bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complete remission of experimental arthritis by joint targeting of glucocorticoids with long‐circulating liposomes
Authors: Metselaar Josbert M. , Wauben Marca H. M. , Wagenaar‐Hilbers Josee P. A. , Boerman Otto C. , Storm Gert 
Published: July 2003

AbstractObjectiveTo increase the therapeutic activity of glucocorticoids in experimental arthritis by encapsulation in long‐circulating polyethylene glycol liposomes, which have shown the ability to preferentially accumulate in inflamed joints after intravenous administration.MethodsRats with adjuvant‐induced arthritis (AIA) were treated intravenously with liposomal and free prednisolone phosphate (PLP) a few days after the first signs of disease. The effect on paw inflammation scores during the weeks after treatment was evaluated. Liposome biodistribution and joint localization were investigated by labeling the preparation with radioactive 111In‐oxine. By studying PLP encapsulated in other types of liposomes, which show a distinctive tissue distribution pattern and reduced accumulation in inflamed joints, the importance of targeted delivery to inflamed joints for achieving an increased therapeutic effect was illustrated.ResultsLiposomal PLP proved to be highly effective in the rat AIA model. A single injection of 10 mg/kg resulted in complete remission of the inflammatory response for almost a week. In contrast, the same dose of unencapsulated PLP did not reduce inflammation, and only a slight effect was observed after repeated daily injections. Evidence was found that preferential glucocorticoid delivery to the inflamed joint was the key factor explaining the observed strong therapeutic benefit obtained with the liposomal preparation, while other possible mechanisms, such as splenic accumulation or prolonged release of prednisolone in the circulation, were excluded.ConclusionTargeted delivery using long‐circulating liposomes is a promising, novel means to successfully intervene in arthritis with glucocorticoid therapy.
Osteoprotegerin protects against generalized bone loss in tumor necrosis factor–transgenic mice
Authors: Schett Georg , Redlich Kurt , Hayer Silvia , Zwerina Jochen , Bolon Brad , Dunstan Colin , Görtz Birgit , Schulz Andreas , Bergmeister Helga , Kollias Giorgos , Steiner Günter , Smolen Josef S. 
Published: July 2003

AbstractObjectiveTo investigate the role of tumor necrosis factor (TNF) in systemic bone loss of chronic inflammatory conditions, such as rheumatoid arthritis (RA), and to address the therapeutic potential of osteoclast blockade.MethodsWe investigated systemic bone changes in human TNF transgenic (hTNFtg) mice, which spontaneously developed severe inflammatory arthritis.ResultsOsteodensitometry revealed a significant decrease in trabecular bone mineral density (BMD) (−37%) in hTNFtg mice, and histomorphometry revealed a dramatic loss of bone volume (−85%) compared with wild‐type controls. Osteoclast‐covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly elevated, suggesting increased osteoclast‐mediated bone resorption in hTNFtg mice. Osteoprotegerin (OPG) completely blocked TNF‐mediated bone loss by increasing BMD (+89%) and bone volume (+647%). Most strikingly, formation of primary spongiosa was dramatically increased (+563%) in hTNFtg mice after OPG treatment. Osteoclast‐covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly decreased by OPG, suggesting effective blockade of osteoclast‐mediated bone resorption. OPG did not influence levels of hTNF, TNF receptor I (TNFRI), interleukin‐1β (IL‐1β), and IL‐6. However, OPG decreased bone formation parameters (osteoblast‐covered bone surface and serum osteocalcin levels), which were elevated in hTNFtg mice. In contrast to OPG, bisphosphonates and anti‐TNF treatment did not affect generalized bone loss in hTNFtg mice. Anti‐TNF, however, did not affect levels of TNF and TNFRI at the concentrations tested. These data indicate that generalized bone loss due to increased TNF can be blocked by OPG.ConclusionOPG may represent a potent tool for preventing generalized loss of bone mass in chronic inflammatory disorders, especially RA.
Salmonella septicemia in rheumatoid arthritis patients receiving anti–tumor necrosis factor therapy: Association with decreased interferon‐γ production and toll‐like receptor 4 expression
Authors: Netea Mihai G. , Radstake Timothy , Joosten Leo A. , van der Meer Jos W. M. , Barrera Pilar , Kullberg Bart Jan 
Published: July 2003

