bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rho kinase–dependent activation of SOX9 in chondrocytes
Authors: Haudenschild Dominik R. , Chen Jianfen , Pang Nina , Lotz Martin K. , D'Lima Darryl D. 
Published: December 2009

AbstractObjectiveThe transcription factor SOX9 directly regulates the expression of the major proteoglycans and collagens comprising the cartilage extracellular matrix. The DNA binding activity and cellular localization of SOX9 is controlled through posttranslational modifications, including phosphorylation. The activity of Rho kinase (ROCK) has profound effects on the actin cytoskeleton, and these effects are instrumental in determining the phenotype and differentiation of chondrocytes. However, the mechanisms linking ROCK to altered chondrocyte gene expression remain unknown. The purpose of the present study was to test for a direct interaction between ROCK and SOX9.MethodsHuman SW1353 chondrosarcoma cells were transfected with constructs coding for RhoA, ROCK, Lim kinase, and SOX9. The interaction between ROCK and SOX9 was tested on purified proteins, and was verified within a cellular context using induced overexpression and activation of the Rho pathway. The effects of SOX9 transcriptional activation were quantified with a luciferase reporter plasmid containing SOX9 binding sites from the COL2A1 enhancer element.ResultsSOX9 was found to contain a consensus phosphorylation site for ROCK. In vitro, ROCK directly phosphorylated SOX9 at Ser181, and the overexpression of ROCK or the activation of the RhoA pathway in SW1353 chondrosarcoma cells increased SOX9Ser181 phosphorylation. ROCK caused a dose‐dependent increase in the transcription of a SOX9‐luciferase reporter construct, and increased phosphorylation and nuclear accumulation of SOX9 protein in response to transforming growth factor β treatment and mechanical compression.ConclusionThese results demonstrate a new interaction that directly links ROCK to increased cartilage matrix production via activation of SOX9 in response to mechanical and growth factor stimulation.
Nonrenal disease activity following mycophenolate mofetil or intravenous cyclophosphamide as induction treatment for lupus nephritis: Findings in a multicenter, prospective, randomized, open‐label, parallel‐group clinical trial
Authors: Ginzler Ellen M. , Wofsy David , Isenberg David , Gordon Caroline , Lisk Laura , Dooley Mary‐Anne 
Published: December 2009

AbstractObjectiveTo assess the effect of mycophenolate mofetil compared with intravenous pulses of cyclophosphamide on the nonrenal manifestations of lupus nephritis.MethodsPatients with active lupus nephritis (renal biopsy class III, IV, or V) were recruited for the study (n = 370) and treated with mycophenolate mofetil (target dosage 3 gm/day) or intravenous cyclophosphamide (0.5–1.0 gm/m2/month), plus tapered prednisone, for 24 weeks. Nonrenal outcomes were determined using measures of whole body disease activity, including the British Isles Lupus Assessment Group (BILAG) disease activity index, the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and immunologic variables.ResultsBoth treatments were effective on whole body disease activity in the systems examined, as indicated by changes in the classic BILAG index. With either treatment, remission was induced, notably in the mucocutaneous, musculoskeletal, cardiovascular/respiratory, and vasculitis systems, and flares were rare, as measured by the SELENA–SLEDAI. Levels of complement C3, C4, and CH50 and titers of anti–double‐stranded DNA antibodies were normalized after treatment with either mycophenolate mofetil or intravenous cyclophosphamide.ConclusionIn addition to the efficacy of both treatments on the renal system, this analysis showed that remission could also be induced in other systems. There was no clear difference in efficacy between mycophenolate mofetil and intravenous cyclophosphamide in ameliorating either the renal or nonrenal manifestations. Mycophenolate mofetil is, therefore, a suitable alternative to cyclophosphamide for the treatment of renal and nonrenal disease manifestations in patients with biopsy‐proven lupus nephritis.
Rapid and sustained improvement in bone and cartilage turnover markers with the anti–interleukin‐6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: Results from a substudy of the multicenter double‐blind, placebo‐controlled trial of tocilizumab in inadequate responders to methotrexate alone
Authors: Garnero Patrick , Thompson Elizabeth , Woodworth Thasia , Smolen Josef S. 
Published: December 2009

