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ID PMID Title PublicationDate abstract
21391201 Critical proinflammatory role of thymic stromal lymphopoietin and its receptor in experime 2011 Jul OBJECTIVE: The interleukin-7 (IL-7)-related cytokine thymic stromal lymphopoietin (TSLP) is a potent activator of myeloid dendritic cells, enhancing Th2-mediated hypersensitivity, and it has been implicated in the pathogenesis of atopic diseases. Although intraarticular concentrations of TSLP have been shown to be increased in patients with rheumatoid arthritis (RA), the functional capacities of TSLP in arthritis are poorly studied. The purpose of this study was to investigate the effects of TSLP administration and TSLP receptor deficiency on immune activation, arthritis severity, and tissue destruction in T cell-driven arthritis models of RA. METHODS: Immunopathology was studied in arthritic mice that were given multiple injections of murine recombinant TSLP and in mice that were deficient in the TSLP receptor (TSLPR(-/-)). Arthritis severity and incidence were determined by visual examination of the paws. Joint destruction was determined by assessing radiographs and the immunohistochemistry of ankle joints. Total cellularity and numbers of T cell subsets were assessed. Proinflammatory mediators were measured by multianalyte profiling of serum or paw protein extracts. RESULTS: Administration of TSLP significantly exacerbated the severity of collagen-induced arthritis and the joint damage that was associated with increased T cell activation. Furthermore, TSLPR(-/-) mice had less severe arthritis than did wild-type mice. TSLPR(-/-) mice had diminished concentrations of local proinflammatory and catabolic mediators, including IL-17, IL-1β, IL-6, basic fibroblast growth factor, and matrix metalloproteinase 9, while levels of the regulatory cytokines IL-10 and IL-13 were increased. CONCLUSION: TSLP and its receptor enhance Th17-driven arthritis and tissue destruction in experimental arthritis. The increased expression of TSLP as well as the increased number of TSLPR-expressing cells in the joints of patients with RA suggest that TSLP and its receptor constitute novel therapeutic targets in RA.
21149847 Transcriptional profiling of liver and effect of glucocorticoids in a rat adjuvant-induced 2011 Jul Glucocorticoids (GCs), despite having many undesirable side effects, remain effective for the treatment of many inflammatory diseases and are commonly used as benchmark drugs in animal models of disease. However, the molecular mechanisms underling systemic GC effects in these models are poorly characterized. In this study, prednisolone and dexamethasone were evaluated in the fully established Lewis rat adjuvant-induced arthritis (AIA) model. In AIA, adjuvant administration induced polyarticular and systemic inflammation, which included spleen and liver. In the liver, multifocal hepatic granulomas were observed. To characterize the systemic response and the pathways responsible for GC effects, histology, transcriptional profiling, and immunohistochemistry (IHC) were performed. There was a decrease in the incidence and histologic severity score for granulomas with GC treatment. There was no effect on cellular composition of granulomas as assessed by IHC for CD3+ lymphocytes, macrophages, and B cells, but there was a significant reduction in infiltrating lymphocytes in the hepatic parenchyma. By Affymetrix microarray analysis, 10% of hepatic transcripts were altered (P<.01) in livers from AIA rats, with ~31% of them partially reversed with treatment with dexamethasone and ~13% with prednisolone. Many of these altered hepatic transcripts correspond to human genes that are dysregulated in the synovium in human rheumatoid arthritis (RA), indicating that the rat AIA model shares features with human RA. These data establish molecular changes in the liver and the effect of GCs in rat AIA, which can be used to aid in understanding the mechanism of action of novel anti-inflammatory compounds in this animal model.
