bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety profile of treatment with etoricoxib 120 mg once daily compared with indomethacin 50 mg three times daily in acute gout: A randomized controlled trial
Authors: Rubin Bernard R. , Burton Robert , Navarra Sandra , Antigua Joseph , Londoño John , Pryhuber Keith G. , Lund Margaret , Chen Erluo , Najarian Daryl K. , Petruschke Richard A. , Ozturk Zafer E. , Geba Gregory P. 
Published: February 2004

AbstractObjectiveTo evaluate the efficacy and safety of etoricoxib and indomethacin in the treatment of patients with acute gout.MethodsA randomized, double‐blind, active‐comparator study was conducted at 42 sites. A total of 189 men and women (≥18 years of age) who were experiencing an acute attack (≤48 hours) of clinically diagnosed gout were treated for 8 days with etoricoxib, 120 mg/day (n = 103), or indomethacin, 50 mg 3 times a day (n = 86). The primary efficacy end point was the patient's assessment of pain in the study joint (0–4‐point Likert scale) over days 2–5. Safety was assessed by adverse experiences (AEs) occurring during the trial.ResultsEtoricoxib demonstrated clinical efficacy comparable to that of indomethacin in terms of the patient's assessment of pain in the study joint. The difference in the mean change from baseline over days 2–5 was –0.08 (95% confidence interval –0.29, 0.13) (P = 0.46), which fell within the prespecified comparability bounds of –0.5 to 0.5. Secondary end points over the 8‐day study, including the onset of efficacy, reduction in signs of inflammation, and patient's and investigator's global assessments of response to therapy, confirmed the comparable efficacy of the two treatments. The etoricoxib‐treated patients had a numerically lower incidence of AEs (43.7%) than did the indomethacin‐treated patients (57.0%) and a significantly lower incidence of drug‐related AEs (16.5% versus 37.2%; P < 0.05).ConclusionEtoricoxib at a dosage of 120 mg once daily was confirmed to be an effective treatment for acute gout. Etoricoxib was comparable in efficacy to indomethacin at a dosage of 50 mg 3 times daily, and it was generally safe and well tolerated.
Specific autoantibodies precede the symptoms of rheumatoid arthritis: A study of serial measurements in blood donors
Authors: Nielen Markus M. J. , van Schaardenburg Dirkjan , Reesink Henk W. , van de Stadt Rob J. , van der Horst‐Bruinsma Irene E. , de Koning Margret H. M. T. , Habibuw Moud R. , Vandenbroucke Jan P. , Dijkmans Ben A. C. 
Published: February 2004

AbstractObjectiveAutoantibodies have been demonstrated in single serum samples from healthy subjects up to 10 years before they developed rheumatoid arthritis (RA). However, the time course for the development of antibodies before onset of clinical RA is unknown, nor is it known which antibody, or combinations of antibodies, might be most sensitive or specific for predicting future development of the disease. The present study was undertaken to investigate this.MethodsPatients with RA who had been blood donors before the onset of disease symptoms were enrolled. Frozen serum samples from each donor were retrieved, together with 2 serum samples from controls matched for age, sex, and date of donation. All samples were tested for IgM rheumatoid factor (IgM‐RF) and anti–cyclic citrullinated peptide (anti‐CCP) antibodies.ResultsSeventy‐nine patients with RA (62% female; mean age at onset of symptoms 51 years) were included. A median of 13 samples (range 1–51) per patient were available; the earliest samples had been collected a median of 7.5 years (range 0.1–14.5) before the onset of symptoms. Thirty‐nine patients (49%) were positive for IgM‐RF and/or anti‐CCP on at least one occasion before the development of RA symptoms, a median of 4.5 years (range 0.1–13.8) before symptom onset. Of the 2,138 control samples, 1.1% were positive for IgM‐RF, and 0.6% were positive for anti‐CCP.ConclusionApproximately half of patients with RA have specific serologic abnormalities several years before the onset of symptoms. A finding of an elevated serum level of IgM‐RF or anti‐CCP in a healthy individual implies a high risk for the development of RA. We conclude that IgM‐RF and anti‐CCP testing with appropriately high specificity may assist in the early detection of RA in high‐risk populations.
Increased apoptosis in human osteoarthritic cartilage corresponds to reduced cell density and expression of caspase‐3
Authors: Sharif Mohammed , Whitehouse Anne , Sharman Patrick , Perry Mark , Adams Mike 
Published: February 2004