AbstractObjectiveTo investigate the effects of tocilizumab (TCZ) added to a stable dosage of methotrexate (MTX) on biochemical markers of bone and cartilage metabolism in patients in the multicenter double‐blind, placebo‐controlled OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders) study who have moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response to MTX.MethodsIncluded in this study were 416 of the 623 patients with active RA enrolled in the OPTION study. Patients were randomized to receive TCZ (4 mg/kg or 8 mg/kg) or placebo intravenously every 4 weeks, with MTX continued at the stable prestudy doses (10–25 mg for 20 weeks, with a final followup at week 24). Serum biochemical markers of bone formation (osteocalcin, N‐terminal propeptide of type I collagen [PINP]), bone resorption (C‐terminal crosslinking telopeptide of type I collagen [CTX‐I] and C‐terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases [ICTP]), cartilage metabolism (N‐terminal propeptide of type IIA collagen [PIIANP]), collagen helical peptide [HELIX‐II]), and matrix metalloproteinase 3 (MMP‐3) were measured at baseline and at weeks 4, 16, and 24.ResultsTCZ induced marked dose‐dependent reductions in PIIANP, HELIX‐II, and MMP‐3 levels at week 4 that were maintained until week 24, an effect associated with increased levels of bone formation markers that were significant as compared with placebo only for PINP and only at 4 weeks (P < 0.01 for both TCZ doses). TCZ induced significant decreases in the bone degradation markers CTX‐I and ICTP, providing initial evidence of a beneficial effect on bone turnover. TCZ‐treated patients who met the American College of Rheumatology 50% improvement criteria (achieved an ACR50 response) or achieved clinical remission (as determined by a Disease Activity Score in 28 joints <2.6) at week 24 had greater reductions in ICTP, HELIX‐II, and MMP‐3 levels as compared with ACR50 nonresponders.ConclusionTCZ combined with MTX reduces systemic bone resorption, cartilage turnover, and proteolytic enzyme MMP‐3 levels, which provides evidence of a limitation of joint damage and possible beneficial effects on skeletal structure in patients with established moderate‐to‐severe RA.
The transcription factor Fra‐2 regulates the production of extracellular matrix in systemic sclerosis
Authors: Reich Nicole , Maurer Britta , Akhmetshina Alfiya , Venalis Paulius , Dees Clara , Zerr Pawel , Palumbo Katrin , Zwerina Jochen , Nevskaya Tatiana , Gay Steffen , Distler Oliver , Schett Georg , Distler Jörg H. W. 
Published: December 2009

AbstractObjectiveFra‐2 belongs to the activator protein 1 family of transcription factors. Mice transgenic for Fra‐2 develop a systemic fibrotic disease with vascular manifestations similar to those of systemic sclerosis (SSc). The aim of the present study was to investigate whether Fra‐2 plays a role in the pathogenesis of SSc and to identify the molecular mechanisms by which Fra‐2 induces fibrosis.MethodsDermal thickness and the number of myofibroblasts were determined in skin sections from Fra‐2–transgenic and wild‐type mice. The expression of Fra‐2 in SSc patients and in animal models of SSc was analyzed by real‐time polymerase chain reaction and immunohistochemistry. Fra‐2, transforming growth factor β (TGFβ), and ERK signaling in SSc fibroblasts were inhibited using small interfering RNA, neutralizing antibodies, and small‐molecule inhibitors.ResultsFra‐2–transgenic mice developed a skin fibrosis with increases in dermal thickness and increased myofibroblast differentiation starting at age 12 weeks. The expression of Fra‐2 was up‐regulated in SSc patients and in different mouse models of SSc. Stimulation with TGFβ and platelet‐derived growth factor (PDGF) significantly increased the expression of Fra‐2 in SSc fibroblasts and induced DNA binding of Fra‐2 in an ERK‐dependent manner. Knockdown of Fra‐2 potently reduced the stimulatory effects of TGFβ and PDGF and decreased the release of collagen from SSc fibroblasts.ConclusionWe demonstrate that Fra‐2 is overexpressed in SSc and acts as a novel downstream mediator of the profibrotic effects of TGFβ and PDGF. Since transgenic overexpression of Fra‐2 causes not only fibrosis but also vascular disease, Fra‐2 might be an interesting novel candidate for molecular‐targeted therapies for SSc.
Long‐term efficacy of the interleukin‐1 receptor antagonist anakinra in ten patients with neonatal‐onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome
Authors: Neven Bénédicte , Marvillet Isabelle , Terrada Celine , Ferster Alice , Boddaert Nathalie , Couloignier Vincent , Pinto Graziella , Pagnier Anne , Bodemer Christine , Bodaghi Bahram , Tardieu Marc , Prieur Anne Marie , Quartier Pierre 
Published: December 2009

