bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rho‐associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts
Authors: Akhmetshina Alfiya , Dees Clara , Pileckyte Margarita , Szucs Gabriella , Spriewald Bernd M. , Zwerina Jochen , Distler Oliver , Schett Georg , Distler Jörg H. W. 
Published: August 2008

AbstractObjectiveRho‐associated kinases (Rock) are the major cellular mediators of Rho GTPases and play an important role in the organization of the actin cytoskeleton. Inhibitors of Rock are currently being evaluated for the treatment of pulmonary arterial hypertension. This study was undertaken to analyze the role of Rock in the activation of fibroblasts in systemic sclerosis (SSc).MethodsRock signaling was inhibited using chemical inhibitors and small interfering RNA. The expression of extracellular matrix (ECM) proteins and α‐smooth muscle actin was analyzed by real‐time polymerase chain reaction, Western blotting, and SirCol assay. Metabolic activity was quantified by MTT assay. Cell viability was assessed by staining with annexin V and propidium iodide. The role of MAP kinases was investigated using selective inhibitors and Western blotting.ResultsInhibition of Rock strongly reduced the synthesis of the major ECM proteins at the messenger RNA level as well as the protein level. Counterregulatory changes in the expression of tissue inhibitors of metalloproteinases and matrix metalloproteinases were not observed. Inhibition of Rock prevented myofibroblast differentiation. Transforming growth factor β activated ERK in a Rock‐dependent manner, and ERK mediated in part the stimulatory effects of Rock on myofibroblast differentiation. Toxic adverse effects of the inhibition of Rock were not observed.ConclusionOur findings demonstrate that Rock potently stimulates the differentiation of resting fibroblasts into myofibroblasts and the production of ECM at biologically relevant concentrations without cell toxicity. These findings, along with the beneficial effects of Rock inhibition on vascular disease, indicate that inhibition of Rock might be an interesting novel therapeutic approach for the treatment of SSc.
Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus
Authors: Petri Michelle , Stohl William , Chatham Winn , McCune W. Joseph , Chevrier Marc , Ryel Jeff , Recta Virginia , Zhong John , Freimuth William 
Published: August 2008

AbstractObjectiveTo determine the association of plasma B lymphocyte stimulator (BLyS) levels, immunosuppressive therapy, and other clinical parameters with disease activity in systemic lupus erythematosus (SLE).MethodsTwo hundred forty‐five SLE patients were evaluated prospectively over a 2‐year period at 4 centers. Assessments were performed every 3–6 months. Univariate analysis was used to determine the association among the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, serum anti–double‐stranded DNA (anti‐dsDNA), and plasma BLyS levels. A multivariate repeated‐measures model incorporating immunosuppressive therapy was utilized.ResultsNinety‐two percent of the patients were female. Sixty‐seven percent were white, 31% African American, and 2% Asian (all of these groups may include Hispanic). Mean values at baseline were as follows: age 41.5 years, disease duration 8.1 years, SELENA–SLEDAI 3.3 (median 2, range 0–18), BLyS 5.57 ng/ml, IgG 1,439 mg/dl, C3 104.4 mg/dl, and C4 21.3 mg/dl; among those positive for anti‐dsDNA, the median titer was 1:40 (range 1:10–1:1,280). Univariate analysis showed that plasma BLyS levels were associated with anti‐dsDNA titers (P = 0.0465) and SELENA–SLEDAI scores (P = 0.0002). In multivariate analyses, a greater increase in the SELENA–SLEDAI score from the previous visit was associated with higher BLyS levels at the previous visit (P = 0.0042) and with a greater increase in the BLyS level from the previous visit (P = 0.0007).ConclusionThe findings of association between a greater increase in the BLyS level from the previous visit and a greater increase in the SELENA–SLEDAI score at the subsequent visit, and between an elevated BLyS level at the previous visit and a greater SELENA–SLEDAI score at the subsequent visit, demonstrate a relationship between circulating BLyS levels and SLE disease activity. These results lend support to the notion that BLyS is a candidate for therapeutic targeting in SLE.
Validation of a prediction rule for disease outcome in patients with recent‐onset undifferentiated arthritis: Moving toward individualized treatment decision‐making
Authors: van Der Helm‐van Mil Annette H. M. , Detert Jacqueline , Cessie Saskia Le , Filer Andrew , Bastian Hans , Burmester Gerd R. , Huizinga Tom W. J. , Raza Karim 
Published: August 2008

