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Chronic Arthritis (chronic + arthritis)
Selected AbstractsEffect of inflammation on kidney function and pharmacokinetics of COX-2 selective nonsteroidal anti-inflammatory drugs rofecoxib and meloxicamJOURNAL OF APPLIED TOXICOLOGY, Issue 7 2008Sam Harirforoosh Abstract Chronic arthritis adversely affects glomerular function and nonsteroidal anti-inflammatory drugs (NSAIDs) reduce electrolyte urinary excretion. In addition, both acute and chronic inflammations may alter clearance of drugs. We studied (a) the effects of inflammation on the renal function and pharmacokinetics of rofecoxib and meloxicam; (b) whether inflammation could exacerbate reduced electrolytes excretion changes observed with NSAIDs; and (c) the influence of inflammation on distribution of these drugs into the kidney. Single oral doses of rofecoxib (10 mg kg,1), meloxicam (3 mg kg,1) or placebo were administered to normal or pre-adjuvant arthritic rats. Blood and urine samples were collected for the measurement of plasma nitrite, BUN and creatinine. The urinary excretion of sodium and potassium was also determined. Nitrite, BUN and plasma creatinine were increased starting on day 9 in the groups with inflammation. Sodium and potassium excretion rates were not affected by inflammation. Meloxicam did not alter the electrolyte excretion in any of the groups. Rofecoxib significantly decreased sodium and potassium excretion in normal rats and potassium excretion in inflamed rats. Inflammation significantly increased plasma concentrations of rofecoxib, but not meloxicam. The ratios of the kidney:plasma concentrations were not significantly altered by inflammation following either drug. Inflammation altered kidney function, demonstrated by increases in BUN and plasma creatinine. However, it did not influence the urinary electrolytes excretion. Since we have observed similar patterns of the effect of NSAIDs on kidney under healthy and inflammatory conditions, one may conclude that inflammation does not exacerbate the adverse effect. Copyright © 2008 John Wiley & Sons, Ltd. [source] Chronic arthritis aggravates vascular lesions in rabbits with atherosclerosis: A novel model of atherosclerosis associated with chronic inflammationARTHRITIS & RHEUMATISM, Issue 9 2008Raquel Largo Objective To determine whether systemic inflammation induced by chronic antigen-induced arthritis (AIA) accelerates vascular lesions in rabbits with atherosclerosis. Methods Two models of atherosclerosis and chronic AIA were combined. Atherosclerosis was induced by coupling a hyperlipemic diet with an endothelial lesion at the femoral arteries, while chronic AIA was induced by ovalbumin injection. Markers in sera and peripheral blood mononuclear cells (PBMCs) as well as vessels and synovial membranes from the rabbits with the double phenotype (both chronic AIA and atherosclerosis) were compared with those from rabbits with each disease alone. Results Serum levels of interleukin-6, C-reactive protein, and prostaglandin E2 increased in rabbits with both chronic AIA and atherosclerosis as compared with healthy animals or animals with either chronic AIA alone or atherosclerosis alone. NF-,B binding and CCL2 and cyclooxygenase 2 (COX-2) expression were higher in PBMCs from rabbits with both chronic AIA and atherosclerosis than in PBMCs from healthy rabbits. The intima-media thickness ratio of femoral arteries was equally increased in rabbits with atherosclerosis alone and in rabbits with both chronic AIA and atherosclerosis, but the latter group showed a higher level of macrophage infiltration. Femoral CCL2 and COX-2 expression was increased in rabbits with both chronic AIA and atherosclerosis as compared with rabbits with atherosclerosis alone. In the aortas, vascular lesions were found in 27% of rabbits with atherosclerosis alone and in 60% of rabbits with both chronic AIA and atherosclerosis. Rabbits with both chronic AIA and atherosclerosis exhibited more severe synovitis and higher synovial expression of CCL2 than did rabbits with chronic AIA alone. Conclusion The onset of chronic AIA in animals with atherosclerosis resulted in the local and systemic up-regulation of mediators of tissue inflammation and plaque instability associated with a higher incidence of aortic