AbstractObjectivePatients treated with antibodies to tumor necrosis factor α (TNFα) have an increased susceptibility to intracellular infections. We describe 2 patients with rheumatoid arthritis (RA) who developed Salmonella septicemia during anti‐TNF treatment. The aim of this study was to identify the mechanisms involved in the increased susceptibility of anti‐TNF–treated patients to intracellular microorganisms.MethodsWe evaluated an additional 6 RA patients receiving anti‐TNF antibodies, 5 RA patients not receiving anti‐TNF therapy, and 6 age‐ and sex‐matched healthy volunteers. The in vitro production of cytokines (interleukin‐1β [IL‐1β], IL‐6, interferon‐γ [IFNγ], and IL‐10) upon bacterial stimulation of whole blood and the expression of Toll‐like receptor 4 (TLR‐4) on dendritic cells from RA patients treated with infliximab, RA patients not treated with infliximab, and healthy controls were compared.ResultsStimulation with heat‐killed Salmonella typhimurium or Candida albicans led to a significantly decreased production of IFNγ, but not to a decreased production of IL‐10, IL‐β, or IL‐6, in anti‐TNF–treated RA patients compared with RA patients who were not receiving anti‐TNF antibodies and compared with healthy controls. TNF‐blocking treatment ex vivo significantly inhibited TLR‐4 expression on dendritic cells from RA patients and healthy controls.ConclusionSince recognition of microorganisms by TLR‐4 and activation of phagocytes by IFNγ are essential mechanisms for the defense against intracellular and fungal pathogens, we propose that this pathway is crucial for the increased susceptibility to these microorganisms in patients receiving anti‐TNF therapy.
Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts
Authors: Mori Yasuji , Chen Shu‐Jen , Varga John 
Published: July 2003

AbstractObjectiveScleroderma is characterized by excessive synthesis and accumulation of matrix proteins in lesional tissues. Transforming growth factor β (TGFβ) plays a central role in the pathogenesis of fibrosis by inducing and sustaining activation of fibroblasts; however, the underlying mechanisms are poorly understood. We undertook this study to examine the expression and function of SMADs, recently characterized intracellular effectors of TGFβ signaling, in scleroderma fibroblasts.MethodsPrimary dermal fibroblasts obtained from 14 patients with scleroderma and from 4 healthy adult volunteers were studied. Northern analysis was used to determine the expression of endogenous SMAD messenger RNA (mRNA), and Western analysis was used to determine SMAD protein expression. Intracellular compartmentalization of cellular SMAD proteins in the presence and absence of TGFβ was studied by antibody‐mediated immunofluorescence confocal microscopy. The effect of TGFβ blockade on SMAD subcellular distribution was determined using anti‐TGFβ antibodies as well as a dominant‐negative TGFβ receptor type II (TGFβRII) vector to disrupt TGFβ responses. SMAD‐regulated luciferase reporter expression was examined to investigate the potential functional significance of activation and nuclear accumulation of endogenous SMADs in scleroderma fibroblasts.ResultsProtein and mRNA levels of SMAD3, but not of SMAD4 or SMAD7, were variably elevated in scleroderma fibroblasts compared with those from healthy controls. In sharp contrast to control fibroblasts, which displayed predominantly cytoplasmic localization of SMAD3/4 in the absence of exogenous TGFβ, in scleroderma fibroblasts SMAD3 and SMAD4 consistently showed elevated nuclear localization. Furthermore, phosphorylated SMAD2/3 levels were elevated and nuclear localization of phosphorylated SMAD2/3 was increased, suggesting activation of the SMAD pathway in scleroderma fibroblasts. Blockade of autocrine TGFβ signaling with antibodies or by expression of dominant‐negative TGFβRII failed to normalize SMAD subcellular distribution, suggesting that elevated nuclear SMAD import was due to alterations downstream of the TGFβ receptors. The activity of a SMAD‐responsive minimal promoter–reporter construct was enhanced in transiently transfected scleroderma fibroblasts.ConclusionThis study is the first to demonstrate apparently ligand‐independent constitutive activation of the intracellular TGFβ/SMAD signaling axis in scleroderma fibroblasts. SMAD signaling may be a mechanism contributing to the characteristic phenotype of scleroderma fibroblasts and playing a role in the pathogenesis of fibrosis.
Association of the –2849 interleukin‐10 promoter polymorphism with autoantibody production and joint destruction in rheumatoid arthritis
Authors: Lard L. R. , van Gaalen F. A. , Schonkeren J. J. M. , Pieterman E. J. , Stoeken G. , Vos K. , Nelissen R. G. H. H. , Westendorp R. G. J. , Hoeben R. C. , Breedveld F. C. , Toes R. E. M. , Huizinga T. W. J. 
Published: July 2003

