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ID PMID Title PublicationDate abstract
27118040 Identifying factors associated with concordance with the American College of Rheumatology 2016 Apr 26 BACKGROUND: Factors associated with care concordant with the American College of Rheumatology (ACR) recommendations for the use of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) are unknown. METHODS: We identified a national cohort of biologic-naive patients with RA with visits between December 2008 and February 2013. Treatment acceleration (initiation or dose escalation of biologic and nonbiologic DMARDs) in response to moderate to high disease activity (using the Clinical Disease Activity Index) was assessed. The population was divided into two subcohorts: (1) methotrexate (MTX)-only users and (2) multiple nonbiologic DMARD users. In both subcohorts, we compared the characteristics of patients who received care consistent with the ACR recommendations (e.g., prescriptions for treatment acceleration) and their providers with the characteristics of those who did not at the conclusion of one visit and over two visits, using logistic regression and adjusting for clustering of patients by rheumatologist. RESULTS: Our study included 741 MTX monotherapy and 995 multiple nonbiologic DMARD users cared for by 139 providers. Only 36.2 % of MTX monotherapy users and 39.6 % of multiple nonbiologic DMARD users received care consistent with the recommendations after one visit, which increased over two visits to 78.3 % and 76.2 %, respectively (25-30 % achieved low disease activity by the second visit without DMARD acceleration). Increasing time since the ACR publication on RA treatment recommendations was not associated with improved adherence. CONCLUSIONS: Allowing two encounters for treatment acceleration was associated with an increase in care concordant with the recommendations; however, time since publication was not.
26395833 Analysis of clinical trials of biosimilar infliximab (CT-P13) and comparison against histo 2015 OBJECTIVE: To examine whether efficacy, safety and pharmacokinetic (PK) data observed with CT-P13 (Remsima(®); Inflectra(®)), an infliximab biosimilar, are similar to those from published reports with the reference medicinal product (RMP; Remicade(®)) in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS). METHODS: Literature searches were performed to identify clinical studies with infliximab RMP. Efficacy, safety and PK data were indirectly compared with data from head-to-head clinical trials of CT-P13 and RMP. RESULTS: CT-P13 and RMP produce similar efficacy in patients with RA and AS when compared across clinical studies. There are no substantial differences in the incidence of infusion-related reactions, infections, serious infections, malignancy or lymphoma. PK data in patients with RA are similar in direct comparisons and comparisons with historical data. CONCLUSION: Efficacy, safety and PK data are highly comparable between CT-P13 and RMP, both in head-to-head clinical studies, and indirect comparisons with historical clinical data for RMP.
27786276 Revealing the diversity of extracellular vesicles using high-dimensional flow cytometry an 2016 Oct 27 Extracellular vesicles (EV) are small membrane vesicles produced by cells upon activation and apoptosis. EVs are heterogeneous according to their origin, mode of release, membrane composition, organelle and biochemical content, and other factors. Whereas it is apparent that EVs are implicated in intercellular communication, they can also be used as biomarkers. Continuous improvements in pre-analytical parameters and flow cytometry permit more efficient assessment of EVs; however, methods to more objectively distinguish EVs from cells and background, and to interpret multiple single-EV parameters are lacking. We used spanning-tree progression analysis of density-normalized events (SPADE) as a computational approach for the organization of EV subpopulations released by platelets and erythrocytes. SPADE distinguished EVs, and logically organized EVs detected by high-sensitivity flow cytofluorometry based on size estimation, granularity, mitochondrial content, and phosphatidylserine and protein receptor surface expression. Plasma EVs were organized by hierarchy, permitting appreciation of their heterogeneity. Furthermore, SPADE was used to analyze EVs present in the synovial fluid of patients with inflammatory arthritis. Its algorithm efficiently revealed subtypes of arthritic patients based on EV heterogeneity patterns. Our study reveals that computational algorithms are useful for the analysis of high-dimensional single EV data, thereby facilitating comprehension of EV functions and biomarker development.