lesions. This model could represent a novel approach to the study of inflammation-associated atherosclerosis. [source] Type II collagen without adjuvant induces eosinophilic arthritisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2007Robert Bockermann Abstract Eosinophilia is a characteristic feature of many inflammatory diseases including inflammatory bowel disease and asthma. It also occurs in a subtype of rheumatoid arthritis but the role of eosinophils has been unclear and animal models have been lacking. Here, we introduce a new mouse model to study the role of eosinophilia in arthritis. Intraperitoneal injection of type II collagen alone, without any adjuvant, was sufficient to induce chronic arthritis in a mouse with transgenic T cells specific for type II collagen. The arthritis was accompanied by infiltration of eosinophils into the synovial tissue and the disease could be blocked with neutralizing anti-IL-5 antibodies. To our knowledge, this is the first description of an eosinophilic disease form of destructive arthritis. [source] Inflammation alters somatostatin mRNA expression in sensory neurons in the ratEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2005Seham A. Abd El-Aleem Abstract Proinflammatory neuropeptides, such as substance P and calcitonin gene-related peptide, are up-regulated in primary afferent neurons in acute and chronic inflammation. While these neuropeptides have been intensively studied, potentially anti-inflammatory and/or anti-nociceptive neuropeptides such as somatostatin (SS) have been less widely investigated. Endogenous somatostatin is thought to exert a tonic antinociceptive effect. Exogenous SS is anti-inflammatory and antinociceptive and is thought to exert these actions through inhibition of proinflammatory neuropeptide release. In this study we have compared the expression of somatostatin in two inflammatory models: arthritis, a condition associated with increased nociception, and periodontitis, in which there is little evidence of altered nociceptive thresholds. In acute arthritis (< 24 h) SS mRNA was down-regulated in ipsilateral dorsal root ganglia (DRG; 52 ± 7% of control, P < 0.05), and up-regulated in contralateral DRG (134 ± 10% of control; P < 0.05). In chronic arthritis (14 days) this pattern of mRNA regulation was reversed, with SS being up-regulated ipsilaterally and down-regulated contralaterally. In chronic mandibular periodontitis (7,10 days), SS mRNA was up-regulated in only the mandibular division of the ipsilateral trigeminal ganglion (TG) (day 7, 219 ± 9% and day 10, 217 ± 12% of control; P < 0.02) but showed no change in other divisions of the trigeminal ganglion or in the mesencephalic nucleus. These data show that antinociceptive and anti-inflammatory neuropeptides are also regulated in inflammation. It is possible that the degree of inflammation and nociception seen may depend on the balance of pro- and anti-inflammatory and nociceptive peptide expression in a particular condition. [source] Is it possible to identify early predictors of the future cost of chronic arthritis?FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2009The VErA project Abstract This study was conducted to identify early predictors of the total cost of inflammatory arthritis (IA). One hundred and eighty patients affected by undifferentiated arthritis (UA) or rheumatoid arthritis (RA) were included in the French Very Early rheumatoid Arthritis (VErA) cohort between 1998 and 2001. Health economic data for 2003 were collected using a patient self-questionnaire. Results were analysed in terms of direct, indirect and total costs in 2003 euros (2003,) for the population as a whole and in diagnostic subgroups. A payor perspective (the French National Health Insurance, in this case) was adopted. Multiple linear regression models were used to identify predictors of total cost from among the criteria assessed on recruitment. Results of the study showed that for the study population as a whole, the mean total cost was ,4700 per patient. The costs attributable to the RA and UA sub-groups were ,5928 and ,2424 per patient, respectively. In a univariate analysis, certain parameters were significantly correlated with a higher cost of illness. In the multivariate analysis, some of these parameters were further