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ID PMID Title PublicationDate abstract
21940677 Pathogenic autoreactive B cells are not negatively selected toward matrix protein collagen 2011 Nov 1 We have addressed the importance of B cell tolerance to collagen type II, a matrix protein, which is a target in rheumatoid arthritis (RA) and its mouse models. We generated a germline-encoded anti-collagen type II (CII) IgH replacement anti-C1 B cell mouse strain (ACB) to investigate how B cell tolerance to CII, a matrix protein, is subverted and to further understand pathogenesis of RA. Phenotypic analysis revealed that CII-specific B cells were surprisingly neither deleted nor anergized. Instead, they were readily detected in all lymphoid organs. Spontaneously produced autoantibodies could bind directly to cartilage surface without detectable pathology. However, exaggerated arthritis was seen after injection of anti-CII Abs specific for other epitopes. In addition, Abs from CII-specific hybridomas generated from ACB mice induced arthritis. Interestingly, IgH/L chain sequence data in B cell hybridomas revealed a lack of somatic mutations in autoreactive B cells. The ACB model provides the first possibility, to our knowledge, to study B cell tolerance to a matrix protein, and the observations made in the study could not be predicted from previous models. B cell-reactive epitopes on CII are largely shared between human RA and rodent CII-induced arthritis; this study, therefore, has important implications for further understanding of pathological processes in autoimmune diseases like RA.
23079134 Osteogenesis and osteoclast inhibition in rheumatoid arthritis patients treated with bisph 2012 Oct 18 INTRODUCTION: To investigate the effects of bisphosphonates (Bis) (etidronate, alendronate, and risedronate), alone and in combination with statin, on the BMD (bone mineral density) and bone metabolism of rheumatoid arthritis (RA) patients. METHODS: Seventy-seven RA patients who had been receiving prednisolone (PSL) and Bis for over 4 years were divided into two groups: Bis and Bis + statin (n = 42 and 35; average age, 66.4 and 65.3 years; average disease duration, 24.9 and 20.8 years; average PSL dose, 2.4 and 2.7 mg, respectively). Serum levels of NTX (N-terminal telopeptide of type I collagen), TRACP-5b (tartrate-resistant acid phosphate-5b), PICP (C-terminal propeptide of type I procollagen), and RANKL (receptor activator of NF-κB ligand) were measured over an 18-month period of treatment and follow-up. The BMD levels of the two groups at the radius, lumbar spine, and femoral neck were compared using DXA (dual-energy x-ray absorptiometry). RESULTS: A significant increase was only observed in the BMD of the lumbar spine at 18-months, but the BMDs of the radius and femoral neck decreased during the follow-up period in the Bis group. Meanwhile, a significant increase was observed in the BMD of the lumbar spine in the Bis + statin group during administration and the BMDs of the radius and femoral neck stayed at baseline. Among the markers of bone metabolism, serum NTX was up-regulated after 6 months in the Bis + statin group. Serum TRACP-5b was significantly increased during the follow-up period in the Bis + statin group, but only at 18 months in the Bis group. Serum PICP recovered to base line in the Bis + statin group, whereas that in the Bis group did not observably recover during the post-administration follow-up, but rather decreased. CONCLUSION: Our findings suggest that both bone resorption and bone formation were inhibited by long-term administration of Bis alone, whereas combination therapy with Bis + statin may be associated with a less marked inhibition of bone metabolism. Cardiovascular disease is highly prevalent in RA patients and some patients are prescribed statins and bisphosphonate. Bis + statin may confer more benefit to the bone metabolism of these patients compared to Bis alone.