27851983 Osteopontin inhibition of miR-129-3p enhances IL-17 expression and monocyte migration in r 2017 Feb BACKGROUND: Osteopontin (OPN) is an important proinflammatory cytokine in rheumatoid arthritis (RA). Levels of OPN have been shown to be significantly correlated with interleukin-17 (IL-17) production and expression of Th17 cells in the synovial fluid of RA patients. Here, we investigated the role of OPN in monocyte migration, IL-17 production and osteoblasts. METHODS: OPN and IL-17 expression profiles in osteoarthritis (OA) and RA synovial fluid were determined by enzyme-linked immunosorbent assay (ELISA). The expression of the microRNA, miR-129-3p, in osteoblasts was analyzed by real-time quantitative polymerase chain reaction (qPCR). Immunoreactive proteins were spotted by Western blotting. We used the collagen-induced arthritis (CIA) mouse model to investigate the role of OPN in monocyte migration during RA. RESULTS: OPN and IL-17 expression were higher in RA synovial fluid as compared to OA samples. We also found that OPN promotes IL-17 expression in osteoblasts and thereby enhances monocyte migration via the Syk/PI3K/Akt signaling pathway. miR-129-3p expression was found to be negatively regulated by OPN via the Syk/PI3K/Akt signal cascade. In contrast, lentiviral vectors expressing short hairpin RNA inhibited OPN expression and ameliorated articular swelling, cartilage erosion and monocyte infiltration in the ankle joints of CIA mice. CONCLUSION: To our knowledge, our study is the first to describe how OPN promotes monocyte migration by upregulating IL-17 expression in osteoblasts in RA disease. SIGNIFICANCE: These findings indicate that OPN could serve as a potential therapeutic target for the treatment of RA.
26944378 Corynebacterium striatum empyema and osteomyelitis in a patient with advanced rheumatoid a 2016 Mar 4 Corynebacterium striatum, which is a common coloniser of human skin and mucous membranes, is increasingly being recognised as an emerging pathogen. We present a case of a 69-year-old woman with empyema and osteomyelitis caused by C. striatum. To the best of our knowledge, this is the first case where these two infections from this bacterium were identified together in the same individual.
27860244 Role of protein arginine methyltransferase 5 in inflammation and migration of fibroblast-l 2017 Apr To probe the role of protein arginine methyltransferase 5 (PRMT5) in regulating inflammation, cell proliferation, migration and invasion of fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA). FLSs were separated from synovial tissues (STs) from patients with RA and osteoarthritis (OA). An inhibitor of PRMT5 (EPZ015666) and short interference RNA (siRNA) against PRMT5 were used to inhibit PRMT5 expression. The standard of protein was measured by Western blot or immunofluorescence. The excretion and genetic expression of inflammatory factors were, respectively, estimated by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR). Migration and invasion in vitro were detected by Boyden chamber assay. FLSs proliferation was detected by BrdU incorporation. Increased PRMT5 was discovered in STs and FLSs from patients with RA. In RA FLSs, the level of PRMT5 was up-regulated by stimulation with IL-1β and TNF-α. Inhibition of PRMT5 by EPZ015666 and siRNA-mediated knockdown reduced IL-6 and IL-8 production, and proliferation of RA FLSs. In addition, inhibition of PRMT5 decreased in vitro migration and invasion of RA FLSs. Furthermore, EPZ015666 restrained the phosphorylation of IκB kinaseβ and IκBα, as well as nucleus transsituation of p65 as well as AKT in FLSs. PRMT5 regulated the production of inflammatory factors, cell proliferation, migration and invasion of RA FLS, which was mediated by the NF-κB and AKT pathways. Our data suggested that targeting PRMT5 to prevent synovial inflammation and destruction might be a promising therapy for RA.