AbstractObjectiveTo analyze the –2849 A/G interleukin‐10 (IL‐10) promoter polymorphism, which is associated with high (AG/GG) and low (AA) IL‐10 production, in a cohort of rheumatoid arthritis (RA) patients and controls in order to gain a better understanding of its role in the incidence and progression of RA.MethodsAllele frequencies of the promoter polymorphism –2849 A/G and carriage rates were compared in 283 RA patients, 413 patients with other rheumatic diseases, and 1,220 healthy controls. The rate of joint damage and baseline levels of IgG and IgM rheumatoid factors and anti–citrullinated peptide antibodies were measured and were correlated with the IL‐10 gene polymorphism. Furthermore, the correlation between the invasiveness of fibroblast‐like synoviocytes (FLS) and the −2849 IL‐10 genotype was tested.ResultsThe IL‐10 genotype was not associated with the incidence of RA, but instead, correlated with disease progression, as determined by the extent of joint destruction. A higher rate of joint destruction was observed in patients with the genotype associated with high IL‐10 production. Since FLS are thought to be involved in joint destruction, we analyzed IL‐10 genotypes in conjunction with FLS invasiveness. Although adenoviral gene transfer of IL‐10 to FLS inhibited their invasiveness, no differences were observed in vitro in the FLS from RA patients who were –2849 non‐G carriers compared with those who were G carriers. Instead, patients with the –2849 AG/GG genotype, which is associated with high IL‐10 production, had higher autoantibody titers at baseline.ConclusionThe –2849 IL‐10 promoter polymorphism is associated with autoantibody production and subsequent joint damage in RA.
Successful treatment of collagen‐induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity
Authors: Kokkola R. , Li J. , Sundberg E. , Aveberger A.‐C. , Palmblad K. , Yang H. , Tracey K. J. , Andersson U. , Harris H. Erlandsson 
Published: July 2003

AbstractObjectiveExtracellular high mobility group box chromosomal protein 1 (HMGB‐1) is a recently identified, endogenous, potent tumor necrosis factor– and interleukin‐1 (IL‐1)–inducing protein detectable in inflamed synovia in both human and experimental disease. In the present study, we examined clinical effects in collagen‐induced arthritis (CIA) using therapeutic administration of neutralizing HMGB‐1 antibodies or truncated HMGB‐1–derived A‐box protein, a specific, competitive antagonist of HMGB‐1.MethodsCIA was induced in DBA/1j mice or dark agouti rats, and animals were examined daily for signs of arthritis. Treatment with polyclonal anti–HMGB‐1 antibodies or the A‐box protein was initiated at the onset of disease and was administered intraperitoneally twice daily for 7 days. Animals were killed 8 days after initiation of therapy, and immunohistochemical analysis of synovial tissue specimens was performed.ResultsSystemic administration of anti–HMGB‐1 antibodies or A‐box protein significantly reduced the mean arthritis score, the disease‐induced weight loss, and the histologic severity of arthritis. Beneficial effects were observed in both mice and rats. Immunohistochemical analysis revealed pronounced synovial IL‐1β expression and articular cartilage destruction in vehicle‐treated mice. Both these features were significantly less manifested in animals treated with anti–HMGB‐1 antibodies or A‐box protein.ConclusionCounteracting extracellular HMGB‐1 with either neutralizing antibodies or a specific HMGB‐1 antagonist may offer a new method for the successful treatment of arthritis. Inflammation and tissue destruction were suppressed in CIA after HMGB‐1 blockade.
Bone edema scored on magnetic resonance imaging scans of the dominant carpus at presentation predicts radiographic joint damage of the hands and feet six years later in patients with rheumatoid arthritis
Authors: McQueen Fiona M. , Benton Nick , Perry David , Crabbe Jeff , Robinson Elizabeth , Yeoman Sue , McLean Lachy , Stewart Neal 
Published: July 2003

