Dec OBJECTIVE: To examine pregnancy outcomes and pregnancy-related health service utilization among women with rare autoimmune diseases. METHODS: This population-based cohort study of an Australian obstetric population (2001-2011) used birth records linked to hospital records for identification of rare autoimmune diseases including systemic vasculitis, vasculitis limited to the skin, Sjögren's syndrome, systemic sclerosis, Behçet's disease, polymyositis/dermatomyositis, and other systemic involvement of connective tissue. We excluded births in women with systemic lupus erythematosus or rheumatoid arthritis as well as births occurring ≥6 months before the diagnosis of the rare autoimmune disease. Modified Poisson regression was used to compare study outcomes between women with autoimmune diseases and the general obstetric population. RESULTS: There were 991,701 births, including 409 births (0.04%) in 293 women with rare autoimmune diseases. Of the 409 births, 202 (49%) were delivered by cesarean section and 72 (18%) were preterm; these rates were significantly higher than those in the general obstetric population (28% and 7%, respectively). Compared to the general population, women with autoimmune diseases had higher rates of hypertensive disorders, antepartum hemorrhage, and severe maternal morbidity and required longer hospitalization at delivery, more hospital admissions, and tertiary obstetric care. Compared to other infants, those whose mothers had a rare autoimmune disease were at increased risk of admission to a neonatal intensive care unit, severe neonatal morbidity, and perinatal death. CONCLUSION: While the majority of women with rare autoimmune diseases delivered healthy infants, they were at increased risk of having both maternal complications and adverse neonatal outcomes, suggesting that their pregnancies should be closely monitored.
26132809 Anti-citrullinated-protein-antibody-specific intravenous immunoglobulin attenuates collage 2015 Dec Administration of intravenous immunoglobulin (IVIg) is a recognized safe and efficient immunomodulation therapy for many autoimmune diseases. Anti-idiotypic antibody binding to pathogenic autoantibodies was proposed as one of the mechanisms attributed to the protective activity of IVIg in autoimmunity. The aim of this study was to fractionate the anti-anti-citrullinated protein anti-idiotypic-antibodies (anti-ACPA) from an IVIg preparation and to test it as a treatment for collagen-induced arthritis in mice. IVIg was loaded onto an ACPA column. The eluted fraction was defined as ACPA-specific-IVIg (ACPA-sIVIg). Collagen-induced-arthritis (CIA) was induced in mice. Mice were treated weekly with ACPA-sIVIg, low-dose-IVIg, high-dose-IVIg and phosphate-buffered saline (PBS). Sera-ACPA titres, anti-collagen anitbodies and cytokine levels were analysed by enzyme-linked immunosorbent assay (ELISA); antibody-forming-cell activity by enzyme-linked imunospot (ELISPOT) assay; and expansion of regulatory T cell (Treg ) population by fluorescence activated cell sorter (FACS). ACPA-sIVIg inhibited ACPA binding to citrullinated-peptides (CCP) in vitro 100 times more efficiently than the IVIg compound. ACPA-sIVIg was significantly more effective than the IVIg-preparation in attenuating the development of collagen-induced arthritis. Splenocytes from CIA mice treated with ACPA-sIVIg reduced the ACPA and anti-collagen-antibody titres, including the number of anti-collagen and ACPA antibody-forming cells. In parallel, splenocytes from ACPA-sIVIg treated mice secreted higher levels of anti-inflammatory cytokines and lower proinflammatory cytokines. The ACPA-sIVIg inhibitory potential was accompanied with expansion of the Treg population. Low-dose IVIg did not affect the humoral and cellular response in the CIA mice in comparison to the PBS-treated mice. Based on our results, IVIg may be considered as a safe compound for treating patients with rheumatoid arthritis by neutralizing pathogenic autoantibodies, reducing proinflammatory cytokines and expanding the Treg population.