27420628 [Enrichment of extracellular DNA from the cultivation medium of human peripheral blood mon 2016 Mar Previously, it was found that blood plasma extracellular DNA (ecDNA) of patients with rheumatoid arthritis (RA) is enriched with CpG-rich genomic DNA fragments, which contain TLR9 ligands (Veiko et al., 2006). In this study we have demonstrated that ecDNA of a RA patient and model fragments added to a cultivation medium of peripheral blood mononuclear cells (PBMC) of healthy donors stimulate expression of genes for the TLR9-MyD88-NF-kB signaling pathway; this leads to a significant increase in concentrations of the proinflammatory cytokines IL-6 and TNF-a in the cultivation medium. Human genomic DNA non-enriched with the CpG sequences did not stimulate IL-6 and TNF-a synthesis in PBMC. A scheme explaining the potential role ecDNA in the induction and maintenance of increased levels of the proinflammatory cytokines under conditions damaging the human cells has been proposed.
27463856 Characterization and non-clinical assessment of the proposed etanercept biosimilar GP2015 2016 Oct BACKGROUND AND OBJECTIVE: Biosimilars are approved biologics that are comparable to an originator product with respect to quality, safety and efficacy. Herein, the authors describe the functional and non-clinical studies designed to determine the biosimilarity of GP2015 and originator etanercept (Enbrel®). METHODS: The development of an Enbrel biosimilar (GP2015) involved extensive characterization of the originator. A step-wise target-directed and iterative technical development program involving state-of-the-art functional characterization studies and non-clinical evaluations (pharmacokinetics, pharmacodynamics and safety/toxicology) was applied with the aim of confirming that GP2015 is comparable to originator (Enbrel) at the non-clinical level. RESULTS: In in vitro tests, GP2015 and Enbrel had comparable binding affinities to TNF-α, C1q complement and a complete panel of Fc-Receptors. Comprehensive functional characterization testing confirmed the comparability of GP2015 with Enbrel in terms of its ability to bind to and neutralize TNF-α, which reflects the primary mechanism of action of etanercept. Non-clinical data confirmed that the proposed biosimilar to Enbrel, GP2015, is comparable with regards to its pharmacokinetic properties and pharmacodynamic activity, and efficacy as well as safety/toxicity. CONCLUSION: The proposed Enbrel biosimilar, GP2015, was shown to be comparable to its originator product in studies designed to confirm biosimilarity.
27756166 Kocuria kristinae infection during adalimumab treatment. 2017 Mar A common inhabitant of skin, the Kocuria kristinae of the Micrococcaceae family, has gained attention in recent years because it can induce pathology in humans. Reported is a Kocuria kristinae-caused abdominal abscess in a patient treated for rheumatoid arthritis with adalimumab. The tumor necrosis factor (TNF) inhibitor drugs are known to cause various bacterial, viral, and fungal infections. This is the first known case where an opportunistic infection with Kocuria has presented with an abdominal abscess in an immunocompromised individual who is on long term TNF inhibitors.
25997838 [Safety and Efficacy of Etanercept in Rheumatoid Arthritis With End-stage Chronic Renal Fa 2015 May The use of etanercept in rheumatoid arthritis patients with end-stage renal failure has not been well reported. We report here the case of 58-years-old patient who was treated with 50 mg of etanercept once a week to control the activity of her disease. The patient improved after starting the treatement. No serious infectious complication or side effects were seen. The follow-up was 18 months. Our case showed the safety and efficacity of etanercept rheumatoid arthritis in patient with end-stage renal failure.
27496347 Basement membranes and autoimmune diseases. 2017 Jan Basement membrane components are targets of autoimmune attack in diverse diseases that destroy kidneys, lungs, skin, mucous membranes, joints, and other organs in man. Epitopes on collagen and laminin, in particular, are targeted by autoantibodies and T cells in anti-glomerular basement membrane glomerulonephritis, Goodpasture's disease, rheumatoid arthritis, post-lung transplant bronchiolitis obliterans syndrome, and multiple autoimmune dermatoses. This review examines major diseases linked to basement membrane autoreactivity, with a focus on investigations in patients and animal models that advance our understanding of disease pathogenesis. Autoimmunity to glomerular basement membrane type IV is discussed in depth as a prototypic organ-specific autoimmune disease yielding novel insights into the complexity of anti-basement membrane immunity and the roles of genetic and environmental susceptibility.