AbstractObjectiveMagnetic resonance imaging (MRI) is capable of revealing synovitis and tendinitis in early rheumatoid arthritis (RA), as well as bone edema and erosion. These features are visible before radiographic joint damage occurs. We sought to examine whether MRI of one body region (the wrist) can be used to predict whole‐body radiography scores reflecting joint damage at 6 years.MethodsWe conducted a 6‐year prospective study of a cohort of patients who fulfilled the criteria for RA at presentation, using clinical parameters, radiographs, and MRI scans of the dominant wrist. Of the 42 patients enrolled at baseline, full MRI, radiographic, and clinical data were available for 31 at 6‐year followup. MRI scans were scored by 2 radiologists, using a validated scoring system. Radiographs of the hands and feet were graded using the modified Sharp scoring method. MRI and radiography scores obtained at baseline and 6 years were compared, and baseline MRI scores were examined for their ability to predict radiographic outcome at 6 years.ResultsAt 6 years, the total Sharp score correlated significantly with the total MRI score and the MRI erosion score (r = 0.81, P < 0.0001 and r = 0.79, P < 0.0001, respectively). The 6‐year Sharp score also correlated with the baseline total MRI and MRI erosion scores (r = 0.56, P < 0.0001 and r = 0.33, P = 0.03, respectively). MRI synovitis and bone edema scores remained constant for the group as a whole over 6 years, but bone erosion scores progressed (P = 0.0001), consistent with radiographic deterioration. Erosions on 6‐year MRI scans were frequently preceded by MRI bone edema at baseline (odds ratio 6.5, 95% confidence interval 2.78–18.1). Regression models indicated that the baseline MRI bone edema score was predictive of the 6‐year total Sharp score (P = 0.01), as was the C‐reactive protein (CRP) level (P = 0.0002). Neither shared epitope status nor swollen or tender joint counts predicted radiographic outcome in this cohort. A model incorporating baseline MRI scores for erosion, bone edema, synovitis, and tendinitis plus the CRP level and the erythrocyte sedimentation rate explained 59% of the variance in the 6‐year total Sharp score (R2 = 0.59, adjusted R2 = 0.44).ConclusionMRI scans performed at the first presentation of RA can be used to help predict future radiographic damage, allowing disease‐modifying therapy to be targeted to patients with aggressive disease.
Anti–tumor necrosis factor α therapy in fifteen patients with AA amyloidosis secondary to inflammatory arthritides: A followup report of tolerability and efficacy
Authors: Gottenberg Jacques‐Eric , Merle‐Vincent Florence , Bentaberry Fabrice , Allanore Yannick , Berenbaum Francis , Fautrel Bruno , Combe Bernard , Durbach Antoine , Sibilia Jean , Dougados Maxime , Mariette Xavier 
Published: July 2003

AbstractObjectiveBecause anti–tumor necrosis factor α (anti‐TNF) has emerged as a highly effective treatment for numerous inflammatory arthritides, which are a common cause of AA amyloidosis, we retrospectively evaluated the safety and efficacy of anti‐TNF in a nationwide study.MethodsThe rheumatology departments of all French teaching hospitals were contacted by mail to obtain the files of patients with histologically proven secondary AA amyloidosis and renal involvement who were treated with anti‐TNF. Efficacy was assessed as a sustained decrease in 24‐hour proteinuria and a stable/improved glomerular filtration rate (GFR).ResultsAmong the 15 patients studied, the 24‐hour proteinuria was 4.5 ± 3.6 gm (mean ± SD), creatininemia was 178.4 ± 74.9 μmoles/liter, and GFR was 46 ± 23 ml/minute before starting anti‐TNF. Ten patients received infliximab, 4 received etanercept, and 1 received both types of treatment. The mean followup was 10.4 months. No severe adverse events were recorded; one episode of herpes zoster in the first branch of the trigeminal nerve occurred after one infusion of infliximab. Amyloidosis progressed in 7 patients and was stabilized in 5 patients. Three patients (receiving infliximab alone, infliximab plus methotrexate [MTX], or etanercept plus MTX) experienced rapid, dramatic, and sustained decreases in proteinuria (≥80%), with the GFR increasing 15–78%.ConclusionAnti‐TNF was well‐tolerated and safe in the 15 patients with AA amyloidosis and renal involvement. The pathogenic role of TNF in AA amyloidosis, the sustained proteinuria decrease in 3 patients, and the stabilization of renal parameters in 5 other patients make anti‐TNF a promising candidate to treat AA amyloidosis secondary to inflammatory arthritides.
Monocyte chemoattractant protein 3 as a mediator of fibrosis: Overexpression in systemic sclerosis and the type 1 tight‐skin mouse
Authors: Ong Voon H. , Evans Lowri A. , Shiwen Xu , Fisher Ivan B. , Rajkumar Vineeth , Abraham David J. , Black Carol M. , Denton Christopher P. 
Published: July 2003