AbstractObjectiveCryopyrin‐associated periodic syndromes (CAPS) are a group of rare autoinflammatory diseases. Neonatal‐onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) is the most severe phenotype, with fever, rash, articular manifestations, and neurologic and neurosensory involvement. CAPS are caused by mutations in CIAS1, the gene encoding NLRP3, which plays a critical role in interleukin‐1 (IL‐1) processing. Anakinra, an IL‐1 receptor antagonist, has been shown to be an effective treatment; however, data on long‐term efficacy and safety have been sparse. This study was undertaken to assess the long‐term efficacy and safety of anakinra treatment in patients with NOMID/CINCA syndrome.MethodsWe retrospectively analyzed the medical records of NOMID/CINCA syndrome patients referred to 2 centers, who had started anakinra treatment before June 2007.ResultsThere were 10 patients with NOMID/CINCA syndrome who had been treated with anakinra. The patients' ages at the time anakinra treatment was initiated ranged from 3 months to 20 years. They had been followed up for 26–42 months. Sustained efficacy in the treatment of systemic inflammation and, in some cases, neurologic involvement and growth parameters, was achieved. The dosage of anakinra required for efficacy ranged from 1 to 3 mg/kg/day in the 8 oldest patients and from 6 to 10 mg/kg/day in the 2 youngest. Residual central nervous system inflammation and deafness persisted in some patients, especially if there had been a delay in diagnosis and treatment. Secondary amyloidosis persisted in cases in which it was present at treatment initiation, but no new lesions developed. No effect on overgrowth arthropathy was observed. Adverse events consisted of mild injection‐site reactions.ConclusionThe present results indicate that anakinra treatment is effective over the long term in NOMID/CINCA syndrome. However, treatment has to be initiated before irreversible lesions develop, and, particularly in very young patients, dosage adjustment is required.
ANTI‐CD3 therapy expands the numbers of CD4+ and CD8+ treg cells and induces sustained amelioration of collagen‐induced arthritis
Authors: Notley Clare A. , McCann Fiona E. , Inglis Julia J. , Williams Richard O. 
Published: December 2009

AbstractObjectiveTo assess the therapeutic potential of anti‐CD3 monoclonal antibodies (mAb) for rheumatoid arthritis, using collagen‐induced arthritis as an animal model.MethodsArthritis was induced in DBA/1 mice by immunization with type II collagen. After disease onset, a single injection of anti‐CD3 mAb (20 μg/mouse) was administered, and arthritis severity was monitored over a 10‐day period.ResultsAnti‐CD3 mAb treatment resulted in a sustained reduction in disease activity, which was associated with an increase in the proportion of naturally occurring CD4+CD25+FoxP3+ regulatory T (Treg) cells and the generation of a population of CD8+CD25+FoxP3+ Treg cells. Anti‐CD3 mAb treatment did not alter the capacity of CD4+ Treg cells to suppress effector T cell proliferation and interferon‐γ (IFNγ) production in vitro. However, CD4+ Treg cells from both anti‐CD3 mAb–treated and control mice were unable to suppress interleukin‐17 (IL‐17) production. In contrast, CD8+ Treg cells induced by anti‐CD3 therapy suppressed IL‐17 production as well as CD4+ T cell proliferation and IFNγ production.ConclusionThese results show that anti‐CD3 mAb treatment has important therapeutic potential for rheumatoid arthritis and has the capacity to generate antiarthritic CD8+ Treg cells and expand the relative numbers of CD4+ Treg cells.
Evaluation of the efficacy and safety of terguride in patients with fibromyalgia syndrome: Results of a twelve‐week, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study
Authors: Distler Oliver , Eich Wolfgang , Dokoupilova Eva , Dvorak Zdenek , Fleck Martin , Gaubitz Markus , Hechler Manfred , Jansen Jan‐Peter , Krause Andreas , Bendszus Martin , Pache Lothar , Reiter Rudolf , Müller‐Ladner Ulf 
Published: December 2009