29235966 The characteristics of antibodies of mice immunized by human unconventional myosin 1c. 2016 Nov Specific antibodies produced against a protein of interest are invaluable tools for monitoring the protein structure, intracellular location and biological activity. Inoculation of murine lymphoma cells into the peritoneal cavity of immunized mice provides generation of ascitic fluid containing a significant amount of antibody with desired antigen specificity. Here we demonstrated that the intraperitoneal administration of murine lymphoma NK/Ly cells in mice immunized with 48 kDa isoform of human blood serum unconventional myosin 1c leads to generation of ascitic fluid that contained specific IgG-antibodies. These antibodies were capable of binding of the unconventional myosin 1c isolated from blood serum of patients with multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosis, and could be used for diagnostics of several autoimmune diseases, the multiple sclerosis in particular.
26670468 Serum Vaspin Levels Are Associated with the Development of Clinically Manifest Arthritis i 2015 OBJECTIVES: We have previously shown that overweight may increase the risk of developing rheumatoid arthritis (RA) in autoantibody positive individuals. Adipose tissue could contribute to the development of RA by production of various bioactive peptides. Therefore, we examined levels of adipokines in serum and synovial tissue of subjects at risk of RA. METHODS: Fifty-one individuals positive for immunoglobulin M rheumatoid factor (IgM-RF) and/or anti-citrullinated protein antibodies (ACPA), without arthritis, were included in this prospective study. Levels of adiponectin, vaspin, resistin, leptin, chemerin and omentin were determined in baseline fasting serum samples (n = 27). Synovial tissue was obtained by arthroscopy at baseline and we examined the expression of adiponectin, resistin and visfatin by immunohistochemistry. RESULTS: The development of clinically manifest arthritis after follow-up was associated with baseline serum vaspin levels (HR1.5 (95% CI 1.1 to 2.2); p = 0.020), also after adjustment for overweight (HR1.7 (95% CI 1.1 to 2.5); p = 0.016). This association was not seen for other adipokines. Various serum adipokine levels correlated with BMI (adiponectin r = -0.538, leptin r = 0.664; chemerin r = 0.529) and systemic markers of inflammation such as CRP levels at baseline (adiponectin r = -0.449, omentin r = -0.557, leptin r = 0.635, chemerin r = 0.619, resistin r = 0.520) and ESR (leptin r = 0.512, chemerin r = 0.708), p-value<0.05. Synovial expression of adiponectin, resistin and visfatin was not associated with development of clinically manifest arthritis. CONCLUSIONS: In this exploratory study, serum adipokines were associated with an increased inflammatory state in autoantibody-positive individuals at risk of developing RA. Furthermore, serum vaspin levels may assist in predicting the development of arthritis in these individuals.
25994913 Functional Mechanism(s) of the Inhibition of Disease Progression by Combination Treatment 2015 We previously reported that combination treatment with fingolimod (FTY720) plus antigenic peptide of glucose-6-phosphate isomerase (residues 325-339) (GPI325-339) from the onset of symptoms significantly inhibited disease progression in a mouse model of GPI325-339-induced arthritis. In this study, we investigated the mechanism(s) involved. The model mice were treated from arthritis onset with FTY720 alone, GPI325-339 alone, or the combination of FTY720 plus GPI325-339. At the end of treatment, inguinal lymph nodes (LNs) were excised and examined histologically and in flow cytometry. Levels of apoptotic cells, programmed death-1-expressing CD4(+)forkhead box P3(-) nonregulatory T cells (non-Tregs), and cytotoxic T-lymphocyte antigen 4-expressing non-Tregs in inguinal LNs were markedly increased in the combination treatment group mice. Regulatory T cells (Tregs) were also increased. These results indicate that combination treatment with FTY720 plus GPI325-339 inhibits the progression of arthritis by inducing clonal deletion and anergy of pathogenic T cells and also by immune suppression via Tregs.
