bluuebunny/crossref_metadata_2025 huggingface dataset:
Urinary lipocalin‐2 is associated with renal disease activity in human lupus nephritis
Authors: Pitashny Milena , Schwartz Noa , Qing Xiaoping , Hojaili Bernard , Aranow Cynthia , Mackay Meggan , Putterman Chaim
Published: May 2007

Objective

Pathogenic monoclonal anti–double‐stranded DNA (anti‐dsDNA) antibodies up‐regulate the expression of lipocalin‐2 in glomerular mesangial cells. This study was undertaken to investigate whether polyclonal anti‐dsDNA antibodies promote the local secretion of lipocalin‐2 in the kidneys of patients with systemic lupus erythematosus (SLE), and whether urinary lipocalin‐2 represents a marker of kidney involvement in SLE.

Methods

Hispanic, African American, and white patients with SLE and normal healthy control subjects from affiliated hospitals of the Albert Einstein College of Medicine were recruited for this cross‐sectional study. Patients were classified based on the presence of active renal disease according to the SLE Disease Activity Index (SLEDAI). Correlations of clinical and laboratory data with urinary and serum levels of lipocalin‐2 were assessed.

Results

Among SLE patients, urinary lipocalin‐2 levels were significantly higher in those with lupus nephritis (LN) (median 17.1 ng/mg creatinine, interquartile range [IQR] 10.3–45.4; n = 32) than in those without LN (median 11.2 ng/mg creatinine, IQR 3.1–20.3; n = 38) (P = 0.023). Compared with the values in normal controls (median 4 ng/ml, IQR 0–11.1; n = 14), urinary levels of lipocalin‐2 in SLE patients were significantly higher (non‐normalized median 19.3 ng/ml, IQR 8–34.2) (P = 0.004). The presence of lipocalin‐2 in the urine of patients with LN correlated significantly with the renal SLEDAI score (r = 0.452, P = 0.009), but not with extrarenal disease activity.

Conclusion

The high prevalence of LN in SLE patients and the prognostic significance of kidney disease support the need for identifying early biomarkers to assess the risk of nephritis development and for following up patients with established disease. These findings indicate that urinary lipocalin‐2 is a potential marker of the presence and severity of renal involvement in adult patients with SLE.
Anti–tumor necrosis factor α therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis
Authors: Schneeweiss Sebastian , Setoguchi Soko , Weinblatt Michael E. , Katz Jeffrey N. , Avorn Jerry , Sax Paul E. , Levin Raisa , Solomon Daniel H.
Published: May 2007

Objective

To assess the association between the initiation of anti–tumor necrosis factor α (anti‐TNFα) therapy and the risk of serious bacterial infections in routine care.

Methods

This was a cohort study of patients with rheumatoid arthritis (RA) in whom specific disease‐modifying antirheumatic drugs (DMARDs) were initiated. Patients were Medicare beneficiaries ages 65 years and older (mean age 76.5 years) who were concurrently enrolled in the Pharmaceutical Assistance Contract for the Elderly provided by the state of Pennsylvania. A total of 15,597 RA patients in whom a DMARD was initiated between January 1, 1995 and December 31, 2003 were identified using linked data on all prescription drug dispensings, physician services, and hospitalizations. Initiation of anti‐TNFα therapy, cytotoxic agents other than methotrexate (MTX), noncytotoxic agents, and glucocorticoids was compared with initiation of MTX. The main outcome measure was serious bacterial infections that required hospitalization.

Results

The incidence of serious bacterial infections was, on average, 2.2 per 100 patient‐years in this population (95% confidence interval [95% CI] 2.0–2.4). Glucocorticoid use doubled the rate of serious bacterial infections as compared with MTX use, independent of previous DMARD use (rate ratio [RR] 2.1 [95% CI 1.5–3.1]), with a clear dose‐response relationship for dosages >5 mg/day (for ≤5 mg/day, RR 1.34; for 6–9 mg/day, RR 1.53; for 10–19 mg/day, RR 2.97; and for ≥20 mg/day, RR 5.48 [Pfor trend < 0.0001]). Adjusted models showed no increase in the rate of serious infections among initiators of anti‐TNFα therapy (RR 1.0 [95% CI 0.6–1.7]) or other DMARDs as compared with initiators of MTX.

Conclusion

In a large cohort of patients with RA, we found no increase in serious bacterial infections among users of anti‐TNFα therapy compared with users of MTX. Glucocorticoid use was associated with a dose‐dependent increase in such infections.
Targeted mast cell silencing protects against joint destruction and angiogenesis in experimental arthritis in mice
Authors: Kneilling Manfred , Hültner Lothar , Pichler Bernd J. , Mailhammer Reinhard , Morawietz Lars , Solomon Samuel , Eichner Martin , Sabatino Joseph , Biedermann Tilo , Krenn Veit , Weber Wolfgang A. , Illges Harald , Haubner Roland , Röcken Martin
Published: May 2007

Objective

Induction of arthritis with autoantibodies against glucose‐6‐phosphate isomerase (GPI) is entirely independent of T cells and B cells but is strictly dependent on the presence of mast cells. Here, we used this disease model to analyze whether exclusive intraarticular mast cell reconstitution is sufficient for disease induction and whether targeted mast cell silencing can prevent neoangiogenesis and joint destruction, 2 hallmarks of rheumatoid arthritis.

Methods

Ankle swelling and clinical index scores were determined after injection of either K/BxN mouse–derived serum or control serum in wild‐typeKit+/Kit+mice, congenic mast cell–deficientKitW/KitW‐vmice, or mast cell–deficientKitW/KitW‐vmice reconstituted with mast cells, either by intraperitoneal or selective intraarticular injection. Angiogenesis was quantified in vivo by measuring activated αvβ3 integrin using18F–galacto‐RGD and positron emission tomography. In addition, staining of joint tissue with hematoxylin and eosin, Giemsa, β3, and α‐actin was performed. The effect of mast cell stabilization by treatment with cromolyn or salbutamol was investigated in C57BL/6 or BALB/c mice.

