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ID PMID Title PublicationDate abstract
20410244 A twin study of the association between PTSD symptoms and rheumatoid arthritis. 2010 Jun OBJECTIVES: To assess the association between posttraumatic stress disorder (PTSD) and rheumatoid arthritis (RA) and to determine if this was due to PTSD or confounding by environmental and genetic factors. METHODS: Data were obtained from 3143 twin pairs in the Vietnam Era Twin Registry, which included male twin pairs who served during the Vietnam War era (mean age, 40.6 years; standard deviation, 2.9). Measurements included a PTSD symptom scale, history of physician-diagnosed RA, sociodemographics, and health confounding factors. Co-twin control analytic methods used generalized estimating equation logistic regression to account for the paired twin data and to examine the association between PTSD symptoms and RA in all twins. Separate analyses were conducted within twin pairs. RESULTS: The prevalence of RA among this population was 1.9% (95% confidence interval, 1.6-2.3) and the mean PTSD symptom level was 25.5 (standard deviation, 9.6). PTSD symptoms were associated with an increased likelihood of adult RA even after adjustment for confounding (p(trend) < .001). Among all twins, those in the highest PTSD symptom quartile were 3.8 times more likely (95% confidence interval, 2.1-6.1) to have RA compared with those in the lowest. These findings also persist when examined within twin pairs (p(trend) < .022). CONCLUSIONS: PTSD symptoms were associated with adult RA onset. Even after adjustment for familial/genetic factors and other confounders, an association between PTSD symptoms and RA remained. This is one of the first studies to demonstrate a link between PTSD and RA onset among a community-based population sample, independent of familial and genetic factors.
19647729 Apigenin-induced apoptosis is mediated by reactive oxygen species and activation of ERK1/2 2009 Nov 10 Fibroblast-like synovial cells play a crucial role in the pathophysiology of rheumatoid arthritis (RA), as these cells are involved in inflammation and joint destruction. Apigenin, a dietary plant-flavonoid, is known to have many functions in animal cells including anti-proliferative and anticancer activities, but its role in human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) has not been reported. In this study, we investigated the roles of apigenin in RA-FLSs. The survival rate decreased, and apoptotic cell death was induced by apigenin treatment in RA-FLSs. Apigenin treatment resulted in activation of the mitogen-activated protein kinase (MAPK) ERK1/2, and pretreatment with an ERK inhibitor PD98059 dramatically reduced apigenin-induced apoptosis. We found that apigenin-mediated production of a large amount of intracellular reactive oxygen species (ROS) caused activation of ERK1/2 and apoptosis; treatment with the antioxidant Tiron strongly inhibited the apigenin-induced generation of ROS, phosphorylation of ERK1/2, and apoptotic cell death. Apigenin-induced apoptotic cell death was mediated through activation of the effectors caspase-3 and caspase-7, and was blocked by pretreatment with Z-VAD-FMK (a pan-caspase inhibitor). These results showed that apigenin-induced ROS and oxidative stress-activated ERK1/2 caused apoptotic cell death in apigenin-treated RA-FLSs.
20959960 Systemic bone effects of biologic therapies in rheumatoid arthritis and ankylosing spondyl 2011 Apr Inflammatory joint diseases are responsible of chronic systemic inflammation, joint degradations, deformities, and altered quality of life. Patients suffering from chronic rheumatic diseases also present increased bone fragility and increased fracture risk. Registration of biologic therapies has deeply modified care in rheumatic diseases, especially in rheumatoid arthritis and ankylosing spondylitis. The available biologics are the anti proinflammatory cytokine therapies (TNFα blockers, anakinra and tocilizumab) and the biologics active on T cell activation (abatacept and rituximab). These drugs succeeded in blocking disease activity and joint degradation. They are also able to stop systemic bone loss among patients with inflammatory rheumatic diseases. In this review, we present the current understanding of the inflammatory-induced bone loss and the skeletal effects of biologic therapies in inflammatory joint diseases.