25776950 Autoimmunity: lungs and citrullination. 2015 May Anti-citrullinated protein antibodies are a distinctive feature of a subset of patients with rheumatoid arthritis (RA). A new report investigates how lung inflammation in patients with chronic obstructive pulmonary disease affects protein citrullination, providing an additional piece of information on the potential link between airway inflammation and RA.
26796582 Application of synthetic peptides for detection of anti-citrullinated peptide antibodies. 2016 Feb Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA) and represent an important tool for the serological diagnosis of RA. In this study, we describe ACPA reactivity to overlapping citrullinated Epstein-Barr virus nuclear antigen-1 (EBNA-1)-derived peptides and analyze their potential as substrates for ACPA detection by streptavidin capture enzyme-linked immunosorbent assay. Using systematically overlapping peptides, containing a 10 amino acid overlap, labelled with biotin C-terminally or N-terminally, sera from 160 individuals (RA sera (n=60), healthy controls (n=40), systemic lupus erythematosus (n=20), Sjögren's syndrome (n=40)) were screened for antibody reactivity. Antibodies to a panel of five citrullinated EBNA-1 peptides were found in 67% of RA sera, exclusively of the IgG isotype, while 53% of the patient sera reacted with a single peptide, ARGGSRERARGRGRG-Cit-GEKR, accounting for more than half of the ACPA reactivity alone. Moreover, these antibodies were detected in 10% of CCP2-negative RA sera. In addition, 47% of the RA sera reacted with two or three citrullinated EBNA-1 peptides from the selected peptide panel. Furthermore, a negative correlation between the biotin attachment site and the location of citrulline in the peptides was found, i.e. the closer the citrulline was located to biotin, the lower the antibody reactivity. Our data suggest that citrullinated EBNA-1 peptides may be considered a substrate for the detection of ACPAs and that the presence of Epstein-Barr virus may play a role in the induction of these autoantibodies.
27287745 Subcutaneous Phaeohyphomycosis Caused by Pyrenochaeta romeroi in a Rheumatoid Arthritis Pa 2016 Oct Pyrenochaeta romeroi is a rare fungal agent of chronic, suppurative subcutaneous infections leading to mycetoma. It is an unusual cause of deep, non-mycetomatous infections. We herein present review of the literature along with a case of 61-year-old Indian female with rheumatoid arthritis who developed subcutaneous phaeohyphomycosis caused by Pyrenochaeta romeroi. It posed a diagnostic challenge, as the culture from fine-needle aspirate revealed a non-sporulating dematiaceous mould, which was the only supportive tool for its diagnosis and initiation of the therapy. However, it was the molecular sequencing which played the pivotal role in clinching the final aetiological diagnosis. To the best of our knowledge, this is the 20th case of Pyrenochaeta species infection occurring worldwide and first case report of subcutaneous phaeohyphomycosis caused by Pyrenochaeta romeroi in a rheumatoid arthritis patient.
26922200 Impact of MTHFR rs1801133, MTHFR rs1801131 and ABCB1 rs1045642 polymorphisms with increase 2015 Oct Rheumatoid arthritis (RA) is an autoimmune disease that results in a chronic systemic inflammation. A few genetic epidemiologic studies found a potential association between genetic polymorphisms C677T (rs1801133) and A1298C (rs1801131) of methylenetatrahydrofolate reductase (MTHFR) gene and C3435T (rs1045642) of ATP-Binding cassette (ABCB1) gene and the increased risk for RA. The aim of this case-control study was to determine the relationship between these polymorphisms and RA susceptibility in West Algerian population. The dataset of the current study is composed of 110 RA patients and 101 healthy controls. All samples were genotyped for theses polymorphisms by TaqMan® allelic discrimination assay. Data were compared between cases and controls by the calculation of the odds ratio (OR) with a confidence interval at 95%. After age and RA erosion-stratified analyzes, no differences in genotypes or alleles frequencies distribution were found for MTHFR C677T (rs1801133) and ABCB1 C3435T (rs1045642) polymorphisms between RA cases and controls. However, the MTHFR A1298C (rs1801131) polymorphism presented a significant distribution in RA with age ≥ 40 (Genotypic data: p=0.007, OR=13.53[1.44-63.31], Allelic data: p=0.001, OR=2.39[1.39-4.1]), and in RA erosive form (Genotypic data: p=0.002, OR=6.92[1.68-30.23], Allelic data: p=0.0001, OR=2.43[1.54-3.85]).These results were confirmed after the Bonferroni correction. In this study we have showed, for the first time in the West Algerian population, that the MTHFR A1298C (rs1801131) polymorphism can be associated with rheumatoid arthritis.
