bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical subsets, skin thickness progression rate, and serum antibody levels in systemic sclerosis patients with anti–topoisomerase I antibody
Authors: Perera Achini , Fertig Noreen , Lucas Mary , Rodriguez‐Reyna Tatiana S. , Hu Paul , Steen Virginia D. , Medsger Thomas A. 
Published: July 2007

AbstractObjectiveTo describe the clinical and laboratory features and natural history of the disease in systemic sclerosis (SSc; scleroderma) patients with anti–topoisomerase I (anti–topo I) antibody who have different skin thickness progression rates (STPRs).MethodsSSc patients (n = 212) who were anti–topo I antibody positive were divided into 5 subgroups based on STPRs. Skin thickness was measured using the modified Rodnan skin thickness score (MRSS). Anti–topo I IgG antibody levels were determined.ResultsSixty patients who were anti–topo I antibody positive had diffuse cutaneous SSc (dcSSc) with rapid progression, 82 had dcSSC with intermediate progression, and 29 had dcSSc with slow progression, 14 had limited cutaneous SSc (lcSSc) that became dcSSc, and 27 had lcSSc that did not change throughout. Patients beginning with lcSSc were younger at disease onset and had longer disease duration when diagnosed as having SSc. Interstitial lung disease was common and was equally distributed across the subgroups. Renal crisis occurred most often in patients with rapid progression (22%) and was absent in lcSSc patients. Cardiac involvement was most frequent in the dcSSc subgroups. Both kidney and heart disease occurred most often within 3 years after the onset of skin thickening. The 10‐year cumulative survival rate was <40% for patients with rapid and intermediate progression. Renal and cardiac causes of death were disproportionately frequent in these 2 subgroups. Anti–topo I antibody levels correlated with the STPR and the MRSS.ConclusionAnti–topo I antibody–positive patients with SSc with a rapid STPR have reduced survival rates, primarily due to early and often fatal renal and cardiac involvement. Anti–topo I antibody levels parallel the MRSS at the first visit and the STPR. This information is important for managing physicians and researchers planning clinical trials involving patients with early dcSSc.
Inflammation and ectopic lymphoid structures in rheumatoid arthritis synovial tissues dissected by genomics technology: Identification of the interleukin‐7 signaling pathway in tissues with lymphoid neogenesis
Authors: Timmer Trieneke C. G. , Baltus Belinda , Vondenhoff Mark , Huizinga Tom W. J. , Tak Paul P. , Verweij Cornelis L. , Mebius Reina E. , van der Pouw Kraan Tineke C. T. M. 
Published: July 2007

AbstractObjectiveIn ∼25% of synovial tissues from rheumatoid arthritis (RA) patients, infiltrates of T cells, B cells, and follicular dendritic cells (FDCs) are spatially organized into structures resembling lymph nodes with germinal centers. The remainder of the tissues lack FDCs and show either a diffuse or an aggregated T cell and B cell infiltrate. To gain more insight into this specific disease process, we sought to identify the genes expressed in RA tissues with ectopic lymphoid structures.MethodsGene expression profiling of RA synovial tissues was determined by complementary DNA microarray analysis and quantitative real‐time polymerase chain reaction. The presence of lymphoid follicles and localization of interleukin‐7 (IL‐7) in synovial tissue sections was determined by immunofluorescence staining using specific antibodies.ResultsFindings of gene expression analysis confirmed previous reports that tissues with lymphoid structures showed elevated expression of CXCL13, CCL21, CCR7, and lymphotoxin α and β messenger RNA. In addition, the tissues also showed enhanced expression of the chemokines CXCL12 and CCL19 and the associated receptors CXCR4 and CXCR5, which are important for the attraction of T cells, B cells, and dendritic cells. Pathway analysis revealed increased expression of genes involved in JAK/STAT signaling, T cell– and B cell–specific pathways, Fcε receptor type I signaling in mast cells, and IL‐7 signal transduction in the tissues with ectopic lymphoid follicles, accompanied by increased expression of IL‐7 receptor α (IL‐7Rα)/IL‐2Rγ chains and IL‐7. Protein expression of IL‐7 in RA tissues was localized within fibroblast‐like synoviocytes, macrophages, and blood vessels and was colocalized with extracellular matrix structures around the B cell follicles.ConclusionActivation of the IL‐7 pathway may play an important role in lymphoid neogenesis, analogous to its role in the development of normal lymphoid tissue.
Pharmacologic induction of heme oxygenase 1 reduces acute inflammatory arthritis in mice
Authors: Benallaoua Mourad , François Mathias , Batteux Frédéric , Thelier Natacha , Shyy John Y.‐J. , Fitting Catherine , Tsagris Lydia , Boczkowski Jorge , Savouret Jean‐François , Corvol Marie‐Thérèse , Poiraudeau Serge , Rannou François 
Published: July 2007