AbstractObjectiveThe decision to start disease‐modifying antirheumatic drugs in patients with recent‐onset undifferentiated arthritis (UA) is complicated by a varied natural disease course in which the disease in one‐third of patients progresses to rheumatoid arthritis (RA), whereas 40–50% of patients experience spontaneous remission. Recently, a prediction rule was developed to estimate the chance of progression to RA in individual patients presenting with UA. This study investigates the accuracy of this prediction rule in independent cohorts of patients with UA.MethodsIn 3 cohorts of patients with recent‐onset UA, from the UK, Germany, and The Netherlands, the prediction score and the corresponding chance of developing RA were calculated. These data were compared with the observed disease outcome after ≥1 year of followup. Positive predictive values (PPVs) and negative predictive values (NPVs) were calculated and the overall discriminative ability of the prediction rule was assessed using area under the receiver operating characteristic curves (AUCs).ResultsSince data on the severity of morning stiffness were not available in all validation cohorts, the prediction rule was rederived with the duration of morning stiffness as a substitute. The AUC for this rule was 0.88 (SEM 0.015). For each validation cohort, the AUC was 0.83 (SEM 0.041), 0.82 (SEM 0.037), and 0.95 (SEM 0.031) in the British, German, and Dutch cohorts, respectively. The NPV (for a prediction score ≤6) in these 3 cohorts was 83%, 83%, and 86%, respectively; the PPV (for a prediction score ≥8) was 100%, 93%, and 100%, respectively.ConclusionThe recently derived prediction rule, when applied to 3 independent cohorts of patients with UA, has an excellent discriminative ability for assessing the likelihood of progression to RA. Application of this rule will allow individualized treatment decision‐making for patients with UA.
Power doppler ultrasonographic monitoring of response to anti–tumor necrosis factor therapy in patients with rheumatoid arthritis
Authors: Naredo Esperanza , Möller Ingrid , Cruz Ana , Carmona Loreto , Garrido Jesüs 
Published: August 2008

AbstractObjectiveTo evaluate the validity, responsiveness, and predictive value of power Doppler ultrasonography (PDUS) monitoring of response to tumor necrosis factor (TNF) blocking agents in rheumatoid arthritis (RA).MethodsThree hundred sixty‐seven RA patients were prospectively recruited at 25 Spanish centers; complete clinical, laboratory, and PDUS data were obtained on 278 patients. The patients underwent clinical, laboratory, and PDUS assessment at baseline and after 1, 3, 6, and 12 months of anti‐TNF treatment, and radiographic assessment of the hands and feet at baseline and 12 months. The Disease Activity Score in 28 joints (DAS28) was recorded at each visit. PDUS examination included 86 intraarticular and periarticular sites in 28 joints. US synovial fluid (SF), synovial hypertrophy (SH), and PD signal were scored in all synovial sites. US count and index for SF, SH, and PD signal were obtained. Sensitivity to change of the PDUS variables was assessed by estimating the smallest detectable difference (SDD) from the intraobserver variability.ResultsA significant parallel improvement in DAS28 and PDUS parameters was found at followup assessment (P < 0.0005 for within‐subject between‐visit changes). The SDD for PDUS parameters was lower than the mean changes throughout followup. Time‐integrated values of US joint count for PD signal and rheumatoid factor (RF) showed predictive value in relation to progression of radiographic erosion (R = 0.64), and time‐integrated values of US joint count for PD signal, RF, and erythrocyte sedimentation rate were predictors of progression of the total radiographic score (R = 0.59).ConclusionThese findings indicate that PDUS is a valid method for monitoring response to anti‐TNF therapy in RA; results obtained by PDUS are reproducible and sensitive to change. PDUS findings may have predictive value in relation to radiologic outcome.
Bone density, structure, and strength in juvenile idiopathic arthritis: Importance of disease severity and muscle deficits
Authors: Burnham Jon M. , Shults Justine , Dubner Sarah E. , Sembhi Harjeet , Zemel Babette S. , Leonard Mary B. 
Published: August 2008

