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ID PMID Title PublicationDate abstract
26849368 Changes in Soluble CD18 in Murine Autoimmune Arthritis and Rheumatoid Arthritis Reflect Di 2016 INTRODUCTION: In rheumatoid arthritis (RA) immune activation and presence of autoantibodies may precede clinical onset of disease, and joint destruction can progress despite remission. However, the underlying temporal changes of such immune system abnormalities in the inflammatory response during treat-to-target strategies remain poorly understood. We have previously reported low levels of the soluble form of CD18 (sCD18) in plasma from patients with chronic RA and spondyloarthritis. Here, we study the changes of sCD18 before and during treatment of early RA and following arthritis induction in murine models of rheumatoid arthritis. METHODS: The level of sCD18 was analyzed with a time-resolved immunoflourometric assay in 1) plasma from early treatment naïve RA patients during a treat-to-target strategy (the OPERA cohort), 2) plasma from chronic RA patients, 3) serum from SKG and CIA mice following arthritis induction, and 4) supernatants from synovial fluid mononuclear cells (SFMCs) and peripheral blood mononuclear cells (PBMCs) from 6 RA patients cultured with TNFα or adalimumab. RESULTS: Plasma levels of sCD18 were decreased in chronic RA patients compared with early RA patients and in early RA patients compared with healthy controls. After 12 months of treatment the levels in early RA patients were similar to healthy controls. This normalization of plasma sCD18 levels was more pronounced in patients with very early disease who achieved an early ACR response. Plasma sCD18 levels were associated with radiographic progression. Correspondingly, the serum level of sCD18 was decreased in SKG mice 6 weeks after arthritis induction compared with healthy littermates. The sCD18 levels in both SKG and CIA mice exhibited a biphasic course after arthritis induction with an initial increase above baseline followed by a decline. Shedding of CD18 from RA SFMC and RA PBMC cultures was increased by TNFα and decreased by adalimumab. CONCLUSIONS: The plasma sCD18 levels were altered in patients with RA, in mice with autoimmune arthritis and in cell cultures treated with TNFα and adalimumab. Decreased levels of plasma sCD18 could reflect autoimmunity in transition from early to chronic disease and normalization in response to treatment could reflect autoimmunity in remission.
26740821 Patient and clinician views on the quality of foot health care for rheumatoid arthritis ou 2016 BACKGROUND: Feet are often the first site of joint involvement in rheumatoid arthritis (RA) and get progressively worse if unmanaged, leading to permanent disability and negatively impacting patients' quality of life. Podiatrists are specialists in the assessment, diagnosis and management of foot and ankle problems, however, RA outpatients often rely on referral from rheumatology clinicians to gain access to musculoskeletal podiatry services on the UK National Health Service (NHS). Therefore, the aim of this evaluation was to identify the foot health needs of rheumatoid arthritis patients and if they are being met by rheumatology clinicians. METHODS: A mixed methods approach was used: collecting qualitative data from patients and quantitative data from clinicians. Two focus groups were conducted with nine RA patients from a tertiary rheumatology outpatient clinic in the UK and the data were thematically analysed to inform a clinician survey. Thirteen rheumatology clinicians, from the same centre, completed the online survey. Resultant data were analysed to produce descriptive statistics. RESULTS: Patient focus group data generated four main themes: (1) need for foot health information, (2) feet ignored during routine consultations, (3) frequency of foot examination and (4) access to podiatry. Survey data highlighted that (i) 69-85 % of clinicians provided patients with foot health information sometimes, (ii) feet were examined in 47 % of routine consultations, (iii) 54 % of clinicians did not examine feet routinely because they are not included in the disease activity score with 28 joints (DAS-28), (iv) 31 % of clinicians referred patients to podiatry upon RA diagnosis, (v) 0 % of clinicians referred patients to podiatry for periodic review, (vi) 54 % of clinicians believed patients will self-report foot problems and (vii) 62 % of clinicians felt competent in foot examination. CONCLUSIONS: RA patients' foot health needs were not being fully met by rheumatology clinicians. Patients want foot health information and easy access to podiatry services. Rheumatology outpatient consultations need to have a wider focus than the DAS-28 and incorporate foot examination as standard. Clinicians need to ensure they have sufficient training and follow current national foot health guidance to provide optimal foot health care and outcomes for their RA patients.