27722902 Vitamin K homologs as potential biomarkers for disease activity in patients with rheumatoi 2017 Sep The aim of this study was to evaluate the possible role of vitamin K homologs as potential biomarkers for disease activity in patients with rheumatoid arthritis (RA). In this study, 42 patients with RA and 40 healthy controls were enrolled. Serum levels of vitamin K homologs were measured using a high-performance liquid chromatography-fluorescence method. Different biochemical and clinical markers for disease activity were measured and correlated with serum levels of vitamin K homologs. There were no significant differences between RA patients and healthy subjects in demographic data. Patients with RA showed significantly higher levels of biochemical markers compared with healthy subjects (p < 0.001). These markers included rheumatoid factor (RF), anticyclic citrullinated polypeptide (anti-CCP), undercarboxylated osteocalcin (ucOC), matrix metalloproteinase (MMP-3), C-reactive protein (CRP), and disease activity score assessing 28 joints with erythrocyte sedimentation rate (DAS28-ESR). In addition, serum levels of vitamin K homologs were reduced in RA patients, and the levels of menaquinone-4 (MK-4) and menaquinone-7 (MK-7) were moderately to strongly inversely correlated with the clinical articular features in RA patients, whereas phylloquinone (PK) levels were weakly correlated. Serum levels of MK-4, MK-7 and PK were strongly inversely correlated with ucOC, MMP-3 and DAS28-ESR in RA patients. In contrast, serum levels of MK-4, MK-7 and PK were weakly correlated with CRP, RF and anti-CCP. These results suggest that serum levels of vitamin K homologs may be considered as potential biomarkers for disease activity. In addition, the results confirm the role of vitamin K deficiency in the etiology of RA.
25989352 B-cell epitope spreading and inflammation in a mouse model of arthritis is associated with 2015 Aug Autoantibody-mediated inflammation contributes to the development of rheumatoid arthritis (RA), and anti-type II collagen (CII) antibodies are present in the serum, synovial fluid, and cartilage of RA patients. We had previously generated and characterized knock-in mice expressing a germline-encoded, CII-specific IgH (B10Q.ACB), which demonstrated positive selection of self-reactive B cells. Here, we show that despite the spontaneous production of CII-specific autoantibodies, B10Q.ACB mice are protected from collagen-induced arthritis. Introducing a mutation in the Ncf1 gene, leading to ROS deficiency, breaks this strong arthritis resistance. Disease development in Ncf1-mutated B10Q.ACB mice is associated with an enhanced germinal center formation but without somatic mutations of the auto-reactive B cells, increased T-cell responses and intramolecular epitope-spreading. Thus, ROS-mediated B-cell tolerance to a self-antigen could operate by limiting the expansion of the auto-reactive B-cell repertoire, which has important implications for the understanding of epitope spreading phenomena in rheumatoid arthritis and other autoimmune diseases.
29259682 Therapeutic intervention of inflammatory/immune diseases by inhibition of the fractalkine 2016 Inflammatory and immune responses are generated locally by the selective invasion and accumulation of the immune cells into the lesion site. The infiltration process of the immune cells into the tissue from the blood through the vascular endothelial cells is closely regulated by a number of chemotactic factors and cell adhesion molecules. Fractalkine (FKN)/CX3CL1 is a membrane-bound chemokine possessing a chemokine/mucin hybrid structure and a transmembrane domain and has a dual function as an adhesion molecule and a chemoattractant. FKN is mainly expressed on activated endothelial cells, activated fibroblasts, and osteoblasts. Its receptor, CX3CR1, is expressed on cytotoxic effector lymphocytes, monocytes/macrophages, and osteoclasts. To date, a lot of key functional aspects of the FKN-CX3CR1 axis has been identified: (1) the rapid capture and firm adhesion of immune cells to vascular endothelial cells, (2) chemotaxis, (3) the enhancement of the transmigration to other chemokines, (4) the crawling behavior of the monocytes that patrol on vascular endothelial cells, (5) the retention of monocytes as the accessory cells of the inflamed endothelium to recruit inflammatory cells, and (6) the survival of the macrophage. In this review, we will focus on the pathological role of FKN in rheumatoid arthritis (RA) and the physiological role of FKN on osteoclast differentiation. Furthermore, we will discuss the therapeutic potential of anti-FKN mAb for RA patients and its distinct mode of action from other cytokine inhibitors.