bluuebunny/crossref_metadata_2025_split huggingface dataset:
High ten‐year risk of cardiovascular disease in newly diagnosed rheumatoid arthritis patients: A population‐based cohort study
Authors: Kremers Hilal Maradit , Crowson Cynthia S. , Therneau Terry M. , Roger Veronique L. , Gabriel Sherine E. 
Published: August 2008

AbstractObjectiveTo estimate the 10‐year absolute risk of cardiovascular (CV) events in newly diagnosed rheumatoid arthritis (RA) patients and the potential contribution of CV risk factors to absolute risk assessment.MethodsA population‐based incidence cohort of RA patients (defined according to the American College of Rheumatology 1987 criteria) was assembled and compared with an age‐ and sex‐matched non‐RA cohort. Data were collected on CV risk factors and CV events. Cox regression models were used to estimate the 10‐year risk of a combined CV end point, adjusting for CV risk factors. Subjects were classified into 5 risk categories based on their 10‐year absolute risk.ResultsThe absolute CV risk in RA patients was similar to that in non‐RA subjects who were 5–10 years older. The absolute risk varied substantially according to the presence of CV risk factors. The 10‐year absolute CV risk among 60–69‐year‐old RA patients with no risk factors was 16.8%, but rose to 60.4% if risk factors such as smoking, hypertension, dyslipidemia, diabetes, and obesity were present. Among RA patients with a low body mass index, in addition to the above risk factors, the 10‐year absolute CV risk rose to 86.2%.ConclusionMore than half of the newly diagnosed RA patients who were 50–59 years of age and all of those >60 years of age had a >10% risk of CV disease within 10 years of their RA incidence and should be targeted for specific CV risk reduction strategies tailored to their personal risk profiles.
Cytokine‐controlled RANKL and osteoprotegerin expression by human and mouse synovial fibroblasts: Fibroblast‐mediated pathologic bone resorption
Authors: Tunyogi‐Csapo Miklos , Kis‐Toth Katalin , Radacs Marianna , Farkas Balint , Jacobs Joshua J. , Finnegan Alison , Mikecz Katalin , Glant Tibor T. 
Published: August 2008

AbstractObjectiveTo determine whether proinflammatory cytokine treatment or the complete absence of select cytokines modulates the expression of RANKL and osteoprotegerin (OPG) in synovial fibroblasts.MethodsFibroblasts were isolated from normal and rheumatoid human synovium and from normal or arthritic joints of wild‐type and cytokine gene–deficient (interleukin‐4–knockout [IL‐4 −/−] and interferon‐γ–knockout [IFNγ −/−]) mice. Fibroblasts were stimulated with proinflammatory cytokines (tumor necrosis factor α [TNFα], IL‐1β, and IL‐17) or antiosteoclastogenic cytokines (IL‐4 and IFNγ), alone or in combination, and the expression of RANKL and OPG was measured.ResultsProinflammatory cytokine–stimulated fibroblasts from rheumatoid and arthritic mouse joints expressed higher levels of RANKL and OPG than those from normal joints. IL‐4 suppressed RANKL expression and increased OPG expression, IFNγ reduced the production of both RANKL and OPG, and IL‐17 had only a modest effect on the expression of RANKL or OPG. Additive effects of combination treatment (TNFα/IL‐17 or IL‐1β/IL‐17) were observed only in the human system. Extensive destruction was observed in the arthritic joints of IL‐4 −/− mice, with a corresponding upward shift of the RANKL:OPG ratios. However, an IL‐17 deficiency did not attenuate arthritis or reduce bone resorption.ConclusionProinflammatory cytokines induce the expression of RANKL and OPG in both human and murine synovial fibroblasts. The RANKL:OPG ratios are shifted in favor of bone protection by IL‐4 treatment, and, to a lesser extent, by IFNγ treatment. Unexpectedly, an IL‐17 deficiency alone does not induce reduced inflammatory bone destruction. Our results suggest that synovial fibroblasts may significantly contribute to bone resorption through modulation of RANKL and OPG production in a cytokine‐rich milieu of inflamed joints.
Characterization of metalloprotease cleavage products of human articular cartilage
Authors: Zhen Eugene Y. , Brittain Isabelle J. , Laska Dennis A. , Mitchell Peter G. , Sumer Eren U. , Karsdal Morten A. , Duffin Kevin L. 
Published: August 2008

