bluuebunny/crossref_metadata_2025_split huggingface dataset:
Febrile temperatures control antineutrophil cytoplasmic autoantibody–induced neutrophil activation via inhibition of phosphatidylinositol 3‐kinase/Akt
Authors: von Vietinghoff Sibylle , Choi Mira , Rolle Susanne , Luft Friedrich C. , Kettritz Ralph 
Published: August 2007

AbstractObjectiveNeutrophil activation by antineutrophil cytoplasmic autoantibodies (ANCAs) is central to the pathogenesis of the ANCA‐associated vasculitides. Febrile infections occur frequently during these diseases, often in the context of immunosuppressive treatment. Heat exposure may affect the underlying pathophysiologic processes of the vasculitis. In this study we tested the hypothesis that short‐term exposure to heat inhibits ANCA‐induced neutrophil activation.MethodsAfter exposure to temperatures from 37°C to 42°C, human neutrophils were primed with either tumor necrosis factor α (TNFα) or granulocyte–macrophage colony‐stimulating factor (GM‐CSF) and stimulated with monoclonal antibodies to myeloperoxidase or to proteinase 3. Respiratory burst activity was assayed using rhodamine and a nitroblue tetrazolium reduction assay. Specific inhibition experiments against p38 MAPK, ERK, and phosphatidylinositol 3‐kinase (PI 3‐kinase)/Akt, and Western blotting with phospho‐specific antibodies were used to identify key components in the antibody‐induced respiratory burst.ResultsA temperature‐dependent reduction in ANCA‐induced respiratory burst was observed over a range of heat exposures from 37°C to 42°C. Inhibition of human ANCA–induced neutrophil stimulation was significant at 40°C (after priming with 2 ng/ml TNFα, mean [± SEM] fluorescence intensity [MFI] 114 ± 12 at 37°C versus 53 ± 6 at 40°C; after priming with 20 ng/ml GM‐CSF, MFI 92 ± 16 at 37°C versus 35 ± 6 at 40°C; both P < 0.01). In the priming phase, the transient activation of the p38 MAPK, ERK, and PI 3‐kinase/Akt pathways by TNFα was blocked by prior exposure of the neutrophils to heat, but GM‐CSF–induced activation was unaltered by heat. However, in the second, antibody‐induced wave of kinase activation, exposure to heat inhibited only the PI 3‐kinase/Akt pathway, and these effects were independent of the priming agent used.ConclusionShort‐term spikes of modest heat abrogate ANCA‐induced activation of neutrophils via inhibition of PI 3‐kinase/Akt signaling. Febrile responses in ANCA‐mediated diseases may therefore have a physiologic purpose.
HLA–DRB4 as a genetic risk factor for Churg‐Strauss syndrome
Authors: Vaglio Augusto , Martorana Davide , Maggiore Umberto , Grasselli Chiara , Zanetti Adele , Pesci Alberto , Garini Giovanni , Manganelli Paolo , Bottero Paolo , Tumiati Bruno , Sinico Renato A. , Savi Mario , Buzio Carlo , Neri Tauro M. 
Published: August 2007