20926833 Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid art 2010 Oct 6 Interleukin-17A (IL-17A) is elaborated by the T helper 17 (T(H)17) subset of T(H) cells and exhibits potent proinflammatory properties in animal models of autoimmunity, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, and experimental autoimmune uveitis. To determine whether IL-17A mediates human inflammatory diseases, we investigated the efficacy and safety of AIN457, a human antibody to IL-17A, in patients with psoriasis, rheumatoid arthritis, and chronic noninfectious uveitis. Patients with chronic plaque-type psoriasis (n = 36), rheumatoid arthritis (n = 52), or chronic noninfectious uveitis (n = 16) were enrolled in clinical trials to evaluate the effects of neutralizing IL-17A by AIN457 at doses of 3 to 10 mg/kg, given intravenously. We evaluated efficacy by measuring the psoriasis area and severity index (PASI), the American College of Rheumatology 20% response (ACR20) for rheumatoid arthritis, or the number of responders for uveitis, as defined by either vision improvement or reduction in ocular inflammation or corticosteroid dose. AIN457 treatment induced clinically relevant responses of variable magnitude in patients suffering from each of these diverse immune-mediated diseases. Variable response rates may be due to heterogeneity in small patient populations, differential pathogenic roles of IL-17A in these diseases, and the different involvement or activation of IL-17A-producing cells. The rates of adverse events, including infections, were similar in the AIN457 and placebo groups. These results support a role for IL-17A in the pathophysiology of diverse inflammatory diseases including psoriasis, rheumatoid arthritis, and noninfectious uveitis.
21083889 Association of serum markers with improvement in clinical response measures after treatmen 2010 INTRODUCTION: The goal of this study was to identify serum markers that are modulated by treatment with golimumab with or without methotrexate (MTX) and are associated with clinical response. METHODS: Sera were collected at weeks 0 and 4 from a total of 336 patients (training dataset, n = 100; test dataset, n = 236) from the GO-FORWARD study of patients with active rheumatoid arthritis despite MTX. Patients were randomly assigned to receive placebo plus MTX; golimumab, 100 mg plus placebo; golimumab, 50 mg plus MTX; or golimumab, 100 mg plus MTX. Subcutaneous injections were administered every 4 weeks. Samples were tested for select inflammatory, bone, and cartilage markers and for protein profiling using multianalyte profiles. RESULTS: Treatment with golimumab with or without MTX resulted in significant decreases in a variety of serum proteins at week 4 as compared with placebo plus MTX. The American College of Rheumatology (ACR) 20, ACR 50, and Disease Activity Score (DAS) 28 responders showed a distinct biomarker profile compared with nonresponding patients. CONCLUSIONS: ACR 20 and ACR 50 responders among the golimumab/golimumab + MTX-treated patients had a distinct change from baseline to week 4 in serum protein profile as compared with nonresponders. Some of these changed markers were also associated with multiple clinical response measures and improvement in outcome measures in golimumab/golimumab + MTX-treated patients. Although the positive and negative predictive values of the panel of markers were modest, they were stronger than C-reactive protein alone in predicting clinical response to golimumab. TRIAL REGISTRATION: http://ClinicalTrials.gov identification number: NCT00264550.
21063827 [The safety of biologics : a risk-benefit assessment of treating rheumatoid arthritis with 2010 Nov The aim of this study is a risk-benefit assessment of treating rheumatoid arthritis with biologics based on registry data on mortality.UK, Sweden and Spain have published evaluable data on mortality. A parallel control group was conducted in the UK. Sweden and Spain used an historical cohort for comparison.Central registries supported British and Swedish research by sending details on all deaths. The variety of possible confounders prevents direct comparisons of the registers and safe predictions for individual patients.The death rate in TNF-inhibitor-treated patients is higher than in the general population but lower than in the control groups with RA. Thus comorbidities are not balanced, the weighted mortality rate scaled down the difference between exposed patients and controls. When TNF-inhibitors are given for the usual indication, mortality is reduced compared to conventional therapy.
20374381 Tumour necrosis factor inhibitors and risk of serious infection in rheumatoid arthritis. 2010 Feb 1 Tumour necrosis factor inhibitors have demonstrated significant clinical and radiological benefits in rheumatoid arthritis (RA). However, they have important adverse effects including an association with infection. Results from current studies, including meta-analyses of randomized controlled trials and observational studies, are conflicting regarding the risk of serious infection in RA patients treated with TNF inhibitors. The majority of data suggest an increased risk, in particular of respiratory, skin and soft tissue infections, including tuberculosis. This increased risk of tuberculosis is of particular concern in the APLAR region. However, adverse event analysis remains a difficult area to study and decisions regarding initiation of TNF inhibitors must be made on a case-by-case basis after carefully considering the risks and benefits.
