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ID PMID Title PublicationDate abstract
24534192 Epitope-specific antibody response is controlled by immunoglobulin V(H) polymorphisms. 2014 Mar 10 Autoantibody formation is essential for the development of certain autoimmune diseases like rheumatoid arthritis (RA). Anti-type II collagen (CII) antibodies are found in RA patients; they interact with cartilage in vivo and are often highly pathogenic in the mouse. Autoreactivity to CII is directed to multiple epitopes and conserved between mice and humans. We have previously mapped the antibody response to CII in a heterogeneous stock cohort of mice, with a strong association with the IgH locus. We positioned the genetic polymorphisms and determined the structural requirements controlling antibody recognition of one of the major CII epitopes. Polymorphisms at positions S31R and W33T of the associated variable heavy chain (VH) allele were identified and confirmed by gene sequencing. The Fab fragment binding the J1 epitope was crystallized, and site-directed mutagenesis confirmed the importance of those two variants for antigen recognition. Back mutation to germline sequence provided evidence for a preexisting recognition of the J1 epitope. These data demonstrate a genetic association of epitope-specific antibody responses with specific VH alleles, and it highlights the importance of germline-encoded antibodies in the pathogenesis of antibody-mediated autoimmune diseases.
24431281 Fas signaling in macrophages promotes chronicity in K/BxN serum-induced arthritis. 2014 Jan OBJECTIVE: A nonapoptotic role of Fas signaling has been implicated in the regulation of inflammation and innate immunity. This study was undertaken to elucidate the contribution of Fas signaling in macrophages to the development of arthritis. METHODS: K/BxN serum-transfer arthritis was induced in a mouse line in which Fas was conditionally deleted in the myeloid lineage (Cre(LysM) Fas(flox/flox) mice). The arthritis was assessed clinically and histologically. Expression of interleukin-1β (IL-1β), CXCL5, IL-10, IL-6, and gp96 was determined by enzyme-linked immunosorbent assay. Bone marrow-derived macrophages were activated with IL-1β and gp96. Cell phenotype and apoptosis were analyzed by flow cytometry. RESULTS: Arthritis onset in Cre(LysM) Fas(flox/flox) mice was comparable with that observed in control mice; however, resolution was accelerated during the chronic phase. The attenuated arthritis was associated with reduced articular expression of the endogenous Toll-like receptor 2 (TLR-2) ligand gp96 and the neutrophil chemotactic chemokine CXCL5, and enhanced expression of IL-10. Activation with IL-1β or gp96 induced increased IL-10 expression in Fas-deficient murine macrophages compared with control macrophages. IL-10 suppressed IL-6 and CXCL5 expression induced by IL-1β plus gp96. IL-1β-mediated activation of ERK, which regulates IL-10 expression, was increased in Fas-deficient mouse macrophages. CONCLUSION: Taken together, our findings indicate that impaired Fas signaling results in enhanced expression of antiinflammatory IL-10 and reduced expression of gp96, and these effects are associated with accelerated resolution of inflammation during the chronic phase of arthritis. These observations suggest that strategies to reduce endogenous TLR ligands and increase IL-10 may be beneficial in the treatment of rheumatoid arthritis.
