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ID PMID Title PublicationDate abstract
28968465 The macrophage marker translocator protein (TSPO) is down-regulated on pro-inflammatory 'M 2017 The translocator protein (TSPO) is a mitochondrial membrane protein, of as yet uncertain function. Its purported high expression on activated macrophages, has lent utility to TSPO targeted molecular imaging in the form of positron emission tomography (PET), as a means to detect and quantify inflammation in vivo. However, existing literature regarding TSPO expression on human activated macrophages is lacking, mostly deriving from brain tissue studies, including studies of brain malignancy, and inflammatory diseases such as multiple sclerosis. Here, we utilized three human sources of monocyte derived macrophages (MDM), from THP-1 monocytes, healthy peripheral blood monocytes and synovial fluid monocytes from patients with rheumatoid arthritis, to undertake a detailed investigation of TSPO expression in activated macrophages. In this work, we demonstrate a consistent down-regulation of TSPO mRNA and protein in macrophages activated to a pro-inflammatory, or 'M1' phenotype. Conversely, stimulation of macrophages to an M2 phenotype with IL-4, dexamethasone or TGF-β1 did not alter TSPO expression, regardless of MDM source. The reasons for this are uncertain, but our study findings add some supporting evidence for recent investigations concluding that TSPO may be involved in negative regulation of inflammatory responses in macrophages.
28847852 Association between chronic immune-mediated inflammatory diseases and cardiovascular risk. 2018 Jan OBJECTIVE: To examine the association between chronic immune-mediated diseases (rheumatoid arthritis, systemic lupus erythematosus or the following chronic immune-mediated inflammatory diagnoses groups: inflammatory bowel diseases, inflammatory polyarthropathies, systemic connective tissue disorders and spondylopathies) and the 6-year coronary artery disease, stroke, cardiovascular disease incidence and overall mortality; and to estimate the population attributable fractions for all four end-points for each chronic immune-mediated inflammatory disease. METHODS: Cohort study of individuals aged 35-85 years, with no history of cardiovascular disease from Catalonia (Spain). The coded diagnoses of chronic immune-mediated diseases and cardiovascular diseases were ascertained and registered using validated codes, and date of death was obtained from administrative data. Cox regression models for each outcome according to exposure were fitted to estimate HRs in two models (1) : after adjustment for sex, age, cardiovascular risk factors and (2) further adjusted for drug use. Population attributable fractions were estimated for each exposure. RESULTS: Data were collected from 991 546 participants. The risk of cardiovascular disease was increased in systemic connective tissue disorders (model 1: HR=1.38 (95% CI 1.21 to 1.57) and model 2: HR=1.31 (95% CI 1.15 to 1.49)), rheumatoid arthritis (HR=1.43 (95% CI 1.26 to 1.62) and HR=1.31 (95% CI 1.15 to 1.49)) and inflammatory bowel diseases (HR=1.18 (95% CI 1.06 to 1.32) and HR=1.12 (95% CI 1.01 to 1.25)). The effect of anti-inflammatory treatment was significant in all instances (HR=1.50 (95% CI 1.24 to 1.81); HR=1.47 (95% CI 1.23 to 1.75); HR=1.43 (95% CI 1.19 to 1.73), respectively). The population attributable fractions for all three disorders were 13.4%, 15.7% and 10.7%, respectively. CONCLUSION: Systemic connective tissue disorders and rheumatoid arthritis conferred the highest cardiovascular risk and population impact, followed by inflammatory bowel diseases.