AbstractObjectiveChondrocyte apoptosis has been described in both human and experimentally induced osteoarthritis (OA), but its importance in the etiopathogenesis of OA is uncertain. The aims of this study were to determine the rate of chondrocyte apoptosis using different methods, and to investigate the relationship between this process and cartilage cellularity, expression of proapoptotic molecules, and expression of antiapoptotic molecules in articular cartilage obtained from patients with OA and from nonarthritic controls.MethodsWe examined the extent of apoptosis in OA and nonarthritic control cartilage using expression of caspase‐3, an enzyme that mediates the final stage of cell death by apoptosis, as well as the TUNEL method. We used immunohistochemistry to analyze the expression of a panel of proapoptotic and antiapoptotic molecules that regulate apoptosis in articular cartilage, in order to determine whether the rate of apoptosis is associated with the expression of these molecules.ResultsThe median (range) percentage of TUNEL‐positive chondrocytes in knee OA cartilage (n = 10 specimens), hip OA cartilage (n = 9), and control cartilage (n = 7) was 3.11 (1.67–3.67), 1.86 (1.22–2.89), and 0.39 (0.00–1.78), respectively. When all cartilage samples were pooled, apoptosis showed a strong inverse correlation with cellularity (r = −0.74, P < 0.0001). The percentage (range) of cells expressing caspase‐3 in the 3 groups was 15.70 (7.40–20.50), 15.77 (7.42–20.5), and 7.40 (5.90–8.00), respectively. One‐way analysis of variance showed that the differences between groups for both TUNEL‐positive cells and expression of caspase‐3 were statistically significant (P < 0.0001). There was a significant positive correlation between TUNEL‐positive cells and expression of caspase‐3 (r = 0.654, P< 0.01).ConclusionThe data suggest that apoptosis is increased, on average, 2–4‐fold in OA cartilage. Considering that OA develops over many years, such an increase in the rate of apoptosis in the articular cartilage could play an important role in the disease process.
Association of autoantibodies to glucose‐6‐phosphate isomerase with extraarticular complications in rheumatoid arthritis
Authors: van Gaalen Floris A. , Toes Rene E. M. , Ditzel Henrik J. , Schaller Monica , Breedveld Ferdinand C. , Verweij Cor L. , Huizinga Tom W. J. 
Published: February 2004

AbstractObjectiveIn the K/BxN mouse model, autoantibodies against glucose‐6‐phosphate isomerase (GPI) cause arthritis. The relevance of this model for human disease remains a subject of controversy. We set out to determine whether GPI autoantibodies occur in patients with rheumatoid arthritis (RA) and, if so, at what stage of the RA.MethodsUsing an enzyme‐linked immunosorbent assay, serum from 131 RA patients and 28 healthy controls was tested for autoantibodies against recombinant human GPI. Patients were grouped according to disease duration and presence of rheumatoid nodules, rheumatoid vasculitis, and Felty's syndrome, which are extraarticular complications of RA.ResultsElevated levels of autoantibodies against GPI were present in 5% of patients with uncomplicated RA and 4% of controls. In RA complicated by extraarticular manifestations, anti‐GPI antibodies were observed in 18% of patients with rheumatoid nodules, 45% of patients with rheumatoid vasculitis, and 92% of patients with Felty's syndrome.ConclusionIn patients with RA, autoantibodies to GPI are associated with the occurrence of extraarticular complications.
Cooperation between C1q and DNase I in the clearance of necrotic cell–derived chromatin
Authors: Gaipl Udo S. , Beyer Thomas D. , Heyder Petra , Kuenkele Susanne , Böttcher Andrea , Voll Reinhard E. , Kalden Joachim R. , Herrmann Martin 
Published: February 2004