22153301 Chlamydophila psittaci subclinical infection in chronic polyarthritis. 2011 Nov OBJECTIVES: Recent evidence indicates that Chlamydophila psittaci (Cp) may establish chronic infections, which may promote autoimmunity and/or B cell lymphoproliferation. METHODS: The presence of a subclinical Cp infection was investigated in 293 patients with chronic inflammatory polyarthritis, including 175 patients with rheumatoid factor (RF)-positive and/or anti-CCP-positive rheumatoid arthritis (RA) and 118 with seronegative polyarthritis (46 RF-negative/anti-CCP-negative RA, 36 psoriatic arthritis and 36 undifferentiated spondyloarthritis). One hundred and eighty-five healthy controls were also investigated. The presence of Cp infection was assessed in peripheral blood mononuclear cells using several PCR protocols targeting different regions of the Cp genome (16S-23S spacer rRNA, OMP-A, and Gro-EL). The DNA of other Chlamydia species (C. Pneumoniae and C. Trachomatis) was also investigated. Amplicons were sequenced to confirm the specificity of PCR products. RESULTS: The presence of a subclinical chronic Cp infection was observed in a significantly higher percentage of patients with chronic polyarthritis (38/293; 13%) compared to healthy controls (1/185, 0.5%; OR=27.4, 95%CI:3.73-201.6, p<0.0001). Furthermore, the prevalence of Cp was higher in seronegative polyarthritis (23/118; 19.5%) than in seropositive RA patients (15/175; 7.4%; OR=2.58, 95%CI: 1.28-5.19, p=0.0078). The highest prevalence of Cp infection was found in RF/anti-CCP double-negative RA patients (13/46, 28.3%), followed by patients with psoriatic arthritis (6/36; 16.7%). No differences in age, sex, disease duration and undergoing therapies were noticed between Cp-positive and Cp-negative patients; nor between seropositive and seronegative patients. CONCLUSIONS: Cp may be an infectious trigger possibly involved in the pathogenesis of a fraction of inflammatory polyarthritis, particularly in seronegative patients.
20165950 A case of psoriasis vulgaris with diffuse idiopathic skeletal hyperostosis involved with o 2012 May Diffuse idiopathic skeletal hyperostosis (DISH) is difficult to distinguish from various forms of inflammatory arthritis, including psoriatic arthritis (PsA), rheumatoid arthritis, and ankylosing spondylitis. A 67-year-old Japanese male had been treated for psoriasis vulgaris for 13 years. Numbness of his right arm and lower limbs and spinal stiffening had developed 7 years prior to his initial evaluation at our facility. He noticed pain mainly while exercising. There were symmetrical marginal syndesmophytes in the spine, from the thoracic vertebrae to the upper lumbar vertebrae, on radiological examinations. We therefore suspected DISH. Furthermore, ossifications of the posterior and anterior longitudinal ligaments were noted in the cervical spine. Laboratory examinations revealed a normal peripheral white blood cell count, serum C-reactive protein, and erythrocyte sedimentation rate, and he was negative for rheumatoid factor. We detected human leukocyte antigen B39 but not B27. All distal interphalangeal joints were swollen but without pain. X-ray imaging showed narrowing of the joint space, and the consolidation of the joint was recognized, but there was no new juxta-articular bone formation. Based on clinical and radiological findings, we concluded that he had DISH and not PsA. DISH was indicated by marked radiological features of the axial skeleton, particularly the thoracic spine, but may also have involved the peripheral joints. DISH is one of the entheseal disorders, and 10% of Japanese middle-aged and elderly men have DISH. Therefore, the differentiation of DISH from PsA is necessary in psoriasis patients with spinal involvement.