Results

Comparing wild‐type mice, mast cell–deficientKitW/KitW‐vmice, and mast cell–reconstitutedKitW/KitW‐vmice, we first showed that intraarticular and intraperitoneal mast cell engraftment fully restores susceptibility to antibody‐induced arthritis, angiogenesis, and αvβ3 integrin activation. Importantly, selective mast cell silencing with either salbutamol or cromolyn prevented αvβ3 integrin activation, angiogenesis, and joint destruction.

Conclusion

Mast cell engraftment fully restores susceptibility to αvβ3 integrin activation, angiogenesis, and joint destruction in GPI antibody–induced arthritis. Importantly, selective mast cell stabilization prevents αvβ3 integrin activation, angiogenesis, and joint destruction.
Fluvastatin reverses endothelial dysfunction and increased vascular oxidative stress in rat adjuvant‐induced arthritis
Authors: Haruna Yoshisuke , Morita Yoshitaka , Yada Toyotaka , Satoh Minoru , Fox David A. , Kashihara Naoki
Published: May 2007

Objective

To investigate the effect of statins on vascular dysfunction in rat adjuvant‐induced arthritis (AIA).

Methods

Fluvastatin (5 mg/kg/day) was administered orally to rats with AIA, for 21 days after the onset of arthritis. The vasodilatory response to acetylcholine of aortic rings isolated from rats with AIA that were not treated or were treated with fluvastatin and from normal rats was determined. The amounts of 4‐hydroxy‐2‐nonenal (HNE) and nitrotyrosine in aortas were measured by Western blotting. In vitro and in situ superoxide production in aortas was evaluated based on fluorogenic oxidation of dihydroethidium to ethidium. Expression of NAD(P)H components and endothelial nitric oxide synthase (eNOS) in aortas was examined by real‐time reverse transcriptase–polymerase chain reaction and Western blotting. Serum levels of tetrahydrobiopterin, a critical eNOS cofactor, were determined by high‐performance liquid chromatography.

Results

Fluvastatin reversed endothelial dysfunction in AIA without affecting the clinical severity of arthritis or serum cholesterol concentration. Fluvastatin reduced the amounts of HNE and nitrotyrosine in the aorta, and the levels of superoxide expressed in endothelial cells and smooth muscle cells in the tissue, in rats with AIA. NADH‐ or L‐arginine–induced superoxide production was not observed in the aortic samples from fluvastatin‐treated rats with AIA. Fluvastatin decreased the levels of expression of messenger RNA for p22phox, a NAD(P)H oxidase component, in the aortas of rats with AIA, but did not affect the expression of eNOS. Serum levels of tetrahydrobiopterin were significantly reduced in rats with AIA, and were increased by administration of fluvastatin.

Conclusion

Our findings demonstrate that fluvastatin has potent vascular protective effects in AIA and provide additional scientific rationale for the use of statins to reduce cardiovascular mortality in patients with rheumatoid arthritis.
Reduced expression of decay‐accelerating factor 1 on CD4+ T cells in murine systemic autoimmune disease
Authors: Cauvi David M. , Cauvi Gabrielle , Pollard K. Michael
Published: May 2007

Objective

Deficiency of decay‐accelerating factor 1 (termed Daf1 in mice) has been shown to exacerbate autoimmunity, and recent studies have suggested that this may be explained by Daf1 acting as a regulator of T cell immunity. The aim of this study was to determine whether Daf1 expression on T cells is modulated during development of autoimmunity in mice.

Methods

To test this hypothesis, we examined Daf1 levels in NZB, DBA/2, and B10.S mice before and after induction of murine mercury‐induced autoimmunity (mHgIA). Daf1 was measured by real‐time polymerase chain reaction and flow cytometry, and levels of Daf1 were correlated with markers of lymphocyte activation and cytokine production.

Results

Autoimmune‐prone NZB mice had low endogenous levels of Daf1 irrespective of the induction of mHgIA. Induction of autoimmunity reduced Daf1 expression in mHgIA‐sensitive B10.S mice, particularly on activated/memory (CD44high) CD4+ T cells that accumulate as a result of exposure to mercury. Murine mercury‐induced autoimmunity–resistant DBA/2 mice, which fail to accumulate CD44high T cells, showed no change in Daf1 expression. Modulation of Daf1 expression was found to require CD4+ T cell costimulation, since B10.S mice deficient in CD28 were unable to down‐regulate Daf1 or accumulate activated/memory CD4+ T cells. In B10.S mice exposed to mercury, the production of interleukin‐4 (IL‐4), but not that of IL‐2 or interferon‐γ, in the spleen was associated with CD44high,Daf1low,CD4+ T cells.

Conclusion

These findings demonstrate that reduction of Daf1 expression is closely associated with CD4+ T cell activation and the accumulation of CD44high(activated/memory),CD4+ T cells in both spontaneous and induced systemic autoimmune disease.
A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent‐onset rheumatoid arthritis
Authors: Wessels Judith A. M. , van der Kooij Sjoerd M. , le Cessie Saskia , Kievit Wietske , Barerra Pilar , Allaart Cornelia F. , Huizinga Tom W. J. , Guchelaar Henk‐Jan ,   Pharmacogenetics Collaborative Research Group
Published: May 2007

Objective

To develop a clinical pharmacogenetic model to predict the efficacy of methotrexate (MTX) in rheumatoid arthritis (RA).