19236197 Workplace impacts of anti-TNF therapies in rheumatoid arthritis: review of the literature. 2009 Feb BACKGROUND: Rheumatoid arthritis (RA) causes pain and serious functional impacts and substantially affects patients' daily lives, including their ability to work. OBJECTIVE: This review examines recent studies of patients with RA treated with TNF antagonists and the impacts these therapies have on the workplace. METHODS: A total of 133 articles and 14 poster abstracts were reviewed that matched specific criteria. RESULTS/CONCLUSION: The results of early studies of TNF antagonists varied regarding their effects on patients with RA in the workplace. However, recent studies of adalimumab showed positive impacts across a range of workplace burdens. Treatments such as adalimumab may help employees with RA to remain in the workforce and lead to reduced workplace costs to the employers and employees.
19884271 Adaptation of human CD4+ T cells to pathophysiological hypoxia: a transcriptome analysis. 2009 Dec OBJECTIVE: Inflamed tissues are usually characterized by low oxygen levels. We investigated whether pathophysiological hypoxia (pO(2) < 1%) as found in the rheumatoid synovium modulates the transcriptome of human CD4+ T cells. METHODS: We analyzed the extent to which hypoxia influences the transcriptome in the rheumatoid synovium according to a gene cluster reflecting adaptation to low oxygen levels. Hypoxia-inducible factor-1alpha (HIF-1alpha) was detected in the rheumatoid synovium using immunohistochemistry. Isolated human CD4+ T cells were exposed to hypoxia and analyzed using microarray analysis, quantitative polymerase chain reaction, and immunoblot detection. RESULTS: In rheumatoid arthritis (RA) synovial tissue samples, hypoxia modulates the transcription profile. This profile is similar, but not identical, to that found in isolated CD4+ T cells incubated under hypoxic conditions. We show that HIF-1alpha is expressed in synovial tissue samples and in hypoxic CD4+ cells; and that hypoxia directly affects differential gene expression in human T cells with up to 4.8% modulation of the transcriptome. Functional genome analysis revealed substantial effects of hypoxia on immune response, transcriptional regulation, protein modification, cell growth and proliferation, and cell metabolism. CONCLUSION: Severe hypoxia, a feature of joint inflammation, considerably modulates the transcriptome of cells found in the rheumatoid synovium. Human CD4+ T cells adapt to hypoxic conditions mainly by HIF-1-driven effects on the transcriptome reflecting a profound influence on immune functions. Thus, hypoxia must be taken into account when therapeutically targeting inflammation.
19858121 Fibrocyte activation in rheumatoid arthritis. 2010 Apr OBJECTIVES: RA is a common, relapsing autoimmune disease primarily affecting the joints. Fibroblast-like synovial (FLS) cells are thought to be responsible for pannus formation and secretion of factors that recruit leucocytes to affected joints, thereby promoting bone and cartilage destruction. Fibrocytes are multipotent circulating stem cells that may have a role in RA pathogenesis, perhaps as the precursors of the FLS cells, or by regulating FLS cell function. METHODS: We utilized multidimensional phospho-specific flow cytometry to characterize the activation status of peripheral blood (PB) fibrocytes derived from human RA patients at different stages of disease and from mice with CIA. RESULTS: Human PB fibrocytes from RA patients exhibited phosporylation activation of the p44/42 and p38 MAP kinases (MAPKs), and STAT3 (signal transducer and activator of transcription) and STAT-5 early in disease, within the first year of diagnosis. Similarly, in murine CIA, an increase in the total number of PB phosphoSTAT5-positive fibrocytes was observed at early time points in disease. Notably, in the affected paws of mice with CIA, we identified an increased number of fibrocytes, in contrast to the paws of control mice. CONCLUSIONS: These data suggest that activated fibrocytes may influence the disease process in RA and may serve as surrogate markers for disease in the PB of affected patients.