AbstractObjectiveTo identify, characterize, and compare proteolysis peptide products generated by metalloprotease digests of human articular cartilage.MethodsHuman articular cartilage was digested by the addition of exogenous metalloproteases, including matrix metalloproteinases 2, 3, 8, 9, 12, and 13 and aggrecanases ADAMTS‐4 and ADAMTS‐5. Proteolyzed peptide products were identified by proteomics methods using mass spectrometry.ResultsComplete sequences of the peptides proteolyzed from human articular cartilage, including N‐ and C‐termini and hydroxylated posttranslational modifications, were determined. A wide variety of peptides, originating from types I, II, and III collagen, biglycan, prolargin, fibromodulin, fibronectin, decorin, cartilage oligomeric matrix protein, cartilage intermediate‐layer protein, megakaryocyte‐stimulating factor, mimecan, aggrecan, and lumican, was analyzed following metalloprotease digestion. Release of peptides varied as a function of time, enzyme specificity, and abundance. Specific type II collagen peptide biomarkers, including those containing the three‐quarter–length fragment cleavage site and those containing the domains for helical peptide of type II collagen and C‐telopeptide of type II collagen, were observed after release by selected proteases.ConclusionThe use of intact cartilage instead of purified protein substrates in the assay allowed for the identification of novel potential substrates and cleavage sites for individual enzymes under more physiologically relevant conditions. Characterization of these cartilage matrix peptides may help in the development of pharmacodynamic biomarkers of cartilage degradation, and also may contribute to an understanding of the bioactive peptides important in chondrocyte signaling.
Increased numbers of circulating polyfunctional Th17 memory cells in patients with seronegative spondylarthritides
Authors: Jandus Camilla , Bioley Gilles , Rivals Jean‐Paul , Dudler Jean , Speiser Daniel , Romero Pedro 
Published: August 2008

AbstractObjectiveA distinct subset of proinflammatory CD4+ T cells that produce interleukin‐17 was recently identified. These cells are implicated in different autoimmune disease models, such as experimental autoimmune encephalomyelitis and collagen‐induced arthritis, but their involvement in human autoimmune disease has not yet been clearly established. The purpose of this study was to assess the frequency and functional properties of Th17 cells in healthy donors and in patients with different autoimmune diseases.MethodsPeripheral blood was obtained from 10 psoriatic arthritis (PsA), 10 ankylosing spondylitis (AS), 10 rheumatoid arthritis (RA), and 5 vitiligo patients, as well as from 25 healthy donors. Synovial tissue samples from a separate group of patients were also evaluated (obtained as paraffin‐embedded sections). Peripheral blood cells were analyzed by multiparameter flow cytometry and immunohistochemistry. Cytokine production was examined by enzyme‐linked immunosorbent assay and intracellular cytokine staining using specific monoclonal antibodies. Synovial tissue was examined for infiltrating T cells by immunohistochemical analysis.ResultsWe found increased numbers of circulating Th17 cells in the peripheral blood of patients with seronegative spondylarthritides (PsA and AS), but not in patients with RA or vitiligo. In addition, Th17 cells from the spondylarthritis patients showed advanced differentiation and were polyfunctional in terms of T cell receptor–driven cytokine production.ConclusionThese observations suggest a role of Th17 cells in the pathogenesis of certain human autoimmune disorders, in particular the seronegative spondylarthritides.
Inhibition of experimental Sjögren's syndrome through immunization with HSP60 and its peptide amino acids 437–460
Authors: Delaleu Nicolas , Madureira Ana Carina , Immervoll Heike , Jonsson Roland 
Published: August 2008