AbstractObjectiveTo explore the association between HLA alleles and Churg‐Strauss syndrome (CSS), and to investigate the potential influence of HLA alleles on the clinical spectrum of the disease.MethodsLow‐resolution genotyping of HLA–A, HLA–B, and HLA–DR loci and genotyping of TNFA −238A/G and TNFA −308A/G single‐nucleotide polymorphisms were performed in 48 consecutive CSS patients and 350 healthy controls.ResultsThe frequency of the HLA–DRB1*07 allele was higher in the CSS patients than in controls (27.1% versus 13.3%; χ2 = 12.64, P = 0.0003, corrected P [Pcorr] = 0.0042, odds ratio [OR] 2.42, 95% confidence interval [95% CI] 1.47–3.99). The HLA–DRB4 gene, present in subjects carrying either HLA–DRB1*04, HLA–DRB1*07, or HLA–DRB1*09 alleles, was also far more frequent in patients than in controls (38.5% versus 20.1%; χ2 = 16.46, P = 0.000058, Pcorr = 0.000232, OR 2.49, 95% CI 1.58–3.09). Conversely, the frequency of the HLA–DRB3 gene was lower in patients than in controls (35.4% versus 50.4%; χ2 = 7.62, P = 0.0057, Pcorr = 0.0228, OR 0.54, 95% CI 0.35–0.84). CSS has 2 major clinical subsets, antineutrophil cytoplasmic antibody (ANCA)–positive, with features of small‐vessel vasculitis, and ANCA‐negative, in which organ damage is mainly mediated by tissue eosinophilic infiltration; analysis of HLA–DRB4 in patients categorized by different numbers of vasculitic manifestations (purpura, alveolar hemorrhage, mononeuritis multiplex, rapidly progressive glomerulonephritis, and constitutional symptoms) showed that its frequency strongly correlated with the number of vasculitis symptoms (P for trend = 0.001).ConclusionThese findings indicate that HLA–DRB4 is a genetic risk factor for the development of CSS and increases the likelihood of development of vasculitic manifestations of the disease.
A randomized, placebo‐controlled trial of infliximab plus methotrexate for the treatment of polyarticular‐course juvenile rheumatoid arthritis
Authors: Ruperto Nicolino , Lovell Daniel J. , Cuttica Ruben , Wilkinson Nick , Woo Patricia , Espada Graciela , Wouters Carine , Silverman Earl D. , Balogh Zsolt , Henrickson Michael , Apaz Maria‐Teresa , Baildam Eileen , Fasth Anders , Gerloni Valeria , Lahdenne Pekka , Prieur Anne‐Marie , Ravelli Angelo , Saurenmann Rotraud K. , Gamir Maria Luz , Wulffraat Nico , Marodi Laszlo , Petty Ross E. , Joos Rik , Zulian Francesco , McCurdy Deborah , Myones Barry L. , Nagy Kalman , Reuman Peter , Szer Ilona , Travers Suzanne , Beutler Anna , Keenan Greg , Clark Jason , Visvanathan Sudha , Fasanmade Adedigbo , Raychaudhuri Aparna , Mendelsohn Alan , Martini Alberto , Giannini Edward H. 
Published: August 2007

AbstractObjectiveTo evaluate the safety and efficacy of infliximab in the treatment of juvenile rheumatoid arthritis (JRA).MethodsThis was an international, multicenter, randomized, placebo‐controlled, double‐blind study. One hundred twenty‐two children with persistent polyarticular JRA despite prior methotrexate (MTX) therapy were randomized to receive infliximab or placebo for 14 weeks, after which all children received infliximab through week 44. Patients received MTX plus infliximab 3 mg/kg through week 44, or MTX plus placebo for 14 weeks followed by MTX plus infliximab 6 mg/kg through week 44.ResultsAlthough a higher proportion of patients in the 3 mg/kg infliximab group than in the placebo group had achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement at week 14 (63.8% and 49.2%, respectively), the between‐group difference in this primary efficacy end point was not statistically significant (P = 0.12). By week 16, after the crossover from placebo to infliximab 6 mg/kg when all patients were receiving infliximab, an ACR Pedi 30 response was achieved in 73.2% of all patients. By week 52, ACR Pedi 50 and ACR Pedi 70 responses had been reached in 69.6% and 51.8%, respectively, of patients. Infliximab was generally well tolerated, but the safety profile of infliximab 3 mg/kg appeared less favorable than that of infliximab 6 mg/kg, with more frequent occurrences of serious adverse events, infusion reactions, antibodies to infliximab, and newly induced antinuclear antibodies and antibodies to double‐stranded DNA observed with the 3 mg/kg dose.ConclusionWhile infliximab at 3 mg/kg and 6 mg/kg showed durable efficacy at 1 year, achievement of the primary efficacy end point at 3 months did not differ significantly between infliximab‐treated and placebo‐treated patients. Safety data indicated that the 6‐mg/kg dose may provide a more favorable risk/benefit profile. These results warrant further investigation in children with JRA.
Interleukin‐1β impairment of transforming growth factor β1 signaling by DOWN‐REGULATION of transforming growth factor β receptor type II and up‐regulation of Smad7 in human articular chondrocytes
Authors: Baugé C. , Legendre F. , Leclercq S. , Elissalde J. M. , Pujol J. P. , Galéra P. , Boumédiene K. 
Published: August 2007