AbstractObjectiveTo determine the consequences of pharmacologic up‐regulation of heme oxygenase 1 (HO‐1), and inhibition of HO‐1 by injection of an anti–HO‐1 small interfering RNA (siRNA), in vivo in the acute phase of a mouse model of nonautoimmune arthritis.MethodsIn the K/BxN mouse serum transfer model, which mimics human inflammatory arthritis without lymphocyte influence, HO‐1 was up‐regulated by intraperitoneal injection of cobalt protoporphyrin IX (CoPP), a potent pharmacologic inducer, and was inhibited using a specific siRNA. The clinical progress of arthritis was monitored by measurement of paw thickness. Interleukin‐1β (IL‐1β), IL‐6, tumor necrosis factor α (TNFα), serum antioxidant, and nitric oxide (NO) levels, prostaglandin E2 (PGE2) production, and matrix metalloproteinase 9 (MMP‐9) activity were measured in serum. At the end of the experiments, joints were examined for immunohistopathologic changes.ResultsIntraperitoneal injection of CoPP alleviated disease symptoms, such as joint swelling, cartilage degradation, and proliferation of inflammatory tissue in joints, in the acute phase of inflammatory arthritis. The CoPP‐induced expression of HO‐1 in the joints and liver was associated with marked decreases in IL‐1β, IL‐6, and TNFα levels, PGE2 secretion, and MMP‐9 activity in serum, and with a marked increase in systemic antioxidant activity. In contrast, NO production in serum and inducible NO synthase expression in chondrocytes were not affected by HO‐1 induction. Specific inhibition of HO‐1 by in vivo delivery of anti–HO‐1 siRNA repressed the protective effects.ConclusionOur data provide the first evidence that pharmacologically induced up‐regulation of HO‐1 triggers a robust protective antiinflammatory response in a model of nonautoimmune arthritis in mice. This suggests that exogenously induced HO‐1 may have potential as therapy in the acute phase of inflammatory arthritis in humans.
Abatacept treatment does not exacerbate chronic Mycobacterium tuberculosis infection in mice
Authors: Bigbee Carolyn L. , Gonchoroff Daryl G. , Vratsanos George , Nadler Steven G. , Haggerty Helen G. , Flynn JoAnne L. 
Published: July 2007