AbstractObjectiveTo investigate a potential immunomodulatory effect of the 60‐kd heat‐shock protein (Hsp60) on experimental spontaneous Sjögren's syndrome (SS).MethodsSeven‐week‐old nonobese diabetic (NOD) mice were immunized with eukaryotic Hsp60 or an Hsp60‐derived peptide (amino acid residue [aa] 437–460). At 21 weeks of age, nondiabetic mice were investigated for salivary gland inflammation, exocrine function, and extraglandular disease manifestations. In addition, biomarker profiles comprising 87 analytes in serum and 75 in saliva were analyzed.ResultsIn mice immunized with Hsp60 and aa 437–460, SS‐related histopathologic features were significantly reduced compared with NOD controls. In addition, 50% of Hsp60‐injected mice and 33% of aa 437–460–injected mice retained normal exocrine function. Both treatments induced similar changes in biomarker profiles. Notably, levels of circulating interferon‐γ–inducible 10‐kd protein (IP‐10) and eotaxin were decreased significantly after treatment. Anti–type 3 muscarinic acetylcholine receptor (anti‐M3R) IgG1, interleukin‐10, and leptin discriminated best between the different treatment groups. Successful prevention of hyposalivation was accompanied by quantitative alterations in 36 biomarkers, of which 19 mediators of inflammation declined to levels comparable with those found in BALB/c mice. Low secreted vascular endothelial growth factor A was the most accurate predictor of successful prevention of hyposalivation. Low salivary granulocyte chemotactic protein 2 was identified as the best predictor of normal secretory function across the strains.ConclusionImmunization with Hsp60 and its peptide aa 437–460 led to inhibition of SS in NOD mice. Comprehensive analyses revealed specific biomarker signatures capable of predicting treatment group and treatment outcome. Molecules involved in inflammatory chemotaxis, neovascularization, and regulatory pathways caused the differences displayed by the biomarker profiles.
Mitochondrial DNA haplogroups: Role in the prevalence and severity of knee osteoarthritis
Authors: Rego‐Pérez Ignacio , Fernández‐Moreno Mercedes , Fernández‐López Carlos , Arenas Joaquín , Blanco Francisco J. 
Published: August 2008

AbstractObjectiveSome studies indicate that the mitochondrion is implicated in osteoarthritis (OA). To test the hypothesis that mitochondrial DNA (mtDNA) haplogroups contribute to the prevalence and severity of knee OA, we analyzed the European mtDNA haplogroups in a Spanish population of patients with knee OA and healthy control subjects.MethodsWe combined the single‐base extension assay with the polymerase chain reaction–restriction fragment length polymorphism technique to obtain the different single‐nucleotide polymorphisms that characterize the European haplogroups in 457 patients with knee OA and 262 radiologic controls. Knee OA radiographs had previously been classified as grades 1–4 according to Kellgren/Lawrence (K/L) scoring system.ResultsIndividuals carrying haplogroup J showed a significantly decreased risk of knee OA (odds ratio [OR] 0.460 [95% confidence interval (95% CI) 0.282–0.748], P = 0.002). In terms of K/L scores, patients carrying haplogroup J had a less severe progression of knee OA (OR 0.351 [95% CI 0.156–0.787], P = 0.012), while those carrying haplogroup U had a more severe progression (OR 1.788 [95% CI 1.094–2.922], P = 0.025).ConclusionPeople carrying haplogroup J may be at a lower risk of developing knee OA, and those carrying this haplogroup in whom knee OA does not develop may have a less severe progression of the disease. Patients with knee OA carrying haplogroup U may have a more severe progression of the disease. These results indicate that mtDNA haplogroups contribute to the pathogenesis of OA.
Efficient suppression of murine arthritis by combined anticytokine small interfering RNA lipoplexes
Authors: Khoury Maroun , Escriou Virginie , Courties Gabriel , Galy Anne , Yao Roseline , Largeau Céline , Scherman Daniel , Jorgensen Christian , Apparailly Florence 
Published: August 2008