AbstractObjectiveExtracellular matrix deposition is tightly controlled by a network of regulatory cytokines. Among them, interleukin‐1β (IL‐1β) and transforming growth factor β1 (TGFβ1) have been shown to play antagonistic roles in tissue homeostasis. The purpose of this study was to determine the influence of IL‐1β on TGFβ receptor type II (TGFβRII) regulation and TGFβ1 responsiveness in human articular chondrocytes.MethodsTGFβ1‐induced gene expression was analyzed through plasminogen activator inhibitor 1 and p3TP‐Lux induction. Receptor‐activated Smad (R‐Smad) phosphorylation, TGFβ receptors, and Smad expression were determined by Western blotting and real‐time reverse transcription–polymerase chain reaction techniques. Signaling pathways were investigated using specific inhibitors, messenger RNA (mRNA) silencing, and expression vectors.ResultsIL‐1β down‐regulated TGFβRII expression at both the protein and mRNA levels and led to inhibition of the TGFβ1‐induced gene expression and Smad2/3 phosphorylation. Moreover, IL‐1β strongly stimulated the expression of inhibitory Smad7. TGFβRII overexpression abolished the loss of TGFβ1 responsiveness induced by IL‐1β. The decrease in TGFβRII required de novo protein synthesis and involved both the NF‐κB and JNK pathways.ConclusionWe demonstrate that IL‐1β impairs TGFβ1 signaling through down‐regulation of TGFβRII, which is mediated by the p65/NF‐κB and activator protein 1/JNK pathways, and secondarily through the up‐regulation of Smad7. These findings show that there is cross‐talk in the signaling of 2 regulatory cytokines involved in inflammation.
Early changes in serum type ii collagen biomarkers predict radiographic progression at one year in inflammatory arthritis patients after biologic therapy
Authors: Mullan Ronan H. , Matthews Clare , Bresnihan Barry , FitzGerald Oliver , King Lindsay , Poole A. Robin , Fearon Ursula , Veale Douglas J. 
Published: August 2007

AbstractObjectiveTo investigate whether short‐term changes in serum biomarkers of type II collagen degradation (C2C) and types I and II collagen degradation (C1,2C), as well as the biomarker for the synthesis of type II procollagen (CPII) can predict radiographic progression at 1 year following initiation of biologic therapy in patients with inflammatory arthritis.MethodsSerum levels of biomarkers were measured at baseline and at 1, 3, 6, 9, and 12 months after initiation of biologic therapy. A composite score reflecting changes from baseline in all 3 biomarkers (ΔCOL) was calculated. Associations with clinical responses according to the 28‐joint count Disease Activity Score and with radiographic progression according to the modified Sharp/van der Heijde score (SHS) were assessed.ResultsThe 1‐year increase in the SHS correlated with the 1‐month change in C2C results (r = 0.311, P = 0.028) and the ΔCOL score (r = 0.342, P = 0.015). Radiographic progression was predicted by increases in serum C2C at 1 month (P = 0.031). The ΔCOL score was significantly associated with 1‐year radiographic progression after 1 (P = 0.022), 3 (P = 0.015), 6 (P = 0.048), and 9 (P = 0.019) months of therapy. Clinical remission was predicted by 1‐month decreases in serum levels of C2C (P = 0.008) and C1,2C (P = 0.036). By regression analysis, 1‐month changes in C2C, C1,2C, and CPII levels were independently associated with, and correctly predicted radiographic outcome in, 88% of the patients.ConclusionShort‐term changes in serum levels of collagen biomarkers following initiation of biologic therapy may better predict long‐term clinical and radiographic outcomes. These collagen biomarkers may therefore be valuable new early indicators of short‐term biologic treatment efficacy in clinical trials and in individual patients with inflammatory erosive arthritis.
Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis
Authors: Xue Meilang , March Lyn , Sambrook Philip N. , Jackson Christopher J. 
Published: August 2007