29196382 Relatedness of Antibodies to Peptides Containing Homocitrulline or Citrulline in Patients 2018 Mar OBJECTIVE: Antibodies that target citrullinated protein/peptide (ACPA) and homocitrullinated/carbamylated protein/peptide (AHCPA) are associated with rheumatoid arthritis (RA). The relationship between ACPA and AHCPA remains unclear. We examined the expression and cross-reactivity of these antibodies using citrulline- and homocitrulline-containing synthetic peptides, CitJED and HomoCitJED, respectively, which have equal numbers of citrulline or homocitrulline residues on the same peptide backbone. METHODS: Serum from healthy subjects (n = 51) and patients with RA (n = 137), systemic lupus erythematosus (SLE; n = 37), and psoriatic arthritis (PsA; n = 37) were screened for IgG anti-CitJED and anti-HomoCitJED antibodies by ELISA. Cross-reactivity of these antibodies was examined by inhibition with various concentrations of CitJED and HomoCitJED. RESULTS: Out of 137 patients with RA, antibodies to CitJED and HomoCitJED were detected in 69 (50%) and 78 (57%), respectively. Anti-CitJED and HomoCitJED antibodies were 77% concordant and their levels were strongly correlated [Spearman correlation coefficient (r(s)) = 0.6676]. Sera from 25/27 patients (93%) with RA were inhibited by both CitJED and HomoCitJED with equal or higher affinity for the cognate (homologous) peptide. CONCLUSION: Antibodies to CitJED and HomoCitJED frequently occurred in RA, but were not found in SLE or PsA, suggesting that these antibodies are specific to RA. Cross-reactivity between anti-HomoCitJED and anti-CitJED antibodies suggests that ACPA and AHCPA are derived from the same B cell population and both may contribute to the pathogenesis of RA.
28320444 OX40 signaling is involved in the autoactivation of CD4(+)CD28(-) T cells and contributes 2017 Mar 21 BACKGROUND: CD4(+)CD28(-) T cells exhibit autoreactive potential in autoimmune disorders, including rheumatoid arthritis (RA). It is not well known which costimulator functions as an alternative second signal in the activation of this subset after CD28 expression is downregulated. Tumor necrosis factor receptor superfamily member OX40 is a key costimulator in the activation of T cells. The aim of this study was to investigate the costimulatory effects of OX40 on CD4(+)CD28(-) T cells in autoimmune arthritis. METHODS: Clinical samples were collected from patients with RA and control subjects. Collagen-induced arthritis (CIA) was induced with collagen type II (CII) in DBA/1 mice. The CD4(+)CD28(-)OX40(+) T-cell subset and its cytokine production were detected by flow cytometry. After T-cell purification, adoptive transfer was performed in CIA mice. The regulatory role of OX40 was determined by blocking experiments in vitro and in vivo. RESULTS: OX40 and OX40L were abnormally expressed in patients with RA and CIA mice. Further analysis showed that CD4(+)CD28(-)OX40(+) T cells accumulated in patients with RA and in animal models. These cells produced higher levels of proinflammatory cytokines and were closely correlated with the clinicopathological features of the affected individuals. Adoptive transfer of CII-specific CD4(+)CD28(-)OX40(+) T cells remarkably aggravated arthritic development and joint pathology in CIA mice. Moreover, OX40 blockade significantly reduced the proinflammatory responses and ameliorated arthritis development. CONCLUSIONS: OX40 acts as an alternative costimulator of CD4(+)CD28(-) T cells and plays a pathogenic role in autoimmune arthritic development, suggesting that it is a potential target for immunomodulatory therapy of RA.
28518156 Interleukin 17 is a chief orchestrator of immunity. 2017 May 18 Increased understanding of the biology of interleukin 17 (IL-17) has revealed that this cytokine is a central player in immunity at the sites most exposed to microorganisms. Although it has been strongly associated with immunopathology, IL-17 also has an important role in host defense. The regulation of IL-17 secretion seems to be shared among various cell types, each of which can concomitantly secrete additional products. IL-17 has only modest activity on its own; its impact in immunity arises from its synergistic action with other factors, its self-sustaining feedback loop and, in some cases, its role as a counterpart of interferon-γ (IFN-γ). Together these attributes provide a robust response against microorganisms, but they can equally contribute to immune pathology. Here we focus on a discussion of the role of IL-17 during infection.