identified as being predictive of higher cost. Two strong significant, early predictors of total cost were identified: higher pain (P = 0.002) and the presence of rheumatoid factor (P = 0.004). In the RA sub-group, lower grip strength of the dominant hand (P = 0.039) was another predictor of the illness's subsequent economic impact. In conclusion, our data show that simple clinical and laboratory parameters can be used early in the course of IA to predict the condition's impact on healthcare budgets. [source] Synovial mast cells: role in acute and chronic arthritisIMMUNOLOGICAL REVIEWS, Issue 1 2007Peter A. Nigrovic Summary:, Mast cells reside in the normal synovium and increase strikingly in number in rheumatoid arthritis and other joint diseases. Given the broad spectrum of activity of this lineage, it has for decades been considered probable that mast cells are involved in the pathophysiology of synovitis. Recent work in murine arthritis has substantiated this suspicion, showing that mast cells can contribute importantly to the initiation of inflammatory arthritis. However, the role of the greatly expanded population of synovial mast cells in established arthritis remains unknown. Here we review the current understanding of mast cell function in acute arthritis and consider the potentially important influence of this cell on key processes within the chronically inflamed synovium, including leukocyte recruitment and activation, fibroblast proliferation, angiogenesis, matrix remodeling, and injury to collagen and bone. We also consider recent evidence supporting an immunomodulatory or anti-inflammatory role for mast cells as well as pharmacologic approaches to the mast cell as a therapeutic target in inflammatory arthritis. [source] Invasive aspergillosis with polyarthritisMYCOSES, Issue 11-12 2004S. F. Mekan Aspergillosis; Aspergillus fumigatus; invasive Infektion; polyarthritis Summary We report a case of septic arthritis of multiple joints in an 18-year-old male caused by Aspergillus fumigatus. His initial presentation was of low-grade fever followed by involvement of both knee and ankle joints. Later, there was also involvement of metacarpophalangeal joints. Diagnosis was based on biopsy and culture of the skin and joint lesions. The symptoms resolved readily under administration of itraconazole. We recommend that clinicians should be alerted of potential fungal etiology in cases of fever and chronic arthritis, which is unresponsive to conventional medical therapy. Zusammenfassung Es wird über einen Fall von Aspergillus fumigatus -bedingter septischer Arthritis mehrerer Gelenke bei einem 18-jährigen Mann berichtet. Die Anfangssymptomatik präsentierte sich als mäßiges Fieber gefolgt von Beschwerden in beiden Knie- und Fußgelenken. Später traten Beschwerden an den Mittelhandgelenken auf. Die Diagnose stützte sich auf Biopsie- und Kulturbefunde aus Haut- und Gelenkläsionen. Die Beschwerden heilten unter Itraconazol-Therapie rasch ab. Bei fieberhafter chronicher Arthritis sollte deshalb stets eine Pilziätiologie erwogen werden, wenn das Krankheitsbild nicht auf eine konventionelle Therapie anspricht. [source] Monoclonal anti-CD8 therapy induces disease amelioration in the K/BxN mouse model of spontaneous chronic polyarthritisARTHRITIS & RHEUMATISM, Issue 10 2010Bruno R. Raposo Objective CD8+ T cells are part of the T cell pool infiltrating the synovium in rheumatoid arthritis (RA). However, their role in the pathogenesis of RA has not been fully delineated. Using the K/BxN mouse model of spontaneous chronic arthritis, which shares many similarities with RA, we studied the potential of CD8+ T cell depletion with monoclonal antibodies (mAb) to stop and reverse the progression of experimental arthritis. Methods CD8+ T cells from the blood and articular infiltrate of K/BxN mice were characterized for cell surface phenotypic markers and for cytokine production. Additionally, mice were treated with specific anti-CD8 mAb (YTS105 and YTS169.4), with and without thymectomy. Results CD8+ T cells from the peripheral blood and joints of K/BxN mice were mainly CD69+ and CD62L,CD27+ T cells expressing proinflammatory cytokines (interferon-, [IFN,], tumor necrosis factor , [TNF,], interleukin-17a [IL-17A], and IL-4), and granzyme B. In mice receiving anti-CD8 mAb, the