bluuebunny/crossref_metadata_2025_split huggingface dataset:
Current risk factors for work disability associated with rheumatoid arthritis: Recent data from a US national cohort
Authors: Allaire Saralynn , Wolfe Frederick , Niu Jingbo , LaValley Michael P. , Zhang Bin , Reisine Susan 
Published: February 2009

AbstractObjectiveTo explore, using recent data, whether and how risk factors for rheumatoid arthritis (RA) work disability may differ from previous studies.MethodsSubjects were 953 individuals with RA from a US cohort who provided data semiannually over 18 months (years 2002–2005). A nested case–control design was used with matching on time of baseline data collection. All subjects were employed at baseline; cases were consistently not employed at followup, whereas controls remained employed. Hierarchical conditional logistic regression assessed the roles of demographic, RA disease, general health, and work factors as predictors of work disability. Recursive partitioning and causal modeling procedures were also used.ResultsSample characteristics were mean age 51 years, 82% female, and 92% white. Older age (odds ratio [OR] 1.2, 95% confidence interval [95% CI] 1.1–1.4) and lower income (OR 1.7, 95% CI 1.0–2.7) predicted work disability, whereas more hours worked (OR 0.9, 95% CI 0.8–0.9) and preference to work full time (OR 0.2, 95% CI 0.1–0.4) or part time (OR 0.4, 95% CI 0.2–0.6) versus not to work were protective in the regression analysis. In recursive partitioning analyses, RA disease factors predicted work disability among older subjects, and functional limitation was the fourth most important factor. Job physical demand was not a significant or important factor.ConclusionIn this contemporary data from a large RA cohort, older age, lower income, fewer working hours, and preference not to work were the risk factors for work disability. The impact of disease factors was limited to subjects ages ≥56 years. Job physical demand level had little impact.
Interleukin‐7 stimulates secretion of S100A4 by activating the JAK/STAT signaling pathway in human articular chondrocytes
Authors: Yammani Raghunatha R. , Long David , Loeser Richard F. 
Published: February 2009

AbstractObjectiveS100A4 has been shown to be increased in osteoarthritic (OA) cartilage and to stimulate chondrocytes to produce matrix metalloproteinase 13 (MMP‐13) through activation of the receptor for advanced glycation end products (RAGE). The aim of this study was to examine the mechanism of S100A4 secretion by chondrocytes.MethodsHuman articular chondrocytes isolated from ankle cartilage were stimulated with 10 ng/ml of interleukin‐1β (IL‐1β), IL‐6, IL‐7, or IL‐8. Cells were pretreated with either a JAK‐3 inhibitor, brefeldin A, or cycloheximide. Immunoblotting with phospho‐specific antibodies was used to determine the activation of signaling proteins. Secretion of S100A4 was measured in conditioned media by immunoblotting, and MMP‐13 was measured by enzyme‐linked immunosorbent assay.ResultsChondrocyte secretion of S100A4 was observed after treatment with IL‐6 or IL‐8 but was much greater in cultures treated with equal amounts of IL‐7 and was not observed after treatment with IL‐1β. IL‐7 activated the JAK/STAT pathway, with increased phosphorylation of JAK‐3 and STAT‐3, leading to increased production of S100A4 and MMP‐13. Overexpression of a dominant‐negative RAGE construct inhibited the IL‐7–mediated production of MMP‐13. Pretreatment of chondrocytes with a JAK‐3 inhibitor or with cycloheximide blocked the IL‐7–mediated secretion of S100A4, but pretreatment with brefeldin A did not.ConclusionIL‐7 stimulates chondrocyte secretion of S100A4 via activation of JAK/STAT signaling, and then S100A4 acts in an autocrine manner to stimulate MMP‐13 production via RAGE. Since both IL‐7 and S100A4 are up‐regulated in OA cartilage and can stimulate MMP‐13 production by chondrocytes, this signaling pathway could contribute to cartilage destruction during the development of OA.
Association of the autoimmunity locus 4q27 with juvenile idiopathic arthritis
Authors: Albers H. M. , Kurreeman F. A. S. , Stoeken‐Rijsbergen G. , Brinkman D. M. C. , Kamphuis S. S. M. , van Rossum M. A. J. , Girschick H. J. , Wouters C. , Saurenmann R. K. , Hoppenreijs E. , Slagboom P. , Houwing‐Duistermaat J. J. , Verduijn W. , Huizinga T. W. J. , ten Cate R. , Toes R. E. M. , Schilham M. W. 
Published: February 2009