AbstractObjectiveTo determine the gene‐expression profile in dermal fibroblasts from type 1 tight‐skin (Tsk1) mice, and to examine the expression and potential fibrotic activity of monocyte chemoattractant protein 3 (MCP‐3) in Tsk1 mouse and human systemic sclerosis (SSc) skin.MethodsComplementary DNA microarrays (Atlas 1.2) were used to compare Tsk1 fibroblasts with non‐Tsk1 littermate cells at 10 days, 6 weeks, and 12 weeks of age. Expression of MCP‐3 protein was assessed by Western blotting of fibroblast culture supernatants, and localized in the mouse and human skin biopsy samples by immunohistochemistry. Activation of collagen reporter genes by MCP‐3 was explored in transgenic mouse fibroblasts and by transient transfection assays.ResultsMCP‐3 was highly overexpressed by neonatal Tsk1 fibroblasts and by fibroblasts cultured from the lesional skin of patients with early‐stage diffuse cutaneous SSc. Immunolocalization confirmed increased expression of MCP‐3 in the dermis of 4 of 5 Tsk1 skin samples and 14 of 28 lesional SSc skin samples, compared with that in matched healthy mice (n = 5) and human controls (n = 11). Proα2(I) collagen promoter–reporter gene constructs were activated by MCP‐3 in transgenic mice and by transient transfection assays. This response was maximal between 16 and 24 hours of culture and mediated via sequences within the proximal promoter. The effects of MCP‐3 could be diminished by a neutralizing antibody to transforming growth factor β.ConclusionWe demonstrate, for the first time, overexpression of MCP‐3 in early‐stage SSc and in Tsk1 skin, and suggest a novel role for this protein as a fibrotic mediator activating extracellular matrix gene expression in addition to promoting leukocyte trafficking. This chemokine may be an important early member of the cytokine cascade driving the pathogenesis of SSc.
Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis
Authors: Leech Michelle , Lacey Derek , Xue Jin Rong , Santos Leilani , Hutchinson Paul , Wolvetang Ernst , David John R. , Bucala Richard , Morand Eric F. 
Published: July 2003

AbstractObjectiveTo study the capacity of macrophage migration inhibitory factor (MIF) to regulate proliferation, apoptosis, and p53 in an animal model of rheumatoid arthritis (RA) and in fibroblast‐like synoviocytes (FLS) from humans with RA.MethodsAntigen‐induced arthritis (AIA) was induced in MIF–/– mice and littermate controls. FLS were obtained from patients with RA. Western blotting and immunohistochemistry were used to measure p53 in cells and tissues. Apoptosis was detected in cells by flow cytometry using TUNEL and annexin V/propidium iodide labeling. Apoptosis in tissue was detected using TUNEL. Proliferation was assessed in cultured cells and tissue by 3H‐thymidine incorporation and Ki‐67 immunostaining, respectively.ResultsMIF inhibited p53 expression in human RA FLS. Levels of p53 were correspondingly increased in MIF–/– mouse tissues and cells. Spontaneous and sodium nitroprusside–induced apoptosis were significantly increased in MIF–/– cells. In vitro exposure of FLS to MIF reduced apoptosis and significantly induced FLS proliferation. Synoviocyte proliferation in MIF–/– mice was correspondingly reduced. A decrease in the severity of AIA in MIF–/– mice was associated with an increase in p53 and apoptosis in synovium. Evidence of in situ proliferation was scant in this model, and no difference in in situ proliferation was detectable in MIF–/– mice compared with wild‐type mice.ConclusionThese results indicate a role for MIF in the regulation of p53 expression and p53‐mediated events in the inflamed synovium and support the hypothesis that MIF is of critical importance in the pathogenesis of RA.