arthritis score improved 5 days after treatment. Recovery of the CD8+ T cells was associated with a new increase in the arthritis score after 20 days. In thymectomized and anti-CD8 mAb,treated mice, the arthritis score improved permanently. Histologic analysis showed an absence of inflammatory infiltrate in the anti-CD8 mAb,treated mice. In anti-CD8 mAb,treated mice, the serologic levels of TNF,, IFN,, IL-6, and IL-5 normalized. The levels of the disease-related anti,glucose-6-phosphate isomerase antibodies did not change. Conclusion These results indicate that synovial activated effector CD8+ T cells locally synthesize proinflammatory cytokines (IFN,, TNF,, IL-17, IL-6) and granzyme B in the arthritic joint, thus playing a pivotal role in maintaining chronic synovitis in the K/BxN mouse model of arthritis. [source] Protective targeting of high mobility group box chromosomal protein 1 in a spontaneous arthritis modelARTHRITIS & RHEUMATISM, Issue 10 2010Therese Östberg Objective High mobility group box chromosomal protein 1 (HMGB-1) is a DNA binding nuclear protein that can be released from dying cells and activated myeloid cells. Extracellularly, HMGB-1 promotes inflammation. Clinical and experimental studies demonstrate that HMGB-1 is a pathogenic factor in chronic arthritis. Mice with combined gene deficiency for DNase II and IFNRI spontaneously develop chronic, destructive polyarthritis with many features shared with rheumatoid arthritis. DNase II is needed for macrophage degradation of engulfed DNA. The aim of this study was to evaluate a potential pathogenic role of HMGB-1 in this novel murine model. Methods The course of arthritis, assessed by clinical scoring and histology, was studied in DNase II,/, × IFNRI,/, mice, in comparison with heterozygous and wild-type mice. Synovial HMGB-1 expression was analyzed by immunohistochemistry. Serum levels of HMGB-1 were determined by Western immunoblotting and enzyme-linked immunosorbent assay (ELISA), and anti,HMGB-1 autoantibodies were detected by ELISA. Macrophage activation was studied by immunostaining for intracellular interleukin-1, and HMGB-1. HMGB-1 was targeted with truncated HMGB-1,derived BoxA protein, acting as a competitive antagonist, with intraperitoneal injections every second day for 5 weeks. Results DNase II,/, × IFNRI,/, mice developed symmetric polyarthritis with strong aberrant cytosolic and extracellular HMGB-1 expression in synovial tissue, in contrast to that observed in control animals. Increased serum levels of HMGB-1 and HMGB-1 autoantibodies were recorded in DNase II,/, × IFNRI,/, mice, both prior to and during the establishment of disease. Systemic HMGB-1,specific blockade significantly ameliorated the clinical disease course, and a protective effect on joint destruction was demonstrated by histologic evaluation. Conclusion HMGB-1 is involved in the pathogenesis of this spontaneous polyarthritis, and intervention with an HMGB-1 antagonist can mediate beneficial effects. [source] Efficacy of traditional and biologic agents in different clinical phenotypes of adult-onset Still's diseaseARTHRITIS & RHEUMATISM, Issue 8 2010Stefano Franchini Objective To evaluate the efficacy of antiinflammatory agents, steroids, immunosuppressants, and biologic agents in patients with adult-onset Still's disease (AOSD) who have either chronic articular disease or nonchronic disease. Methods Forty-five patients with AOSD were seen and followed up for at least 2 years at our institution, from 1991 to 2008. The majority of patients were treated with several therapeutic regimens; a total of 152 efficacy trials were administered. Data regarding the type of medication, the dosage used, and the outcome of these trials were collected and analyzed. Results Our data showed that the efficacy of monotherapy with a nonsteroidal antiinflammatory drug was very low (16%) and confirmed good efficacy of steroid therapy (63%), particularly in patients without chronic articular disease (78%). Patients whose disease did not respond to steroid therapy at the time of disease onset were at risk of the subsequent development of chronic arthritis. Disease-modifying antirheumatic drug (DMARD) monotherapy was successful in controlling steroid-resistant or steroid-dependent disease in 60% of patients. Methotrexate and