AbstractObjectiveJuvenile idiopathic arthritis (JIA) is characterized by chronic arthritis and an autoimmune etiology. In several autoimmune diseases, including rheumatoid arthritis (RA), an association with the 4q27 locus has been reported. We undertook this study to investigate the possible role of the 4q27 locus in JIA.MethodsA case–control association study was conducted, with a total of 655 Caucasian JIA patients and 791 healthy controls divided into 2 independent sample sets. The rs6822844 marker in the 4q27 locus was genotyped.ResultsIn the first and larger sample set, a 5% decrease in T allele frequency was observed in patients compared with controls (allelic odds ratio [OR] 0.72 [95% confidence interval 0.55–0.95], P = 0.019), and in the second set, a 3% decrease was observed (allelic OR 0.81 [95% confidence interval 0.61–1.09], P = 0.169). The combined data set generated an OR of 0.76 (95% confidence interval 0.62–0.93, P = 7.08 × 10−3). When the different JIA subtypes were analyzed individually, significant decreases were seen in the subtypes with a polyarticular course of disease (extended oligoarthritis [P = 0.019] and rheumatoid factor–negative polyarthritis [P = 0.038]).ConclusionOur findings suggest that the 4q27 locus, previously reported to be associated with RA, type 1 diabetes mellitus, celiac disease, and psoriatic arthritis, is also associated with susceptibility to JIA.
The meaning of clinical remission in polyarticular juvenile idiopathic arthritis: Gene expression profiling in peripheral blood mononuclear cells identifies distinct disease states
Authors: Knowlton Nicholas , Jiang Kaiyu , Frank Mark Barton , Aggarwal Amita , Wallace Carol , McKee Ryan , Chaser Brad , Tung Catherine , Smith Laura , Chen Yanmin , Osban Jeanette , O'Neil Kathleen , Centola Michael , McGhee Julie L. , Jarvis James N. 
Published: February 2009

AbstractObjectiveThe development of biomarkers to predict response to therapy in polyarticular juvenile idiopathic arthritis (JIA) is an important issue in pediatric rheumatology. A critical step in this process is determining whether there is biologic meaning to clinically derived terms such as “active disease” and “remission.” The aim of this study was to use a systems biology approach to address this question.MethodsWe performed gene transcriptional profiling on children who fulfilled the criteria for specific disease states as defined by the consensus criteria developed by Wallace and colleagues. The study group comprised children with active disease (n = 14), children with clinical remission on medication (CRM; n = 9), children with clinical remission off medication (CR; n = 6), and healthy control children (n = 13). Transcriptional profiles in peripheral blood mononuclear cells (PBMCs) were obtained using Affymetrix U133 Plus 2.0 arrays.ResultsHierarchical cluster analysis and predictive modeling demonstrated that the clinically derived criteria represent biologically distinct states. Minimal differences were seen between children with active disease and those with disease in CRM. Thus, underlying immune/inflammatory abnormalities persist despite a response to therapy. The PBMC transcriptional profiles of children whose disease was in remission did not return to normal but revealed networks of proinflammatory and antiinflammatory genes, suggesting that remission is a state of homeostasis, not a return to a normal state.ConclusionGene transcriptional profiling of PBMCs revealed that clinically derived criteria for JIA disease states reflect underlying biology. We also demonstrated that neither CRM nor CR status results in resolution of the underlying inflammatory process, but that these conditions are more likely to be states of balanced homeostasis between proinflammatory and antiinflammatory mechanisms.
Tumor necrosis factor α–induced interleukin‐32 is positively regulated via the Syk/protein kinase Cδ/JNK pathway in rheumatoid synovial fibroblasts
Authors: Mun Se Hwan , Kim Jie Wan , Nah Seong Su , Ko Na Young , Lee Jun Ho , Kim Ju Dong , Kim Do Kyun , Kim Hyuk Soon , Choi Ji Da , Kim Soo Hyun , Lee Chang Keun , Park Seung Hwa , Kim Bo Kyung , Kim Hyung Sik , Kim Young Mi , Choi Wahn Soo 
Published: February 2009