24970348 Regular examinations for toxic maculopathy in long-term chloroquine or hydroxychloroquine 2014 Oct IMPORTANCE: According to evidence-based, expert recommendations, long-term users of chloroquine or hydroxychloroquine sulfate should undergo regular visits to eye care providers and diagnostic testing to check for maculopathy. OBJECTIVE: To determine whether patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) taking chloroquine or hydroxychloroquine are regularly visiting eye care providers and being screened for maculopathy. DESIGN, SETTING, AND PARTICIPANTS: Patients with RA or SLE who were continuously enrolled in a particular managed care network for at least 5 years between January 1, 2001, and December 31, 2011, were studied. Patients' amount of chloroquine or hydroxychloroquine use in the 5 years since the initial RA or SLE diagnosis was calculated, along with their number of eye care visits and diagnostic tests for maculopathy. Those at high risk for maculopathy were identified. Logistic regression was performed to assess potential factors associated with regular eye care visits (annual visits in ≥3 of 5 years) among chloroquine or hydroxychloroquine users, including those at highest risk for maculopathy. MAIN OUTCOMES AND MEASURES: Among chloroquine or hydroxychloroquine users and those at high risk for toxic maculopathy, the proportions with regular eye care visits and diagnostic testing, as well as the likelihood of regular eye care visits. RESULTS: Among 18 051 beneficiaries with RA or SLE, 6339 (35.1%) had at least 1 record of chloroquine or hydroxychloroquine use, and 1409 (7.8%) had used chloroquine or hydroxychloroquine for at least 4 years. Among those at high risk for maculopathy, 27.9% lacked regular eye care visits, 6.1% had no visits to eye care providers, and 34.5% had no diagnostic testing for maculopathy during the 5-year period. Among high-risk patients, each additional month of chloroquine or hydroxychloroquine use was associated with a 2.0% increased likelihood of regular eye care (adjusted odds ratio, 1.02; 95% CI, 1.01-1.03). High-risk patients whose SLE or RA was managed by rheumatologists had a 77.4% increased likelihood of regular eye care (adjusted odds ratio, 1.77; 95% CI, 1.27-2.47) relative to other patients. CONCLUSIONS AND RELEVANCE: In this insured population, many patients at high risk for maculopathy associated with the use of chloroquine or hydroxychloroquine are not undergoing routine monitoring for this serious adverse effect. Future studies should explore factors contributing to suboptimal adherence to expert guidelines and the potential effect on patients' vision-related outcomes.
24864133 Differential associations of inflammatory and endothelial biomarkers with disease activity 2014 OBJECTIVES: To estimate endothelial dysfunction in patients with rheumatoid arthritis (RA) of short duration in relation to disease activity based on the assessment of 28 joints (DAS28). METHODS: We studied 29 patients (22 women, mean age 41 (SD, 9) years) with RA of short duration and 29 healthy controls. The RA subjects were divided into those with low (DAS28: 2.6-5.1, n = 18) or high (DAS28 > 5.1, n = 11) disease activity. Exclusion criteria included clinically overt atherosclerosis and other coexistent diseases. Biochemical markers of inflammatory activation and endothelial dysfunction were measured. RESULTS: There were no significant intergroup differences in the majority of classical cardiovascular risk factors. High-sensitivity C-reactive protein, tumor necrosis factor- α , and interleukin-6 were increased in RA subjects. Compared to the controls, levels of soluble vascular cell adhesion molecule-1, von Willebrand factor, and pentraxin-3 were significantly elevated in RA subjects with low disease activity, exhibiting no further significant rises in those with high disease activity. Asymmetric dimethyl-L-arginine, soluble E-selectin, monocyte chemotactic protein-1, and osteoprotegerin were increased only in RA patients with high disease activity. CONCLUSIONS: Our findings might suggest a dissociation of pathways governing generalized and joint-specific inflammatory reactions from those involved in endothelial activation and inflammation within the vascular wall.
24026258 Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patie 2013 Aug 20 BACKGROUND: Many patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA. OBJECTIVE: To evaluate the efficacy and safety of tofacitinib in combination with nonbiologic DMARDs. DESIGN: 1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544). SETTING: 114 centers in 19 countries. PATIENTS: 792 patients with active RA despite nonbiologic DMARD therapy. INTERVENTION: Patients were randomly assigned 4:4:1:1 to oral tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib, 5 mg or 10 mg twice daily. MEASUREMENTS: Primary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)-defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments. RESULTS: Mean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P < 0.001) and 25.8% (CI, 16.8% to 34.8%; P < 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg tofacitinib, 10-mg tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patient-years of exposure, respectively. In the tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low- and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the tofacitinib groups. LIMITATIONS: Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than tofacitinib plus methotrexate was limited. CONCLUSION: Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate. PRIMARY FUNDING SOURCE: Pfizer.