cyclosporine showed the best response rates. The combination of high-dose steroids and cyclosporine was administered to successfully control some acute life-threatening complications. Only 6 patients had disease that was both steroid resistant and DMARD resistant. Treatment with biologic agents eventually led to satisfactory control of disease manifestations in 5 (83%) of these 6 patients. Conclusion Steroids were less effective in patients with chronic articular disease than in those with nonchronic disease. The administration of DMARDs early after disease onset could be beneficial in patients with steroid-resistant disease who are at risk of the development of chronic articular disease. Biologic agents proved to be highly effective in both steroid-resistant and DMARD-resistant AOSD. [source] Anti,neuropilin-1 peptide inhibition of synoviocyte survival, angiogenesis, and experimental arthritisARTHRITIS & RHEUMATISM, Issue 1 2010Jin-Sun Kong Objective To delineate the role of neuropilin-1 (NP-1), a vascular endothelial growth factor receptor (VEGFR), in rheumatoid inflammation and to determine whether blockade of NP-1 could suppress synoviocyte survival and angiogenesis. Methods VEGF111,165 peptide, which encompasses the NP-1 binding domain of VEGF165, was generated by cleaving VEGF165 with plasmin. The effect of this peptide on the interaction between VEGF165 and its receptor was determined by 125I-VEGFR binding assay. Assays to determine synoviocyte apoptosis, adhesion, and migration were performed in the presence of VEGF165 and/or the peptide. VEGF165 -induced angiogenesis was assessed by measuring the proliferation, tube formation, and wounding migration of endothelial cells (ECs). Mice were immunized with type II collagen to induce experimental arthritis. Results VEGF111,165 peptide specifically inhibited the binding of 125I-VEGF165 to NP-1 on rheumatoid synoviocytes and ECs. The peptide eliminated the VEGF165 -mediated increase in synoviocyte survival and activation of p-ERK and Bcl-2. The peptide also completely inhibited a VEGF165 -induced increase in synoviocyte adhesion and migration. In addition, the anti,NP-1 peptide blocked VEGF165 -stimulated proliferation, capillary tube formation, and wounding migration of ECs in vitro. VEGF165 -induced neovascularization in a Matrigel plug in mice was also blocked by treatment with the peptide. Finally, subcutaneous injection of anti,NP-1 peptide suppressed arthritis severity and autoantibody formation in mice with experimental arthritis and inhibited synoviocyte hyperplasia and angiogenesis in arthritic joints. Conclusion Anti,NP-1 peptide suppressed VEGF165 -induced increases in synoviocyte survival and angiogenesis, and thereby blocked experimental arthritis. Our findings suggest that anti,NP-1 peptide could be useful in alleviating chronic arthritis. [source] Inflammatory arthritis in caspase 1 gene,deficient mice: Contribution of proteinase 3 to caspase 1,independent production of bioactive interleukin-1,ARTHRITIS & RHEUMATISM, Issue 12 2009Leo A. B. Joosten Objective Caspase 1, a known cysteine protease, is a critical component of the inflammasome. Both caspase 1 and neutrophil serine proteases such as proteinase 3 (PR3) can process pro,interleukin-1, (proIL-1,), a crucial cytokine linked to the pathogenesis of rheumatoid arthritis. This study was undertaken to establish the relative importance of caspase 1 and serine proteases in mouse models of acute and chronic inflammatory arthritis. Methods Acute and chronic arthritis were induced in caspase 1,/, mice, and the lack of caspase 1 was investigated for its effects on joint swelling, cartilage metabolism, and histopathologic features. In addition, caspase 1 activity was inhibited in mice lacking active cysteine proteases, and the effects of dual blockade of caspase 1 and serine proteases on arthritis severity and histopathologic features were evaluated. Results Surprisingly, caspase 1,/, mice, in a model of acute (neutrophil-dominated) arthritis, developed joint swelling to an extent similar to that in wild-type control mice. Joint fluid concentrations of bioactive IL-1, were comparable in caspase 1,/, mice and controls. In contrast, induction of chronic arthritis (characterized by minimal numbers of neutrophils) in caspase 1,/, mice led to