AbstractObjectiveTreatment of rheumatoid arthritis and other autoimmune disorders with anti–tumor necrosis factor (anti‐TNF) agents is associated with an increased risk of reactivation of latent Mycobacterium tuberculosis. While the mechanism of action of abatacept is fundamentally different from that of anti‐TNF therapies, its effect on the protective response to latent tuberculosis is not known. We undertook this study to determine the effect of abatacept treatment in a murine model of chronic M tuberculosis infection.MethodsChronic M tuberculosis infection was established in C57BL/6 mice. Four months after infection, mice were treated for up to 16 weeks with abatacept, anti–murine TNF antibody, or vehicle. The primary end point was survival; body weight, bacterial load, histologic features, interferon‐γ (IFNγ) production by T cells, and cellular infiltration were also assessed.ResultsAbatacept‐ and vehicle‐treated groups both maintained control of M tuberculosis infection, with 100% survival after 16 weeks of treatment. These 2 groups had no significant differences in body weight, no clinically relevant differences in bacterial load in the lungs, lymph nodes, or spleen, and no differences in the mean percentage of total or activated T cells, macrophages, neutrophils, or B cells, or in IFNγ production in the lung or lymph nodes. In contrast, 100% mortality was seen in the anti‐TNF antibody–treated group by week 9, with significant body weight loss and increased bacterial load in the lungs, lymph nodes, and spleen. Furthermore, the anti‐TNF antibody–treated group had increased pathology consistent with the exacerbation of M tuberculosis infection.ConclusionAbatacept did not impair the ability of mice to control a chronic M tuberculosis infection. In contrast, mice treated with anti‐TNF therapy showed increased pathology and bacterial load, with 100% mortality by week 9. The clinical significance of these findings has not yet been determined.
Seasonal birth patterns in myositis subgroups suggest an etiologic role of early environmental exposures
Authors: Vegosen Leora J. , Weinberg Clarice R. , O'Hanlon Terrance P. , Targoff Ira N. , Miller Frederick W. , Rider Lisa G. 
Published: July 2007

AbstractObjectiveTo evaluate whether seasonal early environmental exposures might influence later development of autoimmune disease, by assessing distributions of birth dates in groups of patients with idiopathic inflammatory myopathies (IIMs).MethodsWe assessed birth patterns in groups of patients with juvenile‐onset IIM (n = 307) and controls (n = 3,942) who were born between 1970 and 1999, and in groups of patients with adult‐onset IIM (n = 668) and controls (n = 6,991) who were born between 1903 and 1982. Birth dates were analyzed as circular data. Seasonal clustering was assessed by the Rayleigh test, and differences between groups by a rank‐based uniform scores test.ResultsThe overall birth distributions among patients with juvenile IIM and among patients with adult IIM did not differ significantly from those among juvenile and adult controls, respectively. Some subgroups of patients with juvenile IIM had seasonal birth distributions. Hispanic patients with juvenile‐onset IIM had a seasonal birth pattern (mean birth date October 16) significantly different from that of Hispanic controls (P = 0.002), who had a uniform birth distribution, and from that of non‐Hispanic patients with juvenile‐onset IIM (P < 0.001), who had a mean birth date of May 2. Juvenile dermatomyositis patients with p155 autoantibody had a birth distribution that differed significantly from that of p155 antibody–negative juvenile dermatomyositis patients (P = 0.003). Juvenile IIM patients with the HLA risk factor allele DRB1*0301 had a birth distribution significantly different from those without the allele (P = 0.021). Similar results were observed for juvenile and adult IIM patients with the linked allele DQA1*0501, versus juvenile and adult IIM patients without DQA1*0501, respectively. No significant patterns in birth season were found in other subgroups.ConclusionBirth distributions appear to have stronger seasonality in juvenile than in adult IIM subgroups, suggesting greater influence of perinatal exposures on childhood‐onset illness. Seasonal early‐life exposures may influence the onset of some autoimmune diseases later in life.
Adjunctive methotrexate for treatment of giant cell arteritis: An individual patient data meta‐analysis
Authors: Mahr Alfred D. , Jover Juan A. , Spiera Robert F. , Hernández‐García César , Fernández‐Gutiérrez Benjamin , LaValley Michael P. , Merkel Peter A. 
Published: July 2007