AbstractObjectiveInterleukin‐32 (IL‐32) is a recently discovered cytokine that appears to play a critical role in human rheumatoid arthritis (RA). It is highly expressed in synovium and fibroblast‐like synoviocytes (FLS) from RA patients, but not in patients with osteoarthritis (OA). This study was undertaken to assess IL‐32 levels in RA synovial fluid (SF) and to investigate the secretion and regulation of IL‐32 in RA FLS.MethodsFLS and SF were obtained from the joints of RA patients. The secretion and expression of IL‐32 and activation of signaling molecules were examined by enzyme‐linked immunosorbent assay, immunoblotting, immunoprecipitation, reverse transcriptase–polymerase chain reaction, and small interfering RNA (siRNA) transfection.ResultsIL‐32 levels were high in RA SF compared with OA SF. Furthermore, RA FLS expressed and secreted IL‐32 when stimulated with tumor necrosis factor α (TNFα). TNFα‐induced expression of IL‐32 was significantly suppressed, in a dose‐dependent manner, by inhibitors of Syk, protein kinase Cδ (PKCδ), and JNK and by knockdown of these kinases and c‐Jun with siRNA. We also observed that PKCδ mediated the activation of JNK and c‐Jun, and experiments using specific inhibitors and siRNA demonstrated that Syk was the upstream kinase for the activation of PKCδ.ConclusionThe present findings suggest that IL‐32 may be a newly identified prognostic biomarker in RA, thereby adding valuable knowledge to the understanding of this disease. The results also demonstrate that the production of IL‐32 in RA FLS is regulated by Syk/PKCδ‐mediated signaling events.
Activation of cartilage matrix metalloproteinases by activated protein C
Authors: Jackson Miriam T. , Smith Margaret M. , Smith Susan M. , Jackson Christopher J. , Xue Meilang , Little Christopher B. 
Published: February 2009

AbstractObjectiveTo investigate the role of activated protein C (APC) in cartilage degradation.MethodsChondrocyte expression of protein C, endothelial protein C receptor (EPCR), and thrombomodulin (TM) were evaluated by reverse transcription–polymerase chain reaction (RT‐PCR). APC was immunolocalized in developing joints and in osteoarthritic (OA) cartilage from humans. The effect of APC on aggrecan and collagen degradation was examined in explant cultures of ovine cartilage in control cultures and in cultures stimulated with interleukin‐1α (IL‐1α), tumor necrosis factor α (TNFα), or retinoic acid (RetA), using colorimetric assays and Western blotting. Chondrocyte expression of matrix metalloproteinases (MMPs), ADAMTS, and tissue inhibitor of metalloproteinases (TIMPs) was measured by RT‐PCR. MMP‐2 and MMP‐9 activity was evaluated by gelatin zymography and MMP‐13 by fluorogenic assay.ResultsPositive cellular immunostaining for APC was found at sites of MMP activity in developing joints and in OA, but not normal, cartilage. Chondrocytes expressed messenger RNA for protein C, EPCR, and TM, with the latter 2 levels increased by IL‐1α and TNFα stimulation. APC augmented aggrecan release and initiated collagen breakdown in IL‐1α–treated and TNFα‐treated cartilage, but not in normal or in RetA‐treated cartilage. APC‐stimulated aggrecan and collagen breakdown were due to MMP activity but were not associated with modulation of MMP, ADAMTS, or TIMP expression. APC resulted in MMP‐13 activation in cartilage cultures. APC could not directly activate proMMP‐13, but it was associated with increased MMP‐2 and MMP‐9 activity.ConclusionAPC may be a relevant activator of MMPs in cartilage and may play a role in progressive cartilage degradation in arthritis.
Prevention of cartilage degeneration in a rat model of osteoarthritis by intraarticular treatment with recombinant lubricin
Authors: Flannery Carl R. , Zollner Richard , Corcoran Chris , Jones Aled R. , Root Adam , Rivera‐Bermúdez Moisés A. , Blanchet Tracey , Gleghorn Jason P. , Bonassar Lawrence J. , Bendele Alison M. , Morris Elisabeth A. , Glasson Sonya S. 
Published: February 2009