22402741 Disease-promoting and -protective genomic loci on mouse chromosomes 3 and 19 control the i 2012 Jun Proteoglycan (PG)-induced arthritis (PGIA) is a murine model of rheumatoid arthritis. Arthritis-prone BALB/c mice are 100% susceptible, whereas the major histocompatibility complex-matched DBA/2 strain is completely resistant to PGIA. To reduce the size of the disease-suppressive loci for sequencing and to find causative genes of arthritis, we created a set of BALB/c.DBA/2-congenic/subcongenic strains carrying DBA/2 genomic intervals overlapping the entire Pgia26 locus on chromosome 3 (chr3) and Pgia23/Pgia12 loci on chr19 in the arthritis-susceptible BALB/c background. Upon immunization of these subcongenic strains and their wild-type (BALB/c) littermates, we identified a major Pgia26a sublocus on chr3 that suppressed disease onset, incidence and severity via controlling the complex trait of T-cell responses. The region was reduced to 3 Mbp (11.8 Mbp with flanking regions) in size and contained gene(s) influencing the production of a number of proinflammatory cytokines. Additionally, two independent loci (Pgia26b and Pgia26c) suppressed the clinical scores of arthritis. The Pgia23 locus (∼3 Mbp in size) on chr19 reduced arthritis susceptibility and onset, and the Pgia12 locus (6 Mbp) associated with low arthritis severity. Thus, we have reached the critical sizes of arthritis-associated genomic loci on mouse chr3 and chr19, which are ready for high-throughput sequencing of genomic DNA.
21364051 Diagnostic and predictive value of acute-phase reactants in adult undifferentiated periphe 2011 Mar OBJECTIVE: To review the available literature on the diagnostic and predictive value of acute-phase reactants in adult undifferentiated peripheral inflammatory arthritis (UPIA) as an evidence base for generating multinational clinical practice recommendations in the 3e Initiative in Rheumatology. METHODS: A systematic literature search was carried out using Medline, Embase, the Cochrane Library, and abstracts presented at the 2007 and 2008 meetings of the American College of Rheumatology and European League Against Rheumatism, searching for prognostic and diagnostic markers of acute-phase reactants in adult UPIA. Articles that fulfilled predefined inclusion criteria were systematically reviewed, and the quality was appraised. Likelihood ratios (LR), sensitivity, and specificity for diagnostic and prognostic outcomes were calculated. RESULTS: A total of 18 publications out of 3699 identified references were included in the review. Only a small number of studies with significant heterogeneity, including different outcome measures and different cutoff values, were eligible for review, so pooling data was not possible. Overall, LR showed poor diagnostic and prognostic performance for most investigated acute-phase reactants. Available data showed some value for erythrocyte sedimentation rate in establishing a diagnosis in patients with undifferentiated arthritis; some prognostic and diagnostic value for C-reactive protein; some prognostic value for plasma viscosity in predicting persistence of arthritis; and some diagnostic value for sulfhydryl levels and matrix metalloproteinase-3 in establishing a diagnosis of rheumatoid arthritis. CONCLUSION: There is little published evidence concerning the diagnostic and predictive value of acute-phase reactants in patients with UPIA. Studies were heterogeneous, and "undifferentiated arthritis" was not well defined or was equivocally defined. The role of acute-phase reactants in diagnosing and predicting outcome in patients presenting with undifferentiated arthritis is limited.
22213084 Spinal cathepsin S and fractalkine contribute to chronic pain in the collagen-induced arth 2012 Jun OBJECTIVE: The induction of rheumatoid arthritis (RA) by active and passive immunization of mice results in the development of pain at the same time as the swelling and inflammation, with both peripheral and central sensitization contributing to joint pain. The purpose of this study was to examine the development of pain in the rat model of collagen-induced arthritis (CIA) and to evaluate the contribution of neuroimmune interactions to established arthritis pain. METHODS: Mechanical hypersensitivity was assessed in female Lewis rats before and up to 18 days after induction of CIA by immunization with type II collagen. The effect of selective inhibitors of microglia were then evaluated by prolonged intrathecal delivery of a cathepsin S (CatS) inhibitor and a fractalkine (FKN) neutralizing antibody, from day 11 to day 18 following immunization. RESULTS: Rats with CIA developed significant mechanical hypersensitivity, which started on day 9, before the onset of clinical signs of arthritis. Mechanical hypersensitivity peaked with the severity of the disease, when significant microglial and astrocytic responses, alongside T cell infiltration, were observed in the spinal cord. Intrathecal delivery of microglial inhibitors, a CatS inhibitor, or an FKN neutralizing antibody attenuated mechanical hypersensitivity and spinal microglial response in rats with CIA. CONCLUSION: The inhibition of microglial targets by centrally penetrant CatS inhibitors and CX(3) CR1 receptor antagonists represents a potential therapeutic avenue for the treatment of pain in RA.