27143819 IL-32: A Novel Pluripotent Inflammatory Interleukin, towards Gastric Inflammation, Gastric 2016 A vast variety of nonstructural proteins have been studied for their key roles and involvement in a number of biological phenomenona. Interleukin-32 is a novel cytokine whose presence has been confirmed in most of the mammals except rodents. The IL-32 gene was identified on human chromosome 16 p13.3. The gene has eight exons and nine splice variants, namely, IL-32α, IL-32β, IL-32γ, IL-32δ, IL-32ε, IL-32ζ, IL-32η, IL-32θ, and IL-32s. It was found to induce the expression of various inflammatory cytokines including TNF-α, IL-6, and IL-1β as well as macrophage inflammatory protein-2 (MIP-2) and has been reported previously to be involved in the pathogenesis and progression of a number of inflammatory disorders, namely, inflammatory bowel disease (IBD), gastric inflammation and cancer, rheumatoid arthritis, and chronic obstructive pulmonary disease (COPD). In the current review, we have highlighted the involvement of IL-32 in gastric cancer, gastric inflammation, and chronic rhinosinusitis. We have also tried to explore various mechanisms suspected to induce the expression of this extraordinary cytokine as well as various mechanisms of action employed by IL-32 during the mediation and progression of the above said problems.
27267896 The isotype repertoire of antibodies against novel UH-RA peptides in rheumatoid arthritis. 2016 Jun 7 BACKGROUND: Recently, autoantibodies against novel UH-RA peptides (UH-RA.1 and UH-RA.21) were identified as candidate biomarkers for patients with rheumatoid arthritis (RA) who are seronegative for the current diagnostic markers rheumatoid factor and anticitrullinated protein antibodies. Previously, screening for anti-UH-RA autoantibodies was based on measuring the immunoglobulin (Ig) G response. We aimed to investigate whether measurement of other isotypes could improve the performance of diagnostic testing. In addition, assigning the isotype profile might provide valuable information on effector functions of the antibodies. METHODS: The isotype profile of antibodies against UH-RA.1 and UH-RA.21 was studied. The IgG, IgM, and IgA classes, together with the 4 different IgG subclasses, were determined in 285 patients with RA, 88 rheumatic control subjects, and 90 healthy control subjects. RESULTS: Anti-UH-RA.1 antibodies were primarily of the IgM isotype and twice as prevalent as IgG (IgG3-dominated) and IgA. RA sensitivity when testing for anti-UH-RA.1 IgM was shown to be higher than when testing for the IgG isotype: 18 % versus 9 % sensitivity when RA specificity was set to 90 %. Within antibodies against UH-RA.21, IgG and IgA were more common than IgM. Different anti-UH-RA.21 IgG subclasses were found, with the highest prevalence found for IgG2. Combined testing for IgG and IgA slightly increased RA sensitivity of UH-RA.21-specific antibody testing to 27 % compared with solely testing for IgG (23 %). Notably, a higher number of anti-UH-RA.21 antibody isotypes was related to increased levels of erythrocyte sedimentation rate. Finally, for both antibody responses, the full antibody isotype use was demonstrated in early and seronegative disease. CONCLUSIONS: The isotype distribution of anti-UH-RA.1 and anti-UH-RA.21 antibodies was successfully outlined, and, for antibodies against UH-RA.1, we found that isotype-specific testing might have implications for diagnostic testing. The exact mechanisms by which the different antibody isotypes act still have to be unraveled.
26628607 Effect of Milnacipran on Pain in Patients with Rheumatoid Arthritis with Widespread Pain: 2016 Jan OBJECTIVE: Clinical trials have shown that serotonin norepinephrine reuptake inhibitors, such as milnacipran, decrease pain in noninflammatory pain conditions such as fibromyalgia and osteoarthritis. We examined the effect of milnacipran on self-reported pain intensity and experimental pain sensitivity among patients with rheumatoid arthritis (RA) with widespread pain and stable RA disease activity. METHODS: In this double-blind, crossover study, patients with RA with widespread pain, receiving a stable treatment regimen, were randomized (by a random number generator) to receive milnacipran 50 mg twice daily or placebo for 6 weeks, followed by a 3-week washout and crossed over to the other arm for the remaining 6 weeks. The primary outcome was change in average pain intensity, assessed by the Brief Pain Inventory short form. The sample size was calculated to detect a 30% improvement in pain with power = 0.80 and α = 0.05. RESULTS: Of the 43 randomized subjects, 41 received the study drug, and 32 completed the 15-week study per protocol. On a 0-10 scale, average pain intensity decreased by 0.39 (95% CI -1.27 to 0.49, p = 0.37) more points during 6 weeks of milnacipran treatment compared with placebo. In the subgroup of subjects with swollen joint count ≤ 1, average pain intensity decreased by 1.14 more points during 6 weeks of milnacipran compared with placebo (95% CI -2.26 to -0.01, p = 0.04). Common adverse events included nausea (26.8%) and loss of appetite (9.7%). CONCLUSION: Compared with placebo, milnacipran did not improve overall, self-reported pain intensity among subjects with widespread pain receiving stable RA medications. TRIAL REGISTRATION: ClinicalTrials.gov NCT01207453.