AbstractObjectiveTo assess the efficacy and safety of terguride, a partial dopamine agonist, in patients with fibromyalgia syndrome (FMS).MethodsIn a 12‐week, multicenter, double‐blind, placebo‐controlled, parallel‐group study, 99 patients were randomized at a ratio of 2 to 1 to receive terguride or placebo. Over 21 days, the dosage was titrated to a maximum daily dose of 3 mg of terguride or placebo, and this fixed dosage was continued over 9 weeks. The primary efficacy variable was the intensity of pain (100‐mm visual analog scale). Secondary efficacy variables included the Fibromyalgia Impact Questionnaire (FIQ) score, the tender point score (TPS), and the Hamilton Depression Scale (HDS) score. During the study, patients were evaluated for the presence of cervical spine stenosis by magnetic resonance imaging (MRI).ResultsNo significant differences in the change in pain intensity, FIQ score, TPS, or HDS score between baseline and 12 weeks were observed in the terguride group as compared with the placebo group. Cervical spine stenosis was detected in 22% of the patients. Only patients with cervical spine stenosis responded to terguride treatment. FIQ scores improved significantly (per‐protocol analysis), and pain intensity, the TPS score, and the HDS score showed a trend toward improvement in the terguride group as compared with the placebo group. Terguride treatment was safe. Only those adverse events already known to be side effects of terguride were observed. Premature termination of the study in patients receiving terguride (26%) occurred predominantly during up‐titration and in the absence of comedication for treatment of nausea.ConclusionTerguride treatment did not improve pain, the FIQ score, the TPS, or the HDS score in the total study population. However, a subgroup of patients with cervical spine stenosis seemed to benefit from terguride treatment.
Response of Th17 cells to a citrullinated arthritogenic aggrecan peptide in patients with rheumatoid arthritis
Authors: von Delwig Alexei , Locke James , Robinson John H. , Ng Wan‐Fai 
Published: December 2009

AbstractObjectiveRheumatoid arthritis (RA) is considered to be a prototypical autoimmune disease. However, the autoantigens that play an important role in the development of RA remain unclear. The aim of this study was to investigate whether T cells specific for citrullinated epitopes from self proteins are present in patients with RA.MethodsPeripheral blood mononuclear cells (PBMCs) from 28 RA patients and 18 healthy controls were stimulated with citrullinated or noncitrullinated aggrecan peptide Agg84–103, and proliferative and cytokine responses were assessed using 3H‐thymidine incorporation assay, enzyme‐linked immunosorbent assay, and intracellular cytokine analysis.ResultsA proliferative response to the citrullinated aggrecan peptide was detected in >60% of RA patients but not in healthy controls. Furthermore, citrullinated aggrecan peptide–stimulated PBMCs from RA patients produced high levels of the proinflammatory cytokine interleukin‐17 (IL‐17), accompanied by an induction of IL‐17+CD4+ T cells. In contrast, PBMCs from RA patients and healthy controls exhibited no response to stimulation with the noncitrullinated aggrecan peptide.ConclusionProinflammatory T cell responses to stimulation with a citrullinated arthritogenic aggrecan peptide were detected in RA patients but not in healthy individuals, suggesting a role for these autoantigen‐specific T cells in the pathogenesis of RA. Our results suggest that the lack of response to the noncitrullinated analog peptide not only implicates the citrulline residue in T cell recognition but also highlights the potential value of citrullinated aggrecan peptide–specific responses as biomarkers of RA. To our knowledge, this is the first study to demonstrate the presence of citrullinated antigen–specific T cells in human RA.
Effect of long‐term belimumab treatment on b cells in systemic lupus erythematosus: Extension of a phase II, double‐blind, placebo‐controlled, dose‐ranging study
Authors: Jacobi Annett M. , Huang Weiqing , Wang Tao , Freimuth William , Sanz Inaki , Furie Richard , Mackay Meggan , Aranow Cynthia , Diamond Betty , Davidson Anne 
Published: December 2009

AbstractObjectiveTo understand the effects of long‐term BLyS inhibition in human systemic lupus erythematosus (SLE).MethodsSeventeen patients with SLE who were enrolled in a clinical trial of belimumab, a BLyS‐specific inhibitor, plus standard of care therapy were studied. Phenotypic analysis of lymphocytes was performed using flow cytometry. Circulating antibody‐secreting cells were enumerated using enzyme‐linked immunospot assay. Serum was analyzed by enzyme‐linked immunosorbent assay using an antibody that recognizes products of the VH4–34 gene. Lymphocyte counts, Ig levels, and anti–double‐stranded DNA antibody levels were available as part of the clinical trial analyses.ResultsSamples were collected on days 0, 84, 168, 365, and 532 and after day 730. The total number of B cells started to decrease from baseline between days 84 and 168. This was due to a decrease in naive and transitional B cells. CD27+IgD+ memory B cells and plasmablasts decreased only after 532 days, whereas CD27+IgD− memory B cells were not affected, and there were no changes in T cells. Serum IgM levels began to decline between days 84 and 168, but there were no changes in serum levels of IgG, IgG anti‐DNA antibodies, or VH4–34 antibodies during the study. SLE patients had more IgM‐, IgG‐, and autoantibody‐producing B cells than did normal controls on day 0. There was only a modest decrease in the frequency of total IgM‐producing, but not IgG‐producing, cells on days 365 and 532, consistent with the phenotypic and serologic data.ConclusionOur data confirm the dependence of newly formed B cells on BLyS for survival in humans. In contrast, memory B cells and plasma cells are less susceptible to selective BLyS inhibition.
Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: Results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry
Authors: Hetland Merete Lund , Christensen Ib Jarle , Tarp Ulrik , Dreyer Lene , Hansen Annette , Hansen Ib Tønder , Kollerup Gina , Linde Louise , Lindegaard Hanne M. , Poulsen Uta Engling , Schlemmer Annette , Jensen Dorte Vendelbo , Jensen Signe , Hostenkamp Gisela , ØStergaard Mikkel 
Published: December 2009