AbstractObjectiveTo identify determinants of musculoskeletal deficits (muscle cross‐sectional area [mCSA], trabecular volumetric bone mineral density [vBMD], and cortical bone strength [section modulus]) in patients with juvenile idiopathic arthritis (JIA) and to determine if cortical bone strength is appropriately adapted to muscle forces.MethodsPeripheral quantitative computed tomography (pQCT) of the tibia was performed in 101 patients with JIA (79% female; 24 with oligoarticular JIA, 40 with polyarticular JIA, 18 with systemic JIA, and 19 with spondylarthritis [SpA]) and 830 healthy control subjects; all were ages 5–22 years. Outcomes of pQCT were expressed as sex‐ and race‐specific Z scores. Multivariable linear regression models assessed mCSA and bone status in JIA patients compared with controls and identified factors associated with musculoskeletal deficits in JIA.ResultsThe median duration of JIA was 40 months; 29% of the JIA patients had active arthritis, and 28% had received glucocorticoid therapy during the previous year. Compared with the controls, the mCSA and section modulus Z scores were significantly lower in patients with polyarticular JIA and those with SpA. Trabecular vBMD Z scores were significantly lower in patients with polyarticular JIA, those with systemic JIA, and those with SpA. Significant predictors of musculoskeletal deficits included active arthritis in the previous 6 months (mCSA), temporomandibular joint disease (mCSA and section modulus), functional disability (mCSA and vBMD), short stature (vBMD), infliximab exposure (vBMD), and JIA duration (section modulus). The section modulus was significantly reduced relative to mCSA in patients with JIA after adjustment for age and limb length.ConclusionMarked deficits in vBMD and bone strength occur in JIA in association with severe and longstanding disease. Contrary to the findings of previous studies, bone deficits were greater than expected relative to the mCSA, which illustrates the importance of adjusting for age and bone length.
Efficacy and safety of rilonacept (interleukin‐1 trap) in patients with cryopyrin‐associated periodic syndromes: Results from two sequential placebo‐controlled studies
Authors: Hoffman Hal M. , Throne Martin L. , Amar N. J. , Sebai Mohamed , Kivitz Alan J. , Kavanaugh Arthur , Weinstein Steven P. , Belomestnov Pavel , Yancopoulos George D. , Stahl Neil , Mellis Scott J. 
Published: August 2008

AbstractObjectiveTo assess the efficacy and safety of rilonacept (Interleukin‐1 [IL‐1] Trap), a long‐acting and potent inhibitor of IL‐1, in patients with cryopyrin‐associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS) and Muckle‐Wells syndrome (MWS).MethodsForty‐seven adult patients with CAPS, as defined by mutations in the causative NLRP3 (CIAS1) gene and pathognomonic symptoms, were enrolled in 2 consecutive phase III studies. Study 1 involved a 6‐week randomized double‐blind comparison of weekly subcutaneous injections of rilonacept (160 mg) versus placebo. Study 2 consisted of 9 weeks of single‐blind treatment with rilonacept (part A), followed by a 9‐week, randomized, double‐blind, placebo‐controlled withdrawal procedure (part B). Primary efficacy was evaluated using a validated composite key symptom score.ResultsForty‐four patients completed both studies. In study 1, rilonacept therapy reduced the group mean composite symptom score by 84%, compared with 13% with placebo therapy (primary end point; P < 0.0001 versus placebo). Rilonacept also significantly improved all other efficacy end points in study 1 (numbers of multisymptom and single‐symptom disease flare days, single‐symptom scores, physician's and patient's global assessments of disease activity, limitations in daily activities, and C‐reactive protein and serum amyloid A [SAA] levels). In study 2 part B, rilonacept was superior to placebo for maintaining the improvements seen with rilonacept therapy, as shown by all efficacy parameters (primary end point; P < 0.0001 versus placebo). Rilonacept was generally well tolerated; the most common adverse events were injection site reactions.ConclusionTreatment with weekly rilonacept provided marked and lasting improvement in the clinical signs and symptoms of CAPS, and normalized the levels of SAA from those associated with risk of developing amyloidosis. Rilonacept exhibited a generally favorable safety and tolerability profile.
Treatment of pulmonary fibrosis for twenty weeks with imatinib mesylate in a patient with mixed connective tissue disease
Authors: Distler Jörg H. W. , Manger Bernhard , Spriewald Bernd M. , Schett Georg , Distler Oliver 
Published: August 2008