AbstractObjectiveThe efficient uptake of dying cells by phagocytes is essential to the avoidance of chronic inflammation. Some human autoimmune responses are thought to be driven by autoantigens from apoptotic or necrotic cells. We analyzed the role of C1q and DNase I in the disposal of necrotic cell–derived chromatin because deficiencies in these serum factors predispose to the development of systemic autoimmune disorders, such as systemic lupus erythematosus.MethodsHuman necrotic peripheral blood lymphocytes were incubated in cell culture medium supplemented with various sera or serum components. Chromatin degradation was monitored by measuring the residual DNA content by flow cytometry. The uptake of necrotic cell–derived nuclei was analyzed by in vitro phagocytosis assays.ResultsReconstitution of C1q‐depleted serum with C1q strongly increased its ability to degrade necrotic cell–derived chromatin. Although C1q itself displayed no DNase activity, it strongly augmented the activity of serum DNase I. Whereas an excess of recombinant DNase I degraded chromatin in the absence of C1q, efficient uptake of the predigested material by monocyte‐derived phagocytes required the presence of C1q. These data show that C1q and DNase I cooperate in the degradation of chromatin from necrotic cells. Furthermore, C1q was found to be necessary for effective uptake of degraded chromatin by monocyte‐derived phagocytes.ConclusionC1q or DNase I deficiencies may precipitate autoimmunity in humans by a mechanism similar to that of other molecules that are involved in the safe, efficient, and rapid disposal of dying cells.
Minocycline is not effective in systemic sclerosis: Results of an open‐label multicenter trial
Authors: Mayes Maureen D. , O'Donnell Daniel , Rothfield Naomi F. , Csuka M. E. 
Published: February 2004

AbstractObjectiveTo determine if minocycline therapy improved skin thickness in early, diffuse systemic sclerosis (SSc) by ≥30%, a level of improvement unlikely to occur in the natural history of the disease as determined by recent controlled trials.MethodsSubjects with diffuse SSc of ≤5 years' duration were treated with oral minocycline for 1 year. The primary outcome measure was the modified Rodnan skin thickness score (MRSS).ResultsOf 36 subjects initially enrolled, 31 returned for at least 1 followup visit and were included in the analysis (modified intent‐to‐treat analysis). The group consisted of 23 women and 8 men, with a mean age of 51.7 years (range 26–82 years) and a mean disease duration of 23.5 months (range 6–60 months). The mean MRSS at entry was 22.7 (range 12–43), and at the final visit it was 18.6 (range 2–48). There was no statistically significant difference in the change in skin scores between the minocycline‐treated subjects and subjects previously reported in the D‐penicillamine (D‐Pen) trial. In addition, when adjusted for disease duration, a comparison of MRSS in the minocycline trial subjects (including all subjects active at each time point) and the previously reported D‐Pen trial subjects showed no difference and no treatment effect.Fourteen subjects did not complete all 12 months of treatment; 10 of them withdrew due to disease progression. Disease duration was significantly shorter for the noncompleters than for the completers (P < 0.03).ConclusionThe degree of change in the MRSS was similar to that expected in the natural course of this disease. Based on these data, minocycline is not an effective therapy for SSc.
Novel tumor necrosis factor α–regulated genes in rheumatoid arthritis
Authors: Zhang Huang‐Ge , Hyde Karren , Page Grier P. , Brand Jacob P. L. , Zhou Juling , Yu Shaohua , Allison David B. , Hsu Hui‐Chen , Mountz John D. 
Published: February 2004