25218914 Comprehensive review of genetic association studies and meta-analysis on miRNA polymorphis 2016 Jan BACKGROUND: MicroRNAs (miRNAs), small RNA molecules, play a role in the development and differentiation of immune cells in both innate and adaptive immune responses. Our study was aimed to investigate the association between three miRNA polymorphism and rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) by using meta-analysis approach. METHODS: A PubMed database search was conducted during August 2013 to identify case-control studies of miRNAs and RA or SLE risk. Two authors independently extracted information on the study design, the characteristics of the study participants, exposure and outcome assessments. The fix-effects and random-effects models were used for the risk estimates by Stata 11.0 software. RESULTS: Our meta-analysis of six case-control studies involving a total of 998 RA cases and 1493 controls identified no significant association between mir-146a rs2910164 and RA, with an overall OR of 0.843 (95% CI=0.642-1.105; CC vs. GG). No association was observed in three studies with a total of 1532 cases and 2168 controls between miR-146a rs2910164 and SLE risk (OR=0.911, 95% CI=0.710-1.171; CC vs. GG). Three studies with a total of 529 cases and 595 controls evaluated the mir-499 rs3746444 polymorphism and its association with RA. There was a decreased overall risk of RA under the allelic and genotypic models [OR=0.616, 95% CI=0.384-0.981, (T vs. C allele) and OR=0.386, 95% CI=0.226-0.659, (TT vs. CC)]. Two studies with 4826 cases and 4181 controls evaluated miR-146a rs57095329 and its association with SLE. There was a significant association between miR-146a rs57095329 and SLE (OR=1.263, 95% CI=1.136-1.405, G vs. A allele). CONCLUSIONS: The present meta-analysis suggests important roles for the mir-499 rs3746444 polymorphism in RA, especially in the Caucasian population and for miR-146a rs57095329 polymorphism in SLE. Further studies with large sample size are needed to confirm these associations.
25790669 [The correlation study on syndrome differentiation of rheumatoid arthritis and joint high 2015 Jan OBJECTIVE: To observe the differential effect of joint ultrasound on the syndrome differentiation of rheumatoid arthritis (RA) by observing the high frequency ultrasound performances among inactive stage and different syndromes in active stage. METHODS: Totally 83 RA patients in the active stage were assigned to the dampness heat syndrome group (DHS, 59 cases)and the cold dampness syndrome group (CDS, 24 cases) according to Chinese medicine (CM) syndrome typing. Besides, 20 RA patients in the remission stage were recruited as the control group (abbreviated as the remission group). By using high frequency ultrasound and power Doppler ultrasound technology, a comparative observation of synovitis, tenosynovitis, synovial blood flow, and bone erosion in the 2nd-5th metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, wrist joints, knee joints, the second and the fifth metatarsophalangeal (MTP) joints (a total of 24 joints) was performed in all patients. Correlation analyses were performed between the ultrasound performance, laboratory indices, and the disease activity. Ultrasound data of each RA patient were analyzed by their total scores. Χ2 test was used for enumeration data. The measurement data was expressed as x ± s. One-way ANOVA was used for data of normal distribution, while non- parametric test was used for data of non-normal distribution. Correlation analysis of two variables was performed for clinical indicators and ultrasound indicators. Its significance was detected using Pearson correlation. RESULTS: Compared with the remission group, the severity degree of synovitis, tenosynovitis, synovial blood flow, and bone erosion significantly increased in the DHS group (P < 0.01). There was statistical difference in ESR, CRP, anti-CCP, DAS28 score, and the positive rate of RF (P < 0.05, P < 0.01). There was statistical difference in the severity degree of synovitis and synovial blood flow, and DAS28 score in the CDS group (P < 0.05). Compared with the CDS group, there was statistical difference in the four ultrasound indices (P < 0.05, P < 0.01), ESR, CRP, anti-CCP, DAS28 score, and the positive rate of RF in the DHS group (P < 0.05, P < 0.01). There was no statistical difference in G, IgG, IgA, or IgM among the three groups (P > 0.05). There existed positive correlation between ESR and the synovitis degree, synovial blood flow, and bone erosion in the DHS group (r = 0.444, 0.397, 0.486, P < 0.05).There existed positive correlation between ESR and the synovitis degree, bone erosion, and synovial blood flow in the DHS group (r = 0.378, 0.270, P < 0.05). There existed positive correlation between the DAS28 score and the synovitis degree and synovial blood flow in the DHS group (r = 0.304, 0.351, P < 0.05). CONCLUSIONS: The inflammation degree was the most severe in RA patients of DHS. High frequency ultrasound could provide better evidence for Chinese medical syndrome differentiation of RA patients.