28752242 Patients' Understanding and Attitudes Towards Infliximab and Etanercept Biosimilars: Resul 2017 Oct BACKGROUND: Infliximab and etanercept biosimilars present significant potential cost savings to the NHS. Patients need to be involved in the decision to use these medicines but there is limited published literature on their knowledge and attitudes about these biosimilars. OBJECTIVES: The aim of this study was to investigate ankylosing spondylitis and rheumatoid arthritis patients' knowledge and attitudes towards infliximab and etanercept biosimilars in the UK. METHODS: A self-administered web survey was conducted among the members of the National Rheumatoid Arthritis Society and the National Ankylosing Spondylitis Society in the UK between 2 March 2017 and 2 June 2017. RESULTS: A total of 182 patients participated in this survey. The majority of participants (73%) were on etanercept, and 66 and 80% of patients on originator biologic and biosimilars, respectively, understood what biosimilars were. Patients who were currently on biosimilars had greater confidence in their effectiveness and the doctor's decision to initiate than those who were originally on originator biologics that doctors proposed to switch to biosimilars. The majority (82%) of participants on biosimilars thought that biosimilars help to save money for the NHS, while just over half (54%) of participants on the originator biologics thought the cost of treatment should not be considered when prescribing biosimilars. CONCLUSIONS: Survey participants had a good knowledge and understanding of biosimilars. Participants on biosimilars were confident and positive about biosimilars' safety, efficacy and switching, whereas participants on the originator biologics were more reluctant to switch to biosimilars. Those patients who expressed concerns felt that more clinical trials on switching biosimilars, better communication and reassurance by healthcare professional teams and further involvement in decision making would increase their acceptance of biosimilars.
28667024 Unusual Findings in Synovial Fluid Analysis: A Review. 2017 May Synovial fluid analysis is one of the most useful laboratory test in the diagnosis of joint diseases. It allows to determine the degree of synovial inflammation, the presence of pathogenic crystals and microorganisms, and to evaluate the effect of pharmacological treatments as well as the progression of the disease. Synovial fluid therefore represents a precious substrate able to give valuable information from both the clinical and the research points of view.In this educational review we present and discuss some unusual findings, at times associated with rare rheumatic conditions, observed while routine synovial fluid examination is performed. These findings can be highlighted under ordinary or polarized light using simple wet preparations and supravital staining.
28349061 Physicochemical and Biological Characterization of the Proposed Biosimilar Tocilizumab. 2017 HS628 has been developed as a proposed biosimilar product of originator tocilizumab (Actemra®). An extensive physicochemical and biological characterization was conducted to assess similarity between HS628 and originator tocilizumab. The amino acid sequence was shown to be identical between HS628 and originator tocilizumab. The higher order structure was found to be indistinguishable from originator tocilizumab. Concerning purity and heterogeneity, HS628 was demonstrated to have similar posttranslational modifications, charge heterogeneity, size heterogeneity, and glycosylation to originator tocilizumab. Moreover, HS628 exhibited highly similar binding affinity and antiproliferative activity as well as capability of inhibiting STAT3 phosphorylation compared to originator tocilizumab. Taken together, HS628 can be considered as a highly similar molecule to originator tocilizumab in terms of physicochemical and biological properties.