AbstractObjectiveTo reevaluate the efficacy and safety of adjunctive low‐dose methotrexate (MTX) in giant cell arteritis (GCA).MethodsAn individual patient data meta‐analysis of 3 randomized placebo‐controlled trials in patients with newly diagnosed GCA was performed. Treatment consisted of initial high‐dose corticosteroids and randomly assigned oral MTX therapy (7.5–15 mg/week) or placebo. Time‐to‐event outcomes were compared between groups using Cox proportional hazards models stratified by trial, and continuous outcomes were compared by calculating weighted mean differences.ResultsThe combined data set comprised 161 patients, of whom 84 received MTX and 77 received placebo. The mean duration of followup was 54.7 weeks (SD 39.2 weeks). Hazard ratios (HRs) for a first and second relapse of GCA were 0.65 (P = 0.04) and 0.49 (P = 0.02), respectively, in patients receiving MTX as compared with patients receiving placebo. Accordingly, a predicted 3.6 individuals (95% confidence interval [95% CI] 2.2–56.8) and 4.7 individuals (95% CI 3.3–21.9) need to be treated with MTX to prevent the occurrence of one first or one second relapse, respectively, up to 48 weeks. Use of MTX resulted in a reduction in the corticosteroid cumulative dose by 842 mg within 48 weeks (P < 0.001). Moreover, MTX treatment was associated with a higher probability of achieving sustained discontinuation of corticosteroids for ≥24 weeks (HR 2.84, P = 0.001). Dropout rates and occurrence of adverse events did not differ between treatment groups.ConclusionIn GCA, adjunctive treatment with MTX lowers the risk of relapse and reduces exposure to corticosteroids. These findings indicate that MTX could be considered as a therapeutic option in addition to standard‐of‐care treatment with corticosteroids for patients with GCA.
Trichostatin A prevents the accumulation of extracellular matrix in a mouse model of bleomycin‐induced skin fibrosis
Authors: Huber Lars C. , Distler Jörg H. W. , Moritz Falk , Hemmatazad Hossein , Hauser Thomas , Michel Beat A. , Gay Renate E. , Matucci‐Cerinic Marco , Gay Steffen , Distler Oliver , Jüngel Astrid 
Published: July 2007

AbstractObjectiveTissue fibrosis is a hallmark compromising feature of many disorders. In this study, we investigated the antifibrogenic effects of the histone deacetylase inhibitor trichostatin A (TSA) on cytokine‐driven fibrotic responses in vitro and in vivo.MethodsSkin fibroblasts from patients with systemic sclerosis (SSc) and normal healthy control subjects were stimulated with profibrotic cytokines in combination with TSA. Human Colα1(I) and fibronectin were measured using real‐time polymerase chain reaction, and levels of soluble collagen were estimated using the SirCol collagen assay. Electromobilty shift assay and confocal fluorescence microscopy were used to investigate the intracellular distribution of Smad transcription factors. For in vivo analysis, skin fibrosis was quantified by histologic assessment of mouse skin tissue in a model of bleomycin‐induced fibrosis.ResultsReductions in the cytokine‐induced transcription of Colα1(I) and fibronectin were observed in both normal and SSc skin fibroblasts following the addition of TSA. Similarly, the expression of total collagen protein in TSA‐stimulated SSc skin fibroblasts was reduced to basal levels. The mechanism of action of TSA included inhibition of the nuclear translocation and DNA binding of profibrotic Smad transcription factors. Western blot analysis revealed an up‐regulation of the cell cycle inhibitor p21 by TSA, leading to reduced proliferation of fibroblasts. In addition, in bleomycin‐induced fibrosis in mice, TSA prevented dermal accumulation of extracellular matrix in vivo.ConclusionThese findings provide novel insights into the epigenetic regulation of fibrosis. TSA and similar inhibitory compounds appear to represent early therapeutic strategies for achieving reversal of the cytokine‐driven induction of matrix synthesis that leads to fibrosis.
Increased expression of the collagen receptor discoidin domain receptor 2 in articular cartilage as a key event in the pathogenesis of osteoarthritis
Authors: Xu Lin , Peng Haibing , Glasson Sonya , Lee Peter L. , Hu Kenpan , Ijiri Kosei , Olsen Bjorn R. , Goldring Mary B. , Li Yefu 
Published: July 2007

