bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating levels of B lymphocyte stimulator in patients with rheumatoid arthritis following rituximab treatment: Relationships with B cell depletion, circulating antibodies, and clinical relapse
Authors: Cambridge Geraldine , Stohl William , Leandro Maria J. , Migone Thi‐Sau , Hilbert David M. , Edwards Jonathan C. W. 
Published: February 2006

AbstractObjectiveTo assess the effects of B lymphocyte depletion on serum B lymphocyte stimulator (BLyS; trademark of Human Genome Sciences, Rockville, MD) levels in patients with rheumatoid arthritis (RA), and to assess the relationship of serum BLyS levels with peripheral blood B cell depletion, levels of autoantibodies and antimicrobial antibodies, the return of peripheral blood B cells, and clinical relapse.MethodsFifteen patients with active RA underwent rituximab‐based B cell depletion therapy (BCDT). Disease activity was assessed clinically, peripheral blood CD19+ B cell counts were determined by flow cytometry, and serum levels of BLyS, IgM, IgA, and IgG rheumatoid factors (RFs), anti–cyclic citrullinated peptide, and antimicrobial antibodies were assessed using enzyme‐linked immunosorbent assays.ResultsPeripheral blood B cell depletion was achieved in all 15 patients, and an American College of Rheumatology 20% response was achieved in 13 patients. Following clinical relapse, 7 patients underwent at least 1 additional cycle of BCDT. In every case, serum BLyS levels markedly rose post‐BCDT and remained elevated for at least 1–2 months. Serum levels of RF, but not those of anti–tetanus toxoid or anti–pneumococcal polysaccharide antibodies, fell significantly. A decline in serum BLyS levels was associated with the reemergence of B cells in peripheral blood, which, in turn, antedated clinical relapse by variable periods of time. The patterns of B cell depletion, serum BLyS and antibody levels, and clinical relapse for each BCDT cycle were remarkably similar in re‐treated patients.ConclusionRituximab‐based BCDT leads to marked increases in serum BLyS levels. This may contribute significantly to the survival and/or regeneration of B cell populations capable of triggering clinical relapse.
Higher chondrogenic potential of fibrous synovium– and adipose synovium–derived cells compared with subcutaneous fat–derived cells: Distinguishing properties of mesenchymal stem cells in humans
Authors: Mochizuki Tomoyuki , Muneta Takeshi , Sakaguchi Yusuke , Nimura Akimoto , Yokoyama Akiko , Koga Hideyuki , Sekiya Ichiro 
Published: February 2006

AbstractObjectiveMesenchymal stem cells from synovium have a greater proliferation and chondrogenic potential than do those from bone marrow, periosteum, fat, and muscle. This study was undertaken to compare fibrous synovium and adipose synovium (components of the synovium with subsynovium) to determine which is a more suitable source for mesenchymal stem cells, especially for cartilage regeneration, and to examine the features of adipose synovium–derived cells, fibrous synovium–derived cells, and subcutaneous fat–derived cells to determine their similarities.MethodsHuman fibrous synovium, adipose synovium, and subcutaneous fat were harvested from 4 young donors and 4 elderly donors. After digestion, the nucleated cells were plated at a density considered proper to expand at a maximum rate without colony‐to‐colony contact. The surface epitopes, proliferative capacity, cloning efficiency, and chondrogenic, osteogenic, and adipogenic differentiation potentials of the cells were compared.ResultsFibrous synovium– and adipose synovium–derived cells were higher in STRO‐1 and CD106 and lower in CD10 compared with subcutaneous fat–derived cells. Cells derived from fibrous and adipose synovium had higher proliferative potential and colony‐forming efficiency compared with subcutaneous fat–derived cells, both in mixed‐population and in single‐cell–derived cultures. In chondrogenic assays, pellets from fibrous synovium– and adipose synovium–derived cells produced more cartilage matrix than did cell pellets from subcutaneous fat. Osteogenic ability was also higher in fibrous synovium– and adipose synovium–derived cells, whereas adipogenic potential was nearly indistinguishable among the 3 populations. Differentiation potential of the cells was similar between young and elderly donors.ConclusionCells derived from the fibrous synovium and from the adipose synovium demonstrate comparable chondrogenic potential. Adipose synovium–derived cells are more similar to fibrous synovium–derived cells than to subcutaneous fat–derived cells.
Treatment of murine collagen‐induced arthritis by the stress protein BiP via interleukin‐4–producing regulatory T cells: A novel function for an ancient protein
Authors: Brownlie Rebecca J. , Myers Linda K. , Wooley Paul H. , Corrigall Valerie M. , Bodman‐Smith Mark D. , Panayi Gabriel S. , Thompson Stephen J. 
Published: February 2006