AbstractObjectiveTo determine novel genes regulated by tumor necrosis factor α (TNFα) signaling in primary rheumatoid arthritis synovial fibroblasts (RASFs).MethodsOligonucleotide microarrays were used to measure gene expression levels in 6 independent replicate samples of RASFs. RASFs were transfected for 18 hours with AdIκB–dominant negative (AdIκB‐DN) (n = 3) or with control AdTet expressing the reverse tetracycline trans‐activator (n = 3). The cells were stimulated for 3 hours with TNFα, and total RNA was prepared. Several novel parametric and nonparametric methods were used to rank genes in terms of the magnitude and significance of intergroup differences. Microarray expression differences were confirmed by real‐time quantitative reverse transcription–polymerase chain reaction. Small interfering RNA (siRNA) was used to specifically down‐modulate microarray‐identified genes to demonstrate their role in the promotion of apoptosis, proliferation, or matrix metalloproteinase (MMP) expression.ResultsBlocking of NF‐κB by AdIκB‐DN was associated with a down‐modulation of antiapoptosis genes, including BIRC‐3, and several novel genes, including GG2‐1, a TNFα‐inducible FLIP‐like gene. Other families of genes that were significantly down‐regulated by AdIκB‐DN included cytokines/chemokines (interleukin‐1β [IL‐1β], IL‐8, IL‐15, and RANTES), adhesion molecule (vascular cell adhesion molecule 1, intercellular adhesion molecule 1), and unique genes that have not previously been reported to be regulated by TNFα in RA. Inhibition of the GG2‐1 gene using the siRNA technique resulted in significantly enhanced apoptosis, decreased proliferation, and decreased production of MMP‐1 in TNFα‐stimulated RASFs.ConclusionThese studies provide a comprehensive analysis of genes that are differentially regulated by TNFα signaling and NF‐κB nuclear translocation in RASFs and demonstrate methods for confirming the expression and functional significance of such genes.
Basic fibroblast growth factor mediates transduction of mechanical signals when articular cartilage is loaded
Authors: Vincent Tonia L. , Hermansson Monika A. , Hansen Ulrich N. , Amis Andrew A. , Saklatvala Jeremy 
Published: February 2004

AbstractObjectiveTo determine whether the basic fibroblast growth factor (bFGF) mediates signal transduction in articular cartilage in response to mechanical loading.MethodsArticular cartilage from porcine metacarpophalangeal or knee joints was cyclically loaded (62.5–250N) for 2 minutes in the absence or presence of a bFGF receptor inhibitor, SB 402451 (250 nM). Activation of the extracellularly regulated kinase MAP kinase ERK was measured by Western blot analysis. Changes in protein synthesis were assessed by measuring the incorporation of 35S‐Met/Cys into proteins secreted by cartilage explants or by isolated chondrocytes.ResultsRapid activation of the ERK MAP kinase occurred when articular cartilage was loaded. This was dependent upon release of the bFGF because it was restricted by the FGF receptor inhibitor. Loaded explants were shown to release bFGF. Loading or bFGF stimulation of explants induced synthesis and secretion of tissue inhibitor of metalloproteinases 1 (TIMP‐1), which was inhibited by SB 402451.ConclusionCyclical loading of articular cartilage causes bFGF‐dependent activation of ERK and synthesis of TIMP‐1.
TRAIL induces apoptosis of chondrocytes and influences the pathogenesis of experimentally induced rat osteoarthritis
Authors: Lee Sung Won , Lee Hye Jeong , Chung Won Tae , Choi Sun Mee , Rhyu Seung Hoon , Kim Duk K. , Kim Kyung Taek , Kim Ji Young , Kim Jong‐Min , Yoo Young Hyun 
Published: February 2004