AbstractObjectiveTo investigate the role of the collagen receptor discoidin domain receptor 2 (DDR‐2) in the pathogenesis of osteoarthritis (OA).MethodsHistologic and immunohistochemical analyses were performed to characterize femoral head cartilage from 7 patients with OA and 4 patients with fracture, as well as articular cartilage from the knee joints of mice with surgically induced OA. Gene constructs encoding human Raf kinase inhibitor protein (RKIP), DDR‐2 lacking the discoidin (DS) domain (ΔDS‐DDR‐2) or the protein tyrosine kinase (PTK) core (ΔPTK‐DDR‐2), DDR‐2 containing a substitution of tyrosine for alanine at position 740 (Y740A), and luciferase driven by the matrix metalloproteinase 13 (MMP‐13) promoter were transfected into human chondrocyte cell lines. Activated and neutralized α2β1 integrin polyclonal antibodies, interleukin‐1 receptor antagonist, and the chemical inhibitors SB203580, for p38, and SP600125, for JNKs, were used in cell cultures. Real‐time polymerase chain reaction was performed to examine MMP‐13 and DDR‐2 messenger RNA (mRNA).ResultsIncreased immunostaining for DDR‐2, MMP‐13, and MMP‐derived type II collagen fragments was detected in cartilage from patients with OA and from mice with surgically induced OA. The discoidin domain and PTK core of DDR‐2 were essential for signal transmission and the resulting increased expression of MMP‐13 in chondrocytes. Y740A mutation of DDR‐2 reduced levels of mRNA for MMP‐13 and endogenous DDR‐2. The overexpression of RKIP or preincubation with the p38 inhibitor reduced MMP‐13 mRNA levels. DDR‐2 signaling was independent of the α2β1 integrin and the interleukin‐1–induced signaling pathways in chondrocytes.ConclusionThese findings suggest that increased expression of DDR‐2, resulting in the elevated expression of MMP‐13, may be one of the common events in OA progression.
Novel conformation of histidyl–transfer RNA synthetase in the lung
Authors: Levine Stuart M. , Raben Nina , Xie Dan , Askin Frederic B. , Tuder Rubin , Mullins Marissa , Rosen Antony , Casciola‐Rosen Livia A. 
Published: July 2007

AbstractObjectiveWe previously proposed that novel expression and/or conformation of autoantigens in the target tissue may play a role in generating phenotype‐specific immune responses. The strong association of autoantibodies to histidyl–transfer RNA synthetase (HisRS, Jo‐1) with interstitial lung disease in patients with myositis led us to study HisRS expression and conformation in the lung.MethodsNormal human tissue specimens were probed with a novel anti‐HisRS antibody recognizing its granzyme B–cleavable conformation by immunoblotting and immunohistochemistry. The HisRS granzyme B site was mapped using site‐directed mutagenesis, and its relationship to the antibody recognition domain was evaluated in tandem immunoprecipitation/granzyme B cleavage studies.ResultsThe HisRS α‐helical coiled‐coil N‐terminal domain recognized by autoantibodies is bounded by a granzyme B cleavage site. In immunoprecipitation studies with patient sera, HisRS was found to exist in 2 conformations, defined by sensitivity to cleavage by granzyme B and modification by autoantibody binding. Despite similar global expression of HisRS in different tissue, expression of its granzyme B–cleavable form was enriched in the lung and localized to the alveolar epithelium.ConclusionA proteolytically sensitive conformation of HisRS exists in the lung, the target tissue associated with this autoantibody response. We thus propose that autoimmunity to HisRS is initiated and propagated in the lung.
Freund's complete adjuvant induces arthritis in mice lacking a functional interferon‐γ receptor by triggering tumor necrosis factor α–driven osteoclastogenesis
Authors: Geboes Lies , Klerck Bert De , Balen Maarten Van , Kelchtermans Hilde , Mitera Tania , Boon Louis , Wolf‐Peeters Chris De , Matthys Patrick 
Published: July 2007