21294892 A polymorphism in the interleukin-4 receptor affects the ability of interleukin-4 to regul 2011 Feb 4 INTRODUCTION: Rheumatoid arthritis (RA) is now suspected to be driven by pathogenic Th17 cells that secrete interleukin (IL)-17 and can be regulated by IL-4. A single-nucleotide polymorphism (SNP), I50V, in the coding region of the human IL-4 receptor (IL-4R) is associated with rapid development of erosive disease in RA. The present study was undertaken to determine whether this SNP renders the IL-4R less able to transduce signals that regulate IL-17 production. METHODS: Peripheral blood mononuclear cells were activated under Th17-stimulating conditions in the presence or absence of IL-4, and IL-17 production was measured by both enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Serum IL-17 was also measured by ELISA. Paired comparisons were performed using the two-tailed t-test. IL-4 receptor gene alleles were determined by polymerase chain reaction. RESULTS: In healthy individuals, IL-4 significantly inhibited IL-17 production by cells from subjects with the I/I genotype (P = 0.0079) and the I/V genotype (P = 0.013), but not the V/V genotype (P > 0.05). In a cross-sectional sample of patients with established RA, the magnitude of the in vitro effect of IL-4 was lower and was not associated with a specific IL-4R allele. Serum IL-17 levels were higher in RA patients than in healthy individuals, as was the percentage of CD4+ cells that produced IL-17. CONCLUSIONS: These results indicate that an inherited polymorphism of the IL-4R controls the ability of the human immune system to regulate the magnitude of IL-17 production. However, in established RA, this pattern may be altered, possibly due to secondary effects of both RA itself as well as immunomodulatory medications. Ineffective control of Th17 immune responses is a potential mechanism to explain why IL-4R is an important severity gene in RA, but this issue will require careful study of a cohort of new-onset RA patients.
21986594 Carbonic anhydrase II autoantibody and oxidative stress in rheumatoid arthritis. 2011 Dec OBJECTIVES: To investigate the relationship between carbonic anhydrase (CA) II autoantibody and lipid peroxidation, certain antioxidant parameters, and cytokines in rheumatoid arthritis (RA) patients. DESIGN AND METHODS: Serum levels of CA II autoantibody, cytokines (TNFα, IL-6, IFN-γ, IL-1β) and bone markers (crosslaps, osteocalcine) and erythrocyte levels of antioxidant enzyme activities (SOD, CAT, GPx), GSH and MDA, and CA activities were measured in RA patients and healthy controls. RESULTS: The CA II autoantibody titers were significantly higher (P<0.05), and erythrocyte SOD activities were significantly lower (P<0.05) in RA patients. A significant negative correlation between CA II autoantibody titers and SOD activities in RA group was established (r=-0.430, p=0.006). The elevated cytokine levels could not be correlated with CA II autoantibody levels in RA. CONCLUSION: These results suggest that increased erythrocyte oxidative stress observed in RA may be effective in the mechanism of CA II autoantibody formation.
22586171 Mesenchymal stem cells are conditionally therapeutic in preclinical models of rheumatoid a 2012 Oct OBJECTIVE: The role of mesenchymal stem cells (MSC) in experimental arthritis is undoubtedly conflicting. This study explored the effect of bone marrow-derived MSC in previously untested and pathogenetically different models of rheumatoid arthritis (RA). METHODS: MSC were tested both in an induced (adjuvant-induced) and a spontaneous (K/BxN) arthritis model. Arthritis was assessed clinically and histologically. The proliferation of splenocytes and fibroblast-like synoviocytes (FLS) in the presence of MSC was measured by radioactivity incorporation. Toll-like receptor (TLR) expression was measured by real-time PCR. T-regulatory cell (Treg) frequency, T-cell apoptosis and cytokine secretion were monitored by flow cytometry. RESULTS: MSC, in vitro, strongly inhibited critical cell populations; splenocytes and FLS. In contrast, MSC proved ineffective in vivo, unless they were administered before disease onset, an effect implying that the inflammatory arthritic milieu potentially abrogates MSC immunomodulatory properties. In order to alleviate inflammation before MSC infusion, the authors administered, at arthritis onset, a short course with a proteasome inhibitor, bortezomib, whereas MSC were infused when established disease was expected. The bortezomib plus MSC group demonstrated a significantly decreased arthritis score over arthritic, MSC-only, bortezomib-only groups, also confirmed by histology and immunohistochemistry. The bortezomib plus MSC combination restored TLR expression and Treg frequency in blood and normalised FLS and splenocyte proliferation, apoptosis and cytokine secretion. CONCLUSION: MSC lose their immunomodulatory properties when infused in the inflammatory micromilieu of autoimmune arthritis. Conditioning of the recipient with bortezomib alters the disease microenvironment enabling MSC to modulate arthritis. Should milieu limitations also operate in human disease, this approach could serve as a strategy to treat RA by MSC.