29425654 Anti-inflammatory and anti-arthritic effects of the ethanolic extract of Aralia continenta 2018 Jan 1 BACKGROUND: Blocking the formation and invasive growth of pannus and its secretion of inflammatory cytokines and MMPs is important for treating rheumatoid arthritis. HYPOTHESIS/PURPOSE: Anti-arthritic activity of Aralia continentalis Kitag., an oriental herbal medicine, and the underlying mechanisms involved were investigated. STUDY DESIGN: Anti-inflammatory and anti-nocicpetive activities of the ethanolic extract (50% v/v) of Aralia continentalis Kitag. harvested from Imsil, Korea (ACI) were investigated in IL-1β-stimulated human fibroblast-like synoviocyte (FLS) cells and rodent models of collagen-induced polyarthritis and carrageenan-induced acute paw pain. METHODS: In IL-1β-stimulated FLS cells derived from rheumatoid arthritis patients, the anti-inflammatory activity of ACI was examined by analyzing the expression levels of inflammatory mediators such as TNF-α, IL-6, IL-8, MMP-1, MMP-3, MMP-13, PGE2, and COX-2 using ELISA and RT-PCR analysis. The anti-arthritic activity of ACI was investigated by measuring body weight, squeaking score, paw volume, and arthritis index in collagen-induced polyarthritis mice. The anti-nociceptive activity of ACI was examined in the paw-pressure test and Tail-flick latency test in rats. RESULTS: The ethanolic extract (50% v/v) of ACI reduced the levels of TNF-α, IL-6, IL-8, MMP-1, and MMP-13 secreted by IL-1β-stimulated FLS cells, whereas MMP-3, COX-2, and PGE2 were not significantly affected. ACI inhibited the migration of NF-κB into the nucleus through the inhibition of ERK- and JNK-dependent MAP kinase pathways in IL-1β-stimulated FLS cells. In collagen-induced polyarthritis mice, oral administration of ACI extract (200 mg/kg) significantly alleviated arthritic behaviors. Histological observations of arthritic mouse knees were consistent with their behaviors. The anti-arthritic and anti-inflammatory activities of 200 mg/kg ACI extract were comparable to those of 10 mg/kg prednisolone when administered to mice. However, ACI administration did not significantly affect carrageenan-induced hyperalgesia or thermal nociception in rats. CONCLUSION: These results suggest that the ethanolic extract of ACI have significant anti-inflammatory and anti-arthritic effects in a rodent arthritis model and in IL-1β-stimulated FLS cells. Thus, ACI may be a useful candidate for developing pharmaceuticals or dietary supplements for the treatment of inflammatory arthritis.
29109281 Peptidyl arginine deiminase immunization induces anticitrullinated protein antibodies in m 2017 Nov 21 Autoantibodies to citrullinated proteins (ACPAs) are present in two-thirds of patients with rheumatoid arthritis (RA). ACPAs are produced in the absence of identified T cell responses for each citrullinated protein. Peptidyl arginine deiminase 4 (PAD4), which binds proteins and citrullinates them, is the target of autoantibodies in early RA. This suggests a model for the emergence of ACPAs in the absence of detectable T cells specific for citrullinated antigens: ACPAs could arise because PADs are recognized by T cells, which help the production of autoantibodies to proteins bound by PADs, according to a "hapten/carrier" model. Here, we tested this model in normal mice. C3H are healthy mice whose IEβk chain is highly homologous to the β1 chain HLA-DRB1*04:01, the allele most strongly associated with RA in humans. C3H mice immunized with PADs developed antibodies and T cells to PAD and IgG antibodies to citrullinated fibrinogen peptides, in the absence of a T cell response to fibrinogen. To analyze the MHC background effect on hapten/carrier immunization, we immunized DBA/2 mice (whose IEβd chain is similar to that of HLA-DRB1*04:02, an HLA-DR4 subtype not associated with RA). DBA/2 mice failed to develop antibodies to citrullinated fibrinogen peptides. Thus, T cell immunization to PAD proteins may trigger ACPAs through a hapten/carrier mechanism. This may constitute the basis for a new mouse model of ACPA-positive RA.