AbstractInterstitial lung disease, which is common in patients with mixed connective tissue disease (MCTD), can progress to severe pulmonary fibrosis. The tyrosine kinase inhibitor imatinib mesylate has recently been shown to prevent experimental pulmonary, dermal, and renal fibrosis. Our patient, a 64‐year‐old woman with MCTD and rapidly progressive pulmonary fibrosis, presented with rapid deterioration despite treatment with immunosuppressants. During 20 weeks of treatment with imatinib mesylate at 400 mg/day, our patient improved significantly according to several outcome measures, including New York Heart Association classification, diffusing capacity for carbon monoxide, 6‐minute walking distance, arterial oxygen pressure, and reduction of ground‐glass opacities seen on high‐resolution computed tomography. No adverse effects of imatinib mesylate were observed. These findings suggest that imatinib mesylate might be effective in patients with fibrotic diseases and warrant the initiation of larger clinical studies on the safety and efficacy of imatinib mesylate in connective tissue diseases.
Imatinib mesylate treatment of nephrogenic systemic fibrosis
Authors: Kay Jonathan , High Whitney A. 
Published: August 2008

AbstractObjectiveTo examine the effectiveness of imatinib mesylate in the treatment of nephrogenic systemic fibrosis (NSF).MethodsTwo patients with stage 5 chronic kidney disease and NSF were treated with oral imatinib mesylate at a dosage of 400 mg/day. Skin thickening and tethering were assessed using the modified Rodnan skin thickness score (MRSS), and knee joint flexion contractures were measured with a goniometer.ResultsEach patient displayed progressive reduction of skin thickening and tethering, with a steady decrease in the MRSS, following the initiation of imatinib mesylate treatment. The patient who had knee joint contractures achieved increased knee extension with passive range‐of‐motion exercises once his skin thickening and tethering had begun to decrease. Within weeks of stopping imatinib mesylate, the skin changes recurred in each patient. Recurrent skin thickening and tethering again improved in the patient who resumed taking imatinib mesylate for longer than 2 weeks. Skin biopsies performed both before and after initial dosing of that patient revealed less fibrosis and less staining for type I procollagen after imatinib mesylate treatment, but essentially unchanged tissue gadolinium content.ConclusionImatinib mesylate treatment decreases fibrosis and results in the relatively rapid and steady improvement of skin changes and knee joint contractures in patients with stage 5 chronic kidney disease and NSF, despite the persistence of gadolinium in the tissues. Because skin changes recurred after discontinuation of imatinib mesylate, the duration for which treatment may be required is undetermined.
Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate
Authors: Pannu Jaspreet , Asano Yoshihide , Nakerakanti Sashidhar , Smith Edwin , Jablonska Stefania , Blaszczyk Maria , ten Dijke Peter , Trojanowska Maria 
Published: August 2008

AbstractObjectiveActivation of Smad1 signaling has recently been implicated in the development of fibrosis. The goal of the present study was to gain further insights into activation of the Smad1 pathway in fibrosis in systemic sclerosis (SSc) and to determine whether this pathway is targeted by the antifibrotic drug imatinib mesylate.MethodsLevels of phosphorylated Smad1 and total Smad1 were examined in SSc and control skin biopsy samples by immunohistochemistry and in cultured fibroblasts by Western blotting. Activity of the CCN2 promoter was examined by a luciferase reporter gene assay. Interactions of Smad1 with the CCN2 promoter were examined by in vitro and in vivo DNA binding assays. Expression of the nonreceptor tyrosine kinase c‐Abl and Smad1 was blocked using respective small interfering RNA.ResultsTotal and phosphorylated Smad1 levels were significantly elevated in SSc skin biopsy samples and in cultured SSc fibroblasts and correlated with elevated CCN2 protein and CCN2 promoter activity. DNA binding assays demonstrated that Smad1 was a direct activator of the CCN2 gene. Small interfering RNA–mediated depletion of Smad1 in SSc fibroblasts normalized the production of CCN2 and collagen. Imatinib mesylate blocked activation of the Smad1 pathway in transforming growth factor β–stimulated control fibroblasts and reversed activation of this pathway in SSc fibroblasts. Likewise, blockade of c‐Abl abrogated activation of the Smad1 pathway in SSc fibroblasts.ConclusionOur findings demonstrate that activation of Smad1 signaling occurs in a subset of SSc patients and contributes to persistent activation of SSc fibroblasts. Demonstration that the Smad1/CCN2 pathway is blocked by imatinib mesylate further clarifies the mechanism of the antifibrotic effects of this compound. This study suggests that SSc patients with activated Smad1 signaling may benefit from imatinib mesylate treatment.
Comparison of duplex sonography and high‐resolution magnetic resonance imaging in the diagnosis of giant cell (temporal) arteritis
Authors: Bley T. A. , Reinhard M. , Hauenstein C. , Markl M. , Warnatz K. , Hetzel A. , Uhl M. , Vaith P. , Langer M. 
Published: August 2008