19106168 Transforming growth factor-beta1 869T/C, but not interleukin-6 -174G/C, polymorphism assoc 2009 Feb OBJECTIVES: Part of the deleterious effects of systemic inflammation on the cardiovascular system of patients with RA may be exerted via increased propensity to hypertension. IL-6 and TGF-beta1 are important regulators of the inflammatory response. In some, but not all, studies, IL6 -174G/C (rs1800795) and TGFB1 869T/C (rs1982073) gene polymorphisms have been associated with hypertension in the general population. The present study addressed their potential association with hypertension in RA patients. METHODS: TGFB1 869T/C and IL6 -174G/C were identified in 400 RA patients and 422 local, non-RA controls using real-time PCR and melting curve analysis. Binary logistic and linear regression models were used to identify the independence of the effects of the polymorphisms on hypertension. RESULTS: Genotypic and allelic frequencies of the two polymorphisms were similar in RA and controls. Within the RA group, there was no significant association between IL6 -174G/C and hypertension, but TGF 869T-allele carriers had significantly increased prevalence of hypertension compared with CC homozygotes (70.2 vs 55.2%; P = 0.023). This association remained significant after adjustment for other hypertension risk factors and medication (odds ratio = 1.96; 95% CI 1.02, 3.77; P = 0.044), and was more pronounced in patients with increased systemic inflammation. CONCLUSIONS: This study suggests an association of TGFB1 869T/C, but not of IL6 -174G/C, with hypertension in RA patients. If this finding is confirmed in prospective studies, this polymorphism could be used as a screening tool for RA patients with higher risk of developing hypertension and lead to increased surveillance and earlier treatment.
20966628 The influence of mean blood pressure on arterial stiffening and endothelial dysfunction in 2010 OBJECTIVE: To investigate the carotid-radial pulse wave velocity, augmentation index, and flow-mediated dilation of the brachial artery and factors possibly influencing them in women with rheumatoid arthritis and systemic lupus erythematosus. MATERIAL AND METHODS: A total of 63 women with rheumatoid arthritis, 31 with systemic lupus erythematosus, and 72 controls, aged 18-55 years, were examined. Parameters of arterial stiffness, augmentation index and carotid-radial pulse wave velocity, were obtained by applanation tonometry (Sphygmocor (v.7.01) AtCor Medical). Flow-mediated dilatation of the brachial artery, reflecting endothelial function was determined by ultrasound system (Logiq 7, General Electric). RESULTS: The groups of women with rheumatoid arthritis and systemic lupus erythematosus lupus differed from controls regarding augmentation index (P<0.001; P=0.008) and did not differ between each other. Women with systemic lupus erythematosus differed from controls regarding pulse wave velocity (P=0.018), while women with rheumatoid arthritis - did not. Flow-mediated dilatation in both the groups of diseases was not different from controls. In rheumatoid arthritis patients, mean blood pressure was the main explanatory factor for augmentation index and pulse wave velocity; vessel diameter and high-density lipoprotein cholesterol - for flow-mediated dilatation. In women with systemic lupus erythematosus, pulse wave velocity was not related to any of the pending parameters; augmentation index was dependent on organ damage index, age, and mean blood pressure, and flow-mediated dilatation on vessel diameter, body mass index, and disease duration. CONCLUSIONS: The mean blood pressure was the major and the only one risk factor of arterial stiffening in rheumatoid arthritis, while the disease damage index played the most important role in the systemic lupus erythematosus group. The mean blood pressure in the systemic lupus erythematosus group was not as important as in the rheumatoid arthritis group, though may have a partial influence.
21135882 Getting arthritis gene therapy into the clinic. 2011 Apr Gene transfer technologies enable the controlled, targeted and sustained expression of gene products at precise anatomical locations, such as the joint. In this way, they offer the potential for more-effective, less-expensive treatments of joint diseases with fewer extra-articular adverse effects. A large body of preclinical data confirms the utility of intra-articular gene therapy in animal models of rheumatoid arthritis and osteoarthritis. However, relatively few clinical trials have been conducted, only one of which has completed phase II. This article summarizes the status in 2010 of the clinical development of gene therapy for arthritis, identifies certain constraints to progress and suggests possible solutions.