AbstractObjectiveTo investigate whether TRAIL influences the pathogenesis of osteoarthritis (OA).MethodsA recombinant adenoviral vector system (Ad‐TRAIL) was used. Expression of TRAIL in a rat chondrocyte cell line (RCJ3.1C.18) and alterations in the expression of death and decoy receptors after Ad‐TRAIL infection were measured by Western blot assay. To explore the underlying mechanism, Western blot assays (to detect caspase 8, poly[ADP‐ribose] polymerase [PARP], and caspase 3 activation), mitochondrial membrane potential (ΔΨm) measurement, Hoechst staining, and DNA electrophoresis were conducted. Next, expression of TRAIL and death and decoy receptors was examined by immunochemistry in primary cultured chondrocytes and on cartilage obtained from rats with experimentally induced OA.ResultsAd‐TRAIL infection induced expression of TRAIL in RCJ3.1C.18 cells, increased expression of death receptor 4 (DR4), and decreased expression of DR5 and decoy receptor 1 (DcR1). Ad‐TRAIL, at doses of 10 and 100 multiplicities of infection, decreased the viability of chondrocytes 4 days after infection. Reduction of ΔΨm, cytochrome c release, nuclear condensation, activation of caspase 3 and PARP, and DNA fragmentation proved the induction of apoptosis. Activation of caspase 8 was also observed. Ad‐TRAIL also induced apoptosis in primary cultured chondrocytes, in which alterations in expression of TRAIL and death receptors were similar to those observed in RCJ3.1C.18 cells. Cartilage obtained from rats with experimentally induced OA showed increased expression of TRAIL and DR4 and decreased expression of DR5 and DcR1 compared with control cartilage.ConclusionTRAIL induces chondrocyte apoptosis, and TRAIL‐induced chondrocyte apoptosis may play a role in the pathogenesis of OA.
Validation and reproducibility of ultrasonography in the detection of synovitis in the knee: A comparison with arthroscopy and clinical examination
Authors: Karim Z. , Wakefield R. J. , Quinn M. , Conaghan P. G. , Brown A. K. , Veale D. J. , Connor P. O' , Reece R. , Emery P. 
Published: February 2004

AbstractObjectiveAccurate detection of synovitis is important in both the diagnosis and outcome assessment of arthritis. This study was undertaken to assess the validity and reproducibility of ultrasonography (US) as a means of detecting synovitis in the knee, by comparing US findings with findings of arthroscopy and clinical examination.MethodsSixty consecutive patients with knee pain due to various arthritides had a clinical examination and US of their knee performed immediately prior to arthroscopy. All 3 assessments were performed by different clinicians who were blinded to the results obtained with the other modalities. US and clinical examination were compared with arthroscopically detected synovitis as the gold standard. Data from a subset of patients were used for calculating the inter‐ and intrareader reproducibility of US results, using a standard dichotomous (absence/presence of synovitis) as well as a graded (absence/grade of synovitis) scoring system.ResultsWith the use of arthroscopy as the gold standard, US had a higher sensitivity (98% versus 85%), specificity (88% versus 25%), accuracy (97% versus 77%), positive predictive value (98% versus 88%), and negative predictive value (88% versus 20%) compared with clinical examination. The Cohen kappa values for inter‐ and intrareader reproducibility of US for distinguishing between presence and absence of synovitis were 0.71 and 0.85, respectively (P < 0.05 for both). The weighted kappa values for distinguishing grade of synovitis were 0.65 for inter‐ and 0.74 for intrareader reproducibility. The kappa value for intrareader reproducibility of arthroscopy results was 0.88.ConclusionUltrasonography is a valid and reproducible technique for detecting synovitis in the knee, and is more accurate than clinical examination. It may be valuable as a tool in studies investigating pain, diagnosis, and treatment response in knee arthritis.
PM–Scl‐75 is the main autoantigen in patients with the polymyositis/scleroderma overlap syndrome
Authors: Raijmakers Reinout , Renz Manfred , Wiemann Claudia , Egberts Wilma Vree , Seelig Hans Peter , van Venrooij Walther J. , Pruijn Ger J. M. 
Published: February 2004