AbstractObjectiveBlocking tumor necrosis factor (TNF) effectively inhibits inflammation and joint damage in rheumatoid arthritis (RA), but 40% of RA patients respond only transiently or not at all to the current anti‐TNF biotherapies. The purpose of this study was to develop an alternative targeted therapy for this subgroup of RA patients. As proof of concept, we tested the efficiency of an RNA interference (RNAi)–based intervention that targets proinflammatory cytokines in suppressing murine collagen‐induced arthritis (CIA).MethodsTwo synthetic short interfering RNA (siRNA) sequences were designed for each of the proinflammatory cytokines interleukin‐1 (IL‐1), IL‐6, and IL‐18. Their silencing specificity was assessed according to lipopolysaccharide‐induced messenger RNA expression in J774.1 mouse macrophages as compared with control siRNA. For in vivo administration, siRNA were formulated as lipoplexes with the RPR209120/DOPE liposome and a carrier DNA and were injected intravenously (0.5 mg/kg) into DBA/1 mice with CIA.ResultsWeekly injections of anti–IL‐1, anti–IL‐6, or anti–IL‐18 siRNA‐based lipoplexes significantly reduced the incidence and severity of arthritis, abrogating joint swelling and destruction of cartilage and bone, both in the preventative and the curative settings. The most striking therapeutic effect was observed when the 3 siRNA were delivered in combination. The siRNA lipoplex cocktail reduced all pathologic features of RA, including inflammation, joint destruction, and the Th1 response, and overall parameters of RA were improved as compared with anti‐TNF siRNA lipoplex–based treatment.ConclusionOur results present a novel option for in vivo RNAi‐based antiinflammatory immunotherapy. Our findings indicate that intravenous administration of a lipoplex cocktail containing several anticytokine siRNA is a promising novel antiinflammatory therapy for RA, as well as a useful and simple tool for understanding the pathophysiology of RA and for evaluating new therapeutic candidates.
Potential for glomerular C4d as an indicator of thrombotic microangiopathy in lupus nephritis
Authors: Cohen Danielle , Koopmans Marije , Kremer Hovinga Idske C. L. , Berger Stefan P. , van Groningen Marian Roos , Steup‐Beekman Gerda M. , de Heer Emile , Bruijn Jan Anthonie , Bajema Ingeborg M. 
Published: August 2008

AbstractObjectiveIn patients with systemic lupus erythematosus (SLE) and lupus nephritis, the presence of antiphospholipid antibodies (aPL) is considered to be an indication of increased risk of thrombotic microangiopathy, a serious complication of SLE. Previous studies have demonstrated a critical role for activation of the classical pathway of complement that leads to thrombotic injury in the presence of aPL. This study was undertaken to investigate whether C4d deposition in lupus nephritis is related to circulating aPL and the presence of renal microthrombi.MethodsDeposition patterns of C4d in 44 renal biopsy samples obtained from 38 patients with biopsy‐proven lupus nephritis were determined by staining with a polyclonal anti‐C4d antibody. A phosphotungstic acid–hematoxylin stain was used to identify fibrin microthrombi. Clinical data (serum creatinine levels and presence or absence of aPL) were obtained and correlated with findings in the renal biopsy specimens. Patients were categorized as having aPL (n = 20) or not having aPL (n = 18).ResultsA strong relationship between the intensity of glomerular C4d staining and the presence of microthrombi was found (P < 0.002). Intense glomerular C4d deposition was present in 7 of 8 biopsy samples showing renal microthrombi. Neither C4d deposition nor the presence of microthrombi was correlated with aPL status.ConclusionOur findings suggest that activation of the classical pathway of complement plays a pathogenic role in the development of renal tissue injury leading to thrombosis, irrespective of the type of circulating antibodies present. Immunodetection of glomerular C4d deposition in renal biopsy samples could be a convenient method of identifying patients at risk of thrombotic microangiopathy.
Potential novel biomarkers of disease activity in rheumatoid arthritis patients: CXCL13, CCL23, transforming growth factor α, tumor necrosis factor receptor superfamily member 9, and macrophage colony‐stimulating factor
Authors: Rioja Inmaculada , Hughes Fiona J. , Sharp Catriona H. , Warnock Linda C. , Montgomery Doug S. , Akil Mohammed , Wilson Anthony G. , Binks Michael H. , Dickson Marion C. 
Published: August 2008