20191466 Predictors of rheumatoid arthritis patient-physician communication about medication costs 2010 May OBJECTIVE: To examine the frequency with which medication costs are discussed, and the predictors of these discussions, during visits between rheumatologists and their patients with rheumatoid arthritis (RA). METHODS: Audiotapes of medical visits, patient questionnaires, medical records, and physician questionnaires were collected from March 2003 to December 2005. Data were collected from 200 RA patients from 4 rheumatology clinics. Audiotapes were coded for the presence of communication about medication costs using a detailed coding instrument. The final analysis sample included 193 patients and 8 rheumatologists. Stepwise multivariable logistic regression was used to examine the role of patient, physician, medication, and relationship characteristics on discussions of medication costs. RESULTS: Despite medication changes being made in more than 50% of the visits, only 34% of those visits included discussions of medication-related costs; 48% of these discussions were initiated by patients. In multivariable logistic regression models, communication about medication costs occurred more often when patients were white (compared with nonwhite) and reported an annual income of $20,000-$59,999 (compared with those earning > or =$60,000). Discussions about medication costs also were more common when physicians were white. CONCLUSION: Although medication changes were common, medication costs were only discussed in one-third of the visits. Communication about medication costs was more common among patients who were white and in a middle income category. Disparities in communication about medication costs have the potential to negatively impact prescribing and subsequent medication use. Further research should examine potential disparities in communication about medication costs.
19479865 Induction of complete and sustained remission of rheumatoid pachymeningitis by rituximab. 2009 Jun Aseptic pachymeningitis is a rare and serious complication of rheumatoid arthritis (RA). Herein, we describe a patient with rheumatoid factor-positive and anti-cyclic citrullinated peptide-positive RA who experienced a focal seizure, with aphasia and convulsions of the right side of the body. The findings of magnetic resonance imaging and histologic analysis led to a diagnosis of rheumatoid pachymeningitis. Because the patient had a large number of CD20-expressing B lymphocytes, therapy with rituximab was started and has resulted in complete and sustained remission of both the pachymeningitis and the RA for >2 years. Despite a decrease in immunoglobulins, the patient has remained free of infections, which illustrates the favorable outcome that can result from therapeutic B cell depletion in this potentially lethal manifestation of RA.
20092399 Increased expression of proto-oncogene survivin predicts Joint destruction and persistent 2010 BACKGROUND: Rheumatoid arthritis (RA) is characterized by an uncontrolled spread of destructive joint inflammation resembling malignancy. Epidemiological studies have established strong correlation between inflammation and predisposition for cancer. Here we assess the predictive role of the circulating proto-oncogene survivin for clinical and radiological outcome of early RA. PATIENTS AND METHODS: Serum survivin was measured by sandwich ELISA in 651 patients with early RA (mean duration 6 months). X-rays of hands and feet were prospectively obtained at base-line and after 1, 2, and 5 years and evaluated for the presence of bone destruction by a modified Sharp method. The predictive value of survivin for radiological destruction was calculated using multivariate regression models including antibodies against cyclic citrullinated peptides (aCCP) and rheumatoid factor (RF). Remission was assessed by the EULAR (European League Against Rheumatism) criteria and by criteria proposed by Mäkinen. RESULTS: At base-line, 391 patients (60%) had high levels of survivin. Radiological progression at 5 years was significantly more frequent (P= 0.001) among survivin-positive patients than among survivin-negative. Survivin positivity predicted radiological progression independently of aCCP and RF. The positive predictive value of survivin was proved both in the group of patients with and in the group without erosions at base-line. The combination of positive tests for both survivin and aCCP had the highest prediction for radiological progression (positive predictive value 0.75). Additionally, a positive test for survivin was an independent predictor of not being in remission. CONCLUSION: Detection of survivin in early RA predicted joint destruction and failure of achieving remission after 5 years in patients with early RA.