24951881 Teaching methotrexate self-injection with a web-based video maintains patient care while r 2015 Jan The aim of the study was to compare standard nurse-led methotrexate self-injection patient education to a web-based methotrexate self-injection education video in conjunction with standard teaching on patient self-confidence for self-injection, as well as patient satisfaction, patient knowledge and teaching time. Consecutive rheumatology patients seen for methotrexate self-injection education were enrolled. Prior to education, patient self-confidence for self-injection, age, gender and education were recorded. Patients were randomized 1:1 to standard teaching or the intervention: a 12-min methotrexate self-injection education video followed by further in-person nurse education. Patients recorded their post-education confidence for self-injection, satisfaction with the teaching process and answered four specific questions testing knowledge on methotrexate self-injection. The time spent providing direct education to the patient was recorded. Twenty-nine patients participated in this study: 15 had standard (C) teaching and 14 were in the intervention group (I). Average age, gender and education level were similar in both groups. Both groups were satisfied with the quality of teaching. There was no difference in pre-confidence (C = 5.5/10 vs. I = 4.7/10, p = 0.44) or post-confidence (C = 8.8, I = 8.8, p = 0.93) between the groups. There was a trend toward improved patient knowledge in the video group versus the standard group (C = 4.7/6, I = 5.5/6, p = 0.15). Nurse teaching time was less in the video group (C = 60 min, I = 44 min, p = 0.012), with men requiring longer education time than women across all groups. An education video may be a good supplement to standard in-person nurse teaching for methotrexate self-injection. It equals the standard teaching practise with regard to patient satisfaction, confidence and knowledge while decreasing teaching time by 25 %.
23380431 Exposure to ultraviolet-B and risk of developing rheumatoid arthritis among women in the N 2013 Apr OBJECTIVE: To examine the association between ultraviolet-B (UV-B) light exposure and rheumatoid arthritis (RA) risk among women in two large prospective cohort studies, the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHSII). METHODS: A total of 106 368 women from NHS, aged 30-55 years in 1976, and 115 561 women from NHSII, aged 25-42 in 1989, were included in the analysis. We identified women with incident RA from the start of each cohort until 2008 (NHS) and 2009 (NHSII). Cumulative average UV-B flux, a composite measure of ambient UV exposure based on latitude, altitude and cloud cover, was estimated according to state of residence and categorised as low, medium or high. Estimates of UV-B at birth and age 15 years were also examined. We used multivariable-adjusted Cox proportional hazards models to estimate HR and 95% CI. RESULTS: 1314 incident RA cases were identified in total. Among NHS participants, higher cumulative average UV-B exposure was associated with decreased RA risk; those in the highest versus lowest category had a 21% decreased RA risk (HR (95% CI); 0.79 (0.66 to 0.94)). UV-B was not associated with RA risk among younger women in NHSII (1.12 (0.87 to 1.44)). Results were similar for UV-B at birth and at age 15. CONCLUSIONS: These results suggest that ambient UV-B exposure is associated with a lower RA risk in NHS, but not NHSII. Differences in sun-protective behaviours (eg, greater use of sun block in younger generations) may explain the disparate results.
24364915 Increased risk for chronic comorbid disorders in patients with inflammatory arthritis: a p 2013 Dec 23 BACKGROUND: Studies determining the development of a wide variety of different comorbid disorders in inflammatory arthritis (IA) patients are scarce, however, this knowledge could be helpful in optimising preventive care in IA patients. The aim of this study is to establish the risk that new chronic comorbid disorders in newly diagnosed patients with IA in a primary care setting are developed. METHODS: This is a nested-case-control study from 2001-2010 using data from electronic medical patient records in general practice. In total, 3,354 patients with newly diagnosed IA were selected. Each patient was matched with two control patients of the same age and sex in the same general practice. The development of 121 chronic comorbid disorders of index and control patients was compared using Cox regression. RESULTS: After a median follow-up period of 2.8 years, 56% of the IA-patients had developed at least one chronic comorbid disorder after the onset of IA, compared to 46% of the control patients (p < 0.05). The most frequent developed comorbid disorders after the onset of IA were of cardiovascular (23%), and musculoskeletal (17%) origin. The highest hazard ratios (HRs) were found for anaemia (HR 2.0 [95% CI: 1.4-2.7]) osteoporosis (HR 1.9 [1.4-2.4]), and COPD (HR 1.8 [1.4-2.3]). CONCLUSION: Patients with IA developed more chronic comorbid disorders after the onset of IA than one might expect based on age and sex. Since comorbidity has a large impact on the disease course, quality of life, and possibly on treatment itself, prevention of comorbidity should be one of the main targets in the treatment of IA patients.