AbstractObjectiveLubricin, also referred to as superficial zone protein and PRG4, is a synovial glycoprotein that supplies a friction‐resistant, antiadhesive coating to the surfaces of articular cartilage, thereby protecting against arthritis‐associated tissue wear and degradation. This study was undertaken to generate and characterize a novel recombinant lubricin protein construct, LUB:1, and to evaluate its therapeutic efficacy following intraarticular delivery in a rat model of osteoarthritis (OA).MethodsBinding and localization of LUB:1 to cartilage surfaces was assessed by immunohistochemistry. The cartilage‐lubricating properties of LUB:1 were determined using a custom friction testing apparatus. A cell‐binding assay was performed to quantify the ability of LUB:1 to prevent cell adhesion. Efficacy studies were conducted in a rat meniscal tear model of OA. One week after the surgical induction of OA, LUB:1 or phosphate buffered saline vehicle was administered by intraarticular injection for 4 weeks, with dosing intervals of either once per week or 3 times per week. OA pathology scores were determined by histologic analysis.ResultsLUB:1 was shown to bind effectively to cartilage surfaces, and facilitated both cartilage boundary lubrication and inhibition of synovial cell adhesion. Treatment of rat knee joints with LUB:1 resulted in significant disease‐modifying, chondroprotective effects during the progression of OA, by markedly reducing cartilage degeneration and structural damage.ConclusionOur findings demonstrate the potential use of recombinant lubricin molecules in novel biotherapeutic approaches to the treatment of OA and associated cartilage abnormalities.
Inhibition of interleukin‐33 signaling attenuates the severity of experimental arthritis
Authors: Palmer Gaby , Talabot‐Ayer Dominique , Lamacchia Céline , Toy Dean , Seemayer Christian A. , Viatte Sébastien , Finckh Axel , Smith Dirk E. , Gabay Cem 
Published: February 2009

AbstractObjectiveInterleukin‐33 (IL‐33; or, IL‐1F11) was recently identified as the ligand of the IL‐1 family receptor T1/ST2. The aim of this study was to examine IL‐33 production in human and mouse joints and to investigate the role of IL‐33 and T1/ST2 in experimental arthritis.MethodsIL‐33 expression was examined in human synovial tissue, rheumatoid arthritis (RA) synovial fibroblasts, and arthritic mouse joints. Mice with collagen‐induced arthritis (CIA) were treated with blocking anti‐ST2 antibody or control antibody beginning at the onset of disease. Arthritis severity was assessed by clinical and histologic scoring. Draining lymph node (LN) cell responses were examined ex vivo, and joint messenger RNA (mRNA) was used for expression profiling.ResultsIL‐33 was highly expressed in human RA synovium. In cultured synovial fibroblasts, IL‐33 expression was strongly induced by IL‐1β and/or tumor necrosis factor α. Furthermore, IL‐33 mRNA was detected in the joints of mice with CIA and increased during the early phase of the disease. Administration of a blocking anti‐ST2 antibody at the onset of disease attenuated the severity of CIA and reduced joint destruction. Anti‐ST2 antibody treatment was associated with a marked decrease in interferon‐γ production as well as with a more limited reduction in IL‐17 production by ex vivo–stimulated draining LN cells. Finally, RANKL mRNA levels in the joint were reduced by anti‐ST2 treatment.ConclusionIL‐33 is produced locally in inflamed joints, and neutralization of IL‐33 signaling has a therapeutic effect on the course of arthritis. These observations suggest that locally produced IL‐33 may contribute to the pathogenesis of joint inflammation and destruction.
Familial associations of rheumatoid arthritis with autoimmune diseases and related conditions
Authors: Hemminki Kari , Li Xinjun , Sundquist Jan , Sundquist Kristina 
Published: February 2009

AbstractObjectiveIn the era of genome‐wide association studies, familial risks are used to estimate disease heritability and the likelihood of candidate‐gene identification. This study was undertaken to estimate associations of rheumatoid arthritis (RA) with any of 33 autoimmune diseases and related conditions among parents and offspring, singleton siblings, twins, and spouses.MethodsThe Multigeneration Register in Sweden was used as a reliable source of information on Swedish families throughout the last century. Data on autoimmune diseases in individual family members were obtained through linkage to the Hospital Discharge Register. The standardized incidence ratio (SIR) was calculated as a measure of the relative risk of RA in family members of patients with RA or any of 33 other autoimmune diseases or related conditions, as compared with the relative risk of RA in those lacking an affected family member.ResultsAmong a total of 447,704 patients, 47,361 were diagnosed as having RA. The SIRs for RA were 3.02 in offspring of affected parents, 4.64 in siblings, 9.31 in multiplex families, 6.48 in twins, and 1.17 in spouses. Significant associations with the familial risk of RA in offspring according to parental proband were observed for ankylosing spondylitis (SIR 2.96), localized scleroderma (SIR 2.40), Sjögren's syndrome (SIR 2.25), systemic lupus erythematosus (SIR 2.13), systemic sclerosis (SIR 1.65), Hashimoto thyroiditis/hypothyroidism (SIR 1.54), pernicious anemia (SIR 1.53), sarcoidosis (SIR 1.40), psoriasis (SIR 1.36), Wegener's granulomatosis (SIR 1.34), and asthma or polymyalgia rheumatica (SIR 1.32).ConclusionThis is the first study to compare the familial risks of RA in relation to a large number of autoimmune diseases and related conditions using data from a single population. The high discordant familial risks in this population suggest that there is extensive genetic sharing between RA and the associated diseases.
Is obesity a risk factor for progressive radiographic knee osteoarthritis?
Authors: Niu J. , Zhang Y. Q. , Torner J. , Nevitt M. , Lewis C. E. , Aliabadi P. , Sack B. , Clancy M. , Sharma L. , Felson D. T. 
Published: February 2009