Methods

Two hundred five patients with newly diagnosed RA and active disease were treated with MTX (initiated at a dosage of 7.5 mg/week and increased to 15 mg/week after 4 weeks) and folic acid (1 mg/day). If the Disease Activity Score (DAS) was >2.4 at 3 months, the dosage of MTX was increased up to 25 mg/week. Twenty‐four baseline variables possibly influencing disease state and drug response were selected. In addition, 17 polymorphisms in 13 genes related to the MTX mechanism of action, purine and pyrimidine synthesis, were determined. Factors were compared between responders (defined as patients with a DAS ≤2.4 at 6 months) and nonresponders. In case of differences, a stepwise selection procedure identified the predictors for response. A clinical score was designed by simplifying regression coefficients of the independent variables. Cutoff levels were chosen based on the clinical score, and positive and negative response rates were calculated. An evaluation of the model was performed in a second group of patients.

Results

The model for MTX efficacy consisted of sex, rheumatoid factor and smoking status, the DAS, and 4 polymorphisms in the AMPD1, ATIC, ITPA, and MTHFD1 genes. This prediction model was transformed into a scoring system ranging from 0 to 11.5. Scores of ≤3.5 had a true positive response rate of 95%. Scores of ≥6 had a true negative response rate of 86%. Sixty percent of the patients were categorized as either responders or nonresponders, whereas 32% of the patients were categorized using a nongenetic model. Evaluation of the model in 38 additional patients with RA supported the results.

Conclusion

This study established a model for predicting the efficacy of MTX in patients with RA. This pharmacogenetic model may lead to better‐tailored initial treatment decisions in patients with RA.
Specific gene expression profiles in systemic juvenile idiopathic arthritis
Authors: Ogilvie Emma Mary , Khan Arshad , Hubank Mike , Kellam Paul , Woo Patricia
Published: May 2007

Objective

Patients with systemic juvenile idiopathic arthritis (JIA) have arthritis, quotidian fevers, and other extraarticular features. This disease often remains severe and debilitating. The purpose of this study was to compare gene expression profiles in peripheral blood mononuclear cells (PBMCs) from patients with active and inactive systemic JIA to define and better understand the cause of active disease.

Methods

Gene expression profiles of PBMCs were determined in cells from 9 patients with active systemic JIA and 8 patients with inactive systemic JIA. Unsupervised clustering and significance analysis were performed. We compared the systemic JIA profile with data from patients with polyarticular JIA, chronic infantile neurologic, cutaneous, articular syndrome, Kawasaki disease, and systemic lupus erythematosus to identify disease‐specific genes. Quantitative reverse transcription–polymerase chain reaction of selected genes was performed on negatively selected B cells, T cells, and monocytes.

Results

Unsupervised clustering of expressed genes resulted in 2 groups that corresponded to the clinical status of the patients (active and inactive disease) and was independent of their medications. A total of 286 genes were identified as significantly up‐regulated in patients with active disease and 86% of them were specific to systemic JIA. Interleukin‐6 (IL‐6) was expressed in monocytes and B cells, IL‐10 in monocytes, and suppressor of cytokine signaling 3 in monocytes and T cells from patients with active disease.

Conclusion

Gene expression profiles in PBMCs identified disease‐specific genes in patients with systemic JIA. Cell type analyses should allow further insight into the mechanisms of the disease.
Tumor necrosis factor α activates release of B lymphocyte stimulator by neutrophils infiltrating the rheumatoid joint
Authors: Assi Lakhvir K. , Wong See Heng , Ludwig Andreas , Raza Karim , Gordon Caroline , Salmon Michael , Lord Janet M. , Scheel‐Toellner Dagmar
Published: May 2007

Objective

The tumor necrosis factor (TNF) family member B lymphocyte stimulator (BLyS) is an important regulator of B cell–dependent autoimmunity. Similar to other TNF family members, it is generally expressed as a transmembrane protein and cleaved from the surface to release its active soluble form. This study was undertaken to investigate the expression of BLyS and regulation of BLyS release from the surface of neutrophils infiltrating the rheumatoid joint.

Methods

BLyS expression was studied in neutrophils from the synovial fluid and peripheral blood of patients with rheumatoid arthritis (RA) and healthy controls, by flow cytometry, Western blotting, and immunofluorescence analyses. Peripheral blood neutrophils cultured with 50% RA synovial fluid were study for membrane expression of BLyS. Neutrophils were exposed to a range of proinflammatory cytokines to study the mechanisms of surface loss of BLyS.

Results

Expression of BLyS was detected on the surface of peripheral blood neutrophils from both RA patients and healthy controls, whereas BLyS expression on synovial fluid neutrophils was very low. Constitutive expression of BLyS was observed in neutrophils, both on the cell membrane and in intracellular stores; however, BLyS release from each of these sites was found to be regulated independently. Of the various cytokine stimuli, only TNFα triggered release of BLyS from the neutrophil membrane. This process led to release of physiologically relevant quantities of soluble BLyS, which was dependent on the presence of the pro‐protein convertase furin. In contrast, stimulation of neutrophils with granulocyte colony‐stimulating factor induced BLyS release from the intracellular stores. Incubation of peripheral blood neutrophils with RA synovial fluid led to TNFα‐dependent shedding of BLyS from the cell surface.

Conclusion

These findings indicate that as neutrophils enter the site of inflammation, they release surface‐expressed BLyS in a TNFα‐dependent manner, and thus may contribute to local stimulation of autoimmune B cell responses.
Protection against renal disease in (NZB × NZW)F1 lupus‐prone mice after somatic B cell gene vaccination with anti‐DNA immunoglobulin consensus peptide
Authors: Ferrera Francesca , Hahn Bevra H. , Rizzi Marta , Anderson Marissa , FitzGerald John , Millo Enrico , Indiveri Francesco , Shi Fu‐Dong , Filaci Gilberto , La Cava Antonio
Published: May 2007

Objective

Ig molecules contain epitopes that can induce T cell–mediated immune responses. B cells can process and present such epitopes and activate T cells. The purpose of the present study was to test our hypothesis that T cells that recognize an Ig consensus sequence presented by B cells will modulate lupus‐like disease in mice.