23406933 The T-cell immunoglobulin and mucin domain (Tim) gene family in asthma, allergy, and autoi 2013 Jan The T-cell immunoglobulin and mucin domain (Tim) gene family is a relatively newly discovered group of molecules with a conserved structure and important immunologic functions. Tim molecules express on many types of immune cells including T cells, B cells, dendritic cells, macrophages, and mast cells that have been shown to be involved in asthma, allergic rhinitis, food allergy, and autoimmunity. Tim-1-Tim-4 interaction promotes Th2 cytokine responses, and blocking this interaction can decrease airway inflammation in asthma and in allergic rhinitis. Tim-3 stimulates mast cells to produce Th2 cytokines, and anti-Tim-3 is able to dampen asthmatic inflammation. The Tim-3 ligand was shown to be greatly enhanced on intestinal epithelial cells in patients with food allergy and Tim-4 may play a role in maintaining oral tolerance and prevention of food allergy. Tim-3 deregulation plays a role in the pathogenesis of multiple sclerosis. Increased Tim-1 expression has been shown in mononuclear cells from systemic lupus erythematosus patients and Tim-3 may be involved in a protective role in rheumatoid arthritis.
23815183 Meta-analysis: rapid infliximab infusions are safe. 2013 Aug BACKGROUND: Infliximab is typically administered intravenously via 2- to 3-h duration infusions. Infusions are time-consuming and costly. Shorter duration infusions are administered at some centres. Limited safety data are available on shorter duration infusions. AIM: To determine risk of infusion reaction associated with standard 2- to 3-h infusions vs. rapid infusions in patients receiving infliximab therapy for inflammatory bowel disease (IBD), rheumatoid arthritis, spondylarthopathy and psoriatic disease. METHODS: MEDLINE, Embase, and Web of Science were searched. Inclusion required human subjects, documentation of number of standard and rapid infliximab infusions and number of incident infusion reactions. Studies of overlapping populations were excluded. Three reviewers independently extracted data. Study quality was assessed. Relative risk (RR) was pooled using random effects models. RESULTS: We identified 10 studies comprising 13 147 standard 2- to 3-h and 8497 ≤ 1-h infliximab infusions. Nine studies reported the risk of infusion reaction in standard vs. 1-h infusions, demonstrating decreased RR of infusion reaction with 1-h vs. standard infusions (0.9% vs. 2.2% of infusions; RR = 0.48, P = 0.009). Seven studies limited to IBD also demonstrated decreased risk of reaction (RR = 0.49, P = 0.002). Other comparisons demonstrated no difference in RR of reaction, including concomitant medication use (P = 0.30) or analysis limited to high and medium quality studies (P = 0.07). CONCLUSIONS: Rapid infliximab infusions of ≤1-h duration are not associated with increased risk of infusion reaction when compared to standard 2- to 3-h infusions in selected patients who previously tolerated three to four standard infusions. One-hour infusions will conserve health care resources and may lead to improved adherence and quality of life in patients receiving infliximab.