AbstractObjectiveTo investigate the hypothesis that Freund's complete adjuvant (CFA) plays an essential role in the induction of collagen‐induced arthritis in mice, by testing whether CFA by itself is able to induce arthritis in interferon‐γ receptor–knockout (IFNγR‐KO) mice.MethodsIFNγR‐KO and wild‐type mice were sensitized with a single intradermal injection of CFA containing heat‐killed Mycobacterium butyricum. Flow cytometric analysis and in vitro osteoclastogenesis assays were performed on blood, spleen, and bone marrow cells. Tumor necrosis factor (TNF) levels were measured in the serum, and levels of RANKL, osteoprotegerin (OPG), and TNFα in the synovium were determined by quantitative reverse transcriptase–polymerase chain reaction. Effects of treatment with the TNFα antagonist etanercept were assessed.ResultsSymptoms of arthritis appeared in IFNγR‐KO mice but not in wild‐type mice, and reached an incidence of 55%. The onset coincided with an expansion of CD11b+ splenocytes that spontaneously produced TNFα and with increased osteoclastogenesis in spleen and blood cells. Expansion of CD11b+ splenocytes and osteoclast precursor cells was more pronounced in arthritic than in nonarthritic mice. There was a >100‐fold increase in the RANKL:OPG ratio in the synovia of CFA‐sensitized mice compared with those of naive animals. Treatment with etanercept prevented the development of arthritis and mitigated the increased expansion of myeloid cells as well as the increase in osteoclast precursor numbers in the spleen and blood.ConclusionThese results indicate that sensitization of mice with CFA creates a condition in which dysregulation of a single cytokine leads to arthritis by triggering TNFα‐driven osteoclastogenesis.
Prostaglandin E2 exacerbates collagen‐induced arthritis in mice through the inflammatory interleukin‐23/interleukin‐17 axis
Authors: Sheibanie Amir F. , Khayrullina Tanzilya , Safadi Fayez F. , Ganea Doina 
Published: July 2007

AbstractObjectiveRecently, Th17 cells, a new subset of CD4+ T cells, emerged as major players in inflammation/autoimmunity. Maintenance of the Th17 phenotype requires interleukin‐23 (IL‐23), whereas the Th1‐promoting cytokine IL‐12p70 exerts a negative effect on Th17 cell differentiation. The lipid mediator prostaglandin E2 (PGE2) acts primarily as a proinflammatory agent in autoimmune conditions, through mechanisms that remain to be elucidated. The aim of this study was to investigate whether PGE2 released in inflammatory foci activates resident dendritic cells (DCs) to express IL‐23 (at the expense of IL‐12) and IL‐6, resulting in a shift toward Th17 cell responses.MethodsThe effect of PGE2 on IL‐23 production by DCs and subsequent induction of T cell–derived IL‐17 was assessed in vitro and in vivo. The effect of the stable PGE analog misoprostol was evaluated in a murine model of rheumatoid arthritis, in conjunction with IL‐23 and IL‐17 expression in affected joints and draining lymph nodes.ResultsIn vivo administration of PGE2 induced IL‐23–dependent IL‐17 production. Administration of misoprostol exacerbated collagen‐induced arthritis (CIA). CIA exacerbation was associated with increased levels of IL‐23p19/p40 messenger RNA and reduced expression of IL‐12p35, and with increased levels of the proinflammatory cytokines IL‐17, IL‐1β, IL‐6, and tumor necrosis factor in the affected joint. Following ex vivo restimulation, draining lymph node cells from misoprostol‐treated mice secreted higher levels of IL‐17 and lower levels of interferon‐γ.ConclusionOur results indicate that PGE2 enhances DC‐derived IL‐6 production and induces a shift in the IL‐23/IL‐12 balance in favor of IL‐23, resulting in increased IL‐17 production, presumably through the amplification of self‐reactive Th17 cells.