AbstractObjectiveTo determine whether the plasma levels of a range of inflammatory proteins have utility as biomarkers of disease activity in rheumatoid arthritis (RA) patients.MethodsPlasma proteins (n = 163) were profiled in 44 patients with RA diagnosed according to the American College of Rheumatology 1987 criteria (22 with active and 22 with quiescent disease) and in 16 age‐ and sex‐matched healthy controls. The utility of a subset of differentially expressed proteins as predictors of RA disease activity was investigated using partial least‐squares discriminant analysis, and their response to therapeutic intervention was evaluated in plasma from an additional cohort of 16 patients with active RA treated with anti–tumor necrosis factor α (anti‐TNFα).ResultsThe protein profiling study identified 25 proteins that were differentially expressed in plasma samples from patients with active RA (P for the false discovery rate ≤ 0.01) compared with those with quiescent RA, including the previously described interleukin‐6 (IL‐6), oncostatin M, and IL‐2, and the 5 less‐established markers macrophage colony‐stimulating factor (M‐CSF), tumor necrosis factor receptor superfamily member 9, CCL23, transforming growth factor α, and CXCL13. Systemic levels of these 5 markers correlated with the C‐reactive protein level, erythrocyte sedimentation rate, rheumatoid factor level, tender joint count in 68 joints, and Disease Activity Score in 28 joints (DAS28), and their combined plasma levels were shown to be good predictors of disease activity (κ = 0.64). In anti‐TNFα–treated RA patients, plasma levels of CXCL13 were reduced after 1 and 7 days of therapy, and levels of CCL23, M‐CSF, and CXCL13 showed a statistically significant positive correlation with the DAS28 score.ConclusionThis exploratory study for biomarker discovery led to the identification of several proteins predictive of RA disease activity that may be useful in the definition of disease subphenotypes and in the measurement of response to therapy in clinical studies.
Abetimus sodium for renal flare in systemic lupus erythematosus: Results of a randomized, controlled phase III trial
Authors: Cardiel Mario H. , Tumlin James A. , Furie Richard A. , Wallace Daniel J. , Joh Tenshang , Linnik Matthew D. 
Published: August 2008