24417834 Hip resurfacing arthroplasty at a non-specialist centre. 2014 Jan INTRODUCTION: Few studies have reported the outcome of hip resurfacing arthroplasty (HRA) with respect to implant characteristics from non-specialist centres. We report the survival, clinical and radiological outcomes of a single surgeon series of HRA with an average follow-up duration of five years. METHODS: All consecutive HRAs performed by a single surgeon between 2003 and 2011 at a district general hospital were retrospectively examined clinically and radiologically. RESULTS: A total of 85 patients underwent 109 HRAs (58 male [53.2%] and 51 female patients [46.8%]) with a mean follow-up period of 62 months (range: 12-102 months). The median age was 57 years (range: 25-75 years). The mean acetabular and femoral head component sizes were 54 mm (range: 48-64 mm) and 48 mm (range: 42-58 mm) respectively with a mean acetabular inclination angle of 42.9° (range: 20-75°). The survival rate was 95% with five revisions due to aseptic loosening (n=3) and fracture (n=2): these were predominantly for female patients (n=4), with significantly smaller mean acetabular (51 mm, p=0.04) and femoral (44 mm, p=0.02) implant sizes. Furthermore, they had a higher mean acetabular inclination angle of 48.1° (p=0.74). The mean Oxford hip score was 43.8 (range: 25-48) and the mean University of California Los Angeles (UCLA) activity score was 6.8 (range: 3-10). Radiological findings included heterotopic ossification in 13 (11.9%), radiolucent lines in 6 (5.5%), femoral neck thinning in 2 (1.8%) and femoral neck notching in 5 patients (4.6%). CONCLUSIONS: We have shown that HRA at a non-specialist centre has short to medium-term outcomes comparable with those at specialist centres. HRA therefore remains a viable option although vigilance is required in case selection and follow-up according to national guidance.
24997655 Prolactin increases tumor necrosis factor alpha expression in peripheral CD14 monocytes of 2014 Jul Tumor necrosis factor (TNF)-α is one of the major proinflammatory mediators of rheumatic arthritis (RA); the regulatory factors for TNF-α release is not fully understood. This study aims to investigate the role of prolactin receptor (PRLR) activation in regulating the expression and release of TNF-α from CD14(+) monocytes. The results showed that the expression of PRLR was detectable in CD14(+) monocytes of healthy subjects, which was markedly increased in RA patients. Exposure to PRL in the culture increased the expression and release of TNF-α from CD14(+) monocytes, which was abolished by the PRLR gene silencing or blocking the mitogen activated protein (MAPK) pathway. We conclude that exposure to PRL increases TNF-α release from CD14(+) monocytes of RA patients, which can be abolished by PRLR gene silencing or treating with MAPK inhibitor.
25263394 A large candidate-gene association study suggests genetic variants at IRF5 and PRDM1 to be 2014 Dec AIM: Epidemiological and clinical studies indicated a relationship of periodontitis with rheumatoid arthritis (RA). We aimed to identify shared genetic susceptibility loci of RA and periodontitis. MATERIALS AND METHODS: Forty-seven risk genes of genome-wide significance of RA and SLE were genotyped in a German case-control sample of aggressive periodontitis (AgP), using Immunochip genotyping arrays (Illumina, 600 cases, 1440 controls) and Affymetrix 500 K Genotyping Arrays (280 cases and 983 controls). Significant associations were replicated in 168 Dutch AgP cases and 679 controls and adjusted for the confounders smoking and sex. RESULTS: Variants at IRF5 and PRDM1 showed association with AgP. Upon covariate adjustment for smoking and sex, the most strongly associated variant at IRF5 was the rare variant rs62481981 (ppooled  = 0.0012, odds ratio [OR] = 3.1, 95% confidence interval [95% CI] = 1.6-6.1; 801 cases, 1476 controls).Within PRDM1 it was rs6923419 (ppooled  = 0.004, OR = 0.7, 95% CI = 0.6-0.9; 833 cases, 1440 controls). The associations lost significance after correction for multiple testing in the replication. Both genes are implicated in beta-interferon signalling and are also genome-wide associated with SLE and inflammatory bowel disease. CONCLUSION: The study gives no definite evidence for a pathogenic genetic link of periodontitis and RA but suggests IRF5 and PRDM1 as shared susceptibility factors.