27190098 Economic considerations and patients' preferences affect treatment selection for patients 2017 Jan OBJECTIVE: To compare the value that rheumatologists across Europe attach to patients' preferences and economic aspects when choosing treatments for patients with rheumatoid arthritis. METHODS: In a discrete choice experiment, European rheumatologists chose between two hypothetical drug treatments for a patient with moderate disease activity. Treatments differed in five attributes: efficacy (improvement and achieved state on disease activity), safety (probability of serious adverse events), patient's preference (level of agreement), medication costs and cost-effectiveness (incremental cost-effectiveness ratio (ICER)). A Bayesian efficient design defined 14 choice sets, and a random parameter logit model was used to estimate relative preferences for rheumatologists across countries. Cluster analyses and latent class models were applied to understand preference patterns across countries and among individual rheumatologists. RESULTS: Responses of 559 rheumatologists from 12 European countries were included in the analysis (49% females, mean age 48 years). In all countries, efficacy dominated treatment decisions followed by economic considerations and patients' preferences. Across countries, rheumatologists avoided selecting a treatment that patients disliked. Latent class models revealed four respondent profiles: one traded off all attributes except safety, and the remaining three classes disregarded ICER. Among individual rheumatologists, 57% disregarded ICER and these were more likely from Italy, Romania, Portugal or France, whereas 43% disregarded uncommon/rare side effects and were more likely from Belgium, Germany, Hungary, the Netherlands, Norway, Spain, Sweden or UK. CONCLUSIONS: Overall, European rheumatologists are willing to trade between treatment efficacy, patients' treatment preferences and economic considerations. However, the degree of trade-off differs between countries and among individuals.
24685910 Risk of solid cancer in patients exposed to anti-tumour necrosis factor therapy: results f 2015 Jun BACKGROUND: Patients with rheumatoid arthritis (RA) have an increased risk of certain solid cancers, in particular lung cancer, compared to the general population. Treatment with tumour necrosis factor (TNF) inhibitors (TNFi) may further enhance this risk. OBJECTIVES: To compare the risk of solid cancer in patients with RA treated with TNFi to that in patients treated with non-biologic (synthetic) disease modifying antirheumatic drugs (sDMARDs). METHODS: Patients with a physician diagnosis of RA enrolled in the British Society for Rheumatology Biologics Register, a national prospective cohort study established in 2001 to monitor the long-term safety of TNFi, were followed via record linkage with the national cancer registries until first solid cancer, death, for 5 years, or until 2011. Rates of solid cancers in 11 767 patients without prior cancer who received TNFi were compared to those in 3249 patients without prior cancer treated with sDMARDs. RESULTS: 427 solid cancers were reported in 52 549 patient-years follow-up for the TNFi group (81 (95% CI 74 to 89) per 10 000 patient-years) and 136 cancers were reported in 11 672 patient-years in the sDMARD cohort (117 (95% CI 98 to 138) per 10 000 patient-years). After adjusting for differences in baseline characteristics there was no difference in risk of solid cancer for TNFi compared to sDMARD treated patients: HR 0.83 (95% CI 0.64 to 1.07). There was no difference in the relative risk of cancer for any of the individual TNFi drugs. CONCLUSIONS: The addition of TNFi to sDMARD does not alter the risk of cancer in RA patients selected for TNFi in the UK.