27680540 Rheumatologists' adherence to a disease activity score steered treatment protocol in early 2017 Feb To compare rheumatologists' adherence to treatment protocols for rheumatoid arthritis (RA) targeted at Disease Activity Score (DAS) ≤2.4 or <1.6. The BeSt-study enrolled 508 early RA (1987) patients targeted at DAS ≤2.4. The IMPROVED-study included 479 early RA (2010) and 122 undifferentiated arthritis patients targeted at DAS <1.6. We evaluated rheumatologists' adherence to the protocols and assessed associated opinions and conditions during 5 years. Protocol adherence was higher in BeSt than in IMPROVED (86 and 70 %), with a greater decrease in IMPROVED (from 100 to 48 %) than in BeSt (100 to 72 %). In BeSt, 50 % of non-adherence was against treatment intensification/restart, compared to 63 % in IMPROVED and 50 vs. 37 % were against tapering/discontinuation. In both studies, non-adherence was associated with physicians' disagreement with DAS or with next treatment step and if patient's visual analogue scale (VAS) for general health was ≥20 mm higher than the physician's VAS. In IMPROVED, also discrepancies between swelling, pain, erythrocyte sedimentation rate, and VASgh were associated with non-adherence. Adherence to DAS steered treatment protocols was high but decreased over 5 years, more in a DAS <1.6 steered protocol. Non-adherence was more likely if physicians disagreed with DAS or next treatment step. In the DAS <1.6 steered protocol, non-adherence was also associated with discrepancies between subjective and (semi)objective disease outcomes, and often against required treatment intensification. These results may indicate that adherence to DAS-steered protocols appears to depend in part on the height of the target and on how physicians perceive the DAS reflects RA activity.
27882446 Impact of the size and number of swollen joints on serum C-reactive protein level and eryt 2017 Feb No studies have yet reported the influence of swelling in individual joints on serum C-reactive protein and erythrocyte sedimentation rate. To examine this association, we used data from the NinJa registry, the largest registry of rheumatoid arthritis patients in Japan. Sixty-six palpable joints were categorized by size into three groups (small, medium-sized, and knees) with surface area cutoffs of 10 and 100 cm(2). Of 10,720 cases registered in NinJa in 2012, 8444 cases with either no swollen joints or swelling limited to one joint-size category were analyzed. Groups with larger numbers of swollen joints showed higher levels of both markers in each joint-size category. Groups with larger swollen joints had higher levels of both markers compared with groups with the same number of (smaller) swollen joints. Linear regression revealed that the increments of C-reactive protein (mg/dL/joint) and erythrocyte sedimentation rate (mm/1 h/joint) were 0.056 and 0.89, 0.24 and 5.0, and 0.46 and 8.9 for small and medium-sized joints and knee joints, respectively. The levels of systemic inflammation markers increased with the involvement of larger and/or more joints. These results were successfully illustrated by the use of large-scale data, which eliminated wide intragroup scattering of the marker values.
27605495 Patients' Perspectives on the Psychological Impact of Inflammatory Arthritis and Meeting t 2017 Sep OBJECTIVES: Psychological support for inflammatory arthritis is recommended in rheumatology treatment guidelines. Previous research found that high numbers of patients would access such support but that provision is often inconsistent and inadequate. The present study explored patients' perspectives on the nature of the psychological impact of inflammatory arthritis and how to meet the associated support needs. METHODS: A cross-sectional survey was conducted, using questionnaires which included three open-ended questions about helpful and unhelpful psychological support. The questionnaires were administered to 1,080 patients at six regional rheumatology units across England, and 1,200 members of a national patient charity. RESULTS: A total of 1,210 (53%) patients completed the questionnaire, with 779 (64%) responding to the open-ended questions: 80% female; mean age 59 years (12.6); disease duration <5 years (40%), 5-10 years (20%), >10 years (40%). Data were analysed using a hybrid content analysis. Four categories emerged: challenges of an altered life course (negative emotions, isolation and loneliness, a dysfunctional body, loss, strained relationships, and fears for the future); poor communication (feeling unheard, clinicians' reluctance to address psychological issues, a lack of help to manage pain and fatigue, and struggling to ask for help); understood by others (sharing with people who have arthritis, supportive family and friends, whole team support, and understanding from clinicians); and acquiring strategies (ways of coping). CONCLUSIONS: Psychological distress was commonplace, and often attributed to fatigue and pain. In addition to peers and family, patients looked to the rheumatology team for validation and support. Further research will address the skills training needs of rheumatology teams to meet patients' psychological support requirements.