25389350 Idiopathic pulmonary fibrosis with emphysema: evidence of synergy among emphysema and idio 2015 Feb BACKGROUND: Emphysema and fibrosis, typically the idiopathic pulmonary fibrosis (IPF) form of usual interstitial pneumonia (UIP), can co-exist as combined pulmonary fibrosis emphysema (CPFE). It is unknown whether there is a pathobiologic basis for CPFE beyond the coexistence of fibrosis and emphysema. The aim of this study was to ascertain radiologic differences in severity of fibrosis and emphysema in smokers with IPF versus other forms of UIP. METHODS: Computed tomography thorax images were prospectively rescored in retrospectively identified smokers (minimum 5-pack-year history) with radiologic UIP (any etiology). Radiologic severity (emphysema/fibrosis/reticulation) was scored in consensus by two radiologists, blinded to clinical details, across 5 lung regional levels, and then correlated with clinical data. RESULTS: For the whole cohort (IPF, n=102; non-IPF UIP [mainly rheumatoid arthritis/asbestosis/scleroderma], n=30), IPF and non-IPF UIP smokers were similar regarding pack-year, age, gender, and lung function (P>.1). IPF smokers had greater whole lung fibrosis and reticulation scores (P<.04 in all cases). CPFE was present in n=61 (IPF, n=49; non-IPF UIP, n=12). Compared with smokers with non-IPF CPFE, smokers with IPF and emphysema (IPFE) were similar regarding confounders (P>.1). There were significantly greater regional reticulation severity (P=.009), cumulative emphysema severity (P=.04), and cumulative reticulation severity (P<.001) scores in IPFE versus non-IPF CPFE. CONCLUSIONS: When controlled for confounders, smokers with IPFE have worse radiologic CPFE than other smokers with non-IPF UIP and emphysema, suggesting an interactive synergy among IPF, emphysema, and smoking, with more extensive emphysema due to either inherent susceptibility and/or traction effects. IPFE should be considered separately from other CPFE in future work. It is currently unknown whether CPFE is a distinct pathobiologic entity; therefore, we identified subjects with radiologic UIP (any etiology) who had been similarly exposed to smoke, and asked whether there are differences in the extent/severity of radiologic fibrosis and/or emphysema in those with IPF versus individuals with non-IPF UIP. Although relevant confounders were similar, IPF smokers had greater whole lung fibrosis and reticulation scores than smokers with secondary forms of UIP, and in the CPFE subgroup, smokers with IPF/emphysema had worse radiologic CPFE findings than smokers with non-IPF UIP/emphysema. It is shown for the first time that relevant confounding variables do not explain the observed excess radiologic severity of emphysema and fibrosis in smokers with IPF compared with smokers with non-IPF UIP, lending support to the hypothesis that there is a pathobiologic mechanism or synergy involved in IPF with emphysema that is distinct from the mere co-existence of UIP and emphysematous processes.
24667331 Boswellia serrata extract attenuates inflammatory mediators and oxidative stress in collag 2014 May 15 Rheumatoid arthritis (RA) is a chronic inflammatory disease which leads to destruction of joints. Current treatment modalities for RA either produce symptomatic relief (NSAIDs) or modify the disease process (DMARDs). Though effective, their use is also limited by their side effects. As a result, the interest in alternative, well tolerated anti-inflammatory remedies has re-emerged. Our aim was to evaluate the antioxidant and antiarthritic activity of Boswellia serrata gum resin extract (BSE) in collagen induced arthritis. Arthritis was induced in male Wistar rats by collagen induced arthritis (CIA) method. BSE was administered at doses of 100 and 200mg/kg body weight once daily for 21 days. The effects of treatment in the rats were assessed by biochemical (articular elastase, MPO, LPO, GSH, catalase, SOD and NO), inflammatory mediators (IL-1β, IL-6, TNF-α, IL-10, IFN-γ and PGE2), and histological studies in joints. BSE was effective in bringing significant changes on all the parameters (articular elastase, MPO, LPO, GSH, catalase, SOD and NO) studied. Oral administration of BSE resulted in significantly reduced levels of inflammatory mediators (IL-1β, IL-6, TNF-α, IFN-γ and PGE2), and increased level of IL-10. The protective effects of BSE against RA were also evident from the decrease in arthritis scoring and bone histology. The abilities to inhibit proinflammatory cytokines and modulation of antioxidant status suggest that the protective effect of Boswellia serrata extract on arthritis in rats might be mediated via the modulation of immune system.