23009010 [The alterations of proteins glycosylation in rheumatic diseases]. 2012 Aug The alterations in glycosylation of serum glycoproteins were reported in several pathological conditions including rheumatic diseases. The many studies demonstrated the occurrence of some differentially glycosylated plasma immunoglobulins, especially IgG in rheumatoid arthritis. The most characteristic features are the decrease in galactose content, the presence of N-acetylglucosamine and the increase in fucose content. The structure of oligosaccharides attached to the antibody Fc region affect the pharmacokinetics and antibody effector functions of antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. The changes in immunoglobulin glycosylation was suggested to be important in the etiology of rheumatoid athritis and correlated with the disease severity. In addition to impaired glycosylation of imunoglubulins, in rheumatic diseases exist the disturbances in glycosylation of both acute-phase and non acute-phase response, such as alpha-1 acid glycoprotein, haptoglobin and alpha-2 macroglobulin. The alterations in glycosylation of these glycoproteins were also correlated with the disease activity.
23071697 Bile salt-stimulated lipase plays an unexpected role in arthritis development in rodents. 2012 OBJECTIVE: The present study aimed to explore the hypothesis that bile salt-stimulated lipase (BSSL), in addition to being a key enzyme in dietary fat digestion during early infancy, plays an important role in inflammation, notably arthritis. METHODS: Collagen-induced arthritis (CIA) and pristane-induced arthritis (PIA) in rodents are commonly used experimental models that reproduce many of the pathogenic mechanisms of human rheumatoid arthritis, i.e. increased cellular infiltration, synovial hyperplasia, pannus formation, and erosion of cartilage and bone in the distal joints. We used the CIA model to compare the response in BSSL wild type (BSSL-WT) mice with BSSL-deficient 'knock-out' (BSSL-KO) and BSSL-heterozygous (BSSL-HET) littermates. We also investigated if intraperitoneal injection of BSSL-neutralizing antibodies affected the development or severity of CIA and PIA in mice and rats, respectively. RESULTS: In two consecutive studies, we found that BSSL-KO male mice, in contrast to BSSL-WT littermates, were significantly protected from developing arthritis. We also found that BSSL-HET mice were less prone to develop disease compared to BSSL-WT mice, but not as resistant as BSSL-KO mice, suggesting a gene-dose effect. Moreover, we found that BSSL-neutralizing antibody injection reduced both the incidence and severity of CIA and PIA in rodents. CONCLUSION: Our data strongly support BSSL as a key player in the inflammatory process, at least in rodents. It also suggests the possibility that BSSL-neutralizing agents could serve as a therapeutic model to reduce the inflammatory response in humans.