Methods

(NZB × NZW)F1 (NZB/NZW) lupus mice received somatic B cell gene transfer of a DNA plasmid encoding a consensus sequence of T cell determinants of murine anti‐DNA IgG or control plasmids. Treated animals were monitored for the production of antibody, the development of renal disease, and the phenotype, number, and function of T cells.

Results

Treatment of mice with Ig consensus plasmid induced transforming growth factor β–producing CD8+,CD28– T cells that suppressed the antigen‐specific stimulation of CD4+ T cells in a cell‐contact–independent manner, reduced antibody production, retarded the development of nephritis, and improved survival. Significantly, adoptive transfer of CD8+,CD28– T cells from protected mice into hypergammaglobulinemic NZB/NZW mice effectively protected the transferred mice from the development of renal disease.

Conclusion

Gene expression of anti‐DNA Ig consensus sequence induces immunoregulatory T cells that delay the development of lupus nephritis by suppressing hypergammaglobulinemia and renal disease.
Chondrogenic differentiation of bovine synovium: Bone morphogenetic proteins 2 and 7 and transforming growth factor β1 induce the formation of different types of cartilaginous tissue
Authors: Shintani Nahoko , Hunziker Ernst B.
Published: May 2007

Objective

To compare the potential of bone morphogenetic proteins 2 and 7 (BMP‐2 and BMP‐7) and transforming growth factor β1 (TGFβ1) to effect the chondrogenic differentiation of synovial explants by analyzing the histologic, biochemical, and gene expression characteristics of the cartilaginous tissues formed.

Methods

Synovial explants derived from the metacarpal joints of calves were cultured in agarose. Initially, BMP‐2 was used to evaluate the chondrogenic potential of the synovial explants under different culturing conditions. Under appropriate conditions, the chondrogenic effects of BMP‐2, BMP‐7, and TGFβ1 were then compared. The differentiated tissue was characterized histologically, histomorphometrically, immunohistochemically, biochemically, and at the gene expression level.

Results

BMP‐2 induced the chondrogenic differentiation of synovial explants in a dose‐ and time‐dependent manner under serum‐ and dexamethasone‐free conditions. The expression levels of cartilage‐related genes increased in a time‐dependent manner. BMP‐7 was more potent than BMP‐2 in inducing chondrogenesis, but the properties of the differentiated tissue were similar in each case. The type of cartilaginous tissue formed under the influence of TGFβ1 differed in terms of both cell phenotype and gene expression profiles.

Conclusion

The 3 tested members of the TGFβ superfamily have different chondrogenic potentials and induce the formation of different types of cartilaginous tissue. To effect the full differentiation of synovial explants into a typically hyaline type of articular cartilage, further refinement of the stimulation conditions is required. This might be achieved by the simultaneous application of several growth factors.
Altered coronary vasomotor function in young patients with systemic lupus erythematosus
Authors: Hirata Kumiko , Kadirvelu Amudha , Kinjo Mitsuyo , Sciacca Robert , Sugioka Kenichi , Otsuka Ryo , Choy AnnaMaria , Chow Sook K. , Yoshiyama Minoru , Yoshikawa Junichi , Homma Shunichi , Lang Chim C.
Published: May 2007

Objective

Accelerated atherosclerosis is an important cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Altered coronary microvascular function may act as a marker of changes that predispose to the development of significant coronary vascular disease. The purpose of this study was to compare coronary flow reserve (CFR) in a group of premenopausal women with SLE and a group of age‐, sex‐, and race‐matched healthy control subjects.

Methods

Coronary flow velocity in 18 premenopausal women with SLE (mean ± SD age 29.4 ± 5.9 years) and 19 matched healthy controls (mean ± SD age 28.2 ± 4.3 years) was assessed by transthoracic Doppler echocardiography after an overnight fast. The CFR was calculated as the ratio of hyperemic to baseline coronary blood flow velocity in the left anterior descending coronary artery. Hyperemia was induced by intravenous administration of adenosine triphosphate.

Results

The mean ± SD duration of SLE was 8.2 ± 7.2 years (range 0.25–25 years), and the mean ± SD score on the Systemic Lupus Erythematosus Disease Activity Index was 11.0 ± 5.3 (range 4.0–21.0). Adequate recordings of flow velocity in the left anterior descending artery under both conditions were obtained using an ultrasound procedure in all study subjects. CFR was significantly lower in SLE patients as compared with control subjects (mean ± SD 3.4 ± 0.8 versus 4.5 ± 0.5; P < 0.0001).

Conclusion

These findings provide evidence that coronary vasomotor function is impaired in patients with SLE and support the notion that many of these young patients have subclinical coronary artery disease.
Interaction between smoking, the shared epitope, and anti–cyclic citrullinated peptide: A mixed picture in three large North American rheumatoid arthritis cohorts
Authors: Lee Hye‐Soon , Irigoyen Patricia , Kern Marlena , Lee Annette , Batliwalla Franak , Khalili Houman , Wolfe Frederick , Lum Raymond F. , Massarotti Elena , Weisman Michael , Bombardier Claire , Karlson Elizabeth W. , Criswell Lindsey A. , Vlietinck Robert , Gregersen Peter K.
Published: May 2007

Objective

Recently, Swedish members of the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) provided evidence that smoking may trigger RA‐specific immune reactions to citrullinated protein in carriers of HLA–DR shared epitope alleles. In an effort to confirm this interaction between smoking and shared epitope alleles, we performed a case‐only analysis of 3 North American RA cohorts.