24874661 Bacteria in the adventitia of cardiovascular disease patients with and without rheumatoid 2014 The incidence of atherosclerosis is significantly increased in rheumatoid arthritis (RA). Infection is one factor that may be involved in the pathogenesis of both diseases. The cause of RA and atherosclerosis is unknown, and infection is one of the factors that may be involved in the pathogenesis of both diseases. The aims of this study were to identify bacteria in the aortic adventitia of patients with cardiovascular disease (CVD) in the presence and absence of RA, and to determine the effect of identified candidate pathogens on Toll-like receptor (TLR)-dependent signalling and the proinflammatory response. The aortic adventitia of 11 CVD patients with RA (RA+CVD) and 11 CVD patients without RA (CVD) were collected during coronary artery bypass graft surgery. Bacteria were detected in four samples from CVD patients and three samples from RA+CVD patients and identified by 16S rRNA gene sequencing. Methylobacterium oryzae was identified in all three RA+CVD samples, representing 44.1% of the bacterial flora. The effect of M. oryzae on TLR-dependent signalling was determined by transfection of HEK-293 cells. Although mild TLR2 signalling was observed, TLR4 was insensitive to M. oryzae. Human primary macrophages were infected with M. oryzae, and a TLDA qPCR array targeting 90 genes involved in inflammation and immune regulation was used to profile the transcriptional response. A significant proinflammatory response was observed, with many of the up-regulated genes encoding proinflammatory cytokines (IL-1α, IL-1β, IL-6, TNF-α) and chemokines (CCR7, IL-8). The aortic adventitia of CVD patients contains a wide range of bacterial species, and the bacterial flora is significantly less diverse in RA+CVD than CVD patients. M. oryzae may stimulate an proinflammatory response that may aggravate and perpetuate the pathological processes underlying atherosclerosis in RA patients.
24115082 Mechanism-based approach using a biomarker response to evaluate tocilizumab subcutaneous i 2014 Jan A multicenter, open-label, dose-escalation phase 1/2 study was undertaken to evaluate the optimal subcutaneous tocilizumab dose that would result in exposure comparable to the intravenous tocilizumab 8-mg/kg approved dose in patients with rheumatoid arthritis. A pharmacokinetic and biomarker approach was used to estimate the clinical optimal dose regimen of subcutaneous tocilizumab. Safety and efficacy of subcutaneous tocilizumab were assessed as secondary end points. Patients received subcutaneous tocilizumab at 81 mg every 2 weeks (q2w) (n = 8), 162 mg q2w (n = 12), or 162 mg weekly (qw) (n = 12) for 24 weeks. 88% of 162-mg q2w patients and 100% of 162-mg qw patients maintained mean serum trough tocilizumab concentrations of ≥1 µg/mL, and had exposure comparable with the approved intravenous tocilizumab dose of 8 mg/kg; this resulted in normalized C-reactive protein levels and improvement in ACR20/50/70 responses. The most common adverse events were abnormal laboratory results, which were mild in severity. Anti-tocilizumab antibodies were detected in a few patients in the 81-mg q2w and 162-mg qw groups. In conclusion, coupled with efficacy and tolerability results, the appropriate dose of subcutaneous tocilizumab was determined to be 162 mg q2w for Japanese patients.