22915625 Performance of the 2011 ACR/EULAR preliminary remission criteria compared with DAS28 remis 2013 Jul OBJECTIVE: To compare the performance of the preliminary American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria with the 28-joint count Disease Activity Score (DAS28) remission in unselected 'real-life' patients. METHODS: Remission was calculated according to the DAS28 and to both versions of the ACR/EULAR criteria (Boolean or Simplified Disease Activity Index (SDAI)-based) for 6864 patients with rheumatoid arthritis (RA) who were enrolled in the national database of the German Collaborative Arthritis Centres between 2007 and 2009. Logistic regression analyses identified factors that were responsible for patients in DAS28 remission to miss the new criteria. In addition, the functional status of patients who fulfilled the different remission criteria was compared with that of an age- and sex-matched population sample. RESULTS: Of all patients, 28% were in DAS28, 7% in Boolean and 11% in SDAI remission. Of those in DAS28 remission, 21.0% were also in Boolean and 34% also in SDAI remission. Higher scores for pain and fatigue, the presence of degenerative spine disease, longer disease duration and male gender were significantly associated with missing the new criteria despite being in DAS28 remission. Compared with age- and sex-matched samples from the general population, patients in DAS28 remission had a similar functional ability while patients in remission according to the new criteria had better functional scores. CONCLUSIONS: Patients fulfilling the new remission criteria tend to be not only free from active RA, but also from other disabling diseases. If these criteria are applied in clinical practice to guide treatment decisions, the impact of comorbidity should be taken into account.
20638217 Translating patient education theory into practice: developing material to address the car 2011 Jul OBJECTIVE: This paper describes the rationale and design of a theory-informed patient education programme addressing cardiovascular disease for people with rheumatoid arthritis (RA) to illustrate how theory can explicitly be translated into practice. METHODS: A steering group of rheumatologists and psychologists was convened to design the programme. The Common Sense Model, the Theory of Planned Behaviour and the Stages of Change Model were used to underpin the topics and activities in the programme. User involvement was sought. The programme was formatted into a manual and the reading age of the materials was calculated. RESULTS: A small group 8-week programme was designed. The structure of the patient education programme, including topics, underlying psychological theory as well as behaviour change techniques, is described. CONCLUSION: This patient education programme addresses a currently unmet educational need for patients with RA and uses theory to design, not just evaluate, the programme. This will allow both enhanced interpretation of the results when the programme is implemented and replication by other units if successful. PRACTICE IMPLICATIONS: The actual design and detail of education programmes merit wider dissemination to facilitate progress in the process of development and application.
21285230 Biological mechanisms of chronic fatigue. 2011 Jun Chronic fatigue is a common, poorly understood and disabling phenomenon in many diseases. We aim to provide an overview of fatigue in chronic autoimmune and inflammatory disease. Fatigue measurement, prevalence and confounding factors such as depression, sleep disorders and pain are reviewed in the first half of the article. In the second half of the article, we describe explanatory models of fatigue and fatigue signalling, with an emphasis on cytokines and sickness behaviour, oxidative stress, mitochondrial dysfunction and the impact of certain genes on fatigue.
21768167 Non-psychiatric comorbidity associated with Alzheimer's disease. 2011 Nov The burden of medical comorbidity in individuals with Alzheimer's disease is greater than that observed in matched individuals without dementia. This has important implications for all clinicians and healthcare providers who deal with this common condition. The prevalence of vascular risk factors and vascular disease is particularly high. Additionally, associations with a number of other chronic medical conditions have been described, including thyroid disorders, sleep apnoea, osteoporosis and glaucoma. This review gives an overview of evidenced medical (non-psychiatric) comorbidity associated with Alzheimer's disease and briefly explores the underlying mechanisms that may account for these associations.