27140173 Integrative genomic deconvolution of rheumatoid arthritis GWAS loci into gene and cell typ 2016 Apr 30 BACKGROUND: Although genome-wide association studies (GWAS) have identified over 100 genetic loci associated with rheumatoid arthritis (RA), our ability to translate these results into disease understanding and novel therapeutics is limited. Most RA GWAS loci reside outside of protein-coding regions and likely affect distal transcriptional enhancers. Furthermore, GWAS do not identify the cell types where the associated causal gene functions. Thus, mapping the transcriptional regulatory roles of GWAS hits and the relevant cell types will lead to better understanding of RA pathogenesis. RESULTS: We combine the whole-genome sequences and blood transcription profiles of 377 RA patients and identify over 6000 unique genes with expression quantitative trait loci (eQTLs). We demonstrate the quality of the identified eQTLs through comparison to non-RA individuals. We integrate the eQTLs with immune cell epigenome maps, RA GWAS risk loci, and adjustment for linkage disequilibrium to propose target genes of immune cell enhancers that overlap RA risk loci. We examine 20 immune cell epigenomes and perform a focused analysis on primary monocytes, B cells, and T cells. CONCLUSIONS: We highlight cell-specific gene associations with relevance to RA pathogenesis including the identification of FCGR2B in B cells as possessing both intragenic and enhancer regulatory GWAS hits. We show that our RA patient cohort derived eQTL network is more informative for studying RA than that from a healthy cohort. While not experimentally validated here, the reported eQTLs and cell type-specific RA risk associations can prioritize future experiments with the goal of elucidating the regulatory mechanisms behind genetic risk associations.
27053094 Frequency of methotrexate intolerance in rheumatoid arthritis patients using methotrexate 2016 May The objective of the study was to determine the frequency of methotrexate intolerance in rheumatoid arthritis (RA) patients by applying the methotrexate intolerance severity score (MISS) questionnaire and to see the effect of dose and concomitant use of other disease-modifying antirheumatic drugs (DMARDS) on methotrexate (MTX) intolerance. For the descriptive study, non-probability sampling was carried out in the Female Rheumatology Department of Fauji Foundation Hospital (FFH), Rawalpindi, Pakistan. One hundred and fifty diagnosed cases of RA using oral MTX were selected. The MISS questionnaire embodies five elements: abdominal pain, nausea, vomiting, fatigue and behavioural symptoms. The amplitude of each element was ranked from 0 to 3 being no complaint (0 points), mild (1 point), moderate (2 points) and severe (3 points). A cut-off score of 6 and above ascertained intolerance by the physicians. A total of 33.3 % of the subjects exhibited MTX intolerance according to the MISS questionnaire. Out of which, the most recurring symptom of all was behavioural with a value of 44 % whereas vomiting was least noticeable with a figure of 11 %. About 6.6 % of the women with intolerance were consuming DMARDs in conjunction with MTX. Those using the highest weekly dose of MTX (20 mg) had supreme intolerance with prevalence in 46.2 % of the patients. The frequency of intolerance decreased with a decrease in weekly dose to a minimum of 20 % with 7.5 mg of MTX. MTX intolerance has moderate prevalence in RA patients and if left undetected, the compliance to use of MTX as a first-line therapy will decrease. Methotrexate intolerance is directly proportional to the dose of MTX taken. Also, there is no upstroke seen in intolerance with the use of other disease-modifying agents.
27643491 Immunogenicity and Lupus-Like Autoantibody Production Can Be Linked to Each Other along Wi 2016 Besides anti-drug antibodies, anti-nuclear antibodies and anti-DNA antibodies are often induced in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors. We examined the association between immunogenicity, autoantibody production, and serum cytokine profiles in patients with rheumatoid arthritis treated with infliximab. Japanese patients with rheumatoid arthritis (n = 57) were retrospectively examined. Serum trough levels of infliximab, anti-drug antibody, anti-nuclear antibody, and anti-DNA (Farr), anti-single-stranded DNA and anti-double-stranded DNA antibodies were measured. Interleukin-6, interferon-γ, interferon-α, and B-cell activating factor levels were also measured in the same sera. Then, we validated the association between anti-drug antibody and these serum markers along with clinical response to infliximab. Anti-drug antibodies developed in twenty-one patients (36.8%), whose serum trough levels of infliximab were significantly lower than those in anti-drug antibody-negative patients (0.09 ± 0.03 vs. 2.48 ± 0.326 μg/mL, p < 0.0001). There were no significant differences in clinical backgrounds between the two groups. The anti-drug antibody-positive patients were more likely to develop anti-nuclear antibody titers of ≥ ×160 compared to the negative patients (14 to 57% vs. 17 to 33%). In addition, anti-DNA antibodies (Farr) (from 1.5 ± 0.4 to 35 ± 17 IU/mL, p = 0.0001), especially IgM-anti-double stranded DNA antibody (from 5.1 ± 0.7 to 41 ± 8.9 IU/mL, p < 0.0001), and IgG-anti-single stranded DNA antibody (from 13 ± 1.1 to 35 ± 13, p = 0.0145) were significantly increased in anti-drug antibody-positive but not in negative patients. Moreover, the anti-drug antibody-positive, but not the negative patients, showed significant increased levels of interferon-α (from 248.7 ± 102.3 to 466.8 ± 135.1 pg/mL, p = 0.0353) and B-cell activating factor (from 1073 ± 75.1 to 1387 ± 136.5 pg/mL, p = 0.0208) following infliximab treatment. The development of anti-drug antibody against infliximab and lupus-like autoantibody production in patients with rheumatoid arthritis treated with infliximab can be linked each other along with increased lupus-associated cytokine levels including type I interferons.