25033972 Th17 and non-classic Th1 cells in chronic inflammatory disorders: two sides of the same co 2014 Th17 lymphocytes, beyond their protective role in the clearance of extracellular pathogens, also play a role in the pathogenesis of several autoimmune and inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases, psoriasis and contact dermatitis. Nevertheless, they are very rare at inflammatory sites in comparison with other T cell subsets. Recently, this rarity has been explained by the finding that Th17 cells rapidly shift into the Th1 phenotype in the presence of IL-12 and/or TNF-α as well as by the fact that they possess self-regulatory mechanisms limiting their own expansion. Th17 lymphocytes that have shifted towards a Th1 phenotype seem to be particularly aggressive and more pathogenic than the Th17 unshifted cells. As a consequence, the Th17-derived Th1 cells, named non-classic Th1 cells, can become a possible target for the therapy of some inflammatory disorders. In particular, convincing evidence has recently been accumulated indicating that this subset can play a role in Crohn's disease and juvenile idiopathic arthritis. More importantly, it has been shown that TNF-α inhibitors, which are used for the treatment of such diseases, appear to be able to inhibit the transition of Th17 lymphocytes to the non-classic Th1 phenotype, and thus they possibly help to dampen inflammation and arrest disease progression. Based on this context, the definition of the soluble factors involved in the shifting from Th17 towards non-classic Th1 subset as well as the comprehension of their respective pathogenic role in human inflammatory disorders would be of great help for developing novel therapeutic strategies.
23619188 MRP8 promotes Th17 differentiation via upregulation of IL-6 production by fibroblast-like 2013 Apr 26 Myeloid-related protein (MRP)8/MRP14 is an endogenous Toll-like receptor 4 (TLR4) ligand and is abundant in synovial fluid (SF) of rheumatoid arthritis (RA) patients. Belonging to damage-associated molecular patterns, it amplifies proinflammatory mediators and facilitates a wide range of inflammatory and autoimmune diseases. Interleukin (IL)-17-producing T-helper (Th)17 cells have a crucial role in RA pathogenesis, and IL-6 is the key factor promoting Th17 differentiation. We investigated whether the level of MRP8/MRP14 is positively associated with IL-6 and IL-17 levels in RA SF and found that MRP8/MRP14 level had a significant correlation with IL-6 and IL-17 levels in RA SF. We also observed that MRP8-induced IL-17 production by peripheral blood mononuclear cells but MRP14 did not. Upon stimulation with MRP8, IL-6 production was enhanced by RA fibroblast-like synoviocytes (FLS) and was further elevated by coculturing RA FLS with activated CD4+ T cells. Moreover, we demonstrated that MRP8-activated IL-6 production by RA FLS promoted differentiation of Th17 cells using the coculture system consisting of CD4+ T cells and RA FLS. In addition, IL-6 blockade attenuated Th17 polarization of CD4+ T cells in the cocultures. Inhibitor studies revealed that MRP8 increased IL-6 production in RA FLS via TLR4/phosphoinositide 3-kinase/nuclear factor-κB and mitogen-activated protein kinase signaling pathways. Our results show that MRP8 has a crucial role in stimulating IL-6 expression by RA FLS, and subsequently promotes Th17 differentiation in RA, suggesting that neutralizing MRP8 level in RA synovium may be an effective therapeutic strategy in RA treatment.
25053832 CD147 up-regulates calcium-induced chemotaxis, adhesion ability and invasiveness of human 2014 Dec OBJECTIVES: We aimed to investigate whether CD147 can up-regulate the chemotactic, adhesive and invasive properties of human neutrophils and to determine the mechanism underlying this process. METHODS: Human promyelocytic leukaemia cells (HL-60) cells and peripheral blood or synovial fluid neutrophils were isolated from RA patients. Under cyclophilin A (CypA) stimulation, chemotaxis, adhesion potential and invasion ability were assessed using chemotaxis, adhesion and invasiveness assays. Lipid raft isolation and western blot were used to determine the mechanism underlying the effects of CypA stimulation. RESULTS: CD147 up-regulates the calcium-induced chemotaxis, adhesion ability and invasiveness of human neutrophils in RA patients. Transient receptor potential melastatin 7 may be responsible for this phenomenon. CONCLUSION: These findings suggest that in RA patients, abundant CypA up-regulates the calcium-induced chemotactic, adhesive and invasive properties of neutrophils via direct binding to CD147. Cyclophilin-CD147 interactions might contribute to the destruction of cartilage and bone in RA.