22284820 Local administration of glucocorticoids decreases synovial citrullination in rheumatoid ar 2012 Jan 27 INTRODUCTION: Protein citrullination is present in the rheumatoid synovium, presumably contributing to the perpetuation of chronic inflammation, in the presence of specific autoimmunity. As a result, the present study examined the possibility that effective antirheumatic treatment will decrease the level of synovial citrullination. METHODS: Synovial biopsies were obtained from 11 rheumatoid arthritis (RA) patients before and after 8 weeks of treatment with 20 mg methotrexate weekly, 15 RA patients before and 2 weeks after an intraarticular glucocorticoid injection, and eight healthy volunteers. Synovial inflammation was assessed with double-blind semiquantitative analysis of lining thickness, cell infiltration, and vascularity by using a 4-point scale. Expression of citrullinated proteins (CPs) with the monoclonal antibody F95 and peptidylarginine deiminase (PAD) 2 and 4 was assessed immunohistochemically with double-blind semiquantitative analysis. In vitro synovial fluid (SF), peripheral blood (PB), mononuclear cells (MCs), and synovial explants obtained from RA patients were incubated with dexamethasone and analyzed with immunohistochemistry for expression of CP as well as PAD2 and PAD4 enzymes. RESULTS: The presence of synovial CP was almost exclusive in RA compared with healthy synovium and correlated with the degree of local inflammation. Treatment with glucocorticoids but not methotrexate alters expression of synovial CP and PAD enzymes, in parallel with a decrease of synovial inflammation. Ex vivo and in vitro studies suggest also a direct effect of glucocorticoids on citrullination, as demonstrated by the decrease in the level of citrullination and PAD expression after incubation of SFMC and synovial explants with dexamethasone. CONCLUSION: Synovial citrullination and PAD expression are dependent on local inflammation and targeted by glucocorticoids.
22679710 Psychometric properties of three medication adherence scales in patients with rheumatoid a 2012 Patient adherence to their health care protocols is important to encourage the best health outcomes in rheumatoid arthritis (RA); however, little attention has been given to assessing the psychometric properties of adherence measures in this patient population. The purpose of this study was to evaluate the psychometric properties of three existing self-report measures of medication adherence in a sample of patients with RA--the compliance-questionnaire-rheumatology (CQR), the Medication Adherence Report Scale (MARS), and the medication adherence scale (MAS). A cross-sectional study of 108 clinic patients with rheumatoid arthritis was conducted to evaluate the reliability and validity of the measures. Cronbach's alpha was .77 for both the CQR and a modified version of the MARS. For the MAS, the Kuder-Richardson 20 reliability was .25. Although not strong, test-retest reliability was adequate for all measures. Factor analysis indicated that both the MARS and the CQR measure two factors. All three instruments were moderately correlated with each other, with correlations ranging between .48 and .56. Although these scales were significantly correlated, moderate correlations among the scales indicate that they may not measure the same aspects of adherence. Among the three adherence measures, the modified MARS demonstrated the best evidence of reliability and validity and ease of administration in this sample of persons with RA.
22156289 Epidemiologic studies of psychosocial factors associated with quality of life among patien 2012 A link between affective disturbances and physical disorders has been suggested since the Greco-Roman era. However, evidence supporting an association between mind and body is limited and mostly comes from North America and Europe. Additional local epidemiologic studies are needed so that more evidence can be collected on effective treatments and health management. Epidemiologic studies of Japanese with rheumatoid arthritis (RA) and those on chronic hemodialysis examined the association between psychosocial factors and patient quality of life (QOL). Strong associations among depression, social support, and patient QOL were confirmed, which supports the findings of studies performed in Western countries. In addition, disparities between the perspectives of patients with RA and their doctors were observed. Alexithymia, a personality construct that reflects a deficit in the cognitive processing of emotion, had a stronger independent association with increased risk of 5-year mortality than did depression among patients with chronic hemodialysis. Physiological, biological, and psychosocial factors are associated and independently and interactively determine our health. Epidemiology is a powerful tool for identifying effective points of intervention, after considering all possible confounders. Future studies must clarify how health can be improved by using a psychosocial approach.
21622522 New drugs beyond biologics in rheumatoid arthritis: the kinase inhibitors. 2011 Sep Orally available small molecule compounds have recently been developed for the treatment of RA, and inhibitors of signalling cascades, specifically inhibitors of kinases, have reached advanced stages of clinical development. The p38 mitogen-activated protein kinase blockers have shown poor clinical response despite encouraging preclinical data. In contrast, inhibitors of the non-receptor tyrosine kinases, spleen tyrosine kinase and janus kinase 3, have demonstrated a significant clinical efficacy together with an acceptable safety profile. We herein present a review on published preclinical and clinical data on these new drugs.