Methods

A total of 2,476 white patients with RA were studied, 1,105 from the North American Rheumatoid Arthritis Consortium (NARAC) family collection, 753 from the National Inception Cohort of Rheumatoid Arthritis Patients (Inception Cohort), and 618 from the Study of New Onset Rheumatoid Arthritis (SONORA). All patients were HLA–DRB1 typed, and tested for anti–cyclic citrullinated peptide (anti‐CCP) and rheumatoid factor. Information about smoking history was obtained by questionnaire.

Results

A significant association was found between smoking and the presence of anti‐CCP in the NARAC and the Inception Cohort, but not in the SONORA. The shared epitope alleles consistently correlated with anti‐CCP in all 3 populations. Using multiple logistic regression analyses, shared epitope alleles were still the most significant risk factor for anti‐CCP positivity. Weak evidence of gene–environment interaction between smoking and shared epitope alleles for anti‐CCP formation was found only in the NARAC.

Conclusion

Unlike the EIRA data, we could not confirm a major gene–environment interaction for anti‐CCP formation between shared epitope alleles and smoking in 3 North American RA cohorts. Our data indicate a need for further studies to address the full range of environmental factors other than smoking that may be associated with citrullination and RA.
Interleukin‐18 induces angiogenic factors in rheumatoid arthritis synovial tissue fibroblasts via distinct signaling pathways
Authors: Amin Mohammad A. , Mansfield Pamela J. , Pakozdi Angela , Campbell Phillip L. , Ahmed Salahuddin , Martinez Rita J. , Koch Alisa E.
Published: May 2007

Objective

Interleukin‐18 (IL‐18) is a proinflammatory cytokine implicated in the pathogenesis of rheumatoid arthritis (RA). This study was undertaken to examine the role of IL‐18 in up‐regulating secretion of the angiogenic factors stromal cell–derived factor 1α (SDF‐1α)/CXCL12, monocyte chemoattractant protein 1 (MCP‐1)/CCL2, and vascular endothelial growth factor (VEGF) in RA synovial tissue (ST) fibroblasts, and the underlying signaling mechanisms involved.

Methods

We used enzyme‐linked immunosorbent assays, Western blotting, and chemical inhibitors/antisense oligodeoxynucleotides to signaling intermediates to assess the role of IL‐18.

Results

IL‐18 significantly enhanced the production of SDF‐1α/CXCL12, MCP‐1/CCL2, and VEGF in RA ST fibroblasts, in a time‐ and concentration‐dependent manner. IL‐18–induced SDF‐1α/CXCL12 up‐regulation was dependent on JNK, p38 MAPK, phosphatidylinositol 3‐kinase (PI3K), and NFκB. While IL‐18–induced production of SDF‐1α/CXCL12 was also dependent on protein kinase Cδ (PKCδ), production of MCP‐1/CCL2 was dependent on PKCα, not PKCδ. Additionally, RA ST fibroblast IL‐18–induced MCP‐1/CCL2 production was mediated by JNK, PI3K, and NFκB. In contrast, IL‐18 did not induce secretion of RA ST fibroblast MCP‐1/CCL2 or VEGF via p38 MAPK. IL‐18–induced RA ST fibroblast production of VEGF was mediated mainly by JNK‐2, PKCα, and NFκB. IL‐18 induced phosphorylation of JNK, PKCδ, p38 MAPK, and activating transcription factor 2 (ATF‐2) in RA ST fibroblasts in a time‐dependent manner, with JNK‐2 being upstream of PKCδ, ATF‐2, and NFκB.

Conclusion

These data support the notion that IL‐18 has a unique role in inducing the secretion of angiogenic SDF‐1α/CXCL12, MCP‐1/CCL2, and VEGF in RA ST fibroblasts, via distinct signaling intermediates.
The role of vascular cell adhesion molecule 1/ very late activation antigen 4 in endothelial progenitor cell recruitment to rheumatoid arthritis synovium
Authors: Silverman Matthew D. , Haas Christian S. , Rad Ali M. , Arbab Ali S. , Koch Alisa E.
Published: May 2007

Objective

Marrow‐derived endothelial progenitor cells (EPCs) are important in the neovascularization that occurs in diverse conditions such as cardiovascular disorders, inflammatory diseases, and neoplasms. In rheumatoid arthritis (RA), synovial neovascularization propels disease by nourishing the inflamed and hyperproliferative synovium. This study was undertaken to investigate the hypothesis that EPCs selectively home to inflamed joint tissue and may perpetuate synovial neovascularization.

Methods

In a collagen‐induced arthritis (CIA) model, neovascularization and EPC accumulation in mouse ankle synovium was measured. In an antibody‐induced arthritis model, EPC recruitment to inflamed synovium was evaluated. In a chimeric SCID mouse/human synovial tissue (ST) model, mice were engrafted subcutaneously with human ST, and EPC homing to grafts was assessed 2 days later. EPC adhesion to RA fibroblasts and RA ST was evaluated in vitro.

Results

In mice with CIA, cells bearing EPC markers were significantly increased in peripheral blood and accumulated in inflamed synovial pannus. EPCs were 4‐fold more numerous in inflamed synovium from mice with anti–type II collagen antibody–induced arthritis versus controls. In SCID mice, EPC homing to RA ST was 3‐fold greater than to normal synovium. Antibody neutralization of vascular cell adhesion molecule 1 (VCAM‐1) and its ligand component α4 integrin potently inhibited EPC adhesion to RA fibroblasts and RA ST cryosections.

Conclusion

These data demonstrate the selective recruitment of EPCs to inflamed joint tissue. The VCAM‐1/very late activation antigen 4 adhesive system critically mediates EPC adhesion to cultured RA fibroblasts and to RA ST cryosections. These findings provide evidence of a possible role of EPCs in the synovial neovascularization that is critical to RA pathogenesis.
Global analyses of gene expression in early experimental osteoarthritis
Authors: Appleton C. T. G. , Pitelka V. , Henry J. , Beier F.
Published: May 2007

Objective

To analyze genome‐wide changes in chondrocyte gene expression in a surgically induced model of early osteoarthritis (OA) in rats, to assess the similarity of this model to human OA, and to identify genes and mechanisms leading to OA pathogenesis.