27960151 IL-35 Inhibits Angiogenesis through VEGF/Ang2/Tie2 Pathway in Rheumatoid Arthritis. 2016 BACKGROUND/AIMS: The pro-angiogenic factors vascular endothelial growth factor (VEGF) and angiopoietins (Angs) play a prominent role in synovial angiogenesis, an early and critical event in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)-35 is an anti-inflammatory cytokine that attenuates collagen-induced arthritis, however, the mechanisms involved are not fully understood. METHODS: The effects of IL-35 on endothelial cell migration, adhesion, and tube formation were examined using human umbilical vein endothelial cells (HUVEC) in vitro. The effects of IL-35 on vessel formation in vivo were examined using a murine Matrigel plugs model. MMP2/MMP9 and IL-6/IL-8 secretion were assessed by zymography and ELISA, respectively. The crosstalk between IL-35, VEGF, and Ang2 in HUVECs and RA synovial tissue explants was investigated. RESULTS: IL-35 inhibited basal and VEGF-induced HUVEC migration and adhesion in vitro as well as tube formation in vitro and in vivo. VEGF increased Ang2 secretion by HUVECs and RA synovial tissue explants, and exogenous Ang2 promoted HUVEC migration, adhesion, and tube formation with similar potency to VEGF. Blocking the Ang/Tie2 pathway with a Tie2 kinase antibody inhibited the proangiogenic effects of exogenous Ang2 and VEGF in HUVECs. IL-35 inhibited basal and VEGF-induced Ang2 secretion by HUVECs and RA synovial tissue explants; it also antagonized the proangiogenic effects of exogenous Ang2 in HUVECs. Moreover, IL-35 reduced basal and VEGF/Ang2-induced MMP2/MMP9 and IL-6/IL-8 secretion. CONCLUSION: These results suggested that IL-35 restrains RA angiogenesis and inflammation by downregulating basal and VEGF-induced Ang2 secretion as well as disrupting Ang2/Tie2 signal transduction. Our findings extend current understanding of mechanisms regulating RA angiogenesis and may support development of novel angiogenesis-targeting therapeutics for RA treatment.
26773841 Initial evidence for the link between activities and health: Associations between a balanc 2016 Mar Growing evidence shows interrelations of psychological factors, neurological and immunological processes. Therefore, constructs like a balance of activities, the so called "occupational balance", could also have biological correlates. The aim of this study was to investigate potential associations between occupational balance, functioning, cytokines and C-reactive protein (CRP) in patients suffering from a chronic inflammatory disease like rheumatoid arthritis (RA) and healthy people. Moreover, we wanted to explore potential differences in gender and employment status. A descriptive study in patients with RA and healthy people was conducted using the Occupational Balance-Questionnaire (OB-Quest) and the Short-Form 36 Health Survey (SF-36). Serum levels of cytokines, such as interleukin 6 (IL-6) and 8 (IL-8), interferon alpha (INFα), tumour necrosis factor alpha (TNFα), rheumatoid factor (RF) and of CRP were measured. Descriptive statistics, as well as Mann-Whitney U tests and Spearmen's rank correlation coefficients (rs) were calculated. One-hundred-thirty-two patients with RA and 76 healthy people participated. Occupational balance was associated with functioning, cytokines and CRP. The strongest associations were identified in the unemployed healthy-people sample with cytokines and CRP being within the normal range. For example, the OB-Quest item challenging activities was associated with IL-8 (rs=-0.63, p=0.04) and the SF-36 sub-scale bodily pain was associated with IFNα (rs=-0.69, p=0.02). The items rest and sleep (rs=-0.71, p=0.01) and variety of different activities (rs=-0.74, p<0.01) correlated with the SF-36 sub-scale social functioning. Employed and unemployed people differed in their age and CRP levels. Additionally, gender differences were found in two OB-Quest items in that fewer women were able to adapt their activities to changing living conditions and fewer men were overstressed. In conclusion, we found preliminary biological evidence for the link between occupation and health in that the concepts encompassed in the construct of occupational balance were associated with functioning, cytokines and CRP.