28863153 Triple DMARD treatment in early rheumatoid arthritis modulates synovial T cell activation 2017 OBJECTIVES: This study sought to investigate the genome-wide transcriptional effects of a combination of disease modifying anti-rheumatic drugs (tDMARD; methotrexate, sulfasalazine and hydroxychloroquine) in synovial tissues obtained from early rheumatoid arthritis (RA) patients. While combination DMARD strategies have been investigated for clinical efficacy, very little data exists on the potential molecular mechanism of action. We hypothesized that tDMARD would impact multiple biological pathways, but the specific pathways were unknown. METHODS: Paired synovial biopsy samples from early RA patients before and after 6 months of tDMARD therapy were collected by arthroscopy (n = 19). These biopsies as well as those from subjects with normal synovium (n = 28) were profiled by total RNA sequencing. RESULTS: Large differences in gene expression between RA and control biopsies (over 5000 genes) were identified. Despite clinical efficacy, the expression of a restricted set of less than 300 genes was reversed after 6 months of treatment. Many genes remained elevated, even in patients who achieved low disease activity. Interestingly, tDMARD downregulated genes included those involved in T cell activation and signaling and plasmablast/plasma cell differentiation and function. CONCLUSIONS: We have identified transcriptomic signatures that characterize synovial tissue from RA patients with early disease. Analysis after 6 months of tDMARD treatment highlight consistent alterations in expression of genes related to T cell activation and plasmablast/plasma cell differentiation. These results provide novel insight into the biology of early RA and the mechanism of tDMARD action and may help identify novel drug targets to improve rates of treatment-induced disease remission.
28812210 Increased IL-6 expression on THP-1 by IL-34 stimulation up-regulated rheumatoid arthritis 2018 Jan IL-34 is a pleiotropic cytokine, which is a key regulator of monocytes/macrophages and might participate in the pathogenesis of RA. In this study, we aimed to explore the effect of IL-34 on the monocyte-like cell line THP-1 and the quantitative variation of Th17 cells in THP-1 and RA CD4(+)T cells coculture system. CD4(+)T cells were purified from RA PBMC using immunomagnetic beads. THP-1 were cultured with RA CD4(+)T cells. The frequency of Th17 cells was determined by FACS. Fluorscence indensity and expression of ROS were detected by FACS and cell staining, respectively. The expression of IL-6, IL-23, IL-21, TNF-α and IL-1β in the coculture supernatants were detected by ELISA. We found that CSF-1R was constitutively expressed on peripheral monocytes as well as THP-1, but not on the T/B cells. IL-34-CSF-1R binding could activate THP-1 to secret IL-6. IL-34 could up-regulate the numbers of Th17 cells in coculture system, which was possibly via the production of IL-6. We further observed ROS levels were increased in the coculture system. The percentage of Th17 cells was reduced when ROS production was inhibited by NAC, a specific inhibitor of ROS production. In addition, TNFRII antagonist but not IL-1βR antagonist could restrict the production of ROS, expression of IL-6 and generation of Th17 cells. In conclusion, IL-34-stimulated THP-1 can produce higher levels of ROS, which promoted IL-6 secretion and up-regulated Th17 cells. Our study suggests a novel mechanistic insight into how the interaction of IL-34-stimulated monocytes and CD4(+)T cells participates in the RA pathogenesis.
27623446 Cell-contact-dependent activation of CD4(+) T cells by adhesion molecules on synovial fibr 2017 May OBJECTIVE: To determine how cell-cell contact with synovial fibroblasts (SF) influence on the proliferation and cytokine production of CD4(+ )T cells. METHODS: Naïve CD4(+ )T cells were cultured with SF from rheumatoid arthritis patients, stimulated by anti-CD3/28 antibody, and CD4(+ )T cell proliferation and IFN-γ/IL-17 production were analyzed. To study the role of adhesion molecules, cell contact was blocked by transwell plate or anti-intracellular adhesion molecule-1 (ICAM-1)/vascular cell adhesion molecule-1(VCAM-1) antibody. To study the direct role of adhesion molecules for CD4(+ )T cells, CD161(+ )or CD161(-) naïve CD4(+ )T cells were stimulated on plastic plates coated by recombinant ICAM-1 or VCAM-1, and the source of IFN-γ/IL-17 were analyzed. RESULTS: SF enhanced naïve CD4(+ )T cell proliferation and IFN-γ/IL-17 production in cell-contact and in part ICAM-1-/VCAM-1-dependent manner. Plate-coated ICAM-1 and VCAM-1 enhanced naïve CD4(+ )T cell proliferation and IFN-γ production, while VCAM-1 efficiently promoting IL-17 production. CD161(+ )naïve T cells upregulating LFA-1 and VLA-4 were the major source of IFN-γ/IL-17 upon interaction with ICAM-1/VCAM-1. CONCLUSION: CD4(+ )T cells rapidly expand and secrete IFN-γ/IL-17 upon cell-contact with SF via adhesion molecules. Interfering with ICAM-1-/VCAM-1 may be beneficial for inhibiting RA synovitis.