Methods

OA was surgically induced in 5 rats by anterior cruciate ligament transection and partial medial meniscectomy. Sham surgery was performed in 5 additional animals, which were used as controls. Both groups underwent 4 weeks of forced mobilization, 3 times per week. RNA was extracted directly from articular chondrocytes in the OA (operated), contralateral, and sham‐operated knees. Affymetrix GeneChip expression arrays were used to assess genome‐wide changes in gene expression. Expression patterns of selected dysregulated genes, including Col2a1, Mmp13, Adamts5, Ctsc, Ptges, and Cxcr4, were validated by real‐time polymerase chain reaction, immunofluorescence, or immunohistochemistry 2, 4, and 8 weeks after surgery.

Results

After normalization, comparison of OA and sham‐operated samples showed 1,619 differentially expressed probe sets with changes in their levels of expression ≥1.5‐fold, 722 with changes ≥2‐fold, 135 with changes ≥4‐fold, and 20 with changes of 8‐fold. Dysregulated genes known to be involved in human OA included Mmp13, Adamts5, and Ptgs2, among others. Several dysregulated genes (e.g., Reln, Phex, and Ltbp2) had been identified in our earlier microarray study of hypertrophic chondrocyte differentiation. Other genes involved in cytokine and chemokine signaling, including Cxcr4 and Ccl2, were identified. Changes in gene expression were also observed in the contralateral knee, validating the sham operation as the appropriate control.

Conclusion

Our results demonstrate that the animal model mimics gene expression changes seen in human OA, supporting the relevance of newly identified genes and pathways to early human OA. We propose new avenues for OA pathogenesis research and potential targets for novel OA treatments, including cathepsins and cytokine, chemokine, and growth factor signaling pathways, in addition to factors controlling the progression of chondrocyte differentiation.
Activation of invariant natural killer T cells by synthetic glycolipid ligands suppresses autoantibody‐induced arthritis
Authors: Kaieda Shinjiro , Tomi Chiharu , Oki Shinji , Yamamura Takashi , Miyake Sachiko
Published: May 2007

Objective

Stimulation of invariant natural killer T (iNKT) cells with SGL‐S23, a novel synthetic glycolipid analog of α‐galactosylceramide with an elongated sphingosine chain, has been shown to strongly suppress K/BxN serum transfer arthritis. This study was designed to evaluate the protective effects of SGL‐S23 in an effector phase of arthritis.

Methods

To induce arthritis, C57BL/6 mice were injected with 150 μl of serum from K/BxN mice (KRN TCR–transgenic mice crossed with nonobese diabetic mice). Subsequently, synthetic glycolipid ligands were administered intraperitoneally twice, either 3 times starting on day 0 (the day of K/BxN serum injection) or twice starting on day 3. Neutralizing antibody against interferon‐γ (IFNγ) interleukin‐4 (IL‐4), IL‐10, or transforming growth factor β was administered 4 hours before injection of SGL‐S23. Recombinant IFNγ was administered subcutaneously every day. The severity of arthritis was monitored using a macroscopic scoring system. Cytokine production and plasma histamine levels were measured by enzyme‐linked immunosorbent assay.

Results

SGL‐S23 strongly suppressed K/BxN serum transfer arthritis by inhibiting inflammatory cell infiltration and subsequent destruction of cartilage and bone. The inhibitory effect mediated by SGL‐S23 was abolished by neutralization of IFNγ. Systemic administration of IFNγ prevented the development of inflammatory arthritis. Histamine release was suppressed by administration of SGL‐S23 or IFNγ. Degranulated mast cells in the synovium were significantly reduced in SGL‐S23–treated mice, suggesting that suppression of mast cell activation contributed to the inhibition of arthritis.

Conclusion

These findings suggest that activation of iNKT cells with glycolipid ligands holds promise with regard to the treatment of autoimmune diseases such as rheumatoid arthritis. SGL‐S23 has clinical benefit over α‐galactosylceramide since it induces a weaker cytokine production response in iNKT cells, therefore reducing potential side effects caused by excessive cytokine release.
Female mice are more susceptible to developing inflammatory disorders due to impaired transforming growth factor β signaling in salivary glands
Authors: Nandula Seshagiri R. , Amarnath Shoba , Molinolo Alfredo , Bandyopadhyay Bidhan C. , Hall Bradford , Goldsmith Corinne M. , Zheng Changyu , Larsson Jonas , Sreenath Taduru , Chen WanJun , Ambudkar Indu S. , Karlsson Stefan , Baum Bruce J. , Kulkarni Ashok B.
Published: May 2007

Objective

Transforming growth factor β (TGFβ) plays a key role in the onset and resolution of autoimmune diseases and chronic inflammation. The aim of this study was to delineate the precise function of TGFβ signaling in salivary gland inflammation.

Methods

We impaired TGFβ signaling in mouse salivary glands by conditionally inactivating expression of TGFβ receptor type I (TGFβRI), either by using mouse mammary tumor virus–Cre mice or by delivering adenoviral vector containing Cre to mouse salivary glands via retrograde infusion of the cannulated main excretory ducts of submandibular glands.

Results

TGFβRI–conditional knockout (TGFβRI‐coko) mice were born normal; however, female TGFβRI‐coko mice developed severe multifocal inflammation in salivary and mammary glands and in the heart. The inflammatory disorder affected normal growth and resulted in the death of the mice at ages 4–5 weeks. Interestingly, male TGFβRI‐coko mice did not exhibit any signs of inflammation. The female TGFβRI‐coko mice also showed an increase in Th1 proinflammatory cytokines in salivary glands and exhibited an up‐regulation of peripheral T cells. In addition, these mice showed an atypical distribution of aquaporin 5 in their salivary glands, suggesting likely secretory impairment. Administration of an adenoviral vector encoding Cre recombinase into the salivary glands resulted in inflammatory foci only in the glands of female TGFβRI–loxP‐flanked (floxed) mice (TGFβRI‐f/f mice), but not in those of male and female wild‐type mice or male TGFβRI‐f/f mice.