AbstractObjectiveFollowing the demonstration that the stress protein, BiP, prevented induction of collagen‐induced arthritis (CIA) in HLA–DRB*0101+/+ (HLA–DR1+/+) mice, we investigated the immunotherapeutic ability of BiP to suppress disease during the active phase of CIA in HLA–DR1+/+ and DBA/1 mice.MethodsBiP was administered either subcutaneously or intravenously to DBA/1, HLA–DR1+/+, or interleukin‐4 (IL‐4)–knockout mice at the onset of arthritis. Immune cells were used in adoptive transfer studies or were restimulated in culture with BiP or type II collagen (CII). Proliferation and cytokine release were measured. In addition, serum anti‐CII antibodies were measured by enzyme‐linked immunosorbent assay. Disease progression was scored using a visual analog scale.ResultsBiP was successful in suppressing established CIA in HLA–DR1+/+ and DBA/1 mice. Serum levels of anticollagen IgG antibodies were reduced in BiP‐treated mice. T cells from BiP‐immunized mice produced Th2 cytokines, in particular, IL‐4. Treatment with BiP was also shown to increase the production of CII‐specific IL‐5, IL‐10, and interferon‐γ at the termination of the study. Development of severe CIA was prevented by the intravenous transfer of BiP‐specific cells at the time of CIA induction in HLA–DR1+/+ mice or by transferring BiP‐specific cells to DBA/1 mice at the onset of disease. BiP failed to ameliorate the development of CIA in IL‐4−/−, HLA–DR1+/+ mice.ConclusionThese novel results show that BiP can suppress active CIA by the induction of regulatory cells that act predominantly via IL‐4. Thus, BiP is a potential immunotherapeutic agent for the treatment of patients with rheumatoid arthritis.
Acute occlusive large vessel disease leading to fatal stroke in a patient with systemic lupus erythematosus: Arteritis or atherosclerosis?
Authors: Conen Katrin L. , Jeanneret Christina , Hecker Burkhard , Cathomas Gieri , Biedermann Barbara C. 
Published: February 2006

AbstractA woman with a history of systemic lupus erythematosus presented with extensive bilateral strokes due to acute inflammatory, occlusive large vessel disease affecting several aortic branches including the carotid, subclavian, renal, and iliac arteries. We quantitatively characterized the arterial inflammation in this patient and compared it with the inflammatory infiltrates from 22 patients with conventional atherosclerosis. Profound histomorphologic differences from conventional atherosclerosis (predominance of CD8‐positive lymphocytes, relative absence of macrophages, no ectopic neovascularization, no signs of plaque hemorrhage, concentric instead of eccentrical stenosis) suggest that this patient's accelerated arteriopathy was precipitated by pathogenic events other than conventional atherosclerosis.
The impact of body mass index on later total hip arthroplasty for primary osteoarthritis: A cohort study in 1.2 million persons
Authors: Flugsrud Gunnar B. , Nordsletten Lars , Espehaug Birgitte , Havelin Leif I. , Engeland Anders , Meyer Haakon E. 
Published: February 2006