28478516 Tim3(+) Foxp3 (+) Treg Cells Are Potent Inhibitors of Effector T Cells and Are Suppressed 2017 Aug Rheumatoid arthritis (RA) is a chronic autoimmune disorder. Earlier studies have demonstrated that regulatory T (Treg) cells, the main cell type mediating immune tolerance, appeared to be enriched in the inflamed synovial tissues. It is still unclear why the Treg cells in RA patients are unable to limit exacerbated inflammation. Here, we found that the frequency of Tim3(+)Foxp3(+) Treg cells, which were potent suppressors of proinflammatory responses, was downregulated in RA patients. Reduction in Tim3(+)Foxp3(+) Treg frequency was correlated with increased RA disease activity. Furthermore, we observed that Tim3(+)Foxp3(+) Tregs were expressed more interleukin (IL)-10 than Tim3(-)Foxp3(+) Tregs. CD4(+)CD25(+)Tim3(+) T cells had higher capability of inhibiting interferon (IFN)-γ and tumor necrosis factor (TNF)-α secretion from T cells and peripheral blood mononuclear cells (PBMCs) than CD4(+)CD25(+)Tim3(-) T cells. Compared to that in healthy individuals, CD4(+)CD25(+) T cells in RA patients were less potent in suppressing IFN-γ and TNF-α production from PBMCs. Blocking Tim3 on CD4(+)CD25(+) T cells from healthy controls resulted in an elevation of IFN-γ and TNF-α production from PBMCs, suggesting that Tim3 expression on CD4(+)CD25(+) T cells was required for optimal Treg function. However, this phenomenon was not observed in RA patients. In conclusion, our study suggested that the CD4(+)CD25(+)Foxp3(+) Treg cells from RA patients demonstrated a reduction of Tim3 and were less functional than Treg cells from healthy controls in a Tim3-related manner.
29447631 Does daily folic acid supplementation reduce methotrexate efficacy? 2017 Nov 15 Methotrexate is a mainstay treatment for autoimmune and inflammatory conditions in the field of Dermatology. However, in some patients, its use is associated with significant side effects and toxicity. Folate supplementation with either folic acid or folinic acid often mitigates side effects and reduces the incidence of systemic toxicity related to methotrexate. Although the value of methotrexate is clear, debate remains about folate supplementation. There is little agreement about the proper dosing or frequency of folate supplementation as many believe that daily folate supplementation can reduce methotrexate efficacy. Although daily use of folic acid does not appear to affect methotrexate efficacy, dosing of folinic acid close to methotrexate administration may hinder methotrexate efficacy. Therefore, folic acid should be used daily with methotrexate to ameliorate side effects, whereas folinic acid should only be used for methotrexate toxicity.