22185348 A novel model of rheumatoid arthritis-associated interstitial lung disease in SKG mice. 2012 Mar Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is associated with increased mortality in up to 10% of patients with rheumatoid arthritis. Lung exposure to cigarette smoke has been implicated in disease development. Little is known about the mechanisms underlying the development of RA-ILD, in part due to the lack of an appropriate mouse model. The objectives of this study were (i) to test the suitability of SKG mice as a model of cellular and fibrotic interstitial pneumonia in the setting of autoimmune arthritis, and (ii) to determine the role of lung injury in the development of arthritis in SKG mice. Lung tissues were evaluated in arthritic SKG mice by quantifying cell accumulation in bronchoalveolar lavage, static compliance, collagen levels, and infiltrating cell phenotypes by flow cytometry and histology. Lung injury was induced by exposure to cigarette smoke or bleomycin. Arthritic SKG mice developed a patchy cellular and fibrotic interstitial pneumonia associated with reduced static compliance, increased collagen levels, and accumulation of inflammatory cells. Infiltrating cells comprised CD4+ T cells, B cells, macrophages, and neutrophils. Chronic exposure to cigarette smoke or initiation of lung injury with bleomycin did not cause arthritis. The pattern of lung disease suggests that arthritic SKG mice represent an authentic model of nonspecific interstitial pneumonia in RA-ILD patients. The lack of arthritis development after cigarette smoke or lung injury suggests that a model where breaches in immunologic tolerance are induced by lung inflammation and injury alone may be overly simplistic.
21695554 [Endoprosthetic replacement of rheumatoid finger joints]. 2011 Jul Resection arthroplasty, arthrodesis and prosthetic reconstruction are able to guarantee the maintenance of good functional ability of finger joints even in late stages and with severe destruction. Destruction of soft tissues of the finger joints cannot be corrected by prosthetic measures alone. A stabile situation of the wrist joint is one of the most important prerequisites for a normal performance of daily life activities. Silastic endoprostheses are still the gold standard for finger replacement in rheumatoid arthritis.
21360252 Pharmacokinetic-pharmacodynamic disease progression model for effect of etanercept in Lewi 2011 Jul PURPOSE: To develop a pharmacokinetic-pharmacodynamic disease progression (PK/PD/DIS) model to characterize the effect of etanercept in collagen-induced arthritis (CIA) rats on rheumatoid arthritis (RA) progression. METHODS: The CIA rats received either 5 mg/kg intravenous (IV), 1 mg/kg IV, or 5 mg/kg subcutaneous (SC) etanercept at day 21 post-disease induction. Effect on disease progression was measured by paw swelling. Plasma concentrations of etanercept were assayed by enzyme-linked immunosorbent assay (ELISA). PK profiles were fitted first; parameter estimates were applied to fit paw edema data for PD and DIS-related parameter estimation using ADAPT 5 software. RESULTS: The model contained a two-compartment PK model with Michaelis-Menten elimination. For SC administration, two additional mathematical functions for absorption were added. The disease progression component was an indirect response model with a time-dependent change in paw edema production rate constant (k(in)) assumed to be inhibited by etanercept. CONCLUSIONS: Etanercept has modest effects on paw swelling in CIA rats. The PK and PD profiles were well described by the developed PK/PD/DIS model, which may be used for other anti-cytokine biologic agents for RA.
21813053 Antinuclear antibodies are associated with tumor necrosis factor receptor I gene polymorph 2011 Jul OBJECTIVES: Antinuclear antibodies (ANA) are a common feature of autoimmune diseases such as rheumatoid arthritis (RA). Herein, we investigate the relationship between ANA and polymorphism in the tumour necrosis factor receptor (TNFR) genes. METHODS: Serum titers of ANA at diagnosis were measured in 267 patients with RA and a single nucleotide polymorphism (SNP) in each of the TNFR-I (36A/G) and TNFR-II (676T/G) genes was genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. Circulating levels of soluble TNFR (sTNFR) and TNF-α were also measured in some patients. RESULTS: Our initial analyses revealed the presence of ANA was associated with the TNFR-I 36A/G SNP, with a trend of increasing ANA frequency with G allele dosage (p=0.004). ANA status was also associated with lower sTNFR-I levels and a raised sTNFR-II/sTNFR-I ratio. The TNFR-II 676T/G SNP and circulating levels of sTNFR-II and TNF-α were not associated with ANA status. In an adjusted multivariate regression model the TNFR-I 36 GG genotype (OR 7.8, p=0.008) and levels of sTNFR-I (p=0.018) were independently associated with ANA status. CONCLUSIONS: Our findings suggest a possible link between the production of ANA and the TNF-α/TNFR-I signalling system, which may be related to the apoptosis-inducing ability of this cytokine.