AbstractObjectiveTo examine whether obesity increases the risk of progression of knee osteoarthritis (OA).MethodsWe used data from the Multicenter Osteoarthritis Study, a longitudinal study of persons with or at high risk of knee OA. OA was characterized at baseline and 30 months using posteroanterior fixed‐flexion radiographs and Kellgren/Lawrence (K/L) grading, with alignment assessed on full‐extremity films. In knees with OA at baseline (K/L grade 2 or 3), progression was defined as tibiofemoral joint space narrowing on the 30‐month radiograph. In knees without OA at baseline (K/L grade 0 or 1), incident OA was defined as the development of radiographic OA at 30 months. Body mass index (BMI) at baseline was classified as normal (<25 kg/m2), overweight (25–<30 kg/m2), obese (30–<35 kg/m2), and very obese (≥35 kg/m2). The risk of progression was tested in all knees and in subgroups categorized according to alignment. Analyses were adjusted for age, sex, knee injury, and bone density.ResultsAmong the 2,623 subjects (5,159 knees), 60% were women, and the mean ± SD age was 62.4 ± 8.0 years. More than 80% of subjects were overweight or obese. At baseline, 36.4% of knees had tibiofemoral OA, and of those, only one‐third were neutrally aligned. Compared with subjects with a normal BMI, those who were obese or very obese were at an increased risk of incident OA (relative risk 2.4 and 3.2, respectively [P for trend < 0.001]); this risk extended to knees from all alignment groups. Among knees with OA at baseline, there was no overall association between a high BMI and the risk of OA progression; however, an increased risk of progression was observed among knees with neutral but not varus alignment. The effect of obesity was intermediate in those with valgus alignment.ConclusionAlthough obesity was a risk factor for incident knee OA, we observed no overall relationship between obesity and the progression of knee OA. Obesity was not associated with OA progression in knees with varus alignment; however, it did increase the risk of progression in knees with neutral or valgus alignment. Therefore, weight loss may not be effective in preventing progression of structural damage in OA knees with varus alignment.
Radiologic assessment of age‐related knee joint space changes in women: A 4‐year longitudinal study
Authors: Gensburger Déborah , Arlot Monique , Sornay‐Rendu Elisabeth , Roux Jean‐paul , Delmas Pierre 
Published: February 2009

AbstractObjectiveTo analyze a population‐based cohort of women in order to establish normal values of joint space width (JSW) and to evaluate the existence of age‐related joint space loss (JSL).MethodsKnee radiographs were performed 4 years apart in women from the OFELY (Os des Femmes de Lyon) Cohort. Posteroanterior radiographs of both knees were taken in semiflexion with a standardized fluoroscopically assisted protocol. Radiographs were qualitatively evaluated using a scoring system based on the Altman score that assessed joint space narrowing, osteophytes, and sclerosis for each tibiofemoral compartment and each side. For quantitative assessment, radiographs were digitized using a video camera, and specific software was used to measure JSW in every compartment.ResultsWe evaluated the radiographs of 606 women (ages 39–90 years, mean 62 years) and found that in all subjects, JSW significantly decreased with age in every compartment (r = −0.12 to −0.16, P < 0.001), including in 358 subjects without any radiographic abnormality related to osteoarthritis (OA) at baseline. The longitudinal analysis confirmed a significant loss over 4 years of ∼0.30 mm (6%) for the medial compartment. Multiple regression analysis did not identify significant predictors of JSL among clinical risk factors and biochemical markers of bone and cartilage turnover.ConclusionIn this first longitudinal study of a population‐based cohort of women, we have established normal values of JSW and shown that JSW decreases with aging, especially at the medial compartment, even in subjects without any radiographic abnormalities related to OA.