AbstractObjectiveTo investigate the in vitro effect of activated protein C (APC), a natural anticoagulant and novel antiinflammatory agent, on the regulation of the gelatinases matrix metalloproteinase 2 (MMP‐2) and MMP‐9.MethodsSynovial fibroblasts and peripheral blood monocytes isolated from patients with rheumatoid arthritis (RA) or osteoarthritis (OA) and Mono Mac6 cells were used in this study. After treatment, cells and culture supernatants were collected for zymography, enzyme‐linked immunosorbent assay, reverse transcription–polymerase chain reaction, and Western blot analysis.ResultsFibroblasts and monocytes from RA patients produced substantially more MMP‐9 than did those from OA patients; however, there was no difference in MMP‐2 production. The addition of recombinant APC markedly reduced MMP‐9 at the gene and protein levels. In contrast, APC up‐regulated and activated MMP‐2. Using a blocking antibody to the endothelial protein C receptor (EPCR), we showed that the inhibition of MMP‐9 by APC was EPCR‐dependent. Furthermore, APC directly suppressed the production of tumor necrosis factor (TNF) and the activation of NF‐κB and MAP kinase p38, and inhibitors of NF‐κB or p38 reduced the production of MMP‐9, suggesting that APC inhibits MMP‐9 by blocking TNF, NF‐κB, and p38. Thus, APC acts on MMP‐9 by binding to EPCRs on the cell surface and, subsequently, inhibiting the intracellular activation of the proinflammatory signaling molecules NF‐κB and p38.ConclusionAPC appears to be the first physiologic agent to inhibit the production of proinflammatory MMP‐9, yet increase antiinflammatory MMP‐2 activity. Our results provide the initial evidence that APC may be beneficial in the prevention of inflammation and joint destruction in RA.
Association of smoking with the constitution of the anti–cyclic citrullinated peptide response in the absence of HLA–DRB1 shared epitope alleles
Authors: Verpoort K. N. , Papendrecht‐van der Voort E. A. M. , van der Helm‐van Mil A. H. M. , Jol‐van der Zijde C. M. , van Tol M. J. D. , Drijfhout J. W. , Breedveld F. C. , de Vries R. R. P. , Huizinga T. W. J. , Toes R. E. M. 
Published: August 2007

AbstractObjectiveSmoking is a risk factor for anti–cyclic citrullinated peptide (anti‐CCP) antibody–positive rheumatoid arthritis (RA) in patients with HLA–DRB1 shared epitope (SE) alleles. It is unknown whether smoking influences not only the presence of these antibodies, but also other characteristics of the anti‐CCP response, such as isotype usage. The aim of this study was to determine the influence of smoking on anti‐CCP isotypes in RA patients, and to determine whether this influence is observed in the presence and/or absence of SE alleles.MethodsIgA, IgM, and IgG subclasses of anti‐CCP antibodies were measured by enzyme‐linked immunosorbent assay in serum obtained at the first visit to the Leiden Early Arthritis Clinic from 216 patients with anti‐CCP–positive RA whose smoking habits were also assessed. HLA genotyping data were available for 202 of these patients.ResultsIgA and IgM anti‐CCP were more frequent in RA patients who were smokers than in those who were nonsmokers (odds ratio 2.8 and 1.8, respectively). In addition, levels of all isotypes of anti‐CCP, except IgG3, were significantly higher (P < 0.05) in smokers. The number of anti‐CCP isotypes was higher in smokers compared with nonsmokers, both in SE‐negative RA (P = 0.04) and in SE‐positive RA (P = 0.07).ConclusionPatients with anti‐CCP–positive RA who have a current or former tobacco exposure display a more extensive anti‐CCP isotype usage in general, and IgA and IgM in particular, compared with patients with anti‐CCP–positive RA who have never smoked. In contrast to its influence on the incidence of anti‐CCP positivity, the influence of tobacco exposure on the constitution of the anti‐CCP response is significant in SE‐negative RA. These findings suggest a differential effect of tobacco exposure on the induction as compared with the propagation of the anti‐CCP antibody response.
Development of an ex vivo cellular model of rheumatoid arthritis: Critical role of cd14‐positive monocyte/macrophages in the development of pannus tissue
Authors: Nozaki Toshiko , Takahashi Kyoko , Ishii Osamu , Endo Sachio , Hioki Kyoji , Mori Toshihito , Kikukawa Tadahiro , Boumpas Dimitrios T. , Ozaki Shoichi , Yamada Hidehiro 
Published: August 2007

AbstractObjectiveTo establish an ex vivo cellular model of pannus, the aberrant overgrowth of human synovial tissue (ST).MethodsInflammatory cells that infiltrated pannus tissue from patients with rheumatoid arthritis (RA) were collected without enzyme digestion, and designated as ST‐derived inflammatory cells. Single‐cell suspensions of ST‐derived inflammatory cells were cultured in medium alone. Levels of cytokines produced in culture supernatants were measured using enzyme‐linked immunosorbent assay kits. ST‐derived inflammatory cells were transferred into the joints of immunodeficient mice to explore whether these cells could develop pannus. CD14 and CD2 cells were depleted by negative selection.ResultsCulture of ST‐derived inflammatory cells from 92 of 111 patients with RA resulted in spontaneous reconstruction of inflammatory tissue in vitro within 4 weeks. Ex vivo tissue contained fibroblasts, macrophages, T cells, and tartrate‐resistant acid phosphatase–positive multinucleated cells. On calcium phosphate–coated slides, ST‐derived inflammatory cell cultures showed numerous resorption pits. ST‐derived inflammatory cell cultures continuously produced matrix metalloproteinase 9 and proinflammatory cytokines associated with osteoclastogenesis, such as tumor necrosis factor α, interleukin‐8, and macrophage colony‐stimulating factor. More importantly, transferring ST‐derived inflammatory cells into the joints of immunodeficient mice resulted in the development of pannus tissue and erosive joint lesions. Both in vitro development and in vivo development of pannus tissue by ST‐derived inflammatory cells were inhibited by depleting CD14‐positive, but not CD2‐positive, cells from ST‐derived inflammatory cells.ConclusionThese findings suggest that overgrowth of inflammatory cells from human rheumatoid synovium simulates the development of pannus. This may prove informative in the screening of potential antirheumatic drugs.
Correlation of the development of knee pain with enlarging bone marrow lesions on magnetic resonance imaging
Authors: Felson David T. , Niu Jingbo , Guermazi Ali , Roemer Frank , Aliabadi Piran , Clancy Margaret , Torner James , Lewis C. Elizabeth , Nevitt Michael C. 
Published: August 2007