Conclusion

These results suggest that female mice are uniquely more susceptible to developing inflammatory disorders due to impaired TGFβ signaling in their salivary glands.
Coffee, tea, and caffeine consumption and serum uric acid level: The third national health and nutrition examination survey
Authors: Choi Hyon K. , Curhan Gary
Published: May 2007

Objective

Coffee is one of the most widely consumed beverages in the world and may affect serum uric acid levels and risk of gout via various mechanisms. Our objective was to evaluate the relationship between coffee, tea, and caffeine intake and serum uric acid level in a nationally representative sample of men and women.

Methods

Using data from 14,758 participants ages ≥20 years in the Third National Health and Nutrition Examination Survey (1988–1994), we examined the relationship between coffee, tea, and caffeine intake and serum uric acid level using linear regression. Additionally, we examined the relationship with hyperuricemia (serum uric acid >7.0 mg/dl among men and >5.7 mg/dl among women) using logistic regression. Intake was assessed by a food frequency questionnaire.

Results

Serum uric acid level decreased with increasing coffee intake. After adjusting for age and sex, serum uric acid level associated with coffee intake of 4 to 5 and ≥6 cups daily was lower than that associated with no intake by 0.26 mg/dl (95% confidence interval [95% CI] 0.11, 0.41) and 0.43 mg/dl (95% CI 0.23, 0.65; P for trend < 0.001), respectively. After adjusting for other covariates, the differences remained significant (P for trend < 0.001). Similarly, there was a modest inverse association between decaffeinated coffee intake and serum uric acid levels (multivariate P for trend 0.035). Total caffeine from coffee and other beverages and tea intake were not associated with serum uric acid levels (multivariate P for trend 0.15). The multivariate odds ratio for hyperuricemia in individuals with coffee intake ≥6 cups daily compared with those with no coffee use was 0.57 (95% CI 0.35, 0.94; P for trend 0.001).

Conclusion

These findings from a nationally representative sample of US adults suggest that coffee consumption is associated with lower serum uric acid level and hyperuricemia frequency, but tea consumption is not. The inverse association with coffee appears to be via components of coffee other than caffeine.
Exploring the use of videotaped objective structured clinical examination in the assessment of joint examination skills of medical students
Authors: Vivekananda‐Schmidt Pirashanthie , Lewis Martyn , Coady David , Morley Catherine , Kay Lesley , Walker David , Hassell Andrew B.
Published: May 2007

Objective

Objective structured clinical examination (OSCE) is a key part of medical student assessment. Currently, assessment is performed by medical examiners in situ. Our objective was to determine whether assessment by videotaped OSCE is as reliable as live OSCE assessment.

Methods

Participants were 95 undergraduate medical students attending their musculoskeletal week at Freeman Hospital, Newcastle (UK). Student performance on OSCE stations for shoulder or knee examinations was assessed by experienced rheumatologists. The stations were also videotaped and scored by a rheumatologist independently. The examinations consisted of a 14‐item checklist and a global rating scale (GRS).

Results

Mean values for the shoulder OSCE checklist were 17.9 by live assessment and 17.4 by video (n = 50), and 20.9 and 20.0 for live and video knee assessment, respectively (n = 45). Intraclass correlation coefficients for shoulder and knee checklists were 0.55 and 0.58, respectively, indicating moderate reliability between live and video scores for the OSCE checklists. GRS scores were less reliable than checklist scores. There was 84% agreement in the classification of examination grades between live and video checklist scores for the shoulder and 87% agreement for the knee (κ = 0.43 and 0.51, respectively; P < 0.001).

Conclusion

Video OSCE has the potential to be reliable and offers some advantages over live OSCE including more efficient use of examiners' time, increased fairness, and better monitoring of standards across various schools/sites. However, further work is needed to support our findings and to implement and evaluate the quality assurance issues identified in this work before justifiable recommendations can be made.
Do proton‐pump inhibitors confer additional gastrointestinal protection in patients given celecoxib?
Authors: Rahme Elham , Barkun Alan N. , Toubouti Youssef , Scalera Alissa , Rochon Sophie , Lelorier Jacques
Published: May 2007

Objective

Celecoxib has a superior upper‐gastrointestinal (GI) safety profile compared with nonselective nonsteroidal antiinflammatory drugs (NS‐NSAIDs). It is unclear whether the utilization of a proton‐pump inhibitor (PPI) with celecoxib confers additional protection in elderly patients. We assessed the association between GI hospitalizations and use of celecoxib with a PPI versus celecoxib alone, and NS‐NSAIDs with a PPI or NS‐NSAIDs alone in elderly patients.

Methods

We conducted a population‐based retrospective cohort study using the government of Quebec health services administrative databases. Elderly patients were included at their first dispensing date for celecoxib or an NS‐NSAID between April 1999 and December 2002. Prescriptions were separated into 4 groups: celecoxib, celecoxib plus PPI, NS‐NSAIDs, and NS‐NSAIDs plus PPI. Cox regression models with time‐dependent exposure were used to compare the hazard rates of GI hospitalization between the 4 groups adjusting for patient characteristics at baseline.