AbstractObjectiveTo compare the diagnostic performance of high‐resolution magnetic resonance imaging (MRI) and color‐coded duplex sonography (CCDS) in patients with giant cell (temporal) arteritis (GCA).MethodsResults of high‐resolution MRI and CCDS in 59 patients with suspected GCA were compared with the final clinical diagnosis (based on the American College of Rheumatology GCA criteria and a 6‐month followup study). Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated for each method. In 41 of the patients, imaging results were also compared with the findings of a temporal artery (TA) biopsy.ResultsThirty‐six of the 59 patients (61%) were ultimately diagnosed as having GCA. Sensitivity of high‐resolution MRI and CCDS was 69% and 67%, respectively, specificity was 91% and 91%, PPV was 93% and 92%, and NPV was 66% and 64%, respectively. TA biopsy findings were positive in 24 of the 41 biopsied patients (59%). Sensitivity of high‐resolution MRI and CCDS compared with TA biopsy was 83% and 79%, respectively, specificity was 71% and 59%, PPV was 80% and 73%, and NPV was 75% and 67%, respectively. The differences between high‐resolution MRI and CCDS were not significant.ConclusionThe diagnostic power of high‐resolution MRI and CCDS in detecting GCA was comparable. Either of these noninvasive techniques may have value in the evaluation of patients with suspected GCA, and decisions regarding which technique to use may depend on the clinical setting.
Small‐vessel vasculitis surrounding an uninflamed temporal artery: A new diagnostic criterion for polymyalgia rheumatica?
Authors: Chatelain Denis , Duhaut Pierre , Loire Robert , Bosshard Sylvie , Pellet Hélène , Piette Jean‐Charles , Sevestre Henri , Ducroix Jean‐Pierre 
Published: August 2008

AbstractObjectiveTo assess the prevalence and clinical significance of small‐vessel vasculitis (SVV) surrounding an uninflamed temporal artery (TA) in patients diagnosed as having giant cell (temporal) arteritis (GCA) and/or polymyalgia rheumatica (PMR).MethodsPatients with GCA and/or PMR (n = 490) were included in this multicenter prospective study. Slides of TA biopsy specimens were reviewed by 2 pathologists who were blinded with regard to clinical information. SVV was defined as aggregates of mononuclear inflammatory cells surrounding a capillary, distant from an uninflamed temporal artery. Clinical and biologic data of patients in the SVV group (n = 35) were compared with data of patients with biopsy‐proven GCA (n = 280) and with negative TA biopsy findings (n = 175).ResultsSVV was diagnosed in 18 women and 17 men (mean ± SD age 74.5 ± 9.4 years). The group of patients with SVV had a higher proportion of men than in the entire GCA series, had systemic symptoms, headache, jaw claudication, and an abnormal temporal artery less frequently at clinical examination, but had symptoms of PMR more often than patients in the biopsy‐proven GCA group (P = 2.6 × 10−7, odds ratio 9.17 [95% confidence interval 3.44–24.4]). Levels of inflammation markers were significantly lower in the SVV group. Patients in the SVV group had fever less frequently than patients in the group with negative TA biopsy findings, but otherwise shared the same clinical (including PMR symptoms) and biologic features. Eighteen of the 94 patients with pure PMR (19%) had SVV.ConclusionSVV is often neglected by pathologists, and appears to be strongly associated with PMR symptoms in patients with a clinical diagnosis of GCA and/or PMR. However, SVV as a new diagnostic criterion for PMR must be assessed in prospective studies.