AbstractObjectiveTo investigate the effects of body mass index (BMI), height, and age on the risk of later total hip arthroplasty for primary osteoarthritis (OA).MethodsWe matched screening data on body height and weight from 1,152,006 persons ages 18–67 years who attended a compulsory screening for tuberculosis in 1963–1975 with data from the Norwegian Arthroplasty Register for the years 1987–2003. We identified 28,425 total hip replacements because of primary OA.ResultsWe found dose‐response associations between both height and BMI and later hip arthroplasty. The relative risk (RR) among men with a BMI ≥32 kg/m2versus a BMI of 20.5–21.9 kg/m2was 3.4 (95% confidence interval [95% CI] 2.9–4.0). The corresponding RR in women was 2.3 (95% CI 2.1–2.4). There was a decreasing trend in the RR with an increasing age at screening. Among men, the RR for an increase of 5 kg/m2in the BMI was 2.1 (95% CI 1.7–2.5) when measured at age <25 years and 1.5 (95% CI 1.3–1.7) when measured at ages 55–59 years. Among women, the corresponding RR values were 1.7 (95% CI 1.5–1.9) and 1.1 (95% CI 1.1–1.2).ConclusionThere was a strong dose‐response association between BMI and later total arthroplasty for OA of the hip. Being overweight entailed the highest RR among young participants, and the participants who were overweight at a young age maintained an excess RR for arthroplasty throughout the followup period.
Infliximab treatment maintains employability in patients with early rheumatoid arthritis
Authors: Smolen Josef S. , Han Chenglong , Van Der Heijde Désirée , Emery Paul , Bathon Joan M. , Keystone Edward , Kalden Joachim R. , Schiff Michael , Bala Mohan , Baker Daniel , Han John , Maini Ravinder N. , St.Clair E. William 
Published: February 2006

AbstractObjectiveTo evaluate the impact of infliximab therapy on the employment status of patients with early rheumatoid arthritis (RA).MethodsMethotrexate (MTX)–naive patients with active early RA were randomly allocated to receive MTX plus placebo or MTX plus infliximab (3 mg/kg or 6 mg/kg) at weeks 0, 2, and 6 and then every 8 weeks through week 46. Data for patients younger than age 65 years were included in the analyses. A patient was categorized as employable if he or she was employed or felt well enough to work if a job were available.ResultsThe change in actual employment was not significantly different between patients receiving MTX plus infliximab and those receiving MTX plus placebo (0.5% versus 1.3%; P > 0.5). However, the proportion of patients whose status changed from employable at baseline to unemployable at week 54 was smaller in the group receiving MTX plus infliximab compared with that in the group receiving MTX alone (8% versus 14%; P = 0.05). Patients who were treated with infliximab plus MTX had a significantly greater likelihood of improvement rather than deterioration in employability (odds ratio 2.4; P < 0.001); this likelihood was not significantly greater in patients receiving MTX alone. The proportion of employed patients who lost workdays during the trial was smaller in the MTX plus infliximab group than in the MTX‐alone group (P = 0.010).ConclusionThe actual employment rates among patients in the 2 treatment groups were not different. However, patients with early RA who were treated with MTX plus infliximab had a higher probability of maintaining their employability compared with those who were treated with MTX alone.
CXCL16‐mediated cell recruitment to rheumatoid arthritis synovial tissue and murine lymph nodes is dependent upon the MAPK pathway
Authors: Ruth Jeffrey H. , Haas Christian S. , Park Christy C. , Amin M. Asif , Martinez Rita J. , Haines G. Kenneth , Shahrara Shiva , Campbell Phillip L. , Koch Alisa E. 
Published: February 2006