AbstractObjectiveResults of cross‐sectional studies have suggested that bone marrow lesions (BMLs) visualized on magnetic resonance imaging (MRI) are related to knee pain, but no longitudinal studies have been done. This study was undertaken to determine whether enlarging BMLs are associated with new knee pain.MethodsSubjects ages 50–79 years with knee osteoarthritis (OA) or at high risk of knee OA were asked twice at baseline about the presence of knee pain, aching, or stiffness (classified as frequent knee pain) on most days; absence of knee pain was the baseline eligibility criterion. At 15 months' followup, subjects were again queried twice about frequent knee pain. A case knee was defined as absence of knee pain at baseline but presence of knee pain both times at followup. Controls were selected randomly from among knees with absence of pain at baseline. All MR images were scored for volume of BMLs in the medial, lateral, and patellofemoral compartments. We focused on the maximal change in BML score among the knee compartments from baseline to 15 months. Multiple logistic regression, with adjustments for demographic and clinical variables, was used to assess whether an increased BML score is predictive of the development of knee pain.ResultsAmong case knees, 54 of 110 (49.1%) showed an increase in BML score within a compartment, whereas only 59 of 220 control knees (26.8%) showed an increase (P < 0.001 by chi‐square test). A BML score increase of at least 2 units was much more common in case knees than in control knees (27.5% versus 8.6%; adjusted odds ratio 3.2, 95% confidence interval 1.5–6.8). Among case knees with increased BMLs, most already had BMLs at baseline, with enlarging BMLs at followup, but among the subset of knees with no BMLs at baseline, new BMLs were more common in case knees (11 [32.4%] of 34) than in control knees (9 [10.8%] of 83).ConclusionDevelopment of knee pain is associated with an increase in BMLs as revealed on MRI.
Rituximab for the treatment of juvenile dermatomyositis: A report of four pediatric patients
Authors: Cooper Megan A. , Willingham Donna L. , Brown Diane E. , French Anthony R. , Shih Fei F. , White Andrew J. 
Published: August 2007

AbstractObjectiveJuvenile dermatomyositis (DM) is a chronic inflammatory myopathy of childhood primarily affecting the muscles and skin. Treatment for juvenile DM is often difficult, and conventional therapies include corticosteroids and other immune suppressants. We reviewed the records of 4 patients with juvenile DM who received the B cell–depleting anti‐CD20 monoclonal antibody rituximab to determine whether this therapy resulted in improved control of their juvenile DM.MethodsThis is a retrospective review of 4 pediatric patients ages 10–17 years with juvenile DM who were treated with rituximab. All patients were tested for myositis autoantibodies and received weekly rituximab infusions for a total of 4 doses. Two patients received repeat courses of rituximab 1 year after their first dose. Patients were followed up between 12 and 24 months after their first course of rituximab, and their strength, muscle enzymes, and rash were reviewed.ResultsOne patient was positive for a myositis‐specific antibody, anti–Mi‐2, and demonstrated striking reductions in her muscle enzyme levels for 1 year after rituximab therapy. Following a second course of rituximab, this patient remained disease free for 14 months before requiring a third course of rituximab. Two myositis antibody–negative patients showed clinical improvement and tolerated lower doses of corticosteroids following treatment with rituximab. Finally, 1 patient had worsening of her disease following rituximab.ConclusionThese cases highlight the potential for anti–B cell therapies in the treatment of juvenile DM in both myositis‐specific autoantibody–positive and –negative patients.