AbstractObjectiveTo compare tumor necrosis factor α inhibitors directly regarding the rates of treatment response, remission, and the drug survival rate in patients with rheumatoid arthritis (RA), and to identify clinical prognostic factors for response.MethodsThe nationwide DANBIO registry collects data on rheumatology patients receiving routine care. For the present study, we included patients from DANBIO who had RA (n = 2,326) in whom the first biologic treatment was initiated (29% received adalimumab, 22% received etanercept, and 49% received infliximab). Baseline predictors of treatment response were identified. The odds ratios (ORs) for clinical responses and remission and hazard ratios (HRs) for drug withdrawal were calculated, corrected for age, disease duration, the Disease Activity Score in 28 joints (DAS28), seropositivity, concomitant methotrexate and prednisolone, number of previous disease‐modifying drugs, center, and functional status (Health Assessment Questionnaire score).ResultsSeventy percent improvement according to the American College of Rheumatology criteria (an ACR70 response) was achieved in 19% of patients after 6 months. Older age, concomitant prednisolone treatment, and low functional status at baseline were negative predictors. The ORs (95% confidence intervals [95% CIs]) for an ACR70 response were 2.05 (95% CI 1.52–2.76) for adalimumab versus infliximab, 1.78 (95% CI 1.28–2.50) for etanercept versus infliximab, and 1.15 (95% CI 0.82–1.60) for adalimumab versus etanercept. Similar predictors and ORs were observed for a good response according to the European League Against Rheumatism criteria, DAS28 remission, and Clinical Disease Activity Index remission. At 48 months, the HRs for drug withdrawal were 1.98 for infliximab versus etanercept (95% 1.63–2.40), 1.35 for infliximab versus adalimumab (95% CI 1.15–1.58), and 1.47 for adalimumab versus etanercept (95% CI 1.20–1.80).ConclusionOlder age, low functional status, and concomitant prednisolone treatment were negative predictors of a clinical response and remission. Infliximab had the lowest rates of treatment response, disease remission, and drug adherence, adalimumab had the highest rates of treatment response and disease remission, and etanercept had the longest drug survival rates. These findings were consistent after correction for confounders and sensitivity analyses and across outcome measures and followup times.
Rheumatoid arthritis–specific autoantibodies to peptidyl arginine deiminase type 4 inhibit citrullination of fibrinogen
Authors: Auger Isabelle , Martin Marielle , Balandraud Nathalie , Roudier Jean 
Published: December 2009

AbstractObjectiveAutoantibodies to citrullinated proteins are specific for rheumatoid arthritis (RA) and recognize epitopes centered by citrulline, a posttranslationally modified form of arginine. Peptidyl arginine deiminase type 4 (PAD‐4), the enzyme that converts arginine into citrulline, is in itself a target for RA‐specific autoantibodies. This study was undertaken to assess whether anti–PAD‐4 autoantibodies interfere with citrullination in vitro in patients with RA, and to identify peptide targets of anti–PAD‐4 antibodies that can activate or inhibit citrullination.MethodsTo test whether autoantibodies to PAD‐4 influence citrullination, an in‐house citrullination assay was developed using purified autoantibodies to PAD‐4. To map B cell epitopes on PAD‐4, 65 overlapping 20‐mer peptides encompassing the entire PAD‐4 were analyzed for their reactivity in RA sera.ResultsAutoantibodies to PAD‐4 inhibited PAD‐4–mediated citrullination. Three linear peptides on PAD‐4 were recognized almost uniquely by PAD‐4 autoantibodies in the sera of patients with RA. One peptide was located in the N‐terminal, calcium‐binding domain of PAD‐4, while 2 other peptides were located in the C‐terminal, substrate‐binding domain of PAD‐4.ConclusionAutoantibodies to PAD‐4 inhibit in vitro citrullination of fibrinogen by PAD‐4. Most anti–PAD‐4–positive sera recognize peptides located both in the N‐terminal domain (211–290) and the C‐terminal domain (601–650) of PAD‐4.