AbstractObjectiveRheumatoid arthritis (RA) is characterized by profound mononuclear cell (MNC) recruitment into synovial tissue (ST), thought to be due in part to tumor necrosis factor α (TNFα), a therapeutic target for RA. Although chemokines may also be involved, the mechanisms remain unclear. We undertook this study to examine the participation of CXCL16, a novel chemokine, in recruitment of MNCs to RA ST in vivo and to determine the signal transduction pathways mediating this process.MethodsUsing a human RA ST–SCID mouse chimera, immunohistochemistry, enzyme‐linked immunosorbent assay, real‐time reverse transcription–polymerase chain reaction, flow cytometry, and in vitro chemotaxis assays, we defined the expression and function of CXCL16 and its receptor, CXCR6, as well as the signal transduction pathways utilized by them for MNC homing in vitro and in vivo.ResultsCXCL16 was markedly elevated in RA synovial fluid (SF) samples, being as high as 145 ng/ml. Intense macrophage and lining cell staining for CXCL16 in RA ST correlated with increased CXCL16 messenger RNA levels in RA ST compared with those in osteoarthritis and normal ST. By fluorescence‐activated cell sorting analysis, one‐half of RA SF monocytes and one‐third of memory lymphocytes expressed CXCR6. In vivo recruitment of human MNCs to RA ST implanted in SCID mice occurred in response to intragraft injection of human CXCL16, a response similar to that induced by TNFα. Lipofection of MNCs with antisense oligodeoxynucleotides for ERK‐1/2 resulted in a 50% decline in recruitment to engrafted RA ST and a 5‐fold decline in recruitment to regional lymph nodes. Interestingly, RA ST fibroblasts did not produce CXCL16 in response to TNFα in vitro, suggesting that CXCL16 protein may function in large part independently of TNFα.ConclusionTaken together, these results point to a unique role for CXCL16 as a premier MNC recruiter in RA and suggest additional therapeutic possibilities, targeting CXCL16, its receptor, or its signaling pathways.
Sphingosine 1‐phosphate/sphingosine 1‐phosphate receptor 1 signaling in rheumatoid synovium: Regulation of synovial proliferation and inflammatory gene expression
Authors: Kitano Masayasu , Hla Timothy , Sekiguchi Masahiro , Kawahito Yutaka , Yoshimura Rikio , Miyazawa Keiji , Iwasaki Tsuyoshi , Sano Hajime 
Published: February 2006

AbstractObjectiveSphingosine 1‐phosphate (S1P) is involved in various pathologic conditions and has been implicated as an important mediator of angiogenesis, inflammation, cancer, and autoimmunity. This study was undertaken to examine the role of S1P/S1P1 signaling in the pathogenesis of rheumatoid arthritis (RA).MethodsWe examined S1P1 messenger RNA (mRNA) and protein levels in RA synoviocytes and MH7A cells by reverse transcriptase–polymerase chain reaction and Western blotting. We also performed S1P1 immunohistochemistry analysis in synovial tissue from 28 RA patients and 18 osteoarthritis (OA) patients. We investigated the effects of S1P on proliferation by WST‐1 assay, and its effects on tumor necrosis factor α (TNFα)– or interleukin‐1β (IL‐1β)–induced cyclooxygenase 2 (COX‐2) expression and prostaglandin E2 (PGE2) production in RA synoviocytes and MH7A cells by Western blotting and enzyme‐linked immunosorbent assay, respectively. Finally, we examined whether these effects of S1P were sensitive to pertussis toxin (PTX), an inhibitor of the Gi/Go proteins.ResultsS1P1 mRNA and protein were detected in RA synoviocytes and MH7A cells. S1P1 was more strongly expressed in synovial lining cells, vascular endothelial cells, and inflammatory mononuclear cells of RA synovium compared with OA synovium. S1P increased the proliferation of RA synoviocytes and MH7A cells. S1P alone significantly enhanced COX‐2 expression and PGE2 production. Moreover, S1P enhanced expression of COX‐2 and production of PGE2 induced by stimulation with TNFα or IL‐1β in RA synoviocytes and MH7A cells. These effects of S1P were inhibited by pretreatment with PTX.ConclusionThese findings suggest that S1P signaling via S1P receptors plays an important role in cell proliferation and inflammatory cytokine–induced COX‐2 expression and PGE2 production by RA synoviocytes. Thus, regulation of S1P/S1P1 signaling may represent a novel therapeutic target in RA.
Expression of platelet‐derived growth factors C and D in the synovial membrane of patients with rheumatoid arthritis and osteoarthritis
Authors: Pohlers Dirk , Huber René , Ukena Bärbel , Kinne Raimund W. 
Published: February 2006