reduced joint inflammation and less cartilage damage, implying a caspase 1,dependent role in this process. In mice lacking neutrophil serine PR3, inhibition of caspase 1 activity resulted in decreased bioactive IL-1, concentrations in the synovial tissue and less suppression of chondrocyte anabolic function. In addition, dual blockade of both PR3 and caspase 1 led to protection against cartilage and bone destruction. Conclusion Caspase 1 deficiency does not affect neutrophil-dominated joint inflammation, whereas in chronic arthritis, the lack of caspase 1 results in reduced joint inflammation and cartilage destruction. These findings suggest that inhibitors of caspase 1 are not able to interfere with the whole spectrum of IL-1, production, and therefore such inhibitors may be of therapeutic value only in inflammatory conditions in which limited numbers of neutrophils are present. [source] Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritisARTHRITIS & RHEUMATISM, Issue 9 2009Ruolin Guo Objective This study was undertaken to investigate the effect of lymphatic inhibition on joint and draining lymph node (LN) pathology during the course of arthritis progression in mice. Methods Tumor necrosis factor (TNF),transgenic mice were used as a model of chronic inflammatory arthritis. Mice were subjected to contrast-enhanced magnetic resonance imaging to obtain ankle and knee joint synovial volumes and draining popliteal LN volumes before and after 8 weeks of treatment with vascular endothelial growth factor receptor 3 (VEGFR-3) neutralizing antibody, VEGFR-2 neutralizing antibody, or isotype IgG. Animals were subjected to near-infrared lymphatic imaging to determine the effect of VEGFR-3 neutralization on lymph transport from paws to draining popliteal LNs. Histologic, immunohistochemical, and reverse transcriptase,polymerase chain reaction analyses were used to examine lymphatic vessel formation and the morphology of joints and popliteal LNs. Results Compared with IgG treatment, VEGFR-3 neutralizing antibody treatment significantly decreased the size of popliteal LNs, the number of lymphatic vessels in joints and popliteal LNs, lymphatic drainage from paws to popliteal LNs, and the number of VEGF-C,expressing CD11b+ myeloid cells in popliteal LNs. However, it increased the synovial volume and area of inflammation in ankle and knee joints. VEGFR-2 neutralizing antibody, in contrast, inhibited both lymphangiogenesis and joint inflammation. Conclusion These findings indicate that lymphangiogenesis and lymphatic drainage are reciprocally related to the severity of joint lesions during the development of chronic arthritis. Lymphatic drainage plays a beneficial role in controlling the progression of chronic inflammation. [source] Association of the autoimmunity locus 4q27 with juvenile idiopathic arthritisARTHRITIS & RHEUMATISM, Issue 3 2009H. M. Albers Objective Juvenile idiopathic arthritis (JIA) is characterized by chronic arthritis and an autoimmune etiology. In several autoimmune diseases, including rheumatoid arthritis (RA), an association with the 4q27 locus has been reported. We undertook this study to investigate the possible role of the 4q27 locus in JIA. Methods A case,control association study was conducted, with a total of 655 Caucasian JIA patients and 791 healthy controls divided into 2 independent sample sets. The rs6822844 marker in the 4q27 locus was genotyped. Results In the first and larger sample set, a 5% decrease in T allele frequency was observed in patients compared with controls (allelic odds ratio [OR] 0.72 [95% confidence interval 0.55,0.95], P = 0.019), and in the second set, a 3% decrease was observed (allelic OR 0.81 [95% confidence interval 0.61,1.09], P = 0.169). The combined data set generated an OR of 0.76 (95% confidence interval 0.62,0.93, P = 7.08 × 10,3). When the different JIA subtypes were analyzed individually, significant decreases were seen in the subtypes with a polyarticular course of disease (extended oligoarthritis [P = 0.019] and rheumatoid factor,negative polyarthritis [P = 0.038]). Conclusion Our findings suggest that the 4q27 locus, previously reported to be associated with RA, type 1 diabetes mellitus, celiac disease, and psoriatic arthritis, is also associated with susceptibility to JIA. [source] | ||||||||||