21618146 Adiposity, joint and systemic inflammation: the additional risk of having a metabolic synd 2011 Adiposity is a predisposing condition to atherosclerosis, and rheumatoid arthritis (RA) also predisposes to accelerated atherosclerosis. Adiposity is one of the key features of the metabolic syndrome (MetS) and it is well recognised that a metabolic syndrome (and fat tissue) is a major player in this complex network. Endothelial dysfunction and carotid intima-media thickness, early pre-clinical markers of atherosclerosis which are the main determinants of cardiovascular (CV) morbidity and mortality, occur early on in RA. RA patients have an incidence of CV diseases at least two times higher than the general population. MetS and RA have a low and a severe-moderate degree of inflammation in common, respectively. Adipose tissue has emerged as a dynamic organ that releases several inflammatory and immune mediators (adipokines). In addition, fat has been recognised as a producer of B cell activating factor (BAFF) and of chemerin, an inducer at the chondrocyte level of IL1β, TNFα, IL6, IL8 and MMP13, thus possibly contributing to cartilage damage. Since fat produces inflammation, to obtain a full control of the CV risk in RA, data suggest that it is therefore mandatory to have a "tight control" of both RA and MetS-related inflammation, especially if RA presents MetS as a co-morbidity.
22825303 Quantification of IFNγ- and IL17-producing cells after stimulation with citrullinated pro 2013 Oct Antibodies against citrullinated proteins are highly specific for rheumatoid arthritis (RA) and are currently used as a diagnostic marker. In this study, we wanted to quantify the numbers of T cells that react to a wide range of citrullinated proteins in a wide range of HLA-DR subtypes in order to investigate whether citrullination might create T-cell neo-epitopes and could initiate a universal T-cell response. Therefore, PBMCs from healthy volunteers and RA patients were stimulated with a citrullinated and non-citrullinated cell extract on IFNγ-ELISpot. We found a significantly higher number of IFNγ-secreting cells after stimulation with citrullinated proteins compared to non-citrullinated proteins in RA patients (1:14,441 cells vs. 1:32,880 cells) as well as in healthy subjects (1:6,261 reactive cells compared to 1:16,212 cells). Additionally, a higher number of IL17-secreting cells were found after stimulation with citrullinated proteins compared to their non-citrullinated counterparts. Our data indicate that citrulline-dependent T-cell response is not restricted to RA patients but that citrullination as such gives rise to a universal break in tolerance.
22568099 [IgG4-related disease]. 2012 Feb IgG4-related disease is a recently recognized systemic syndrome characterized by mass-forming lesions, mainly in exocrine tissue, that consist of lymphoplasmacytic infiltrates and sclerosis. There are numerous IgG4+ plasma cells in the affected tissues, and the serum IgG4 level is elevated in these patients. Ocular adnexal IgG4-related disease frequently involves bilateral lacrimal glands, and obliterative phlebitis is rare. Moreover, some malignant lymphomas, especially mucosa-associated lymphoid tissue lymphoma, arise from ocular adnexal IgG4-related disease. It is known that hyper IL-6 syndromes, such as multicentric Castleman's disease, rheumatoid arthritis, and other autoimmune diseases, fulfill the histological diagnostic criteria for IgG4-related disease; therefore, hyper IL-6 syndromes and IgG4-related disease cannot be differentially diagnosed by immunohistochemical staining alone. However, upon laboratory examination, hype IL-6 syndromes show elevation of the CRP level, polyclonal hyper gamma-globulinemia, anemia, and hypoalbuminemia. These findings are quite different from IgG4-related disease, which is not characterized by elevated serum IgA, IgM, and CRP levels. Therefore, laboratory findings are crucial for the differential diagnosis.