22985876 Comparison of the efficacy and skin permeability of topical NSAID preparations used in Eur 2012 Dec 18 This study compared the efficacy and skin permeability of nine topical preparations of nonsteroidal anti-inflammatory drugs (NSAIDs) (ketoprofen, diclofenac, flurbiprofen, and piroxicam patches; and ketoprofen, diclofenac, piroxicam, niflumic acid, and ibuprofen gels) available in the European Union. The anti-inflammatory effect of these NSAID preparations was evaluated in rat models of acute inflammation (carrageenan or yeast treatment) and chronic inflammation (collagen or adjuvant treatment). Skin permeability of the preparations was evaluated in vitro using mouse skin. In rats with acute inflammation, both ketoprofen preparations significantly inhibited carrageenan-induced edema and yeast-induced hyperalgesia. Flurbiprofen and diclofenac preparations also showed a significant anti-inflammatory effect, but the ketoprofen products were the most potent among the four patch preparations and five gel preparations. With repeated application, the ketoprofen patch significantly decreased edema from day 3 in collagen-treated rats, while other preparations (ketoprofen gel, diclofenac patch, and diclofenac gel) decreased edema from day 7. In rats with adjuvant-induced arthritis, only the ketoprofen patch significantly decreased edema after 2 weeks of application. In the skin permeation study, the ketoprofen preparations showed higher skin permeability compared with the other NSAID preparations. These results suggested that ketoprofen preparations had the most potent anti-inflammatory and analgesic activity related to good skin permeability. Efficacy of the ketoprofen patch was comparable to or better than that of ketoprofen gel at a lower dose and frequency of administration. Ketoprofen products, especially the patch preparation, could be useful for treating inflammatory pain in diseases like osteoarthritis and rheumatoid arthritis.
21656600 Linseed oil: an investigation of its antiarthritic activity in experimental models. 2012 Feb Food sources rich in omega-3 fatty acids have been valued for their beneficial effect in the management of inflammatory disorders. The present study evaluates the antiarthritic and immunomodulatory activity of Linum usitatissimum fixed oil (LUFO) in experimental models. The LUFO produced a dose-dependent reduction in joint swelling and circulating TNF-α levels in both preventive and curative protocols of arthritis induced by complete Freund's adjuvant (CFA). Expression of TNF-R1 and Interleukin (IL) 6 proteins in the arthritic paw was also significantly reduced in the LUFO-treated animals. In the cotton pellet induced granuloma model, LUFO treatment significantly reduced the dry granuloma weight as compared with the control group. Results of our present study thus demonstrate the antiarthritic and disease modifying activity of LUFO. We believe that dietary incorporation of LUFO may be beneficial in the prevention and management of rheumatoid arthritis and other chronic inflammatory disorders.
22390734 Dutch translation and cross-cultural adaptation of the PROMIS® physical function item ban 2012 Mar 5 INTRODUCTION: Patient-reported physical function is an established outcome domain in clinical studies in rheumatology. To overcome the limitations of the current generation of questionnaires, the Patient-Reported Outcomes Measurement Information System (PROMIS®) project in the USA has developed calibrated item banks for measuring several domains of health status in people with a wide range of chronic diseases. The aim of this study was to translate and cross-culturally adapt the PROMIS physical function item bank to the Dutch language and to pretest it in a sample of patients with arthritis. METHODS: The items of the PROMIS physical function item bank were translated using rigorous forward-backward protocols and the translated version was subsequently cognitively pretested in a sample of Dutch patients with rheumatoid arthritis. RESULTS: Few issues were encountered in the forward-backward translation. Only 5 of the 124 items to be translated had to be rewritten because of culturally inappropriate content. Subsequent pretesting showed that overall, questions of the Dutch version were understood as they were intended, while only one item required rewriting. CONCLUSIONS: Results suggest that the translated version of the PROMIS physical function item bank is semantically and conceptually equivalent to the original. Future work will be directed at creating a Dutch-Flemish final version of the item bank to be used in research with Dutch speaking populations.
22884682 Therapeutic role of a vaccine targeting RANKL and TNF-α on collagen-induced arthritis. 2012 Nov Targeting tumor necrosis factor-α (TNF-α) and activator of NF-κB ligand (RANKL) has been proved highly successful in rheumatoid arthritis (RA) models and patients. This raises a possibility whether a single agent simultaneously targeting TNF-α and RANKL provides a potential therapeutic opportunity. This study aimed to design a dual functional vaccine and evaluate its therapeutic effects in RA mice model. Standard molecular biological techniques were used to generate human RANKL-TNF-like core fusion protein (RTFP-2) vaccine. High titers of antibodies against human TNF-α and RANKL were elicited and the RTFP-2 antiserum decreased TNF-α mediated apoptosis of L929 cells to 41% compared with 90% in positive controls. In addition, the antiserum completely abrogated osteoclastogenesis in vitro. Immunization with RTFP-2 also reduced the mortality of TNF-α induced cachexia from 56% to 28%. The RANKL-mediated hypercalcemic effects were significantly attenuated in RTFP-2 vaccinated mice. Furthermore, RTFP-2 vaccine significantly mitigated the incidence and severity of CIA via inhibition of inflammation and bone resorption. Our results showed the RTFP-2 vaccine of dual targets ameliorated the symptoms of CIA mice, suggesting the potential possibility to treat inflammatory bone diseases such as RA.