27856432 Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatme 2017 May OBJECTIVES: To compare efficacy and safety of sarilumab monotherapy with adalimumab monotherapy in patients with active rheumatoid arthritis (RA) who should not continue treatment with methotrexate (MTX) due to intolerance or inadequate response. METHODS: MONARCH was a randomised, active-controlled, double-blind, double-dummy, phase III superiority trial. Patients received sarilumab (200 mg every 2 weeks (q2w)) or adalimumab (40 mg q2w) monotherapy for 24 weeks. The primary end point was change from baseline in 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) at week 24. RESULTS: Sarilumab was superior to adalimumab in the primary end point of change from baseline in DAS28-ESR (-3.28 vs -2.20; p<0.0001). Sarilumab-treated patients achieved significantly higher American College of Rheumatology 20/50/70 response rates (sarilumab: 71.7%/45.7%/23.4%; adalimumab: 58.4%/29.7%/11.9%; all p≤0.0074) and had significantly greater improvement in Health Assessment Questionnaire-Disability Index (p=0.0037). Importantly, at week 24, more patients receiving sarilumab compared with adalimumab achieved Clinical Disease Activity Index remission (7.1% vs 2.7%; nominal p=0.0468) and low disease activity (41.8% vs 24.9%; nominal p=0.0005, supplemental analysis). Adverse events occurred in 63.6% (adalimumab) and 64.1% (sarilumab) of patients, the most common being neutropenia and injection site reactions (sarilumab) and headache and worsening RA (adalimumab). Incidences of infections (sarilumab: 28.8%; adalimumab: 27.7%) and serious infections (1.1%, both groups) were similar, despite neutropenia differences. CONCLUSIONS: Sarilumab monotherapy demonstrated superiority to adalimumab monotherapy by improving the signs and symptoms and physical functions in patients with RA who were unable to continue MTX treatment. The safety profiles of both therapies were consistent with anticipated class effects. TRIAL REGISTRATION NUMBER: NCT02332590.
28468794 Effect of methotrexate discontinuation on efficacy of seasonal influenza vaccination in pa 2017 Sep OBJECTIVE: To investigate whether temporary discontinuation of methotrexate (MTX) improves the efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis (RA). METHODS: In this prospective randomised parallel-group trial, patients with RA taking stable dose of MTX were randomly assigned at a ratio of 1:1:1:1 to continue MTX (group 1), suspend MTX for 4 weeks before vaccination (group 2), suspend MTX for 2 weeks before and 2 weeks after vaccination (group 3) or suspend MTX for 4 weeks after vaccination (group 4). All participants were vaccinated with trivalent influenza vaccine containing H1N1, H3N2 and B-Yamagata. The primary outcome was frequency of satisfactory vaccine response (≥4-fold titre increase 4 weeks postvaccination). Secondary endpoints included fold change in antibody titres from baseline. RESULTS: The per-protocol population consisted of 199 patients (n=54, 44, 49 and 52 in groups 1, 2, 3 and 4, respectively). Group 3 achieved higher satisfactory vaccine response against all three antigens than group 1 (51.0% vs 31.5%, p=0.044). The anti-H3N2 antibody fold increase (95% CI) was significantly higher in groups 3 and 4 (12.2 (8.4 to 17.5), p <0.001 and 10.0 (6.8 to 14.8), p=0.043, respectively) than group 1 (5.9 (4.3 to 8.1)). The anti-B-Yamagata antibody responses of groups 3 and 4 were higher (4.7 (3.3 to 6.7), p=0.048; 6.1 (4.2 to 8.8), p <0.001, respectively) than group 1 (2.9 (2.2 to 3.8)). RA flare occurred in 24.1%, 21.2%, 34.1% and 38.8% in groups 1, 2, 3 and 4, respectively (p=NS). CONCLUSIONS: Temporary MTX discontinuation improves the immunogenicity of seasonal influenza vaccination in patients with RA. TRIAL REGISTRATION: Trial registration number is: www.clinicaltrials.gov, NCT02748785.