26178284 Differential Antigen-presenting B Cell Phenotypes from Synovial Microenvironment of Patien 2015 Oct OBJECTIVE: To study the qualitative and quantitative phenotypic changes that occur in molecules involved in antigen presentation and costimulation in synovial B cells from rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: The presence of HLA-DR, CD86, and CD40 in CD20+ cells was studied in RA synovium biopsies using immunohistochemistry and immunofluorescence. Expression was assessed by flow cytometry of the Class II molecules CD40, CD86, CD23, and CD27 on B cells from the synovial fluid (SF), with respect to peripheral blood, from 13 patients with RA and 15 patients with PsA. Expression of interferon-induced protein with tetratricopeptide repeats 4 (IFIT4) in immune-selected CD20+ cells from patients with RA was assessed by quantitative realtime PCR. RESULTS: Infiltrating synovial RA, B cells expressed HLA-DR, CD40, and CD86. Increased expression of CD86, HLA-DR, and HLA-DQ in B cells from SF was found in patients with RA and PsA. HLA-DP was also elevated in rheumatoid SF B cells; conversely, a significantly lower expression was observed in SF from patients with PsA. CD40 expression was increased in SF B cells from PsA, but not in patients with RA. Interestingly, CD20 surface expression level was significantly lower in SF B cells (CD19+, CD138-) from RA, but not in patients with PsA. CD27 upregulation and CD23 downregulation were observed in synovial B cells in both pathologies. Finally, a 4-fold increase in IFIT4 mRNA content was shown in B cells from SF in patients with RA. CONCLUSION: Synovial B cells from patients with RA and patients with PsA express different antigen-presenting cell phenotypes, suggesting that this cell type plays a dissimilar role in the pathogenesis of each disease.
26537917 Smoking, Porphyromonas gingivalis and the immune response to citrullinated autoantigens be 2015 Nov 4 BACKGROUND: Antibodies to citrullinated proteins (ACPA) occur years before RA diagnosis. Porphyromonas gingivalis expresses its own peptidylarginine deiminase (PPAD), and is a proposed aetiological factor for the ACPA response. Smoking is a risk factor for both ACPA-positive RA and periodontitis. We aimed to study the relation of these factors to the risk of RA in a prospective cohort. METHODS: We performed a nested case-control study by identifying pre-RA cases in four populations from the European Prospective Investigation into Cancer and nutrition, matched with three controls. Data on smoking and other covariates were obtained from baseline questionnaires. Antibodies to CCP2 and citrullinated peptides from α-enolase, fibrinogen, vimentin and PPAD were measured. Antibodies to arginine gingipain (RgpB) were used as a marker for P.gingivalis infection and validated in a separate cohort of healthy controls and subjects with periodontitis. RESULTS: We studied 103 pre-RA cases. RA development was associated with several ACPA specificities, but not with antibodies to citrullinated PPAD peptides. Antibody levels to RgpB and PPAD peptides were higher in smokers but were not associated with risk of RA or with pre-RA autoimmunity. Former but not current smoking was associated with antibodies to α-enolase (OR 4.06; 95 % CI 1.02, 16.2 versus 0.54; 0.09-3.73) and fibrinogen peptides (OR 4.24; 95 % CI 1.2-14.96 versus 0.58; 0.13-2.70), and later development of RA (OR 2.48; 95 % CI 1.27-4.84 versus 1.57; 0.85-2.93), independent of smoking intensity. CONCLUSIONS: Smoking remains a risk factor for RA well before the clinical onset of disease. In this cohort, P.gingivalis is not associated with pre-RA autoimmunity or risk of RA in an early phase before disease-onset. Antibodies to PPAD peptides are not an early feature of ACPA ontogeny.