Results

There were 1,161,508 prescriptions for celecoxib, 360,799 for celecoxib plus PPI, 715,176 for NS‐NSAIDs, and 148,470 for NS‐NSAIDs plus PPI. The adjusted hazard ratios (HRs; 95% confidence intervals [95% CIs]) were 0.69 (0.52–0.93) for celecoxib plus PPI versus celecoxib, 0.98 (0.67–1.45) for NS‐NSAIDs plus PPI versus celecoxib, and 2.18 (1.82–2.61) for NS‐NSAIDs versus celecoxib. Subgroup analyses showed that use of a PPI with celecoxib may be beneficial in patients ages ≥75 years but was not better than celecoxib alone among those ages 66–74 years (HR 0.98, 95% CI 0.63–1.52).

Conclusion

Addition of a PPI to celecoxib conferred extra protection for patients ages ≥75 years. PPI did not seem necessary with celecoxib for patients ages 66–74 years.
Quality of care for gout in the US needs improvement
Authors: Singh Jasvinder A. , Hodges James S. , Toscano John P. , Asch Steven M.
Published: May 2007

Objective

To examine evidence‐based quality indicators (QIs) in US veterans with gout diagnosis, and to examine the effect of demographics, heath care utilization/access, comorbid conditions, or physican characteristics as predictors of quality of gout care.

Methods

Using the Minneapolis Veterans Affairs electronic medical record system, we identified a cohort of veterans receiving medication to treat gout between January 1, 1999 and December 31, 2003, and evaluated 3 recently published evidence‐based QIs for gout management: QI 1 = allopurinol dose <300 mg in gout patients with renal insufficiency, QI 2 = uric acid check within 6 months of starting a new allopurinol prescription, and QI 3 = complete blood count and creatine kinase check every 6 months for gout patients receiving prolonged colchicine therapy. We calculated the proportion of patients whose therapy adhered to each QI and to all applicable indicators (overall physician adherence). Logistic regression analysis examined association of overall physician adherence with sociodemographics, health care utilization, comorbidity, and provider characteristics.

Results

Of 3,658 patients with a diagnosis of gout, 663 patients qualified for examination of ≥1 QI. Of these 663 patients, therapy in only 144 (22%) adhered to all applicable QIs; 59 (78%) of 76 adhered to QI 1, 155 (24%) of 643 adhered to QI 2, and 18 (35%) of 52 adhered to QI 3. Overall physician adherence to QIs was significantly lower in older veterans and in those with more inpatient visits per year, but was higher in those with more primary care visits or more health care providers.

Conclusion

Suboptimal physician adherence to QIs was seen for all 3 QIs tested in this cohort of veterans with gout. These findings can guide quality improvement efforts.
Risk of tuberculosis in patients treated with tumor necrosis factor antagonists due to incomplete prevention of reactivation of latent infection
Authors: Gómez‐Reino Juan J. , Carmona Loreto , Ángel Descalzo Miguel
Published: May 2007

Objective

To evaluate the causes of new cases of active tuberculosis (ATB) in patients treated with tumor necrosis factor (TNF) antagonists included in the national registry BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) after the dissemination of recommendations to prevent reactivation of latent tuberculosis infection (LTBI).

Methods

Incidence rate of ATB per 100,000 patient‐years and 95% confidence intervals (95% CIs) were calculated in patients entering BIOBADASER after March 2002 and were stratified by compliance with recommendations (complete or incomplete). ATB rates in BIOBADASER were compared with the background rate and the rate in the rheumatoid arthritis cohort EMECAR (Estudio de la Morbilidad y Expresión Clínica de la Artritis Reumatoide) not treated with TNF antagonists. In addition, rates of ATB among patients treated with adalimumab, etanercept, and infliximab were estimated and compared only for treatments started after September 2003, when all 3 drugs became fully available.

Results

Following March 2002, a total of 5,198 patients treated with a TNF antagonist were registered in BIOBADASER. Fifteen ATB cases were noted (rate 172 per 100,000 patient‐years, 95% CI 103–285). Recommendations were fully followed in 2,655 treatments. The probability of developing ATB was 7 times higher when recommendations were not followed (incidence rate ratio 7.09, 95% CI 1.60–64.69). Two‐step tuberculosis skin test for LTBI was the major failure in complying with recommendations.

Conclusion

New cases of ATB still occur in patients treated with all available TNF antagonists due to lack of compliance with recommendations to prevent reactivation of LTBI. Continuous evaluation of recommendations is required to improve clinical practice.
Using Rasch analysis to compare the psychometric properties of the Short Form 36 physical function score and the Health Assessment Questionnaire disability index in patients with psoriatic arthritis and rheumatoid arthritis
Authors: Taylor William J. , McPherson Kathryn M.
Published: May 2007

Objective

Item‐response theory is increasingly used in the development of robust measurement tools. The extent to which the Health Assessment Questionnaire (HAQ) disability index (DI) and Short Form 36 (SF‐36) physical functioning subscale (PF) fit a Rasch model in psoriatic arthritis (PsA) is uncertain. Our objective was to compare the psychometric properties of the HAQ DI and SF‐36 PF in PsA and rheumatoid arthritis (RA) using Rasch analysis.

Methods

Patients with RA (n = 142) and PsA (n = 134) were identified from a disease register based at a regional rheumatology service that serves a population of ∼400,000 individuals. Responses to the HAQ DI and SF‐36 PF were analyzed for item fit, differential item functioning (DIF), scale length (item separation), floor effects, and item difficulty by fitting the data to a Rasch model. The extent to which each instrument measured the same concept (disability) was also assessed in the PsA cohort using the Rasch model.

Results

Item separation was much better for the SF‐36 PF than the HAQ DI in PsA (9.12 logits versus 2.06 logits). There was evidence of marked DIF for the HAQ DI items activities, grip, and rising and relatively minor DIF for 4 items of the SF‐36 PF. The distribution of SF‐36 PF was better than HAQ DI in PsA, with floor effects of 3.1% versus 30.4%. Common person equating demonstrated that the 2 instruments measure the same construct in PsA.

Conclusion

The SF‐36 PF has significant psychometric advantages over the HAQ DI in PsA.