AbstractObjectiveTo investigate the messenger RNA (mRNA) and protein expression of the recently discovered platelet‐derived growth factor C (PDGF‐C) and PDGF‐D in the synovial membrane (SM) of patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and to assess the localization and cellular source of these proteins in the SM and their functional influence on synovial fibroblasts.MethodsExpression of mRNA for PDGFs A, B, C, and D as well as for PDGF receptor (PDGFR) α and β chains in RA and OA SM samples was assessed by real‐time reverse transcription–polymerase chain reaction. Protein levels of PDGF‐C and PDGF‐D were quantified by immunoblotting. Regional and cellular localization of PDGF‐C and PDGF‐D in the SM was investigated by double‐staining immunohistochemistry. In addition, the influence of PDGF‐D on the proliferation of synovial fibroblasts and their matrix metalloproteinase (MMP‐1) mRNA expression were determined.ResultsThe expression of mRNA for PDGFs A, B, and C and for PDGFR α and β chains was comparable in RA and OA SM samples; in contrast, the expression of mRNA for PDGF‐D was significantly higher in OA SM. PDGF‐C protein was not differentially expressed in OA and RA. The expression of PDGF‐D protein was significantly higher in RA SM (full‐length and activated form). PDGF‐C and PDGF‐D were expressed throughout the SM (lining layer, diffuse infiltrates, and stroma) by both synovial fibroblasts and macrophages. In addition, PDGF‐D increased the proliferation of synovial fibroblasts and the expression of mRNA for MMP‐1.ConclusionPDGF‐C and PDGF‐D are expressed by synovial fibroblasts and macrophages in RA and OA SMs. The levels of PDGF‐D protein were significantly higher in RA SM. In addition, PDGF‐D stimulated synovial fibroblast proliferation and expression of MMP‐1. These findings may have pathogenetic implications for cellular transformation and matrix remodeling in the RA SM.
Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis
Authors: Wolbink Gerrit Jan , Vis Marijn , Lems Willem , Voskuyl Alexandre E. , De Groot Els , Nurmohamed Michael T. , Stapel Steven , Tak Paul P. , Aarden Lucien , Dijkmans Ben 
Published: February 2006

AbstractObjectiveTreatment of patients with infliximab, a chimeric monoclonal IgG1 antibody against tumor necrosis factor, may result in the formation of infliximab‐specific IgG antibodies. This study evaluated the clinical significance of these antibodies in patients with rheumatoid arthritis (RA).MethodsAntiinfliximab antibodies were measured using a newly developed radioimmunoassay in a cohort of 51 consecutive patients with RA treated with infliximab, with a followup of 1 year. In addition, serum infliximab levels were determined by enzyme‐linked immunosorbent assay. The results were analyzed in relation to the clinical response to treatment according to the European League Against Rheumatism criteria.ResultsAntibodies against infliximab were detected in 22 patients (43%). Patients without detectable antiinfliximab antibodies (n = 29 [57%]) were significantly more often classified as responders (20 of 29 [69%]) compared with patients with detectable antiinfliximab antibodies (8 of 22 [36%]; P = 0.04). Three patients had an infusion‐related allergic reaction, all of whom had detectable antiinfliximab antibodies.ConclusionIn this study, nearly half of the RA patients treated with infliximab developed antiinfliximab antibodies within the first year of treatment. This seems to be clinically relevant, since development of antiinfliximab antibodies is associated with a reduced response to treatment.
Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon
Authors: Jones Gavin C. , Corps Anthony N. , Pennington Caroline J. , Clark Ian M. , Edwards Dylan R. , Bradley Michelle M. , Hazleman Brian L. , Riley Graham P. 
Published: February 2006