19642078 Prevalence of risk factors for statin-induced myopathy in rheumatoid arthritis patients. 2010 Mar OBJECTIVES: Statins are widely prescribed in patients with rheumatoid arthritis (RA). Although statins offer overwhelming cardiovascular benefits, their use can be associated with the development of a statin-induced myopathy. Several factors increase the risk of developing statin-induced myopathy, including the single nucleotide polymorphism (SNP) rs4149056, located within the gene encoding solute carrier organic anion transporter (SLCO1B1). We aimed to identify the frequency of risk factors for statin-induced myopathy and establish whether the rs4149056 genotype is more prevalent in RA. METHODS: A total of 396 RA patients and 438 non-RA controls were studied. DNA samples were obtained from all patients. The SNP rs4149056 was identified using real-time polymerase chain reaction and melting curve analysis. Genotypic and allelic frequencies were calculated using the chi-squared test. RESULTS: Almost 80% of RA patients had one or more risk factor (range 1-5) for the development of statin-induced myopathy. Of the 74 RA patients treated with statins, 90% had one or more (range 1-4) risk factors. No differences in genotype or allelic frequencies were observed between RA patients and controls. CONCLUSIONS: RA patients harbour multiple risk factors for statin-induced myopathy. However, the frequency of the rs4149056 genotypes does not differ according to the presence of RA. Despite this, no cases of statin-induced myopathy were observed in this cohort over a period of four years of follow-up. Thus, we conclude that statin use among RA patients is probably safe, but large-scale prospective studies are needed to confirm this. In the meantime, it may be good practice systematically to consider and record myopathy risk factors in these patients.
20737189 Dystrophic calcinosis in a patient with rheumatoid arthritis. 2011 Feb We report a rare case of dystrophic calcinosis in a patient with rheumatoid arthritis in bilateral buttock lesions and the right elbow joint. The calcinosis was surgically removed because it caused severe local pain, possible infection, and difficulty in sitting. Because no recommended standard pharmacotherapy exists for dystrophic calcinosis, surgical treatment should be taken into consideration when calcinosis causes severe local pain or restricts activities of daily life.
19345539 Early rheumatoid arthritis and its differentiation from other joint abnormalities. 2009 Aug The introduction of disease-modifying antirheumatic drugs has created new demands on imaging to early identify patients with rheumatoid arthritis and opened new prospects in therapeutic management of patients with aggressive disease. Therefore, new imaging modalities such as magnetic resonance imaging and ultrasound have developed during the past few years in this field. In some cases, both magnetic resonance imaging and ultrasound may be also useful in making the distinction between early rheumatoid arthritis and other joints abnormalities, including early psoriatic arthritis. This article will review key aspects of important advances in imaging in rheumatoid arthritis, particularly focusing on magnetic resonance imaging and ultrasound.
19950325 Effects of high-intensity resistance training in patients with rheumatoid arthritis: a ran 2009 Dec 15 OBJECTIVE: To confirm, in a randomized controlled trial (RCT), the efficacy of high-intensity progressive resistance training (PRT) in restoring muscle mass and function in patients with rheumatoid arthritis (RA). Additionally, to investigate the role of the insulin-like growth factor (IGF) system in exercise-induced muscle hypertrophy in the context of RA. METHODS: Twenty-eight patients with established, controlled RA were randomized to either 24 weeks of twice-weekly PRT (n = 13) or a range of movement home exercise control group (n = 15). Dual x-ray absorptiometry-assessed body composition (including lean body mass [LBM], appendicular lean mass [ALM], and fat mass); objective physical function; disease activity; and muscle IGFs were assessed at weeks 0 and 24. RESULTS: Analyses of variance revealed that PRT increased LBM and ALM (P < 0.01); reduced trunk fat mass by 2.5 kg (not significant); and improved training-specific strength by 119%, chair stands by 30%, knee extensor strength by 25%, arm curls by 23%, and walk time by 17% (for objective function tests, P values ranged from 0.027 to 0.001 versus controls). In contrast, body composition and physical function remained unchanged in control patients. Changes in LBM and regional lean mass were associated with changes in objective function (P values ranged from 0.126 to <0.0001). Coinciding with muscle hypertrophy, previously diminished muscle levels of IGF-1 and IGF binding protein 3 both increased following PRT (P < 0.05). CONCLUSION: In an RCT, 24 weeks of PRT proved safe and effective in restoring lean mass and function in patients with RA. Muscle hypertrophy coincided with significant elevations of attenuated muscle IGF levels, revealing a possible contributory mechanism for rheumatoid cachexia. PRT should feature in disease management.