27871200 Denosumab: targeting the RANKL pathway to treat rheumatoid arthritis. 2017 Jan Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by focal pathologic bone resorption due to excessive activity of osteoclasts (OC). Receptor activator of nuclear factor kappa B ligand (RANKL) is essential for the proliferation, differentiation, and survival of OC. Denosumab (DMab) is a humanized monoclonal antibody that binds to RANKL with high affinity and blocks its subsequent association with its receptor RANK on the surface of OC precursors. Area covered: The authors review the molecular and cellular mechanisms underlying therapeutic applications of DMab, provide recent highlights on pharmacology, efficacy and safety of DMab, and discuss the potential of DMab as a novel therapeutic option for the treatment of rheumatoid arthritis. Expert opinion: Clinical results suggest that DMab is efficient both in systemic and articular bone loss in RA with limited side effects. Diminished bone erosion activity was also noted in RA patients on corticosteroids and bisphosphonates. Combination of DMab with an anti-TNF agent was not associated with increased infection rates. Collectively, these data indicate that DMab, in combination with methotrexate and possibly other conventional synthetic Disease Modifying Anti-Rheumatic Drugs (csDMARDs), is an effective, safe and cost-effective option for the treatment of RA.
26316581 Rituximab done: what's next in rheumatoid arthritis? A European observational longitudinal 2016 Feb OBJECTIVE: To compare the effectiveness of biologics after rituximab (RTX) treatment in RA. METHODS: The effectiveness of TNF-α inhibitors (TNFi), abatacept (ABA) or tocilizumab (TCZ) was examined in patients previously treated with RTX using clinical data collected in the Collaborative Registries for the Evaluation of Rituximab in RA Collaborative registry. Patients had stopped RTX 6 months or less prior to the new biologic and had a baseline visit within 21 days of starting the new biologic. RESULTS: Two hundred and sixty-five patients were analysed after 6 months of treatment. Patients on TCZ (n = 86) had a greater decline of DAS28-ESR and clinical disease activity index than patients on TNFi (n = 89) or ABA (n = 90). This effect was also seen after adjusting for baseline prednisone use and the number of previous biologics. The mean DAS28-ESR scores in patients on TCZ were 1.0 (95% CI: 0.2, 1.7) and 1.8 (95% CI: 1.0, 2.5) points lower than in patients on TNFi or ABA, respectively. In patients on TCZ, the clinical disease activity index was 9.4 (95% CI: 1.7, 16.1) and 8.1 (95% CI: 0.9, 15.3) points lower than on TNFi and ABA, respectively. Patients on TCZ more frequently had good EULAR responses than patients on TNFi or ABA (66 vs 31 vs 14%, P < 0.001). The HAQ disability index improved in all treatment groups (P < 0.001), but did not differ between biologics, as did drug retention rates. The reasons for discontinuation of RTX and the number of previous biologics had no influence on outcomes. CONCLUSION: In this observational cohort of patients who discontinued RTX, TCZ provided a better control of RA than ABA or TNFi.
25988241 Rheumatoid Arthritis, Anti-Cyclic Citrullinated Peptide Positivity, and Cardiovascular Dis 2015 Sep OBJECTIVE: To evaluate the incidence of cardiovascular disease (CVD) morbidity and mortality over the course of 10 years among the more than 160,000 postmenopausal women in the Women's Health Initiative (WHI) in relation to self-reported rheumatoid arthritis (RA), taking disease-modifying antirheumatic drugs (DMARDs), anti-cyclic citrullinated peptide (anti-CCP) positivity, rheumatoid factor (RF) positivity, CVD risk factors, joint pain, and inflammation (white blood cell count and interleukin-6 levels). METHODS: Anti-CCP and RF were measured in a sample of WHI participants with self-reported RA (n = 9,988). RA was classified as self-reported RA plus anti-CCP positivity and/or taking DMARDs. Anti-CCP-negative women with self-reported RA and not taking DMARDs were classified as having "unverified RA." RESULTS: Age-adjusted rates of coronary heart disease (CHD), stroke, CVD, fatal CVD, and total mortality were higher in women with RA than in women with no reported RA, with multivariable-adjusted hazard ratios of 1.46 (95% confidence interval [95% CI] 1.17-1.83) for CHD and 2.55 (95% CI 1.86-3.51) for fatal CVD. Among women with RA, anti-CCP positivity and RF positivity were not significantly associated with higher risk of any outcomes, despite slightly higher risk of death for those who were anti-CCP positive than for those who were anti-CCP negative. Joint pain severity and CVD risk factors were strongly associated with CVD risk, even in women with no reported RA. CVD incidence was increased in women with RA versus women with no reported RA at almost all risk factor levels, except for low levels of joint pain or inflammation. Among women with RA, inflammation was more strongly associated with fatal CVD and total mortality than with CHD or CVD. CONCLUSION: Among postmenopausal women, RA was associated with 1.5-2.5-fold higher CVD risk. CVD risk was strongly associated with CVD risk factors, joint pain severity, and inflammation, but not with anti-CCP positivity or RF positivity.