AbstractObjectiveTo profile the messenger RNA (mRNA) expression for the 23 known genes of matrix metalloproteinases (MMPs), 19 genes of ADAMTS, 4 genes of tissue inhibitors of metalloproteinases (TIMPs), and ADAM genes 8, 10, 12, and 17 in normal, painful, and ruptured Achilles tendons.MethodsTendon samples were obtained from cadavers or from patients undergoing surgical procedures to treat chronic painful tendinopathy or ruptured tendon. Total RNA was extracted and mRNA expression was analyzed by quantitative real‐time reverse transcription–polymerase chain reaction, normalized to 18S ribosomal RNA.ResultsIn comparing expression of all genes, the normal, painful, and ruptured Achilles tendon groups each had a distinct mRNA expression signature. Three mRNA were not detected and 14 showed no significant difference in expression levels between the groups. Statistically significant (P< 0.05) differences in mRNA expression, when adjusted for age, included lower levels of MMPs 3 and 10 and TIMP‐3 and higher levels of ADAM‐12 and MMP‐23 in painful compared with normal tendons, and lower levels of MMPs 3 and 7 and TIMPs 2, 3, and 4 and higher levels of ADAMs 8 and 12, MMPs 1, 9, 19, and 25, and TIMP‐1 in ruptured compared with normal tendons.ConclusionThe distinct mRNA profile of each tendon group suggests differences in extracellular proteolytic activity, which would affect the production and remodeling of the tendon extracellular matrix. Some proteolytic activities are implicated in the maintenance of normal tendon, while chronically painful tendons and ruptured tendons are shown to be distinct groups. These data will provide a foundation for further study of the role and activity of many of these enzymes that underlie the pathologic processes in the tendon.
Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis
Authors: Baecklund Eva , Iliadou Anastasia , Askling Johan , Ekbom Anders , Backlin Carin , Granath Fredrik , Catrina Anca Irinel , Rosenquist Richard , Feltelius Nils , Sundström Christer , Klareskog Lars 
Published: February 2006

AbstractObjectiveChronic inflammatory conditions such as rheumatoid arthritis (RA) have been associated with malignant lymphomas. This study was undertaken to investigate which patients are at highest risk, and whether antirheumatic treatment is hazardous or protective.MethodsWe performed a matched case–control study of 378 consecutive Swedish RA patients in whom malignant lymphoma occurred between 1964 and 1995 (from a population‐based RA cohort of 74,651 RA patients), and 378 controls. Information on disease characteristics and treatment from onset of RA until lymphoma diagnosis was abstracted from medical records. Lymphoma specimens were reclassified and tested for Epstein‐Barr virus (EBV). Relative risks (odds ratios [ORs]) for lymphomas (by subtype) associated with deciles of cumulative disease activity were assessed, as were ORs associated with drug treatments.ResultsThe relative risks of lymphoma were only modestly elevated up to the seventh decile of cumulative disease activity. Thereafter, the relative risk increased dramatically (OR ninth decile 9.4 [95% confidence interval 3.1–28.0], OR tenth decile 61.6 [95% confidence interval 21.0–181.0]). Most lymphomas (48%) were of the diffuse large B cell type, but other lymphoma subtypes also displayed an association with cumulative disease activity. Standard nonbiologic treatments did not increase lymphoma risk. EBV was present in 12% of lymphomas.ConclusionRisk of lymphoma is substantially increased in a subset of patients with RA, those with very severe disease. High inflammatory activity, rather than its treatment, is a major risk determinant.