21809323 Regulation of systemic and local myeloid cell subpopulations by bone marrow cell-derived g 2011 Aug OBJECTIVE: Even though there are clinical trials assessing granulocyte-macrophage colony-stimulating factor (GM-CSF) blockade in rheumatoid arthritis (RA), questions remain as to how GM-CSF acts as a proinflammatory cytokine. The aims of this study on the regulation of arthritis progression by GM-CSF were to determine the source of the GM-CSF, whether there are systemic effects, the changes in synovial tissue leukocyte populations, and the arthritis model dependence on GM-CSF. METHODS: Bone marrow chimeras were used to determine the source of GM-CSF required for the development of collagen-induced arthritis (CIA). The K/BxN serum-transfer model of arthritis was tested in GM-CSF(-/-) mice and using anti-GM-CSF monoclonal antibodies. Cell populations from arthritic mice were assessed by differential staining and flow cytometry. RESULTS: In the CIA model, GM-CSF produced by bone marrow-derived cells was required for arthritis development. GM-CSF blockade, while ameliorating the development of CIA, was found to have systemic effects, limiting the increase in circulating Ly-6C(high) monocytes and neutrophils. GM-CSF blockade led to fewer synovial macrophages (both Ly-6C(high) and Ly-6C(low)), neutrophils, and lymphocytes. In the absence of GM-CSF, K/BxN serum-transfer arthritis initially developed normally; however, the numbers of Ly-6C(high) monocytes and synovial macrophages (both Ly-6C(high) and Ly-6C(low)) were again reduced, along with the peak disease severity and maintenance. CONCLUSION: GM-CSF is a key player in two arthritis models, participating in interactions between hemopoietic cells, both locally and systemically, to control myeloid cell numbers as well as presumably to "activate" them. These results could be useful for the analysis of current clinical trials targeting GM-CSF in patients with RA.
22978269 7,3'-dimethoxy hesperetin inhibits inflammation by inducing synovial apoptosis in rats wit 2013 Feb Rheumatoid arthritis (RA) is an autoimmune disease characterized by pronounced inflammation and excessive synovial hyperplasia within affected joint. We previously reported 7, 3'-dimethoxy hesperetin (DMHP) as a highly anti-inflammatory active derivative of hesperidin showed apparent pro-apoptotic effect in vitro on fibroblast-like synoviocytes of rats with adjuvant arthritis (AA), an animal model of RA. Here, we investigated the therapeutic effects of DMHP on inflammation and synovial apoptosis in rats with AA in vivo. Paw swelling, arthritis index, TNF-α and IL-1β serum levels were measured to evaluate the effect of DMHP on inflammation in AA rats. DNA ladder detection and TUNEL assay were used to investigate the pro-apoptotic effect of DMHP on synovial apoptosis in vivo. Bcl-2, Bax mRNA and protein expressions in synovium were determined by real-time Q-PCR and western blot, respectively. We found DMHP inhibited secondary hind paw swelling and arthritis index, and decreased TNF-α and IL-1β serum levels in AA rats. Typical DNA ladder formation was found in DNA extraction of synovium from DMHP treated groups. The number of apoptotic synovial cells was elevated with DMHP treatment in TUNEL assay. DMHP markedly decreased Bcl-2 expression whereas increased Bax expression in synovium of AA rats at both transcription and protein levels. Moreover, DMHP treatment on AA rats significantly decreased the protein ratio of Bcl-2/Bax in synovium. In conclusion, DMHP has an apparent therapeutic effect on inflammation in rats with AA. Mechanisms of this effect are partly related to induction of synovial apoptosis through modulation of Bcl-2 and Bax expression.