AbstractObjectiveTo compare the autoantigenicity of the recently described N‐terminally elongated PM–Scl‐75 protein with that of PM–Scl‐100 and the originally defined PM–Scl‐75 polypeptide, and to determine its value for analyzing sera from patients with the polymyositis (PM)/scleroderma overlap syndrome.MethodsSerum samples obtained from patients with the PM/scleroderma overlap syndrome and from patients with several other diseases were analyzed for the presence of autoantibodies reactive with recombinant PM–Scl‐100 and PM–Scl‐75 (both the original and the longer form) proteins, in an enzyme‐linked immunosorbent assay (ELISA).ResultsAutoantibodies recognizing the longer PM–Scl‐75 protein isoform were detected in 28% of the patients with PM/scleroderma. This percentage is slightly higher than that for PM–Scl‐100 (25%) and is significantly higher than that for the previously defined PM–Scl‐75 protein (11%). In addition, we identified a significant number of patients who had anti–PM–Scl‐75 but not anti–PM–Scl‐100 antibodies. This finding contrasts with what has been previously reported for the shorter version of the PM–Scl‐75 protein.ConclusionOur data indicate that use of the long PM–Scl‐75 isoform in addition to PM–Scl‐100 in ELISAs significantly increases the number of patients in whom anti–PM‐Scl autoantibodies can be detected.
Interleukin‐18 enhances monocyte tumor necrosis factor α and interleukin‐1β production induced by direct contact with T lymphocytes: Implications in rheumatoid arthritis
Authors: Dai Sheng‐Ming , Matsuno Hiroaki , Nakamura Hiroshi , Nishioka Kusuki , Yudoh Kazuo 
Published: February 2004

AbstractObjectiveAt sites of inflammation, T cells exert pathologic effects through direct contact with monocyte/macrophages, inducing massive up‐regulation of interleukin‐1 (IL‐1) and tumor necrosis factor α (TNFα). We examined the regulatory effects of IL‐18 on monocyte activation by direct contact with T lymphocytes in rheumatoid arthritis (RA).MethodsActivated T cells were isolated from RA synovial fluid. Resting T cells and monocytes were isolated from peripheral blood mononuclear cells. RA synovial T cells or phytohemagglutinin (PHA)–stimulated T cells were fixed by paraformaldehyde and then cocultured with monocytes at a ratio of 4:1. Levels of TNFα, IL‐1β, IL‐10, and IL‐18 were measured by enzyme‐linked immunosorbent assay. Expression of adhesion molecules, IL‐18 receptor, and TNF receptors was analyzed by flow cytometry. Expression of NF‐κB p65, phosphorylated IκBα, and phosphatidylinositol 3‐kinase (PI 3‐kinase) p110 was analyzed by Western blotting.ResultsIL‐18 dose‐dependently enhanced the production of IL‐1β and TNFα, but not IL‐10, by monocytes following contact with RA synovial T cells or PHA‐prestimulated T cells. NF‐κB inhibitors N‐acetyl‐L‐cysteine and Bay 11‐7085 and PI 3‐kinase inhibitor LY294002 inhibited the enhancing effects of IL‐18, but MAPK p38 inhibitor SB203580, ERK inhibitor PD98059, and JNK inhibitor SP600125 did not. Increased levels of NF‐κB in the nucleus, phosphorylated IκB, and PI 3‐kinase were confirmed in monocytes cocultured with PHA‐prestimulated T cells, and the levels were further increased by stimulation with IL‐18. Neutralizing antibody to IL‐18 inhibited monocyte activation induced by direct contact with PHA‐prestimulated T cells. Via cell–cell contact, PHA‐prestimulated T cells increased autocrine production of IL‐18 by monocytes, which was mediated by activation of the NF‐κB and PI 3‐kinase pathways, and up‐regulated the expression of the IL‐18 receptor in monocytes. IL‐18 up‐regulated the expression of the TNF receptors vascular cell adhesion molecule 1 (VCAM‐1) and intercellular adhesion molecule 1 (ICAM‐1) on monocytes. Blocking the binding of the TNF receptors VCAM‐1 or ICAM‐1 on monocytes to their ligands on stimulated T cells suppressed the IL‐18–enhanced production of TNFα and IL‐1β in monocytes induced by contact with PHA‐prestimulated T cells.ConclusionIL‐18 augments monocyte activation induced by contact with activated T cells in RA synovitis, which is dependent on activation of the NF‐κB and PI 3‐kinase pathways. IL‐18 up‐regulates the expression of the TNF receptors VCAM‐1 and ICAM‐1 on monocytes, which mediate the enhancing effects of IL‐18 on T cell–monocyte contact.