AbstractObjectiveTo investigate whether treatment with abetimus delays renal flare in patients with lupus nephritis. Secondary objectives included evaluation of the effect of abetimus on C3 levels, anti–double‐stranded DNA (anti‐dsDNA) antibody levels, use of high‐dose corticosteroids and/or cyclophosphamide, and major systemic lupus erythematosus (SLE) flare.MethodsWe conducted a randomized, placebo‐controlled study of treatment with abetimus at 100 mg/week for up to 22 months in SLE patients. Three hundred seventeen patients with a history of renal flare and anti‐dsDNA levels >15 IU/ml were randomized to a treatment group (158 abetimus, 159 placebo); 298 (94%) were enrolled in the intent‐to‐treat (ITT) population (145 abetimus, 153 placebo), based on the presence of high‐affinity antibodies for the oligonucleotide epitope of abetimus at baseline screening.ResultsAbetimus did not significantly prolong time to renal flare, time to initiation of high‐dose corticosteroid and/or cyclophosphamide treatment, or time to major SLE flare. However, there were 25% fewer renal flares in the abetimus group compared with the placebo group (17 of 145 abetimus‐treated patients [12%] versus 24 of 153 placebo‐treated patients [16%]). Abetimus treatment decreased anti‐dsDNA antibody levels (P < 0.0001), and reductions in anti‐dsDNA levels were associated with increases in C3 levels (P < 0.0001). More patients in the abetimus group experienced ≥50% reductions in proteinuria at 1 year, compared with the placebo group (nominal P = 0.047). Trends toward reduced rates of renal flare and major SLE flare were noted in patients treated with abetimus who had impaired renal function at baseline. Treatment with abetimus for up to 22 months was well tolerated.ConclusionAbetimus at 100 mg/week significantly reduced anti‐dsDNA antibody levels but did not significantly prolong time to renal flare when compared with placebo. Multiple positive trends in renal end points were observed in the abetimus treatment group.
Development of autoimmune hepatitis–like disease and production of autoantibodies to nuclear antigens in mice lacking B and T lymphocyte attenuator
Authors: Oya Yoshihiro , Watanabe Norihiko , Owada Takayoshi , Oki Mie , Hirose Koichi , Suto Akira , Kagami Shin‐Ichiro , Nakajima Hiroshi , Kishimoto Takashi , Iwamoto Itsuo , Murphy Theresa L. , Murphy Kenneth M. , Saito Yasushi 
Published: August 2008

AbstractObjectiveB and T lymphocyte attenuator (BTLA), a coreceptor expressed on lymphocytes, was recently described as an inhibitory coreceptor that negatively regulates lymphocyte activation. The purpose of this study was to investigate the role of BTLA in the regulation of immune homeostasis and the pathogenesis of autoimmunity.MethodsWe examined the levels of immunoglobulins and autoantibodies to nuclear antigens and the activation status of T cells in BTLA−/− mice. We also examined histopathologic changes in the organs of BTLA−/− mice.ResultsWe observed that BTLA−/− mice gradually developed hypergammaglobulinemia, antinuclear antibodies, anti‐SSA antibodies, anti–double‐stranded DNA antibodies, and an increased number of activated CD4+ T cells in the periphery with age. Lack of BTLA led to spontaneous development of autoimmune hepatitis–like disease characterized by an elevation in the level of transaminases, interface hepatitis, and spotty necrosis of the liver. BTLA−/− mice also showed inflammatory cell infiltration of multiple organs, including the salivary glands, lungs, and pancreas; these features are similar to those of Sjögren's syndrome, which is a frequent complication of autoimmune hepatitis. Furthermore, the survival rate of BTLA−/− mice was significantly reduced after the age of 7 months.ConclusionOur results indicate that BTLA plays an important role in the maintenance of immune tolerance and the prevention of autoimmune diseases.
HLA class I deficiency syndrome mimicking Wegener's granulomatosis
Authors: Villa‐Forte Alexandra , de la Salle Henri , Fricker Dominique , Hentges Francois , Zimmer Jacques 
Published: August 2008

AbstractHerein we report the case of a 20‐year‐old woman who presented with multiple skin ulcers on her legs, severe pansinusitis, and chronic lung disease. She was initially thought to have Wegener's granulomatosis (WG). However, serologic studies indicated an HLA class I deficiency, which was confirmed by flow cytometry. Complementation studies and reverse transcriptase–polymerase chain reaction followed by direct DNA sequencing revealed a mutation in the gene encoding subunit 1 of the peptide transporter associated with antigen processing (TAP1). This mutation, which has not been previously described in the literature, results in a stop codon in the catalytic domain of TAP1. Although TAP mutations are rare, clinicians may encounter them in the evaluation of patients with suspected WG. In patients with WG‐like symptoms it is important to consider this alternative genetic diagnosis as early as possible, not only so that appropriate antibiotic therapy can be initiated to prevent bronchiectasis, but also to avoid inappropriate immunosuppressive therapy that worsens the disease.