28994615 MTRR A66G, RFC1 G80A, and MTHFR C677T and A1298C Polymorphisms and Disease Activity in Mex 2017 Nov AIM: To investigate the relationships of polymorphisms in genes whose protein products are related in the metabolic pathway of folic acid, particularly MTRR A66G, RFC1 G80A, and MTHFR C677T and A1298C, and disease activity in Mexican patients with rheumatoid arthritis (RA) treated with methotrexate (MTX). MATERIALS AND METHODS: Sixty-eight patients with RA were included in the study who were being treated with MTX, either with or without other drugs. In addition to general data, disease activity was measured by the disease activity score 28 (DAS28). Single nucleotide polymorphisms (SNPs) genotyping was performed by allelic discrimination using real-time polymerase chain reaction. RESULTS: Differences in genotype (homozygotic or heterozygotic for each allele), allele distributions, and phenotype were not statistically different between the RA group and control populations. We did not find any association between the studied polymorphisms and disease activity nor with the intragroup variables (e.g., clinical activity, body mass index, and single- or combined-drug treatment) or between genetic markers; we also did not find any association within the RA group or between the RA group and control populations. CONCLUSION: Additional studies of more polymorphisms related to this or other metabolic pathways are required to determine the influence of genetics on disease activity in RA.
28455435 CD40L-Dependent Pathway Is Active at Various Stages of Rheumatoid Arthritis Disease Progre 2017 Jun 1 The inflammatory CD40-CD40L pathway is implicated in various autoimmune diseases, but the activity status of this pathway in various stages of rheumatoid arthritis (RA) progression is unknown. In this study, we used gene signatures of CD40L stimulation derived from human immature dendritic cells and naive B cells to assess the expression of CD40-downstream genes in synovial tissues from anti-citrullinated protein Ab-positive arthralgia, undifferentiated arthritis (UA), early RA, and established RA cohorts in comparison with healthy donors. Interestingly, the expression of CD40LG and active full-length CD40 was increased in the disease tissues, whereas that of a dominant-negative CD40 isoform was decreased. Gene set variation analysis revealed that CD40L-responsive genes in immature dendritic cells and naive B cells were significantly enriched in synovial tissues from UA, early RA, and established RA patients. Additionally, CD40L-induced naive B cell genes were also significantly enriched in synovial tissues from arthralgia patients. In our efforts to characterize downstream mediators of CD40L signaling, we have identified GPR120 and KDM6B as novel components of the pathway. In conclusion, our data suggest that therapeutic CD40-CD40L blocking agents may prove efficacious not only in early and established RA, but also in inhibiting the progression of the disease from arthralgia or UA to RA.
28151455 Association of human leukocyte antigen DRB1 with anti-cyclic citrullinated peptide autoant 2017 Jan BACKGROUND: The genetic association between human leukocyte antigen (HLA)-DRB1 alleles and the risk of development of autoantibodies has been investigated, but there are few studies from the Gulf region. OBJECTIVES: To investigate the association between the HLA-DRB1 shared epitope and the risk for development of autoantibodies in rheumatoid arthritis (RA) patients in a Saudi population. DESIGN: Analytical cross-sectional study. SETTING: Tertiary care hospital in Riyadh, Saudi Arabia. PATIENTS AND METHODS: We enrolled consecutive Saudi RA patients attending the rheumatology clinic between January and April 2015. Previously published data on HLA typing on unmatched healthy controls were used for comparison. HLA typing was performed using sequence-specific oligonucleotide probes (SSOP). Rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, and antinuclear antibodies (ANA) were also measured. Logistic regression analysis was used to study the autoantibodies as possible explanatory variables for the presence of the HLA-DRB1 shared epitope. MAIN OUTCOME MEASURE(S): The association between the presence of the shared epitope and the risk of developing anti-CCP antibodies, ANA, and RF. RESULTS: In 76 patients with RA, carrying the shared epitope was associated with a significantly higher risk of having RA [OR=2.65, 95% CI (1.42-4.94), P=.0009]. However, only HLA-DRB1*04:05 was significantly as.sociated with RA [OR=3.73, 95% CI (1.61-8.96), Pc=.016]. In the logistic regression analysis, only anti-CCP was significantly associated with the shared epitope [OR=14.51, 95% CI (1.53-137.49), P=.02]. CONCLUSIONS: Our analysis indicates that the presence of the HLA-DRB1 shared epitope is strongly associated with the development of anti-CCP antibodies in Saudi patients with RA. LIMITATIONS: A larger sample size is needed to confirm our finding.