22729466 Circulating fibrocytes contribute to the pathogenesis of collagen antibody-induced arthrit 2012 Nov OBJECTIVE: Rheumatoid arthritis (RA) is a systemic autoimmune disease resulting in joint inflammation. Fibroblast-like synoviocytes in affected joints are responsible for pannus formation and cytokine/chemokine production, resulting in leukocyte recruitment and bone/cartilage destruction. Previously, we identified a multipotent stem cell population of activated fibrocytes in the blood of patients with RA that may have a role in disease pathogenesis, perhaps as fibroblast-like synoviocyte precursors. The aim of this study was to further characterize the contribution of circulating fibrocytes to the pathogenesis of RA. METHODS: Circulating fibrocytes were isolated from mice with collagen-induced arthritis and transferred intravenously into recipient mice with collagen antibody-induced arthritis (CAIA). The activation status of circulating fibrocytes was determined using multidimensional phosphoflow cytometric analysis of the signaling effectors STAT-5, STAT-1, AKT, and JNK. Circulating fibrocyte trafficking and matrix metalloproteinase (MMP) activity were assessed in real time using fluorescence molecular tomography, specifically labeling circulating fibrocytes with CellVue Maroon and measuring MMP activity using MMPSense 680. RESULTS: The numbers of circulating fibrocytes were increased early during the onset of CAIA, concomitant with their activation, as measured by phosphorylation of STAT-5. Adoptive transfer of circulating fibrocytes augmented disease scores and increased class II major histocompatibility complex expression and peripheral blood phosphoactivation profiles in recipient mice with CAIA. Notably, adoptively transferred fluorescence-labeled circulating fibrocytes rapidly migrated into the affected joints of recipient mice with CAIA, and this was associated with augmented neutrophil recruitment into affected joints and MMP activation. CONCLUSION: Circulating fibrocytes migrate to joints and influence the onset of disease processes in arthritis.
22532629 Cardiovascular comorbidities in patients with psoriatic arthritis: a systematic review. 2013 Feb OBJECTIVE: Data regarding cardiovascular comorbidity and cardiovascular risk factors in patients with psoriatic arthritis (PsA) are limited. To evaluate the cardiovascular risk profile, a systematic literature search was performed to provide an extensive summary of all studies available on cardiovascular risk in PsA. METHODS: Medline, EMBASE and the Cochrane library were searched from January 1966 to April 2011 for English language articles on data concerning cardiovascular diseases and cardiovascular risk factors in PsA. Review articles, case reports and studies on psoriasis alone were excluded. RESULTS: Twenty-eight articles were included in this review. Studies on all-cause mortality revealed mixed results. Available data on cardiovascular disease appeared more consistent, indicating an increased cardiovascular mortality and morbidity in PsA. Commensurate with this, surrogate markers of subclinical atherosclerosis, arterial stiffness and cardiovascular risk factors, for example hypertension, dyslipidaemia, obesity and metabolic-related factors, were more prominent in PsA compared with controls. Suppression of inflammation was linked with a favourable effect on cardiovascular surrogate markers, for example carotid intima media thickness and endothelial dysfunction, in several (un)controlled studies. CONCLUSION: Most studies point towards an increased cardiovascular risk in PsA, broadly on a par with the risk level in rheumatoid arthritis, emphasising the need for similar cardiovascular risk management in both conditions. Further studies are needed to indicate whether inflammatory suppression or modification of traditional cardiovascular risk factors, or both, will reduce cardiovascular risk.
22349671 The forgotten chamber: right-ventricular functions in juvenile idiopathic arthritis. 2012 Jun Cardiac involvement, such as pericarditis, myocarditis, and endocarditis, is seen in juvenile idiopathic arthritis. Although there have been some reports about right-ventricular systolic and diastolic functions of adults with rheumatoid arthritis and left-ventricular systolic and diastolic functions of children with JIA, there have been no studies about RV functions of children with JIA. The aim of this study was to determine RV functions in children with JIA. We performed conventional echocardiography and tissue Doppler imaging measurements of the right ventricle of patients with JIA. All patients were in sinus rhythm at the time of examination without overt LV heart failure and with normal LV ejection fraction. Fifty-five children with the diagnosis of JIA and 33 healthy control subjects were included in the study. Peak systolic, early, and late diastolic tricuspid annular velocities were significantly decreased in JIA patients compared with healthy controls (p < 0.05). Isovolumic accelaration (IVA), as a measure of myocardial acceleration during isovolumic contraction of the right ventricle, was also significantly lower in JIA patients than in healthy controls (p < 0.05). RV systolic and diastolic functions, in addition to the previously shown LV functions, are affected in JIA patients. IVA decreases in JIA patients and may be used as an alternative, noninvasive parameter for the assessment of RV systolic function in children with JIA.
21960045 Effects of testosterone, estrogen and progesterone on TNF-α mediated cellular damage in r 2012 Oct Sexual dimorphism is a well-established phenomenon in rheumatoid arthritis, with women exhibiting higher disease severity. Understanding the role of sex hormones using in vivo animal models is limited due to the systemic effects as well as the difficulty in exploring different dose combinations of the hormones simultaneously. However, cell culture systems pose ideal systems for exploring different combinations and concentrations of the hormones simultaneously. In this study, the procedure for isolation of arthritic fibroblasts was standardized using a combination of collagenase and trypsin based on maximal yield and viability after employing different enzymatic disaggregation procedures. The cultured synovial fibroblasts from arthritic rats did not differ significantly from normal rat fibroblasts in terms of proliferation or secretion of inflammatory mediators. Stimulation of fibroblasts with TNF-α was standardized and TNF-α stimulated rat arthritic synovial fibroblasts exhibited an ideal in vitro system for screening antiinflammatory molecules. The effects of physiological and pharmacological concentrations of testosterone, estrogen and progesterone were studied on TNF-α induced cellular damage in rat arthritic synovial fibroblasts. The results showed that estrogen and testosterone exerted antiinflammatory effects on rat arthritic synovial fibroblasts at physiological and pharmacological concentrations. However, there was no significant difference in the effects between physiological and pharmacological concentrations. Progesterone independently did not show any protective effects. In combination with physiological concentrations of estrogen, progesterone abrogated estrogen's protective effect but it exhibited protection in combination with pharmacological concentrations of estrogen.
21730326 Identification of a lysosomal pathway that modulates glucocorticoid signaling and the infl 2011 Jul 5 The antimalaria drug chloroquine has been used as an anti-inflammatory agent for treating systemic lupus erythematosus and rheumatoid arthritis. We report that chloroquine promoted the transrepression of proinflammatory cytokines by the glucocorticoid receptor (GR). In a mouse collagen-induced arthritis model, chloroquine enhanced the therapeutic effects of glucocorticoid treatment. By inhibiting lysosome function, chloroquine synergistically activated glucocorticoid signaling. Lysosomal inhibition by either bafilomycin A1 (an inhibitor of the vacuolar adenosine triphosphatase) or knockdown of transcription factor EB (TFEB, a master activator of lysosomal biogenesis) mimicked the effects of chloroquine. The abundance of the GR, as well as that of the androgen receptor and estrogen receptor, correlated with changes in lysosomal biogenesis. Thus, we showed that glucocorticoid signaling is regulated by lysosomes, which provides a mechanistic basis for treating inflammation and autoimmune diseases with a combination of glucocorticoids and lysosomal inhibitors.